piperacillin--tazobactam-drug-combination 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

Orbital cellulitis is a rare complication of aqueous tube shunt surgery. Nine cases have been described in the literature, though the microbiologic etiology is rarely reported. Management with intravenous antibiotics and/or explantation has been described.. This is a case report and literature review.. A 64-year-old woman developed pain, periorbital swelling, limited extraocular motility, proptosis, and conjunctival injection 3 days following implantation of an Ahmed Glaucoma Valve. Computed tomography of the orbits with contrast showed soft tissue fat stranding consistent with orbital inflammation. Initial medical management with topical and intravenous ceftriaxone and vancomycin was unsuccessful. Surgical removal of the implant was performed and intraoperative cultures demonstrated florid Pseudomonas aeruginosa growth. Antibiotic coverage was changed to Piperacillin-Tazobactam for 3 days, with eventual resolution of her orbital symptoms.. We report the first case of orbital cellulitis after implantation of a glaucoma device associated with P. aeruginosa. Failure of intravenous and topical antibiotics led to explantation of the valve and targeted intravenous antibiotic therapy with subsequent clinical improvement.

Topics: Aged, 80 and over; Anti-Bacterial Agents; Device Removal; Eye Infections, Bacterial; Female; Glaucoma Drainage Implants; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Orbital Cellulitis; Piperacillin, Tazobactam Drug Combination; Prosthesis Implantation; Prosthesis-Related Infections; Pseudomonas aeruginosa; Pseudomonas Infections; Tomography, X-Ray Computed

Identifying risk factors predicting acquisition of resistant. MEDLINE®, EMBASE®, and Cochrane Central were searched between 2000 and 2016 for studies examining independent risk factors associated with acquisition of resistant. Of the 54 eligible articles, 28 publications (31studies) examined multi-drug resistant (MDR) or extensively drug resistant (XDR). Prior use of antibiotics and prior hospital or ICU stay was the most significant risk factors for acquisition of resistant

Topics: Adult; Aged; Anti-Bacterial Agents; Carbapenem-Resistant Enterobacteriaceae; Carbapenems; Cephalosporins; Critical Care; Cross Infection; Drug Resistance, Multiple, Bacterial; Female; Humans; Intensive Care Units; Male; Middle Aged; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Quinolones; Risk Factors; Vancomycin

The incidence of endophthalmitis after pars plana vitrectomy is low. Silicone oil is a tamponading agent which has anti-microbial activity. Post-operative endophthalmitis following vitrectomy with silicone oil tamponade has been rarely reported. We describe the case of a young male who underwent pars plana vitrectomy with silicone oil for retinal detachment with a giant retinal tear. He developed a clinical picture suggestive of endophthalmitis on the first post-operative day, and vitreous culture grew multidrug-resistant Pseudomonas aeruginosa. He was treated with intravitreal piperacillin/tazobactam, along with appropriate surgical management. This was followed by resolution of the infection with a remarkable improvement in visual acuity. This is the first case of multidrug-resistant Pseudomonas aeruginosa endophthalmitis following pars plana vitrectomy with silicone oil treated successfully with piperacillin/tazobactam.

Topics: Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Endophthalmitis; Humans; Male; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Postoperative Complications; Pseudomonas aeruginosa; Pseudomonas Infections; Retinal Detachment; Retinal Perforations; Silicone Oils; Visual Acuity; Vitrectomy; Young Adult

A 77-year-old man had undergone left-lobe liver resection and a choledochojejunostomy six years previously, and thereafter he suffered from a postoperative relapse of cholangitis. He was admitted to our hospital due to liver abscesses and bacteremia caused by multidrug-resistant Pseudomonas aeruginosa. Empirical treatment with piperacillin/tazobactam was started, and the patient initially recovered. However, he developed a second case of sepsis caused by piperacillin/tazobactam-resistant P. aeruginosa bacteremia originating from a new liver abscess. We changed the piperacillin/tazobactam to colistin and flomoxef and continued the two antibiotics for one month. During the antibiotic therapy, the patient successfully underwent bile duct stent placement.

