meropenem and Pseudomonas-Infections

Antipseudomonal β-lactams have been used for the treatment of febrile neutropenia (FN); however, the efficacy and safety of antipseudomonal β-lactams in pediatric patients remain unclear. The aim of this study was to comprehensively compare the efficacy and side effects of optional antipseudomonal β-lactams for pediatric FN.. PubMed, Embase, Medline, and Cochrane Library were systematically searched from their inception to December 18, 2020. Eligible randomized controlled trials in which pediatric FN patients were treated with an empiric monotherapy of antipseudomonal β-lactams were selected. Data synthesis was performed using WinBUGS 14.0 software and meta packages implemented in R 3.6.2. Random-effects network meta-analysis was performed, and dichotomous data were pooled as odds ratios with 95% confidence intervals. The primary outcome was treatment success without modification; the secondary outcomes were adverse events (AEs), all-cause mortality, and new infections. The GRADE tool was used to assess the quality of the evidence. The protocol was registered with PROSPERO ID CRD42021226763.. Eighteen studies with 2517 patients were included. The results showed no statistically significant difference between the optional antipseudomonal β-lactams in the outcomes of treatment success without modification, all AEs, all-cause mortality, and new infections for pediatric FN. Based on the results of Bayesian rank probability, meropenem was ranked highest among all the treatment options with regard to treatment success without modification benefit; ceftazidime and meropenem were associated with a lower risk of AEs; cefoperazone/sulbactam and piperacillin/tazobactam were associated with a lower risk of mortality, and piperacillin/tazobactam and meropenem were associated with a lower risk of new infections. The quality of evidence was moderate.. Meropenem and piperacillin/tazobactam were found to be better with regard to treatment success without modification, with a comparable safety profile. Therefore, our findings support the use of meropenem and piperacillin/tazobactam as a treatment option for pediatric FN patients.

Topics: Anti-Bacterial Agents; beta-Lactams; Ceftazidime; Child; Drug Therapy, Combination; Febrile Neutropenia; Female; Humans; Imipenem; Male; Meropenem; Network Meta-Analysis; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Randomized Controlled Trials as Topic; Treatment Outcome

To summarize the current literature on the use and clinical efficacy of extended-infusion (EI) beta-lactam antibiotics, including piperacillin-tazobactam, meropenem, and cefepime.. Gram-negative infections are a serious concern among hospitalized patients and require innovative pharmacokinetic dosing strategies to achieve clinical success, especially as the emergence of resistant gram-negative pathogens has outpaced the development of new antibiotics. Beta-lactam antibiotics exhibit time-dependent activity, which means that optimal efficacy is achieved when free drug concentrations stay above the minimum inhibitory concentration for an extended duration of the recommended dosage interval. EI piperacillin-tazobactam therapy has demonstrated improved clinical outcomes and decrease mortality in critically ill patients with gram-negative infections, particularly Pseudomonas aeruginosa infections. EI meropenem has shown higher therapeutic success rates for patients with febrile neutropenia and shorter intensive care unit (ICU) length of stay (LOS) with a reduction in ventilator days in patients with multidrug-resistant ventilator-associated pneumonia. However, a larger study showed no difference in clinical outcomes between standard-infusion and EI meropenem. EI cefepime has been associated with decreased mortality and shorter ICU LOS in patients with Pseudomonas aeruginosa infections. Common challenges associated with EI beta-lactam antibiotics include Y-site incompatibilities, lack of intravenous access, and tubing residuals. It is important to note that factors such as diverse patient populations and study methodology, along with various antibiotic dose regimens, may have contributed to conflicting data on EI beta-lactam therapy.. Based on most published literature, there appears to be a favorable trend toward use of EI beta-lactam therapy in clinical practice, particularly in critically ill patients with gram-negative infections.

Topics: Anti-Bacterial Agents; Cefepime; Critical Illness; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Multiple, Bacterial; Humans; Infusions, Intravenous; Intensive Care Units; Length of Stay; Meropenem; Microbial Sensitivity Tests; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Time Factors; Treatment Outcome

Carbapenem-resistant Pseudomonas aeruginosa (CRPA) is an endemic problem in certain countries including Greece. CRPA and multidrug-resistant P. aeruginosa (MDRPA) firstly emerged in our region during the 80s, right after the launch of imipenem and meropenem as therapeutic agents against P. aeruginosa infections. The role of outer membrane protein (Opr) inactivation has been known to contribute to imipenem resistance since many years, while efflux overexpression systems have been mainly associated with meropenem resistance. Among carbapenemases, metallo-β-lactamases (MBL) and mostly Verona integron-mediated (VIM) MBL's have played the most crucial role in CRPA emergence. VIM-2 and VIM-4 producing CRPA, usually belonging to clonal complexes (CC) 111 and 235 respectively, have most frequently been isolated. Bla

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Carbapenems; Drug Resistance, Multiple, Bacterial; Greece; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Molecular Epidemiology; Porins; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

With the development of invasive medical procedures, an increasing number of healthcare-associated infective endocarditis cases have been reported. In particular, non-nosocomial healthcare-associated infective endocarditis in outpatients with recent medical intervention has been increasingly identified.. A 66-year-old man with diabetes mellitus and a recent history of intermittent urethral self-catheterization was admitted due to a high fever. Repeated blood cultures identified Pseudomonas aeruginosa, and transesophageal echocardiography uncovered a new-onset severe aortic regurgitation along with a vegetative valvular structure. The patient underwent emergency aortic valve replacement surgery and was successfully treated with 6 weeks of high-dose meropenem and tobramycin. Historically, most cases of P. aeruginosa endocarditis have occurred in the right side of the heart and in outpatients with a history of intravenous drug abuse. In the case presented, the repeated manipulations of the urethra may have triggered the infection. Our literature review for left-sided P. aeruginosa endocarditis showed that non-nosocomial infection accounted for nearly half of the cases and resulted in fatal outcomes as often as nosocomial cases. A combination therapy with anti-pseudomonal beta-lactams or carbapenems and aminoglycosides may be the preferable treatment. Medical treatment alone may be effective, and surgical treatment should be carefully considered.. We presented a rare case of native aortic valve endocarditis caused by P. aeruginosa. This case illustrates the importance of identifying the causative pathogen(s), especially for outpatients with a recent history of medical procedures.

Topics: Aged; Anti-Bacterial Agents; Aortic Valve; Drug Therapy, Combination; Echocardiography, Transesophageal; Endocarditis; Endocarditis, Bacterial; Foramen Ovale, Patent; Heart Valve Prosthesis; Heart Valve Prosthesis Implantation; Humans; Intermittent Urethral Catheterization; Magnetic Resonance Imaging; Male; Meropenem; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins; Tobramycin; Ultrasonography, Doppler

Topics: Anti-Bacterial Agents; Biopsy; Colitis, Ischemic; Colonic Diseases; Colonoscopy; Colostomy; Combined Modality Therapy; Escherichia coli Infections; Gastrointestinal Hemorrhage; Humans; Intestinal Mucosa; Male; Meropenem; Mesentery; Middle Aged; Morphine; Panniculitis, Peritoneal; Parenteral Nutrition, Total; Prednisone; Pseudomonas Infections; Tamoxifen; Thienamycins; Travel

Critically ill patients are often affected by infections produced by Pseudomonas, which can be a cause of sepsis and renal failure. Early and adequate antibiotic treatment at correct dosage levels is crucial. Acute kidney injury is also frequent in critically ill patients. In those patients who require renal replacement therapy, continuous techniques are gaining relevance as filtering alternatives to intermittent hemodialysis. It must be taken into account that many antibiotics are largely cleared by continuous renal replacement therapies (CRRT). The aim of this review is to assess the clinical evidence on the pharmacokinetics and dosage recommendations of the main antibiotic groups used to treat Pseudomonas spp. infections in critically ill patients subjected to CRRT.

Topics: Acute Kidney Injury; Anti-Bacterial Agents; Humans; Meropenem; Pseudomonas Infections; Renal Replacement Therapy; Thienamycins

Several beta-lactams are recommended as single agents for the treatment of febrile neutropenia.. To compare the effectiveness of different anti-pseudomonal beta-lactams as single agents in the treatment of febrile neutropenia. To compare the development of bacterial resistance, bacterial and fungal superinfections during or following treatment with the different beta-lactams.. We searched the Cochane Register of Controlled Trials (CENTRAL), Issue 3, 2010. MEDLINE, EMBASE, LILACS, FDA drug applications, conference proceedings and ongoing clinical trial databases up to August 2010. References of included studies were scanned.. Randomised controlled trials (RCTs) comparing an antipseudomonal beta-lactam to another antipseudomonal beta-lactam antibiotic, both given alone or with the addition of the same glycopeptide to both study arms, for the initial treatment of fever and neutropenia among cancer patients.. Two review authors applied inclusion criteria and extracted the data independently. Missing data were sought. Risk ratios (RR) were calculated with 95% confidence intervals (CI), and pooled using the fixed effect model. The primary outcome was all-cause mortality. Risk of bias was assessed using a domain-based evaluation and its effect of results was assessed through sensitivity analyses.. Forty-four trials were included. The antibiotics assessed were cefepime, ceftazidime, piperacillin-tazobactam, imipenem and meropenem. Adequate allocation concealment and generation were reported in about half of the trials and only two trials were double-blinded. The risk for all-cause mortality was significantly higher with cefepime compared to other beta-lactams (RR 1.39, 95% CI 1.04 to 1.86, 21 trials, 3471 participants), without heterogeneity and with higher RRs in trials at low risk for bias. There were no differences in secondary outcomes but for a non-significantly higher rate of bacterial superinfections with cefepime. Mortality was significantly lower with piperacillin-tazobactam compared to other antibiotics (RR 0.56, 95% CI 0.34 to 0.92, 8 trials, 1314 participants), without heterogeneity. Carbapenems resulted in similar all-cause mortality and a lower rate of clinical failure and antibiotic modifications as compared to other antibiotics, but a higher rate of diarrhea caused by Clostridium difficile.. Current evidence supports the use of piperacillin-tazobactam in locations where antibiotic resistance profiles do not mandate empirical use of carbapenems. Carbapenems result in a higher rate of antibiotic-associated and Clostridium difficile-associated diarrhea. There is a high level of evidence that all-cause mortality is higher with cefepime compared to other beta-lactams and it should not be used as monotherapy for patients with febrile neutropenia.

Topics: Anti-Bacterial Agents; beta-Lactams; Cefepime; Ceftazidime; Cephalosporins; Fever; Humans; Imipenem; Meropenem; Neutropenia; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Randomized Controlled Trials as Topic; Thienamycins

The comparative effectiveness and safety of carbapenems with other beta-lactams and fluoroquinolones for the empirical treatment of patients with hospital-acquired pneumonia remains controversial. In the present study, a meta-analysis of 12 relevant randomised controlled trials was performed. Overall, carbapenems were associated with lower mortality than fluoroquinolones or beta-lactams, alone or in combination with aminoglycosides (odds ratio 0.72, 95% confidence interval 0.55-0.95). There was no difference between the compared antibiotics regarding treatment success (1.08, 0.91-1.29), microbiological success (1.04, 0.72-1.50) or development of adverse effects (0.81, 0.46-1.43). In the subset of patients with Pseudomonas aeruginosa pneumonia, carbapenems were associated with lower treatment success (0.42, 0.22-0.82) and lower eradication of P. strains (0.50, 0.24-0.89). Carbapenems are equivalent to fluoroquinolones or beta-lactams, alone or in combination with aminoglycosides, for the empirical treatment of immunocompetent adult patients with hospital-acquired pneumonia. However, there is limited evidence, based predominantly on unblinded randomised controlled trials, that carbapenems are associated with lower mortality than the comparators; this association was not observed in a subset analysis of randomised controlled trials with a high methodological quality score. In patients with Pseudomonas aeruginosa pneumonia, carbapenems are associated with worse outcomes than the comparators.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Adult; Aminoglycosides; beta-Lactams; Carbapenems; Cross Infection; Drug Resistance, Multiple; Drug Therapy, Combination; Fluoroquinolones; Humans; Immunocompetence; Intensive Care Units; Meropenem; Pneumonia, Bacterial; Pseudomonas Infections; Randomized Controlled Trials as Topic; Respiration, Artificial; Survival Rate; Thienamycins; Treatment Outcome

Pseudomonas aeruginosa is one of the leading gram-negative organisms associated with nosocomial infections. The increasing frequency of multi-drug-resistant Pseudomonas aeruginosa (MDRPA) strains is concerning as efficacious antimicrobial options are severely limited. By searching MEDLINE from January 1966-February 2005 and relevant journals for abstracts, we reviewed the frequency, risk factors, and patient outcomes of MDRPA nosocomial infections in critically ill patients, determined the available antimicrobial therapies, and then provided recommendations for clinicians. The definition of MDRPA was established as isolates intermediate or resistant to at least three drugs in the following classes: beta-lactams, carbapenems, aminoglycosides, and fluoroquinolones. Reported rates of MDRPA varied from 0.6-32% according to geographic location and type of surveillance study. Risk factors for MDRPA infection included prolonged hospitalization, exposure to antimicrobial therapy, and immunocompromised states such as human immunodeficiency virus infection. Emergence of MDRPA isolates during therapy was reported in 27-72% of patients with initially susceptible P. aeruginosa isolates. Patients with severe MDRPA infections should be treated with combination therapy, consisting of an antipseudomonal beta-lactam with an aminoglycoside or fluoroquinolone rather than aminoglycoside and fluoroquinolone combinations, to provide adequate therapy and improve patient outcomes. Synergy has been observed when resistant antipseudomonal drugs were combined in vitro against MDRPA with successful clinical application reported in two centers. Colistin with adjunctive therapy, such as a beta-lactam or rifampin, may be a useful agent in MDRPA when antimicrobial options are limited, but patients should be monitored closely for toxicities associated with this agent. Standardization of terminology for MDRPA isolates is needed for consistency and comparability of surveillance and institutional reports. Clinical studies are needed to identify risk factors for MDRPA development and to determine the economic impact of these infections, as well as to determine the most efficacious antimicrobial regimens and duration of therapy to maximize outcomes in the treatment of MDRPA infections.

Topics: Anti-Bacterial Agents; Colistin; Cross Infection; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Humans; Meropenem; Polymyxin B; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

Medical treatment alone is rarely successful in left-sided infective endocarditis caused by Pseudomonas aeruginosa. We report the cure of such a case with high-dose meropenem in combination with tobramycin.

Topics: Adult; Anti-Bacterial Agents; Drug Therapy, Combination; Endocarditis, Bacterial; Humans; Male; Meropenem; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins; Tobramycin

The survival of cystic fibrosis patients has improved through an aggressive, multidisciplinary approach to the therapy of pulmonary sepsis. Intravenous antibiotics play a major role in the care of cystic fibrosis patients, even though it is not possible to achieve persistent bacterial eradication due to the complex microbiology and pathology of these patients. The most important pathogen in older patients is Pseudomonas aeruginosa. The increasing incidence of Pseudomonas cepacia, strains of which can be highly resistant to many antibiotics, also represents an important challenge to the efficacy of antibiotic therapy. Choice of appropriate antimicrobial therapy is hampered by the fact that a single patient may harbour several different pseudomonas phenotypes with variable resistance patterns. Carbapenem antibiotics possess a wide range of activity against most Gram-negative and Gram-positive bacteria and are therefore a useful addition to the antimicrobial armamentarium available to the clinician. The new carbapenem meropenem is well tolerated at high doses by both children and adults. Results from a comparative trial against ceftazidime suggests that meropenem has a place in the management of cystic fibrosis.

Topics: Adult; Ceftazidime; Child; Child, Preschool; Clinical Trials as Topic; Cystic Fibrosis; Humans; Meropenem; Pneumonia, Bacterial; Pseudomonas Infections; Thienamycins

The emergence of nonsusceptibility to ceftolozane/tazobactam and meropenem was evaluated among Pseudomonas aeruginosa (P. aeruginosa) lower respiratory tract isolates obtained from participants in the ASPECT-NP clinical trial.. ASPECT-NP was a phase-3, randomised, double-blind, multicentre trial that demonstrated noninferiority of 3 g ceftolozane/tazobactam q8h versus 1 g meropenem q8h for treatment of ventilated hospital-acquired/ventilator-associated bacterial pneumonia. Molecular resistance mechanisms among postbaseline nonsusceptible P. aeruginosa isolates and clinical outcomes associated with participants with emergence of nonsusceptibility were examined. Baseline susceptible and postbaseline nonsusceptible P. aeruginosa isolate pairs from the same participant underwent molecular typing.. Emergence of nonsusceptibility was not observed among the 59 participants with baseline susceptible P. aeruginosa isolates in the ceftolozane/tazobactam arm. Among 58 participants with baseline susceptible P. aeruginosa isolates in the meropenem arm, emergence of nonsusceptibility was observed in 13 (22.4%). Among participants who received ceftolozane/tazobactam and meropenem, 5.1% and 3.4% had a new infection with a nonsusceptible strain, respectively. None of the isolates with emergence of nonsusceptibility to meropenem developed co-resistance to ceftolozane/tazobactam. The molecular mechanisms associated with emergence of nonsusceptibility to meropenem were decreased expression or loss of OprD and overexpression of MexXY.. Among participants with emergence of nonsusceptibility to meropenem, clinical outcomes were similar to overall clinical outcomes in the ASPECT-NP meropenem arm. Ceftolozane/tazobactam was more stable to emergence of nonsusceptibility versus meropenem; emergence of nonsusceptibility was not observed in any participants with baseline susceptible P. aeruginosa who received ceftolozane/tazobactam in ASPECT-NP.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Cephalosporins; DNA, Bacterial; Double-Blind Method; Drug Resistance, Bacterial; Healthcare-Associated Pneumonia; Humans; Meropenem; Multicenter Studies as Topic; Multilocus Sequence Typing; Porins; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory System; Tazobactam; Treatment Outcome

To use a population pharmacokinetic approach to define maximally effective meropenem dosing recommendations for treatment of Acinetobacter baumannii and Pseudomonas aeruginosa infections in a large cohort of patients with septic shock.. Adult patients with septic shock and conserved renal function, treated with meropenem, were eligible for inclusion. Seven blood samples were collected during a single dosing interval and meropenem concentrations were measured by a validated HPLC-MS/MS method. Monte Carlo simulations were employed to define optimum dosing regimens for treatment of empirical or targeted therapy of A. baumannii and P. aeruginosa. EudraCT-no. 2014-002555-26 and NCT02240277.. Fifty patients were included, 26 male and 24 female, with a median age of 64 years with an all-cause 90 day mortality of 34%. A two-compartment linear model including creatinine clearance (CLCR) as a covariate best described meropenem pharmacokinetics. For empirical treatment of A. baumannii, 2000 mg/6 h was required by intermittent (30 min) or prolonged (3 h) infusion, whereas 6000 mg/day was required with continuous infusion. For P. aeruginosa, 2000 mg/8 h or 1000 mg/6 h was required for both empirical and targeted treatment. In patients with a CLCR of ≤ 100 mL/min, successful concentration targets could be reached with intermittent dosing of 1000 mg/8 h.. In patients with septic shock and possible augmented renal clearance, doses should be increased and/or administration should be performed by prolonged or continuous infusion to increase the likelihood of achieving therapeutic drug concentrations. In patients with normal renal function, however, standard dosing seems to be sufficient.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Chromatography, High Pressure Liquid; Creatinine; Female; Humans; Male; Meropenem; Metabolic Clearance Rate; Middle Aged; Models, Theoretical; Prospective Studies; Pseudomonas aeruginosa; Pseudomonas Infections; Shock, Septic; Tandem Mass Spectrometry; Thienamycins; Young Adult

Only limited data exist on Pseudomonas aeruginosa ventilator-associated pneumonia (VAP) treated with imipenem, meropenem, or doripenem. Therefore, we conducted a prospective observational study in 169 patients who developed Pseudomonas aeruginosa VAP. Imipenem, meropenem, and doripenem MICs for Pseudomonas aeruginosa isolates were determined using Etests and compared according to the carbapenem received. Among the 169 isolates responsible for the first VAP episode, doripenem MICs were lower (P<0.0001) than those of imipenem and meropenem (MIC50s, 0.25, 2, and 0.38, respectively); 61%, 64%, and 70% were susceptible to imipenem, meropenem, and doripenem, respectively (P was not statistically significant). Factors independently associated with carbapenem resistance were previous carbapenem use (within 15 days) and mechanical ventilation duration before VAP onset. Fifty-six (33%) patients had at least one VAP recurrence, and 56 (33%) died. Factors independently associated with an unfavorable outcome (recurrence or death) were a high day 7 sequential organ failure assessment score and mechanical ventilation dependency on day 7. Physicians freely prescribed a carbapenem to 88 patients: imipenem for 32, meropenem for 24, and doripenem for 32. The remaining 81 patients were treated with various antibiotics. Imipenem-, meropenem-, and doripenem-treated patients had similar VAP recurrence rates (41%, 25%, and 22%, respectively; P=0.15) and mortality rates (47%, 25%, and 22%, respectively; P=0.07). Carbapenem resistance emerged similarly among patients treated with any carbapenem. No carbapenem was superior to another for preventing carbapenem resistance emergence.

Topics: Anti-Bacterial Agents; beta-Lactam Resistance; Carbapenems; Disk Diffusion Antimicrobial Tests; Doripenem; Female; Humans; Imipenem; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Pneumonia, Ventilator-Associated; Pseudomonas Infections; Thienamycins

In cystic fibrosis (CF), conventional antibiotic susceptibility results correlate poorly with clinical outcomes. We hypothesized that biofilm testing would more accurately reflect the susceptibilities of bacteria infecting CF airways.. A multicenter randomized pilot trial was conducted to assess the efficacy and safety of using biofilm susceptibility testing of Pseudomonas aeruginosa sputum isolates to guide antibiotic regimens for chronic airway infections in clinically stable adolescent and adult CF patients. Thirty-nine participants were randomized to biofilm or conventional treatment groups; 14-day courses of two antibiotics were selected according to an activity-based algorithm using the corresponding susceptibility results.. Of the agents tested, meropenem was most active against biofilm-grown bacteria, and was included in regimens for about half of each study group. For 19 of 39 randomized participants, randomization to the other study group would not have changed the antibiotic classes of the assigned regimen. Study groups were comparable at baseline, and had similar mean decreases in bacterial density, measured in log(10) colony forming units per gram of sputum (biofilm, -2.94 [SD 2.83] vs. conventional, -3.27 [SD 3.09]), and mean increases in forced expiratory volume in 1 sec, measured in liters (0.18 [SD 0.20] vs. 0.12 [SD 0.22]).. In this pilot study, antibiotic regimens based on biofilm testing did not differ significantly from regimens based on conventional testing in terms of microbiological and clinical responses. The predictive value of biofilm testing may nonetheless warrant evaluation in an adequately powered clinical trial in younger CF patients or those experiencing acute pulmonary exacerbation.

Topics: Adult; Anti-Bacterial Agents; Biofilms; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Female; Forced Expiratory Flow Rates; Humans; Lung; Male; Meropenem; Microbial Sensitivity Tests; Pilot Projects; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Tract Infections; Sputum; Thienamycins; Young Adult

Antibiotic penetration to the infection site is critical for obtaining a good clinical outcome in patients with ventilator-associated pneumonia (VAP). Surprisingly few studies have quantified the penetration of β-lactam agents into the lung, as measured by the ratio of area under the concentration-time curve (AUC) in epithelial lining fluid (ELF) to AUC in plasma (AUC(ELF)/AUC(plasma) ratio). These have typically involved noninfected patients. This study examines the penetration and pharmacodynamics of meropenem in the ELF among patients with VAP. Meropenem plasma and ELF concentration-time data were obtained from patients in a multicenter clinical trial. Concentration-time profiles in plasma and ELF were simultaneously modeled using a three-compartment model with zero-order infusion and first-order elimination and transfer (big nonparametric adaptive grid [BigNPAG]). A Monte Carlo simulation was performed to estimate the range of ELF/plasma penetration ratios one would expect to observe in patients with VAP, as measured by the AUC(ELF)/AUC(plasma) ratio. The range of AUC(ELF)/AUC(plasma) penetration ratios predicted by the Monte Carlo simulation was large. The 10th percentile of lung penetration was 3.7%, while the 90th percentile of penetration was 178%. The variability of ELF penetration is such that if relatively high ELF exposure targets are required to attain multilog kill or resistance suppression for bacteria like Pseudomonas aeruginosa, then even receiving the largest licensed dose of meropenem with an optimal prolonged infusion may not result in target attainment for a substantial fraction of the population.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Area Under Curve; Body Fluids; Chromatography, Liquid; Female; Humans; Male; Meropenem; Middle Aged; Monte Carlo Method; Pneumonia, Ventilator-Associated; Pseudomonas Infections; Tandem Mass Spectrometry; Thienamycins; Young Adult

To compare the plasma and subcutaneous tissue concentration-time profiles of meropenem administered by intermittent bolus dosing or continuous infusion to critically ill patients with sepsis and without renal dysfunction, and to use population pharmacokinetic modelling and Monte Carlo simulations to assess the cumulative fraction of response (CFR) against Gram-negative pathogens likely to be encountered in critical care units.. We randomized 10 patients with sepsis to receive meropenem by intermittent bolus administration (n = 5; 1 g 8 hourly) or an equal dose administered by continuous infusion (n = 5). Serial subcutaneous tissue concentrations were determined using microdialysis and compared with plasma data for first-dose and steady-state pharmacokinetics. Population pharmacokinetic modelling of plasma data and Monte Carlo simulations were then undertaken with NONMEM.. It was found that continuous infusion maintains higher median trough concentrations, in both plasma (intermittent bolus 0 versus infusion 7 mg/L) and subcutaneous tissue (0 versus 4 mg/L). All simulated intermittent bolus, extended and continuous infusion dosing achieved 100% of pharmacodynamic targets against most Gram-negative pathogens. Superior obtainment of pharmacodynamic targets was achieved using administration by extended or continuous infusion against less susceptible Pseudomonas aeruginosa and Acinetobacter species.. This is the first study to compare the relative concentration-time data of bolus and continuous administration of meropenem at the subcutaneous tissue and plasma levels. We found that the administration of meropenem by continuous infusion maintains higher concentrations in subcutaneous tissue and plasma than by intermittent bolus dosing. Administration by extended or continuous infusion will achieve superior CFR against less-susceptible organisms in patients without renal dysfunction.

Topics: Acinetobacter Infections; Anti-Bacterial Agents; Critical Illness; Female; Humans; Male; Meropenem; Middle Aged; Models, Statistical; Monte Carlo Method; Plasma; Pseudomonas Infections; Sepsis; Subcutaneous Tissue; Thienamycins; Treatment Outcome

Cystic fibrosis (CF) is characterized by chronic pulmonary infection with acute pulmonary exacerbations (APEs) requiring IV antibiotic treatment. We report on a blinded comparative trial of IV meropenem (40 mg/kg to 2 g q8h) or ceftazidime (5 mg/kg to 2 g q8h), each of which was administered with IV tobramycin (at a serum peak of > or = 8 microg/mL and a trough of < 2 microg/mL), as treatment for CF patients with APEs.. Patients who were > or = 5 years of age who were infected with ceftazidime-susceptible Pseudomonas aeruginosa were stratified by lung function and randomized to treatment with meropenem/tobramycin or ceftazidime/tobramycin. Patients infected with Burkholderia cepacia complex or ceftazidime-resistant P aeruginosa were assigned to receive open-label meropenem/tobramycin. Clinical response was assessed by spirometry to determine the change in percent predicted FEV1 and by a clinical acute change score (ACS).. One hundred two patients were randomized to meropenem/tobramycin (n = 50) or ceftazidime/tobramycin (n = 52). Nineteen patients received open-label meropenem/tobramycin. FEV1 was improved at the end of treatment (EOT) with meropenem/tobramycin (mean [+/- SD] increase, 38.8 +/- 52.3%) and with ceftazidime/tobramycin (mean increase, 29.4 +/- 35.1%; p < 0.0001 vs baseline values). The proportion of patients with > or = 15% relative increase from baseline FEV1 (satisfactory response) at day 7 was 62% for the meropenem/tobramycin group and 44% for the ceftazidime/tobramycin group (p = 0.04). The median time to FEV1 response was 4 days for meropenem/tobramycin therapy vs 6 days for ceftazidime/tobramycin therapy. Similarly, FEV1 improved in the open-label group (mean increase, 12.5 +/- 25.7%; p = 0.05). ACS improved in all three groups at EOT (p < 0.0001 vs baseline values).. Therapy with both meropenem/tobramycin and ceftazidime/tobramycin improved pulmonary and clinical status and reduced sputum bacterial burden in CF patients with APEs. A larger proportion of patients receiving meropenem/tobramycin therapy demonstrated a satisfactory FEV1 response at day 7. Resistant P aeruginosa emerged infrequently during treatment with both regimens.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Burkholderia cepacia; Burkholderia Infections; Ceftazidime; Child; Child, Preschool; Cystic Fibrosis; Disease Progression; Drug Therapy, Combination; Forced Expiratory Volume; Humans; Meropenem; Middle Aged; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Function Tests; Sputum; Thienamycins; Tobramycin

Meropenem administered as a single iv 3 g dose once every 24 h was used to treat nine ambulatory patients with infective exacerbations of bronchiectasis. Serum meropenem concentrations were measured before dosing and at 30 min after each 30 min infusion. Mean pre-dose concentrations were <0.1 mg/L and mean post-dose concentrations 93.9 +/- 29.5 mg/L (95% confidence interval (CI) 86. 2-101.6, n = 59). A pathogen was cultured from sputum in six patients and eradicated (<100 cfu/g sputum) in all but one by day 6 of therapy. Previous work on animals has shown that a bacteriostatic effect is seen with meropenem when t > MIC is greater than 20-30% of the dose interval. In these nine patients, this could be achieved and was associated with successful outcome for pathogens for which MICs are

Topics: Aged; Bronchiectasis; Female; Haemophilus Infections; Haemophilus influenzae; Half-Life; Humans; Male; Meropenem; Middle Aged; Pneumococcal Infections; Pseudomonas Infections; Respiratory Tract Infections; Thienamycins

Cystic fibrosis patients (children and young adults) with Pseudomonas spp. chest infections were treated with meropenem or ceftazidime. This study was the first to investigate the use of meropenem in cystic fibrosis. Meropenem was well tolerated with only transient elevations of serum transaminases. No patient experienced nausea and vomiting, even when meropenem was administered as a bolus injection. This allowed home therapy to be used. Meropenem appeared to be at least as active as ceftazidime even at the low doses used. Patients showed a greater improvement in respiratory function on meropenem than ceftazidime. Only one patient (out of 60 courses) failed to respond to meropenem (98% success rate) compared with two failures out of 21 episodes with ceftazidime (90% success rate). There was little emergence of resistance to meropenem even though some patients were treated up to eight times over a 2 year period.

Topics: Adolescent; Adult; Carbapenems; Ceftazidime; Cephalosporins; Child, Preschool; Cystic Fibrosis; Drug Tolerance; Humans; Liver; Meropenem; Microbial Sensitivity Tests; Nausea; Pseudomonas Infections; Spirometry; Sputum; Thienamycins; Transaminases; Treatment Outcome; Vomiting

Pharmacokinetic and clinical evaluations in pediatrics were made on meropenem (SM-7338, MEPM), a new parenteral dehydropeptidase-1 stable carbapenem used without any inhibitors, at 33 medical institutions. The results are summarized as follows. 1. Pharmacokinetic studies. MEPM at a dose of 10, 20, or 40 mg/kg was administered to 53 children by 30-minute drip infusion. Peak plasma concentrations (Cmax's) and plasma half-lives (T1/2's) of these doses were 28.5, 47.2 and 130.0 micrograms/ml, and 0.80, 0.93 and 0.94 hours, respectively. A clear dose response was observed in Cmax's and T1/2 values were quite similar to those observed in adults. In the first 6 hours after administration, 54.4 to 68.1% of the administered drug was recovered in urine. The cerebrospinal fluid (CSF) levels of MEPM in patients with purulent meningitis were 0.13 microgram/ml at a dose of 6 mg/kg, and 0.64 to 4.22 micrograms/ml at a dose of 29 to 44 mg/kg within day 4 of onset. The penetration rate of MEPM showed an intermediate value among those for other cephalosporin antibiotics. 2. Clinical study. Clinical efficacies of MEPM were evaluated in 389 cases. The most common doses used were 10 to 20 mg/kg/once, 2 to 3 times a day. The maximum dose was 173 mg/kg/day q.i.d. MEPM gave "excellent" or "good" responses in 242 (97.6%) out of 248 cases in which causative organisms were documented and in 134 (95.0%) out of 141 cases in which causative organisms were not identified. Clinical efficacy rates were 100% in 11 patients with purulent meningitis, 85.7% in 7 with septicemia, 98.8% in 173 with pneumonia, and 100% in 65 with UTI. Bacteriologically, 260 strains (96.7%) out of 269 strains were eradicated by MEPM treatment. Eradication rates were 89.2% for Staphylococcus aureus (37 strains) and 100% for Streptococcus pneumoniae (35 strains). The overall eradication rate for Gram-positive bacteria was 94.6%. Among Gram-negative bacteria, 98.3% out of 172 strains were eradicated. The eradication rate of Haemophilus influenzae (73 strains) was 98.6% and Pseudomonas aeruginosa (11 strains) was 90.9%, and all of Branhamella catarrhalis (15 strains), Escherichia coli (42 strains), and Klebsiella pneumoniae (6 strains) were eradicated. Out of 84 cases for which previous antibiotic therapies of 3 days or longer were not successful, MEPM gave "excellent" or "good" responses in 77 cases (91.7%) and excellent bacteriological responses (95.7%).(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Bacterial Infections; Child; Child, Preschool; Escherichia coli Infections; Female; Haemophilus Infections; Haemophilus influenzae; Humans; Infant; Klebsiella Infections; Klebsiella pneumoniae; Male; Meropenem; Moraxella catarrhalis; Neisseriaceae Infections; Pseudomonas Infections; Staphylococcal Infections; Streptococcal Infections; Thienamycins

Topics: Anti-Bacterial Agents; beta-Lactamases; Drug Resistance, Bacterial; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Taiwan

To evaluate the in-vitro activity of ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam, imipenem-relebactam and comparator agents against contemporary Pseudomonas aeruginosa isolates from US hospitals.. In total, 3184 isolates were collected consecutively from 71 US medical centres in 2020-2021, and susceptibility tested by reference broth microdilution. Clinical Laboratory Standard Institute breakpoints were applied.. Ceftazidime-avibactam [97.0% susceptible (S)], ceftolozane-tazobactam (98.0%S), imipenem-relebactam (97.3%S) and tobramycin (96.4%S) were the most active agents against the aggregate P. aeruginosa isolate collection, and retained good activity against piperacillin-tazobactam-non-susceptible, meropenem-non-susceptible and multi-drug-resistant (MDR) isolates. All other antimicrobials tested showed limited activity against piperacillin-tazobactam-non-susceptible, meropenem-non-susceptible and MDR isolates. The most common infections were pneumonia (45.9%), skin and skin structure infections (19.0%), urinary tract infections (17.0%) and bloodstream infections (11.7%); ceftazidime-avibactam, ceftolozane-tazobactam and imipenem-relebactam showed consistent activity against isolates from these infection types. Susceptibility to piperacillin-tazobactam and meropenem was lower among isolates from pneumonia compared with other infection types.. Ceftazidime-avibactam, ceftolozane-tazobactam and imipenem-relebactam were highly active, and exhibited similar coverage against a large contemporary collection of P. aeruginosa isolates from US hospitals. Cross-resistance among the newer β-lactams/β-lactam inhibitors (BL/BLIs) varied markedly; ≥72.1% of isolates resistant to one of the three newer BL/BLIs approved for P. aeruginosa treatment remained susceptible to at least one of the other two BL/BLIs, indicating that all three should be tested in the clinical laboratory. These three BL/BLIs represent valuable therapeutic options for P. aeruginosa infection.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; Ceftazidime; Cephalosporins; Drug Combinations; Hospitals; Humans; Imipenem; Lactams; Meropenem; Microbial Sensitivity Tests; Piperacillin, Tazobactam Drug Combination; Pneumonia; Pseudomonas aeruginosa; Pseudomonas Infections; Tazobactam

Pseudomonas aeruginosa pneumonia is commonly treated with systemic antibiotics to ensure adequate treatment of multidrug resistant (MDR) bacteria. However, intravenous (IV) antibiotics often achieve suboptimal pulmonary concentrations. We therefore aimed to evaluate the effect of inhaled amikacin (AMK) plus IV meropenem (MEM) on bactericidal efficacy in a swine model of monolateral MDR P. aeruginosa pneumonia.. We ventilated 18 pigs with monolateral MDR P. aeruginosa pneumonia for up to 102 h. At 24 h after the bacterial challenge, the animals were randomized to receive 72 h of treatment with either inhaled saline (control), IV MEM only, or IV-MEM plus inhaled AMK (MEM + AMK). We dosed IV MEM at 25 mg/kg every 8 h and inhaled AMK at 400 mg every 12 h. The primary outcomes were the P. aeruginosa burden and histopathological injury in lung tissue. Secondary outcomes included the P. aeruginosa burden in tracheal secretions and bronchoalveolar lavage fluid, the development of antibiotic resistance, the antibiotic distribution, and the levels of inflammatory markers.. In a swine model of monolateral MDR P. aeruginosa pneumonia, resistant to the inhaled AMK and susceptible to the IV antibiotic, the use of AMK as an adjuvant treatment offered no benefits for either the colonization of pulmonary tissue or the prevention of pathogen dissemination. However, inhaled AMK improved bacterial eradication in the proximal airways and hindered antibiotic resistance.

Topics: Amikacin; Animals; Anti-Bacterial Agents; Meropenem; Microbial Sensitivity Tests; Models, Theoretical; Pneumonia; Pseudomonas aeruginosa; Pseudomonas Infections; Swine

The rapid acquisition of antibiotic resistance of Pseudomonas aeruginosa has been a complex problem in clinics. Two meropenem-resistant P. aeruginosa isolates were collected from the same patient on May 24, 2021, and June 4, 2021, respectively. The first was susceptible to aztreonam, while the second displayed resistance. This study aimed to identify the genetic differences between two P. aeruginosa isolates and uncover alterations formed by the within-host bacterial evolution leading to aztreonam resistance during therapy. Strains were subjected to antimicrobial susceptibility testing using the broth microdilution method. Genomic DNAs were obtained to identify their genetic differences. The relative mRNA levels of β-lactam-resistance genes were determined by real-time PCR. Both isolates belonged to ST 773 high-risk clones with the same antibiotic resistance genes, eliminating the possibility of horizontally obtaining resistance genes. Reverse transcription (RT)-PCR results showed that the

Topics: Aztreonam; Humans; Meropenem; Pseudomonas aeruginosa; Pseudomonas Infections; RNA, Messenger

Carbapenem-resistant Pseudomonas aeruginosa (CRPA) is a bacterial pathogen that may cause serious drug-resistant infections that are potentially fatal. To investigate the genetic characteristics of these organisms, we tested 416 P. aeruginosa strains recovered from 12 types of clinical samples collected in 29 different hospital wards in 10 hospitals in Guangdong Province, China, from 2017 to 2020. These strains were found to belong to 149 known sequence types (STs) and 72 novel STs, indicating that transmission of these strains involved multiple routes. A high rate of resistance to imipenem (89.4%) and meropenem (79.4%) and a high prevalence of pathogenic serotypes (76.4%) were observed among these strains. Six STs of global high-risk clones (HiRiCs) and a novel HiRiC strains, ST1971, which exhibited extensive drug resistance, were identified. Importantly, ST1971 HiRiC, which was unique in China, also exhibited high virulence, which alarmed the further surveillance on this highly virulent and highly resistant clone. Inactivation of the

Topics: Anti-Bacterial Agents; beta-Lactamases; Carbapenems; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections

Topics: Anti-Bacterial Agents; Anti-Infective Agents; Ceftazidime; Cephalosporins; Drug Combinations; Humans; Leadership; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Tazobactam

This study aimed to investigate the in vitro susceptibility and β-lactamase-encoding genes of Pseudomonas aeruginosa (P. aeruginosa) isolates with discrepant resistance to various carbapenems.. Data on P. aeruginosa isolates were obtained from the Antimicrobial Testing Leadership and Surveillance program from 2012-2021. Minimum inhibitory concentrations of P. aeruginosa isolates were determined using the broth microdilution method. β-lactamase-encoding genes were identified using multiplex polymerase chain reaction assays.. Among the P. aeruginosa isolates that were tested, the percentages of isolates resistant to imipenem, meropenem and doripenem were 26.9% (14 447 of 53 617), 20.5% (14 098 of 68 897) and 17.5% (3660 of 20 946), respectively. Imipenem-resistant P. aeruginosa isolates were more susceptible to all tested antimicrobial agents (except colistin) than the meropenem-resistant or doripenem-resistant P. aeruginosa isolates. Carbapenemase genes were detected in 14.3% (2020 of 14 098) of meropenem-resistant P. aeruginosa isolates. Imipenem-resistant meropenem-susceptible P. aeruginosa isolates had higher susceptibility profiles, fewer carbapenemase genes (0.3% [five of 1858] vs. 4.1% [10 of 242]; P < 0.05) and a lower risk of being classified as multidrug-resistant than the imipenem-susceptible meropenem-resistant isolates (16.1% [299 of 1858] vs. 73.6% [178 of 242]; P < 0.05). Among all β-lactam combination agents, ceftazidime-avibactam and ceftolozane-tazobactam had higher susceptibility rates than meropenem-vaborbactam for meropenem-resistant P. aeruginosa (61.8% and 55.5% vs. 30.2%; P < 0.05).. Discrepancy in the resistance of different P. aeruginosa isolates to various carbapenems suggests their different underlying resistance mechanisms. These findings can be useful for effective resistance trend monitoring and accurate antimicrobial treatment in the future.

Topics: Anti-Bacterial Agents; Anti-Infective Agents; Azabicyclo Compounds; beta-Lactamases; Carbapenems; Ceftazidime; Cephalosporins; Doripenem; Humans; Imipenem; Leadership; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Tazobactam

Optimal coverage of Pseudomonas aeruginosa is challenging in febrile neutropenic patients due to a progressive increase in antibiotic resistance worldwide. We aimed to detail current rates of resistance to antibiotics recommended by international guidelines for P. aeruginosa isolated from bloodstream infections (BSI) in patients with hematologic malignancies. Secondarily, we aimed to describe how many patients received inappropriate empirical antibiotic treatment (IEAT) and its impact on mortality. We conducted a retrospective, multicenter cohort study of the last 20 BSI episodes caused by P. aeruginosa in patients with hematologic malignancies from across 14 university hospitals in Spain. Of the 280 patients with hematologic malignancies and BSI caused by P. aeruginosa, 101 (36%) had strains resistant to at least one of the β-lactam antibiotics recommended in international guidelines, namely, cefepime, piperacillin-tazobactam, and meropenem. Additionally, 21.1% and 11.4% of the strains met criteria for MDR and XDR P. aeruginosa, respectively. Even if international guidelines were followed in most cases, 47 (16.8%) patients received IEAT and 66 (23.6%) received inappropriate β-lactam empirical antibiotic treatment. Thirty-day mortality was 27.1%. In the multivariate analysis, pulmonary source (OR 2.22, 95% CI 1.14 to 4.34) and IEAT (OR 2.67, 95% CI 1.37 to 5.23) were factors independently associated with increased mortality. We concluded that P. aeruginosa-causing BSI in patients with hematologic malignancies is commonly resistant to antibiotics recommended in international guidelines, which is associated with frequent IEAT and higher mortality. New therapeutic strategies are needed.

Topics: Anti-Bacterial Agents; Bacteremia; Cohort Studies; Hematologic Neoplasms; Humans; Meropenem; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies; Sepsis

Bacteriophage (phage) therapy has shown promise in treating fracture-related infection (FRI); however, questions remain regarding phage efficacy against biofilms, phage-antibiotic interaction, administration routes and dosing, and the development of phage resistance. The goal of this study was to develop a dual antibiotic-phage delivery system containing hydrogel and alginate microbeads loaded with a phage cocktail plus meropenem and evaluate efficacy against muti-drug resistant Pseudomonas aeruginosa. Two phages (FJK.R9-30 and MK.R3-15) displayed enhanced antibiotic activity against P. aeruginosa biofilms when tested in combination with meropenem. The antimicrobial activity of both antibiotic and phage was retained for eight days at 37 °C in dual phage and antibiotic loaded hydrogel with microbeads (PA-HM). In a mouse FRI model, phages were recovered from all tissues within all treatment groups receiving dual PA-HM. Moreover, animals that received the dual PA-HM either with or without systemic antibiotics had less incidence of phage resistance and less serum neutralization compared to phages in saline. The dual PA-HM could reduce bacterial load in soft tissue when combined with systemic antibiotics, although the infection was not eradicated. The use of alginate microbeads and injectable hydrogel for controlled release of phages and antibiotics, leads to the reduced development of phage resistance and lower exposure to the adaptive immune system, which highlights the translational potential of the dual PA-HM. However, further optimization of phage therapy and its delivery system is necessary to achieve higher bacterial killing activity in vivo in the future.

Topics: Alginates; Animals; Anti-Bacterial Agents; Bacteriophages; Biofilms; Meropenem; Mice; Microspheres; Pseudomonas aeruginosa; Pseudomonas Infections

Bloodstream infection (BSI) caused by carbapenem-resistant P. aeruginosa (CRPA) has high mortality in hematopoietic stem cell transplant (HSCT) recipients. We performed MIC, checkerboard, time-kill assay, PFGE, PCR, and whole genome sequence and described the clinical outcome through Epi Info comparing the antimicrobial combination in vitro. Mortality was higher in BSI caused by CRPA carrying the lasB virulence gene. The isolates were 97% resistant to meropenem displaying synergistic effect to 57% in combination with colistin. Seventy-three percent of the isolates harbored bla

Topics: Adolescent; Adult; Anti-Bacterial Agents; Brazil; Carbapenem-Resistant Enterobacteriaceae; Carbapenems; Colistin; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Pseudomonas aeruginosa; Pseudomonas Infections; Sepsis; Young Adult

We aimed to evaluate the impact of the 10th version of European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints table, where most antipseudomonal drugs but meropenem are now categorised as "Susceptible, increased exposure" and labelled I, on meropenem prescription for Pseudomonas aeruginosa infections.. In this retrospective single-centre observational study, we analysed antimicrobial therapies prescribed after susceptibility testing in all consecutive adult patients treated for P. aeruginosa infections between 01.08.2019 and 30.07.2020 in Lausanne University Hospital, Switzerland. We collected epidemiological, microbiological, clinical data, antimicrobial therapy, and infectious diseases specialists (IDs) consultations' data. The primary outcome was the prescription of meropenem to treat P. aeruginosa infections after release of susceptibility testing results. Secondary outcomes were: the use of increased dosage for non-meropenem anti-pseudomonal drugs, and IDs' consultations rates after susceptibility testing was made available.. Among the 264 patients included, 40 (15.2%) received meropenem, 3.4% (5/148) before EUCAST update versus 30.2% (35/116) after (p < 0.001). Supervision and counselling from IDs and the use of increased dosages of non-carbapenem antibiotics also increased respectively (40.5% (60/148) vs 62.9% (73/116), P < 0.001); (55.5% (76/148) vs 88.9% (72/116), P < 0.001). Factors associated with these increments could not be adequately modelled.. The change to 2020 EUCAST criteria might be associated with increased odds of meropenem prescription for the treatment of P. aeruginosa infections stressing the need of prescribers' education and the importance of antibiotic stewardship interventions.

Topics: Anti-Bacterial Agents; Hospitals; Humans; Meropenem; Microbial Sensitivity Tests; Prescriptions; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies

Antimicrobial resistance is one of the top 10 global public-health threats. Especially high rates of resistance have been reported for isolates from ICU patients, requiring expanded treatment options in this setting. We evaluated the activity of ceftolozane/tazobactam and comparators against Gram-negative isolates collected from patients with lower respiratory tract infections (LRTIs) in ICUs in seven Asian countries.. In 2017-2019, up to 100 consecutive, aerobic Gram-negative LRTI isolates were collected per year at each of 37 hospitals. MICs were determined using the Clinical and Laboratory Standards Institute reference broth microdilution method.. Overall, ceftolozane/tazobactam was active against 72% of 1408 Enterobacterales and 86% of 761 Pseudomonas aeruginosa isolates. Susceptibility to the non-carbapenem β-lactam comparators, including piperacillin/tazobactam, was 52-67% among Enterobacterales isolates, and the activity of all β-lactam comparators, including meropenem, was 57-70% among P. aeruginosa. Ceftolozane/tazobactam maintained activity against 61% of meropenem-nonsusceptible and 64% of piperacillin/tazobactam-nonsusceptible P. aeruginosa. At the country-level, ceftolozane/tazobactam activity ranged from >90% against Enterobacterales from Hong Kong and South Korea to <64% in Thailand and Vietnam, and from >90% against P. aeruginosa from South Korea, Malaysia, Philippines and Taiwan to <75% in Thailand and Vietnam. Correspondingly, the proportions of carbapenemase-positive isolates among Enterobacterales and P. aeruginosa isolates were highest in Thailand and Vietnam.. Ceftolozane/tazobactam provides a potential treatment option for ICU patients in Asia, which is especially important considering the reduced activity of commonly used β-lactams against the studied ICU isolates. Knowledge of local resistance patterns should inform empirical therapy decision-making.