Topics: Aged; Anti-Bacterial Agents; Bacteremia; Cephalosporins; Cholangitis; Colistin; Drug Resistance, Multiple, Bacterial; Humans; Kidney; Liver Abscess, Pyogenic; Male; Microbial Sensitivity Tests; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections

Acute pulmonary exacerbations (APE) are well-described complications of cystic fibrosis (CF) and are associated with progressive morbidity and mortality. Despite aggressive management with two or more intravenous anti-pseudomonal agents, approximately 25% of exacerbations will result in a loss of lung function. The aim of this review is to provide an evidence-based summary of pharmacokinetic/pharmacodynamic (PK/PD), tolerability, and efficacy studies utilizing anti-pseudomonal cephalosporins (i.e., ceftazidime and cefepime) and penicillins (i.e., piperacillin-tazobactam and ticarcillin-clavulanate) in the treatment of APE and to identify areas where further study is warranted. The ceftazidime and cefepime dosing ranges from the literature are 200-400 mg/kg/day divided every 6-8 hr, maximum 8-12 g/day, and 150-200 mg/kg/day divided every 6-8 hr, up to 6-8 g/day, respectively. The literature supported dosing ranges for piperacillin and ticarcillin are 350-600 mg/kg/day divided every 4 hr, maximum 18-24 g/day of piperacillin component, and 400-750 mg/kg/day divided every 6 hr, up to 24-30 g/day of ticarcillin component, respectively. As a large portion of CF patients will not regain their lung function following an APE, we suggest the need to optimize antibiotic dosing and dosing regimens used to treat an APE in efforts to improve outcomes for CF patients infected with Pseudomonas aeruginosa. Future studies are needed to determine the clinical efficacy of higher than FDA-approved doses of ceftazidime, cefepime, and ticarcillin-clavulanate in APE. The usefulness of high dose piperacillin (>600 mg/kg/day) may be limited due to treatment-related adverse effects. Further understanding of these adverse effects in CF patients is needed.

Topics: Anti-Bacterial Agents; beta-Lactam Resistance; Cefepime; Ceftazidime; Cephalosporins; Clavulanic Acids; Cystic Fibrosis; Disease Progression; Drug Therapy, Combination; Humans; Microbial Sensitivity Tests; Penicillanic Acid; Penicillins; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Ticarcillin

To perform a qualitative systematic review of the evidence comparing traditional strategies against prolonged intermittent or continuous infusion strategies for piperacillin/tazobactam, based on clinical and pharmacodynamic outcomes.. MEDLINE (1950-September 2011), EMBASE (1980-September 2011), and International Pharmaceutical Abstracts (1970-September 2011) were searched, using the terms piperacillin, tazobactam, pharmacokinetics, pharmacodynamics, dosing, and infusion. Reference lists from relevant publications were also reviewed.. Articles evaluating the administration of piperacillin/tazobactam to adults and comparing at least 2 dosing regimens (1 of which included the traditional, manufacturer-recommended 30-minute infusion; the other, a prolonged or continuous infusion strategy) were included. Prespecified clinical outcomes of interest included mortality, clinical cures, and adverse events. The pharmacodynamic endpoint of interest was percent time of unbound drug concentration remaining above the minimum inhibitory concentration.. Twelve studies were included in this review, 7 of which assessed clinical outcomes and 5 that assessed pharmacodynamic endpoints using Monte Carlo simulations. Prolonged or continuous infusions of piperacillin/tazobactam consistently achieved higher pharmacodynamic endpoints than did traditional infusions. The association of prolonged or continuous infusions with improved clinical outcomes, however, is unclear. Two retrospective studies found improved mortality rates with prolonged infusions (1 in a subgroup of patients with higher APACHE II [Acute Physiology and Chronic Health Evaluation II] scores), while another retrospective study found improved clinical cure rates with continuous infusions in patients with ventilator-associated pneumonia. These clinical benefits have not been substantiated in prospective randomized trials. No study has provided evidence of reduced adverse effects with prolonged or continuous infusions.. The limited evidence available does not firmly support widespread adoption of administering piperacillin/tazobactam as prolonged intermittent or continuous infusions to improve clinical outcomes despite the achievement of higher pharmacodynamic targets in simulated studies. Retrospective studies indicate that critical care patients are the subgroup most likely to benefit from these dosing strategies. Well-designed prospective clinical trials are required to confirm potential benefits observed in retrospective studies.

Topics: Anti-Bacterial Agents; Drug Administration Schedule; Humans; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Treatment Outcome

The pharmacodynamics and therapeutic effects of extended-infusion (EI) piperacillin-tazobactam therapy are reviewed, with an emphasis on growing evidence of its advantages over traditional infusion schemes.. EI β-lactam therapy is now considered a key aspect of antimicrobial stewardship, and published evidence indicates that i.v. infusion of piperacillin-tazobactam over extended periods (e.g., four hours) instead of the traditionally recommended 30 minutes may offer several advantages, including reduced mortality and length of hospital stay and lower treatment cost. A substantial body of evidence from in vitro and animal studies indicates that EI enhances the pharmacodynamic profile of piperacillin-tazobactam, particularly by extending the time the free drug level remains above the minimum inhibitory concentration. In one published study comparing the use of EI and traditional piperacillin-tazobactam infusion schemes in critically ill patients with Pseudomonas aeruginosa infection, EI therapy was associated with significantly improved 14-day mortality and significantly shorter hospital stays; a few other studies have yielded less favorable results. Pharmacoeconomic evaluations indicate that EI can offer significant cost benefits. However, evidence of the benefits of EI in actual clinical practice remains relatively weak, highlighting the need for large, controlled clinical trials to define its optimal role in patient care.. The pharmacodynamic profile of EI piperacillin-tazobactam therapy; evidence of its benefits over traditional 30-minute infusions in terms of mortality, duration of hospitalization, clinical and microbiological cure rates, and reduction of fever; and EI's lower total treatment cost suggest that EI may be the superior mode of administration.

Topics: Animals; Anti-Bacterial Agents; Humans; Infusions, Intravenous; Length of Stay; Microbial Sensitivity Tests; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Time Factors

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

Pseudomonas aeruginosa is a rare cause of aortic mycotic aneurysms. Optimal treatment, including reconstructive graft material and appropriate length of antibiotic therapy, is being debated.. We describe a 26-year-old kidney-pancreas recipient who developed an aneurysm of the descending thoracic aorta caused by P. aeruginosa.. After surgical debridement and cryopreserved allograft reconstruction, parenteral antibiotics were continued for 12 months, at which time the patient was converted to oral antibiotic therapy. Within 6 months, he redeveloped a thoracic aortic aneurysm, necessitating reoperation and lifelong parenteral antibiotic therapy.. Herein we review and discuss the relevant literature concerning surgical and antibiotic treatment of mycotic thoracic aneurysms.

Topics: Adult; Aneurysm, Infected; Aortic Aneurysm, Thoracic; Aztreonam; Blood Vessel Prosthesis Implantation; Debridement; Drug Therapy, Combination; Humans; Infusions, Parenteral; Male; Organ Transplantation; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas Infections; Secondary Prevention; Treatment Outcome; Vancomycin

There is lack of information on the efficacy and safety of piperacillin–tazobactam administered by continuous infusion.. The aim of this study was to investigate whether continuous infusion of piperacillin–tazobactam is superior in terms of efficacy to a 30 % higher dose administered by intermittent infusion to treat suspected or confirmed infection due to Pseudomonas aeruginosa. Setting Multicenter clinical trial with 11 third level Spanish hospitals.. Randomized, double-blind parallel-group clinical trial, controlled by conventional administration of the drug. Patients randomly assigned in a 1:1 ratio to receive piperacillin–tazobactam as continuous infusion (CI) or intermittent (II).. Primary efficacy endpoint was percentage of patients having a satisfactory clinical response at completion of treatment, defined as clinical cure or clinical improvement. Adverse events were reported. Results 78 patients were included, 40 in the CI group and 38 in the II group. Mean (standard deviation) duration of treatment was 7 (±4.44) days. 58 patients (74.4 %) experienced cure or improvement at the end of the treatment. There were no statistical differences in cure rates between the two treatment arms and no adverse events were reported.. Continuous infusion of piperacillin–tazobactam is an alternative administration drug method at least similar in efficacy and safety to conventional intermittent infusion. Multivariate analysis is needed to determine whether continuous administration might be more beneficial than intermittent in certain patient subgroups.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacterial Load; Cross Infection; Double-Blind Method; Drug Administration Schedule; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Remission Induction; Spain; Time Factors; Treatment Outcome; Young Adult