Topics: Anti-Bacterial Agents; Cephalosporins; Drug Resistance, Multiple, Bacterial; Humans; Intensive Care Units; Meropenem; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Tract Infections; Tazobactam; Thailand

Topics: Anti-Bacterial Agents; Ciprofloxacin; Humans; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Shock, Septic

Pseudomonas aeruginosa has increasingly been associated with the emergence of antibiotic resistance. Antibiotic resistance among P. aeruginosa isolates is an ambiguous and complicated mechanism utilizing several enzymes and structural proteins. This study was conducted to investigate the prevalence of mutations in the chromosomal OprD gene that show resistance to carbapenems among clinical isolates of P. aeruginosa.. Sixty-three clinical isolates of P. aeruginosa resistant to meropenem were collected from public hospitals in Irbid city, north of Jordan. Analysis of antimicrobial susceptibility was carried out and their susceptibility was categorized. Molecular analysis of mutations in the OprD gene was performed using restriction fragment length polymorphism (RFLP) and DNA sequencing.. Molecular analysis of P. aeruginosa isolates showed 52% of the common molecular modifications among the collected isolates. These alterations could be associated and affect meropenem-susceptibility rather than imipenem. The most frequent molecular changes among the resistant isolates were the F170L substitution mutation. This was detected in 22 (35%) of the isolates with an unusual insertion sequence (IS) of 100 bp within the 590 bp DNA segment downstream of the restriction site. The divergent sequence of 10 amino acids 372(VDSSSSYAGL)383 was detected in 7 (11%) of the isolates.. A significant alteration in the OprD gene in P. aeruginosa clinical isolates was found. Alterations in the OprD gene could be linked to protein permeability of the outer membrane of P. aeruginosa associated with meropenem resistance. Further investigations with a larger number of bacterial isolates are needed to validate the proposed association.

Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Hospitals; Humans; Jordan; Meropenem; Microbial Sensitivity Tests; Porins; Pseudomonas; Pseudomonas aeruginosa; Pseudomonas Infections

Here, we investigate the impact of phage-antibiotic combinations (PAC) on bacterial killing, resistance development and outer membrane vesicle (OMV) production in multidrug-resistant (MDR) P. aeruginosa.. After screening 10 well-characterized MDR P. aeruginosa strains against three P. aeruginosa phages, representative strains, R10266 and R9316, were selected for synergy testing based on high phage sensitivity and substantial antibiotic resistance patterns, while phage EM was chosen based on host range. To understand the impact of phage-antibiotic combinations (PAC) against MDR P. aeruginosa, time-kill analyses, OMV quantification and phage/antibiotic resistance testing were performed. Phage and meropenem demonstrated synergistic activity against both MDR strains. Triple combination regimens, phage-meropenem-colistin and phage-ciprofloxacin-colistin, resulted in the greatest CFU reduction for strains R9316 (3.50 log. These findings support the potential of phage-antibiotic synergy (PAS) to augment killing of MDR P. aeruginosa. Systematic in vitro and in vivo studies are needed to better understand phage interactions with antipseudomonal antibiotics, to define the role of OMV production in P. aeruginosa PAC therapy and to outline pharmacokinetic and pharmacodynamic parameters conducive to PAS.. This study identifies novel bactericidal phage-antibiotic combinations capable of thwarting resistance development in MDR and XDR P. aeruginosa strains. Furthermore, phage-mediated OMV reduction is identified as a potential mechanism through which PAC potentiates bacterial killing.

Topics: Anti-Bacterial Agents; Bacteriophages; Ciprofloxacin; Colistin; Drug Resistance, Multiple, Bacterial; Drug Synergism; Humans; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections

Pseudomonas aeruginosa is one of the most worrisome infectious bacteria due to its intrinsic and acquired resistance against several antibiotics and the recalcitrance of its infections; hence, the development of novel antimicrobials effective against multidrug-resistant P. aeruginosa is mandatory. In this work, silver nanoparticles obtained by green synthesis using a leaf extract and fungi were tested against a battery of clinical strains from cystic fibrosis, pneumonia and burnt patients, some of them with multidrug resistance. Both nanoparticles showed a potent antibacterial effect, causing severe damage to the cell wall, membrane and DNA, and inducing the production of reactive oxygen species. Moreover, the nanoparticles derived from fungi showed synergistic antibacterial effects with the antibiotics meropenem and levofloxacin for some clinical strains and both kinds of nanoparticles were nontoxic for larvae of the moth Galleria mellonella, encouraging further research for their implementation in the treatment of P. aeruginosa infections.

Topics: Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Humans; Levofloxacin; Meropenem; Metal Nanoparticles; Microbial Sensitivity Tests; Plant Extracts; Pseudomonas aeruginosa; Pseudomonas Infections; Reactive Oxygen Species; Silver

Pseudomonas aeruginosa is an important nosocomial pathogen with a capacity of resistance to multiple antibiotics and production of various extracellular and cell-associated virulence factors that clearly contribute to its pathogenicity. The objective of this study was to investigate the antibiotic susceptibility, virulence factors, and clonal relationship among clinical isolates of P. aeruginosa. Different clinical specimens from hospitalized patients were investigated for P. aeruginosa. Susceptibility of the isolates was evaluated by disc diffusion and broth microdilution methods, as described by the Clinical and Laboratory Standards Institute (CLSI) guideline. A total of 97 P. aeruginosa isolates were recovered from clinical specimens. The percentage of isolates resistant to antimicrobials was imipenem 25.77%, meropenem 15.46%, gentamicin 16.49%, tobramycin 15.46%, amikacin 16.49%, ciprofloxacin 20.61%, levofloxacin 24.74, ceftazidime 20.61%, piperacillin 15.46%, piperacillin/tazobactam 12.37%, colistin 9.27%, and polymyxin B 11.34%. Of isolates, 87.62% possessed β-hemolytic activity, 78.35% lecithinase, 59.8% elastase, 37.11% DNase, and 28.86% twitching motility. The frequency of virulence genes in isolates was lasB 82.47%, plcH 82.47%, exoA 58.76%, exoS 56.7%, and pilA 10.3%. ERIC-PCR typing clustered P. aeruginosa isolates to 19 common types (CT1-CT19) containing isolates from different hospitals and 43 single types (ST1-ST43). Colistin and polymyxin B were the most effective agents against the majority of P. aeruginosa isolates, emphasizing the effort to maintain their antibacterial activity as last-line therapy. The frequency of some virulence factors and genes was noticeably high, which is alarming. In addition, more effective strategies and surveillance are necessary to confine and prevent the inter-hospital and/or intra-hospital dissemination of P. aeruginosa between therapeutic centers.

Topics: Amikacin; Anti-Bacterial Agents; Ceftazidime; Ciprofloxacin; Colistin; Deoxyribonucleases; Drug Resistance, Bacterial; Genotype; Gentamicins; Humans; Imipenem; Iran; Levofloxacin; Meropenem; Microbial Sensitivity Tests; Pancreatic Elastase; Phospholipases; Piperacillin; Piperacillin, Tazobactam Drug Combination; Polymyxin B; Pseudomonas aeruginosa; Pseudomonas Infections; Tobramycin; Virulence Factors

There is no comprehensive study on PAM-like MBLs.. Our aim was to characterize novel B3 MBL variants, PAM-2 and PAM-3, from Pseudomonas tohonis clinical isolates.. We evaluated the antimicrobial susceptibility and the MBL gene composition of three novel P. tohonis clinical isolates identified at a Japanese hospital, using the broth microdilution method and WGS, respectively. We characterized the PAM-2 and PAM-3 proteins using recombinant protein expression and biochemical evaluations.. Low carbapenem MICs (meropenem MIC = 0.125-1 mg/L) were observed for all three P. tohonis isolates; however, the isolates produced MBLs. We identified blaPAM-2 and blaPAM-3 as potential genes, belonging to a novel subclass of B3 MBLs. Their genomic sequence was similar to that of blaPAM-1 from Pseudomonas alcaligenes. PAM-2 and PAM-3 comprised 287 amino acids and exhibited 90% amino acid identity with PAM-1, 73% identity with POM-1 from Pseudomonas otitidis and 61% identity with L1 from Stenotrophomonas maltophilia. Biochemical evaluations of recombinant PAM-2 and PAM-3 revealed similar kcat/Km ratios and demonstrated catalytic activity against all the tested β-lactams, except for aztreonam. In addition, the kcat/Km ratio for imipenem was 40-fold lower than that for meropenem.. P. tohonis harbours a species-specific PAM-family MBL gene. This enzyme has higher hydrolytic activity against meropenem compared with that against imipenem.

Topics: Anti-Bacterial Agents; beta-Lactamases; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Pseudomonas; Pseudomonas aeruginosa; Pseudomonas Infections

Topics: Anti-Bacterial Agents; Chloramphenicol; Drinking Water; Enrofloxacin; Erythromycin; Gentamicins; Humans; Imipenem; Iran; Meropenem; Microbial Sensitivity Tests; Mineral Waters; Pseudomonas aeruginosa; Pseudomonas Infections; Virulence Factors

We previously reported an increase in meropenem prescriptions for Pseudomonas aeruginosa infections in our hospital after the implementation of the 10th version of the EUCAST breakpoints table for P. aeruginosa in January 2020. As a consequence, antibiotic susceptibility testing results were adapted by masking meropenem for P. aeruginosa isolates susceptible to either ceftazidime, cefepime or piperacillin-tazobactam. We aimed to assess the changes in meropenem prescriptions after the implementation of the selective reporting.. In this retrospective single-centre observational study, we analysed antimicrobial therapies prescribed for P. aeruginosa infections after the susceptibility testing results have been made available over three periods: "before EUCAST update", "after EUCAST update without selective reporting" and "after EUCAST update with selective reporting", at Lausanne University Hospital, Switzerland. We collected epidemiological, microbiological and clinical data. The primary outcome was the prescription of meropenem to treat P. aeruginosa infections after the release of susceptibility testing results. Secondary outcomes were the use of increased dosage of non-meropenem anti-pseudomonal drugs, and IDs' consultations rates after the release of susceptibility testing results.. Among the 457 patients included, 65 (14.2%) received meropenem: 5/148 (3.4%) before EUCAST update, 51/202 (25.3%) after EUCAST update without selective reporting, and 9/107 (8.4%) after EUCAST update with selective reporting. Supervision and counselling from IDs as well as the use of increased dosages of non-carbapenem antibiotics increased in both periods after EUCAST update, compared to the first period, respectively: 40.5% (60/148) versus 61.4% (124/202) versus 51.4% (55/107) (P < 0.001), and 57.9% (84/148) versus 91.1% (183/202) versus 90.7% (97/107) (P < 0.001).. Selective reporting of antibiotic susceptibility testing results might decrease unnecessary meropenem prescriptions for the treatment of P. aeruginosa infections and could be part of multimodal antibiotic stewardship interventions.

Topics: Anti-Bacterial Agents; Hospitals; Humans; Meropenem; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies

The limited armamentarium against multidrug-resistant Gram-negative bacilli led to the development of a new generation of β-lactam/β-lactamase inhibitor combinations (BL/BLI).. To evaluate the in vitro activity of ceftazidime/avibactam, ceftolozane/tazobactam, meropenem/vaborbactam, and imipenem/relebactam against Pseudomonas aeruginosa isolates recovered from patients hospitalized with skin and soft tissue infections (SSTIs) in several countries around the world.. A total of 360 P. aeruginosa isolates were consecutively collected from 47 medical centers located in Western Europe, Eastern Europe, the Asia-Pacific region, and Latin America. Susceptibility testing was performed by broth microdilution method at a monitoring laboratory. EUCAST breakpoints were applied.. Ceftazidime/avibactam (98.3% susceptible), ceftolozane/tazobactam (98.6% susceptible), and imipenem/relebactam (98.3% susceptible) were the most active compounds after colistin (100.0% susceptible) and retained activity against isolates nonsusceptible to piperacillin/tazobactam, meropenem, imipenem, and/or ceftazidime. Meropenem-vaborbactam was active against 94.2% of isolates. Ceftazidime/avibactam was the most active BL/BLI against meropenem-nonsusceptible (92.6% susceptible) and imipenem-resistant (93.8% susceptible) isolates, whereas ceftolozane/tazobactam was the most active BL/BLI against piperacillin/tazobactam-resistant (91.1% susceptible) and ceftazidime-resistant (91.7% susceptible) isolates.. The recently approved BL/BLIs demonstrated potent activity and broad coverage against contemporary P. aeruginosa isolates from patients with SSTIs.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Boronic Acids; Ceftazidime; Cephalosporins; Drug Combinations; Drug Resistance, Multiple, Bacterial; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Soft Tissue Infections; Tazobactam

Hospital admitted patients are at increased risk of nosocomial infections (NIs) with multi-drug resistant (MDR) pathogens which are prevalent in the hospital environment. Pseudomonas aeruginosa (P. aeruginosa) and Acinetobacter baumannii (A. baumannii) are common causes of NIs worldwide. The objective of this study is to determine antimicrobial resistance profiles and associated factors of Acinetobacter spp and P. aeruginosa NIs among hospitalized patients.. A cross-sectional study was conducted at Dessie comprehensive specialized hospital, North-East Ethiopia, from February 1 to April 30, 2020. A total of 254 patients who were suspected of the bloodstream, urinary tract, or surgical site nosocomial infections were enrolled consecutively. Socio-demographic and other variables of interest were collected using a structured questionnaire. Specimens were collected and processed following standard microbiological procedures. Antimicrobial susceptibility was determined using the Kirby-Bauer disk diffusion method following Clinical and Laboratory Standards Institute guidelines. Data were analyzed with SPSS version 23 and p-value < 0.05 was considered statistically significant.. Overall, 13% of patients had nosocomial Acinetobacter spp and/or P. aeruginosa infections. The culture positivity rate was 16(6.3%) for Acinetobacter spp and 18(7.1%) for P. aeruginosa. Patients admitted in the surgical ward (Adjusted odds ratio (AOR):10.66;95% confidence interval (CI):1.22-93.23), pediatric ward (AOR:14.37;95%CI:1.4-148.5), intensive care unit (AOR:41.93;95%CI:4.7-374.7) and orthopedics (AOR:52.21;95%CI:7.5-365) were significantly at risk to develop NIs compared to patients admitted in the medical ward. Patients who took more than two antimicrobial types at admission were 94% (AOR:0.06; 95% CI:0.004-0.84) times more protected from NIs compared to those who did not take any antimicrobial. About 81% of Acinetobacter spp and 83% of P. aeruginosa isolates were MDR. Amikacin and meropenem showed promising activity against Acinetobacter spp and P. aeruginosa isolates.. The high prevalence of MDR Acinetobacter spp and P. aeruginosa nosocomial isolates enforce treating of patients with NIs based on antimicrobial susceptibility testing results.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Adolescent; Adult; Aged; Aged, 80 and over; Amikacin; Anti-Bacterial Agents; Child; Child, Preschool; Cross Infection; Cross-Sectional Studies; Drug Resistance, Multiple, Bacterial; Ethiopia; Female; Hospitals, Special; Humans; Infant; Infant, Newborn; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Patient Admission; Pseudomonas aeruginosa; Pseudomonas Infections; Risk Factors; Treatment Outcome; Young Adult

Pseudomonas aeruginosa is a ubiquitous microorganism that is difficult to treat due to the increasing prevalence of multidrug resistance patterns. A total of 227 samples were taken from different clinical samples during the study period from January 2018 to December 2018. The isolates were identified with antibiotic sensitivity testing with ESBL by the Vitek-2 automated method. MDR, XDR, and PDR were determined. 40 (17.6%) isolates were positive for P. aeruginosa, maximum of ESBL and MBL. Positive isolates were detected in the burn, coexisting ESBL + MBL enzymes in 21 (52.5%) of our isolates. Imipenem followed by Meropenem were found to be effective against ESBL and MBL producers. Resistance was reached between 72-100% to 5 antibiotics. The frequency of PDR, MDR, and XDR were 5%, 50%, and 45%, respectively. The frequency of co-production between MDR, XDR, and PDR with MBL, ESBL, and Biofilm was 35%, 12.5% and 5%, respectively. Among the ESBLs, the frequency of distribution of bla VEB-1gene and blaGES-5 gene was 50% and 40 %, respectively. Bacterial isolates simultaneously carrying blaVEB-1 gene with multiple β-lactamases of different classes of biofilm, MDR, PDR, and XDR as same as a coexisting blaGES-5 gene. One isolate was detected as new isolates registered in global gene bank as locally P. aeruginosa isolates in Erbil city (LOCUS MN900953). The phylogenetic trees of the blaVEB gene isolates were demonstrated a genotype closely related to others, deposited in GenBank similar to the P. aeruginosa gene; gene sequencing revealed a 99% similarity with other isolates deposited in GenBank.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Base Sequence; beta-Lactamases; Biofilms; Burns; Drug Resistance, Multiple, Bacterial; Genotype; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Sequence Homology, Amino Acid

To compare the efficacy of topical meropenem and cefepime treatments with respect to moxifloxacin as new treatment options in an experimental Pseudomonas keratitis model.. Twenty-four rabbits in which keratitis are induced using Pseudomonas aeruginosa were divided into four groups according to treatment options. A solution of 50 mg/mL meropenem was prepared and topically applied to the first group, 50 mg/mL cefepime solution to the second group, topical 0.5% moxifloxacin drop to the third group, and topical isotonic (0.9% saline) solution to the fourth (control) group. The eyes were examined before and after treatment to score the clinical severity. After the subjects were sacrificed, their corneas were excised. To determine the efficacy of treatments, clinical score, bacterial load, and histopathological and immunohistochemical findings were evaluated.. When the three treatment groups were compared, there was a significant difference in the colony-forming unit (CFU) value, polymorph-nuclear leukocyte (PMNL) infiltration, and matrix metalloproteinase (MMP)-9 immunoreactivity (P=0.022, P=0.038, and P=0.037, respectively). The CFU values, PMNL infiltration scores and MMP-9 immunoreactivity were significantly lower in the meropenem and moxifloxacin groups compared with the cefepime group (P<0.05 for all). There was no significant difference between the meropenem and moxifloxacin groups in respect of the CFU values, PMNL infiltration, and MMP-9 immunoreactivity (P=0.842, P=0.784, and P=0.699, respectively).. The results of our study indicate that topical meropenem is at least as effective as topical moxifloxacin in the treatment of Pseudomonas keratitis. The meropenem and moxifloxacin are safer and suitable in the limited corneal invasion than cefepime. Thus, topical meropenem may be an alternative drug in the treatment of this condition. Clinical studies are needed to be conducted to assess this possibility more accurately.

Topics: Administration, Topical; Animals; Anti-Bacterial Agents; Cefepime; Colony Count, Microbial; Disease Models, Animal; Eye Infections, Bacterial; Fluoroquinolones; Keratitis; Meropenem; Pseudomonas; Pseudomonas aeruginosa; Pseudomonas Infections; Rabbits

Ectopic pregnancy (EP) is an emergency condition in the gynecologic field. Methotrexate (MTX) is a drug of choice for the medical treatment of EP. Severe adverse events are rare among patients treated with MTX for this condition.. We describe a woman with severe multi-organ involvement experiencing about six days of instability after treatment with just a single-dose MTX for EP. This life-threatening condition is not common with a single dose of MTX. A 30-year-old healthy woman was treated medically with MTX for an EP. Three days later the patient was admitted to the emergency department of our hospital with generalized pustular rashes, alopecia, hyperpigmentation, nausea and vomiting, oral ulcers, and raised Creatinine level. Four days later due to pancytopenia, fever, and loss of consciousness, she was transferred to the intensive care unit and was intubated.. After 38 days of hospitalization, treatment was successful with leucovorin and supportive care and the patient's symptoms and clinical manifestations were regressed.

Topics: Abortifacient Agents, Nonsteroidal; Adult; Alopecia; Anti-Bacterial Agents; Drug Hypersensitivity; Erythropoietin; Female; Fever; Granulocyte Colony-Stimulating Factor; Humans; Hyperpigmentation; Meropenem; Methotrexate; Pancytopenia; Platelet Transfusion; Pregnancy; Pregnancy, Ectopic; Pseudomonas aeruginosa; Pseudomonas Infections; Unconsciousness

The aims of the present study were the determination of antimicrobial and antibiofilm effects of meropenem-loaded mesoporous silica nanoparticles (MSNs) on carbapenem resistant

Topics: Anti-Bacterial Agents; Anti-Infective Agents; Biofilms; Carbapenem-Resistant Enterobacteriaceae; Carbapenems; Drug Resistance, Bacterial; Humans; Meropenem; Microbial Sensitivity Tests; Nanoparticles; Pseudomonas aeruginosa; Pseudomonas Infections; Silicon Dioxide

The increasing emergence of extensive drug-resistant bacteria (XDR) among chronic diabetic foot ulcer patients (DFU) possess serious threat which leads to foot amputation. The ideal measurement estimations of the presently accessible medications are getting insufficient against extensive drug-resistant strains. For quite a long-time piperacillin monotherapy, Piperacillin-tazobactam, ceftazidime, Carbapenem class of anti-toxin, ceftalozane-Tazobactam, and so on, has been the suggested therapy towards persistent instances of diabetic foot ulcer but because of the resistance mechanism of the potent pathogens the potency and usage of the antibiotic concentration regime is under the radar. Based on this hypothesis two isolates namely VIT PC 7 &VIT PC 9 were found to be resistant to all five classes of antibiotics exhibiting extensive drug resistance (XDR). The whole-genome sequence of Pseudomonas aeruginosa VIT PC 7 and VIT PC 9 data showed the presence of various RND efflux related genes and antibiotic resistance genes. The broth microdilution assay showed minimum inhibitory concentration (MIC) for ciprofloxacin and meropenem, Synergistic test was performed through checkerboard analysis and sub-MIC concentration of ciprofloxacin/meropenem was deduced using ∑ FICI, Time kills analysis was done for varying time interval to check the maximum reduction in CFU/ml of the bacterial cells, sub-MIC level of meropenem and ciprofloxacin showed inhibitory activity at lower concentration respectively. In vitro time-kill analysis showed the decrease in the number of cells, suggesting that the synergistic antimicrobial combinations are effective in decreasing the MIC level, and combinational test involving sub-MIC level of antibiotics also showed maximum reduction in biofilm forming cells, portraying the effectiveness of both the drugs. Accordingly, an expansion in the antimicrobial spectrum can be accomplished by utilizing the ideal measurements of ciprofloxacin/meropenem in persistent condition like diabetic foot ulcer, sub-MIC level of ciprofloxacin/meropenem could be a promising choice for anticipation against the ongoing drug-resistant crisis.

Topics: Anti-Bacterial Agents; Cephalosporins; Ciprofloxacin; Diabetic Foot; Drug Resistance; Humans; Meropenem; Microbial Sensitivity Tests; Piperacillin; Pseudomonas aeruginosa; Pseudomonas Infections; Tazobactam

It is well established that antibiotic treatment selects for resistance, but the dynamics of this process during infections are poorly understood. Here we map the responses of Pseudomonas aeruginosa to treatment in high definition during a lung infection of a single ICU patient. Host immunity and antibiotic therapy with meropenem suppressed P. aeruginosa, but a second wave of infection emerged due to the growth of oprD and wbpM meropenem resistant mutants that evolved in situ. Selection then led to a loss of resistance by decreasing the prevalence of low fitness oprD mutants, increasing the frequency of high fitness mutants lacking the MexAB-OprM efflux pump, and decreasing the copy number of a multidrug resistance plasmid. Ultimately, host immunity suppressed wbpM mutants with high meropenem resistance and fitness. Our study highlights how natural selection and host immunity interact to drive both the rapid rise, and fall, of resistance during infection.

Topics: Anti-Bacterial Agents; Bacterial Outer Membrane Proteins; Bacterial Proteins; Drug Resistance, Multiple, Bacterial; Humans; Hydro-Lyases; Membrane Transport Proteins; Meropenem; Microbial Sensitivity Tests; Middle Aged; Plasmids; Porins; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Tract Infections; Selection, Genetic; Sequence Analysis, DNA; Shock, Hemorrhagic

The aim was to develop and validate a Pseudomonas aeruginosa genotypic resistance score, based on analysis of the whole genome sequence resistome, to predict antimicrobial susceptibility phenotypes.. A scoring system based on the analysis of mutation-driven resistance in 40 chromosomal genes and horizontally acquired resistance (Resfinder) was developed for ceftazidime, ceftolozane/tazobactam, meropenem, ciprofloxacin and tobramycin. Resistance genes/mutations were scored from 0 (no effect) to 1 (EUCAST clinical resistance). One hundred wild-type strains obtained from 51 different hospitals during a 2017 multicentre study were fully sequenced and analysed in order to define a catalogue of natural polymorphisms in the 40 chromosomal resistance genes. The capacity of genotypic score to predict the susceptibility phenotype was tested in 204 isolates randomly selected from the 51 hospitals (four from each hospital).. The analysis of the 100 wild-type isolates yielded a catalogue of 455 natural polymorphisms in the 40 genes involved in mutational resistance. However, resistance mutations and high-risk clones (such as ST235) were also documented among a few wild-type isolates. Overall, the capacity of the genotypic score (<0.5) for predicting phenotypic susceptibility (S + I in the case of meropenem) was very high (95-100%). In contrast, the capacity of the genotypic score to predict resistance (≥1) was far more variable depending on the agent. Prediction of meropenem clinical resistance was particularly low (18/39, 46.1%), whereas it classified clinical ceftolozane/tazobactam resistance in 100% (7/7) of cases.. Although a margin for improvement was evidenced in this proof of concept study, an overall good correlation between the genotypic resistance score and the susceptibility profile was documented. Further refining of the scoring system, automatization and testing of large international cohorts should follow.

Topics: Anti-Bacterial Agents; Cephalosporins; Drug Resistance, Multiple, Bacterial; Genome, Bacterial; Humans; Meropenem; Microbial Sensitivity Tests; Phenotype; Pseudomonas aeruginosa; Pseudomonas Infections; Tazobactam

Skin and soft tissue infections are increasingly prevalent and often complicated by potentially fatal therapeutic hurdles, such as poor drug perfusion and antibiotic resistance. Delivery vehicles capable of versatile loading may improve local bioavailability and minimize systemic toxicities yet such vehicles are not clinically available. Therefore, we aimed to expand upon the use of glutathione-conjugated poly(ethylene glycol) GSH-PEG hydrogels beyond protein delivery and evaluate the ability to deliver traditional therapeutic molecules.. PEG and GSH-PEG hydrogels were prepared using ultraviolet light (UV)-polymerization. Hydrogel loading and release of selected drug candidates was examined using UV-visible spectrometry. Therapeutic molecules and GST-fusion protein loading was examined using UV-visible and fluorescent spectrometry. Efficacy of released meropenem was assessed against meropenem-sensitive and -resistant P. aeruginosa in an agar diffusion bioassay.. For all tested agents, GSH-PEG hydrogels demonstrated time-dependent loading whereas PEG hydrogels did not. GSH-PEG hydrogels released meropenem over 24 h. Co-loading of biologic and traditional therapeutics into a single vehicle was successfully demonstrated. Meropenem-loaded GSH-PEG hydrogels inhibited the growth of meropenem-sensitive and resistant P. aeruginosa isolates.. GSH ligands within GSH-PEG hydrogels allow loading and effective delivery of charged therapeutic agents, in addition to biologic therapeutics.

Topics: Anti-Bacterial Agents; Biological Availability; Biological Products; Delayed-Action Preparations; Drug Delivery Systems; Drug Liberation; Drug Resistance, Bacterial; Drug Therapy, Combination; Glutathione; Humans; Hydrogels; Meropenem; Microbial Sensitivity Tests; Polyethylene Glycols; Pseudomonas aeruginosa; Pseudomonas Infections; Skin Diseases, Bacterial

Antimicrobial resistance is a major public-health concern. We evaluate chlorhexidine role in selection of resistant Pseudomonas aeruginosa mutants and their antibiotic cross-resistance. Mutation frequency and mutation rate after short-term exposure to sub-inhibitory concentrations of chlorhexidine were compared to those after spontaneous chlorhexidine-exposure, in P. aeruginosa PAO1 strain. Chlorhexidine-resistant mutants were generated, either by serial passage in increasing chlorhexidine concentrations or by single exposure to lethal chlorhexidine concentration. The generated mutants were tested for cross-resistance to different antibiotics, by determination of minimum inhibitory concentrations (MIC). The accompanied phenotypic changes in membrane permeability, outer membrane proteins (OMP), and efflux function were evaluated. The effect of exposure to chlorhexidine on MexAB-OprM, MexEF-oprN, and MexXY efflux pumps expression was investigated. No significant change was recorded between the mutation frequencies and mutation rates after short-term exposure to sub-inhibitory concentrations of chlorhexidine and after spontaneous chlorhexidine-exposure, in P. aeruginosa PAO1 strain. Twelve stable mutants, with ≥ eight-fold increase in chlorhexidine MIC, were generated. Several mutants showed increase in the MIC of colistin, cefepime, ceftazidime, meropenem, ciprofloxacin, and amikacin; seven mutants expressed meropenem cross-resistance. This was accompanied by decreased outer membrane permeability and changes in OMP. Using efflux pump inhibitor, chlorhexidine resistance was reverted in most isolates. Exposure to sub-inhibitory concentration of chlorhexidine induced the expression of MexXY efflux pump. Some resistant mutants had overexpressed MexXY efflux pump. Chlorhexidine can select P. aeruginosa strains with antibiotic cross-resistance. This necessitates implementing special protocols for chlorhexidine use and re-evaluation of its benefit versus risk in personal-care products.

Topics: Anti-Bacterial Agents; Bacterial Outer Membrane Proteins; Bacterial Proteins; Ceftazidime; Chlorhexidine; Drug Resistance, Bacterial; Humans; Meropenem; Microbial Sensitivity Tests; Mutation; Pseudomonas aeruginosa; Pseudomonas Infections

Antimicrobial susceptibility testing for Pseudomonas aeruginosa is critical to determine suitable treatment options. Commercial susceptibility tests are typically calibrated against the reference method, broth microdilution (BMD). Imprecision of MICs obtained by BMD for the same isolate on repeat testing is known to exist. Factors that impact the extent of variability include concentration of the inoculum, operator effects, contents of the media, inherent strain properties, and the testing process or materials. We evaluated the variability of BMD for antipseudomonal beta-lactams (aztreonam, cefepime, ceftazidime, meropenem, piperacillin-tazobactam, ceftazidime-avibactam, and ceftolozane-tazobactam) tested against a collection of P. aeruginosa isolates. Multiple replicate BMD tests were performed, and MICs were compared to assess reproducibility, including the impact of the inoculum and operator. Overall, essential agreement (EA) was ≥90% for all beta-lactams tested. Absolute agreement (AA) was as low as 70% for some beta-lactams. Variability from the inoculum and operators impacted the reproducibility of MICs. Piperacillin-tazobactam exhibited the highest degree of variability with 74% AA and 94% EA. The implications of MIC variability are extensive, as the MIC is essential for multiple facets of microbiology, such as the development of new compounds and susceptibility tests, dose optimization, and pharmacokinetic/pharmacodynamic (PK/PD) targets for individual patients.

Topics: Anti-Bacterial Agents; Humans; Meropenem; Pseudomonas aeruginosa; Pseudomonas Infections; Reproducibility of Results

The aim of this study was to investigate optimal loading doses prior to continuous infusion of meropenem in critically ill patients. A previously published and successfully evaluated pharmacokinetic model of critically ill patients was used for stochastic simulations of virtual patients. Maintenance doses administered as continuous infusion of 1.5-6 g/24 h with preceding loading doses (administered as 30 min infusion) of 0.15-2 g were investigated. In addition to the examination of the influence of individual covariates, a best-case and worst-case scenario were simulated. Dosing regimens were considered adequate if the 5th percentile of the concentration-time profile did not drop at any time below four times the S/I breakpoint (= 2 mg/L) of Pseudomonas aeruginosa according to the EUCAST definition. Low albumin concentrations, high body weight and high creatinine clearances increased the required loading dose. A maximum loading dose of 0.33 g resulted in sufficient plasma concentrations when only one covariate showed extreme values. If all three covariates showed extreme values (= worst-case scenario), a loading dose of 0.5 g was necessary. Higher loading doses did not lead to further improvements of target attainment. We recommend the administration of a loading dose of 0.5 g meropenem over 30 min immediately followed by continuous infusion.

Topics: Anti-Bacterial Agents; Body Weight; Critical Illness; Dose-Response Relationship, Drug; Humans; Infusions, Intravenous; Meropenem; Microbial Sensitivity Tests; Patient Simulation; Prospective Studies; Pseudomonas aeruginosa; Pseudomonas Infections

The emergence of multidrug-resistant (MDR) Pseudomonas aeruginosa, coupled with shrinking antibiotic pipelines, has increased the demand for new antimicrobials with novel mechanisms of action. As the indiscriminate nature of broad-spectrum antimicrobial toxicity may have negative clinical consequences and increase the incidence of resistance, we have developed a P. aeruginosa-selective antimicrobial peptide capable of preferentially killing P. aeruginosa relative to benign microorganisms. A targeting peptide (PA2) that binds specifically to OprF porin on P. aeruginosa was identified by phage display peptide library screening, and a hybrid peptide was constructed by addition of the targeting peptide to GNU7, a potent antimicrobial peptide. The resulting hybrid peptide PA2-GNU7 exhibited potent antimicrobial activity against P. aeruginosa without causing host toxicity. Confocal laser scanning microscopy analysis and time-kill experiments demonstrated that PA2-GNU7 exhibited a high degree of specificity for P. aeruginosa, and rapidly and selectively killed P. aeruginosa cells in mixed cultures. In addition, in vivo treatment efficacy of PA2-GNU7 was significantly greater than that of conventional antibiotics in a mouse model of MDR P. aeruginosa infection. Taken together, the data suggest that PA2-GNU7 may be a promising template for further development as a novel anti-MDR P. aeruginosa therapeutic agent.

Topics: Animals; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Dose-Response Relationship, Drug; Female; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Structure-Activity Relationship

The aim of this study was to characterise metallo-β-lactamase (MBL)-harbouring plasmids, their change in copy number in respect to different antibiotic pressure, and the efficiency of different curing agents in eliminating these resistance plasmids from nosocomial Pseudomonas aeruginosa isolates.. Plasmids were extracted from four isolates harbouring bla. Conjugatively transferable MBL genes (bla. The spread of multidrug resistance plasmids has been noted as a key factor associated with increasing carbapenem resistance. Successful curing of resistance plasmids can reverse the bacterial phenotype back to susceptible. This study revealed that different antibiotic pressure induces a change in copy number of MBL-encoding plasmids. SDS can be successfully used as an eliminating agent for these resistance determinants, although therapeutic application of this agent is not possible due to its high toxicity and mutagenic nature.

Topics: Anti-Bacterial Agents; Aztreonam; beta-Lactamases; Cefotaxime; Cross Infection; DNA Copy Number Variations; Drug Resistance, Multiple, Bacterial; Ertapenem; Gene Expression Regulation, Bacterial; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Plasmids; Pseudomonas aeruginosa; Pseudomonas Infections; Sodium Dodecyl Sulfate; Suppuration; Urine

Meropenem generics are often imposed on prescribers, however scarce information is available on key properties such as antimicrobial potency, stability and colouration in solution, and dissolution time. This study aimed to generate comparative information for products available in Europe. The originator (ASTRA) and four generics (HOSPIRA, SANDOZ, FRESENIUS and AUROVIT) were compared for: (i) MICs against Pseudomonas aeruginosa clinical isolates (range, 0.125-191 mg/L); (ii) colouration (visual and photometry) and stability of concentrated solutions for prolonged or continuous infusion and maintained at 25-37 °C for up to 8 h (acceptable limit, ≥90% of original concentration); and (iii) dissolution time of concentrated solutions (50 mg/mL [for bolus administration]: turbidimetry and nursing personnel assessment). No significant difference was observed for MICs (except 2/80 isolates). For concentrated solutions storage: (i) SANDOZ produced about two times more yellow-coloured degradation products than the other preparations; (ii) meropenem loss was time-, concentration- and temperature-dependent; (iii) FRESENIUS was the least stable (limit for 1 g/48 mL, ~8 h at 25 °C and 4.5 h at 37 °C); (iv) at 2 g/48 mL, the storage time limit was 5-6 h at 25 °C and ~3 h at 37 °C for all preparations. Complete dissolution (turbidimetry) required 240 s for generics (120 s for ASTRA), and nurses reported longer but highly variable times for generics. Substantial differences between innovator and generics have been identified that could impact on their clinical use and/or make multicentric studies difficult to interpret, requiring suitability studies in the environments of their intended use.

Topics: Anti-Bacterial Agents; Belgium; Drugs, Generic; Europe; France; Humans; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Solubility; Spain; Temperature

There have been literature reports that some recommended meropenem dosage regimens may fail to meet therapeutic targets in some high-risk children and adults. We evaluated this observation in children using literature studies conducted in infants and children. Observed and, as necessary, simulated data from the literature were combined, yielding a data set of 288 subjects (1 day to ~ 17 years). A population pharmacokinetic model was fit to the data and then used to simulate the recommended dosing regimens and estimate the proportion of subjects achieving recommended target exposures. A two-compartment model best fit the data with weight, postnatal age, gestational age, and serum creatinine as covariates. The US Food and Drug Administration (FDA)-approved dosing regimens achieved targets in ~ 90% or more of subjects less than 3 months of age for organisms with minimum inhibitory concentration (MIC)'s of 2 and 4 mg/L; however, only 68.4% and 41.7% of subjects older than 3 months and weighing < 50 kg achieved target exposures for organisms with MIC's of 2 and 4 mg/L, respectively [Correction added on January 23, 2020, after first online publication: "> 3 months" corrected to "less than 3 months".]. Moreover, for subjects weighing more than 50 kg, only 41.3% and 17% achieved these respective targets. Simulation studies were used to explore the impact of changing dose, dosing interval, and infusion duration on the likelihood of achieving therapeutic targets in these groups. Our findings illustrate that current dosing recommendations for children over 3 months of age fail to meet therapeutic targets in an unacceptable fraction of patients. Further investigation is needed to develop new dosing strategies in these patients.

Topics: Adolescent; Anti-Bacterial Agents; Body Weight; Child; Child, Preschool; Computer Simulation; Datasets as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Dosage Calculations; Female; Humans; Infant; Infant, Newborn; Male; Meropenem; Microbial Sensitivity Tests; Models, Biological; Monte Carlo Method; Pseudomonas aeruginosa; Pseudomonas Infections

Antimicrobial resistance in Pseudomonas aeruginosa is a threat to children with cancer. We explored the association between P. aeruginosa resistance and previous antibiotic exposure. All children with cancer and P. aeruginosa bacteremia in 2007 to 2016 in Denmark, a country with an overall resistance rate of ∼3%, were included. Twenty percent (10/49) of isolates from children previously exposed to meropenem were meropenem nonsusceptible. The only significant risk factor of meropenem nonsusceptibility was previous meropenem therapy (P=0.03). On the basis of these results, we suggest that meropenem should be reserved as a last resort for children with febrile neutropenia in countries with low antimicrobial resistance.

Topics: Adolescent; Anti-Bacterial Agents; Child; Child, Preschool; Denmark; Febrile Neutropenia; Female; Follow-Up Studies; Humans; Infant; Infant, Newborn; Male; Meropenem; Microbial Sensitivity Tests; Prognosis; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies

Topics: Adult; Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Gentamicins; Humans; Male; Meropenem; Pseudomonas aeruginosa; Pseudomonas Infections; Rifampin; Urinary Tract Infections

Surgical activity is increasing in the treatment of many types of fractures, the use of various metal structures, and the potential for infection with the development of osteomyelitis accordingly increases. The urgency of the problem is due to the fact that this disease is the most expensive medical problem, especially when it comes to prosthetics of large joints, with socially significant losses and the occurrence of disability in patients of working age, it requires long-term treatment. The aim of this study was to study one of the most complex pathogens of life-threatening infections due to its high virulence and ability to adapt to changing environmental conditions, in particular the action of antibacterial drugs and the study of its sensitivity to certain groups of antimicrobial drugs. The results of the study showed that over the three years of observation in 2017-2019, the average value of Pseudomonas aeruginosa in the amount of 10.8% was established in the etiology of osteomyelitis. The revealed sensitivity of Pseudomonas aeruginosa is preserved to fluoroquinolone - levofloxanin, aminoglycosides-amikacin, gentamicin, carbapenems - meropenem, doripenem. All of the above drugs can be used as empirical therapy. During this period, a significant decrease in sensitivity was found, which reached in 2019 for cefepime - 51.9%, pefloxacin - 55.8%, ertapenem - 59.7%. The success of the treatment of this pathology directly depends on the timely microbiological diagnosis and the choice of patient treatment tactics with the appointment of effective antibacterial therapy, with an adequate exposure of antibiotic.

Topics: Amikacin; Anti-Bacterial Agents; Chronic Disease; Doripenem; Gentamicins; Humans; Levofloxacin; Meropenem; Microbial Sensitivity Tests; Osteomyelitis; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies

Pseudomonas aeruginosa (PA) is a major cause of healthcare-associated infections. Antipseudomonal carbapenems are among the antimicrobial agents used to treat PA infections, but several mechanisms of resistance, including the production of a carbapenemase (CP), may compromise their clinical efficacy. The objectives of this study were to determine: (i) the dissemination of carbapenem-resistant CP-negative and CP-positive PA isolates; and (ii) the in-vitro activity of ceftolozane-tazobactam (CTT) against carbapenem-susceptible and carbapenem-resistant isolates. Isolates were collected prospectively from January 2016 to April 2017 at 20 German medical laboratories. Each centre was asked to provide 50 consecutive isolates from hospitalized patients. Overall, 985 isolates were collected, of which 34% were obtained from intensive care patients. Seven hundred and thirty-eight (74.9%) isolates were susceptible to both imipenem and meropenem (Subgroup I), and 247 (25.1%) isolates were resistant to carbapenems (Subgroup II): 125 (12.7%) were imipenem-resistant but meropenem-susceptible, 12 (1.2%) were meropenem-resistant but imipenem-susceptible, and 110 (11.2%) were resistant to both carbapenems (Subgroup III). A CP was detected in 28 (2.8%) isolates (predominantly VIM-2). Nine hundred and fifty (96.4%) isolates were CTT-susceptible. Susceptibility to CTT was seen in 99.6% of Subgroup I isolates, 87% of Subgroup II isolates and 74.5% of Subgroup III isolates. Overall, 2.8% of PA produced a CP, while 22.2% were carbapenem-resistant, CP-non-producing isolates. Based on these findings, CTT may be considered for treatment of PA infections, particularly those caused by multi-drug-resistant CP-non-producing isolates.

Topics: Aged; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Carbapenems; Cephalosporins; Cross Infection; Drug Resistance, Multiple, Bacterial; Germany; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Middle Aged; Pseudomonas aeruginosa; Pseudomonas Infections; Tazobactam

To determine whether carbapenem consumption and Pseudomonas aeruginosa resistance rates can be used as benchmarks to compare and improve antimicrobial stewardship programs across multiple pediatric hospitals.. A prospective study.. Healthcare institutions in Japan with >100 pediatric beds.. An annual survey of the total days of therapy (DOT) per 1,000 patient days for carbapenem antibiotics (meropenem, imipenem-cilastatin, panipenem-betamipron, doripenem) and susceptibility rates of Pseudomonas aeruginosa to meropenem and imipenem-cilastatin from each institution was conducted over a 7-year period. Data were reported to the administration, as well as to the infection control team, of each institution annually.. Data were obtained from 32 facilities. The median total carbapenem DOT per 1,000 patient days was 16.6 and varied widely, with a range of 2.7 to 59.0. The median susceptibility to meropenem was 86.6%, ranging from 78.6% to 96.6%. We detected an inverse correlation between total carbapenem DOT versus susceptibility (r = - 0.36; P < .01). Over the 7-year period, the DOT per 1,000 patient days of carbapenem decreased by 27% from a median of 16.0 to 11.7 (P < .01). We also observed an improvement in susceptibility to meropenem from a median of 87% to 89.7% (P = .01) and to imipenem-cilastatin from 79% to 85% (P < .01). The decreases in the use of carbapenem were greater in institutions with antimicrobial stewardship programs led by pediatric infectious disease specialists.. Antimicrobial use and resistance, targeting carbapenems and P. aeruginosa, respectively, can serve as benchmarks that can be utilized to promote antimicrobial stewardship across pediatric healthcare institutions.

Topics: Anti-Bacterial Agents; Carbapenems; Child; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Prospective Studies; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Boronic Acids; Drug Combinations; Drug Resistance, Multiple, Bacterial; Drug Synergism; Humans; Klebsiella Infections; Klebsiella pneumoniae; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections

Pseudomonas aeruginosa has been known as a common unscrupulous pathogen that reasons cause nosocomial infections in patients with immunocompromise. Infection with multi-drug resistant Pseudomonas aeruginosa infection in many patients is a public health problem. The bacterium causes urinary tract infections, respiratory tract infections, skin inflammation and inflammation, soft tissue infections, bacteremia, bone and joint infections, gastrointestinal infections and various systemic infections, especially in patients with severe burns, cancer and AIDS, whose immune systems are suppressed. Among diverse virulence factors, the type III secretion system is known as a significant agent in virulence and development of antimicrobial resistance in P. aeruginosa. A total of 50 isolates of P. aeruginosa were gathered from burn wound and milk specimens. Documentation and antimicrobial susceptibility evidence were performed using the VITEK 2 system. Multiplex PCR was done to detect the secretion toxins-encoding genes. Out of 50 samples: 45/225 (20%) burn wound and 6/120 (5%) raw milk samples were found positive for P. aeruginosa. The multiplex PCR analysis of ExoT and ExoY genes showed that all P. aeruginosa 50 (100%) were positive. The occurrence of the ExoS and ExoU genes was 97.7% and 86.6% among clinical isolates while none of the raw milk isolates harbored the ExoU gene and 60% of them carried the ExoS gene. The results found 20 (40%) of isolates were multidrug resistance and the most effective antibiotics against clinical isolates were Ciprofloxacin and Meropenem. The aim of this study was to prevalence the exotoxin genes encoded type III secretion system and pattern of antimicrobial susceptibility of P. aeruginosa isolated from clinical and raw milk specimens.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Bacterial Toxins; Ciprofloxacin; Drug Resistance, Multiple, Bacterial; Exotoxins; Genes, Bacterial; Humans; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Type III Secretion Systems; Virulence; Virulence Factors

Here, we describe the case of a COVID-19 patient who developed recurring ventilator-associated pneumonia caused by

Topics: Anti-Bacterial Agents; COVID-19; Drug Resistance, Multiple, Bacterial; Humans; Lung; Lymphocyte Activation; Male; Meropenem; Metagenomics; Middle Aged; Piperacillin, Tazobactam Drug Combination; Pneumonia, Ventilator-Associated; Pseudomonas aeruginosa; Pseudomonas Infections; Recurrence; Respiration, Artificial; SARS-CoV-2; T-Lymphocytes

To determine the percentage of patients given standard doses of piperacillin/tazobactam or meropenem by continuous  infusion who achieved the target pharmacokinetic/pharmacodynamic  (PK/PD) index, which was defined as free concentrations four times  more than the minimum inhibitory concentration (CMI) for 100% of the  dosing interval (100% fT≥ 4 x MIC).. Preliminary data from a larger prospective clinical study  analysing the PK/PD behaviour of β-lactams antibiotics continuous  infusion (CI) in critical patients. The study was conducted in the  intensive care units of a tertiary university hospital for adults (June  2015-May 2017). Inclusion criteria: normal renal function (glomerular  renal function (GFR) CKD-EPI formula ≥ 60 mL/min/1.73 m2) and  treatment with standard dose β-lactams CI. Concentrations at steady  state (Css) conditions were determined using UHPLC-MS/MS. We  selected the highest susceptible MIC for all likely organisms according to  European Commitee on Antimicrobial Susceptibility Testing's (i.e.  piperacillin/tazobactam: 8 mg/L for enterobacteriaceae and 16 mg/L for  Pseudomonas aeruginosa; meropenem: 2 mg/L for any  microorganism). In addition, a subanalysis of patients was conducted using actual MIC values.. 61 patients were enrolled (25 to meropenem and 36 to  piperacillin/tazobactam). Average age was 59 (15) years and median  GFR rate was 95 mL/min/1.73 m2 (83-115). Median meropenem and  piperacillin free concentrations were 16 mg/L (11-29) and 40 mg/L (21- 51), respectively. 88% of patients treated with meropenem reached the  PK/PD target, without differences between both microorganisms. For  piperacillin/tazobactam, 61% and 11% of patients reached the target,  with enterobacteriaceae and Pseudomonas as suspected  microorganisms, respectively. The pathogen was isolated in 35 (57%)  patients: 94% reached the target PK/PD, without differences between  both antibiotic therapies.. Standard doses of meropenem CI are sufficient to  achieve a PK/PD target of 100% fT≥ 4 x MIC in suspected infections  with high MICs (Pseudomonas aeruginosa or enterobacteriaceae).  However, higher doses of piperacillin/tazobactam could be considered to  achieve this goal. In patients with isolated microorganisms, a  standard dose of both antibiotic therapies would be sufficient to achieve  the target. Therapeutic drug monitoring is highly recommended for  therapeutic optimization.. Objetivo: Determinar el porcentaje de pacientes, a los que se les  administró dosis estándar de piperacilina/tazobactam o meropenem en  perfusión continua, que alcanzaban el índice  farmacocinético/farmacodinámico diana definido como el 100% del  intervalo de administración en que las concentraciones de antibiótico  libre fueron cuatro veces iguales o superiores a la concentración mínima  inhibitoria (100% fT ≥ 4 x CMI).Método: Datos preliminares obtenidos de un estudio clínico prospectivo que analiza el comportamiento  farmacocinético/farmacodinámico de los antibióticos betalactámicos  administrados en perfusión continua en pacientes críticos. Se realizó en  unidades de cuidados intensivos de un hospital universitario de tercer  nivel, desde junio de 2015 a mayo de 2017. Criterios de inclusión:  adultos con función renal correcta (filtrado glomerular según la fórmula  CKD-EPI ≥ 60 ml/min/1,73 m2) y tratados con dosis estándar de  antibióticos betalactámicos en perfusión continua. Las concentraciones  en estado de equilibrio estacionario fueron determinadas mediante  cromatografía líquida acoplada a espectrometría de masas (UHPLC- MS/MS). Se utilizaron valores de concentración mínima  inhibitoria  teóricos para microorganismos más resistentes (piperacilina/ tazobactam: 16 mg/l para Pseudomonas aeruginosa y 8 mg/l para Enterobacteriaceae; meropenem: 2 mg/l, independientemente del  microorganismo). Además, se realizó un subanálisis de los pacientes con aislamiento microbiológico (concentraciones mínimas inhibitorias  reales).Resultados: Se incluyeron 61 pacientes (25 meropenem y 36  piperacilina/ tazobactam). Edad media 59 años (15), mediana de  filtrado glomerular 95 ml/min/1,73 m2 (83-115). Mediana de  concentraciones en estado de equilibrio estacionario libre: 16 mg/l (11- 29) meropenem y 40 mg/l (21-51) piperacilina. El 88% de los pacientes  tratados con meropenem alcanzaron el objetivo  farmacocinético/farmacodinámico, sin diferencias entre Enterobacteriaceae y Pseudomonas. En el caso de  piperacilina/tazobactam, el 61% y el 11% de los pacientes alcanzaron la  diana, considerando Enterobacteriaceae y Pseudomonas como  microorganismo sospechoso. Un total de 35 (57%) pacientes  presentaron aislamiento microbiológico. El 94% de ellos alcanzaron la  diana, sin diferencias entre los dos antibióticos.Conclusiones: Ante la sospecha de infecciones por microorganismos con concentraciones mínimas inhibitorias elevadas  (Pseudomonas aeruginosa o enterobacterias),

Topics: Adult; Aged; Anti-Bacterial Agents; Clinical Studies as Topic; Critical Illness; Cross Infection; Enterobacteriaceae Infections; Female; Hospitals, University; Humans; Infusions, Intravenous; Intensive Care Units; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Piperacillin, Tazobactam Drug Combination; Prospective Studies; Pseudomonas Infections; Tertiary Care Centers

Topics: Anti-Bacterial Agents; Carbapenems; Cohort Studies; Drug Resistance, Bacterial; Enterobacteriaceae; Enterobacteriaceae Infections; Ertapenem; Humans; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies; United States

Nephrotoxins contribute to 20%-40% of acute kidney injury (AKI) cases in the intensive care unit (ICU). The combination of piperacillin-tazobactam (PTZ) and vancomycin (VAN) has been identified as nephrotoxic, but existing studies focus on extended durations of therapy rather than the brief empiric courses often used in the ICU. The current study was performed to compare the risk of AKI with a short course of PTZ/VAN to with the risk associated with other antipseudomonal β-lactam/VAN combinations.. The study included a retrospective cohort of 3299 ICU patients who received ≥24 but ≤72 hours of an antipseudomonal β-lactam/VAN combination: PTZ/VAN, cefepime (CEF)/VAN, or meropenem (MER)/VAN. The risk of developing stage 2 or 3 AKI was compared between antibiotic groups with multivariable logistic regression adjusted for relevant confounders. We also compared the risk of persistent kidney dysfunction, dialysis dependence, or death at 60 days between groups.. The overall incidence of stage 2 or 3 AKI was 9%. Brief exposure to PTZ/VAN did not confer a greater risk of stage 2 or 3 AKI after adjustment for relevant confounders (adjusted odds ratio [95% confidence interval] for PTZ/VAN vs CEF/VAN, 1.11 [.85-1.45]; PTZ/VAN vs MER/VAN, 1.04 [.71-1.42]). No significant differences were noted between groups at 60-day follow-up in the outcomes of persistent kidney dysfunction (P = .08), new dialysis dependence (P = .15), or death (P = .09).. Short courses of PTZ/VAN were not associated with a greater risk of short- or 60-day adverse renal outcomes than other empiric broad-spectrum combinations.

Topics: Acute Kidney Injury; Aged; Aged, 80 and over; Anti-Bacterial Agents; Cefepime; Cohort Studies; Critical Illness; Female; Humans; Intensive Care Units; Kidney Function Tests; Male; Meropenem; Middle Aged; Piperacillin, Tazobactam Drug Combination; Pseudomonas; Pseudomonas Infections; Severity of Illness Index; Vancomycin

In Pseudomonas aeruginosa, fluoroquinolone exposure promotes resistance to carbapenems through upregulation of efflux pumps and transcriptional downregulation of the porin OprD. Evidence of this effect among hematologic malignancy (HM) patients or hematopoietic cell transplant (HCT) recipients receiving fluoroquinolone prophylaxis for neutropenia is lacking.. We retrospectively evaluated episodes of P. aeruginosa bloodstream infections in HM patients or HCT recipients over a 7-year period at our institution. We determined the association of fluoroquinolone prophylaxis at the time of infection with meropenem susceptibility of P. aeruginosa breakthrough isolates and risk factors for meropenem nonsusceptibility. Whole-genome sequencing (WGS) and phenotypic assessments of meropenem efflux pump activity were performed on select isolates to determine the mechanisms of meropenem resistance.. We analyzed 55 episodes of P. aeruginosa bacteremia among 51 patients. Breakthrough bacteremia while on fluoroquinolone prophylaxis was associated with nonsusceptibility to meropenem, but not to antipseudomonal β-lactams or aminoglycosides. The receipt of fluoroquinolone prophylaxis was independently predictive of bacteremia with a meropenem-nonsusceptible isolate. All meropenem-nonsusceptible isolates analyzed by WGS contained oprD inactivating mutations, and all meropenem-nonsusceptible isolates tested demonstrated reductions in the meropenem minimum inhibitory concentration in the presence of an efflux pump inhibitor. A phylogenetic analysis based on WGS revealed several clusters of closely related isolates from different patients.. Fluoroquinolone prophylaxis in HM patients and HCT recipients is associated with breakthrough bacteremia with meropenem-nonsusceptible P. aeruginosa strains, likely due to both mutations increasing efflux pump activity and the epidemiology of P. aeruginosa bloodstream infections in our patient population.

Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Fluoroquinolones; Genome, Bacterial; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Meropenem; Microbial Sensitivity Tests; Mutation; Polymorphism, Single Nucleotide; Pseudomonas aeruginosa; Pseudomonas Infections

Topics: Aged; Anti-Bacterial Agents; Azabicyclo Compounds; Ceftazidime; Coinfection; Colistin; Drug Combinations; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Enterococcus faecalis; Enterococcus faecium; Eye Neoplasms; Febrile Neutropenia; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Humans; Klebsiella Infections; Leukemia, Myeloid, Acute; Male; Melanoma; Meropenem; Middle Aged; Neoplasms, Second Primary; Pseudomonas Infections; Tigecycline

Alteration of the porin-encoding gene oprD by insertion sequences (ISs) is one mechanism conferring carbapenem resistance in Pseudomonas aeruginosa. Here we describe a carbapenem-resistant clinical P. aeruginosa isolate 36-989 harbouring a novel IS (ISPa195) in oprD.. Minimum inhibitory concentrations (MICs) of antimicrobial agents were determined by the broth microdilution method. Carbapenemase activity was assessed using a MALDI-TOF/MS-based assay of meropenem hydrolysis. Efflux-dependent carbapenem resistance was evaluated using an assay with carbonyl cyanide 3-chlorophenylhydrazone (CCCP). The oprD gene and IS sequence were analysed by the Sanger method. Whole-genome sequencing was performed on an Illumina HiSeq 2500 platform.. Antimicrobial susceptibility testing demonstrated that P. aeruginosa 36-989 was resistant to imipenem (MIC=32mg/L) and meropenem (MIC=16mg/L). No carbapenemase activity was detected, however an efflux-mediated component of carbapenem resistance was revealed. A new IS element (ISPa195) was found in the oprD gene of P. aeruginosa 36-989. ISPa195 was 1190bp in length, belonging to the IS3 family, and contained two open reading frames that overlapped through a ribosomal slippage to translate the full-size transposase enzyme. There was an IS-associated 284-bp deletion in the oprD gene; no direct repeats at flanking regions of the IS were detected.. The absence of direct repeats at flanking regions in combination with the IS-associated deletion distinguished ISPa195 from other ISs previously detected in oprD. Carbapenem resistance in P. aeruginosa 36-989 was conferred by a combination of oprD alteration and carbapenem efflux.

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Carbapenems; DNA Transposable Elements; Drug Resistance, Multiple, Bacterial; Gene Components; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Porins; Pseudomonas aeruginosa; Pseudomonas Infections; Sequence Deletion

Multi-drug resistance among Pseudomonas aeruginosa in hospitals, and particularly intensive care units, has achieved alarming rates. Some combination antimicrobial therapies have demonstrated promising synergistic effects and an ability to overcome resistance without increasing drug-related toxicities. Nevertheless, rapid and feasible methods to identify synergy have not been routinely implemented in clinical microbiology laboratories. Synergistic activity of meropenem plus tobramycin or levofloxacin against clinical P. aeruginosa isolates (N=21) was assessed by two different methods using gradient diffusion strips (GDSs). A 90° angle was created at the intersection of the minimum inhibitory concentration (MIC) of each drug by the standard method, and by a novel method, the cross was placed at clinically relevant steady-state concentrations (C

Topics: Anti-Bacterial Agents; Drug Synergism; Humans; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Tobramycin

Latest trials failed to confirm merits of nebulized amikacin for critically ill patients with nosocomial pneumonia. We studied various nebulized and IV antibiotic regimens in a porcine model of severe Pseudomonas aeruginosa pneumonia, resistant to amikacin, fosfomycin, and susceptible to meropenem.. Prospective randomized animal study.. Animal Research, University of Barcelona, Spain.. Thirty female pigs.. The animals were randomized to receive nebulized saline solution (CONTROL); nebulized amikacin every 6 hours; nebulized fosfomycin every 6 hours; IV meropenem alone every 8 hours; nebulized amikacin and fosfomycin every 6 hours; amikacin and fosfomycin every 6 hours, with IV meropenem every 8 hours. Nebulization was performed through a vibrating mesh nebulizer. The primary outcome was lung tissue bacterial concentration. Secondary outcomes were tracheal secretions P. aeruginosa concentration, clinical variables, lung histology, and development of meropenem resistance.. We included five animals into each group. Lung P. aeruginosa burden varied among groups (p < 0.001). In particular, IV meropenem and amikacin and fosfomycin + IV meropenem groups presented lower P. aeruginosa concentrations versus amikacin and fosfomycin, amikacin, CONTROL, and fosfomycin groups (p < 0.05), without significant difference between these two groups undergoing IV meropenem treatment. The sole use of nebulized antibiotics resulted in dense P. aeruginosa accumulation at the edges of the interlobular septa. Amikacin, amikacin and fosfomycin, and amikacin and fosfomycin + IV meropenem effectively reduced P. aeruginosa in tracheal secretions (p < 0.001). Pathognomonic clinical variables of respiratory infection did not differ among groups. Resistance to meropenem increased in IV meropenem group versus amikacin and fosfomycin + meropenem (p = 0.004).. Our findings corroborate that amikacin and fosfomycin alone efficiently reduced P. aeruginosa in tracheal secretions, with negligible effects in pulmonary tissue. Combination of amikacin and fosfomycin with IV meropenem does not increase antipseudomonal pulmonary tissue activity, but it does reduce development of meropenem-resistant P. aeruginosa, in comparison with the sole use of IV meropenem. Our findings imply potential merits for preemptive use of nebulized antibiotics in order to reduce resistance to IV meropenem.

Topics: Administration, Inhalation; Administration, Intravenous; Amikacin; Animals; Anti-Bacterial Agents; Bacterial Load; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Drug Resistance, Bacterial; Drug Therapy, Combination; Female; Fosfomycin; Lung; Meropenem; Nebulizers and Vaporizers; Pneumonia; Prospective Studies; Pseudomonas aeruginosa; Pseudomonas Infections; Random Allocation; Swine; Trachea

A 13-year old neutropenic boy succumbed to bacteremia and sepsis with a Pseudomonas aeruginosa strain that rapidly developed resistance to carbapenems during meropenem monotherapy. Whole genome sequencing of the susceptible and resistant blood culture isolates revealed the meropenem-resistant phenotype to be caused by truncation of the OprD gene, which added to a preexisting inactivated mexR gene.

Topics: Adolescent; Anti-Bacterial Agents; Bacteremia; beta-Lactam Resistance; Blood Culture; Fatal Outcome; Humans; Male; Meropenem; Mutation; Porins; Pseudomonas aeruginosa; Pseudomonas Infections; Sequence Deletion; Whole Genome Sequencing

In the lungs of cystic fibrosis patients, Pseudomonas aeruginosa is exposed to a myriad of antibiotics leading to alterations in antibiotic susceptibility. This study identifies mutations resulting in hypersusceptibility in isogenic mutants of a P. aeruginosa clinical isolate, PA34.. PA34 was exposed to subinhibitory concentrations of doripenem or meropenem during growth to mid-log phase. Antibiotic susceptibility of surviving colonies was determined by agar dilution. Two carbapenem-resistant colonies hypersusceptible to non-carbapenem antibiotics were selected for further analysis. Antibiotic resistance gene expression was evaluated by RT-rtPCR and OprD production by SDS-PAGE. PA34 and isogenic mutants were evaluated with whole genome sequencing. Sequence variants were confirmed by Sanger sequencing, and cognate genes in eight carbapenem-resistant clinical isolates hypersusceptible to non-carbapenem antibiotics were sequenced. Lipopolysaccharide preparations of PA34 and hypersusceptible mutants were evaluated with ProQ-Emerald stain.. Isogenic mutants showed 4- to 8-fold MIC increase for imipenem, meropenem, and doripenem. However, they were hypersusceptible (≥4-fold MIC decrease) to aminoglycosides, fluoroquinolones, and non-carbapenem β-lactams. Expression of ampC or mex-opr efflux pumps was unchanged, but OprD production was decreased. Mutations causing Q86H AlgU and G77C LptG amino acid substitutions and nonsense mutations within OprD were observed in both mutants. Lipopolysaccharide modifications were observed between isogenic mutants and PA34. Non-synonymous mutations in LptF or LptG were observed in 6/8 hypersusceptible clinical isolates resistant to carbapenem antibiotics.. Evaluation of hypersusceptible mutants identified the association between lptG and a hypersusceptible phenotype. Modifications in lipopolysaccharide profiles suggests LptG modification interferes with lipopolysaccharide transport and contributes to hypersusceptibility.

Topics: Anti-Bacterial Agents; ATP-Binding Cassette Transporters; Cell Membrane; Codon, Nonsense; Cystic Fibrosis; Doripenem; Drug Resistance, Bacterial; Electrophoresis, Polyacrylamide Gel; Humans; Imipenem; Lipopolysaccharides; Meropenem; Microbial Sensitivity Tests; Mutation, Missense; Permeability; Porins; Pseudomonas aeruginosa; Pseudomonas Infections; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Whole Genome Sequencing

Acinetobacter baumannii and Pseudomonas aeruginosa are frequent multiresistant nosocomial pathogens that cause wound and pulmonary infections in hospitalized patients. As being increasingly resistant to most clinically available antibiotics, there is a constant need for exploration of new substances that could kill them or inhibit their growth, or alternatively inhibit some of their essential virulence factors. Chalcones are chemical compounds with well-documented antimicrobial potential. The aim of this study was to examine effectiveness of four newly-synthesized chalcones against the multiresistant clinical strains of A. baumannii and P. aeruginosa. Antibacterial activity of chalcones was investigated with broth-microdilution test and time-dependent killing assay. Synergistic effects of tested compounds with antibiotics (meropenem, amikacin and ciprofloxacin) were determined by checkerboard assay. The effects of chalcones on expression of virulence factors in P. aeruginosa (pyocyanin production, swimming and swarming motility) and A. baumannii (twitching and surface-associated motility), along with their biofilm production, were also examined. The obtained results indicate substantial antimicrobial activity of the tested chalcones (MICs = 100-175 μg/mL) and several synergistic interactions with antibiotics, as well as notable reduction in expression of all investigated virulence factors. These promising results may constitute a good basis for further research.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Amikacin; Anti-Bacterial Agents; Anti-Infective Agents; Biofilms; Chalcones; Ciprofloxacin; Drug Combinations; Drug Resistance, Multiple, Bacterial; Drug Synergism; Hospitals; Humans; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Pyocyanine; Virulence Factors

To evaluate target attainment of empirically dosed continuous infusion piperacillin/tazobactam (TZP) and meropenem (MER) in critically ill patients.. Patients were sampled on a daily basis. TZP or MER concentrations were evaluated during the first two days antibiotic therapy. The lower limit of the target range was defined as unbound concentrations equaling 4 times the epidemiological cutoff value of P. aeruginosa. The upper limit of the target range was based on the risk of toxicity, i.e. unbound concentrations >160 mg/L for TZP and > 45 mg/L for MER. Multivariable logistic regression was used to evaluate factors associated with target attainment.. Data from 253 patients were analyzed. Overall, 76/205 (37.1%) and 36/48 (75%) of the patients receiving TZP or MER respectively, attained target concentrations. In multivariable analysis, estimated creatinine clearance was identified as a risk factor for target non-attainment (OR 0.988, 95%CI [0.982;0.994]). Patients receiving MER were more likely to attain target concentrations compared with patients receiving TZP (OR 6.02, 95%CI [2.12;18.4]).. Target attainment of empiric antibiotic therapy in critically ill patients was low (37%) for TZP and moderate (75%) for MER, despite the use of a loading dose and despite optimization of the mode of infusion.

Topics: Adult; Aged; Anti-Bacterial Agents; Creatinine; Critical Illness; Female; Humans; Kidney Function Tests; Meropenem; Middle Aged; Multivariate Analysis; Piperacillin, Tazobactam Drug Combination; Prospective Studies; Pseudomonas aeruginosa; Pseudomonas Infections; Risk Factors; Treatment Outcome

We assessed the synergistic potential of fosfomycin and parenteral antibiotics among carbapenem-resistant Pseudomonas aeruginosa (CRP).. Minimum inhibitory concentrations (MICs) were determined by broth microdilution for all antibiotics except fosfomycin, for which the gradient diffusion strip (GDS) method was used. The GDS cross method was performed to assess interactions between fosfomycin and: aztreonam, cefepime, ceftazidime, ceftazidime/avibactam, ceftolozane/tazobactam, meropenem, piperacillin/tazobactam and tobramycin. Only organisms that were nonsusceptible to the second drug were assessed.. Fosfomycin synergy was commonly observed in vitro among CRP. These data may guide the selection of combination antibiotic therapy. The susceptibility to other antibiotics was restored in combination with fosfomycin, warranting further in vivo evaluation.

Topics: Anti-Bacterial Agents; Anti-Infective Agents; Azabicyclo Compounds; Carbapenems; Ceftazidime; Cephalosporins; Drug Combinations; Drug Resistance, Bacterial; Drug Synergism; Fosfomycin; Humans; Meropenem; Prevalence; Pseudomonas aeruginosa; Pseudomonas Infections; Tazobactam; Tobramycin; United States

Ecthyma gangrenosum is a cutaneous infection, most commonly occurring during sepsis evolution with Pseudomonas aeruginosa on an immunocompromised background. There have been rare case reports in previously healthy children and rarer are the cases with double etiology.. We present the case of a female Caucasian patient, aged 1 year and 8 months, who developed severe sepsis during flu evolution with predominant respiratory and cerebral manifestations. On admission, at skin level, there was noticed a necrotic coccygeal ulceration (with rapid increasing dimensions 0.5/0.5 cm in 24 hours), and with the transformation from a dry necrosis in a sphacelus at the periphery and progression of necrosis in depth.. The patient was diagnosed with ecthyma gangrenosum from which Pseudomonsa aeruginosa and Enterococcus faecalis were isolated from the samples that were harvested intraoperatively, decision that was taken considering the appearance of CT scan and the extremely rapid expansion of necrosis. Excisional debridement with necrectomy, lavage, and dressing being performed. The invasion of the fascia was excluded intraoperatively.. Treatment with Meropenem for 14 days was initiated, as well as amikacin and linezolid, the latter being replaced with teicoplanin for 14 days. Red blood cells transfusion, intravenous immunoglobulins, anticonvulsants were also administered.. Under treatment the evolution was favorable.. This case brings into discussion a double etiology of ecthyma gangrenosum, in a previously healthy child that occurred in the evolution of influenza. The evolution was favorable under broad-spectrum antibiotic treatment and surgical excision.

Topics: Anti-Bacterial Agents; Debridement; Ecthyma; Enterococcus faecalis; Female; Gram-Positive Bacterial Infections; Humans; Immunocompromised Host; Infant; Influenza, Human; Meropenem; Pseudomonas aeruginosa; Pseudomonas Infections; Sepsis

Extensively drug-resistant (XDR) Pseudomonas aeruginosa (P. aeruginosa) and particularly P. aeruginosa high-risk clones, are of growing concern because treatment options are limited. For years, colistin monotherapy has been the only available treatment, but is well known that is not an optimal treatment. A combination of colistin with another antibiotic could be a possible therapeutic option.. This study aimed to investigate effective antibiotic combinations against 20 XDR P. aeruginosa isolates obtained in a Spanish multicentre study (2015).. Forty-five checkerboards with six antipseudomonal antibiotics (amikacin, aztreonam, ceftazidime, meropenem, colistin, and ceftolozane/tazobactam) were performed to determine whether combinations were synergic or additive by fractional inhibitory concentration indices. On average, 15 different regimens were evaluated in duplicate against the three most prevalent high-risk clones (ST175, ST235, ST111) by time-kill analyses over 24h. The combination showing synergism in the three high-risk clones was validated in all studied XDR isolates.. In time-kill curves, the untreated control failed, as did each study regimen when administered alone. Two combinations were synergistic in the three high-risk clones that were initially studied: amikacin plus ceftazidime and colistin plus meropenem, with the second being the most effective combination. The efficacy of colistin plus meropenem was then tested in all 20 isolates. A synergistic bacterial density reduction for the duration of the study occurred in 80% of the entire XDR collection.. These data suggest that colistin plus meropenem may be a useful combination for the treatment of infections due to XDR P. aeruginosa, including high-risk clones, which warrants evaluation in a clinical trial.

Topics: Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Drug Synergism; Drug Therapy, Combination; Humans; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Spain

Topics: Animals; Antibodies, Bispecific; Bacteremia; Immunotherapy; Meropenem; Pneumonia; Pseudomonas aeruginosa; Pseudomonas Infections; Rabbits; Treatment Outcome

Topics: Anti-Bacterial Agents; Antimicrobial Stewardship; Bacterial Outer Membrane Proteins; Humans; Meropenem; Pseudomonas aeruginosa; Pseudomonas Infections

Topics: Anti-Bacterial Agents; Antimicrobial Stewardship; beta-Lactam Resistance; Child; Drug Administration Schedule; Female; Humans; Intensive Care Units; Male; Meropenem; Microbial Sensitivity Tests; Practice Guidelines as Topic; Practice Patterns, Physicians'; Pseudomonas aeruginosa; Pseudomonas Infections; Tertiary Care Centers; Time Factors; United States

This study evaluated the in vitro activity of ceftolozane-tazobactam and comparator agents tested against Enterobacteriaceae and Pseudomonas aeruginosa isolates from hospitalized patients in the United States. Ceftolozane-tazobactam is an antipseudomonal cephalosporin combined with a well-established β-lactamase inhibitor. A total of 18,960 organisms (15,223 Enterobacteriaceae and 3,737 P. aeruginosa) were consecutively collected from 32 medical centers located in all nine U.S. census divisions from 2013 to 2016. Organisms were tested for susceptibility by broth microdilution. CLSI and EUCAST interpretive criteria were used. Ceftolozane-tazobactam (94.4% susceptible), amikacin (99.0% susceptible), and meropenem (98.0% susceptible) were the most active compounds tested against Enterobacteriaceae. Among the Enterobacteriaceae isolates tested, 1.9% (n = 286) were carbapenem-resistant Enterobacteriaceae (CRE) and 9.5% (n = 1,450) exhibited an extended-spectrum β-lactamase (ESBL) non-CRE phenotype. Although ceftolozane-tazobactam showed good activity against ESBL non-CRE phenotype strains of Enterobacteriaceae (87.5% susceptible), it lacked useful activity against CRE. Ceftolozane-tazobactam was the most potent β-lactam agent tested against P. aeruginosa isolates, with 97.3% susceptible. Only colistin was more active, inhibiting 99.5% of isolates. Ceftolozane-tazobactam also maintained good activity against multidrug-resistant P. aeruginosa, with 88.6% susceptible. Ceftolozane-tazobactam was the most active β-lactam agent tested against P. aeruginosa and was more active than available cephalosporins and piperacillin-tazobactam against Enterobacteriaceae.

Topics: Amikacin; Anti-Bacterial Agents; Cephalosporins; Drug Resistance, Multiple, Bacterial; Enterobacteriaceae; Enterobacteriaceae Infections; Hospitals; Humans; Meropenem; Microbial Sensitivity Tests; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Tazobactam; Thienamycins

Delays in appropriate antimicrobial treatment contribute to increased mortality of septic patients. We aimed to develop a methodology for detection of carbapenem resistance in Gram-negative bacteria directly from positive blood cultures (BCs). Initially, meropenem-resistant Enterobacteriaceae (n = 13) and Pseudomonas aeruginosa (n = 32) isolates as well as the same numbers of meropenem-susceptible isolates were used to establish the detection of carbapenem resistance from agar cultures. Growth-based phenotypic detection of meropenem resistance was performed by a laser scattering (LS) method using a BacterioScan™216R instrument. A subset of the strain collection consisting of meropenem-susceptible and -resistant isolates (each comprising seven P. aeruginosa and three Klebsiella pneumoniae) was used for determination of carbapenem resistance directly from positive BCs. Lysis/centrifugation and filtration/dilution methods were investigated for processing of positive BCs. Four different statistical approaches to discriminate between susceptible and resistant bacteria in real-time were applied and were compared regarding their sensitivity and specificity. After 3 h and 4 h of incubation, respectively, detection of carbapenem resistance in Enterobacteriaceae (sensitivity, 100%; specificity, 100%) and P. aeruginosa (sensitivity, 100%; specificity, ≥90%) agar cultures was attainable. Detection of carbapenem resistance directly from positive BCs was achievable with 100% sensitivity and 100% specificity after 4 h and 5 h, respectively, applying lysis/centrifugation and filtration/dilution methods. In conclusion, LS technology combined with lysis/centrifugation and appropriate statistical real-time analyses represents a promising option for rapid detection of carbapenem resistance in Gram-negative rods directly from positive BCs.

Topics: Anti-Bacterial Agents; Blood Culture; Carbapenem-Resistant Enterobacteriaceae; Drug Resistance, Bacterial; Enterobacteriaceae Infections; Humans; Meropenem; Microbial Sensitivity Tests; Microscopy, Confocal; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

Carbapenem-resistant Pseudomonas aeruginosa (CRPA) infections represent a major therapeutic problem and combination therapy may be the chemotherapeutic option.. Bioluminescent CRPA was developed through sequential subcultures in subinhibitory concentrations of meropenem from an engineered strain of bioluminescent PA Xen5. Then CRPA was injected intraperitoneally to establish an intraperitoneal murine infection model. Treatments of colistin alone or combined with rifampicin or meropenem were started 1 h after infection. In vivo bioluminescence imaging was applied dynamically at 0 h, and 2 and 5 h after treatment. Ex vivo bacterial counts from liver, kidney, spleen, lung and blood samples were also determined 5 h after treatment.. In vivo imaging showed that both low- and high-dose colistin combined with rifampicin resulted in a significant decrease in bioluminescence signals compared with monotherapy of colistin or rifampicin alone, whereas colistin and meropenem combination therapy did not show a greater bactericidal effect compared with monotherapy. Ex vivo bacterial count results also confirmed that combination of both low- and high-dose colistin with rifampicin resulted in significantly reduced colony counts from five kinds of tissue samples. However, only combination of high-dose colistin + meropenem resulted in reduced colony counts merely in lung and blood samples.. Compared with single drugs, colistin and rifampicin combination therapy could exert synergistic effects, which might provide a better alternative when treating CRPA infections in clinical practice. Combination of colistin and meropenem should be considered with caution because it barely shows any synergism in the present in vivo model.

Topics: Animal Structures; Animals; Anti-Bacterial Agents; Bacterial Load; beta-Lactam Resistance; Colistin; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Female; Intraabdominal Infections; Luminescent Measurements; Meropenem; Mice, Inbred BALB C; Pseudomonas aeruginosa; Pseudomonas Infections; Rifampin; Staining and Labeling; Treatment Outcome

The activities of ceftolozane-tazobactam and comparator agents against organisms deemed to be the cause of pneumonia among patients hospitalized in the United States during 2013 to 2015 were evaluated. Organisms included 1,576

Topics: Anti-Bacterial Agents; beta-Lactamases; Cefepime; Ceftazidime; Cephalosporins; Drug Resistance, Multiple, Bacterial; Enterobacteriaceae; Enterobacteriaceae Infections; Gene Expression; Hospitalization; Humans; Isoenzymes; Meropenem; Microbial Sensitivity Tests; Piperacillin, Tazobactam Drug Combination; Plasmids; Pneumonia, Bacterial; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory System; Retrospective Studies; Tazobactam; United States

This case series explored the pharmacokinetic/pharmacodynamic (PK/PD) characteristics of meropenem (MEM) in adult cystic fibrosis (CF) patients hospitalized for a pulmonary exacerbation. From January 2015 to June 2016, all adult patients with cystic fibrosis (CF) and chronic pulmonary infection due to meropenem (MEM)-susceptible/intermediate Pseudomonas aeruginosa who received at least 48 h of MEM as an extended 3-hour infusion for treating a pulmonary exacerbation were enrolled. MEM plasma concentrations were determined by high-performance liquid chromatography. Six adult CF patients with a median age of 47 years were included in the study. MEM showed a high Vd (mean 45.98 L, standard deviation [SD] ±34.45). A minimal PK/PD target of 40% T > minimum inhibitory concentration (MIC) with respect to the MEM MIC of P. aeruginosa strains isolated from sputum during exacerbation was achieved in 5/6 patients (83%). MEM failed to achieve this target only in one patient, whose strain showed the highest MEM MIC in our cohort (8 mg/L). In all patients, MEM was well tolerated, and no adverse events were reported. In conclusion, high-dose, extended-infusion MEM during pulmonary exacerbation showed a high Vd in six adult CF patients with high median age, and was well tolerated.

Topics: Adult; Anti-Bacterial Agents; Cystic Fibrosis; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Bacterial; Female; Humans; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

Topics: Anti-Bacterial Agents; beta-Lactam Resistance; beta-Lactamase Inhibitors; Escherichia coli; Escherichia coli Infections; Humans; Meropenem; Microbial Sensitivity Tests; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

Here we formulate a mechanistic mathematical model to describe the growth dynamics of P. aeruginosa in the presence of the β-lactam antibiotic meropenem. The model is mechanistic in the sense that carrying capacity is taken into account through the dynamics of nutrient availability rather than via logistic growth. In accordance with our experimental results we incorporate a sub-population of cells, differing in morphology from the normal bacillary shape of P. aeruginosa bacteria, which we assume have immunity from direct antibiotic action. By fitting this model to experimental data we obtain parameter values that give insight into the growth of a bacterial population that includes different cell morphologies. The analysis of two parameters sets, that produce different long term behaviour, allows us to manipulate the system theoretically in order to explore the advantages of a shape transition that may potentially be a mechanism that allows P. aeruginosa to withstand antibiotic effects. Our results suggest that inhibition of this shape transition may be detrimental to bacterial growth and thus suggest that the transition may be a defensive mechanism implemented by bacterial machinery. In addition to this we provide strong theoretical evidence for the potential therapeutic strategy of using antimicrobial peptides (AMPs) in combination with meropenem. This proposed combination therapy exploits the shape transition as AMPs induce cell lysis by forming pores in the cytoplasmic membrane, which becomes exposed in the spherical cells.

Topics: Anti-Bacterial Agents; Antimicrobial Cationic Peptides; beta-Lactamases; Cytoplasm; Humans; Meropenem; Microbial Sensitivity Tests; Microscopy, Fluorescence; Models, Theoretical; Phenotype; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

Pseudomonas aeruginosa is the predominant pathogen responsible of chronic colonization of the airways in cystic fibrosis (CF) patients. There are few European data about antibiotic susceptibility evolution of P aeruginosa in CF patients.. The aim of this study is to evaluate the evolution of antibiotic resistance in the period 2010-2013 in CF patients chronically colonized by P aeruginosa and to highlight the characteristics of this evolution in patients younger than 20 years.. Clinical and microbiological data were extracted from two electronic databases and analyzed. Antibiotic resistance was defined according to European Committee of Antimicrobial Susceptibility Testing for levofloxacin, ciprofloxacin, meropenem, amikacin and ceftazidime. The between-group comparison was drawn with the Chi-square test for proportions, with the T-test for unpaired samples for normally distributed data and with Mann-Whitney test for non-normally distributed data. Significancy was defined by P < .05.. Fifty-seven CF patients, including thirteen subjects aged less than 20 years, were enrolled. P.. aeruginosa antibiotic sensitivity decreased significantly for fluoroquinolones, mainly in patients aged <20 years, while it increased for amikacin and colistin. The analysis of minimum inhibitory concentration confirmed these trends. In pediatric patients treated with more than three antibiotic cycles per year, greater resistance was found, except for amikacin and colistin.. An evolution in P aeruginosa antibiotic resistances is observed in the 4-year period studied. Responsible and informed use of antibiotics is mandatory in CF.

Topics: Adolescent; Adult; Amikacin; Anti-Bacterial Agents; Ceftazidime; Child; Ciprofloxacin; Cystic Fibrosis; Drug Resistance, Microbial; Female; Humans; Levofloxacin; Longitudinal Studies; Male; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Young Adult

Carbapenems are among the most powerful antipseudomonal agents. Limited data is available on drug susceptibility testing by routine methods (disc diffusion and Etest) for meropenem and doripenem. We aimed to compare the in vitro activity of imipenem, meropenem, and doripenem against Pseudomonas aeruginosa.. A total of 311 P. aeruginosa strains isolated from respiratory specimens in 170 patients who developed ventilator-associated pneumonia in two intensive care units were collected over a period of 31 months. The susceptibility of these isolates to imipenem, meropenem, and doripenem were determined by Etest and disc diffusion method.. Considering either all isolates or only the first isolates recovered per patient (311 and 170 respectively), the susceptibility rate for doripenem was higher than that for meropenem and imipenem. When MICs determined by Etest were converted into interpretative categories (S, I, R) using French (CA-SFM) guidelines, a poor correlation was observed for meropenem and doripenem. The percentages of correlation with the disc diffusion method were 90.6% and 89.7% for imipenem, 80.5% and 82.6% for meropenem, and 80.5% and 73.3% for doripenem, for the first isolates and all isolates, respectively. The rate of minor errors was as high as 17.7% and 16.1% for meropenem and 17.7% and 25.7% for doripenem for the first isolates and all isolates, respectively.. The accuracy of disc diffusion using CA-SFM guidelines appears unsatisfactory for all three carbapenems justifying guideline update for P. aeruginosa and carbapenems.

Topics: beta-Lactam Resistance; Carbapenems; Disk Diffusion Antimicrobial Tests; Doripenem; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Pneumonia, Ventilator-Associated; Practice Guidelines as Topic; Pseudomonas aeruginosa; Pseudomonas Infections; Reagent Strips; Sensitivity and Specificity

The combination of piperacillin/tazobactam (TZP) and vancomycin (VAN) provides a wide spectrum of activity against many pathogens acquired in healthcare settings. However, there have been reports of increased potential for nephrotoxicity with this combination. The aim of this study was to evaluate the nephrotoxic effect of TZP+VAN and to compare it with that of TZP and VAN monotherapies as well as VAN + meropenem (MEM), another broad-spectrum combination. A total of 402 patients receiving any of the antimicrobial regimens for >48 h were evaluated retrospectively over a 2-year period (2012-2013). Patients admitted to the intensive care unit, those with a baseline serum creatinine >2.0 mg/dL, patients on haemodialysis or peritoneal dialysis, pregnant women and those in septic shock were excluded. The presence and severity of acute kidney injury (AKI) was assessed according to the AKIN criteria. The incidence of AKI was significantly higher in the TZP+VAN group (41.3%) compared with the TZP (16.0%), VAN (15.7%) and VAN+MEM (10.1%) groups (P < 0.001). In the multivariate analysis, the risk of AKI increased 3.5-fold in patients treated with TZP+VAN and 1.7-fold in those who were receiving a potentially nephrotoxic drug when the antibiotic regimen was started compared with patients treated with VAN alone. Combined use of TZP+VAN carries a much higher risk of AKI than either antibiotic monotherapy regimen. Therefore, this broad-spectrum combination should be used cautiously in patients with a high likelihood of developing kidney injury.

Topics: Acute Kidney Injury; Adult; Aged; Creatinine; Drug Therapy, Combination; Female; Humans; Kidney; Logistic Models; Male; Meropenem; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies; Staphylococcal Infections; Thienamycins; Vancomycin

A total of 18,656 Enterobacteriaceae and 4,175 Pseudomonas aeruginosa were consecutively collected from 85 US hospitals and tested for susceptibility by broth microdilution methods in a central monitoring laboratory (JMI Laboratories). The antimicrobial susceptibility and frequency of key resistance phenotypes were assessed and stratified by infection type as follows: bloodstream (BSI; 3,434 isolates; 15.0%), pneumonia (6,439; 28.2%), skin and skin structure (SSSI; 4,134; 18.1%), intra-abdominal (IAI; 951; 4.2%), and urinary tract (UTI; 7,873; 34.5%). Ceftazidime-avibactam was active against 99.9% to 100.0% of Enterobacteriaceae and 97.0% (pneumonia) to 99.4% (UTI) of P. aeruginosa isolates. Susceptibility rates were consistently lower for β-lactams, such as ceftazidime (82.3% vs. 87.1-90.8%), piperacillin-tazobactam (87.5% vs. 90.2-95.6%), and meropenem (96.8% vs. 98.4-99.4%) among Enterobacteriaceae from pneumonia compared to other infection types. Susceptibility to gentamicin was also generally lower among isolates from pneumonia, whereas susceptibility to levofloxacin and colistin were lowest among BSI and SSSI isolates, respectively. The occurrence of multidrug-resistance (MDR; 8.2% overall), extensively drug-resistance (XDR; 1.1% overall), and carbapenem-resistant Enterobacteriaceae (CRE; 1.3% overall) phenotypes were markedly higher among isolates from patients with pneumonia compared to other infection types. Among P. aeruginosa, susceptibility rates for ceftazidime, piperacillin-tazobactam, and gentamicin were lowest among isolates from pneumonia, whereas susceptibility to meropenem was similar among isolates from BSI, pneumonia, and IAI (77.3-77.9%), and susceptibility to levofloxacin was markedly lower among UTI isolates (67.1%). The frequencies of P. aeruginosa isolates with MDR and XDR phenotypes were highest among isolates from patients with pneumonia.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Ceftazidime; Colistin; Cross Infection; Drug Combinations; Drug Resistance, Multiple, Bacterial; Enterobacteriaceae; Enterobacteriaceae Infections; Humans; Meropenem; Microbial Sensitivity Tests; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins; United States

Utilizing a total synthesis approach, the first 8-heterocyclyltetracyclines were designed, synthesized, and evaluated against panels of tetracycline- and multidrug-resistant Gram-positive and Gram-negative pathogens. Several compounds with balanced, highly potent in vitro activity against a broad range of bacterial isolates were identified through structure-activity relationships (SAR) studies. One compound demonstrated the best antibacterial activity against Pseudomonas aeruginosa both in vitro and in vivo for tetracyclines reported to date.

Topics: Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Halogenation; Humans; Pseudomonas aeruginosa; Pseudomonas Infections; Pyrrolidinones; Tetracycline Resistance; Tetracyclines

Over the past several decades, the frequency of antibacterial resistance in hospitals, including multidrug resistance (MDR) and its association with serious infectious diseases, has increased at alarming rates. Pseudomonas aeruginosa is a leading cause of nosocomial infections, and resistance to virtually all approved antibacterial agents is emerging in this pathogen. To address the need for new agents to treat MDR P. aeruginosa, we focused on inhibiting the first committed step in the biosynthesis of lipid A, the deacetylation of uridyldiphospho-3-O-(R-hydroxydecanoyl)-N-acetylglucosamine by the enzyme LpxC. We approached this through the design, synthesis, and biological evaluation of novel hydroxamic acid LpxC inhibitors, exemplified by 1, where cytotoxicity against mammalian cell lines was reduced, solubility and plasma-protein binding were improved while retaining potent anti-pseudomonal activity in vitro and in vivo.

Topics: Amidohydrolases; Animals; Anti-Bacterial Agents; Chemistry Techniques, Synthetic; Crystallography, X-Ray; Drug Design; Drug Evaluation, Preclinical; Drug Resistance, Multiple, Bacterial; Enzyme Inhibitors; Female; Hep G2 Cells; Humans; K562 Cells; Mice, Inbred BALB C; Microbial Sensitivity Tests; Molecular Docking Simulation; Pseudomonas aeruginosa; Pseudomonas Infections; Structure-Activity Relationship

Several diazabicyclooctanes (DBOs) are under development as inhibitors of class A and C β-lactamases. Inhibition of OXA (class D) carbapenemases is variable, with those of Acinetobacter spp. remaining notably resistant. We describe a novel DBO, WCK 4234 (Wockhardt), with distinctive activity against OXA carbapenemases.. MICs of imipenem and meropenem were determined by CLSI agar dilution with WCK 4234 added at 4 or 8 mg/L. Test organisms were clinical Enterobacteriaceae, Acinetobacter baumannii and Pseudomonas aeruginosa with carbapenemases or carbapenem resistance via porin loss plus AmpC or ESBL activity. AmpC mutants were also tested.. WCK 4234, which lacked direct antibacterial activity, strongly potentiated imipenem and meropenem against Enterobacteriaceae with OXA-48/OXA-181 or KPC enzymes, or with combinations of impermeability and AmpC or ESBL activity, with MICs reduced to ≤2 mg/L in almost all cases. Carbapenems likewise were potentiated against P. aeruginosa ( n  =   2) with OXA-181 enzyme, with MICs reduced from 64-128 to 2-8 mg/L and against A. baumannii with OXA carbapenemases, particularly OXA-23 or hyperproduced OXA-51, with MICs reduced to ≤2 mg/L for 9/10 acinetobacters with OXA-23 enzyme. Carbapenems were not potentiated against Enterobacteriaceae or non-fermenters with metallo-β-lactamases.. WCK 4234 distinctively overcame resistance mediated by OXA-type carbapenemases, including those of A. baumannii . It behaved similarly to other DBOs against strains with KPC carbapenemases or combinations of impermeability and ESBL or AmpC activity.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Anti-Bacterial Agents; Azabicyclo Compounds; Bacterial Proteins; beta-Lactamase Inhibitors; beta-Lactamases; Carbapenems; Cyclooctanes; Drug Discovery; Drug Resistance, Multiple, Bacterial; Drug Synergism; Enterobacteriaceae; Enterobacteriaceae Infections; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

Pseudomonas aeruginosa is a Gram-negative bacterium that continues to a leading cause of opportunistic nosocomial infections. The rapid increase in drug resistance in clinical isolates of this pathogen is a worldwide concern. The aim of this study was to investigate the distribution rate, prevalence and resistance patterns of P. aeruginosa in clinical specimens from the University Clinical Centre of Kosovo (UCCK). During a three-year period, 553 P. aeruginosa isolates were collected from patients admitted to a variety of UCCK units. The P. aeruginosa isolates were identified using standard laboratory procedures, and the susceptibility of the isolates to antimicrobial agents was investigated using the Kirby-Bauer disk diffusion assay according to European Committee on Antimicrobial Susceptibility Testing (EUCAST) (2013-2015) guidelines. P. aeruginosa was the second most frequently isolated pathogen. The isolation rate of P. aeruginosa was 7.6%, 10.1% and 8.6% in 2013, 2014 and 2015, respectively. Most clinical samples were from ICU (380, 68.7%). There was a statistically significant difference between ICU and non-ICU (p<0.05). P. aeruginosa isolates were most frequently isolated from the respiratory tract (323, 58.4%). The rate of resistance against most of the tested antimicrobials has increased, especially for carbapenems. Imipenem resistance was 25.2%, 26.5%, and 37.7% and meropenem resistance was 20.1%, 23.4%, and 36% in 2013, 2014 and 2015, respectively. This study provides important data on current antimicrobial resistance, and the results demonstrate that the resistance rates are progressively increasing. There is an urgent need to emphasise the prudent use of antibiotics and strictly adhere to the concept of "reserve drugs" to minimise the misuse of available antimicrobials. The acquisition and analysis of prevalence and resistance data will be an important tool to identify targets for quality improvement in Kosovo and will support the preparation of guidelines and protocols for the prudent use of antibiotics.

Topics: Adult; Anti-Bacterial Agents; Carbapenems; Cross-Sectional Studies; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacteria; Hospitals, University; Humans; Imipenem; Intensive Care Units; Kosovo; Male; Meropenem; Microbial Sensitivity Tests; Prevalence; Pseudomonas Infections; Retrospective Studies; Tertiary Care Centers; Thienamycins

Pseudomonas aeruginosa is an opportunistic human pathogen especially in patients with underlying diseases such as cyctic fibrosis and has been established as a model organism to study bacterial biofilm formation. The aim of this study was to compare the biofilm formation and antibiotic resistance in human and environmental P. aeruginosa isolates. Numbers of positive samples for algD and algU genes in human samples were 98% and the positive samples for algD and algU genes in the environmental samples were 80% and 70%, respectively. Ability to create biofilms by the human and environmental samples were 70% and 28%, respectively. The incidences of various antibiotic resistance genes in human samples including bla

Topics: Anti-Bacterial Agents; Bacterial Proteins; Biofilms; Ceftazidime; DNA, Bacterial; Drug Resistance, Bacterial; Environmental Microbiology; Genes, Bacterial; Gentamicins; Humans; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; RNA, Ribosomal, 16S; Sigma Factor; Soil Microbiology; Thienamycins; Water Microbiology

Although the proportion of Pseudomonas aeruginosa infections has reduced after the introduction of antibiotics with anti-pseudomonal effects, P. aeruginosa bacteremia still causes high mortality in immunocompromised patients. This study determined the clinical characteristics and outcomes of P. aeruginosa bacteremia and the antibiotic susceptibilities of strains isolated from febrile neutropenic patients.. Thirty-one febrile neutropenic children and adolescents with underlying hematologic/oncologic disorders diagnosed with P. aeruginosa bacteremia between 2011 and 2016 were enrolled in the study. Their medical records were retrospectively reviewed to evaluate the demographic and clinical characteristics. Antibiotic susceptibility rates of the isolated P. aeruginosa to eight antibiotic categories (anti-pseudomonal penicillin, anti-pseudomonal penicillin and β-lactamase inhibitor combination, anti-pseudomonal cephalosporin, monobactam, carbapenem, aminoglycoside, fluoroquinolone, and colistin) were also determined. Among the investigated factors, risk factors for mortality and infections by a multidrug-resistance (MDR) strain were determined.. Thirty-six episodes of P. aeruginosa bacteremia were identified. The mean age of the enrolled patients was 9.5 ± 5.4 years, and 26 (72.2%) episodes occurred in boys. Acute myeloid leukemia (41.7%) and acute lymphoblastic leukemia (33.3%) were the most common underlying disorders. The 30-day mortality was 38.9%, and 36.1% of the episodes were caused by MDR strains. The deceased patients were more likely to experience breakthrough infection (P = 0.036) and bacteremia (P = 0.005) due to MDR strains when compared with the patients who survived. The survived patients more likely received appropriate empirical antibiotic therapy (P = 0.024) and anti-pseudomonal β-lactam and aminoglycoside combination therapy (P = 0.039) compared with the deceased patients. The antibiotic susceptibility rates of the isolated P. aeruginosa strains were as follows: piperacillin/tazobactam, 67.6%; meropenem, 72.2%; and amikacin, 100%.. Mortality due to P. aeruginosa bacteremia remained at 38.9% in this study, and more than one-third of the isolated strains were MDR. In this context, empirical antibiotic combination therapy to expand the antibiotic spectrum may be a strategy to reduce mortality due to P. aeruginosa bacteremia in febrile neutropenic patients.