To describe the population pharmacokinetics of the piperacillin component of piperacillin/tazobactam.. This pharmacokinetic study included 21 pediatric (age 3-10 years) patients receiving piperacillin/tazobactam to treat fever with neutropenia. Each patient contributed 1-3 blood samples for piperacillin concentration determination. Population pharmacokinetic analyses were conducted using Pmetrics software. A 5,000 patient Monte Carlo simulation was performed to determine the probability of target attainment (PTA) for multiple dosing regimens, using 50% of free drug time above the minimum inhibitory concentration (MIC) as the primary pharmacodynamic threshold.. Mean ± SD body weight was 28.5 ± 9.7 kg. Piperacillin concentration data best fit a two-compartment model with linear clearance, using total body weight as a covariate for clearance (CLθ ) and volume of the central compartment (Vcθ ). Population estimates for CLθ , Vcθ , and intercompartment transfer constants were 0.204 ± 0.076 L/h/kg, 0.199 ± 0.107 L/kg, 0.897 ± 1.050 h(-1) , and 1.427 ± 1.609 h(-1) , respectively. R(2) , bias, and precision for the Bayesian fit were 0.998, -0.032, and 2.2 µg/ml, respectively. At the MIC breakpoint of 16 µg/ml for Pseudomonas aeruginosa, PTAs for 50 mg/kg q4h as a 0.5 hr infusion was 93.9%; for 100 mg/kg q8h as 0.5 and 4 hr infusion: 64.6% and 100%; for 100 mg/kg q6h as 0.5 and 3 hr infusion: 86.5% and 100%; and for 400 mg/kg continuous infusion: 100%, respectively.. In children with fever and neutropenia, piperacillin/tazobactam dosing regimens that are administered every 4 hr or that employ prolonged or continuous infusions should be considered to optimize pharmacodynamic exposure.

Topics: Anti-Bacterial Agents; Child; Child, Preschool; Female; Fever; Humans; Male; Models, Biological; Neoplasms; Neutropenia; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections

Given the high frequency of acute pulmonary exacerbations due to Pseudomonas aeruginosa in patients with cystic fibrosis (CF), piperacillin/tazobactam is commonly used in empirical regimens. While extended-infusion piperacillin/tazobactam has been employed as one strategy to optimize this agent's pharmacodynamics, this approach has not been well characterized in patients with CF. The objectives of this study were to characterize the pharmacokinetics and pharmacodynamics of extended-infusion piperacillin/tazobactam in adult patients with CF and derive optimized piperacillin/tazobactam dosing recommendations.. Six serum samples were collected from nine adult patients with CF hospitalized for acute pulmonary exacerbations who received 3/0.375 g of piperacillin/tazobactam intravenously for 4 h every 8 h. Population pharmacokinetic models were fitted to the data utilizing first-order, Michaelis-Menten (MM) and parallel first-order/MM clearance. Monte Carlo simulations were performed to determine the probability of target attainment (PTA) for regimens where free piperacillin concentrations were above the MIC for at least 50% of the dosing interval.. The model incorporating MM clearance best described the data. Results of our simulation revealed that piperacillin/tazobactam dosed at 3-4 g for 30 min every 6-8 h led to <90% PTA against MIC values >4 mg/L. More intensive prolonged infusion regimens than are commonly used in practice, such as continuous infusions or 3 h infusions every 6 h, were needed to maximize the PTA for MICs ≥ 8 mg/L.. Intensive prolonged infusion regimens are the best option to ensure optimal exposures against most susceptible isolates in adult patients with CF.

Topics: Adult; Anti-Bacterial Agents; Cystic Fibrosis; Female; Humans; Infusions, Intravenous; Male; Microbial Sensitivity Tests; Middle Aged; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pneumonia, Bacterial; Pseudomonas aeruginosa; Pseudomonas Infections; Serum; Time Factors; Treatment Outcome; Young Adult

When piperacillin/tazobactam has been used to treat hospitalized patients with serious infections, including nosocomial pneumonia caused by Pseudomonas aeruginosa, it has usually been dosed at 3.375 g q4h to provide serum concentrations above commonly encountered organisms' MICs (T > MIC) for at least 40-50% of the dosing interval. Pharmacodynamic principles suggest that a similar efficacy can be realized with extended dosing intervals when a larger dose (e.g. 4.5 g q6h) is administered, which was the objective of this study. Twelve healthy volunteers, 29.4 +/- 8.9 years of age, were enrolled in this multiple-dose, open-labeled, randomized, two-period crossover study. Blood samples were collected after the third dose and concentrations of piperacillin/tazobactam were determined with a validated HPLC method. Pharmacokinetic profiles were determined by noncompartment analysis. T > MIC of piperacillin was calculated for a range of MIC values. Piperacillin/tazobactam was well tolerated in 11 subjects who completed both regimens. The C(max), T(1/2), K, and AUC of P were significantly different according to a paired t test (p < 0.05) between two study regimens. Significant differences (p < 0.05) in tazobactam regimens were noted for C(max), and AUC. The piperacillin/tazobactam regimen of 4.5 g q6h achieved a 44% T > MIC for MIC values of < or = 16 microg/ml, while the 3.375-gram q4h regimen achieved 42% T > MIC, for MIC values of < or = 32 microg/ml. Dosage regimens for treating serious infections can be extended safely and effectively to 4.5 g q6h and obtain at least 40-50% T > MIC in the coverage of pathogens implicated with serious infections, including P. aeruginosa.