Topics: Adolescent; Amikacin; Aminoglycosides; Anti-Bacterial Agents; Bacteremia; Carbapenems; Cephalosporins; Child; Child, Preschool; Drug Resistance, Multiple, Bacterial; Female; Fever; Fluoroquinolones; Humans; Male; Meropenem; Neutropenia; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies; Thienamycins

The recent escalation of occurrences of carbapenem-resistant

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; Catheter-Related Infections; Ceftazidime; Cephalosporins; Cross Infection; Drug Combinations; Humans; Meropenem; Microbial Sensitivity Tests; Penicillanic Acid; Pseudomonas aeruginosa; Pseudomonas Infections; Tazobactam; Thienamycins

Pseudomonas aeruginosa is an opportunistic pathogen that can cause life-threatening infections in patients admitted to intensive care units. Resistance rapidly develops against two drugs of choice: ceftazidime and meropenem. Several therapeutic protocols were compared for reduction in viable cells and limiting development of resistance. Chemostat cultures were exposed to antibiotic concentrations measured in the blood of patients at low (5th percentile), medium (50th percentile) or high (95th percentile) levels in several therapy protocols to simulate therapy. Cultures exposed to ceftazidime recovered after 1 day at low, 2 days at medium and 3 days at high concentrations and developed corresponding levels of resistance. Patterns were very similar for meropenem except that recovery was delayed. Fluctuating levels and intermittent treatment achieved similar reduction of cell numbers at lower resistance costs. Treatment alternating ceftazidime and meropenem reduced cell numbers more than monotherapy, while strongly limiting resistance. Combination therapy was even more effective in both respects. Therapeutic goals are best reached with least risk of resistance when ceftazidime and meropenem are used in combination or alternating, at the highest concentrations the patient can endure. Monotherapy should also apply the highest concentration that is safe for the shortest time that achieves treatment objectives.

Topics: Anti-Bacterial Agents; Bacteriological Techniques; Ceftazidime; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Humans; Meropenem; Microbial Sensitivity Tests; Microbial Viability; Porins; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins; Treatment Outcome

Guidelines for the treatment of sepsis, febrile neutropenia, and hospital-acquired pneumonia caused by

Topics: Anti-Bacterial Agents; Cefepime; Ceftazidime; Cephalosporins; Ciprofloxacin; Drug Combinations; Drug Resistance, Multiple, Bacterial; Febrile Neutropenia; Humans; Iatrogenic Disease; Meropenem; Microbial Sensitivity Tests; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pneumonia; Practice Guidelines as Topic; Pseudomonas aeruginosa; Pseudomonas Infections; Sepsis; Tazobactam; Thienamycins; Tobramycin

Rates of carbapenem-resistant Pseudomonas aeruginosa are increasing. Aggressive prevention strategies, including instituting antimicrobial stewardship programmes, are essential for combating antimicrobial resistance.. We conducted this study to compare the antimicrobial susceptibility pattern of P. aeruginosa before and after carbapenem restriction.. We conducted a two-phase retrospective study in an adult ICU. The first phase was from May until July 2016 (before carbapenem restriction), whereas the second phase was from September until November 2016 (while implementing carbapenem restriction). The antimicrobial susceptibility pattern of P. aeruginosa was reviewed in August and December 2016. The measure of carbapenem-resistant P. aeruginosa was the proportion of resistant isolates (percentage resistant). The measure of antibacterial consumption in the study phases was DDDs/1000 patient days.. The overall carbapenem consumption decreased significantly in the second phase, from 28.44 to 11.67 DDDs/1000 patient days (P = 0.012). The resistance of P. aeruginosa to imipenem and meropenem decreased significantly from 76.0% to 38.5% (P = 0.019) and from 74.1% to 30.0% (P = 0.012), respectively. Susceptibility of P. aeruginosa to other antibacterials was not affected by carbapenem restriction.. These data suggest that restricting carbapenems, even for a short duration, may be an effective strategy for managing the problem of carbapenem resistance in P. aeruginosa.

Topics: Adult; Anti-Bacterial Agents; Antimicrobial Stewardship; Carbapenems; Drug Resistance, Bacterial; Drug Utilization; Humans; Imipenem; Intensive Care Units; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies; Thienamycins

Topics: Academic Medical Centers; Acinetobacter; Acinetobacter baumannii; Acinetobacter Infections; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Carbapenems; Centers for Disease Control and Prevention, U.S.; Drug Resistance, Microbial; Humans; Imipenem; Maryland; Meropenem; Microbial Sensitivity Tests; Pseudomonas; Pseudomonas aeruginosa; Pseudomonas Infections; ROC Curve; Sensitivity and Specificity; Thienamycins; United States

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactam Resistance; beta-Lactamases; Cefepime; Ceftazidime; Cephalosporins; Drug Combinations; Gene Expression; Humans; Los Angeles; Meropenem; Microbial Sensitivity Tests; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Tazobactam; Thienamycins

Topics: Bacteremia; Cephalosporins; Drug Resistance, Bacterial; Humans; Immunocompromised Host; Intensive Care Units; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Tazobactam

Bacterial biofilms are recalcitrant to antibiotic therapy and a major cause of persistent and recurrent infections. New antibody-based therapies may offer potential to target biofilm specific components for host-cell mediated bacterial clearance. For Pseudomonas aeruginosa, human monoclonal antibodies (mAbs) targeting the Psl biofilm exopolysaccharide exhibit protective activity against planktonic bacteria in acute infection models. However, anti-Psl mAb activity against P. aeruginosa biofilms is unknown. Here, we demonstrate that anti-Psl mAbs targeting three distinct Psl epitopes exhibit stratified binding in mature in vitro biofilms and bind Psl within the context of a chronic biofilm infection. These mAbs also exhibit differential abilities to inhibit early biofilm events and reduce biomass from mature biofilms in the presence of neutrophils. Importantly, a mAb mixture with neutrophils exhibited the greatest biomass reduction, which was further enhanced when combined with meropenem, a common anti-Pseudomonal carbapenem antibiotic. Moreover, neutrophil-mediated killing of biofilm bacteria correlated with the evident mAb epitope stratification within the biofilm. Overall, our results suggest that anti-Psl mAbs might be promising candidates for adjunctive use with antibiotics to inhibit/disrupt P. aeruginosa biofilms as a result of chronic infection.

Topics: Adult; Antibodies, Monoclonal; Biofilms; Biomass; Cell Aggregation; Epitopes; Humans; Meropenem; Neutrophils; Phagocytosis; Polysaccharides, Bacterial; Pseudomonas aeruginosa; Pseudomonas Infections

The emergence and rapid spread of carbapenem resistance mediated by metallo-beta-lactamase (MBL) in Pseudomonas aeruginosa is of major concern due to limited therapeutic options. This study was aimed at detecting the presence of MBL and its association with integrons in imipenem-resistant P. aeruginosa isolates and to determine their genetic relatedness.. A total of 213 P. aeruginosa isolates were collected from two tertiary care centres and tested against anti-pseudomonal antibiotics by antimicrobial susceptibility testing, followed by the detection of MBL production by combined disk method. Minimum inhibitory concentration (MIC) of meropenem was determined by E-test. Multiplex polymerase chain reaction (PCR) was performed for the detection of blaSPM, blaIMP, blaVIM, blaNDM, blaGIM and blaSIM. PCR was carried out to characterize the variable region of class 1 integron. Transcongujation assay was carried out for the confirmation of plasmid-mediated resistance. Enterobacterial repetitive intergenic consensus sequence (ERIC)-PCR was performed for determining the genetic relatedness among P. aeruginosa isolates.. Of the 213 P. aeruginosa isolates, 22 (10%) were found to be carbapenem resistant and these were from pus 18 (82%), urine 2 (9%), sputum 1 (5%) and tracheal wash 1 (5%). Among 22 isolates, 18 (81.8%) were found to be MBL producers by phenotypic method and MIC range of meropenem was 8 to >32 μg/ml. PCR amplification showed that 20 (91%) isolates carried any one of the MBL genes tested: blaVIM and blaNDM in seven (32%) and six (27%) isolates, respectively; blaVIM and blaNDMin three (14%); blaIMP and blaNDM in two (9%); blaVIM and blaIMP in one (5%) isolate. The blaVIM, blaIMP and blaNDM were found to co-exist in one isolate. None of the isolates were positive for blaSPM, blaSIM and blaGIM. All 22 isolates carried class I integron. Of the 20 MBL-positive isolates, transconjugants were obtained for 15 isolates. ERIC-PCR analysis showed all isolates to be clonally independent.. Our results showed 10.3 per cent of carbapenem resistance among P. aeruginosa isolates, and the coexistence of MBL-encoding genes among P. aeruginosa mediated by class I integron.

Topics: beta-Lactamases; Carbapenems; Drug Resistance, Bacterial; Humans; Integrons; Meropenem; Pseudomonas aeruginosa; Pseudomonas Infections; Tertiary Care Centers; Thienamycins

Carbapenem-resistant Pseudomonas aeruginosa infections have been a challenge and issue in hospital settings. However, the clinical impact of P. aeruginosa blood isolates resistant only to carbapenems has never been discussed previously.. To assess the risk factors and clinical significance of bacteremia caused by carbapenem resistance only P. aeruginosa (CROPA), a 6-year retrospective case-control study was conducted. The CROPA strains were defined as isolates susceptible to ciprofloxacin, antipseudomonal penicillins and cephalosporins, and aminoglycosides but resistant to one antipseudomonal carbapenem (imipenem or meropenem) or both. The controls were selected among patients with bacteremia due to P. aeruginosa susceptible to all above classes of antipseudomonal antibiotics, which was defined as all-susceptible P. aeruginosa.. Twenty-five patients had at least one blood culture positive for CROPA, and 50 controls had all-susceptible P. aeruginosa bacteremia. CROPA bacteremia had a high 30-day mortality rate (72.0%), as compared to 26.0% for the controls (p < 0.001). Through multivariate analysis, carbapenem exposure was the only risk factor for developing CROPA bacteremia (p = 0.002). A comparison between the surviving and deceased patients with CROPA bacteremia showed that nine (50%) of those who died, but none of the survivors, received carbapenems as the initial empirical therapy (p = 0.027).. Carbapenem exposure was associated with emergence of CROPA infections. Repeated carbapenem use in such patients might increase rates of inappropriate initial empirical treatment and mortality. Prudent carbapenem use is important to reduce the emergence of CROPA.

Topics: Adult; Aged; Aminoglycosides; Anti-Bacterial Agents; Bacteremia; Blood Culture; Carbapenem-Resistant Enterobacteriaceae; Carbapenems; Case-Control Studies; Cephalosporins; Ciprofloxacin; Cross Infection; Female; Hospitals; Humans; Imipenem; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Mortality; Multivariate Analysis; Odds Ratio; Penicillins; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies; Risk Factors; Severity of Illness Index; Taiwan; Thienamycins

Topics: Adult; Anti-Bacterial Agents; Bacteriological Techniques; Female; Granulomatosis with Polyangiitis; Humans; Immunocompromised Host; Immunosuppressive Agents; Magnetic Resonance Imaging; Meropenem; Nocardia Infections; Opportunistic Infections; Pseudomonas Infections; Sepsis; Treatment Outcome

High-dose meropenem (MEPM; 6 g/day) has been approved as a treatment for purulent meningitis; however, little is known regarding its in vivo efficacy in refractory lower respiratory tract infections. The purpose of this study was to evaluate the efficacy of MEPM at 6 g/day in a murine model of severe pneumonia caused by MEPM-resistant Pseudomonas aeruginosa Experimental pneumonia induced by MEPM-resistant P. aeruginosa was treated with normal-dose MEPM (150 mg/kg of body weight, simulating a 3-g/day regimen in humans) or high-dose MEPM (500 mg/kg, simulating a 6-g/day regimen in humans). Mice treated with high-dose MEPM showed significantly restored survival relative to that of untreated mice and tended to show a survival rate higher than that of mice treated with normal-dose MEPM. The viable bacterial counts (of two clinical isolates) in the lungs decreased significantly in mice treated with high-dose MEPM from those for untreated mice (P < 0.001) or mice treated with normal-dose MEPM (P, <0.01 and <0.05). The number of inflammatory cells in the bronchoalveolar lavage fluid (BALF) was also significantly lower in mice treated with high-dose MEPM than in untreated mice. The free MEPM concentration in the epithelial lining fluid (ELF) exceeded 16 μg/ml for 85 min in mice treated with high-dose MEPM, but not for mice treated with normal-dose MEPM. Our results demonstrate that high-dose MEPM (6 g/day) might provide better protection against pneumonia caused by MEPM-resistant strains of P. aeruginosa than the dose normally administered (less than 3 g/day).

Topics: Animals; Anti-Bacterial Agents; Biological Availability; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Drug Administration Schedule; Female; Humans; Lung; Meropenem; Microbial Sensitivity Tests; Pneumonia, Bacterial; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Mucosa; Survival Analysis; Thienamycins; Treatment Outcome

Skull base osteomyelitis is an uncommon disease that usually complicates a malignant external otitis with temporal bone involvement. It affects predominantly diabetic and immunocompromised males and has a high mortality rate. Pseudomonas aeruginosa is the most common causative organism. Currently, there is no consensus about the best therapeutic option. Here we describe a case of severe skull base osteomyelitis caused by Pseudomonas aeruginosa with progressive palsy of cranial nerves that was successfully managed with prolonged outpatient continuous infusion of ceftazidime plus oral ciprofloxacin.. A 69-year-old Caucasian man presented with dysphagia, headache, and weight loss. He complained of left earache and purulent otorrhea. Over the following weeks he developed progressive palsy of IX, X, VI, and XII cranial nerves and papilledema. A petrous bone computed tomography scan showed a mass in the left jugular foramen with a strong lytic component that expanded to the cavum. A biopsy was then performed and microbiological cultures grew Pseudomonas aeruginosa. After 6 weeks of parenteral antibiotic treatment, our patient was discharged and treatment was continued with a domiciliary continuous infusion of a beta-lactam through a peripherally inserted central catheter, along with an oral fluoroquinolone for 10 months. Both radiological and clinical responses were excellent.. Skull base osteomyelitis is a life-threating condition; clinical suspicion and correct microbiological identification are key to achieve an accurate and timely diagnosis. Due to the poor outcome of Pseudomonas aeruginosa skull base osteomyelitis, prolonged outpatient parenteral antibiotic therapy administered by continuous infusion could be a valuable option for these patients.

Topics: Aged; Anti-Bacterial Agents; Ceftazidime; Ciprofloxacin; Diagnostic Errors; Drug Therapy, Combination; Humans; Male; Meropenem; Osteomyelitis; Positron-Emission Tomography; Pseudomonas aeruginosa; Pseudomonas Infections; Skull Base; Thienamycins; Tomography, X-Ray Computed

Ecthyma gangrenosum (EG) is an aggressive cutaneous disease caused by local or systemic infection with Pseudomonas aeruginosa. EG is characterized by cutaneous manifestations ranging from nodule and papule, to necrotic ulceration with surrounding erythema, especially with black eschar or central crust. EG presents with characteristic skin lesions which is important to establish diagnosis of sepsis caused by P aeruginosa, a serious condition that can be treated efficiently if diagnosed early.. A 3-month-old female infant was presented with characteristic skin lesions of EG and developed sepsis 3 days later.. Ecthyma gangrenosum and sepsis caused by Pseudomonas aeruginosa.. Meropenem was used in combination with ceftazidime at first and excision of necrotic skin lesions was performed later.. Cure.. Early recognition of EG plays an important role in providing appropriate empiric antibiotic treatment at early stage of sepsis, and improves the prognosis. Surgical excision may be helpful if no improvement was achieved via antibiotic treatment.

Topics: Anti-Bacterial Agents; Ceftazidime; Female; Gangrene; Humans; Infant; Meropenem; Pseudomonas aeruginosa; Pseudomonas Infections; Pyoderma Gangrenosum; Sepsis; Thienamycins

Therapeutic interventions to treat multidrug-resistant (MDR) Pseudomonas aeruginosa infections are severely limited and often require the use of colistin as drug of last resort. The major challenges impeding the development of novel antipseudomonal agents are the lack of cell penetration and extensive efflux. We have discovered a tobramycin-moxifloxacin hybrid core structure which enhances outer membrane permeability and reduces efflux by dissipating the proton motive force of the cytoplasmic membrane in P. aeruginosa. The optimized hybrid protects Galleria mellonella larvae from the lethal effects of MDR P. aeruginosa. Attempts to select for resistance over a period of 25 days resulted in a 2-fold increase in the minimal inhibitory concentration (MIC) for the hybrid, while moxifloxacin or tobramycin resulted in a 16- and 512-fold increase in MIC. Although the hybrid possesses potent activity against MDR, P. aeruginosa isolates the activity that can be synergized when used in combination with other classes of antibiotics.

Topics: Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Fluoroquinolones; Humans; Moxifloxacin; Pseudomonas aeruginosa; Pseudomonas Infections; Tobramycin

This study investigated the mechanisms underlying the carbapenem resistance of bloodstream isolates of Pseudomonas aeruginosa obtained from two Korean hospitals. Of the 79 P. aeruginosa isolates, 22 and 21 were resistant to imipenem and meropenem, respectively. The 22 imipenem-resistant P. aeruginosa isolates were classified into 7 sequence types (STs) and 13 pulsotypes. Twelve imipenem-resistant isolates from one hospital were found to belong to the international clone ST111. Two imipenem-resistant P. aeruginosa ST235 isolates carried the bla IMP-6 gene, but the remaining 20 isolates did not produce carbapenemases. Mutations in the oprD gene and a related decrease in gene expression were found in 21 and 5 isolates, respectively. However, all imipenemresistant P. aeruginosa isolates showed no significant expression of OprD in the outer membrane as compared with that of carbapenem-susceptible PAO1 strain. Overexpression of genes associated with efflux pumps, including mexB, mexD, mexF, and mexY, was not found in any imipenem-resistant isolate. One imipenem-resistant P. aeruginosa isolate overexpressed the ampC gene. Our results show that the low permeability of drugs due to the mutational inactivation of OprD is primarily responsible for carbapenem resistance in bloodstream isolates of P. aeruginosa from Korean hospitals.

Topics: Anti-Bacterial Agents; Bacteremia; Bacterial Proteins; beta-Lactamases; Carbapenems; Drug Resistance, Multiple, Bacterial; Humans; Imipenem; Meropenem; Multidrug Resistance-Associated Proteins; Mutation; Porins; Pseudomonas aeruginosa; Pseudomonas Infections; Republic of Korea; Thienamycins

Antibiotic dose predictions based on PK/PD indices rely on that the index type and magnitude is insensitive to the pharmacokinetics (PK), the dosing regimen, and bacterial susceptibility. In this work we perform simulations to challenge these assumptions for meropenem and Pseudomonas aeruginosa.. A published murine dose fractionation study was replicated in silico. The sensitivity of the PK/PD index towards experimental design, drug susceptibility, uncertainty in MIC and different PK profiles was evaluated.. The previous murine study data were well replicated with fT > MIC selected as the best predictor. However, for increased dosing frequencies fAUC/MIC was found to be more predictive and the magnitude of the index was sensitive to drug susceptibility. With human PK fT > MIC and fAUC/MIC had similar predictive capacities with preference for fT > MIC when short t1/2 and fAUC/MIC when long t1/2.. A longitudinal PKPD model based on in vitro data successfully predicted a previous in vivo study of meropenem. The type and magnitude of the PK/PD index were sensitive to the experimental design, the MIC and the PK. Therefore, it may be preferable to perform simulations for dose selection based on an integrated PK-PKPD model rather than using a fixed PK/PD index target.

Topics: Animals; Anti-Bacterial Agents; Computer Simulation; Dose-Response Relationship, Drug; Female; Humans; Male; Meropenem; Mice; Microbial Sensitivity Tests; Models, Biological; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

Thein vitroantibacterial activities of ceftazidime-avibactam and comparator agents were evaluated using reference broth microdilution methods against 1,743Pseudomonas aeruginosaisolates collected in 2014 from 69 U.S. medical centers, representing each of the nine census regions. Ceftazidime-avibactam demonstrated potent activity againstP. aeruginosa, including many isolates not susceptible to ceftazidime, meropenem, and piperacillin-tazobactam. In each of the nine census regions, ceftazidime-avibactam demonstrated the highest percentage of susceptible isolates.

Topics: Academic Medical Centers; Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactam Resistance; Ceftazidime; Censuses; Drug Combinations; Humans; Meropenem; Microbial Sensitivity Tests; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Public Health Surveillance; Thienamycins; United States

During treatment of infections with antibiotics in critically ill patients in the intensive care resistance often develops. This study aims to establish whether under those conditions this resistance can develop de novo or that genetic exchange between bacteria is by necessity involved. Chemostat cultures of Pseudomonas aeruginosa were exposed to treatment regimes with ceftazidime and meropenem that simulated conditions expected in patient plasma. Development of antibiotic resistance was monitored and mutations in resistance genes were searched for by sequencing PCR products. Even at the highest concentrations that can be expected in patients, sufficient bacteria survived in clumps of filamentous cells to recover and grow out after 3 to 5 days. At the end of a 7 days simulated treatment, the minimal inhibitory concentration (MIC) had increased by a factor between 10 and 10,000 depending on the antibiotic and the treatment protocol. The fitness costs of resistance were minimal. In the resistant strains, only three mutations were observed in genes associated with beta-lactam resistance. The development of resistance often observed during patient treatment can be explained by de novo acquisition of resistance and genetic exchange of resistance genes is not by necessity involved. As far as conclusions based on an in vitro study using P. aeruginosa and only two antibiotics can be generalized, it seems that development of resistance can be minimized by treating with antibiotics in the highest concentration the patient can endure for the shortest time needed to eliminate the infection.

Topics: Anti-Bacterial Agents; beta-Lactam Resistance; Ceftazidime; Drug Resistance, Microbial; Humans; Meropenem; Microbial Sensitivity Tests; Mutation; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

This study aimed to compare the susceptibility to carbapenems (imipenem, meropenem and doripenem) of clinical strains of Pseudomonas aeruginosa. It also studied whether susceptibility to imipenem or meropenem could predict, reliably, susceptibility to doripenem. Pseudomonal strains were collected from respiratory specimens, half of them from cystic fibrosis patients. MICs were determined according to European Committee on Antimicrobial Susceptibility Testing recommendations. Carbapenems were compared according to the susceptible, intermediate or resistant categories. A new approach also allowed comparing these carbapenems in a 'MIC score' taking into account the differences in breakpoints between drugs. One hundred thirty-nine strains were studied. They were found to be statistically more susceptible to meropenem than to the two other drugs. However, this difference was small: less than one dilution between the agents. This study also highlighted a significant correlation between susceptibility to penems taken in pairs. However, susceptibility to imipenem or meropenem did not reliably predict susceptibility to doripenem. Despite potential differences in resistance mechanisms, the Pseudomonas aeruginosa strains showed close susceptibility to three carbapenems. This was true for both cystic fibrosis patients and others. However, there were variations between strains. That justifies MICs to be determined for each of the three penems. This might be useful in case of elevated MICs and/or for potentially difficult-to-treat infections such as pneumonia in patients with cystic fibrosis patients.

Topics: Anti-Bacterial Agents; Carbapenems; Cystic Fibrosis; Doripenem; Drug Resistance, Multiple, Bacterial; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

Topics: Anti-Bacterial Agents; Ciprofloxacin; Diagnosis, Differential; Drug Therapy, Combination; Female; Humans; Infant; Meropenem; Neutropenia; Pseudomonas aeruginosa; Pseudomonas Infections; Purpura; Shock, Septic; Skin Diseases, Bacterial; Thienamycins

Broth microdilution antimicrobial susceptibility testing was performed for ceftazidime-avibactam and comparator agents against 7,062 clinical isolates of Pseudomonas aeruginosa collected from 2012 to 2014 in four geographic regions (Europe, Asia/South Pacific, Latin America, Middle East/Africa) as part of the International Network for Optimal Resistance Monitoring (INFORM) global surveillance program. The majority of isolates were susceptible to ceftazidime-avibactam, with the proportions susceptible differing marginally across the four regions (MIC90, 8 to 16 μg/ml; 88.7 to 93.2% susceptible), in contrast to lower susceptibilities to the following comparator β-lactam agents: ceftazidime (MIC90, 32 to 64 μg/ml; 71.5 to 80.8% susceptible), meropenem (MIC90, >8 μg/ml; 64.9 to 77.4% susceptible), and piperacillin-tazobactam (MIC90, >128 μg/ml; 62.3 to 71.3% susceptible). Compared to the overall population, susceptibility to ceftazidime-avibactam of isolates that were nonsusceptible to ceftazidime (n = 1,627) was reduced to between 56.8% (Middle East/Africa; MIC90, 64 μg/ml) and 68.9% (Asia/South Pacific; MIC90, 128 μg/ml), but these percentages were higher than susceptibilities to other β-lactam agents (0 to 44% susceptible, depending on region and agent; meropenem MIC90, >8 μg/ml; 26.5 to 43.9% susceptible). For this subset of isolates, susceptibilities to amikacin (MIC90, >32 μg/ml; 53.2 to 80.0% susceptible) and colistin (MIC90, 1 μg/ml; 98.5 to 99.5% susceptible) were comparable to or higher than that of ceftazidime-avibactam. A similar observation was made with isolates that were nonsusceptible to meropenem (n = 1,926), with susceptibility to ceftazidime-avibactam between 67.8% (Middle East/Africa; MIC90, 64 μg/ml) and 74.2% (Europe; MIC90, 32 μg/ml) but again with reduced susceptibility to comparators except for amikacin (MIC90, >32 μg/ml; 56.8 to 78.7% susceptible) and colistin (MIC90, 1 μg/ml; 98.9 to 99.3% susceptible). Of the 8% of isolates not susceptible to ceftazidime-avibactam, the nonsusceptibility of half could be explained by their possession of genes encoding metallo-β-lactamases. The data reported here are consistent with results from other country-specific and regional surveillance studies and show that ceftazidime-avibactam demonstrates in vitro activity against globally collected clinical isolates of P. aeruginosa, including isolates that are resistant to ceftazidime and meropenem.

Topics: Africa; Amikacin; Anti-Bacterial Agents; Asia; Azabicyclo Compounds; beta-Lactams; Ceftazidime; Colistin; Drug Combinations; Humans; Latin America; Meropenem; Microbial Sensitivity Tests; Middle East; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

This study was designed to evaluate the pharmacodynamics of doripenem, imipenem and meropenem as a predictor of clinical success, mortality, 28 day recurrence and development of resistance in patients treated for Pseudomonas aeruginosa ventilator-associated pneumonia (VAP).. Previously published demographic and outcome data derived from patients treated for P. aeruginosa VAP with doripenem, imipenem or meropenem were utilized. Patient-specific data were used in conjunction with published population pharmacokinetic models to construct concentration-time profiles for each patient. Etest MICs were used to determine pharmacodynamic profiles. Classification and regression tree (CART) analysis was utilized to partition pharmacodynamics based on outcomes with P values of 0.05.. Eighty-six patients were included in the analysis. Initial carbapenem MICs ranged from 0.03 to 32 mg/L. VAP recurred in 28 patients; of these, 17 patients were initially infected with susceptible organisms, and 14 of them developed resistance. CART fT>MIC partitions identified for clinical success and survival were 19.2% (P = 0.016) and 47.9% (P < 0.001), respectively. No statistically significant partitions for fT>MIC were identified for recurrence or resistance development.. We identified fT>MIC cut-offs for positive clinical outcomes in patients with P. aeruginosa VAP that were similar to those observed in animal models of infection for stasis (∼20%) and 1 log decreases in cfu (∼40%). Although in vitro studies have suggested a link between drug exposure and development of resistance, we were unable to identify such a relationship clinically.

Topics: Adult; Aged; Aged, 80 and over; Animals; Anti-Bacterial Agents; Carbapenems; Disk Diffusion Antimicrobial Tests; Doripenem; Female; Humans; Imipenem; Male; Meropenem; Middle Aged; Pneumonia, Ventilator-Associated; Prospective Studies; Pseudomonas aeruginosa; Pseudomonas Infections; Recurrence; Thienamycins; Treatment Outcome

The emergence of carbapenem resistance has had a significant impact on both clinical and economic outcomes.. A retrospective, observational cohort study was performed in a 433-bed tertiary care medical center. The cohort was established from all inpatients with Pseudomonas aeruginosa-positive cultures over a 3-year period. Two multivariate models were developed: a logistic regression model to evaluate the primary outcome of in-hospital mortality and a linear regression model to evaluate the secondary outcome of total hospital cost.. The adjusted odds ratio for in-hospital mortality among patients with meropenem-resistant isolates was 2.89 (95% confidence interval [CI], 1.15-7.28). There were significantly more deaths in the meropenem-resistant group (28.1% vs 8.9%, P = .003). Patients with meropenem-resistant P aeruginosa experienced a 4-day increase in median length of stay versus those in the meropenem-susceptible group (14 vs 9 days, P = .004). Likewise, the percentage of patients who required intensive care unit (ICU) admission increased from 42% to 81.3% (P <.001). Meropenem resistance was also associated with a significant increase in total hospital cost by a factor of 1.42 among patients who were not admitted to the ICU (95% CI, 1.03-1.95).. Our results demonstrate that meropenem resistance was a significant predictor of in-hospital mortality. Carbapenem resistance also resulted in a significant increase in hospital cost, but only among patients who were not admitted to the ICU.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; beta-Lactam Resistance; Female; Hospital Costs; Humans; Male; Meropenem; Middle Aged; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies; Survival Analysis; Tertiary Care Centers; Thienamycins; Treatment Outcome

This study aimed to describe the pharmacokinetic (PK) characteristics of meropenem in children with severe infections and to assess the pharmacokinetic/pharmacodynamic (PK/PD) profiles of various meropenem dosage regimens in these patients. Fourteen children with severe infections received intravenous (i.v.) bolus doses of meropenem (20 mg/kg/dose) every 8 h (q8h). Serum samples were obtained before and serially after the second dose of meropenem, and a population PK analysis was performed. The final model was used to simulate serum concentration-time profiles with various dosage regimens. The PK/PD target was to achieve a serum meropenem concentration higher than the minimum inhibitory concentration (MIC) of the causative organism (i.e. Pseudomonas aeruginosa and Enterobacteriaceae) for ≥40% of the dosing interval (40%T>MIC). The median age and weight of the children were 6.0 years and 20.0 kg, respectively. Meropenem serum concentration-time profiles were best described by a two-compartmental model with first-order elimination. The simulations showed that the probabilities of target attainment (PTAs) for organisms with an MIC of 1 mg/L were 0.678 and 1.000 following i.v. bolus and 3-h infusion of meropenem (20 mg/kg/dose), respectively. Using a 3-h infusion of a 20 mg/kg/dose, the PTA was 0.999 and 0.765 for organisms with MICs of 4 mg/L and 8 mg/L, respectively. Meropenem given as i.v. bolus doses of 20 mg/kg/dose q8h appeared to be inadequate for PK/PD target attainment for organisms with an MIC of 1 mg/L. The simulations showed that meropenem administration via a 3-h infusion using the same dose improved the PTA.

Topics: Administration, Intravenous; Anti-Bacterial Agents; Child; Child, Preschool; Computer Simulation; Critical Illness; Enterobacteriaceae; Enterobacteriaceae Infections; Female; Humans; Male; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Serum; Thienamycins; Time Factors

The increase in the number of clinical isolates of multiresistant Enterobacteriaceae and Pseudomonas aeruginosa raises problems in decision-making on empirical treatments for severe Gram-negative bacilli-associated infections. The aim of our study is to determine the resistance of meropenem in our setting and the co-resistance of a combination of this compound with two antibiotics from different families: amikacin and ciprofloxacin. Between 2009 and 2013, a total of 81,310 clinical isolates belonging to the main species of Enterobacteriaceae and 39,191 clinical isolates of P. aeruginosa isolated in 28 hospitals in the Valencian Community on the South East Mediterranean Coast of Spain were analyzed using data provided by RedMiva (microbiological surveillance network of the Valencian Community). Meropenem resistance in Enterobacteriaceae increased from 0.16 % in 2009 to 1.25 % in 2013. Very few Enterobacteriaceae strains resistant to meropenem were sensitive to ciprofloxacin; in contrast, the combination of meropenem and amikacin led to a marked decrease in the risk of the microorganisms being resistant to both drugs (RR = 34 in 2013). In the case of P. aeruginosa, meropenem resistance also increased (from 14.32 % in 2009 to 24.52 % in 2013). Most meropenem-resistant P. aeruginosa isolates were also resistant to fluoroquinolones. However, the addition of amikacin led to a more than three-fold decrease in the risk of resistance. In our setting, empirical treatment with meropenem is adequate in enterobacterial infections, but poses difficulties when infection due to P. aeruginosa is suspected, in which case a combination of meropenem and amikacin has been shown to have a higher microbiological success rate.

Topics: Amikacin; Anti-Bacterial Agents; Ciprofloxacin; Drug Resistance, Bacterial; Drug Therapy, Combination; Enterobacteriaceae; Enterobacteriaceae Infections; Humans; Meropenem; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies; Spain; Thienamycins

Multidrug-resistant Pseudomonas aeruginosa has emerged as one of the most important healthcare-associated pathogens. Colistin is regarded as the last-resort antibiotic for multidrug-resistant Gram-negative bacteria, but is associated with high rates of acute kidney injury. The aim of this in vitro study is to search for an alternative treatment to colistin for multidrug-resistant P. aeruginosa infections.. Multidrug and carbapenem-resistant P. aeruginosa isolates were collected between January 2009 and December 2012 at MacKay Memorial Hospital. Minimal inhibitory concentrations (MICs) were determined for various antibiotic combinations. Carbapenemase-producing genes including bla VIM, other β-lactamase genes and porin mutations were screened by PCR and sequencing. The efficacy of carbapenems (imipenem, meropenem, doripenem) with or without rifampicin was correlated with the type of porin mutation (frameshift mutation, premature stop codon mutation) in multidrug-resistant P. aeruginosa isolates without carbapenemase-producing genes.. Of the 71 multidrug-resistant clinical P. aeruginosa isolates, only six harboured the bla VIM gene. Imipenem, meropenem and doripenem were significantly more effective (reduced fold-change of MICs) when combined with rifampicin in bla VIM-negative isolates, especially in isolates with porin frameshift mutation.. Imipenem + rifampicin combination has a low MIC against multidrug-resistant P. aeruginosa, especially in isolates with porin frameshift mutation. The imipenem + rifampicin combination may provide an alternative treatment to colistin for multidrug -resistant P. aeruginosa infections, especially for patients with renal insufficiency.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Carbapenems; Colistin; Doripenem; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Female; Humans; Imipenem; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Porins; Pseudomonas aeruginosa; Pseudomonas Infections; Rifampin; Taiwan; Thienamycins

Bacteremia due to Pseudomonas aeruginosa resistant to carbapenems is a public health problem due to the limitations it places on therapeutic options, as well as the increased time patients must spend in hospital, costs and the risk of mortality. . To evaluate the risk factors for presentation of bacteremia due to carbapenem-resistant P. aeruginosa acquired in the Hospital Universitario San Ignacio between January 2008 and June 2014. . This was a case control study in which the case patients presented bacteremia due to P. aeruginosa resistant to carbapenems and the control group included patients with P. aeruginosa susceptible to this group of antibiotics. Variables such as the previous use of meropenem and ertapenem, immunosuppression and neoplasia were measured. Mortality and duration of hospital were also described. . In all, 168 patients were evaluated, of which 42 were cases and 126 controls. Using a multivariate model, the risk factors related to bacteremia due to carbapenem-resistant P. aeruginosa acquired in hospital were the following: use of parenteral nutrition (OR=8.28; 95% CI: 2.56-26.79; p=0); use of meropenem (OR=1.15; 95% CI: 1.03-1.28; p=0.01); and use of ciprofloxacin (OR=81.99; 95% CI: 1.14-5884; p=0.043). . In order to prevent the emergence of carbapenem-resistant P. aeruginosa, antimicrobial control programs should be strengthened by promoting the prudent administration of carbapenems and quinolones. The correct use of parenteral nutrition should also be monitored.

Topics: Bacteremia; beta-Lactams; Carbapenems; Case-Control Studies; Ciprofloxacin; Drug Resistance, Bacterial; Ertapenem; Hospitals; Humans; Meropenem; Pseudomonas aeruginosa; Pseudomonas Infections; Risk Factors; Thienamycins

High-level carbapenem resistance is worryingly increasing in clinical isolates and is often attributed to carbapenemase expression. This study aimed to determine the mechanisms leading to high-level meropenem resistance in six carbapenemase-negative Pseudomonas aeruginosa isolated from cystic fibrosis (CF) patients and seven carbapenemase-positive isolates from patients suffering from hospital-acquired pneumonia (HAP). MICs were determined in the absence or presence of l-arginine or glycine-glutamate as competitive substrates for OprD (OccD1) or OpdP (OccD3), respectively, or the efflux pump inhibitor Phe-Arg β-naphthylamide (PAβN). β-Lactamases were screened by phenotypic tests and/or PCR. The oprD gene and its promoter were sequenced; protein expression was evidenced by SDS-PAGE. mexA, mexX, mexC and mexE transcripts were evaluated by real-time and semiquantitative PCR. Meropenem/imipenem MICs were 64-128/16-32 mg/L and 128/128-256 mg/L in CF and HAP isolates, respectively; PAβN reduced meropenem MICs to 4-16 mg/L only and specifically in CF isolates; porin competitors had no effect on MICs. All isolates showed an increase in transcription levels of mexA, mexX and/or mexC and mutations in oprD leading to production of truncated proteins. AmpC-type cephalosporinases were overexpressed in CF isolates and VIM-2 was expressed in HAP isolates. Antibiotic exclusion from bacteria by concomitant efflux and reduced uptake is sufficient to confer high-level resistance to meropenem in isolates overexpressing AmpC-type cephalosporinases. As efflux is preponderant in these isolates, it confers a paradoxical phenotype where meropenem is less active than imipenem. Concomitant susceptibility testing of both carbapenems and rapid elucidation of the most probable resistance mechanisms is thus warranted.

Topics: Anti-Bacterial Agents; beta-Lactamases; Electrophoresis, Polyacrylamide Gel; Enzyme Inhibitors; Gene Expression Profiling; Humans; Meropenem; Microbial Sensitivity Tests; Pneumonia, Bacterial; Polymerase Chain Reaction; Porins; Pseudomonas aeruginosa; Pseudomonas Infections; Sequence Analysis, DNA; Thienamycins

A series of novel hexacyclic tetracycline analogues ("hexacyclines") was designed, synthesized, and evaluated for antibacterial activity against a wide range of clinically important bacteria isolates, including multidrug-resistant, Gram-negative pathogens. Valuable structure-activity relationships were identified, and several hexacyclines displayed potent, broad spectrum antibacterial activity, including promising anti-Pseudomonas aeruginosa activity in vitro and in vivo.

Topics: Animals; Anti-Bacterial Agents; Bacteria; Drug Design; Female; Humans; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Pseudomonas aeruginosa; Pseudomonas Infections; Structure-Activity Relationship; Tetracyclines; Thigh

Metallo-β-lactamase (MBL) inhibitors can restore the function of carbapenem antibiotics and therefore help to treat infections of antibiotic resistant bacteria. In this study, we report novel fragments inhibiting the clinically relevant MBL Verona integron-encoded metallo-β-lactamase (VIM-2). The fragments were identified from a library of 490 fragments using an orthogonal screening approach based on a surface plasmon resonance (SPR) based assay combined with an enzyme inhibition assay. The identified fragments showed IC50 values between 14 and 1500 μM and ligand efficiencies (LE) between 0.48 and 0.23 kcal/mol per heavy atom. For two of the identified fragments, crystal structures in complex with VIM-2 were obtained. The identified fragments represent novel inhibitor scaffolds and are good starting points for the design of potent MBL inhibitors. Furthermore, the established SPR based assay and the screening approach can be adapted to other MBLs and in this way improve the drug discovery process for this important class of drug targets.

Topics: beta-Lactamase Inhibitors; beta-Lactamases; Carbapenems; Crystallography, X-Ray; Drug Design; Drug Resistance, Bacterial; Humans; Models, Molecular; Pseudomonas aeruginosa; Pseudomonas Infections; Small Molecule Libraries; Surface Plasmon Resonance

The objective of this study is to investigate the profile of antimicrobial resistance of Gram-negative bacteria in blood cultures from 2004-2011. Pathogens from positive blood cultures were subcultured, and identified in the First Affiliated Hospital of Nanjing Medical University from January 2004 to December 2011. The antibiotic resistance pattern was analyzed by WHONET 5.4. A total of 1224 cases of Gram-negative bacterial isolates were documented, accounting for 38.6% of the total pathogens isolated from positive blood cultures in the 8-year period. The isolation rates of Klebsiella pneumoniae and Acinetobacter baumannii increased nearly three times over the same time span. Most Gram-negative bacteria isolates, except the isolates of Pseudomonas aeruginosa, showed a significantly increased resistance rate to cephalosporins (in particular third/fourth generation cephalosporins). Noteworthy, the antimicrobial resistance of K. pneumoniae, A. baumannii and P. aeruginosa isolates to carbapenem (imipenem and meropenem) was significantly increased and the resistant rate to carbapenem was >80.0% in A. baumannii in 2011. The results from PCR detection for carbapenemases were as follows: 82.8% (24/29) isolates of K. pneumoniae carried the kpc-2 gene; only three metallo-beta-lactamase-positive P. aeruginosa isolates were detected; and 93.1% (67/72) A. baumannii isolates were blaOXA-23 positive. The antimicrobial resistance rate of Gram-negative bacteria isolated from blood cultures significantly increased from 2004 to 2011, with significant resistance to the third/fourth generation cephalosporins and carbapenem.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Anti-Bacterial Agents; Carbapenems; Cephalosporins; China; Drug Resistance, Bacterial; Gram-Negative Bacteria; Hospitals, University; Humans; Imipenem; Klebsiella Infections; Klebsiella pneumoniae; Meropenem; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies; Thienamycins

Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) has been recently introduced to many diagnostic microbiological laboratories. Besides the identification of bacteria and fungi, that technique provides a potentially useful tool for the detection of antimicrobial resistance, especially of that conferred by β-lactamases. Here, we describe an assay allowing a detection of meropenem hydrolysis in clinical isolates of Enterobacteriaceae, Pseudomonas spp., and Acinetobacter baumannii using MALDI-TOF MS. This method is able to confirm carbapenemases within 3 h. The results are important for proper and fast intervention to limit the spread of carbapenemase-producing bacteria and provide information for appropriate initial therapy of the infections caused by these microbes.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactam Resistance; beta-Lactamases; Biological Assay; Gene Expression; Humans; Hydrolysis; Meropenem; Pseudomonas; Pseudomonas Infections; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Thienamycins

Antibiotic combinations are often used for treating Pseudomonas aeruginosa infections but their efficacy toward intracellular bacteria has not been investigated so far. We have studied combinations of representatives of the main antipseudomonal classes (ciprofloxacin, meropenem, tobramycin, and colistin) against intracellular P. aeruginosa in a model of THP-1 monocytes in comparison with bacteria growing in broth, using the reference strain PAO1 and two clinical isolates (resistant to ciprofloxacin and meropenem, respectively). Interaction between drugs was assessed by checkerboard titration (extracellular model only), by kill curves, and by using the fractional maximal effect (FME) method, which allows studying the effects of combinations when dose-effect relationships are not linear. For drugs used alone, simple sigmoidal functions could be fitted to all concentration-effect relationships (extracellular and intracellular bacteria), with static concentrations close to (ciprofloxacin, colistin, and meropenem) or slightly higher than (tobramycin) the MIC and with maximal efficacy reaching the limit of detection in broth but only a 1 to 1.5 (colistin, meropenem, and tobramycin) to 2 to 3 (ciprofloxacin) log10 CFU decrease intracellularly. Extracellularly, all combinations proved additive by checkerboard titration but synergistic using the FME method and more bactericidal in kill curve assays. Intracellularly, all combinations proved additive only based on both FME and kill curve assays. Thus, although combinations appeared to modestly improve antibiotic activity against intracellular P. aeruginosa, they do not allow eradication of these persistent forms of infections. Combinations including ciprofloxacin were the most active (even against the ciprofloxacin-resistant strain), which is probably related to the fact this drug was the most effective alone intracellularly.

Topics: Anti-Bacterial Agents; Cell Line; Ciprofloxacin; Colistin; Drug Resistance, Bacterial; Drug Synergism; Drug Therapy, Combination; Humans; Meropenem; Microbial Sensitivity Tests; Monocytes; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins; Tobramycin

Meropenem plus levofloxacin treatment was shown to be a promising combination in our in vitro hollow fiber infection model. We strove to validate this finding in a murine Pseudomonas pneumonia model.. A dose-ranging study with meropenem and levofloxacin alone and in combination against Pseudomonas aeruginosa was performed in a granulocytopenic murine pneumonia model. Meropenem and levofloxacin were administered to partially humanize their pharmacokinetic profiles in mouse serum. Total and resistant bacterial populations were estimated after 24 hours of therapy. Pharmacokinetic profiling of both drugs was performed in plasma and epithelial lining fluid, using a population model.. Meropenem and levofloxacin penetrations into epithelial lining fluid were 39.3% and 64.3%, respectively. Both monotherapies demonstrated good exposure responses. An innovative combination-therapy analytic approach demonstrated that the combination was statistically significantly synergistic (α = 2.475), as was shown in the hollow fiber infection model. Bacterial resistant to levofloxacin and meropenem was seen in the control arm. Levofloxacin monotherapy selected for resistance to itself. No resistant subpopulations were observed in any combination therapy arm.. The combination of meropenem plus levofloxacin was synergistic, producing good bacterial kill and resistance suppression. Given the track record of safety of each agent, this combination may be worthy of clinical trial.

Topics: Animals; Anti-Bacterial Agents; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Female; Levofloxacin; Meropenem; Mice; Microbial Sensitivity Tests; Pneumonia; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

Many clinical isolates of Pseudomonas aeruginosa cause infections that are difficult to eradicate due to their resistance to a wide variety of antibiotics. Key genetic determinants of resistance were identified through genome sequences of 390 clinical isolates of P. aeruginosa, obtained from diverse geographic locations collected between 2003 and 2012 and were related to microbiological susceptibility data for meropenem, levofloxacin, and amikacin. β-Lactamases and integron cassette arrangements were enriched in the established multidrug-resistant lineages of sequence types ST111 (predominantly O12) and ST235 (O11). This study demonstrates the utility of next-generation sequencing (NGS) in defining relevant resistance elements and highlights the diversity of resistance determinants within P. aeruginosa. This information is valuable in furthering the design of diagnostics and therapeutics for the treatment of P. aeruginosa infections.

Topics: Amikacin; Anti-Bacterial Agents; Bacterial Typing Techniques; Base Sequence; beta-Lactamases; DNA, Bacterial; Drug Resistance, Multiple, Bacterial; Genome, Bacterial; Humans; Levofloxacin; Meropenem; Microbial Sensitivity Tests; Multilocus Sequence Typing; Pseudomonas aeruginosa; Pseudomonas Infections; Sequence Analysis, DNA; Thienamycins

Most adult patients receiving extracorporeal membrane oxygenation (ECMO) require antibiotic therapy, however the pharmacokinetics of β-lactams have not been well studied in these conditions. In this study, data from all patients receiving ECMO support and meropenem (MEM) or piperacillin/tazobactam (TZP) were reviewed. Drug concentrations were measured 2h after the start of a 30-min infusion and just before the subsequent dose. Therapeutic drug monitoring (TDM) results in ECMO patients were matched with those in non-ECMO patients for (i) drug regimen, (ii) renal function, (iii) total body weight, (iv) severity of organ dysfunction and (v) age. Drug concentrations were considered adequate if they remained 4-8× the clinical MIC breakpoint for Pseudomonas aeruginosa for 50% (TZP) or 40% (MEM) of the dosing interval. A total of 41 TDM results (27 MEM; 14 TZP) were obtained in 26 ECMO patients, with 41 matched controls. There were no significant differences in serum concentrations or pharmacokinetic parameters between ECMO and non-ECMO patients, including Vd [0.38 (0.27-0.68) vs. 0.46 (0.33-0.79)L/kg; P=0.37], half-life [2.6 (1.8-4.4) vs. 2.9 (1.7-3.7)h; P=0.96] and clearance [132 (66-200) vs. 141 (93-197)mL/min; P=0.52]. The proportion of insufficient (13/41 vs. 12/41), adequate (15/41 vs. 19/41) and excessive (13/41 vs. 10/41) drug concentrations was similar in ECMO and non-ECMO patients. Achievement of target concentrations of these β-lactams was poor in ECMO and non-ECMO patients. The influence of ECMO on MEM and TZP pharmacokinetics does not appear to be significant.

Topics: Adult; Anti-Bacterial Agents; beta-Lactams; Case-Control Studies; Extracorporeal Membrane Oxygenation; Female; Humans; Male; Meropenem; Middle Aged; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas Infections; Sepsis; Serum; Thienamycins; Treatment Outcome

A 35-year-old patient in intensive care with severe burn injury developed episodes of sepsis. Blood culture yielded a multidrug-resistant Pseudomonas aeruginosa and treatment was commenced with amikacin (minimum inhibitory concentration (MIC) 2-4 mg/L, dose 20 mg/kg adjusted body weight 24-hourly) and meropenem (MIC 8 mg/L, dose 2 g IV 8-hourly and later 6-hourly). Despite the use of extended infusions with β-lactam therapeutic drug monitoring and doses that were more than 2.5 times higher than standard meropenem doses, resistance emerged. This case report describes the application of therapeutic drug monitoring to optimize β-lactam therapy in a difficult-to-treat critically ill patient.

Topics: Adult; Amikacin; Anti-Bacterial Agents; beta-Lactams; Critical Illness; Dose-Response Relationship, Drug; Drug Monitoring; Drug Resistance, Bacterial; Female; Humans; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Sepsis; Thienamycins

Pseudomonas aeruginosa is an opportunistic bacterial pathogen capable of causing a wide range of disease manifestations, including severe bacterial pneumonia. Recently, clinics have reported a rise in nosocomial infections with multidrug resistant (MDR) species, including MDR strains of P. aeruginosa. In order to quickly evaluate the efficacy of new therapeutics for MDR infections, highly reproducible and validated animal models need to be developed for pre-clinical testing. Here, we describe the characterization of two murine models to study MDR P. aeruginosa respiratory disease. We evaluated and compared these models using a non-invasive intratracheal instillation method and established the 50% lethal dose, course of infection, biometric parameters of disease and degree of pneumonia development for each model. Further, we tested meropenem as a proof-of-concept therapeutic and report efficacy data that suggests that the leukopenic model could serve a robust pre-clinical model to test novel therapeutics.

Topics: Animals; Anti-Bacterial Agents; Biometry; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Resistance, Multiple, Bacterial; Female; Lethal Dose 50; Meropenem; Mice, Inbred BALB C; Pneumonia, Bacterial; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins; Treatment Outcome

We present the case of a 70-year-old non-diabetic patient who presented to the emergency department with unrelenting otalgia. A severe otitis externa (OE) and mastoiditis were treated with broad spectrum antibiotics and surgical drainage. No bacteria was isolated from surgical samples. Because the otalgia persisted, a magnetic resonance (MR) was performed and showed an infiltrating process at the skull base. Biopsies failed to prove malignancy or granulomatosis. The patient's neurological state deteriorated. The suspicion of a skull base osteomyelitis (SBO) was raised and proven by CT-guided biopsies that grew Pseudomonas aeruginosa. Meropenem and ciprofloxacin, given for 8 weeks, lead to a fast clinical improvement and a full recovery. SBO is uncommon, often complicating severe OE. Pseudomonas aeruginosa is the main pathogen. Prompt diagnosis and adequate antibiotherapy are required to lower mortality and morbidity. The diagnosis may be delayed because of unawareness and large differential diagnosis including solid neoplasic tumours, malignant hemopathies and granulomatosis.

Topics: Aged; Anti-Bacterial Agents; Ciprofloxacin; Delayed Diagnosis; Earache; Humans; Magnetic Resonance Imaging; Male; Meropenem; Osteomyelitis; Pseudomonas Infections; Skull Base; Thienamycins

Most post-neurosurgical meningitis research has been focused on large cohorts with numerous cases followed over several years. However, the characteristics of post-neurosurgical meningitis in an entire single year are still unclear, and knowledge of these characteristics might influence the selection of appropriate antibiotics and therapeutic strategies for the successful management of this disease. Our aim is to obtain a better understanding of post-neurosurgical meningitis over a single entire year.. Patients with positive meningitis cultures after neurosurgical operations in our hospital during the entire year of 2012 were included in the analysis. We report demographic characteristics, morbidity during different seasons, clinical and bacteriological profiles, sensitivity to antibiotics and causes of the post-neurosurgical meningitis infections in our cohort.. Of the 6407 patients who underwent neurosurgical procedures during the study period, 146 developed post-neurosurgical meningitis and the overall incidence of meningitis was 2.28%. The incidence of meningitis was significantly higher in patients who underwent surgery in the autumn and winter than spring or summer (p=0.000). The most common organisms causing meningitis were Gram-positive bacteria, followed by the Klebsiella and Baumannii species. Compound sulfamethoxazole (52.6%) and vancomycin (10.5%) were the most active antibiotics against Gram-positive bacteria strains, whereas meropenem (43.8%) and polymyxin (18.8%) were active against Gram-negative bacillus strains.. Post-neurosurgical meningitis usually occurs in the autumn and winter of the year in our hospital. Gram-positive organisms, which are sensitive to compound sulfamethoxazole and vancomycin, are the most common causative pathogens of post-neurosurgical meningitis in the northern mainland of China.

Topics: Acinetobacter Infections; Adolescent; Adult; Aged; Anti-Bacterial Agents; Child; Child, Preschool; China; Drug Resistance, Bacterial; Escherichia coli Infections; Female; Humans; Klebsiella Infections; Male; Meningitis, Bacterial; Meropenem; Middle Aged; Neurosurgical Procedures; Polymyxins; Postoperative Complications; Pseudomonas Infections; Retrospective Studies; Seasons; Staphylococcal Infections; Sulfamethoxazole; Thienamycins; Vancomycin; Young Adult

Ceftazidime is the only anti-pseudomonal beta-lactam that has been reported to be administered by extended infusion in pediatric cystic fibrosis (CF) patients. A small pediatric pharmacokinetic/pharmacodynamic study has been published regarding the use of intermittent extended infusion doripenem in the treatment of an acute pulmonary exacerbation (APE) in pediatric CF patients; however, clinical use of intermittent extended infusion doripenem in pediatric CF patients has not been previously reported. We present three cases administering intermittent extended infusion doripenem in pediatric CF patients for the treatment of an APE in the case of replacing meropenem due to shortage. The delivery of beta-lactam antibiotics via intermittent extended infusion should be considered in order to optimize the pharmacodynamics of beta-lactams in the treatment of an APE.

Topics: Adolescent; Anti-Bacterial Agents; Burkholderia cenocepacia; Burkholderia Infections; Carbapenems; Child; Cystic Fibrosis; Disease Progression; Doripenem; Drug Therapy, Combination; Female; Gram-Negative Bacterial Infections; Humans; Infusions, Intravenous; Meropenem; Pseudomonas aeruginosa; Pseudomonas Infections; Pseudomonas stutzeri; Rhodospirillaceae; Thienamycins; Tobramycin; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination

Aztreonam, cefepime, and ceftazidime are anti-pseudomonal beta-lactam antibiotics which have been previously reported to be administered by continuous infusion (CI) in pediatric CF patients. We present two cases administering intravenous (IV) meropenem and ticarcillin-clavulanate by CI in pediatric CF patients. The delivery of beta-lactam antibiotics via CI should be considered in order to optimize the pharmacodynamics (PD) of beta-lactams in the treatment of acute pulmonary exacerbations (APE).

Topics: Adolescent; Anti-Bacterial Agents; Clavulanic Acids; Cystic Fibrosis; Female; Gram-Negative Bacterial Infections; Humans; Infusions, Intravenous; Meropenem; Pneumonia, Bacterial; Pseudomonas aeruginosa; Pseudomonas Infections; Rhodospirillaceae; Thienamycins; Ticarcillin

Pseudomonas aeruginosa has the potential to achieve resistance to carbapenems via the acquisition of carbapenemase-encoding genes, the downregulation of the OprD porin, the overexpression of efflux systems and the overproduction of cephalosporinases. One hundred and fifty carbapenem-non-susceptible isolates from 2008 to 2010 were screened for carbapenemase production, OprD porin loss, efflux pumps overexpression and inducible AmpC beta-lactamase production. For comparison reasons, the presence of the same mechanisms was also assessed in a previous collection of 30 carbapenem-non-susceptible P. aeruginosa isolated between 2003 and 2005. Results showed the accumulation of various resistance mechanisms among VIM-2 producers isolated between 2008 and 2010 with a parallel considerable increase in imipenem MIC90 and the geometric mean of the MIC values of imipenem and meropenem between the two study groups. The accumulation of carbapenem resistance mechanisms highlights the potential of this formidable pathogen for evolutionary success under antibiotic selective pressure.

Topics: Anti-Bacterial Agents; beta-Lactam Resistance; beta-Lactamases; Carbapenems; Humans; Imipenem; Membrane Transport Proteins; Meropenem; Microbial Sensitivity Tests; Porins; Pseudomonas aeruginosa; Pseudomonas Infections; Selection, Genetic; Thienamycins

Several studies with animal models have demonstrated that bioequivalence of generic products of antibiotics like vancomycin, as currently defined, do not guarantee therapeutic equivalence. However, the amounts and characteristics of impurities and degradation products in these formulations do not violate the requirements of the U.S. Pharmacopeia (USP). Here, we provide experimental data with three generic products of meropenem that help in understanding how these apparently insignificant chemical differences affect the in vivo efficacy. Meropenem generics were compared with the innovator in vitro by microbiological assay, susceptibility testing, and liquid chromatography/mass spectrometry (LC/MS) analysis and in vivo with the neutropenic guinea pig soleus infection model (Pseudomonas aeruginosa) and the neutropenic mouse thigh (P. aeruginosa), brain (P. aeruginosa), and lung (Klebisella pneumoniae) infection models, adding the dihydropeptidase I (DHP-I) inhibitor cilastatin in different proportions to the carbapenem. We found that the concentration and potency of the active pharmaceutical ingredient, in vitro susceptibility testing, and mouse pharmacokinetics were identical for all products; however, two generics differed significantly from the innovator in the guinea pig and mouse models, while the third generic was therapeutically equivalent under all conditions. Trisodium adducts in a bioequivalent generic made it more susceptible to DHP-I hydrolysis and less stable at room temperature, explaining its therapeutic nonequivalence. We conclude that the therapeutic nonequivalence of generic products of meropenem is due to greater susceptibility to DHP-I hydrolysis. These failing generics are compliant with USP requirements and would remain undetectable under current regulations.

Topics: Animals; Anti-Bacterial Agents; Biotransformation; Brain; Cilastatin; Dipeptidases; Drug Stability; Drugs, Generic; GPI-Linked Proteins; Guinea Pigs; Klebsiella Infections; Klebsiella pneumoniae; Lung; Meropenem; Mice; Microbial Sensitivity Tests; Muscle, Skeletal; Protease Inhibitors; Pseudomonas aeruginosa; Pseudomonas Infections; Therapeutic Equivalency; Thienamycins; Thigh; Treatment Outcome

Topics: Adult; Anti-Bacterial Agents; Bacteremia; Cefepime; Cephalosporins; Ciprofloxacin; Colistin; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Female; Humans; Immunocompromised Host; Meropenem; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins; Tobramycin; Treatment Failure

We compared the dynamics and mechanisms of resistance development to ceftazidime, meropenem, ciprofloxacin, and ceftolozane-tazobactam in wild-type (PAO1) and mutator (PAOMS, ΔmutS) P. aeruginosa. The strains were incubated for 24 h with 0.5 to 64× MICs of each antibiotic in triplicate experiments. The tubes from the highest antibiotic concentration showing growth were reinoculated in fresh medium containing concentrations up to 64× MIC for 7 consecutive days. The susceptibility profiles and resistance mechanisms were assessed in two isolated colonies from each step, antibiotic, and strain. Ceftolozane-tazobactam-resistant mutants were further characterized by whole-genome analysis through RNA sequencing (RNA-seq). The development of high-level resistance was fastest for ceftazidime, followed by meropenem and ciprofloxacin. None of the mutants selected with these antibiotics showed cross-resistance to ceftolozane-tazobactam. On the other hand, ceftolozane-tazobactam resistance development was much slower, and high-level resistance was observed for the mutator strain only. PAO1 derivatives that were moderately resistant (MICs, 4 to 8 μg/ml) to ceftolozane-tazobactam showed only 2 to 4 mutations, which determined global pleiotropic effects associated with a severe fitness cost. High-level-resistant (MICs, 32 to 128 μg/ml) PAOMS derivatives showed 45 to 53 mutations. Major changes in the global gene expression profiles were detected in all mutants, but only PAOMS mutants showed ampC overexpression, which was caused by dacB or ampR mutations. Moreover, all PAOMS mutants contained 1 to 4 mutations in the conserved residues of AmpC (F147L, Q157R, G183D, E247K, or V356I). Complementation studies revealed that these mutations greatly increased ceftolozane-tazobactam and ceftazidime MICs but reduced those of piperacillin-tazobactam and imipenem, compared to those in wild-type ampC. Therefore, the development of high-level resistance to ceftolozane-tazobactam appears to occur efficiently only in a P. aeruginosa mutator background, in which multiple mutations lead to overexpression and structural modifications of AmpC.

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Ceftazidime; Cephalosporins; Imipenem; Meropenem; Microbial Sensitivity Tests; Mutation; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Tazobactam; Thienamycins

The effect of a meropenem-ciprofloxacin combination (MCC) on the susceptibility of multidrug-resistant (MDR) Pseudomonas aeruginosa (MRPA) clinical isolates was determined using checkerboard and time-kill curve techniques. Structural changes and differential gene expression that resulted from the synergistic action of the MCC against one of the P. aeruginosa isolates (1071-MRPA]) were evaluated using electron microscopy and representational difference analysis (RDA), respectively. The differentially expressed, SOS response-associated, and resistance-associated genes in 1071-MRPA exposed to meropenem, ciprofloxacin, and the MCC were monitored by quantitative PCR. The MCC was synergistic against 25% and 40.6% of MDR P. aeruginosa isolates as shown by the checkerboard and time-kill curves, respectively. The morphological and structural changes that resulted from the synergistic action of the MCC against 1071-MRPA were a summation of the effects observed with each antimicrobial alone. One exception included outer membrane vesicles, which were seen in a greater amount upon ciprofloxacin exposure but were significantly inhibited upon MCC exposure. Cell wall- and DNA repair-associated genes were differentially expressed in 1071-MRPA exposed to meropenem, ciprofloxacin, and the MCC. However, some of the RDA-detected, resistance-associated, and SOS response-associated genes were expressed at significantly lower levels in 1071-MRPA exposed to the MCC. The MCC may be an alternative for the treatment of MDR P. aeruginosa. The effect of this antimicrobial combination may be not only the result of a summation of the effects of meropenem and ciprofloxacin but also a result of differential action that likely inhibits protective mechanisms in the bacteria.

Topics: Anti-Bacterial Agents; Brazil; Ciprofloxacin; Colony Count, Microbial; DNA, Bacterial; Drug Combinations; Drug Resistance, Multiple, Bacterial; Gene Expression Regulation, Bacterial; Genes, Bacterial; Humans; Meropenem; Microbial Sensitivity Tests; Polymerase Chain Reaction; Pseudomonas aeruginosa; Pseudomonas Infections; RNA, Bacterial; Thienamycins

Meropenem, a broad-spectrum carbapenem, is commonly used for empirical and definitive therapy in the pediatric intensive care unit (ICU). Pharmacokinetic data to guide dosing in children, however, are limited to healthy volunteers or patients who are not in the ICU. Adult data demonstrate that pharmacokinetic parameters such as the volume of distribution and clearance can be significantly altered in individuals receiving extracorporeal membrane oxygenation (ECMO). Alterations in the volume of distribution and clearance of antimicrobials in patients with sepsis and septic shock have also been documented, and these patients have demonstrated lower than expected antimicrobial serum concentrations based on standard dosing regimens. Therefore, an understanding of the pharmacokinetic changes in critically ill children receiving ECMO is crucial to determining the most appropriate dose and dosing interval selection for any antimicrobial therapy. In this case report, we describe the pharmacokinetics of a continuous infusion of meropenem in a pediatric cardiac ICU patient who was receiving concurrent extracorporeal life support. The patient was an 8-month-old male infant who underwent a Glenn procedure and pulmonary artery reconstruction. Postoperatively, he required ECMO with a total run of 21 days. On day 11 of ECMO, a bronchoalveolar lavage was performed, and blood cultures from days 11 and 12 of ECMO grew Pseudomonas aeruginosa, with a meropenem minimum inhibitory concentration (MIC) of 0.5 μg/ml. On ECMO day 13, meropenem was initiated with a loading dose of 40 mg/kg and infused over 30 minutes, followed by a continuous infusion of 200 mg/kg/day. A meropenem serum concentration measured 8 hours after the start of the infusion was 46 μg/ml. Repeat levels were measured on days 3 and 9 of meropenem therapy and were 39 and 42 μg/ml, respectively. Repeat blood and respiratory cultures remained negative. This meropenem regimen (40-mg/kg bolus followed by a continuous infusion of 200 mg/kg/day) was successful in providing a target attainment of 100% for serum and lung concentrations above the MIC for at least 40% of the dosing interval and was associated with a successful clinical outcome.

Topics: Anti-Bacterial Agents; Extracorporeal Membrane Oxygenation; Humans; Infant; Infusions, Intravenous; Life Support Systems; Male; Meropenem; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

Carbapenemase genes are one of the most frequent mechanisms reported in carbapenem-resistant P. aeruginosa; however, description of P. aeruginosa co-harbouring two or more carbapenemases is unusual.. In this study we evaluated the presence of carbapenemase genes and the clonality of P. aeruginosa isolates obtained from a hospital over a 12-year period. A total of 127 isolates of carbapenem-resistant P. aeruginosa recovered from 109 patients feces (four samples), rectal swab (three samples), nasal swab (one sample) and anal abscess (one sample), were evaluated. Minimum inhibitory concentrations of the following antibiotics imipenem, meropenem and polymyxin E were determined by broth microdilution. The molecular profile of isolates was evaluated by pulsed field gel electrophoresis (PFGE). PCR for the following carbapenemase genes blaIMP;blaSPM;blaVIM;blaSIM;blaNDM;blaKPC;blaGES and nucleotide sequencing to confirm the enzyme gene types were performed and compared with the database available on the Internet (BLAST-http://www.ncbi.nlm.nhi.gov/blast/).. All isolates were carbapenem-resistant, their MIC50 and MIC90 were respectively 64 μg/mL and 256 μg/mL to imipenem and 32 μg/mL and 256 μg/mL to meropenem, all isolates except one (MIC = 8 mg/L) were susceptible to polymyxin E. The most frequent carbapenemase genes identified were blaSPM identified in 41 isolates (32%), followed by 10 with blakpc and 5 with blaVIM (3.9%). All belonged to the class SPM-1 and VIM-2. In 2011, one isolate harbouring three carbapenemase genes (SPM-1, VIM-2 and KPC-2) that belonged to a new clone was identified in a hematopoietic stem cell transplanted patient. Then, 19 carbapenem-resistant P. aeruginosa were identified in an outbreak that occurred in the bone marrow transplant unit, all positive for SPM-1 gene, and 9 (47.3%) harbored both SPM-1 and KPC.. Our findings showed that PCR for KPC gene should be performed to evaluate carbapenem resistance in P. aeruginosa and that this agent can harbor more than one carbapenemase gene. Attention should be focused on the possible rapid spread of KPC in P. aeruginosa isolates and for the fact that P. aeruginosa may become a reservoir of this transmissible resistance mechanism.

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactam Resistance; beta-Lactamases; Carbapenems; Colistin; DNA, Bacterial; Electrophoresis, Gel, Pulsed-Field; Genes, Bacterial; Genotype; Hospitals; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Molecular Typing; Polymerase Chain Reaction; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

We investigated the susceptibility of 400 Pseudomonas aeruginosa (P. aeruginosa) clinical isolates to 3 antipseudomonal carbapenems, namely, doripenem (DRPM), meropenem (MEPM), and imipenem (IPM). The test strains were isolated from the following specimens: respiratory (n = 194), urinary (n = 61), digestive (n = 38), pus (n = 36), skin (n = 21), blood (n = 9), upper respiratory tract and oral cavity (n = 8), and others (n = 33) at Osaka City University Hospital from July to October 2013. Test strains were categorized as susceptible, ≤ 2 μg/mL; intermediate, 4 μg/mL; and resistant, ≥ 8 μg/mL according to Clinical and Laboratory Standards Institute criteria (M100-S22), updated on January 2012. To compare the antimicrobial activities of these 3 carbapenems, the susceptibility rate for each agent was analyzed. Susceptibility to DRPM, MEPM, and IPM was 78.3%, 74.3%, and 64.8%, respectively, whereas resistance was 12.5%, 22.8%, and 28.5%, respectively. The frequency of strains resistant to DRPM was significantly lower than that for MEPM (p < 0.001) and IPM (p < 0.001). To compare the activities of the 3 carbapenems against the P. aeruginosa clinical isolates, we plotted the numbers of strains against each minimum inhibitory concentration (MIC) level. The MICs of DRPM were lower than those of MEPM in 19.8% of strains, and lower than those of IPM in 41.8% of strains, and the MICs of MEPM were lower than those of IPM in 33.0% of strains. Further, we found that 7.7% of the MEPM-resistant strains were susceptible to DRPM, 23.7% of the IPM-resistant strains were susceptible to DRPM, and 9.6% of the IPM-resistant strains were susceptible to MEPM; however, none of the MEPM-resistant strains was susceptible to IPM, and none of the DRPM-resistant strains was susceptible to MEPM or IPM. In conclusion, the in vitro activity of DRPM against the P. aeruginosa clinical isolates was superior to those of MEPM and IPM.

Topics: Carbapenems; Doripenem; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

Topics: Aged; Anti-Bacterial Agents; Blindness; Cefepime; Cephalosporins; Eye Infections, Bacterial; Humans; Magnetic Resonance Imaging; Male; Meropenem; Middle Aged; Optic Nerve Diseases; Osteomyelitis; Pseudomonas aeruginosa; Pseudomonas Infections; Skull Base; Thienamycins; Visual Acuity

In Japan, a national surveillance study of antimicrobial consumption has never been undertaken. This study aimed to describe antimicrobial consumption and resistance to Pseudomonas aeruginosa in 203 Japanese hospitals, to identify targets for quality improvement.. We conducted an ecological study using retrospective data (2010). Antimicrobial consumption was collected in the World Health Organization (WHO) anatomical therapeutic chemical/defined daily dose (ATC/DDD) format. Rates of imipenem (IPM), meropenem (MEPM), ciprofloxacin (CPFX), or amikacin (AMK) resistance were expressed as the incidence of non-susceptible isolates. Additionally, hospitals were asked to provide data concerning hospital characteristics and infection control policies. Hospitals were classified according to functional categories of the Medical Services Act in Japan.. Data were collected from 203 Japanese hospitals (a total of 91,147 beds). The total antimicrobial consumption was 15.49 DDDs/100 bed-days (median), with consumptions for penicillins, carbapenems, quinolones, and glycopeptides being 4.27, 1.60, 0.41, and 0.49, respectively. The median incidences of IPM, MEPM, CPFX, and AMK resistance were 0.15, 0.10, 0.13, and 0.03 isolates per 1,000 patient-days, respectively. Antimicrobial notification and/or approval systems were present in 183 hospitals (90.1 %). In the multivariate analysis, the piperacillin/tazobactam, quinolones, and/or total consumptions and the advanced treatment hospitals showed a significant association with the incidence of P. aeruginosa resistant to IPM, MEPM, CPFX, and AMK [adjusted R (2) (aR (2)) values of 0.23, 0.30, 0.22, and 0.35, respectively).. This is the first national surveillance study of antimicrobial consumption in Japan. A continuous surveillance program in Japan is necessary in order to evaluate the association among resistance, antimicrobial restriction, and consumption.

Topics: Amikacin; Anti-Bacterial Agents; Ciprofloxacin; Drug Resistance, Multiple, Bacterial; Drug Utilization; Drug Utilization Review; Hospitals; Humans; Imipenem; Incidence; Japan; Meropenem; Microbial Sensitivity Tests; National Health Programs; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies; Surveys and Questionnaires; Thienamycins

The US Food and Drug Administration reported seizures associated with the use of cefepime (primarily in patients with renal impairment who did not receive appropriate dose adjustments of cefepime).. The maximum dose of cefepime in the USA (6 g per day) is higher than that in Japan (4 g per day). We investigated the prevalence of convulsions associated with the use of cefepime by comparing it with that of meropenem.. A retrospective study was undertaken in 183 patients treated with cefepime and 745 patients treated with meropenem over 2 years at Ehime University Hospital. Cefepime or meropenem-associated convulsions were defined according to the following criteria: (1) administration or dose escalation of diazepam, phenytoin, phenobarbital and thiamylal given via the intravenous route (2) convulsions recorded in medical records during administration of cefepime or meropenem.. The prevalence of convulsions was significantly greater in the cefepime treated group than in the meropenem-treated group. Among the patients who had cefepime-associated convulsions, none had renal failure. Cefepime-associated convulsions occurred only in patients with brain disorders.. Cefepime-associated convulsions should be recognized as potential complications even in patients with normal renal function. Brain disorders may increase the risk of cefepime-associated convulsions.

Topics: Adult; Aged; Anti-Bacterial Agents; Brain Diseases; Cefepime; Cephalosporins; Female; Hospitals, University; Humans; Infusions, Intravenous; Japan; Male; Meropenem; Neurotoxicity Syndromes; Prevalence; Pseudomonas aeruginosa; Pseudomonas Infections; Renal Insufficiency; Retrospective Studies; Risk; Seizures; Staphylococcal Infections; Staphylococcus aureus; Thienamycins

Treatment of Pseudomonas aeruginosa infections is increasingly challenging because of escalating resistance. Antimicrobial stewardship programs provide guidance for clinicians regarding use of the most appropriate antimicrobial at the right dose, duration, and route in addition to being cost-effective. Optimizing antimicrobial therapy by using pharmacokinetic/pharmacodynamic principles such as extending time above the MIC is 1 stewardship strategy to reduce antimicrobial resistance.. The goal of this study was to evaluate our current dosing strategy for cefepime and the formulary carbapenem (imipenem) compared with meropenem and doripenem to determine the best dosing strategy for achieving maximal pharmacodynamic activity against an institution-specific population of P aeruginosa isolates.. Consecutive, nonduplicate, blood (n = 39) or bronchial alveolar lavage (n = 25) isolates of P aeruginosa from adult, hospitalized (2009-2010) critically ill patients underwent MIC testing by using broth microdilution. A pharmacokinetic model was developed and used with Monte Carlo simulation to evaluate the ability of imipenem, meropenem, doripenem, and cefepime to achieve optimal bactericidal activity as varying doses infused over standard infusions (SIs; 0.5-1 hour) or prolonged infusions (PIs; 3-4 hours). A regimen was defined as optimal if the cumulative fraction response (CFR) was ≥90%.. None of the imipenem regimens modeled as SI or PI achieved a CFR ≥90%. Meropenem at 1 to 2 g q8h PI achieved a CFR ≥90%. Doripenem 0.5, 1, or 2 g q8h PI achieved a CFR ≥90%. The only cefepime regimen that achieved a CFR ≥90% was 2 g q8h PI. Overall susceptibility rates to P aeruginosa were highest with cefepime (91%), followed by meropenem (83%), doripenem (78%), and imipenem (72%). Our antimicrobial stewardship programs recommended switching from imipenem to doripenem 0.5g q8h PI, which was 36% more costly in drug acquisition costs. Cefepime dosing was increased from 2 g q12h SI to 2 g q8h PI, a 52% increase in drug acquisition cost.. Antimicrobial stewardship programs should consider pharmacodynamic modeling to select the optimal dosing strategies to guide therapy in an era of escalating antimicrobial resistance. Using the percent susceptibility alone can be misleading and ultimately the most expensive if the patient fails to respond.

Topics: Adult; Anti-Bacterial Agents; Carbapenems; Cefepime; Cephalosporins; Doripenem; Drug Costs; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Monte Carlo Method; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

Two novel IMP-type metallo-β-lactamase variants, IMP-43 and IMP-44, were identified in multidrug-resistant Pseudomonas aeruginosa isolates obtained in medical settings in Japan. Analysis of their predicted amino acid sequences revealed that IMP-43 had an amino acid substitution (Val67Phe) compared with IMP-7 and that IMP-44 had two substitutions (Val67Phe and Phe87Ser) compared with IMP-11. The amino acid residue at position 67 is located at the end of a loop close to the active site, consisting of residues 60 to 66 in IMP-1, and the amino acid residue at position 87 forms a hydrophobic patch close to the active site with other amino acids. An Escherichia coli strain expressing blaIMP-43 was more resistant to doripenem and meropenem but not to imipenem than one expressing blaIMP-7. An E. coli strain expressing blaIMP-44 was more resistant to doripenem, imipenem and meropenem than one expressing blaIMP-11. IMP-43 had more efficient catalytic activities against all three carbapenems than IMP-7, indicating that the Val67Phe substitution contributed to increased catalytic activities against carbapenems. IMP-44 had more efficient catalytic activities against all carbapenems tested than IMP-11, as well as increased activities compared with IMP-43, indicating that both the Val67Phe and Phe87Ser substitutions contributed to increased catalytic activities against carbapenems.

Topics: Amino Acid Substitution; Anti-Bacterial Agents; beta-Lactamases; Carbapenems; Catalytic Domain; Doripenem; Drug Resistance, Multiple, Bacterial; Escherichia coli; Humans; Hydrophobic and Hydrophilic Interactions; Imipenem; Japan; Meropenem; Phylogeny; Plasmids; Pseudomonas aeruginosa; Pseudomonas Infections; Structure-Activity Relationship; Thienamycins

The objective of this study was to explore independent risk factors for the isolation of multidrug-resistant (MDR) Pseudomonas aeruginosa in a Japanese university hospital between January 1997 and December 2010. MDR P. aeruginosa was defined when the organism was resistant or intermediately susceptible to all five antimicrobials tested. In all, 159 patients with MDR P. aeruginosa were identified over the 14-year period. Multivariate logistic regression analysis revealed that prolonged hospital stay, prior exposure to meropenem and fluoroquinolones, and patients suffering from diabetes mellitus or receiving surgery were predictive risk factors for the isolation of MDR P. aeruginosa.

Topics: Anti-Bacterial Agents; Diabetes Complications; Drug Resistance, Multiple, Bacterial; Fluoroquinolones; Hospitals, University; Humans; Japan; Length of Stay; Meropenem; Postoperative Complications; Pseudomonas aeruginosa; Pseudomonas Infections; Risk Factors; Thienamycins

Pseudomonas aeruginosa meningitis is an uncommon complication of neurosurgical procedures or head trauma. Here, a case of infectious mid basilar artery aneurysm from Pseudomonas meningitis, and its angiographic remission from timely antibiotic therapy, is reported.

Topics: Adult; Angiography, Digital Subtraction; Anti-Bacterial Agents; Carotid Artery, Internal, Dissection; Cerebral Angiography; Female; Humans; Image Processing, Computer-Assisted; Intracranial Aneurysm; Meningitis, Bacterial; Meropenem; Ofloxacin; Ophthalmic Artery; Pseudomonas Infections; Thienamycins

Topics: Animals; Anti-Bacterial Agents; Bacterial Load; beta-Lactam Resistance; Carbapenems; Colony Count, Microbial; Disease Models, Animal; Doripenem; Humans; Imipenem; Lung; Meropenem; Pneumonia, Bacterial; Pseudomonas aeruginosa; Pseudomonas Infections; Rabbits; Thienamycins; Treatment Outcome

Doripenem is not available on many automated susceptibility testing panels. We evaluated the surrogate predictive value (SPV) of meropenem and imipenem in predicting doripenem susceptibility using the different breakpoint definitions available globally. MIC data for 736 Pseudomonas aeruginosa were extracted, and categorical interpretations were performed using Clinical and Laboratory Standards Institute (CLSI) proposed 2012, European Committee on Antimicrobial Susceptibility Testing (EUCAST), and Food and Drug Administration (FDA) breakpoints. Regardless of the breakpoint applied, very major and major errors were observed in only 0.1-0.8% and 0.1-4.5% of isolates, respectively. Meropenem's SPV was 98.6% for CLSI 2012 breakpoints, 94.0% for EUCAST, and 95.0% for FDA. Imipenem's SPV was 98.6%, 90.9%, and 97.2%, respectively. These data indicate that meropenem and imipenem would be reliable surrogate markers of doripenem susceptibility when using CLSI 2012 and FDA breakpoints. Meropenem would be recommended over imipenem for EUCAST breakpoints. However, meropenem and imipenem nonsusceptible isolates should be directly tested against doripenem since the latter antibiotic may still retain susceptibility against these isolates.

Topics: Anti-Bacterial Agents; Carbapenems; Doripenem; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Prognosis; Pseudomonas aeruginosa; Pseudomonas Infections; Reference Standards; Thienamycins

Biapenem (BIPM) has high bactericidal activity against Pseudomonas aeruginosa and similar activity in vitro as meropenem (MEPM). We used a murine model to examine the efficacy of biapenem against ventilator-associated pneumonia (VAP) caused by P. aeruginosa. Mice were treated by intraperitoneal injection with 100 mg/kg BIPM or MEPM every 12 h beginning 12 h after inoculation with P. aeruginosa. Survival was evaluated for 7 days, and 24 h after infection, lung histopathology was analyzed and the number of viable bacteria in the lungs and blood was counted. In addition, the pharmacokinetics of BIPM and MEPM were analyzed after the initial treatment. BIPM and MEPM significantly prolonged survival compared to control (P < 0.05). The lungs of mice treated with BIPM or MEPM had significantly fewer viable bacteria (3.54 ± 0.28 vs. 3.77 ± 0.14 log(10) CFU/ml) than in the lungs of control mice (6.65 ± 0.57 log(10) CFU/ml) (P < 0.05). Furthermore, viable bacteria were not detected in the blood of mice treated with BIPM or MEPM (control 2.85 ± 0.85 log(10) CFU/ml) (P < 0.05). Histopathological examination of lung specimens indicated that BIPM and MEPM prevent the progression of lung inflammation, including alveolar neutrophil infiltration and hemorrhage. The % time above MIC for BIPM and MEPM was 15.4% and 18.3% in plasma and 19.8% and 19.8% in lungs, respectively. These results show that BIPM and MEPM significantly prolongs survival and reduces the number of viable bacteria in a murine model of VAP caused by P. aeruginosa. Therefore, BIPM might be a potent and effective treatment for VAP caused by this bacterium.

Topics: Animals; Anti-Bacterial Agents; Bacteremia; Case-Control Studies; Colony Count, Microbial; Disease Models, Animal; Histocytochemistry; Lung; Male; Meropenem; Mice; Microbial Sensitivity Tests; Pneumonia, Ventilator-Associated; Pseudomonas aeruginosa; Pseudomonas Infections; Specific Pathogen-Free Organisms; Statistics, Nonparametric; Thienamycins

The aim of this study was to determine the current susceptibility of hospital isolates of contemporary Gram-negative pathogens to the carbapenems doripenem, imipenem and meropenem. Between May and October 2008, seven centres in Germany were invited to collect and submit Pseudomonas aeruginosa, Enterobacteriaceae and other Gram-negative bacterial Intensive Care Unit (ICU)/non-ICU isolates from patients with complicated intra-abdominal infections (cIAIs), bloodstream infections (BSIs) or nosocomial pneumonia (NP). Susceptibility was determined at each centre by Etest. A central laboratory performed species confirmation as well as limited susceptibility and quality control testing. In total, 363 isolates were collected, comprising 46.0% Enterobacteriaceae, 45.2% P. aeruginosa, 4.7% Acinetobacter spp. and 4.1% other Gram-negatives. Most isolates (47.9%) were collected from NP, 32.8% were from cIAIs and 19.3% from BSIs; 57.3% were obtained from ICU patients. The MIC(90) values (minimum inhibitory concentration for 90% of the isolates) for doripenem, meropenem and imipenem were, respectively, 4, 16 and 32 mg/L against P. aeruginosa, 0.06, 0.06 and 0.5mg/L against Enterobacteriaceae and ≥ 64 mg/L for each carbapenem against other Gram-negative isolates. Using European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints, 81.1%, 75.6% and 79.3% of P. aeruginosa were susceptible to doripenem, imipenem and meropenem, respectively. Against all pathogens combined, MIC(90) values for ICU versus non-ICU isolates, respectively, were 4 mg/L vs. 1mg/L for doripenem, 8 mg/L vs. 1mg/L for meropenem and ≥ 64 mg/L vs. 8 mg/L for imipenem. Doripenem showed comparable activity against P. aeruginosa from patients with BSIs, cIAIs or NP. Similar findings were observed for Enterobacteriaceae and other Gram-negatives, including Acinetobacter spp. Doripenem generally showed similar or slightly better activity than meropenem and better activity than imipenem against Gram-negative pathogens collected in Germany.

Topics: Bacteremia; Carbapenems; Cross Infection; Doripenem; Drug Resistance, Bacterial; Enterobacteriaceae; Enterobacteriaceae Infections; Germany; Humans; Imipenem; Intensive Care Units; Intraabdominal Infections; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Quality Control; Thienamycins

This work reports the identification of the first case of a KΡC-2-producing Pseudomonas putida isolate (PP36) in Brazil. The PP36 isolate was resistant to all the antimicrobials tested except polymyxin B. In addition to the discovered bla(KPC-2) gene, genetic analysis showed the presence of a class 1 integron containing the dhfrXVb gene and the new allele arr-6, which codes for resistance to rifampin. These elements were found in an IncFI 65-kb plasmid.

Topics: Alleles; Anti-Bacterial Agents; beta-Lactamases; Brazil; Burkitt Lymphoma; Child; Humans; Integrons; Male; Meropenem; Microbial Sensitivity Tests; Molecular Sequence Data; Plasmids; Polymerase Chain Reaction; Pseudomonas Infections; Pseudomonas putida; Thienamycins

A patient with septic shock due to extensively drug resistant (XDR) Pseudomonas aeruginosa was cured by optimizing the meropenem (MEM) regimen to obtain at least 40% of the time between two administrations in which drug levels were four times higher than the MIC of the pathogen. As the standard drug dose did not achieve these optimal concentrations, the MEM regimen was progressively increased up to 12 g/day (3 g every 6 h in a 3-h extended infusion), which eventually resulted in sepsis resolution. High MEM dosage may represent a valuable therapeutic option for infection due to multidrug-resistant (MDR) strains, and drug monitoring would allow rapid regimen adjustment in clinical practice.

Topics: Aged; Anti-Bacterial Agents; C-Reactive Protein; Drug Resistance, Multiple, Bacterial; Humans; Male; Meropenem; Microbial Sensitivity Tests; Norepinephrine; Obesity; Pseudomonas aeruginosa; Pseudomonas Infections; Respiration, Artificial; Shock, Septic; Thienamycins; Vasoconstrictor Agents

Among 213 Pseudomonas aeruginosa isolates collected from 10 South Korean hospitals, 57 isolates (26.8%) were carbapenem-resistant. All but three of the isolates had a relevant decrease of oprD expression. However, decreased oprD expression was also detected in five of ten carbapenem-susceptible isolates. Outer membrane protein analysis confirmed porin loss in carbapenem-resistant P. aeruginosa isolates. Based on the mutations of oprD gene sequences, carbapenem-resistant P. aeruginosa isolates could be classified into five oprD mutational groups. However, there was no difference of OprD expression or carbapenem minimum inhibitory concentrations among the five mutational groups. Among the 57 carbapenem-resistant P. aeruginosa isolates, 41 (71.9%) overexpressed efflux systems or ampC. MexAB-OprM and AmpC overexpression (56.1% and 47.4%, respectively) was prevalent and was significantly associated with carbapenem resistance. However, no synergistic effect of efflux systems and AmpC on carbapenem resistance was evident. In conclusion, combination of several mutation-driven mechanisms leading to OprD inactivation and overexpression of efflux systems was the main carbapenem resistance mechanism, but acquisition of a transferable resistance determinant such as metallo-β-lactamase could be problematic in clinical settings in South Korea.

Topics: Anti-Bacterial Agents; Bacteremia; Bacterial Outer Membrane Proteins; Bacterial Proteins; beta-Lactamases; Drug Resistance, Multiple, Bacterial; Gene Expression Regulation, Bacterial; Gene Silencing; Genes, Bacterial; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Mutation; Porins; Pseudomonas aeruginosa; Pseudomonas Infections; Republic of Korea; Reverse Transcriptase Polymerase Chain Reaction; Thienamycins; Urinary Tract Infections

Topics: Amikacin; Facial Dermatoses; Fatal Outcome; Female; Gangrene; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Meropenem; Necrosis; Neutropenia; Pseudomonas aeruginosa; Pseudomonas Infections; Sepsis; Skin Diseases, Bacterial; Skin Ulcer; Thienamycins

The emergence and rapid spread of blaIMP and blaVIM metallo-beta-lactamase (MBL) producing Gram-negative bacteria causing nosocomial infections are of concern worldwide due to limited treatment options.. A total of 179 nonreplicate, consecutive, carbapenem resistant Pseudomonas aeruginosa (61), Acinetobacter baumannii (116), Acinetobacter lwoffii (1) and Pseudomonas stutzeri (1) isolated from patients hospitalized for 48 hours or more were included in the study. The minimum inhibitory concentrations (MIC) to imipenem and meropenem were determined and interpreted according to Clinical Laboratory Standards Institute guidelines. The Modified Hodge Test (MHT) and inhibitor potentiated disk diffusion tests with ethylenediaminetetraacetic acid (EDTA) were used for screening of carbapenamases and MBL production respectively. Polymerase chain reaction (PCR) was performed for the detection of MBL (blaVIM and blaIMP) genes. Gene sequencing was performed for representative isolates.. MHT was positive in 94.4% (n = 169). MBL screening with EDTA was positive in 80.4% (n = 144). MBL genes bla VIM and bla IMP were detected in 92 (51.4%) isolates. Bla VIM alone was detected in 89 isolates while two isolates had bla IMP alone. One isolate had both bla VIM and bla IMP. Among the P. aeruginosa, 36 carried the MBL gene. In A. baumannii, 54 carried the MBL gene. Bla VIM was found in P. stutzeri and A. lwoffii isolates.. Carbapenem resistance in P. aeruginosa and A. baumannii is chiefly mediated by MBL production. The common MBL gene is the blaVIM.

Topics: Acinetobacter; Acinetobacter Infections; Amikacin; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Disk Diffusion Antimicrobial Tests; Drug Resistance, Bacterial; Genes, Bacterial; Humans; Imipenem; India; Intensive Care Units; Meropenem; Phenotype; Polymerase Chain Reaction; Pseudomonas; Pseudomonas Infections; Thienamycins

Doripenem is a carbapenem antibiotic with broad-spectrum coverage of gram-positive and gram-negative bacteria, including Pseudomonas aeruginosa, and is considered to be as effective as meropenem. The in vivo activity of doripenem was thus compared with that of meropenem in a chronic lower respiratory P. aeruginosa infection mouse model. The number of viable bacteria in the lungs of mice after treatment with doripenem, meropenem, and saline was 2.01 ± 0.69, 2.03 ± 0.48, and 3.90 ± 1.40 log₁₀ CFU/lung, respectively. The number of viable bacteria in the lungs of mice treated with doripenem and meropenem was significantly lower than that in lungs of controls. Histopathological examination of lung specimens from the control group revealed promotion of the inflammatory response in chronic bronchial infection. However, the groups treated with doripenem and meropenem showed weaker inflammatory responses. These results suggest that doripenem treatment is effective against chronic airway infection with P. aeruginosa.

Topics: Animals; Anti-Bacterial Agents; Carbapenems; Doripenem; Male; Meropenem; Mice; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Tract Infections; Specific Pathogen-Free Organisms; Thienamycins

A total of 66 (0.35% of overall isolates) Acinetobacter baumannii and 102 (0.55%) meropenem-resistant Pseudomonas aeruginosa were identified among 18 538 isolates collected from medical centers across Canada during the 2007-2009 period. A. baumannii was most frequently recovered from patients in intensive care units (ICUs; 42.4%) and was isolated mostly from blood cultures (53.0%) and respiratory tract specimens (33.3%). Colistin, meropenem, and amikacin were the most active agents against A. baumannii strains (≥ 92.4% coverage). Gentamicin, levofloxacin, and tigecycline were also active against this bacterial species (MIC(50) 1, 0.12, and 0.5 μg/mL, respectively). Multidrug resistance (MDR; resistance to ≥ 3 antimicrobial classes) was noted in only 4 strains (6.1%), and molecular typing revealed 6 clusters of 2 isolates per cluster that displayed >85% similarity on the dendrogram. Meropenem-resistant P. aeruginosa isolates were primarily obtained from patients in ICUs (40.2%) and the most prevalent specimen types were those collected from the respiratory tract (63.7%), followed by blood cultures (18.6%). Most of the meropenem-resistant P. aeruginosa were resistant to all antimicrobial agents tested, and low susceptibility rates were observed for levofloxacin (8.8%) and gentamicin (28.4%). Amikacin and colistin were active against 67.7% and 88.2% of the isolates, respectively. A total of 68.6% (n = 70) of meropenem-resistant P. aeruginosa were MDR. Pulsed-field gel electrophoresis analysis revealed 94 unique isolates and 2 small clusters (6 and 4 isolates, 1 hospital each). In summary, MDR A. baumannii are rare in Canada and, conversely, meropenem-resistant P. aeruginosa were mostly MDR; however, there was minimal clonal spread among these nonfermentative bacilli.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacterial Typing Techniques; Canada; Child; Child, Preschool; DNA Fingerprinting; Drug Resistance, Multiple, Bacterial; Female; Humans; Infant; Infant, Newborn; Intensive Care Units; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Molecular Typing; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

Topics: Acinetobacter baumannii; Acinetobacter Infections; Adult; Aged; Anti-Bacterial Agents; Carbapenems; Doripenem; Drug Resistance, Bacterial; Female; Gram-Negative Bacterial Infections; Humans; Imipenem; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Pneumonia; Pseudomonas aeruginosa; Pseudomonas Infections; Random Allocation; Rectum; Stenotrophomonas maltophilia; Thienamycins

A 66-year-old male with acute type adult T-cell leukemia that was refractory to chemotherapy underwent unrelated allogeneic bone marrow transplantation after non-myeloablative conditioning with fludarabine, busulfan and total body irradiation. During an episode of neutropenia on day 12 after transplantation, pneumonia and sepsis due to multi-drug resistant Pseudomonas aeruginosa developed. Drug susceptibility tests demonstrated resistance to all kinds of intravenous antibiotics available for P. aeruginosa in Japan. Multi-drug susceptibility tests by the breakpoint-checkerboard plate method were then performed and combination therapy with meropenem hydrate and colistin was started based on the test results. After starting treatment, clinical symptoms and laboratory data immediately improved and engraftment of neutrophils was achieved on day 18. Infections with multi-drug-resistant P. aeruginosa are often critical for patients after hematopoietic stem cell transplantation and are difficult to control. In this paper, we report a case of severe multi-drug-resistant P. aeruginosa infection that was successfully treated by combination therapy selected using the breakpoint-checkerboard plate method.