Topics: Adult; Area Under Curve; Chromatography, High Pressure Liquid; Cross-Over Studies; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Male; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections

The significantly higher mortality rate in the critical illness patients with Pseudomonas aeruginosa (PA) infection is linked to inappropriate selecting of empirical treatment. Traditional local antibiogram provides clinicians the resistant rate of a single antimicrobial agent to the pathogen in the specific setting. The information is valuable to the clinicians in selecting suitable empirical antibiotic therapy. However, traditional local antibiogram can only provide information for single agent empirical antibiotic not combination regimens. The combination antibiogram should be developed to facilitate the selection of appropriate antibiotics to broader the coverage rate of resistant PA.. The susceptibility to the β-lactam antibiotics (piperacillin/tazobactam (PTZ), ceftazidime, cefepime, imipenem, or meropenem) or to those administered in combination with an aminoglycoside (gentamicin or amikacin) or fluoroquinolone (ciprofloxacin or levofloxacin) was calculated. The chi-square test was used to compare the differences of combination coverage rates between non-ICU and ICU isolates.. 880 PA isolates were isolated during study period. The susceptibility of single agents ranged from 83.1% to 89.7%. The combination regimens containing amikacin provide the highest cover rate (98.9%-99.1%) and those containing levofloxacin provide less coverage rate (92.3%-93.9%). The susceptibility to five β-lactam single agents in ICU isolates significantly lower than non-ICU isolates. The non-ICU isolates exhibited significantly higher susceptibility to the PTZ-gentamicin (p = 0.002) and ceftazidime-gentamicin (p = 0.025) than ICU isolates.. Our results support the use of aminoglycosides instead of fluoroquinolones as additive agents in empirical combination treatments for patients with critical infections caused by PA.

Topics: Amikacin; Aminoglycosides; Anti-Bacterial Agents; Ceftazidime; Fluoroquinolones; Gentamicins; Hospitals, Teaching; Humans; Levofloxacin; Microbial Sensitivity Tests; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Universities

Topics: Anti-Bacterial Agents; Humans; Microbial Sensitivity Tests; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections

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

In Europe, Serbia occupies a high position in antibiotic utilization and antimicrobial resistance (AMR).. The aim was to analyse utilization trends of meropenem, ceftazidime, aminoglycosides, piperacillin/tazobactam and fluoroquinolones (2006-2020), and the reported AMR in Pseudomonas aeruginosa (2013-2020) in Serbia and to compare with data from eight European countries (2015-2020).. Joinpoint regression was used to analyse antibiotic utilization data (2006-2020) and the reported AMR in Pseudomonas aeruginosa (2013-2020). Data sources were relevant national and international institutions. Antibiotic utilization and AMR in Pseudomonas aeruginosa data in Serbia were compared with eight European countries.. There was a significantly increased trend for ceftazidime utilization and reported resistance in Pseudomonas aeruginosa, Serbia (p < 0.05) (2018-2020). For ceftazidime, piperacillin/tazobactam, and fluoroquinolones resistances in Pseudomonas aeruginosa an increased trend was observed, Serbia (2013-2020). A decrease in both the utilization of aminoglycosides, Serbia (p < 0.05) (2006-2018) and contemporaneous Pseudomonas aeruginosa resistance (p > 0.05) was detected. Fluoroquinolone utilization (2015-2020) was highest in Serbia compared to Netherlands and Finland, 310 and 305% higher, similar compared to Romania, and 2% less compared to Montenegro. Aminoglycosides (2015-2020) were 2550 and 783% more used in Serbia compared to Finland and Netherlands, and 38% less regarding Montenegro. The highest percentage of Pseudomonas aeruginosa resistance was in Romania and Serbia (2015-2020).. The use of piperacillin/tazobactam, ceftazidime and fluoroquinolones should be carefully monitored in clinical practice due to increased Pseudomonas aeruginosa resistance. The level of utilization and AMR in Pseudomonas aeruginosa is still high in Serbia compared to other European countries.

Topics: Aminoglycosides; Anti-Bacterial Agents; Anti-Infective Agents; Ceftazidime; Fluoroquinolones; Humans; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Serbia

Pseudomonas aeruginosa isolates were consecutively collected from patients with pneumonia in 29 medical centers in 2020 and susceptibility tested by broth microdilution method. Ceftazidime-avibactam (95.5% susceptible), imipenem-relebactam (94.3% susceptible), and ceftolozane-tazobactam (93.3% susceptible) were the most active compounds after colistin (99.5% susceptible). Susceptibility rates for the β-lactam/β-lactamase inhibitor combinations (BL/BLIs) varied against isolates resistant to piperacillin-tazobactam, meropenem, imipenem, and/or ceftazidime. Ceftazidime-avibactam was the most active BL/BLI against resistant subsets from Western Europe, whereas imipenem-relebactam was slightly more active than other BL/BLIs against resistant subsets from Eastern Europe. Susceptibility rates were markedly lower in Eastern Europe than Western Europe.