Topics: Aged; Anti-Bacterial Agents; Bone Marrow Transplantation; Colistin; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Humans; Male; Meropenem; Microbial Sensitivity Tests; Neutropenia; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins; Transplantation, Homologous; Treatment Outcome

The laboratory detection of Pseudomonas aeruginosa that produce metallo-β-lactamases (MBLs) is not well defined in regions with a low prevalence of these enzymes. We report a study that developed ethylenediaminetetraacetic acid (EDTA) disk screen tests using doripenem, imipenem and meropenem and investigated the prevalence of these enzymes among clinical isolates of imipenem-resistant P. aeruginosa in Rotterdam during 2008-2009.. Using strains with well-characterized β-lactamases and the Clinical and Laboratory Standards Institute (CLSI) disk methodology similar to extended-spectrum β-lactamase (ESBL) detection, inhibition zone diameters were determined in tests with doripenem, imipenem, and meropenem, alone and in combination with 370 μg of EDTA. These tests were compared with the MBL E-test. A positive test was a ≥5 mm increase in zone diameter in the presence of EDTA.. The imipenem EDTA disk screen test showed a sensitivity of 100% and a specificity of 90% in 96 recent clinical isolates. Imipenem in combination with doripenem performed better than imipenem alone, meropenem, and the MBL E-test (sensitivity of 100%; specificity of 95%). The majority of clinical isolates were isolated from patient respiratory specimens. Of the 96 imipenem-resistant P. aeruginosa isolated, 35 (36%) were positive for bla(VIM) genes.. The EDTA imipenem/doripenem disk test showed accurate and reproducible results with excellent sensitivity and specificity. It is simple to perform and interpret and can be easily introduced into the workflow of a clinical laboratory to screen for MBLs in imipenem-resistant P. aeruginosa. Due to its high specificity the test is also suitable for regions with a low prevalence of these enzymes.

Topics: Anti-Bacterial Agents; beta-Lactamases; Carbapenems; Disk Diffusion Antimicrobial Tests; Doripenem; Edetic Acid; Humans; Imipenem; Laboratories; Meropenem; Microbial Sensitivity Tests; Netherlands; Pseudomonas aeruginosa; Pseudomonas Infections; Reproducibility of Results; Thienamycins

Pseudomonas aeruginosa pneumonia remains a most-difficult-to-treat nosocomial bacterial infection. We used mathematical modeling to identify drug exposure targets for meropenem in the epithelial lining fluid (ELF) of mice with Pseudomonas pneumonia driving substantial [2 to 3 log(10) (CFU/g)] killing and which suppressed resistant subpopulation amplification. We bridged to humans to estimate the frequency with which the largest licensed meropenem dose would achieve these exposure targets. Cell kills of 2 and 3 log(10) (CFU/g) and resistant subpopulation suppression were mediated by achieving time > MIC in ELF of 32%, 50%, and 50%. Substantial variability in meropenem's ability to penetrate into ELF of both mice and humans was observed. Penetration variability and high exposure targets combined to prevent even the largest licensed meropenem dose from achieving the targets at an acceptable frequency. Even a highly potent agent such as meropenem does not adequately suppress resistant subpopulation amplification as single-agent therapy administered at maximal dose and optimal schedule. Combination chemotherapy is likely required in humans if we are to minimize resistance emergence in Pseudomonas aeruginosa pneumonia. This combination needs evaluation both in the murine pneumonia model and in humans.

Topics: Animals; Bronchoalveolar Lavage Fluid; Female; Humans; Meropenem; Mice; Microbial Sensitivity Tests; Models, Theoretical; Monte Carlo Method; Pseudomonas Infections; Thienamycins

To investigate the mechanisms of carbapenem resistance in the 175 Pseudomonas aeruginosa isolates (39%; 175/448) showing non-susceptibility (European Committee on Antimicrobial Susceptibility Testing breakpoints) to imipenem (35%), meropenem (33%) and/or doripenem (33%) recovered in 2008-09 from 16 Spanish hospitals during the Comparative Activity of Carbapenem Testing (COMPACT) surveillance study.. MICs (Etest), clonal relatedness (PFGE) and metallo-β-lactamase (MBL) production (Etest-MBL, PCR and sequencing) were determined. Mutation-driven resistance was studied in 60 non-MBL producers according to the doripenem MICs (15 isolates from each of four MIC groups: ≤ 1, 2-4, 8-16 and ≥ 32 mg/L). The expression of ampC, mexB, mexY, mexD and mexF was determined by real-time reverse transcription-PCR and the presence of mutations in oprD by PCR and sequencing. Isogenic mutants expressing combinations of mutation-driven carbapenem resistance were constructed.. Twelve (6.9%) isolates were MBL (VIM-20, VIM-2 or VIM-13) producers and all showed high-level resistance (MIC 32 mg/L) to all three carbapenems. Regarding mutation-driven resistance, all but 1 of the 60 isolates were non-susceptible (MIC >32 mg/L) to imipenem, linked to oprD inactivation. In addition, 50% of the isolates overexpressed ampC, 33% mexY, 32% mexB and 15% mexF, while none overexpressed mexD. Increasing prevalence of ampC overexpression correlated with increasing doripenem MICs (≤ 1, 13%; 2-4, 53%; 8-16, 60%; and ≥ 32, 73%) while overexpression of efflux pumps correlated only with moderate resistance. Doripenem showed slightly higher activity than meropenem against isolates overexpressing ampC, especially mexB or mexY. The analysis of a collection of isogenic laboratory mutants supported this finding.. Although the prevalence of MBL producers is increasing, mutation-driven resistance is still more frequent in Spain. Imipenem resistance was driven by OprD inactivation, while additional AmpC and particularly efflux pump hyperproduction had a lower impact on the activity of doripenem compared with meropenem.

Topics: Anti-Bacterial Agents; beta-Lactamases; Carbapenems; Doripenem; Drug Resistance, Bacterial; Electrophoresis, Gel, Pulsed-Field; Imipenem; Meropenem; Microbial Sensitivity Tests; Molecular Epidemiology; Mutation; Plasmids; Population Surveillance; Porins; Pseudomonas aeruginosa; Pseudomonas Infections; Reverse Transcriptase Polymerase Chain Reaction; Spain; Thienamycins

We evaluated the ability of the combination disk test (CDT) and the Modified Hodge Test (MHT) to discriminate between various carbapenemase-producing Pseudomonas aeruginosa isolates (KPC, n = 36; metallo-β-lactamase (MBL), n = 38) and carbapenemase non-producers (n = 75). For the CDT, the optimal inhibitor concentrations and cut-off values were: 600 μg of 3-aminophenylboronic acid (APB) per disk (an increment of ≥4 mm), 1000 μg of dipicolinic acid (DPA) per disk (an increment of ≥5 mm) and 3000 μg of cloxacillin per disk (an increment of ≥3 mm). APB had excellent sensitivity (97%) and specificity (97%) for the detection of KPC enzymes. DPA detected MBL enzymes with a sensitivity and specificity of 97% and 81%, respectively. The MHT resulted in a low sensitivity (78%) and specificity (57%). The CDT could be very useful in daily practice to provide fast and reliable detection of KPC and MBL carbapenemases among P. aeruginosa isolates.

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Boronic Acids; Cloxacillin; Disk Diffusion Antimicrobial Tests; Humans; Meropenem; Picolinic Acids; Pseudomonas aeruginosa; Pseudomonas Infections; Sensitivity and Specificity; Thienamycins

Topics: Aged; Anti-Bacterial Agents; Bacterial Proteins; Belgium; beta-Lactamases; Carbapenems; Drug Resistance, Multiple, Bacterial; Female; Humans; Imipenem; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Multilocus Sequence Typing; Pseudomonas aeruginosa; Pseudomonas Infections; Reverse Transcriptase Polymerase Chain Reaction; Thienamycins

Topics: Anti-Bacterial Agents; Decompression, Surgical; Enterobacter cloacae; Enterobacteriaceae Infections; Female; Humans; Lumbar Vertebrae; Meropenem; Middle Aged; Osteotomy; Pseudomonas aeruginosa; Pseudomonas Infections; Scoliosis; Spinal Fusion; Surgical Wound Infection; Thienamycins; Treatment Outcome; Vancomycin

Pseudomonas aeruginosa exists in various environments, and can cause mild or serious infections resulting in a wide range of symptoms. In this study, we collected bacterial isolates from hospitalized patients and unchlorinated drinking water, in Korea, 2010. The water-borne and clinical isolates were compared using colony morphology, antimicrobial susceptibility testing, and random amplification of polymorphic DNA analysis. We first compared morphological features of the water-borne and clinical isolates. The clearest difference in colony morphology was colony shape; five water-borne isolate colonies (83%) had a smooth, circular morphology, while nine (75%) clinical isolate colonies had a rough, irregular morphology. Minimum inhibitory concentrations analyses were performed to determine antimicrobial resistant patterns; using ceftazidime, gentamicin, tigecycline, chloramphenicol, meropenem, and tobramycin according to Clinical and Laboratory Standard Institute (CLSI, 2009) methodology. All waterborne isolates were not resistant to gentamicin, tobramycin, and meropenem. The clinical isolates were resistant to every antibiotic except chloramphenicol. Genotyping was performed using the repetitive extragenic palindromic polymerase-chain-reaction. The DNA fingerprinting patterns did not reveal genetic similarity between the water-borne and clinical P. aeruginosa isolates. On the contrary, they showed that genetically distinct populations have been established in each of these environments. We have revealed significant morphological, clinical and genetic differences between water-borne and clinical isolates of the same bacterial species.

Topics: Aged; Anti-Bacterial Agents; Ceftazidime; DNA Fingerprinting; Drinking Water; Drug Resistance, Bacterial; Female; Genotype; Gentamicins; Humans; Korea; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Nucleic Acid Amplification Techniques; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

The present study investigated the pharmacokinetics of meropenem and biapenem in bile and estimated their pharmacodynamic target attainment at the site. Meropenem (0.5 g) or biapenem (0.3 g) was administered to surgery patients (n = 8 for each drug). Venous blood samples and hepatobiliary tract bile samples were obtained at the end of infusion (0.5 h) and for up to 5 h thereafter. Drug concentrations in plasma and bile were analyzed pharmacokinetically and used for a Monte Carlo simulation to predict the probability of attaining the pharmacodynamic target (40% of the time above the MIC). Both drugs penetrated similarly into bile, with mean bile/plasma ratios of 0.24 to 0.25 (maximum drug concentration) and 0.30 to 0.38 (area under the drug concentration-time curve). The usual regimens of meropenem (0.5 g every 8 h [q8h]) and biapenem (0.3 g q8h) (0.5-h infusions) achieved similar target attainment probabilities in bile (≥ 90%) against Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae isolates. However, against Pseudomonas aeruginosa isolates, meropenem at 1 g q8h and biapenem at 0.6 g q8h were required for values of 80.7% and 71.9%, respectively. The biliary pharmacodynamic-based breakpoint (the highest MIC at which the target attainment probability in bile was ≥ 90%) was 1 mg/liter for 0.5 g q8h and 2 mg/liter for 1 g q8h for meropenem and 0.5 mg/liter for 0.3 g q8h and 1 mg/liter for 0.6 g q8h for biapenem. These results help to define the clinical pharmacokinetics of the two carbapenems in bile while also helping to rationalize and optimize the dosing regimens for biliary tract infections based on site-specific pharmacodynamic target attainment.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Bile; Biliary Tract; Dose-Response Relationship, Drug; Drug Administration Schedule; Enterobacteriaceae; Enterobacteriaceae Infections; Female; Humans; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Monte Carlo Method; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

Extreme drug-resistant Pseudomonas aeruginosa (XDR-PA) with decreased susceptibility to polymyxin B (PB) has emerged in Singapore, causing infections in immunocompromised hosts. Combination therapy may be the only viable therapeutic option until new antibiotics become available. The objective of this study is to assess the in vitro activity of various antibiotics against local XDR-PA isolates.. PA isolates from all public hospitals in Singapore were systematically collected between 2006 and 2007. MICs were determined according to CLSI guidelines. All XDR-PA isolates identified were genotyped using a PCR-based method. Time-kill studies (TKS) were performed with approximately 10(5) CFU/ml at baseline using clinically achievable unbound concentrations of amikacin (A), levofloxacin (L), meropenem (M), rifampicin (R) and PB alone and in combination. Bactericidal activity (primary endpoint) was defined as a ≥3 log(10) CFU/ml decrease in the colony count from the initial inoculum at 24 hours.. 22 clinical XDR-PA isolates with PB MIC 2-16 µg/ml were collected. From clonal typing, 5 clonal groups were identified and nine isolates exhibited clonal diversity. In TKS, meropenem plus PB, amikacin plus meropenem, amikacin plus rifampicin, amikacin plus PB exhibited bactericidal activity in 8/22, 3/22, 1/22 and 6/22 isolates at 24 hours respectively. Against the remaining ten isolates where none of the dual-drug combination achieved bactericidal activity against, only the triple-antibiotic combinations of ARP and AMP achieved bactericidal activity against 7/10 and 6/10 isolates respectively.. Bactericidal activity with sustained killing effect of ≥99.9% is critical for eradicating XDR-PA infections, especially in immunocompromised hosts. These findings underscore the difficulty of developing combination therapeutic options against XDR-PA, demonstrating that at least 3 antibiotics are required in combination and that efficacy is strain dependant.

Topics: Amikacin; Anti-Bacterial Agents; beta-Lactamases; Drug Resistance, Bacterial; Drug Synergism; Drug Therapy, Combination; Humans; Levofloxacin; Meropenem; Microbial Sensitivity Tests; Ofloxacin; Phylogeny; Polymyxin B; Pseudomonas aeruginosa; Pseudomonas Infections; Rifampin; Thienamycins; Time Factors

To identify the outer membrane protein absent in the resistant isolates and to determine both the causes of its absence in the membrane and the presence of other mechanisms of carbapenem resistance in clinical isolates of Pseudomonas aeruginosa.. Twenty isolates from an outbreak of P. aeruginosa previously characterized as metallo-beta-lactamase IMP-13 producers were studied. All the isolates exhibited equal expression of the IMP-13 enzyme, but only five of them were carbapenem-resistant. It was found that the five resistant isolates lacked a outer membrane protein. The oprD and ampC genes were sequenced; the outer membrane proteins were identified using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry; the OprD and AmpC expressions, as well as the Mex efflux system, were assessed by real-time polymerase chain reaction; and finally, the contribution of reduced OprD to carbapenem resistance was determined.. The absent outer membrane protein in group R was identified as OprD-TS; however, no variations in its expression were observed. The oprD gene presented mutations in the five resistant isolates. The production of AmpC PDC-5-type enzyme and the MexAB-OprM efflux system was the same in both carbapenem-sensitive and -resistant isolates. The contribution of the combined presence of IMP-13 and reduced OprD to increased resistance was examined.. Different mechanisms contribute to carbapenem resistance in IMP-13-producing isolates. The possibility that these IMP-13-producing isolates could go undetected poses a latent risk when selecting mutants with added resistance mechanisms in order to enhance carbapenem resistance.

Topics: Bacterial Outer Membrane Proteins; Bacterial Proteins; beta-Lactam Resistance; beta-Lactamases; Carbapenems; DNA Mutational Analysis; DNA, Bacterial; Drug Resistance, Multiple, Bacterial; Electrophoresis, Gel, Pulsed-Field; Genes, Bacterial; Humans; Imipenem; Membrane Transport Proteins; Meropenem; Mutation; Porins; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Thienamycins

Ceftobiprole, a broad-spectrum cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA) (P. Hebeisen et al., Antimicrob. Agents Chemother. 45:825-836, 2001), was evaluated in a subcutaneous skin infection model with Staphylococcus aureus Smith OC 4172 (methicillin-susceptible S. aureus [MSSA]), S. aureus OC 8525 (MRSA), Pseudomonas aeruginosa OC 4351 (having an inducible AmpC beta-lactamase), and P. aeruginosa OC 4354 (overproducing AmpC beta-lactamase). In the MSSA and MRSA infection models, ceftobiprole, administered as the prodrug ceftobiprole medocaril, was more effective in reducing CFU/g skin (P < 0.001) than were cefazolin, vancomycin, or linezolid based on the dose-response profiles. Skin lesion volumes in MSSA-infected animals treated with ceftobiprole were 19 to 29% lower than those for cefazolin-, vancomycin-, or linezolid-treated animals (P < 0.001). In MRSA infections, lesion size in ceftobiprole-treated mice was 34% less than that with cefazolin or linezolid treatment (P < 0.001). Against P. aeruginosa, ceftobiprole at similar doses was as effective as meropenem-cilastatin in reductions of CFU/g skin, despite 8- and 32-fold-lower MICs for meropenem; both treatments were more effective than was cefepime (P < 0.001) against the inducible and overproducing AmpC beta-lactamase strains of P. aeruginosa. Ceftobiprole was similar to meropenem-cilastatin and 47 to 54% more effective than cefepime (P < 0.01) in reducing the size of the lesion caused by either strain of P. aeruginosa in this study. These studies indicate that ceftobiprole is effective in reducing both bacterial load and lesion volume associated with infections due to MSSA, MRSA, and P. aeruginosa in this murine model of skin and soft tissue infection.

Topics: Animals; Anti-Bacterial Agents; Area Under Curve; Bacterial Proteins; beta-Lactamases; Cephalosporins; Colony Count, Microbial; Dose-Response Relationship, Drug; Female; Gram-Negative Bacteria; Gram-Positive Bacteria; Half-Life; Immunocompromised Host; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Hairless; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Skin Diseases, Infectious; Staphylococcal Infections; Staphylococcus aureus

The activity of the new cephalosporin CXA-101 (CXA), previously designated FR264205, was evaluated against a collection of 236 carbapenem-resistant P. aeruginosa isolates, including 165 different clonal types, from a Spanish multicenter (127-hospital) study. The MICs of CXA were compared to the susceptibility results for antipseudomonal penicillins, cephalosporins, carbapenems, aminoglycosides, and fluoroquinolones. The MIC of CXA in combination with tazobactam (4 and 8 microg/ml) was determined for strains with high CXA MICs. The presence of acquired beta-lactamases was investigated by isoelectric focusing and PCR amplification followed by sequencing. Additional beta-lactamase genes were identified by cloning and sequencing. The CXA MIC50/MIC90 for the complete collection of carbapenem-resistant P. aeruginosa isolates was 1/4 microg/ml, with 95.3% of the isolates showing an MIC of 8 microg/ml produced a horizontally acquired beta-lactamase, including the metallo-beta-lactamase (MBL) VIM-2 (one strain), the extended-spectrum beta-lactamase (ESBL) PER-1 (one strain), several extended-spectrum OXA enzymes (OXA-101 [one strain], OXA-17 [two strains], and a newly described OXA-2 derivative [W159R] designated OXA-144 [four strains]), and a new BEL variant (BEL-3) ESBL (one strain), as identified by cloning and sequencing. Synergy with tazobactam in these 11 strains was limited, although 8 microg/ml reduced the mean CXA MIC by 2-fold. CXA is highly active against carbapenem-resistant P. aeruginosa isolates, including MDR strains. Resistance was restricted to still-uncommon strains producing an acquired MBL or ESBL.

Topics: Anti-Bacterial Agents; beta-Lactamases; Carbapenems; Cephalosporins; Drug Resistance, Multiple, Bacterial; Humans; Isoelectric Focusing; Microbial Sensitivity Tests; Polymerase Chain Reaction; Pseudomonas aeruginosa; Pseudomonas Infections

Topics: Anti-Bacterial Agents; Argentina; Bacterial Proteins; beta-Lactam Resistance; beta-Lactamases; Carbapenems; Ceftazidime; Disease Outbreaks; Humans; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections

GES-13 beta-lactamase, a novel GES variant possessing Lys-104 and Asn-170, was identified in Pseudomonas aeruginosa. bla(GES-13) was the single gene cassette of a class 1 integron probably located in the chromosome. GES-13 efficiently hydrolyzed broad-spectrum cephalosporins and aztreonam. Imipenem was a potent inhibitor of GES-13 but was not hydrolyzed at measurable rates.

Topics: Anti-Bacterial Agents; Aztreonam; beta-Lactamases; beta-Lactams; Cephalosporins; Genetic Variation; Humans; Integrons; Microbial Sensitivity Tests; Molecular Sequence Data; Pseudomonas aeruginosa; Pseudomonas Infections; Sequence Analysis, DNA

CXA-101, previously designated FR264205, is a new antipseudomonal cephalosporin. We evaluated the activity of CXA-101 against a highly challenging collection of beta-lactam-resistant Pseudomonas aeruginosa mutants selected in vitro and after antipseudomonal treatment of intensive care unit (ICU) patients. The in vitro mutants investigated included strains with multiple combinations of mutations leading to several degrees of AmpC overexpression (ampD, ampDh2, ampDh3, and dacB [PBP4]) and porin loss (oprD). CXA-101 remained active against even the AmpD-PBP4 double mutant (MIC = 2 microg/ml), which shows extremely high levels of AmpC expression. Indeed, this mutant showed high-level resistance to all tested beta-lactams, except carbapenems, including piperacillin-tazobactam (PTZ), aztreonam (ATM), ceftazidime (CAZ), and cefepime (FEP), a cephalosporin considered to be relatively stable against hydrolysis by AmpC. Moreover, CXA-101 was the only beta-lactam tested (including the carbapenems imipenem [IMP] and meropenem [MER]) that remained fully active against the OprD-AmpD and OprD-PBP4 double mutants (MIC = 0.5 microg/ml). Additionally, we tested a collection of 50 sequential isolates that were susceptible or resistant to penicillicins, cephalosporins, carbapenems, or fluoroquinolones that emerged during treatment of ICU patients. All of the mutants resistant to CAZ, FEP, PTZ, IMP, MER, or ciprofloxacin showed relatively low CXA-101 MICs (range, 0.12 to 4 microg/ml; mean, 1 to 2 microg/ml). CXA-101 MICs of pan-beta-lactam-resistant strains ranged from 1 to 4 microg/ml (mean, 2.5 microg/ml). As described for the in vitro mutants, CXA-101 retained activity against the natural AmpD-PBP4 double mutants, even when these exhibited additional overexpression of the MexAB-OprM efflux pump. Therefore, clinical trials are needed to evaluate the usefulness of CXA-101 for the treatment of P. aeruginosa nosocomial infections, particularly those caused by multidrug-resistant isolates that emerge during antipseudomonal treatments.

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactam Resistance; beta-Lactamases; Cephalosporins; Cross Infection; Humans; Intensive Care Units; Microbial Sensitivity Tests; Mutation; Pseudomonas aeruginosa; Pseudomonas Infections

Expression of ampC, oprD, mexA, mexC, mexE, and mexX was studied in 25 Pseudomonas aeruginosa isolates from cystic fibrosis patients, including 14 isolates of the Liverpool epidemic strain. Overexpressed mexA or ampC and reduced oprD were associated with beta-lactam resistance. A specific combination of mexR, nalC, and nalD mutations occurred in 11 Liverpool strain isolates, including 7 with upregulated mexA.

Topics: Bacterial Outer Membrane Proteins; Bacterial Proteins; beta-Lactamases; Cystic Fibrosis; Drug Resistance, Bacterial; Drug Resistance, Multiple; Electrophoresis, Gel, Pulsed-Field; Humans; Membrane Transport Proteins; Mutation; Porins; Pseudomonas aeruginosa; Pseudomonas Infections; Reverse Transcriptase Polymerase Chain Reaction; Up-Regulation

A carbapenem-resistant Pseudomonas stutzeri strain isolated from a Dutch patient was analyzed in detail. This isolate produced a metallo-beta-lactamase (MBL) whose gene, with 43.5% GC content, was cloned and expressed in Escherichia coli. beta-Lactamase DIM-1 (for Dutch imipenemase) was weakly related to other Ambler class B beta-lactamases, sharing <52% amino acid identity with the most closely related MBL, GIM-1, and 45% identity with IMP-type MBLs. The beta-Lactamase DIM-1 significantly hydrolyzed broad-spectrum cephalosporins and carbapenems and spared aztreonam. This MBL gene was embedded in a class 1 integron containing two other gene cassettes, encoding resistance to aminoglycosides and disinfectants, that was located on a 70-kb plasmid.

Topics: Amino Acid Sequence; Bacterial Proteins; Base Sequence; beta-Lactamases; Cloning, Molecular; DNA, Bacterial; Drug Resistance, Bacterial; Genes, Bacterial; Humans; Integrons; Middle Aged; Molecular Sequence Data; Netherlands; Pseudomonas Infections; Pseudomonas stutzeri; Sequence Homology, Amino Acid; Substrate Specificity

A total of 489 clinical isolates of Pseudomonas aeruginosa was investigated for metallo-beta-lactamase (MBL) production. Molecular analysis detected a blaVIM-1 gene in the chromosome of one isolate and a blaVIM-2 gene carried on the plasmid in seven isolates. Moreover, we showed that an initial screening by combined susceptibility testing of imipenem and ceftazidime followed by a confirmatory EDTA combination disk test represents a valid alternative to the molecular investigation of MBL genes, making MBL detection possible in routine diagnostic laboratories.

Topics: Anti-Bacterial Agents; beta-Lactamases; Ceftazidime; Drug Resistance, Bacterial; Germany; Hospitals, University; Humans; Imipenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections

Pseudomonas aeruginosa strains producing metallo-beta-lactamases (MbetaL) are uncommon in Spain. This study describes the characterization of 9 new clonally related multiresistant P. aeruginosa isolates possessing the bla(VIM-2) gene in Cantabria (Northern Spain).. P. aeruginosa clinical strains (1 per patient) were isolated in the Microbiology Service of Marqués de Valdecilla University Hospital between January 2004 and December 2006. Identification and preliminary susceptibility studies were performed with the MicroScan WalkAway system (Dade Behring, Sacramento, CA) and results were verified by a microdilution reference method.. MICs of imipenem and meropenem for the 9 isolates ranged from 32 to 128 and 16 to 64 microg/mL, respectively. Nine isolates had a single Rep-PCR pattern and were intermediate or resistant to ceftazidime, cefepime, gentamicin, tobramycin, amikacin and ciprofloxacin. Eight of the 9 isolates were susceptible to aztreonam. Hydrolysis activity of imipenem in MbetaL-positive isolates ranged from 162+/-18 to 235+/-28 pmol/min/microg protein and was abolished in the presence of 5 mM EDTA. All isolates possessed an integron with genes aac(6')32, bla(VIM-2) and a putative transposase-encoding gene, flanked by the conserved 5'CS and 3'CS regions.. In the clinical isolates studied, the presence of MbetaL VIM-2 sufficed to explain their resistance to carbapenems.

Topics: Acetyltransferases; Adult; Aged; Aged, 80 and over; Amino Acid Sequence; Bacterial Proteins; beta-Lactam Resistance; beta-Lactamases; Conserved Sequence; Drug Resistance, Multiple, Bacterial; Female; Humans; Integrons; Male; Meropenem; Middle Aged; Molecular Sequence Data; Porins; Pseudomonas aeruginosa; Pseudomonas Infections; Sequence Alignment; Sequence Homology, Amino Acid; Spain; Thienamycins; Transposases

Because of the high frequency of multidrug resistant bacteria in our intensive care units (ICUs), we implemented a ventilator-associated pneumonia (VAP) clinical pathway based on unit-specific minimum inhibitory concentration (MIC) distributions and pharmacodynamic modeling in 3 of our ICUs.. This was a prospective, observational evaluation with a historical control group in adult patients (n = 168) who met clinical and radiologic criteria for VAP. Monte Carlo simulation was used to determine antibiotic regimens having the greatest likelihood of achieving bactericidal exposures against Pseudomonas aeruginosa. Antibiotic regimens were incorporated into an ICU-specific computerized clinical pathway as empiric agents of choice.. Pharmacodynamic modeling found 3-hour infusions of cefepime 2 g every 8 hours or meropenem 2 g every 8 hours plus tobramycin and vancomycin would provide the greatest probability of empirically treating VAP in these ICUs. Infection-related mortality was reduced by 69% (8.5% vs 21.6%; P = .029), infection-related length of stay was shorter (11.7 +/- 8.1 vs 26.1 +/- 18.5; P < .001), and fewer superinfections were observed in patients treated on the pathway. A number of patients with nonsusceptible P aeruginosa were successfully treated with high-dose, 3-hour infusion regimens.. In our ICUs where multidrug resistant bacteria are common, an approach considering ICU-specific antibiotic MICs coupled with pharmacodynamic dosing strategies resulted in improved outcomes and shorter duration of treatments.

Topics: Adult; Aged; Anti-Bacterial Agents; Cefepime; Cephalosporins; Critical Pathways; Drug Administration Schedule; Drug Therapy, Combination; Female; Hospital Mortality; Humans; Intensive Care Units; Length of Stay; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Monte Carlo Method; Observation; Pneumonia, Ventilator-Associated; Prospective Studies; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins; Tobramycin; Treatment Outcome; Vancomycin; Young Adult

The aim of this investigation was to characterize metallo-beta-lactamases (MBLs) in Pseudomonas aeruginosa isolates from Zagreb, Croatia. One hundred P. aeruginosa isolates with reduced susceptibility to either imipenem or meropenem were tested for the production of MBLs by MBL-Etest. The susceptibility to a wide range of antibiotics was determined by broth microdilution method. The presence of bla(MBL) genes was detected by polymerase chain reaction (PCR). Hydrolysis of 0.1 mM imipenem by crude enzyme preparations of beta-lactamases was monitored by UV spectrophotometer. Outer membrane proteins were prepared and analysed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Six out of 100 isolates were positive for MBLs by Etest. All strains were resistant to gentamicin, ceftazidime and cefotaxime, and all except 1 were resistant to imipenem. Six strains positive for MBLs by Etest were identified as VIM MBL-producers by PCR. Sequencing of bla(VIM) genes revealed the production of VIM-2 beta-lactamase in all 6 strains. This investigation proved the occurrence of VIM-2 beta-lactamase among P. aeruginosa strains from Zagreb, Croatia. VIM-2 beta-lactamase with similar properties has previously been described in another region of Croatia and in Italy, France, Spain, Greece, Taiwan and South Korea, suggesting that this type of enzyme is widespread in the Mediterranean region of Europe and in the Far East.

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactam Resistance; beta-Lactamases; Croatia; DNA, Bacterial; Humans; Hydrolysis; Imipenem; Meropenem; Microbial Sensitivity Tests; Polymerase Chain Reaction; Pseudomonas aeruginosa; Pseudomonas Infections; Sequence Analysis, DNA; Spectrophotometry; Thienamycins

In this study we compared the efficacy of a theoretically optimized two-step infusion therapy (OTIT; rapid first-step infusion and slow second-step infusion) to the efficacies of prolonged infusion therapy (PIT) and traditional 0.5 h infusion therapy (TIT) with meropenem against Pseudomonas aeruginosa using an in vitro pharmacodynamic model and a Monte Carlo simulation. In the in vitro pharmacodynamic model, the bactericidal effect against P. aeruginosa was evaluated for 8 h, which is the usual dosing interval of meropenem. It was confirmed that the durability of the bactericidal effect of OTIT (0.25-1 g/0.5 h + 0.25-1 g/4 h t.i.d.) was almost equal to that of PIT and superior to that of TIT (0.5-2 g/0.5-4 h t.i.d.). In addition, the initial bactericidal effects of OTIT were superior to those of the prolonged 4 h infusion. In the Monte Carlo simulation study, the probability of target attainments (PTAs) of all dosing regimens of OTIT at MICs of 2-8 μg/ml were apparently superior to those of TIT and 4- and 6 h-PIT, when the target therapeutic condition for serious life-threatening infections was the achievement of both the percentage of the dosing interval at which the drug concentration exceeds the MIC (%T(>MIC)) ≥ 50% and the peak level divided by the MIC (Cmax/MIC) ≥ 4. Especially, the PTAs of the dosing regimens of 0.25-1 g/0.5 h + 0.25-1 g/4-6 h were excellent at MICs of 2-8 μg/ml. Against recent clinical isolates of P. aeruginosa in Japan, the dosing regimens of OTIT provided higher PTAs compared with those of TIT and 4- and 6 h-PIT. These results suggested that OTIT with sufficient pharmacokinetic conditions could be useful for enhancing the therapeutic efficacy of meropenem against serious life-threatening infections.

Topics: Anti-Bacterial Agents; Drug Administration Schedule; Humans; Infusions, Intravenous; Japan; Meropenem; Microbial Sensitivity Tests; Monte Carlo Method; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

Topics: Anti-Bacterial Agents; Critical Care; Cross Infection; Drug Resistance, Bacterial; Humans; Infection Control; Intensive Care Units; Meropenem; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

New approaches are needed for the treatment of Pseudomonas aeruginosa infections. All available single agents are suboptimal, especially for resistance suppression. Classical beta-lactam/aminoglycoside combinations are not used often enough at least in part because of concern for nephrotoxicity. We evaluated the combination of meropenem and levofloxacin against the P. aeruginosa PAO1 wild type and its isogenic MexAB pump-overexpressed mutant. The drugs were studied using an in vitro hollow-fiber pharmacodynamic infection model. There were 16 different regimens evaluated for both isolates. Both total population and resistant subpopulations were quantified. Drug concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS-MS). The impact of monotherapy versus that of combination therapy for attainment of a 3-log cell kill and for resistance suppression was examined using Kaplan-Meier analysis. Drug exposures were calculated by fitting the concentration-time data using the ADAPT II package of programs. For both isolates, monotherapy allowed resistance emergence with all but the largest exposure or with all exposures. In contrast, there was no resistance emergence with any combination regimen. Kaplan-Meier analysis showed significant differences in time to attainment of a 3-log cell kill as well as time to resistance emergence for monotherapy and combination therapy for both isolates, in favor of the combination regimens. Determination of the pharmacodynamic indices associated with resistance suppression demonstrated a 2- to 3-fold reduction with the use of combinations. Combination therapy with meropenem and levofloxacin provides a significantly faster time to attain a 3-log cell kill and significantly better resistance suppression than does either monotherapy. This combination should be evaluated in a clinical trial.

Topics: Anti-Bacterial Agents; Bacterial Outer Membrane Proteins; Colony Count, Microbial; Drug Resistance, Bacterial; Drug Synergism; Drug Therapy, Combination; Genes, Bacterial; Humans; In Vitro Techniques; Levofloxacin; Membrane Transport Proteins; Meropenem; Microbial Sensitivity Tests; Mutation; Ofloxacin; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

In the light of current concerns regarding ciprofloxacin resistance and the changing face of malignant otitis externa, we reviewed cases of malignant otitis externa treated in our centre, in order both to evaluate the current epidemiology of the condition and to assess the status of drug resistance in our patient population.. Retrospective case review of all malignant otitis externa cases managed in a tertiary referral centre in the north-east of England between 2000 and 2009.. Forty-one patients were identified, but the required data were available for only 37 cases. Patients' ages ranged from 51 to 101 years (median, 81 years). Diabetes was present in 51 per cent of patients (19/37), facial nerve palsy in 40 per cent (15/37) and multiple cranial nerve palsy in 24 per cent (9/37). Pseudomonas aeruginosa was the most commonly isolated organism (54 per cent), sensitive to ciprofloxacin in all cases.. The incidence of cranial nerve palsy in our study was higher than in previous reports. The incidence of diabetes and Pseudomonas aeruginosa in our cohort was much lower than previously reported. The Pseudomonas aeruginosa strains isolated were all sensitive to ciprofloxacin, despite recent reports on emerging resistance.

Topics: Aged; Aged, 80 and over; Anti-Infective Agents; Ciprofloxacin; Cranial Nerve Diseases; Diabetes Mellitus; Drug Resistance, Bacterial; Drug Therapy, Combination; Earache; England; Female; Humans; Male; Meropenem; Middle Aged; Otitis Externa; Pseudomonas aeruginosa; Pseudomonas Infections; Recurrence; Retrospective Studies; Thienamycins

Our aim was to determine the prevalence of multidrug resistance of Acinetobacter baumannii and other pathogens at a tertiary-care teaching hospital in Mexico over a 3-year period. Clinical isolates of A. baumannii (n = 550), Pseudomonas aeruginosa (n = 250), some Enterobacteriaceae species (n = 500) and Staphylococcus aureus (n = 250) collected over a 3-year period were included. Susceptibility tests were performed by the broth microdilution method. 74% of A. baumannii, 40% of Escherichia coli, 34% of P. aeruginosa, 22% of Klebsiella pneumoniae, 9% of Enterobacter cloacae, and 7% of Serratia sp. were multidrug resistant. 59% of A. baumannii clinical isolates were meropenem-resistant. A. baumannii isolates from the lower respiratory tract were the most susceptible, followed by urine clinical isolates. Species from Enterobacteriaceae showed susceptibility rates higher than 90% to meropenem and tigecycline and Serratia sp. showed the highest susceptibility to the drugs evaluated. For P. aeruginosa, the most potent drug was levofloxacin, followed by meropenem and piperacillin-tazobactam. With regard to S. aureus, 96% of the isolates were susceptible to vancomycin, followed by tigecycline and minocycline (91% of strains susceptible). The high multidrug resistance observed underscores the need for surveillance of bacterial drug resistance.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Drug Resistance, Multiple, Bacterial; Enterobacteriaceae; Hospitals, Teaching; Humans; Klebsiella pneumoniae; Meropenem; Mexico; Microbial Sensitivity Tests; Minocycline; Prevalence; Pseudomonas aeruginosa; Pseudomonas Infections; Staphylococcus aureus; Thienamycins; Tigecycline

Doripenem is a new carbapenem with broad spectrum antibacterial activity indicated for the treatment of nosocomial pneumonia and complicated urinary and intraabdominal infections.. Isolates of Pseudomonas aeruginosa, Acinetobacter and Enterobacteriaceae from patients with nosocomial pneumonia, bacteremia and complicated intraabdominal infections attended in 16 Spanish hospitals were included (October 2008-May 2009). Susceptibility to imipenem, meropenem and doripenem was studied with the Etest method, and the results were interpreted according to the EUCAST criteria.. Considering all the isolates, doripenem (MIC(50) 0.12 mg/L) was 2- to 8-fold more active than meropenem (0.25 mg/L) and imipenem (1 mg/L). In relation to Enterobacteriaceae, the MIC(50) and MIC(90) values of doripenem and meropenem were similar (0.03 and 0.12 mg/L, respectively) and clearly superior to those of imipenem (0.25 and 1 mg/L). In the case of P. aeruginosa, MIC(50) and MIC(90) were more favorable to doripenem (0.25 and 16 mg/L) than to meropenem (0.5 and ≥64 mg/L) or imipenem (2 and ≥64 mg/L). In this species, the percentage of strains with lower MIC values for doripenem among those exhibiting intermediate susceptibility and resistance to meropenem was 63.0% (29/46) and 61.7% (63/102), respectively, versus only 4.3% (2/46) and 1.9% (2/102) with higher MIC values for doripenem.. The results obtained in this study are similar to those reported in other countries, and reinforce the superior in vitro activity of doripenem versus the other carbapenems and its position in the treatment guidelines regarding the nosocomial infections for which it is indicated.

Topics: Acinetobacter Infections; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Carbapenems; Doripenem; Enterobacteriaceae Infections; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Pseudomonas Infections; Spain; Thienamycins

The aim of this study was to compare doripenem with imipenem and meropenem in an experimental rabbit model of Pseudomonas aeruginosa pneumonia and then to compare different doripenem doses and methods of intravenous administration.. Using a rabbit experimental model of pneumonia, efficacy was assessed following 2 days of treatment by colony counts of different tissues (lung, spleen and blood culture).. Mean pulmonary bacterial loads were 3.17 ± 0.53, 3.42 ± 0.61 and 2.75 ± 0.59 log(10) cfu/g for imipenem, doripenem (0.5 g three times daily) and meropenem, respectively, compared with 7.57 ± 0.99 cfu/g for control animals. At a higher dose (1 g three times daily), doripenem showed significantly better efficacy (2.70 ± 0.65 log(10) cfu/g) than the standard regimen of doripenem. Sterilization of spleen cultures was achieved with standard regimens of imipenem (1 g three times daily) and a higher dose of doripenem.. In this model of P. aeruginosa pneumonia, doripenem had an efficacy equivalent to that of meropenem and imipenem at a high dose of 1 g three times a day and lower efficacy at a standard dose (0.5 g three times daily) than the other two agents in terms of bacteria cultivated from spleens. Doripenem is a new drug that offers new therapeutic options, especially for difficult-to-treat infections such as pneumonia due to non-fermenting Gram-negative bacteria.

Topics: Animals; Anti-Bacterial Agents; Bacterial Load; Blood; Carbapenems; Disease Models, Animal; Doripenem; Female; Imipenem; Infusions, Intravenous; Lung; Meropenem; Plasma; Pneumonia, Bacterial; Pseudomonas aeruginosa; Pseudomonas Infections; Rabbits; Spleen; Thienamycins; Treatment Outcome

The aim of our study was to determine the prevalence of Pseudomonas aeruginosa bacteremia, risk factors, and outcome of patients treated at the Hospital of Kaunas University of Medicine.. All hospitalized patients with blood culture positive for Pseudomonas aeruginosa during the 5-year period were included. A retrospective data analysis was performed to evaluate patients' risk factors and mortality caused by P. aeruginosa bacteremia.. A total of 47 (58.8%) bacteremia episodes occurred in an intensive care unit (ICU). A primary source of bacteremia was identified in 50 (62.5%) episodes. Overall mortality rate was 58.8%. Univariate risk factors analysis showed the factors, which significantly increased the risk of death: mechanical ventilation (13.67 times, P<0.001), patient hospitalization in the ICU (8.51 times, P<0.001), acute respiratory failure (8.44 times, P<0.001), infection site in the respiratory tract (4.93 times, P=0.003), and central vein catheter (4.44 times, P=0.002). Timely and appropriate treatment and surgery were significant protective factors for 30-day mortality (11.1 and 5.26 times, respectively; P=0.001). Meropenem-resistant Pseudomonas aeruginosa strains caused bacteremia more frequently in patients older than 65 years than meropenem-sensitive strains (57.9%, n=11). All 19 patients with meropenem-resistant Pseudomonas aeruginosa bacteremia received inappropriate empirical antibiotic therapy.. Treatment at the intensive care unit, mechanical ventilation, acute respiratory failure, source of infection in respiratory tract, and central vein catheter are the major risk factors associated with an increased mortality rate in patients with Pseudomonas aeruginosa bacteremia. The patients older than 65 years are at increased risk for bacteremia caused by carbapenem-resistant Pseudomonas aeruginosa strains. Carbapenems are not antibiotics of the choice of treatment for Pseudomonas aeruginosa bacteremia at the Hospital of Kaunas University of Medicine.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacteremia; Data Interpretation, Statistical; Drug Resistance, Bacterial; Drug Therapy, Combination; Female; Humans; Imipenem; Intensive Care Units; Lithuania; Male; Meropenem; Middle Aged; Odds Ratio; Pseudomonas aeruginosa; Pseudomonas Infections; Respiration, Artificial; Retrospective Studies; Risk Factors; Thienamycins; Time Factors

A study was designed to investigate the molecular epidemiological characteristics of multidrug-resistant outbreak-related Pseudomonas aeruginosa isolates collected in a university hospital in northern Greece. Of 29 nonreplicate P. aeruginosa isolates resistant to carbapenems and ceftazidime, 14 were positive for metallo-beta-lactamase production. PCR analyses with primers specific for bla(VIM) and bla(IMP) revealed that 13 isolates carried a novel bla(VIM-2) gene variant, designated bla(VIM-17), and only 1 isolate carried bla(VIM-2), a gene predominant among P. aeruginosa strains in Greek hospitals. Pulsed-field gel electrophoresis of XbaI-digested genomic DNAs showed a close genetic relationship for 12 of 13 bla(VIM-17)-carrying outbreak-related isolates, which were of the O11 serotype; the clonally unrelated isolate carrying bla(VIM-17) was of the O12 serotype. PCR mapping strategies for the detection of class 1 integrons and sequencing approaches revealed the presence of integrons containing one bla(VIM) cassette flanked by two aacA29 cassettes. These integrons were similar but not identical to In59 (GenBank accession number AF263519) initially described in France. All isolates carrying bla(VIM-17), regardless of their genetic profile, had an identical integron, named In59.3, indicating that although the hospital outbreak was mainly due to clonal dissemination, the horizontal transmission of the bla(VIM-17)-containing integron among P. aeruginosa isolates should also have occurred. An outbreak-related isolate and a control strain, both of which carried the bla(VIM-2) gene but which were clonally distinct, had an identical integron, named In59.2, which differed only at the level of the bla(VIM) gene from In59.3 integrons, suggesting a common ancestry. The spread of the bla(VIM-17)-containing integron in clonally unrelated P. aeruginosa isolates without any evidence of plasmid carriage is probably associated with a transposon.

Topics: beta-Lactamases; Disease Outbreaks; Electrophoresis, Gel, Pulsed-Field; Genotype; Humans; Intensive Care Units; Phenotype; Promoter Regions, Genetic; Pseudomonas aeruginosa; Pseudomonas Infections

Topics: Austria; Bacterial Proteins; beta-Lactam Resistance; beta-Lactamases; beta-Lactams; Humans; Microbial Sensitivity Tests; Molecular Sequence Data; Pseudomonas aeruginosa; Pseudomonas Infections; Sequence Analysis, DNA

A retrospective survey was conducted to characterize beta-lactamases in a collection of 43 ceftazidime-resistant Pseudomonas aeruginosa isolates recovered from patients with bloodstream infections hospitalized at a Brazilian teaching hospital between January and December 2005. Resistance rates for carbapenems, aminoglycosides, and quinolones were over 80%, with only colistin remaining active against all isolates. Pulsed-field gel electrophoresis analysis identified seven different genotypes. AmpC overproduction was found to be the sole beta-lactamase-mediated mechanism responsible for ceftazidime resistance in four isolates (9.3%). Nine isolates (20.9%) produced an extended-spectrum beta-lactamase (ESBL), either GES-1 (n = 7, 16.3%) or CTX-M-2 (n = 2, 4.6%). Carbapenemase activity was detected in 30 (70%) additional isolates. Among those isolates, two isolates (4.6%) produced the ESBL GES-5, possessing the ability to hydrolyze imipenem; a single isolate (2.3%) produced the metallo-beta-lactamase (MBL) IMP-1; and 27 isolates produced the MBL SPM-1 (62.8%). None of the isolates coproduced both ESBL and MBL. Insertion sequence elements ISCR4 and ISCR1 were associated with bla(SPM-1) and bla(CTX-M-2) genes, respectively, whereas the bla(GES-1) and bla(GES-5) genes were part of class 1 integron structures. This study underlines the spread of MBL- and ESBL-producing P. aeruginosa isolates as an important source of ceftazidime resistance in Brazil.

Topics: Aminoglycosides; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Brazil; Carbapenems; Ceftazidime; Drug Resistance, Multiple, Bacterial; Electrophoresis, Gel, Pulsed-Field; Humans; Pseudomonas aeruginosa; Pseudomonas Infections; Quinolones

Two clonally related Pseudomonas aeruginosa isolates, recovered from two patients admitted to a pediatric intensive care unit, were found to harbor a new OXA-2 variant (Asn148Asp), designated OXA-161. The plasmid location of bla(OXA-161) was demonstrated through electroporation to PAO1, and its codification in a class I integron (together with aacA4) was demonstrated through PCR and sequencing. bla(OXA-2) and bla(OXA-161) were cloned in parallel to demonstrate the extended-spectrum beta-lactamase properties of OXA-161, conferring resistance to ceftazidime and reduced susceptibility to cefepime and aztreonam.

Topics: Amikacin; Aminoglycosides; Anti-Bacterial Agents; beta-Lactamases; Cefepime; Cephalosporins; Clavulanic Acid; Gentamicins; Humans; Imipenem; Integrons; Meropenem; Molecular Sequence Data; Penicillanic Acid; Piperacillin; Plasmids; Pseudomonas aeruginosa; Pseudomonas Infections; Spain; Tazobactam; Thienamycins

Doripenem is a new carbapenem antimicrobial with activity against a range of gram-negative organisms, including Pseudomonas aeruginosa. Previous animal studies have shown efficacy of a 500-mg dose of doripenem given as a 4-h infusion against P. aeruginosa with MICs of < or = 4 microg/ml. The purpose of this study is to evaluate the efficacy of 1- and 2-g-dose prolonged infusions of doripenem against a wide range of P. aeruginosa isolates in the neutropenic murine thigh model. Eighteen clinical P. aeruginosa isolates (MIC range, 2 to 32 microg/ml) were used; 15 of these were multidrug resistant. After infection, groups of mice were administered doripenem doses designed to simulate the free time above the MIC (fT>MIC) observed in humans given 1 or 2 g of doripenem every 8 h as a 4-h infusion. Efficacy correlated well with published fT>MIC bactericidal targets of 40%. After 24 h, 1- and 2-g doses achieved approximately > or = 2 log decreases in CFU against isolates with MICs of < or = 8 and 16 microg/ml, respectively (fT>MIC range, 52.5 to 95%). Results with organisms with higher MICs, where fT>MIC was 0%, were variable, including both increases and decreases in CFU. Compared with 1-g doses, statistically greater efficacy was noted for 2-g doses against three of the eight isolates with MICs of > or =16 microg/ml. While MIC distributions of P. aeruginosa at present necessitate increased exposures for only the most-resistant isolates, the ability of increased doses to achieve pharmacodynamic targets and the efficacy observed when these targets were attained could prove useful when these resistant isolates are encountered.