Topics: Azabicyclo Compounds; beta-Lactamase Inhibitors; Ceftazidime; Cephalosporins; Drug Combinations; Drug Resistance, Multiple, Bacterial; Hospitalization; Humans; Imipenem; Jupiter; Microbial Sensitivity Tests; Piperacillin, Tazobactam Drug Combination; Pneumonia; Pseudomonas aeruginosa; Pseudomonas Infections; Tazobactam

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

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

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

Bacteria are the commonest etiological factor among the microbes that cause UTIs. The most prevalent bacteria identified in the lab are Escherichia coli, Klebsiella pneumonia and Pseudomonas aeruginosa. Antibiotics are the empiric therapy for such infections but the reoccurrence rate is becoming high owing to the development of resistance due to their irrational and indiscriminate use across the globe. This study was designed on UTI cases of OPD, Medical, Nephrology, Surgical, Main OT, Urology and ICU wards of Allied hospital Faisalabad. 11 antibiotics were used which showed that E. coli is sensitive to Amikacin, Gentamicin, Imipenem, Piperacillin tazobactam, and Polymyxin B. Klebsiella pneumonia showed sensitivity for Amikacin, Gentamicin, Nitrofurantoin, Imipenem, Polymyxin B, Piperacillin tazobactam and Trimethoprim-sulfamethoxazole. While Pseudomonas aurignosa showed resistance to Amikacin, Ciprofloxacin, Gentamicin, Piperacillin tazobactam, Imipenem, and Polymyxin B. E. coli exhibited the highest sensitivity for Piperacillin tazobactam, Klebsiella pneumonia for Imipenem and Pseudomonas aurignosa for Ciprofloxacin. Further, the isolated DNA samples of these microorganisms were confirmed by gel electrophoresis and subjected to molecular characterization by performing trace file and phylogenetic tree analysis.

Topics: Amikacin; Amoxicillin-Potassium Clavulanate Combination; Anti-Bacterial Agents; Ciprofloxacin; Drug Resistance, Multiple, Bacterial; Escherichia coli; Escherichia coli Infections; Gentamicins; Humans; Imipenem; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Nitrofurantoin; Oxacillin; Pakistan; Pipemidic Acid; Piperacillin, Tazobactam Drug Combination; Polymyxin B; Pseudomonas aeruginosa; Pseudomonas Infections; Trimethoprim, Sulfamethoxazole Drug Combination; Urinary Tract Infections

The aim of this study was to evaluate the efficacy and safety of outpatient antimicrobial therapy with piperacillin-tazobactam in continuous infusion using elastomeric pumps and to evaluate the economic impact compared with conventional hospital treatment in patients with Pseudomonas aeruginosa (PA) infections. This is an observational study. Patients with PA infection treated with continuous piperacillin-tazobactam infusion using elastomeric pumps in our hospital between January 2015 and December 2017 were included. Primary outcomes were mortality during antibiotic treatment and mortality at 30 days. Secondary outcomes were reinfection or relapse at 30 days and clinical cure rate. The cost of each episode was compared with theoretical cost of the same treatment using conventional hospitalization. 35 patients were included. One patient (2.9%) died during the treatment. Overall 30-day mortality was 5.7%. No death was related to infection by PA. One patient (2.9%) had a reinfection at 30 days. Cure was achieved in 93% of patients at the end of treatment. There were no severe complications related to elastomeric pumps. Treatment cost with outpatient antimicrobial therapy was 67% lower than theoretical cost with conventional hospital treatment. Oupatient antimicrobial therapy with piperacillin-tazobactam in continuous infusion using elastomeric pumps in patients with PA infections is safe and effective with lower costs.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasm Recurrence, Local; Outpatients; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies

Topics: Administration, Intravenous; Anti-Bacterial Agents; Blood Culture; Cellulitis; Female; Glucocorticoids; Humans; Leg; Lupus Erythematosus, Systemic; Middle Aged; Piperacillin, Tazobactam Drug Combination; Prednisolone; Prognosis; Pseudomonas Infections; Pseudomonas putida