Topics: Animals; Anti-Bacterial Agents; Carbapenems; Doripenem; Drug Administration Schedule; Female; Humans; Mice; Pseudomonas aeruginosa; Pseudomonas Infections

Pseudomonas aeruginosa isolates containing the bla(IMP-6) gene were recovered from 5 patients hospitalized at a tertiary-care hospital in Korea. The bla(IMP-6) gene was in a class 1 integron containing 5 different insert gene cassettes. All of the isolates showed identical pattern in SpeI macrorestriction analysis.

Topics: Aged; Bacterial Proteins; beta-Lactamases; Chromosome Mapping; Disease Outbreaks; Drug Resistance, Bacterial; Hospitals; Humans; Korea; Male; Meropenem; Microbial Sensitivity Tests; Molecular Epidemiology; Polymerase Chain Reaction; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

To determine the associations between the source of infection and antibiotic resistance in patients with Pseudomonas aeruginosa bacteremia.. A retrospective analysis of 50 patients with Pseudomonas aeruginosa bacteremia was carried out. If sepsis was suspected, blood culture was incubated in an automatic system BACTEC 9240. Then bacteria were identified, and their antibiotic resistance was estimated by disc diffusion method. If Pseudomonas aeruginosa strains were resistant to three or more antibiotics, they were considered as multidrug-resistant.. The origin of bacteremia was confirmed in 33 (66%) patients. Lower respiratory tract was the predominant source of Pseudomonas aeruginosa bacteremia (81.8%, n=27) as compared with infection of wound (39.4%, n=13), urinary tract (15.2%, n=5), and drain or cerebrospinal fluid (9.1%, n=3) (P<0.05). Eighteen percent (n=9) of strains, which caused bacteremia, were resistant to ceftazidime; 38% (n=19), to piperacillin; 22% (n=11), to imipenem; 26% (n=13), to meropenem; 24% (n=12), to ciprofloxacin; 40% (n=20), to gentamicin; and only 8% (n=4), to amikacin. Multidrug-resistant Pseudomonas aeruginosa strains were more frequently isolated if a source of infection was wound comparing to a source of other localization (61.5%, n=8 and 20.0%, n=4, respectively; P<0.05). Resistance of Pseudomonas aeruginosa strains to imipenem was associated with resistance to ciprofloxacin (13.2%, n=5 and 50.0%, n=6, retrospectively; P<0.05), but resistance to meropenem--both to ciprofloxacin and amikacin.. The predominant source of Pseudomonas aeruginosa bacteremia was lower respiratory tract, and multidrug-resistant strains caused bacteremia more frequently if a source infection was wound. Pseudomonas aeruginosa resistance to carbapenems was associated with resistance to ciprofloxacin and resistance to meropenem--also to amikacin. Resistance of strains to ceftazidime and piperacillin was associated with resistance to gentamicin.

Topics: Amikacin; Anti-Bacterial Agents; Bacteremia; Bacteriological Techniques; Ceftazidime; Ciprofloxacin; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Gentamicins; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Piperacillin; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Tract Infections; Retrospective Studies; Thienamycins; Wound Infection

The aim of cystic fibrosis (CF) care is to improve both the life expectancy and quality of life of patients. However, rising costs and limited resources of health services must be taken into account. There are many different antibiotic strategies for therapy of Pseudomonas aeruginosa infection in CF patients. In this 5-year retrospective study we found that the cost of treatment of initial infection is considerably lower than the cost of treating chronic P. aeruginosa infections. The percentage distribution of costs of antibiotic treatment in relationship to the administration route was considerably different between outpatients and inpatients. We observed an increase in antibiotic costs with the age of the patient and the decrease in FEV(1)values. The implementation of early eradication treatment, in addition to decreasing the prevalence of patients chronically infected by P. aeruginosa, might also bring about a notable decrease in costs.

Topics: Adult; Anti-Bacterial Agents; Ceftazidime; Child, Preschool; Chronic Disease; Ciprofloxacin; Clavulanic Acids; Colistin; Cost of Illness; Cystic Fibrosis; Humans; Meropenem; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies; Thienamycins; Ticarcillin; Tobramycin

To determine risk factors and outcomes for patients with meropenem high-level-resistant Pseudomonas aeruginosa (MRPA) (minimum inhibitory concentration [MIC] > or = 32 microg/mL).. Case-control-control.. An 867-bed urban, teaching hospital.. Fifty-eight MRPA case patients identified from an earlier P. aeruginosa study; 125 randomly selected control patients with meropenem-susceptible P. aeruginosa (MSPA) (MIC < or = 4 microg/mL), and 57 control patients without P. aeruginosa (sampled by case date/location).. Patient data, outcomes, and costs were obtained via administrative database. Cases were compared to each control group while controlling for time at risk (days between admission and culture, or entire length of stay [LOS] for patients without P. aeruginosa).. A multivariable model predicted risks for MRPA versus MSPA (odds ratio [95% confidence interval]): more admissions (in the prior 12 months) (1.41 [1.15, 1.74]), congestive heart failure (2.19 [1.03, 4.68]), and Foley catheter (2.53 [1.18, 5.45]) (adj. R(2) = 0.28). For MRPA versus no P. aeruginosa, risks were age (in 5-year increments) (1.17 [1.03, 1.33]), more prior admissions (1.40 [1.08, 1.81]), and more days in the intensive care unit (1.10 [1.03, 1.18]) (adj. R(2) = 0.32). Other invasive devices (including mechanical ventilation) and previous antibiotic use (including carbapenems) were nonsignificant. MRPA mortality (31%) did not differ from that of MSPA (15%) when adjusted for time at risk (P = .15) but did from mortality without P. aeruginosa (9%) (P = .01). Median LOS and costs were greater for MRPA patients versus MSPA patients and patients without P. aeruginosa: 30 days versus 16 and 10 (P<.01) and $88,425 versus $28,620 and $22,605 (P<.01).. Although antibiotic use has been shown to promote resistance, our data found that prior antibiotic use was not associated with MRPA acquisition. However, admission frequency and Foley catheters were, suggesting that infection control measures are essential to reducing MRPA transmission.

Topics: Adolescent; Age Factors; Anti-Bacterial Agents; Case-Control Studies; Catheterization; Child; Cross Infection; Drug Resistance, Bacterial; Female; Health Care Costs; Hospitalization; Hospitals, Teaching; Hospitals, Urban; Humans; Length of Stay; Male; Meropenem; Microbial Sensitivity Tests; Multivariate Analysis; Odds Ratio; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies; Risk Factors; Thienamycins; Treatment Outcome; Young Adult

Doripenem is a carbapenem antibiotic that covers a wide range of gram-positive and gram-negative pathogens. In vitro studies have provided insight into certain features of doripenem's activity profile that may have particular relevance in the clinical setting. For instance, in vitro data indicate that doripenem combines the intrinsic activity of meropenem against gram-negative pathogens with the intrinsic activity of imipenem against gram-positive pathogens. Also notable is the fact that the in vitro activity of doripenem against problematic gram-negative pathogens, in particular Pseudomonas aeruginosa, is potent-recent data show that the minimum concentration necessary for inhibition of 90% of all isolates (MIC(90)) of doripenem with respect to P. aeruginosa (4 microg/mL) is 2-4 times lower than the corresponding MIC(90) values of meropenem and imipenem. Furthermore, doripenem shows a limited ability to select for carbapenem-resistant mutants in vitro. Such experimental findings suggest that doripenem may represent a valuable option when carbapenem therapy is warranted for the treatment of serious infection.

Topics: Anti-Bacterial Agents; Carbapenems; Culture Media; Doripenem; Drug Therapy, Combination; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

We have previously demonstrated Pseudomonas aeruginosa resistance selection because of suboptimal carbapenem exposures in an in vitro infection model, but the in vivo relevance of the observations is not well established. In this study, we examined the impact of carbapenem exposures on resistance selection using a neutropenic murine pneumonia model. Neutropenic mice were infected with approximately 10(6) CFU of P. aeruginosa intratracheally. Ten animals each were treated with 400 or 50 mg/kg of meropenem intraperitoneally or placebo every 8 h, given 2 h after infection for 2 to 4 days. Quantitative assessment of bacterial burden in lung tissues was performed at baseline, upon death, or at the end of experiment. Meropenem (400 mg/kg) offered a significant survival benefit, but selective amplification of the OprD(-) mutant population in lung tissue was observed in 20% to 30% of the animals. Our data suggested that suboptimal meropenem exposures might facilitate in vivo selection of resistance in a heterogeneous P. aeruginosa population.

Topics: Animals; Anti-Bacterial Agents; beta-Lactam Resistance; Colony Count, Microbial; Female; Lung; Meropenem; Mice; Pseudomonas aeruginosa; Pseudomonas Infections; Selection, Genetic; Survival Analysis; Thienamycins

Optimal use of carbapenems is an important issue in the prevention of resistance in Pseudomonas aeruginosa. In this study, we investigated the correlation between antimicrobial use density (AUD) of carbapenems and imipenem/cilastatin (IPM/CS) or meropenem (MEPM) susceptibility of P. aeruginosa strains. The AUD of five carbapenems [IPM/CS, panipenem/betamipron, biapenem, MEPM and doripenem (DRPM)] was examined every 6 months between 2006 and 2008. The AUD was calculated using the defined daily doses methodology developed by the World Health Organisation. A minimum inhibitory concentration of IPM/CS or MEPM of < or =4 mg/L was considered to be sensitive. There was a significant negative correlation between MEPM susceptibility and the total AUD of MEPM and DRPM [r=-0.823, 95% confidence interval (CI) -0.035 to -0.980; P=0.044]. Furthermore, there was a significant correlation between MEPM susceptibility and IPM/CS susceptibility (r=0.839, 95% CI 0.084 to 0.981; P=0.037). Cross-resistance was therefore investigated and only 5.6% of MEPM-insensitive strains were susceptible to IPM/CS, although 43.3% of IPM/CS-insensitive strains were susceptible to MEPM. These results suggest that curtailing the use of MEPM and DRPM may curb the emergence not only of MEPM-resistant strains but also IPM/CS-resistant strains.

Topics: Anti-Bacterial Agents; beta-Lactam Resistance; Carbapenems; Doripenem; Drug Utilization; Humans; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Statistics as Topic; Thienamycins

Genetic structures surrounding the carbapenem-hydrolyzing Ambler class A bla KPC gene were characterized in several KPC-positive Klebsiella pneumoniae and Pseudomonas aeruginosa strains isolated from the United States, Colombia, and Greece. The bla KPC genes were associated in all cases with transposon-related structures. In the K. pneumoniae YC isolate from the United States, the beta-lactamase bla KPC-2 gene was located on a novel Tn3-based transposon, Tn4401. Tn4401 was 10 kb in size, was delimited by two 39-bp imperfect inverted repeat sequences, and harbored, in addition to the beta-lactamase bla KPC-2 gene, a transposase gene, a resolvase gene, and two novel insertion sequences, ISKpn6 and ISKpn7. Tn4401 has been identified in all isolates. However, two isoforms of this transposon were found: Tn4401a was found in K. pneumoniae YC and K. pneumoniae GR from the United States and Greece, respectively, and differed by a 100-bp deletion, located just upstream of the bla KPC-2 gene, compared to the sequence of Tn4401b, which was found in the Colombian isolates. In all isolates tested, Tn4401 was flanked by a 5-bp target site duplication, the signature of a recent transposition event, and was inserted in different open reading frames located on plasmids that varied in size and nature. Tn4401 is likely at the origin of carbapenem-hydrolyzing beta-lactamase KPC mobilization to plasmids and its further insertion into various-sized plasmids identified in nonclonally related K. pneumoniae and P. aeruginosa isolates.

Topics: Base Sequence; beta-Lactamases; beta-Lactams; Cloning, Molecular; Colombia; DNA Transposable Elements; Greece; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Molecular Sequence Data; Pseudomonas aeruginosa; Pseudomonas Infections; Sequence Analysis, DNA; United States

A detailed biochemical characterization of the Pseudomonas aeruginosa VIM-11 metallo-beta-lactamase (MbetaL) is reported. The only substitution differentiating VIM-11 from VIM-2 (N165S) promoted a slightly improved catalytic efficiency of the former on 3 out of 12 substrates, notably the bulky cephalosporins. Thus, MbetaL-mediated resistance also may be modulated by remote mutations.

Topics: beta-Lactam Resistance; beta-Lactamases; beta-Lactams; Binding Sites; Escherichia coli; Humans; Kinetics; Microbial Sensitivity Tests; Models, Molecular; Plasmids; Pseudomonas aeruginosa; Pseudomonas Infections

During 2003, 40 carbapenem-resistant Pseudomonas aeruginosa clinical isolates collected in a Mexican tertiary-care hospital were screened for metallo-beta-lactamase production. Thirteen isolates produced IMP-15, and 12 had a single pulsed-field gel electrophoresis pattern. The bla(IMP-15) gene cassette was inserted in a plasmid-borne integron with a unique array of gene cassettes and was named In95.

Topics: Bacterial Proteins; beta-Lactamases; Cross Infection; Electrophoresis, Gel, Pulsed-Field; Humans; Integrons; Mexico; Models, Genetic; Molecular Sequence Data; Pseudomonas aeruginosa; Pseudomonas Infections

During a survey conducted to evaluate the incidence of class B carbapenemase (metallo-beta-lactamase [MBL])-producing Pseudomonas aeruginosa strains from hospitals in Majorca, Spain, five clinical isolates showed a positive Etest MBL screening test result. In one of them, strain PA-SL2, the presence of a new bla(VIM) derivative (bla(VIM-13)) was detected by PCR amplification with bla(VIM-1)-specific primers followed by sequencing. The bla(VIM-13)-producing isolate showed resistance to all beta-lactams (except aztreonam), gentamicin, tobramycin, and ciprofloxacin. VIM-13 exhibited 93% and 88% amino acid sequence identities with VIM-1 and VIM-2, respectively. bla(VIM-13) was cloned in parallel with bla(VIM-1), and the resistance profile conferred was analyzed both in Escherichia coli and in P. aeruginosa backgrounds. Compared to VIM-1, VIM-13 conferred slightly higher levels of resistance to piperacillin and lower levels of resistance to ceftazidime and cefepime. VIM-13 and VIM-1 were purified in parallel as well, and their kinetic parameters were compared. The k(cat)/K(m) ratios for the antibiotics mentioned above were in good agreement with the MIC data. Furthermore, EDTA inhibited the activity of VIM-13 approximately 25 times less than it inhibited the activity of VIM-1. VIM-13 was harbored in a class 1 integron, along with a new variant (Ala108Thr) of the aminoglycoside-modifying enzyme encoding gene aacA4, which confers resistance to gentamicin and tobramycin. Finally, the VIM-13 integron was apparently located in the chromosome, since transformation and conjugation experiments consistently yielded negative results and the bla(VIM-13) probe hybridized only with the genomic DNA.

Topics: Amino Acid Sequence; Anti-Bacterial Agents; Bacterial Proteins; Base Sequence; beta-Lactam Resistance; beta-Lactamases; Cloning, Molecular; DNA Primers; DNA, Bacterial; Genes, Bacterial; Genetic Variation; Humans; Imipenem; Integrons; Kinetics; Meropenem; Molecular Sequence Data; Phylogeny; Pseudomonas aeruginosa; Pseudomonas Infections; Recombinant Proteins; Sequence Homology, Amino Acid; Spain; Thienamycins

The mutation frequency for carbapenem resistance in Pseudomonas aeruginosa strains that were selected with carbapenems was enhanced in the presence of subinhibitory concentrations of fluoroquinolones. The mutants showed either a loss of OprD activity or increased mexAB-oprM expression. The highest mutant isolation frequency was obtained by selection with meropenem, while doripenem inhibited mutant growth.

Topics: Base Sequence; beta-Lactam Resistance; Carbapenems; DNA Primers; DNA, Bacterial; Doripenem; Fluoroquinolones; Genes, Bacterial; Humans; In Vitro Techniques; Meropenem; Mutation; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

Tomopenem (CS-023) is a novel parenteral carbapenem with broad-spectrum activity against Gram-positive and -negative bacteria, as well as potent activity against drug-resistant pathogens, including penicillin-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa. We compared the in vivo activity of tomopenem and that of meropenem in a chronic lower respiratory infection mouse model of P. aeruginosa.. Mice with chronic airway infection by P. aeruginosa were treated with saline (as the control, twice daily), tomopenem (100 mg/kg, twice daily) or meropenem (100 mg/kg, twice daily) for 7 days. After treatment, the number of viable bacteria in lungs and histopathological findings were analysed. The pharmacokinetics of tomopenem and meropenem were also analysed after initial treatment.. The number of viable bacteria in lungs treated with saline, tomopenem or meropenem was 4.21 +/- 1.28, 2.91 +/- 0.87 and 3.01 +/- 1.00 log(10) cfu/lung (mean +/- SEM), respectively (P < 0.05, control versus tomopenem- or meropenem-treated groups). In the histopathological examination of lung specimens, the control group had the features of chronic bronchial infection; however, tomopenem- and meropenem-treated groups had fewer inflammatory cells compared with the control group. The pharmacokinetic parameter of % time above MIC for tomopenem and meropenem was 16% and 17% in sera and 15% and 18% in lungs, respectively.. Tomopenem significantly reduced the number of viable bacteria in a murine model of chronic airway infection by P. aeruginosa, compared with the control. Considering the longer half-life of tomopenem in humans compared with most other carbapenems, tomopenem treatment of chronic airway infection with P. aeruginosa is expected to be efficacious.

Topics: Animals; Anti-Bacterial Agents; Carbapenems; Colony Count, Microbial; Humans; Lung; Male; Meropenem; Mice; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Tract Infections; Serum; Thienamycins

The main mechanism of imipenem resistance in Pseudomonas aeruginosa is via downregulation of the gene for OprD porin. In a previous study, it was shown that the level of resistance did not parallel with the degree of downregulation of the porin gene, thus arguing for the existence of other resistance mechanisms. Penicillin-binding protein (PBP) 2 and PBP3 are involved in carbapenem resistance in Escherichia coli. The genes for PBPs were sequenced in three imipenem-resistant clinical strains and these strains were conjugated with two susceptible P. aeruginosa PA0 strains, selecting for auxotrophic markers. In all the clinical and resistant isolates there was no obvious elevation of AmpC cephalosporinase. The active sites of PBP1b (ponB), PBP2 (pbpA), PBP3 (pbpB) and PBP6 (dacC) had no mutations in any of the examined strains. Production of oprD mRNA was significantly lower in clinical strains and transconjugants after selection for the proB marker (PA4565 at 5113kb). The clinical strains had alterations in OprD that were not found in transconjugants. Our findings suggest that PBPs do not play a role in imipenem resistance in the clinical strains examined here, but that a regulatory gene for oprD contributing to carbapenem resistance is located close to the proB gene.

Topics: Anti-Bacterial Agents; DNA Mutational Analysis; DNA, Bacterial; Down-Regulation; Drug Resistance, Bacterial; Gene Expression Regulation, Bacterial; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Penicillin-Binding Proteins; Porins; Pseudomonas aeruginosa; Pseudomonas Infections; RNA, Bacterial; RNA, Messenger; Sequence Analysis, DNA; Thienamycins

Despite the increasing prevalence of multiple-drug-resistant (MDR) Pseudomonas aeruginosa, the factors predictive of MDR have not been extensively explored. We sought to examine factors predictive of MDR among patients with P. aeruginosa respiratory tract infections and to develop a tool to estimate the probability of MDR among such high-risk patients. This was a single-site, case-control study of patients with P. aeruginosa respiratory tract infections. Multiple-drug resistance was defined as resistance to four or more antipseudomonal antimicrobial classes. Clinical data on demographics, antibiotic history, and microbiology were collected. Classification and regression tree analysis (CART) was used to identify the duration of antibiotic exposure associated with MDR P. aeruginosa. Log-binomial regression was used to model the probability of MDR P. aeruginosa. Among 351 P. aeruginosa-infected patients, the proportion of MDR P. aeruginosa was 35%. A significant relationship between prior antibiotic exposure and MDR P. aeruginosa was found for all of the antipseudomonal antibiotics studied, but the duration of prior exposure associated with MDR varied between antibiotic classes; the shortest prior exposure duration was observed for carbapenems and fluoroquinolones, and the longest duration was noted for cefepime and piperacillin-tazobactam. Within the final model, the predicted MDR P. aeruginosa likelihood was most dependent upon length of hospital stay, prior culture sample collection, and number of CART-derived prior antibiotic exposures. A history of a prolonged hospital stay and exposure to antipseudomonal antibiotics predicts multidrug resistance among patients with P. aeruginosa respiratory tract infections at our institution. Identifying these risk factors enabled us to develop a prediction tool to assess the risk of resistance and thus guide empirical antibiotic therapy.

Topics: Adult; Anti-Bacterial Agents; Case-Control Studies; Drug Resistance, Multiple, Bacterial; Female; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Predictive Value of Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Tract Infections; Retrospective Studies; Risk; Risk Factors

Serious infections with Pseudomonas aeruginosa are frequently treated with the combination of a beta-lactam antimicrobial and an aminoglycoside. P. aeruginosa strain PA0905 was isolated in 2005 from an inpatient in Brazil. It showed a panresistant phenotype that included resistance to beta-lactams, aminoglycosides, and fluoroquinolones. The beta-lactam resistance was conferred by the production of the metallo-beta-lactamase SPM-1. No inhibitory zone was observed when a disk diffusion test was performed with the semisynthetic aminoglycoside arbekacin, raising suspicion of 16S rRNA methylase production. A cloning experiment subsequently revealed the presence of a novel 16S rRNA methylase, RmtD, which accounted for the high-level resistance to all 4,6-disubstituted deoxystreptamine aminoglycosides, such as amikacin, tobramycin, and gentamicin. RmtD shared a moderate degree of identity with RmtA, another 16S rRNA methylase that was initially reported to occur in P. aeruginosa in Japan in 2003. This is the first identification of aminoglycoside resistance mediated by a 16S rRNA methylase in South America. This is also the first report to document coproduction of a metallo-beta-lactamase and a 16S rRNA methylase, a combination that would severely compromise therapeutic options for the infected patients.

Topics: Amino Acid Sequence; Aminoglycosides; beta-Lactamases; Brazil; Carbapenems; Cloning, Molecular; Drug Resistance, Multiple, Bacterial; Methyltransferases; Microbial Sensitivity Tests; Molecular Sequence Data; Plasmids; Pseudomonas aeruginosa; Pseudomonas Infections

Intubated patients frequently become colonized by Pseudomonas aeruginosa, which is subsequently responsible for ventilator-associated pneumonia. This pathogen readily acquires resistance against available antimicrobials. Depending on the resistance mechanism selected for, resistance might either be lost or persist after removal of the selective pressure. We investigated the rapidity of selection, as well as the persistence, of antimicrobial resistance and determined the underlying mechanisms. We selected 109 prospectively collected P. aeruginosa tracheal isolates from two patients based on their prolonged intubation and colonization periods, during which they had received carbapenem, fluoroquinolone (FQ), or combined beta-lactam-aminoglycoside therapies. We determined antimicrobial resistance phenotypes by susceptibility testing and used quantitative real-time PCR to measure the expression of resistance determinants. Within 10 days after the initiation of therapy, all treatment regimens selected resistant isolates. Resistance to beta-lactam and FQ was correlated with ampC and mexC gene expression levels, respectively, whereas imipenem resistance was attributable to decreased oprD expression. Combined beta-lactam-aminoglycoside resistance was associated with the appearance of small-colony variants. Imipenem and FQ resistance persisted for prolonged times once the selecting antimicrobial treatment had been discontinued. In contrast, resistance to beta-lactams disappeared rapidly after removal of the selective pressure, to reappear promptly upon renewed exposure. Our results suggest that resistant P. aeruginosa is selected in less than 10 days independently of the antimicrobial class. Different resistance mechanisms lead to the loss or persistence of resistance after the removal of the selecting agent. Even if resistant isolates are not evident upon culture, they may persist in the lung and can be rapidly reselected.

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Drug Resistance, Bacterial; Humans; Longitudinal Studies; Pneumonia, Ventilator-Associated; Polymerase Chain Reaction; Pseudomonas aeruginosa; Pseudomonas Infections

To determine the epidemiology and risk factors for carbapenem-resistant Pseudomonas aeruginosa (CR-PA) digestive tract colonization, weekly rectal and pharyngeal swabs were obtained in two serial incidence surveys (266 patients). Forty-two (16%) patients were CR-PA colonized (12 [29%] on admission and 30 [71%] in intensive care units). Pulsed-field gel electrophoresis showed extensive clonal diversity, although one specific clone (type B) was isolated from 11 patients. The presence of similar genotypes of CR-PA colonizing 30% of the CR-PA-colonized patients suggests the occurrence of cross-colonization; in addition, 10 pairs of carbapenem-susceptible P. aeruginosa (CS-PA) and subsequent CR-PA strains isolated from the same patients were found to be clonally identical and were considered to have been endogenously acquired (33%). All endogenously acquired CR-PA strains were isolated after exposure to a carbapenem, and 80% showed a phenotype of imipenem resistance (IR pattern) alone, while 67% of the CR-PA strains acquired by cross-transmission exhibited a multiresistant (MR) phenotype, with previous carbapenem exposure in 44%. Logistic regression analysis identified severity of acute illness (odds ratio [OR], 1.0; 95% confidence interval [CI], 1.0 to 1.1), prior carbapenem use (OR, 7.8; 95% CI, 1.7 to 35.3), and prior use of fluoroquinolones (OR, 11.0; 95% CI, 1.7 to 67.9) as independent risk factors for CR-PA digestive tract colonization. Overall, the local epidemiology of CR-PA digestive tract colonization was characterized by polyclonal endemicity with phenotype patterns of IR and MR divided evenly between patients. Restricting the use of particular agents, such as carbapenems and fluoroquinolones, should be considered advisable to minimize the problem of this antibiotic resistance. However, the possible risk for development of collateral unexpected bacterial resistance patterns should be accurately monitored.

Topics: Adult; Aged; Anti-Bacterial Agents; beta-Lactam Resistance; Carbapenems; Carrier State; Critical Illness; Endemic Diseases; Female; Gastrointestinal Tract; Humans; Imipenem; Incidence; Intensive Care Units; Male; Middle Aged; Pharynx; Pseudomonas aeruginosa; Pseudomonas Infections; Rectum; Risk Factors

We studied the mechanisms and dynamics of the development of resistance to ceftazidime (CAZ) alone or combined with tobramycin (TOB) or ciprofloxacin (CIP) in vitro and in vivo (using a mouse model of lung infection with human antibiotic regimens). Pseudomonas aeruginosa strain PAO1 and its hypermutable derivative PAODeltamutS were used, and the results were compared with those previously obtained with CIP, TOB, and CIP plus TOB (CIP-TOB) under the same conditions. An important (200-fold) amplification of the number of resistant mutant cells was documented for PAODeltamutS-infected mice that were under CAZ treatment compared to the number for mice that received placebo, whereas the median number of resistant mutant cells was below the detection limits for mice infected by PAO1. These results were intermediate between the high amplification with CIP (50,000-fold) and the low amplification with TOB (10-fold). All CAZ-resistant single mutant cells selected in vitro or in vivo hyperproduced AmpC. On the other hand, the three combinations studied were found to be highly effective in the prevention of in vivo resistance development in mice infected with PAODeltamutS, although the highest therapeutic efficacy (in terms of mortality and total bacterial load reduction) compared to those of the individual regimens was obtained with CIP-TOB and the lowest was with CAZ-CIP. Nevertheless, mutant cells that were resistant to the three combinations tested were readily selected in vitro for PAODeltamutS (mutation rates from 1.2 x 10(-9) to 5.8 x 10(-11)) but not for PAO1, highlighting the potential risk for antimicrobial resistance development associated with the presence of hypermutable strains, even when combined therapy was used. All five independent CAZ-TOB-resistant PAODeltamutS double mutants studied presented the same resistance mechanism (AmpC hyperproduction plus an aminoglycoside resistance mechanism not related to MexXY), whereas four different combinations of resistance mechanisms were documented for the five CAZ-CIP-resistant double mutants.

Topics: Animals; Anti-Bacterial Agents; Ceftazidime; Ciprofloxacin; Disease Models, Animal; Drug Resistance, Microbial; Drug Synergism; Drug Therapy, Combination; Female; Humans; In Vitro Techniques; Lung; Mice; Mice, Inbred C57BL; Microbial Sensitivity Tests; Mutation; Pseudomonas aeruginosa; Pseudomonas Infections; Tobramycin

Topics: Anti-Bacterial Agents; Carbapenems; DNA Transposable Elements; DNA, Bacterial; Drug Resistance, Bacterial; Gene Dosage; Humans; Imipenem; Meropenem; Porins; Pseudomonas aeruginosa; Pseudomonas Infections; Reverse Transcriptase Polymerase Chain Reaction; Thienamycins

To identify the optimal pharmacodynamic exposures of meropenem, imipenem, and cefepime, and the emergence of resistance in vivo for Pseudomonas aeruginosa overexpressing MexA-MexB-OprM efflux pumps, we used the murine thigh model. Mice were challenged with P. aeruginosa isolates: PAO1 (K767 wild type), K767+ (MexA-MexB-OprM efflux mutant), and DeltaK767 (knockout strain). Efficacy (Delta log colony-forming unit [CFU]) was determined at various exposures of %T > MIC at both standard (10(5) CFU/thigh) and high (10(7) CFU/thigh) inoculums. At 10(5) CFU/thigh, meropenem and imipenem produced a maximal activity against PAO1 (-2.82, -1.88) and K767+ (-2.24, -2.68) at 40%T > MIC; cefepime at 70%T > MIC produced a comparable kill (-2.74 and -2.19, respectively). Similar magnitudes of kill were observed at the 10(7) inocula. Except for DeltaK767 with cefepime, no development of resistance emerged at various %T > MIC. All agents exhibited reduced activity against DeltaK767. DeltaK767 cefepime-resistant strains were isolated up to 100%T > MIC. The overexpression of MexA-MexB-OprM efflux pumps did not result in the loss of efficacy of the antibiotics tested regardless of the amount of bacterial inocula; however, their presence also did not lead to increased selection for resistance. The effects of efflux mechanisms on beta-lactam agents in vivo warrant further research.

Topics: Animals; Anti-Bacterial Agents; Bacterial Outer Membrane Proteins; Cefepime; Cephalosporins; Drug Resistance, Multiple, Bacterial; Female; Imipenem; Membrane Transport Proteins; Meropenem; Mice; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Specific Pathogen-Free Organisms; Thienamycins; Thigh; Treatment Outcome

Fourteen apparently carbapenem-susceptible Pseudomonas aeruginosa clinical isolates that exhibited colonies within the inhibition zone around carbapenem discs were analysed. MICs of carbapenems were determined and the isolates were genotyped by PFGE. Population analysis, one-step selection of carbapenem-resistant mutants and growth curves of progenitors and carbapenem-resistant subpopulations were performed. Agar dilution MICs of imipenem and meropenem ranged from 0.5 to 4 mg l(-1) and from 0.25 to 2 mg l(-1), respectively. Population analysis confirmed subpopulations that grew in concentrations of up to 18 mg l(-1) and 12 mg l(-1) of imipenem and meropenem, respectively, at frequencies ranging from 6.9 x 10(-5) to 1.1 x 10(-7), suggesting that they might not be detected by standard agar dilution MIC testing. The minority subpopulations exhibited MICs for imipenem ranging from 10 to 20 mg l(-1) and for meropenem from 4 to 14 mg l(-1). The one-step 8 mg l(-1) selection of imipenem-resistant mutants test showed growth in all isolates at frequencies ranging from 3.8 x 10(-4) to 5.1 x 10(-7). Growth curves revealed a prolonged lag phase and a short exponential phase for the heterogeneous subpopulations compared with their respective native subpopulations. These findings may be indicative that the use of carbapenems can lead to selection of P. aeruginosa resistant subpopulations that subsequently cause infections and result in treatment failure.

Topics: Anti-Bacterial Agents; Carbapenems; Dose-Response Relationship, Drug; Drug Resistance, Multiple, Bacterial; Genetic Heterogeneity; Genotype; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Microbial Viability; Mutation; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins; Time Factors

Isolates of Pseudomonas aeruginosa (n = 208) were collected from an 810-bed hospital in Connecticut, USA. A model employing the pharmacokinetic properties of meropenem, susceptibility results and Monte Carlo simulation was used to analyse four different dosing regimens of meropenem at pharmacodynamic endpoints. Cumulative fraction of response (CFR) was assessed at bacteriostatic and bactericidal endpoints for the entire population of isolates, as well as for isolates from principal anatomical sites. CFR was also evaluated at endpoints shown to suppress emergence of resistance in 'susceptible'P. aeruginosa with either monotherapy or combination therapy. The bacteriostatic/bactericidal CFR of meropenem 1 g every 8 h (q8h), 2 g q8h, 1 g q8h infused over 3 h (3-h INF), and 2 g q8h 3-h INF were 76%/73%, 80%/76%, 77%/75% and 79%/78%, respectively. At the monotherapeutic suppressive endpoint, CFRs against susceptible isolates were 21%, 35%, 32% and 50%, respectively. When combination therapy with an aminoglycoside was simulated, the CFRs for the same regimens were 50%, 64%, 65% and 79%, respectively. Bactericidal CFRs for all regimens against wound isolates were significantly higher (p <0.03 for each regimen) than CFRs for the entire population. Meropenem 2 g q8h with a 3-h infusion in combination with an aminoglycoside provides the greatest likelihood of P. aeruginosa coverage, and may help to prevent development of resistance, although local MIC data are essential to inform therapeutic decisions.

Topics: Aminoglycosides; Drug Resistance, Bacterial; Drug Therapy, Combination; Humans; Meropenem; Microbial Sensitivity Tests; Microbial Viability; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

Initial antibiotic treatment of severe infections can lead to clinical deterioration due to sudden endotoxin release and concomitant exaggerated inflammatory response. Antibiotic-induced morphological changes may contribute to this phenomenon. High-dose ceftazidime, which inhibits penicillin-binding protein (PBP)-1 in Gram-negative bacteria, causes quick bacteriolysis and low endotoxin release. Low-dose ceftazidime leads to PBP-3 inhibition, which causes bacterial filament formation, associated with high endotoxin releases. PBP-2-specific antibiotics induce spheroplasts, again associated with low endotoxin release. We hypothesized that antibiotic type, concentration and regimen influence bacterial morphology, endotoxin levels and inflammatory response.. Neutropenic mice with Escherichia coli or Pseudomonas aeruginosa sepsis were treated with ceftazidime or meropenem 10-320 mg/kg as an intravenous bolus or as continuous tail vein infusions of 0.1 mL/h. Four hours later, bacterial counts, morphology, plasma endotoxin, pro-inflammatory cytokines [tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6)] and antibiotic concentrations were measured.. Continuous infusion of 80 mg/kg ceftazidime was the lowest dose preventing filaments in E. coli infections. Bolus treatment resulted in filament formation, irrespective of the dose. During continuous treatment, IL-6 and TNF-alpha concentrations were higher compared with bolus treatment and controls for both antibiotics and both strains. A clear relationship between cfu counts in muscle and circulating IL-6 was shown (r=- 0.579, P=0.007), suggesting that plasma IL-6 is a valuable indicator of bacterial killing at the infection site.. Our findings show that not PBP affinity but the method of antibiotic administration is crucial during initial treatment of severe infections.

Topics: Animals; Anti-Bacterial Agents; Ceftazidime; Colony Count, Microbial; Cytokines; Endotoxins; Escherichia coli; Escherichia coli Infections; Female; Meropenem; Mice; Penicillin-Binding Proteins; Pseudomonas aeruginosa; Pseudomonas Infections; Sepsis; Thienamycins

Acinetobacter spp. and Pseudomonas aeruginosa are common pathogens of ventilator-associated pneumonia (VAP). The presentation and outcome of VAP due to Acinetobacter spp. and P. aeruginosa susceptible to carbapenems (Carb-S; imipenem and/or meropenem) and to colistin only (Col-S) were compared in the present retrospective study in three intensive care units. A total of 61 episodes of VAP caused by Acinetobacter spp. or P. aeruginosa were studied, of which 30 isolates were Carb-S and 31 were Col-S. Demographics, worsening of renal function and mortality were not different. The univariate analysis showed that a later onset and a previous episode of VAP, prior antimicrobial therapy for >10 days and previous therapy with carbapenems during the present admission were more frequent in patients with Col-S strains. On multivariate analysis, prior antimicrobial therapy for >10 days and a previous episode of VAP remained significantly associated with Col-S VAP. Approximately 41% of the infections caused by Col-S isolates, but none of those due to Carb-S isolates, had received prior carbapenem therapy. Colistin-susceptible ventilator-associated pneumonia episodes can be effectively treated using colistin without significant renal dysfunction. This susceptibility pattern could be suspected in patients with a previous ventilator-associated pneumonia episode or prior antibiotic therapy for >10 days preceding the present ventilator-associated pneumonia episode.

Topics: Acinetobacter Infections; Analysis of Variance; Anti-Bacterial Agents; Chi-Square Distribution; Colistin; Drug Resistance, Microbial; Female; Humans; Imipenem; Male; Meropenem; Middle Aged; Pneumonia; Pseudomonas aeruginosa; Pseudomonas Infections; Respiration, Artificial; Retrospective Studies; Risk Factors; Thienamycins; Ventilators, Mechanical

Risk factors, therapy and outcome of 15 cases of nosocomial meningitis due to Pseudomonas aeruginosa is reviewed. No difference in risk factors was found, however mortality for Ps. aeruginosa was significantly higher (33.3 vs 15.1% p<0.04).

Topics: Adolescent; Anti-Bacterial Agents; Cefotaxime; Ceftazidime; Chi-Square Distribution; Child, Preschool; Chloramphenicol; Cross Infection; Drug Therapy, Combination; Female; Gentamicins; Humans; Infant; Infant, Newborn; Male; Meningitis, Bacterial; Meropenem; Pseudomonas Infections; Retrospective Studies; Risk Factors; Survival Analysis; Thienamycins

Within last 15 years, analyzing patterns of etiology and resistance in organisms causing neuroinfections, emergence of resistance has been observed in Slovakia in S. haemolyticus to teicoplanin (11%), Ps. aeruginosa and A. baumannii to meropenem (20%) and Candida spp. (non-albicans Candida spp.) to fluconazol (20%). There are no new antibiotics against carbapenem resistant Ps. aeruginosa and Acinetobacter baumannii.

Topics: Anti-Infective Agents; Brain Diseases; Candidiasis; Cross Infection; Drug Resistance, Microbial; Fluconazole; Humans; Meningitis; Meropenem; Pseudomonas Infections; Staphylococcal Infections; Teicoplanin; Thienamycins

Patients with Waldenström's macroglobulinemia may manifest several types of skin lesions. We present our experience with a patient with the disease that adds to the literature on the topic.. A 57-year-old man with history of multiple sclerosis and Waldenström's macroglobulinemia was admitted to the intensive care unit in shock. His family members reported that the patient had complained of fever and the gradual development of gangrenous, hemorrhagic, bullous cellulitis lesions on the abdomen and lower extremities for 7 days prior to his admission to the hospital. Pseudomonas aeruginosa was isolated from fluid specimens collected from the cutaneous lesions. Appropriate antimicrobial treatment including continuous intravenous administration of meropenem (6 g every 24 h) led to the cure of the infection.. We postulate that the underlying Waldenström's macroglobulinemia contributed to the pathophysiology of the development of the rare skin manifestations of the infection observed in our patient.

Topics: Anti-Bacterial Agents; Cellulitis; Humans; Infusions, Intravenous; Male; Meropenem; Middle Aged; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins; Waldenstrom Macroglobulinemia

Strong data are lacking on the cross-reactivity between individual carbapenems. We describe a 48-year-old woman with ventilator-associated Pseudomonas aeruginosa pneumonia who received an 8-day course of imipenem-cilastatin and experienced a delayed (i.e., nonimmediate) hypersensitivity reaction, evidenced by an extensive erythematous macular morbilliform rash and an increased eosinophil count. Eight days after completion of therapy, the pneumonia returned, and it was decided to avoid using imipenem-cilastatin; she was administered a 14-day course of meropenem. To our knowledge, this is the first report of a nonimmediate hypersensitivity reaction to imipenem-cilastatin without cross-reactivity to meropenem. This suggests that if carbapenem therapy is unavoidable, meropenem may be cautiously administered in patients with a known allergy to imipenem-cilastatin.

Topics: Anti-Bacterial Agents; Cilastatin; Cilastatin, Imipenem Drug Combination; Cross Reactions; Drug Combinations; Drug Hypersensitivity; Female; Humans; Hypersensitivity, Delayed; Imipenem; Meropenem; Middle Aged; Pneumonia, Bacterial; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

The aim of this study was to determine the frequency of PER-1 type extended-spectrum beta-lactamase (ESBL) in nosocomial Pseudomonas aeruginosa strains isolated in Hacettepe University Adult Hospital. Sixty-seven non-duplicate P. aeruginosa isolates from patients with nosocomial infections between January 2002 and December 2004 were included in the study. The isolates were identified at species-level by Sceptor (Becton Dickinson, USA) system, and all the strains were stored at -80 degrees C until further testing. Polymerase chain reaction (PCR) was performed for the detection of (bla)PER-1 genes, and PFGE analysis was used to investigate their genetic relatedness. The antimicrobial susceptibilities of the PER-1 positive isolates were determined by Etest (AB Biodisk, Solna, Sweden) method. According to the results of PCR, 22.7% (15/67) of the isolates were positive for PER-1 enzyme. Those 15 (bla)PER-1 positive isolates showed eight different PFGE patterns, indicating the presence of multiple clones. Of the PER-1 positive P. aeruginosa isolates, nine were resistant to imipenem/meropenem, and 11 were resistant to piperacillin-tazobactam and tobramycin. The epidemiological investigation of multidrug resistant P. aeruginosa should give important clues for the initial empirical therapy, especially in certain geographic locations where ESBL-producing P. aeruginosa strains seemed to be highly prevalent.

Topics: Anti-Bacterial Agents; beta-Lactamases; Cross Infection; Drug Resistance, Multiple, Bacterial; Electrophoresis, Gel, Pulsed-Field; Humans; Imipenem; Meropenem; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Polymerase Chain Reaction; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins; Tobramycin

Mixed populations of Pseudomonas aeruginosa, comprising a carbapenem-susceptible and a carbapenem-resistant strain, containing either the IMP or VIM beta-lactamases, were exposed to imipenem. They developed resistance to both imipenem and meropenem. When the same mixed populations were exposed to meropenem, only the mixture containing the VIM beta-lactamases became resistant to both carbapenems.

Topics: Anti-Bacterial Agents; beta-Lactam Resistance; beta-Lactamases; Binding, Competitive; Carbapenems; Imipenem; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

We report a case of prostatic abscess in a 22-year-old man with metastatic testicular cancer being treated by BEP (bleomycin, etoposide and cisplatin) chemotherapy. This abscess was successfully treated by surgical drainage with transurethral resection of the prostate (TURP) under the guidance of transrectal ultrasound, allowing the patient to continue be receiving BEP without significant interruption. Drainage TURP is suggested to be a useful strategy for prostate abscess, when prompt control of symptoms caused by prostatic abscess is required.

Topics: Abscess; Adult; Anti-Bacterial Agents; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Brain Neoplasms; Ceftazidime; Cisplatin; Drainage; Etoposide; Humans; Immunocompromised Host; Lung Neoplasms; Male; Meropenem; Orchiectomy; Prostatic Diseases; Pseudomonas Infections; Testicular Neoplasms; Thienamycins; Transurethral Resection of Prostate

Multi drug resistant Pseudomonas aeruginosa (MDRPA) and pan drug resistant Pseudomonas aeruginosa (PDRPA) isolates in critically ill patients are often difficult to treat. Prevalence of MDRPA and their antibiotic profile was investigated to select an appropriate empirical therapy. Moreover lack of sufficient data on prevalence of PDRPA in tertiary care hospitals indicated the need for this study. Pseudomonas aeruginosa was isolated in 245 patients over a period of one and half years from various clinical materials and their antibiotic profile was determined. Minimum inhibitory concentration (MIC) for Imipenem and Meropenam was determined by broth dilution method. Phenotypic confirmation test and EDTA double disk synergy test was used to detect Extended spectrum a-lactamase (ESBL) and Metallo-a-lactamase (MBL) producers respectively. Out of 245 isolates, 54 strains (22 %) and 11 strains (4%) were found to be MDRPA and PDRPA respectively. Carbapenem resistant isolates showed MICs ranging from 16 to > 64 microg/ml. Thirty eight strains (15.5%) were ESBL producers and six (54.5%) among 11 PDRPA were MBL producers. Prevalence of MDR and PDR isolates of Pseudomonas aeruginosa was found to be 22% and 4% respectively, which is less compared to other studies. Majority of the PDRPA isolates were MBL producers which have propensity to spread to other bacteria.

Topics: Anti-Bacterial Agents; beta-Lactamases; Drug Resistance, Multiple, Bacterial; Hospitals; Humans; Imipenem; India; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

Recently, PK/PD (pharmacokinetics/pharmacodynamics) analysis for the antimicrobial dosage method became one of the popular categories in chemotherapy and infectious disease societies world wide. Carbapenems are often used for empiric therapy because of its broad-spectrum and activities against microorganisms. PK/PD analysis is well studied in some antibiotics including carbapenems and it is necessary also from the point of view of prevention for emergence of resistant strains. We report the result of the analysis for the effective dosage regimens of meropenem, biapenem and doripenem against Pseudomonas aeruginosa infection based on PK/PD theory with the MIC distributions against the strains isolated from the patients blood at Keio University in 2004 and 2006. The highest target attainment rate for the free drug 40% time above the MIC (40%T > or = MIC) in traditional infusion with the MIC distribution against P. aeruginosa isolated from the patients blood at Keio University Hospital in 2004 was as follows: 90.89% in 500 mg every 6 hours regimen for meropenem, 83.25% in 300 mg every 6 hours regimen for biapenem, 81.73% in 250 mg every 6 hours regimen for doripenem in the approved maximum daily dose for each agent. The highest target attainment rate for the free drug 40%T > or = MIC in prolonged infusion with the MIC distribution against P. aeruginosa isolated from the patients blood at Keio University Hospital in 2004 was as follows: 100% in 500 mg every 6 hours regimen for meropenem, 83.97% in 300 mg every 8 hours regimen for biapenem, 99.98% in 500 mg every 8 hours regimen for doripenem in the maximum daily dose for each agents. The highest target attainment rate for the free drug 40%T > or = MIC in traditional infusion with the MIC distribution against P. aeruginosa isolated from the patients blood at Keio University Hospital in 2006 was as follows: 80.57% in 500 mg dose in every 6 hours regimen for meropenem, 56.70% in 300 mg every 6 hours regimen for biapenem, 69.44% in 250 mg every 6 hours regimen for doripenem in the maximum daily dose for each agent. The highest target attainment rate for the free drug 40%T > or = MIC in prolonged infusion with the MIC distribution against P. aeruginosa isolated from the patients blood at Keio University Hospital in 2006 was as follows: 89.35% in 500 mg every 6 hours regimen for meropenem, 60.84% in 300 mg every 6 hours regimen for biapenem, 82.78% in 500 mg every 8 hours regimen for doripenem in the maximum daily d

Topics: Anti-Bacterial Agents; Carbapenems; Doripenem; Drug Administration Schedule; Drug Resistance, Bacterial; Humans; Infusions, Intravenous; Meropenem; Monte Carlo Method; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

The determination of synergistic effects of antimicrobial drug combinations can lead to improved therapeutic options in the antibiotic treatment of cystic fibrosis patients who are chronically infected with multiresistant Pseudomonas aeruginosa isolates. The aim of this study was to evaluate the performance of the E test versus the standard agar dilution checkerboard susceptibility test in the assessment of synergy and, in addition, to determine the activity of two antimicrobial combinations against 163 multiresistant P. aeruginosa isolates from cystic fibrosis patients. The agreement between the checkerboard method and the E test was excellent (>90%) for nonmucoid as well as mucoid isolates from cystic fibrosis patients. The rate of synergy was higher for the antibiotic combination of ceftazidime and tobramycin (28.8% of the cystic fibrosis strains) than for the combination of meropenem and tobramycin (19.0%). However, the probability of synergy for the second antibiotic combination increased significantly when the synergy of the first antibiotic combination had already been demonstrated (Fischer's exact test, p=0.049). The results show that the E test is a valuable and practical method for routine microbiological diagnostics and can aid in the selection of improved antibiotic options in the treatment of cystic fibrosis patients chronically infected with P. aeruginosa.