Piperacillin is a β-lactam antimicrobial frequently used in critically ill patients with acute kidney injury treated with continuous renal replacement therapy (CRRT). However, data regarding piperacillin tissue concentrations in this patient population are limited. A prospective observational study was conducted of free piperacillin concentrations during a single 8-h dosing interval in plasma (8 samples) and subcutaneous tissue (SCT) (13 samples), in 10 patients treated with CRRT following piperacillin 4 g given every 8 h as intermittent administration over 3 min.. A population pharmacokinetic model was developed using NONMEM 7.4.3, to simulate alternative administration modes and dosing regimens. SCT concentrations were obtained using microdialysis. Piperacillin concentrations were compared to the clinical breakpoint minimum inhibitory concentration (MIC) for Pseudomonas aeruginosa (16 mg/l), with evaluation of the following pharmacokinetic/pharmacodynamics targets: 50% fT > 1 × MIC, 100% fT > 1 × MIC, and 100% fT > 4 × MIC.. SCT concentrations were generally lower than plasma concentrations. For the target of 50% free time (fT) > 1 × MIC and 100% fT > 1 × MIC, piperacillin 4 g every 8 h resulted in probability of target attainment (PTA) >90% in both plasma and SCT. PTA > 90% for the target of 100% fT > 4 × MIC was only achieved for continuous infusion.. Piperacillin 4 g every 8 h is likely to provide sufficient exposure in both plasma and SCT to treat P.aeruginosa infections in critically ill patients on CRRT, given that targets of 50% fT > 1 × MIC or 100% fT > 1 × MIC are adequate. However, if a more aggressive target of 100% fT > 4 × MIC is adopted, continuous infusion is needed.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacterial Infections; Computer Simulation; Continuous Renal Replacement Therapy; Female; Humans; Male; Models, Biological; Piperacillin, Tazobactam Drug Combination; Prospective Studies; Pseudomonas aeruginosa; Pseudomonas Infections; Subcutaneous Tissue

We characterized AmpC β-lactamase mutations that resulted in ceftolozane/tazobactam resistance in extensively drug-resistant (XDR) Pseudomonas aeruginosa isolates recovered from patients treated with this agent from June 2016 to December 2018.. Five pairs of ceftolozane/tazobactam susceptible/resistant P. aeruginosa XDR isolates were included among a total of 49 patients treated. Clonal relationship among isolates was first evaluated by pulsed-field gel electrophoresis (PFGE). Multilocus sequence typing (MLST) was further performed. AmpC mutations were investigated by PCR amplification of the blaPDC gene followed by sequencing.. The ST175 high-risk clone was detected in four of the pairs of isolates and the ST1182 in the remaining one. All resistant isolates showed a mutation in AmpC: T96I in two of the isolates, and E247K, G183V, and a deletion of 19 amino acids (G229-E247) in the other three. The G183V mutation had not been described before. The five isolates resistant to ceftolozane/tazobactam showed cross-resistance to ceftazidime/avibactam and lower MICs of imipenem and piperacillin/tazobactam than the susceptible isolates.. Ceftolozane/tazobactam resistance was associated in all of the cases with AmpC mutations, including a novel mutation (G183V) not previously described. There is a vital need for surveillance and characterization of emerging ceftolozane/tazobactam resistance, in order to preserve this valuable antipseudomonal agent.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Bacterial Proteins; beta-Lactamases; Ceftazidime; Cephalosporins; Drug Combinations; Drug Resistance, Multiple, Bacterial; Humans; Imipenem; Microbial Sensitivity Tests; Multilocus Sequence Typing; Mutation; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Tazobactam

Topics: Adult; Anti-Bacterial Agents; Bacteremia; Humans; Microbial Sensitivity Tests; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies

Cystic fibrosis (CF) patients, with Pseudomonas aeruginosa infection, often require repeated aminoglycoside courses for the management of acute pulmonary exacerbations (APEs). Acute kidney injury (AKI) due to aminoglycosides has been reported; little data exist regarding long-term nephrotoxicity with repeated exposure. The objective of this study was to describe the incidence of acute and chronic nephrotoxicity due to cumulative intravenous (IV) aminoglycoside exposure. This is a retrospective, observational study of pediatric and adult CF patients admitted to an academic medical center between January 1, 2006 and October 1, 2018 for APE management. Patients were eligible for inclusion if they received at least five courses of an IV aminoglycoside for at least 7 days each. Cumulative weight-based aminoglycoside dose was reported in milligrams per kilogram. For each admission, baseline and highest serum creatinine were collected to assess the incidence of AKI. The baseline and final estimated glomerular filtration rate (eGFR) were calculated to assess long-term effects on renal function. Sixty-six patients, representing greater than 700 courses, were included in the final analysis. The median cumulative weight-based aminoglycoside dose was 1183 mg/kg of tobramycin or tobramycin equivalent. Twenty percent of courses resulted in AKI; 86% were Stage 1. A repeated measure multivariate model showed colistin, piperacillin/tazobactam, vancomycin, and age were significant AKI risk factors. There was no correlation between cumulative aminoglycoside dose and change in eGFR. AKI from IV aminoglycoside exposure occurred in 20% of courses. Cumulative exposure to IV aminoglycosides in APE management was not correlated with long-term renal dysfunction.