Topics: Anti-Bacterial Agents; Ceftazidime; Cystic Fibrosis; Drug Resistance, Multiple; Drug Synergism; Drug Therapy, Combination; Humans; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Reproducibility of Results; Thienamycins; Tobramycin

We report a patient who had a 4-year history of adult-onset Still's disease (AOSD) and showed a prominent increase in large granular lymphocytes (LGL) when she developed severe Pseudomonas conjunctivitis due to Pseudomonas aeruginosa, skin eruptions, liver damage, and abnormal findings in coagulation studies, without any evidence of active viral activation, hemophagocytosis, or malignancies. The increased LGL cells were CD3(+)CD8(+), and disappeared promptly after the administration of antibiotics combined with prednisolone, with subsequent stabilization of her general condition.

Topics: Adult; Anti-Bacterial Agents; CD3 Complex; CD8 Antigens; Combined Modality Therapy; Decompression, Surgical; Drug Therapy, Combination; Female; Humans; Meropenem; Prednisolone; Pseudomonas aeruginosa; Pseudomonas Infections; Still's Disease, Adult-Onset; T-Lymphocytes; Thienamycins; Treatment Outcome

Owing to increasing resistance rates in Europe, pharmacodynamic analyses were proposed to determine optimal empirical antibiotic therapy against Pseudomonas aeruginosa isolated in Hungary. Minimum inhibitory concentrations for 180 non-duplicate P. aeruginosa collected from 14 hospitals in Hungary were determined by Etest methodology. A 5000-subject Monte Carlo simulation was performed to calculate the bactericidal cumulative fraction of response (CFR) for standard dosing regimens of cefepime, ceftazidime, ciprofloxacin, imipenem, meropenem and piperacillin/tazobactam. In the case of poor CFR, alternative dosage regimens were simulated for selected agents by increasing the infusion time, dose and frequency. Owing to high resistance rates in Hungary, no regimen achieved >90% CFR. CFRs for standard dosing regimens were: meropenem 1g every 8h (q8h), 77.1%; ceftazidime 2g q8h, 75.3%; imipenem 0.5 g every 6h (q6h), 71.7%; and piperacillin/tazobactam 4.5 g and 3.375 g q6h, 72.4% and 71.0%, respectively. Ciprofloxacin achieved significantly lower bactericidal CFRs than any beta-lactam. Prolonged infusion regimens improved the CFR for cefepime, imipenem, meropenem and piperacillin/tazobactam. Overall, the highest CFR (88.1%) was achieved by a 3-h infusion of meropenem 2g q8h. Given the poor CFR predicted with standard dosage regimens against these isolates, it seems prudent to consider alternative dosage strategies such as increasing doses, frequencies or infusion times as well as combination therapy when empirically treating infections caused by P. aeruginosa in Hungary.

Topics: Anti-Bacterial Agents; Cefepime; Ceftazidime; Cephalosporins; Ciprofloxacin; Computer Simulation; Drug Administration Schedule; Drug Resistance, Bacterial; Humans; Hungary; Imipenem; Infusions, Intravenous; Meropenem; Microbial Sensitivity Tests; Models, Biological; Monte Carlo Method; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

This article examines the activity of meropenem and imipenem against Pseudomonas aeruginosa isolates from the Meropenem Yearly Susceptibility Test Information Collection program between 1997 and 2005. In particular, it examines the activity of meropenem against imipenem-resistant strains and vice versa. Meropenem proved to be active against up to a 3rd of imipenem-resistant strains.

Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Imipenem; Meropenem; Microbial Sensitivity Tests; Population Surveillance; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

Topics: Anti-Infective Agents; Ciprofloxacin; Drug Synergism; Humans; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

Imipenem resistance in Pseudomonas aeruginosa is considered to be associated with loss of the porin OprD combined with activity of chromosomal beta-lactamase (AmpC), while overexpression of multidrug efflux pumps is considered to confer meropenem resistance. Carbapenem resistance can also result from production of metallo-beta-lactamases. Transcription of oprD and efflux pump genes mexB, mexY and mexF was analysed in 23 clinical isolates of P. aeruginosa by quantitative RT-PCR. oprD was sequenced in all, and mexR, regulator of efflux pump MexAB-OprM, in selected isolates. Four isolates that were imipenem susceptible had significant reduction of oprD mRNA and presence of oprD mutations causing frameshift or translational stop. In strains only resistant to imipenem no significant difference in transcription of oprD was observed between low-level and high-level resistant isolates. The differences could not be explained by either pattern of oprD mutations. Increased transcription of mexB generally correlated well with meropenem resistance. One high-level meropenem-resistant isolate showed no significant change in mexB mRNA, but sequencing confirmed presence of a nalB mutation. Furthermore, one meropenem-susceptible isolate showed significant increase in mexB transcription, but no mexR mutations. In summary, our findings indicate that the resistance patterns observed cannot be fully explained by the currently described carbapenem resistance mechanisms.

Topics: Amino Acid Sequence; Bacterial Outer Membrane Proteins; Bacterial Proteins; beta-Lactam Resistance; Carbapenems; Humans; Imipenem; Membrane Transport Proteins; Meropenem; Microbial Sensitivity Tests; Molecular Sequence Data; Multidrug Resistance-Associated Proteins; Mutation; Porins; Pseudomonas aeruginosa; Pseudomonas Infections; Repressor Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thienamycins; Transcription, Genetic

To investigate the resistance mechanisms of meropenem-resistant, ceftazidime-susceptible Pseudomonas aeruginosa isolates, in a clinical setting where VIM-2 or VIM-4 metallo-beta-lactamase (MBL)-producing pseudomonads are common.. During May to December 2003, 13 consecutive meropenem-resistant, ceftazidime-susceptible P. aeruginosa isolates were recovered from separate patients at the University Hospital of Larissa, Thessaly, Greece. The isolates were studied by Etest MBL, PCR for blaVIM, blaIMP and blaSPM genes and PFGE. Experiments were performed to detect synergy between meropenem or other antimicrobials and the efflux pump inhibitor carbonyl cyanide-m-chlorophenylhydrazone (CCCP). The isolates were also tested by PCR and RT-PCR for the expression of the genes mexB and mexY, which encode the efflux pumps MexAB-OprM and MexXY-OprM.. Twelve of the isolates, belonging to six distinct PFGE types, gave negative results in the MBL Etest and lacked genes encoding MBLs but exhibited synergy between meropenem and CCCP, indicating that efflux pump activity contributed to the meropenem resistance. All 12 isolates were positive for mexB and 11 were also positive for mexY genes. RT-PCR showed that 10 and five isolates over-expressed mexB and mexY, respectively. One isolate was blaVIM-2-positive and did not show synergy with CCCP, or harbour mexB or mexY.. In our hospital, where MBL-producing P. aeruginosa were previously prevalent, meropenem resistance due to the overexpression of efflux pumps has also now emerged. Early recognition of this resistance mechanism should allow the use of alternative beta-lactams, such as ceftazidime, which would be inactive even against phenotypically susceptible MBL producers.

Topics: Bacterial Outer Membrane Proteins; beta-Lactamases; Carbonyl Cyanide m-Chlorophenyl Hydrazone; Ceftazidime; Drug Resistance, Bacterial; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Enzymologic; Greece; Humans; Membrane Transport Proteins; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

In this report of the OPTAMA (Optimizing Pharmacodynamic Target Attainment using the MYSTIC Antibiogram) program, we utilized Monte Carlo simulation to compare the probabilities of achieving bactericidal time above the minimum inhibitory concentration (MIC) (%T > MIC) exposures for imipenem-cilastatin 500 mg q6h and 1000 mg q8h, meropenem 500 mg q6h and 1000 mg q8h and piperacillin/tazobactam 3.375 g q6h and 4.5 g q8h in the empiric treatment of secondary peritonitis.. The prevalence of pathogens causing secondary peritonitis was identified from the primary surgical and infectious diseases literature. Data for these pathogens with respect to MIC were obtained from the 2003 MYSTIC surveillance study and weighted by the prevalence of each pathogen. A sensitivity analysis varying the prevalence of P. aeruginosa was performed with two additional models to determine the robustness of the data. Pharmacokinetic parameters, obtained from previously published studies in healthy volunteers were used to simulate the %T > MIC for 10,000 patients receiving imipenem-cilastatin, meropenem, and piperacillin/tazobactam. The likelihood of obtaining bactericidal exposure is reported.. Empiric utilization of imipenem-cilastatin and meropenem 500 mg q6h and 1000 mg q8h regimens achieved 99.6%-99.7% likelihood of bactericidal exposure. Piperacillin/ tazobactam 3.375 g q6h and 4.5 g q8h produced bactericidal target attainments of 92.9% and 85.2%, respectively. Models simulating higher prevalence of P. aeruginosa reduced the likelihood of bactericidal exposure for piperacillin/tazobactam regimens significantly and had little effect on the carbapenems.. All of the beta-lactams used in the current analysis were predicted to achieve high target attainment consistently for the empiric treatment of secondary peritonitis. However, imipenem-cilastatin 500 mg q6h and 1000 mg q8h, meropenem 1000 mg q8h and 500 mg q6h, and piperacillin/tazobactam 3.375 g q6h achieved the highest likelihood. These, in particular, would be effective choices for the empiric treatment of secondary peritonitis.

Topics: Anti-Bacterial Agents; beta-Lactams; Cilastatin; Cilastatin, Imipenem Drug Combination; Drug Combinations; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Models, Biological; Monte Carlo Method; Penicillanic Acid; Peritonitis; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

This study examines the susceptibilities of meropenem and other broad-spectrum antimicrobials tested against bacterial isolates collected from hospitalized patients during 2002-2004 from worldwide medical centers participating in the Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) Program. The in vitro activity of meropenem and 5 comparator antimicrobial agents was assessed against Pseudomonas aeruginosa and Acinetobacter spp. Generally, the susceptibility of Australasian and North American isolates was higher than that of the European and South American isolates. The rank order of activity of the antimicrobial agents tested against a worldwide collection of P. aeruginosa was piperacillin/tazobactam (77.7% susceptible) > meropenem (75.4%) > ceftazidime (70.0%) > imipenem (69.7%) > gentamicin (66.1%) > ciprofloxacin (62.0%). Against a worldwide collection of Acinetobacter spp. meropenem (76.1% susceptible) was the most active compound followed by imipenem (74.7%) > gentamicin (51.9%) > ciprofloxacin (40.5%) > piperacillin/tazobactam (39.8%) > ceftazidime (38.1%). The carbapenems appear to be a valuable option for the treatment of serious nosocomial infections caused by P. aeruginosa or Acinetobacter spp. over a broad geographical region.

Topics: Acinetobacter; Acinetobacter Infections; Anti-Bacterial Agents; Asia; Australia; Cross Infection; Drug Resistance, Bacterial; Europe; Humans; Inpatients; Meropenem; Microbial Sensitivity Tests; North America; Population Surveillance; Pseudomonas aeruginosa; Pseudomonas Infections; South America; Thienamycins

Pharmacokinetic and pharmacodynamic (PK/PD) parameters, which are important indices of the therapeutic efficacy of antimicrobials, and the minimum inhibitory concentration (MIC) predictive of clinical efficacy at common clinical doses, were examined for biapenem (BIPM; 300 mg b.i.d.), imipenem/cilastatin (IPM/CS; 500 mg/500 mg b.i.d.), meropenem (MEPM; 500 mg b.i.d.), and ceftazidime (CAZ; 1000 mg b.i.d.), using a mouse model of thigh infection caused by Pseudomonas aeruginosa. The PK/PD parameter that most closely correlated with the therapeutic efficacy of all these antimicrobials was time above MIC (T > MIC). The values of T > MIC predictive of clinical efficacy against P. aeruginosa infection varied among antimicrobials and were >/=17%, >/=17%, >/=23%, and >/=33% for BIPM, IPM/CS, MEPM, and CAZ, respectively. From these values and the known plasma concentrations of the antimicrobials in humans after administration at the common clinical doses, the MIC for bacterial strains at which clinical efficacy can be expected was estimated to be

Topics: Animals; Anti-Bacterial Agents; Ceftazidime; Drug Administration Schedule; Humans; Imipenem; Male; Meropenem; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins; Thigh

Risk factors for multi-drug resistant Pseudomonas aeruginosa (MDRP) infections were investigated using a case-control study design involving MDRP patients (N = 44) and controls (N = 68). A retrospective cohort study was performed to study the predictive factors of clinical outcome in MDRP patients. Multivariate analysis demonstrated that previous exposure to imipenem/meropenem [odds ratio (OR), 44.8] and mechanical ventilation (OR 8.2) were risk factors for nosocomial infections of MDRP. Of 44 cases of MDRP infections, 20 patients died directly from P. aeruginosa infections. Pulsed-field gel electrophoresis (PFGE) analysis on serial isolates from three patients showed that profiles of isolates from the same patient were closely related or indistinguishable. Multivariate analysis demonstrated that patients with adverse clinical outcomes were more likely to have been treated with mechanical ventilation (OR 12.8), and more likely to have MDRP resistance patterns that did not change during treatments (OR 26.5). We concluded that mechanical ventilation and previous exposure to imipenem/meropenem were independent risk factors for MDRP infections, while mechanical ventilation and antibiotic resistance switch were predictive factors of outcomes of MDRP infections.

Topics: Adult; Age Factors; Aged; Anti-Bacterial Agents; Case-Control Studies; China; Comorbidity; Cross Infection; Drug Resistance, Multiple, Bacterial; Electrophoresis, Gel, Pulsed-Field; Female; Hospitals, University; Humans; Imipenem; Logistic Models; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Pseudomonas aeruginosa; Pseudomonas Infections; Respiration, Artificial; Risk Factors; Thienamycins; Treatment Outcome

The Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) Programme was initiated in 1997 (1999 for the United States). This program monitors resistance in participant medical centers where carbapenems are prescribed and drug use data can be obtained. An earlier report found antimicrobial use was not a clear cause of local or aggregate changes in resistance rates. This study addresses the role of dissemination of resistant clones on susceptibility rates for nonfermentors, Acinetobacter spp. (ACB) and Pseudomonas aeruginosa (PSA). Carbapenem (CARB)-multidrug-resistant strains (MDR) from among 236 ACB and 1,111 PSA were tested by reference broth microdilution methods, automated ribotyping, and pulsed field gel electrophoresis to determine possible clonal dissemination. Each strain was also tested for metallo-beta-lactamases (MbetaL) (phenotypic and polymerase chain reaction); and then analyzed by CARB-R rate and defined daily dose (DDD)/100 days use groupings (high, moderate, and low). For the aggregate 15 sites in the MYSTIC Programme each year, the CARB-resistant rate decreased over 5 years; but other drug-resistance rates generally escalated. Changes were not related to antimicrobial use calculations. The discovered clonally spread MDR-PSA strains were more frequent in high- (1.8 clones/site) and moderate-resistance (0.6 clones/site) rate centers (21.7% to 29.5% were clonal), compared with unique strains in low-resistance hospitals. ACB clonality was extreme in one geographic area, with dissemination of 5 different clones (931.7/B, C, or D; 1090.2/A; 167.5/A) in 4 centers (02, 04, 06, and 18). Resistance rates in ACB and PSA were clearly related to clonal occurrence and spread, and one MbetaL (VIM-7) was detected. Decreased CARB resistance rates from 1999 through 2002 were directly attributed to the disappearance of resistance clones in some locations. In conclusion, ACB and PSA CARB and MDR resistance rates in MYSTIC Programme institutions have been greatly influenced by clonal dissemination and less by antimicrobial use patterns. The most serious examples of resistance were the clonality observed among ACB in New York City and the documented endemic nature of VIM-7-producing PSA (0.09% of all PSA isolates). Meropenem remained the most active antimicrobial agent tested in the program, and surveillance networks must implement epidemiologic typing to accurately assess the role of clonal spread on the study results.

Topics: Acinetobacter; Anti-Bacterial Agents; Clone Cells; Drug Resistance, Multiple, Bacterial; Female; Humans; Male; Meropenem; Microbial Sensitivity Tests; Molecular Epidemiology; Multicenter Studies as Topic; Pseudomonas aeruginosa; Pseudomonas Infections; Sensitivity and Specificity; Thienamycins; United States

Pseudomonas stutzeri is a saprophytic microorganism that rarely causes severe infections. In this report, a 28 days old male patient with meningomyelocele at birth was presented. The patient was admitted to the hospital with fever, and diagnosed as meningitis on the basis of physical examination and leukocytosis (blood: 16.380/mm3, cerebrospinal fluid (CSF): 130/mm3; 90% PMNL). Following diagnosis ceftriaxone therapy was started led to improvement in clinical and laboratory findings. However on the 20th day, the clinical signs and symptoms became worse, and the patient was diagnosed to develop a second meningitis attack by laboratory examination of CSF. P. stutzeri was isolated from the CSF culture, and the isolate was found to be resistant to ceftriaxone. Upon this result the therapy has changed to meropenem. On the 5th day of the therapy, the patient has slightly improved and he was discharged due to the wishes of his parents, however he died two days after discharge. This first case of P. stutzeri meningitis in neonates was presented to withdraw attention to this clinical entity.

Topics: Anti-Bacterial Agents; Ceftriaxone; Cerebrospinal Fluid; Drug Resistance, Bacterial; Fatal Outcome; Humans; Infant, Newborn; Male; Meningitis, Bacterial; Meningomyelocele; Meropenem; Pseudomonas Infections; Pseudomonas stutzeri; Recurrence; Thienamycins; Treatment Failure

Antimicrobial susceptibility of Pseudomonas aeruginosa isolated at Kochi Municipal Central Hospital between 2001 and 2003 was assessed according to the NCCLS interpretive criteria. 1. The piperacillin-susceptible rate was 92.9%. 2. Among cephem antibiotics, the ceftazidime-susceptible rate was the highest (96.0%). 3. As for aminoglycosides, susceptibility to tobramycin and amikacin remained with a susceptible rate of 93.2% and 94.8%, respectively. 4. The carbapenem-susceptibility remained high. The susceptible rate for meropenem (94.1%) was higher than that for imipenem (88.3%). 5. Acquisition of resistance was observed in urinary isolates. Four multi-drug resistant P. aeruginosa, which are resistant to all of imipenem, amikacin and ofloxacin were isolated in this study and all were isolated from urine. 6. Of 388 isolates, 34 isolates were resistant to imipenem, but no positive isolate was found in screening of metallo-beta-lactamase-producing bacteria.

Topics: Amikacin; Anti-Bacterial Agents; Ceftazidime; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Piperacillin; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins; Tobramycin

Pseudomonas aeruginosa is one of the important cause of infections in intensive care unit (ICU) patients. The aim of this study was to investigate the effectiveness of ertapenem prior to its use in Turkey, against multiple-resistant P. aeruginosa strains isolated from ICUs. Susceptibility tests were performed by using Kirby-Bauer disk diffusion method and MicroScan MERCH MIC 8 panel (MicroScan 96, Dade Behring, USA). While the resistance rates of ertapenem, imipenem and meropenem were 59.2%, 50% and 48.1% by disk diffusion method, they were 57.4%, 46.2% and 42.5% by MicroScan, respectively. Ertapenem was found less effective against multiple-resistant P. aeruginosa isolates by both of the methods when compared with imipenem and meropenem. Piperacillin/tazobactam was detected as the most effective agent against these isolates by both of the methods. As a result, although carbapenems are frequently used for infections caused by P. aeruginosa, ertapenem, which is a new carbapenem, is not effective as much as the others. In case of confirmation of our results by larger scale studies, the empiric treatment of ICU infections caused by P. aeruginosa with ertapenem, should be carefully evaluated.

Topics: Anti-Bacterial Agents; beta-Lactams; Drug Resistance, Multiple, Bacterial; Ertapenem; Humans; Imipenem; Intensive Care Units; Lactams; Meropenem; Microbial Sensitivity Tests; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

A case of acute generalized exanthematous pustulosis (AGEP) is presented. The case is notable for the recurrent episodes of AGEP, caused by three beta-lactam antibiotics (piperacillin, ceftazidime, and meropenem) in septicemic patient. The case represents the first report of the reaction developing in response to these three antibiotics. The report is also notable for the spontaneous resolution of the rash in all the three episodes.

Topics: Acute Disease; Anti-Bacterial Agents; Bacteremia; Ceftazidime; Diabetes Mellitus; Diagnosis, Differential; Exanthema; Hepatitis, Alcoholic; Humans; Male; Meropenem; Middle Aged; Piperacillin; Pseudomonas aeruginosa; Pseudomonas Infections; Recurrence; Thienamycins

Resistance emergence to carbapenem antibiotics was studied in a rat-thigh abscess model. Abscesses were developed in three groups with a total of 15 P. aeruginosa strains (three rats per strain). Groups were assigned to imipenem or meropenem treatment while one was left antibiotic-free. Test strains were fully susceptible to these antibiotics and the "Mutant Preventing Concentrations" of imipenem and meropenem over these strains were comparable. Antibiotic serum levels, assessed by serum bioassay test, were similar among therats. After four days, rats (n=45) were sacrificed and carbapenem resistant mutants were selected on imipenem (4 mg/L) and meropenem (4 mg/L) supplemented agar plates. Resistant variants of three strains, from four abscesses, were detected; one in the meropenem group, two in the imipenem and one in the untreated group. The MICs of imipenem and meropenem for the mutants were increased fourfold times or even higher of their counterparts. Resistance emergence under antibiotic pressure in P. aeruginosa has been shown in various conditions. To our knowledge, however, resistance emergence in abscess and also the comparison of imipenem and meropenem in this regard has not been studied before.

Topics: Abscess; Animals; Carbapenems; Drug Resistance, Bacterial; Imipenem; Male; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Rats; Rats, Wistar; Selection, Genetic; Thienamycins

Prolonging the infusion of meropenem over 3 hours increases the percentage of the dosing interval that drug concentrations remain above the minimum inhibitory concentration (MIC), thereby maximizing the pharmacodynamics of this agent and adhering to drug stability constraints. Monte Carlo simulation was employed to determine pharmacodynamic target attainment rates for several prolonged infusion (PI) meropenem dosage regimens as compared with the traditional 30-minute infusion (TI) against Enterobacteriaceae, Acinetobacter species, and Pseudomonas aeruginosa populations. Percent time above the MIC (%T>MIC) exposures for 1000 mg TI q8h, 2000 mg TI q8h, 500 mg PI q8h, 1000 mg PI q12h, 1000 mg PI q8h, 2000 mg PI q12h, and 2000 mg PI q8h were simulated for 10,000 subjects. Variability in pharmacokinetic parameters and MIC distributions were derived from studies in healthy volunteers and the MYSTIC surveillance program, respectively. The probabilities of attaining bacteriostatic (30% T>MIC) and bactericidal (50% T>MIC) exposures were high for all dosage regimens against populations of Enterobacteriaceae. Against Acinetobacter species and Pseudomonas aeruginosa, the 2000-mg PI q8h dosage regimen provided the highest target attainment rates. For mild to moderate infections caused by Enterobacteriaceae, prolonged infusion regimens of 500 mg PI q8h and 1000 mg PI q12h would provide equivalent target attainment rates to the traditional 30-minute infusion while requiring less drug over 24 hours. For more serious infections presumably caused by Acinetobacter species or Pseudomonas aeruginosa, a dose of 2000 mg PI q8h is recommended because of its high bactericidal target attainment rate against these pathogens. Further study of these dosage recommendations in clinical trials is suggested.

Topics: Acinetobacter Infections; Anti-Infective Agents; Drug Administration Schedule; Enterobacteriaceae Infections; Humans; Infusions, Intravenous; Male; Meropenem; Microbial Sensitivity Tests; Monte Carlo Method; Pseudomonas Infections; Research Design; Thienamycins; Time Factors; Treatment Outcome

The MYSTIC program monitors worldwide in vitro susceptibilities of clinical bacterial isolates from centers that prescribe meropenem. This report focuses on 107 isolates of multi-drug resistant (MDR) Pseudomonas aeruginosa, which commonly causes infections that are difficult to treat in hospitalized patients. We chose samples from patients from 33 European intensive care units (ICUs). There was considerable inter-country variation in the proportion of P. aeruginosa that were MDR, ranging from 50% in Turkey to < or =3% in Spain, the UK, Germany, Bulgaria and Malta. Amongst the MDR isolates, the percentage resistance (MIC50/90 in mg/L) to the antibiotics tested were amikacin 18.7% (32/>128), meropenem 29.1% (8/64), imipenem 44.9% (16/64), cefepime 49.5% (32/64) and piperacillin/tazobactam 57.9% (128/>128).

Topics: Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Europe; Humans; Intensive Care Units; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

The prevalence of multidrug-resistant Pseudomonas aeruginosa strains has been increasing every year, and treatment with various antimicrobial combinations has been offered alternatively in the clinical practice. The aim of this study was to evaluate the in vitro effects of combinations of meropenem, cefepime, or piperacillin-tazobactam with ciprofloxacin against multidrug-resistant P. aeruginosa strains by the time-kill method. The results show that both the combination of two beta lactams with ciprofloxacin and three beta lactams with ciprofloxacin against 4 of 5 multidrug-resistant P. aeruginosa strains has no effect in vitro. The combination of one beta lactam (meropenem, cefepime, piperacillin-tazobactam) with ciprofloxacin has a synergistic effect against one strain of multidrug-resistant P. aeruginosa that is ciprofloxacin susceptible and resistant to meropenem, cefepime, and piperacillin-tazobactam. None of the combinations had an antagonistic effect against these multidrug-resistant strains.

Topics: Anti-Bacterial Agents; Cefepime; Cephalosporins; Drug Interactions; Drug Resistance, Multiple; Drug Therapy, Combination; Humans; Lactams; Meropenem; Microbial Sensitivity Tests; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

This study evaluated the in vitro effects of the combination of a carbapenem (imipenem or meropenem) with a quinolone (ciprofloxacin or levofloxacin) using a microbroth dilution chequerboard technique and multidrug-resistant Pseudomonas aeruginosa strains. The ciprofloxacin and meropenem combination was only synergistic against 2 strains (6.2%) and ciprofloxacin and imipenem against 1 strain (3.1%). Levofloxacin and imipenem or meropenem were not synergistic for against any strain. None of the combinations showed an antagonistic effect.

Topics: Anti-Bacterial Agents; Ciprofloxacin; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Humans; Imipenem; Levofloxacin; Meropenem; Microbial Sensitivity Tests; Ofloxacin; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

Topics: Aged; Anesthesia, Spinal; Drug Administration Schedule; Drug Resistance, Microbial; Humans; Male; Meningitis, Bacterial; Meropenem; Pseudomonas aeruginosa; Pseudomonas Infections; Recurrence; Thienamycins

The aim of this study was to determine synergistic effects of meropenem and ciprofloxacin against Pseudomonas aeruginosa and Acinetobacter strains isolated from intensive care unit (ICU) infections. A total of 18 P. aeruginosa and 17 Acinetobacter strains were tested. MICs were determined using the broth microdilution method. The synergy of meropenem and ciprofloxacin was investigated in glass tubes using time-kill methodology. The synergistic effect of meropenem and ciprofloxacin in combination was found to be 22% at 0.5 x the MIC and 61% at 1 x the MIC in P. aeruginosa strains. Two strains (11%) showed synergy at both 0.5 and 1 x the MIC. Of the 18 P. aeruginosa strains, 1 strain (6%) did not show a synergistic effect at either 0.5 or 1 x the MIC. In Acinetobacter strains, the synergistic effect of meropenem and ciprofloxacin in combination was found to be 29% at 0.5 x the MIC and 18% at 1 x the MIC. One strain (6%) showed synergy at both 0.5 and 1 x the MIC. Of the 17 Acinetobacter strains, 8 strains (47%) did not show a synergistic effect at either 0.5 or 1 x the MIC. According to the results of this study, the combination of meropenem and ciprofloxacin is more effective than either antibiotic alone in ICU infections due to P. aeruginosa strains.

Topics: Acinetobacter; Acinetobacter Infections; Anti-Bacterial Agents; Anti-Infective Agents; Ciprofloxacin; Drug Synergism; Drug Therapy, Combination; Humans; In Vitro Techniques; Intensive Care Units; Meropenem; Microbial Sensitivity Tests; Prospective Studies; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

Resistance to imipenem and meropenem was observed in 211 (16.5%) isolates of Pseudomonas aeruginosa recovered in a Greek university hospital during 1996 to 1998. In six isolates selected from throughout this period, high-level resistance to both carbapenems (MICs >/= 128 microg/ml) was associated with production of the class B beta-lactamase VIM-1. bla(VIM)-bearing isolates belonged to serotype O:12 and were indistinguishable by pulsed-field gel electrophoresis.

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Disease Outbreaks; Drug Resistance, Microbial; Greece; Hospitals, University; Humans; Imipenem; Inpatients; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Serotyping; Thienamycins

The relationship between morphological changes and endotoxin release induced in vitro by carbapenems in a clinical isolate of Pseudomonas aeruginosa was examined. The time-course and magnitude of endotoxin release induced varied among imipenem, panipenem, meropenem and biapenem and related to the morphological changes caused by these agents which variously affected cell shape, cell-wall disintegration and cell lysis. The amount of endotoxin released by carbapenem-treated cells correlated with both the cell-wall morphology and bacterial shape immediately before lysis. Meropenem and biapenem caused markedly increased endotoxin release during cell lysis and cell-wall disintegration, whereas imipenem and panipenem caused much less release of endotoxin.

Topics: Carbapenems; Endotoxins; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

We evaluated the in-vitro effects of various combinations of five types of widely used antipseudomonal antibiotics (piperacillin, meropenem, ceftazidime, aztreonam and amikacin) against six Pseudomonas aeruginosa strains that were resistant to each of these antibiotics. Among two-drug combinations, the combinations of two beta-lactam antibiotics inhibited growth of one to three P. aeruginosa strains, while those of one beta-lactam antibiotic and amikacin inhibited growth of two to four strains. Among three-drug combinations, the combinations of three beta-lactam antibiotics inhibited growth of four to five strains, and those of two beta-lactam antibiotics and amikacin inhibited growth of five strains. These results suggest the potential usefulness of a combination of two beta-lactam antibiotics and amikacin or that of three beta-lactam antibiotics in treating multi-drug resistant P. aeruginosa infections.

Topics: Amikacin; Anti-Bacterial Agents; Aztreonam; Ceftazidime; Drug Combinations; Drug Resistance, Microbial; Drug Resistance, Multiple; Humans; Meropenem; Microbial Sensitivity Tests; Piperacillin; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

Topics: Aged; Blood-Brain Barrier; Cefepime; Cefotaxime; Cephalosporins; Cerebrospinal Fluid; Cerebrospinal Fluid Shunts; Drug Resistance, Microbial; Drug Therapy, Combination; Humans; Hydrocephalus; Male; Meningitis, Bacterial; Meropenem; Postoperative Complications; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

In 1997 in western Austria, 9.9% of Pseudomonas aeruginosa strains from patients of general practitioners were resistant to imipenem as well as 18.2% of the isolates from hospitals and 20.2% of the strains at a university teaching hospital. Within the hospital the imipenem resistance varied from 9.9% among out-patients to 28.7% in isolates from intensive care units. In medical/surgical words, up to 15.1% of P. aeruginosa strains were resistant to imipenem. The incidence of imipenem-resistant P. aeruginosa strains correlates to the use of carbapenems. In June 1997, 10 consecutive isolates from 8 patients were obtained and typed using restriction fragment length polymorphism analysis (RFLP) and Pyocin typing. All 10 isolates were resistant to meropenem as well as to imipenem. The finding (by RFLP and Pyocin typing) of individual bacterial types in each isolate strongly contradicts the spread of infection by cross infection. However, all patients were proven to have been treated with imipenem during the 3 months prior to testing. In 1997, 13,880 g of imipenem were used at the university hospital in Innsbruck. The use of carbapenems appears to be the main cause for the increased incidence of imipenem-resistant P. aeruginosa strains.

Topics: Austria; Bacterial Typing Techniques; Cross Infection; Drug Resistance, Microbial; Humans; Imipenem; Meropenem; Polymorphism, Restriction Fragment Length; Pseudomonas Infections; Thienamycins

The in vitro effects of meropenem on Pseudomonas aeruginosa were examined by studying (i) the inhibitory and bactericidal concentrations of meropenem versus those of imipenem for clinical isolates; (ii) changes in bacterial morphology during in vitro culture; and (iii) release of endotoxin induced by meropenem compared with that induced by other antipseudomonal compounds. Meropenem MIC90 and MBC90 values for 108 clinical isolates were 2 and 4.8 mg/l compared to 4.5 and 9.6 mg/l for imipenem. Morphological studies using phase-contrast and scanning electron microscopy showed that meropenem induced the formation of indeterminate bacterial cell forms at drug concentrations of 1-2.5 mg/l (0.5- to 1.25-fold the MIC), while spheroplasts predominated at drug levels exceeding 5 mg/l (2.5-fold the MIC). Determination of free and EDTA-releasable endotoxin activity by means of the Limulus lysate test showed that both meropenem and imipenem liberated significantly less endotoxin than did ceftazidime. Therefore, although meropenem binds to penicillin-binding proteins (PBPs) 2 and 3 (in contrast to imipenem, which binds to PBP2 only), endotoxin release should not be a cause of concern when treating systemic gram-negative infections with this drug.

Topics: Anti-Infective Agents; Ceftazidime; Cephalosporins; Ciprofloxacin; Endotoxins; Humans; Imipenem; Lipopolysaccharides; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

The pharmacokinetics of meropenem were studied after single i.v. infusions of 15 mg meropenem/kg body weight in eight subjects with cystic fibrosis (CF) and eight healthy volunteers matched for age, sex, and weight. Significantly shorter terminal half-lives (mean, 0.74 h vs. 0.99 h) and mean residence times (mean, 1.09 h vs. 1.39 h) were noted in CF subjects. Plasma and renal clearances tended to be higher and distribution volumes smaller among the patients, but differences were not statistically significant. The results are consistent with the findings for many other beta-lactam agents used in CF patients. Assuming a MIC90 of 4 mg/l for meropenem against Pseudomonas aeruginosa, the time above the MIC was less than 3.3 h in six of the eight CF patients. This finding should be kept in mind when designing treatment regimens with meropenem in CF subjects.

Topics: Adult; Area Under Curve; Cystic Fibrosis; Female; Humans; Male; Meropenem; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

The in vitro and in vivo activity of BO-2727, a carbapenem antibiotic, against resistant clinical isolates of Pseudomonas aeruginosa was studied. The geometric mean MICs against three groups of clinical isolates resistant to imipenem, meropenem and both carbapenems were 4.28, 4.08 and 5.44 micrograms/ml, respectively. BO-2727 also inhibited multiply antibiotic resistant isolates and laboratory mutants including a nalB-type mutant, which showed resistance to antibiotics such as imipenem, meropenem, ceftazidime, and/or ciprofloxacin, at less than 1.56 micrograms/ml. Overall, BO-2727 was 4-fold more active than biapenem, meropenem, panipenem and imipenem with an MIC90 of less than 6.25 micrograms/ml. The presence of basic amino acids in minimal medium less affected the antipseudomonal activity to a minimal extent, suggesting that BO-2727 has diverse penetration routes through the outer membrane other than OprD channel, which facilitates the diffusion of basic amino acids and carbapenems. The in vitro activity of BO-2727 reflected well in its therapeutic efficacy in experimental systemic infection in mice. These results suggest a possibility for the development of antipseudomonal carbapenems having activity against imipenem- and/or meropenem-resistant P. aeruginosa as well as a broad spectrum encompassing Gram-positive and -negative bacteria.

Topics: Animals; Carbapenems; Ceftazidime; Cephalosporins; Culture Media; Drug Resistance, Microbial; Drug Resistance, Multiple; Humans; Imipenem; In Vitro Techniques; Male; Meropenem; Mice; Mutation; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

The synthesis and in vitro antibacterial activity of a novel series of 2-alkoxymethyl-4-pyrrolidinylthio-1 beta-methyl carbapenems are described. As a result of these studies, we discovered that FR27743 (19j) containing a novel 2-fluoroethoxymethyl substituent possesses a broad spectrum of antibacterial activity against both Gram-positive and Gram-negative organisms, including Pseudomonas aeruginosa. Furthermore, FR27743 exhibited excellent stability against renal dehydropeptidase-I (DHP-I), good urinary recovery, and superior in vivo activity compared to that for Meropenem against several systemic infections.

Topics: Animals; Carbapenems; Dipeptidases; Drug Stability; Male; Meropenem; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Pseudomonas Infections; Rats; Staphylococcal Infections; Thienamycins; Urine

Infected, neutropenic animals are used as experimental models to evaluate the relative efficacies of antimicrobial agents and host-pathogen-antibiotic interactions. In the past, these models used death as the study end point. Because of the concern about use of death as an end point, we evaluated the accuracy with which various signs of infection predicted mortality in a neutropenic guinea pig model of treated and untreated Pseudomonas aeruginosa sepsis. The potential surrogate markers studied included ruffled fur, respiratory distress, diarrhea, hunched posture, lethargy, abnormal neurologic movements (twitching, paralysis of a limb), inappetence for > 48 h, the inability to ambulate, and the inability of a supine animal to stand. In addition, we evaluated whether percentage of weight loss or change in daily food and water consumption were predictive of mortality. Animals were inspected for these signs at least every 4 h during the day and every 8 h in the evening. In treated and untreated animals, 100% of subjects that were unable to ambulate or to rise from the supine position died (positive predictive value for death was 100% for either sign). Guinea pigs that could not rise from a supine position expired between 1 and 8 h after this sign was observed. Those that could not ambulate died between 4 and 40 h after that sign was observed. In treated and untreated animals, none of the survivors manifested either sign of disease (100% specificity for each sign). However, 59% of untreated and 69% of treated animals that were ambulatory were found dead at the next observation period, underscoring the rapidity with which this infection progresses to death when it enters its final stage. No other signs of infection distinguished animals that survived or died. Thus, the inability of neutropenic, infected guinea pigs to rise from a supine position and the inability to ambulate were the only signs that accurately predicted death and, therefore, are the only signs that can be used as surrogates for death in this experimental model of P. aeruginosa sepsis.

Topics: Animals; Anti-Bacterial Agents; Biomarkers; Ceftazidime; Cephalosporins; Diarrhea; Disease Models, Animal; Female; Guinea Pigs; Imipenem; Meropenem; Movement Disorders; Neutropenia; Predictive Value of Tests; Pseudomonas Infections; Regression Analysis; Respiration; Thienamycins; Time Factors; Tobramycin; Weight Loss

Topics: Adult; Humans; Lung Diseases; Male; Meropenem; Pseudomonas Infections; Thienamycins

In order to compare the in vitro killing activity of meropenem and imipenem against multiresistant P.aeruginosa 14 strains were used. All nosocomial isolates were susceptible to meropenem and imipenem minimum inhibitory concentration (MIC < or = 4 micrograms/ml) and resistant to at least two other antimicrobial agents of diverse chemical class with antipseudomonal activity. Forty-two killing curves were performed by exposing a 5 x 10(5) CFU/ml log-phase inoculum to 1x minimum bactericidal concentration (MBC) of each carbapenem. Meropenem was found to possess a slower killing rate than imipenem over the first 5 hours of P.aeruginosa exposure, but to be equally effective as imipenem after 24 hours of incubation. Forty percent and 11.1% of P.aeruginosa strains developed resistance to imipenem and meropenem respectively after a 24-hour exposure to carbapenem. The authors speculate about the underlying mechanisms explaining the higher rate of resistance development to imipenem than to meropenem.

Topics: Cross Infection; Drug Resistance, Microbial; Drug Resistance, Multiple; Humans; Imipenem; In Vitro Techniques; Meropenem; Pseudomonas Infections; Thienamycins; Time Factors

Topics: Animals; Ceftazidime; Cephalosporins; Female; Imipenem; Meropenem; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

Several pharmacodynamic parameters are being studied and applied to the design of dosage regimens. The thigh infection model in neutropenic mice has been used in this study to investigate the in vivo postantibiotic effect (PAE) of meropenem against S. aureus, E. coli and P. aeruginosa. The sub-minimum inhibitory concentration (sub-MIC) postantibiotic effect (PA SME) of 1/2, 1/4 and 1/8 x MIC was also determined in vitro on S. aureus and E. coli after pre-exposure of these microorganisms to 10 x MIC of meropenem. The in vitro PAE was also determined. In vivo killing curves using 2 different short dosage regimens were also studied to relate the lethal effect to the time that serum levels were above the MIC. No significant in vivo and in vitro PAEs were observed. The PA SMEs were higher for S. aureus than for E. coli. The 2 short dosage regimens, in vivo, were equally effective in killing S. aureus, but not E. coli. These results suggest that the pharmacodynamics of meropenem on Gram-negative strains may need further study to elucidate the mechanisms and characteristics of these parameters. On the other hand, we need to standardize a reliable in vitro method to monitor regrowth with a good correlation with the in vivo conditions.

Topics: Animals; Drug Evaluation, Preclinical; Drug Resistance, Microbial; Escherichia coli; Escherichia coli Infections; Female; In Vitro Techniques; Meropenem; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Staphylococcal Infections; Staphylococcus aureus; Thienamycins

Topics: Cancer Care Facilities; Cross Infection; Disease Outbreaks; Drug Resistance, Microbial; Humans; Infection Control; Meropenem; Pseudomonas aeruginosa; Pseudomonas Infections; Serotyping; Thienamycins

Topics: Accidental Falls; Adult; Brain Injuries; Cross Infection; Humans; Male; Meningitis, Bacterial; Meropenem; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

Topics: Adult; Humans; Male; Meningitis, Bacterial; Meropenem; Pseudomonas Infections; Thienamycins

We studied a newly developed carbapenem, meropenem (MEPM), and obtained the following results. 1. Pharmacokinetics of MEPM in pediatrics was examined in 3 patients. MEPM was injected intravenously at a dose of 16-22 mg/kg by drip infusion for 30 minutes, and its concentrations in serum and urine were determined using bioassay. The average peak value of serum levels of MEPM was 38.4 micrograms/ml and T1/2 beta of MEPM was 1.26 hours. The urinary recovery rate for the first 6 hours after administration was 65.6%. 2. Clinical evaluations of MEPM in pediatrics were done in 14 patients with ages ranging, 1 month to 14 years, with various bacterial infections. Excellent or good clinical responses were observed in all patients, and bacteriological eradication were obtained in 7 out of 8 cases. No serious side effects were observed in any cases, but 2 showed mild and transient GOT, GPT elevations.

Topics: Adolescent; Bacterial Infections; Child; Child, Preschool; Citrobacter freundii; Enterobacteriaceae Infections; Female; Humans; Infant; Male; Meropenem; Pseudomonas Infections; Staphylococcal Infections; Staphylococcus epidermidis; Thienamycins

A new carbapenem antibiotic, meropenem (MEPM), was evaluated for its safety and efficacy in 33 infants and children. MEPM was effective in all the 32 evaluable cases including 4 cases of bacterial meningitis and 5 cases of Pseudomonas aeruginosa infections. The mean half life of plasma concentrations of MEPM was 0.84 +/- 0.09 hours after 30 minutes intravenous drip infusion. Mild diarrhea (2 cases), transient elevation of transaminases (8 cases), and transient eosinophilia (2 cases) were associated with the MEPM therapy, but none of them was problematic. These data suggest that MEPM is safe in infants and children and could be one of the therapeutic agents for severe infections or infections in compromised hosts.

Topics: Adolescent; Bacterial Infections; Child; Child, Preschool; Drug Evaluation; Female; Half-Life; Humans; Infant; Male; Meningitis, Bacterial; Meropenem; Pseudomonas Infections; Thienamycins

The novel carbapenem meropenem, which is stable to dehydropeptadase action, was studied in vitro against 173 nosocomial isolates of Pseudomonas aeruginosa derived from pus, expectorated sputum, bronchial secretions, urine or blood of infected patients. Susceptibilities to meropenem, imipenem, ceftazidime, cefotaxime, piperacillin, gentamicin, amikacin and ciprofloxacin were determined by the agar dilution technique with an inoculum of 10(4) cfu/spot. The proportion of sensitive isolates with MICs below the breakpoint was highest for meropenem (91% less than or equal to 8 mg/l); the proportion of sensitive isolates for the remaining antibacterials was as follows: ciprofloxacin 87% less than or equal to 2 mg/l; imipenem 85% less than or equal to 8 mg/l; ceftazidime 77.5% less than or equal to 16 mg/l; piperacillin 60% less than or equal to 64 mg/l; amikacin 44% less than or equal to 8 mg/l; gentamicin 34% less than or equal to 4 mg/l and cefotaxime 15% less than or equal to 16 mg/l. Strains moderately resistant to imipenem (MIC 16-32 mg/l) were mostly sensitive to meropenem, but highly resistant strains (MIC 128-256 mg/l) were invariably resistant (MIC greater than 128 mg/l) to the new carbapenem.

Topics: Anti-Bacterial Agents; Carbapenems; Drug Resistance, Microbial; Humans; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

Meropenem is a new carbapenem antibiotic with activity similar to that of imipenem. Development of resistance to imipenem by Pseudomonas aeruginosa has occurred in therapy and is associated with loss of a 45,000-48,000 molecular weight outer membrane protein (OMP) and decreased imipenem penetration. Seven pairs of isolates of P. aeruginosa obtained before treatment and after emergence of resistance were examined for changes in MIC of both imipenem and meropenem, and for changes in OMP profile. Resistant mutants were obtained also from the pre-therapy strains on Mueller-Hinton agar containing increasing amounts of either drug, and maintained under antibiotic pressure. OMP preparations of all pre- and post-therapy strains and laboratory mutants were separated by polyacrylamide gel electrophoresis. Loss of a 45,000-48,000 molecular weight protein occurred in variants selected under carbapenem pressure and in all post-therapy isolates. Meropenem remained four-fold more active than imipenem against the resistant strains and mutants.

Topics: Bacterial Outer Membrane Proteins; Carbapenems; Drug Resistance, Microbial; Electrophoresis, Polyacrylamide Gel; Humans; Meropenem; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

Four major mechanisms cause resistance to beta-lactams in Pseudomonas aeruginosa: (i) cell wall impermeability gives broad-spectrum intrinsic resistance to all beta-lactams except imipenem, (i) loss of D-group outer membrane proteins correlates with narrow spectrum imipenem resistance, (iii) plasmid mediated beta-lactamases compromise antipseudomonal penicillins, cefoperazone and cefsulodin, and (iv) chromosomal beta-lactamase hyper-production compromises most beta-lactams except carbenicillin and imipenem. Meropenem was tested in vitro against P. aeruginosa isolates, mutants and transconjugants with these mechanisms. Meropenem had impaired activity (MIC 1-2 mg/l compared to 0.25 mg/l for sensitive isolates) for organisms with broad-spectrum intrinsic resistance. MICs of meropenem also were elevated (to 1-2 mg/l) for mutants with D2-protein-deficiency-associated imipenem resistance. Most plasmids encoding TEM, OXA or PSE beta-lactamases did not increase the MIC (0.12 mg/l) of meropenem for P. aeruginosa PU21. Decreased susceptibility (MIC 4 mg/l), however, was observed when plasmids coding the uncommon NPS-1, PSE-2 and OXA-3 enzymes were present in this strain. MICs of meropenem remained identical for chromosomal beta-lactamase-inducible P. aeruginosa strains and their enzyme-derepressed and basal mutants, indicating that the chromosomal beta-lactamase could not protect against the new carbapenem, regardless of its mode of expression.

Topics: Bacterial Outer Membrane Proteins; beta-Lactamases; Carbapenems; Carbenicillin; Cell Membrane Permeability; DNA Transposable Elements; Drug Resistance, Microbial; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Enzymologic; Genes, Bacterial; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Plasmids; Pseudomonas aeruginosa; Pseudomonas Infections; Thienamycins

Meropenem and comparative antibiotics were evaluated in five models of infection. All antibiotics were administered parenterally; imipenem was used in combination with cilastatin but meropenem and other agents were given alone. Generalized infections in mice caused by Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Serratia marcescens, Proteus mirabilis or Pseudomonas aeruginosa all responded to low doses of meropenem or imipenem. Immunocompromised mice infected with Ps. aeruginosa responded to slightly higher doses of meropenem or gentamicin but required four to seven times the dose of other agents. Those given a greater challenge of Ps. aeruginosa were treated most successfully by meropenem. Treatment with meropenem, imipenem or ceftazidime caused significant reductions of E. coli in the urinary bladder and kidneys of mice challenged per urethram. Infection with Ps. (Xanthomonas) maltophilia localized to the subcutaneous neck tissue of guinea pigs was also treated successfully. Lung infections caused by Ps. aeruginosa in guinea pigs were treated effectively by meropenem, imipenem, and ceftazidime at the dose of 10 mg/kg but only meropenem eradicated bacteria from all the tissues examined. These results demonstrate that meropenem has excellent antibacterial activity in vivo in both normal and immunocompromised animals and in some models of infection is superior to imipenem.

Topics: Animals; Anti-Bacterial Agents; Bacterial Infections; Carbapenems; Escherichia coli Infections; Guinea Pigs; Immunosuppression Therapy; Lung Diseases; Male; Meropenem; Mice; Mice, Inbred Strains; Microbial Sensitivity Tests; Pseudomonas Infections; Respiratory Tract Infections; Thienamycins; Urinary Tract Infections