Topics: Acute Kidney Injury; Adolescent; Adult; Age Factors; Anti-Bacterial Agents; Child; Child, Preschool; Colistin; Cystic Fibrosis; Female; Humans; Incidence; Infant; Male; Middle Aged; Piperacillin, Tazobactam Drug Combination; Pseudomonas Infections; Retrospective Studies; Risk Factors; Tobramycin; Vancomycin; Young Adult

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

Topics: Anti-Bacterial Agents; Child; Child, Preschool; Cross Infection; Female; Humans; Infant; Male; Microbial Sensitivity Tests; Piperacillin; Piperacillin, Tazobactam Drug Combination; Prospective Studies; Pseudomonas aeruginosa; Pseudomonas Infections; Tazobactam

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

Pseudomonas aeruginosa bacteraemia is associated with a very high mortality, conditioned by comorbidity, source, severity of the episode and lack of adequate treatment. The aim of the study is to know the mortality and prognostic factors of bacteraemia by P.aeruginosa in our hospital.. We conducted a retrospective study of P.aeruginosa bacteraemia detected between 2009 and 2014. Epidemiological, clinical and microbiological characteristics were described. A risk factor analysis for mortality was performed.. We analysed 110 episodes of bacteraemia, which was more frequent in men of advanced age and with a history of hospitalisation, comorbidity and immunosuppression. Most of the bacteraemias were secondary (mainly of respiratory or urinary source) and led to a significant clinical deterioration. The presence of antibiotic resistance was very high, with 27.3% of multiresistant strains. Empirical treatment was adequate in 60.0% and 92.3% for definite treatment. Overall mortality was 37.3% and attributable mortality was 29.1%. The most important prognostic factors were Charlson index ≥3, history of haematologic malignancy, neutropenia and previous use of corticosteroids, source of bacteraemia, Pitt index ≥4, renal insufficiency, adequate definite treatment, empiric treatment with piperacillin/tazobactam in severe episodes and focus control.. P.aeruginosa bacteraemia is associated with a very high mortality, possibly more related to previous comorbidity and severity of the episode than to the treatment chosen. However, the main goal in management remains to optimise treatment, including focus control.

Topics: Adrenal Cortex Hormones; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacteremia; Community-Acquired Infections; Comorbidity; Cross Infection; Drug Resistance, Multiple, Bacterial; Female; Hospitalization; Humans; Immunocompromised Host; Male; Middle Aged; Neoplasms; Piperacillin, Tazobactam Drug Combination; Prognosis; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies; Spain; Tertiary Care Centers

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

Pseudomonas aeruginosa is one of the most important pathogens in cystic fibrosis. This study was conducted to analyse the genetic basis and phylogenetic profile of resistance to ceftazidime/avibactam, ceftolozane/tazobactam and carbapenems in cystic fibrosis P. aeruginosa isolates. Whole genome sequence analysis was conducted of isolates resistant to piperacillin/tazobactam collected from seven hospitals in Scotland since the introduction of these two cephalosporin/β-lactamase inhibitor combinations. Ceftazidime resistance was primarily related to AmpC induction, as tested by cloxacillin inhibition assays, while high-level ceftazidime resistance not reversed by cloxacillin was associated with amino acid variations in AmpC. Only isolates resistant to both ceftazidime/avibactam and ceftolozane/tazobactam carried AmpD mutations, likely resulting in ampC overexpression. All isolates resistant to ceftazidime/avibactam and/or ceftolozane/tazobactam were resistant to carbapenems and showed inactivating mutations in the chromosomal oprD gene. None of the isolates bore class A, B, D plasmid-encoded carbapenemases. This study showed that mutational resistance emerged in phylogenetically distant lineages, which indicates the mutations occur independently without conferring a selective advantage to any phylogenetic lineage. These findings confirm the strong contribution of mutation-driven evolution to the population structure of P. aeruginosa.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Azabicyclo Compounds; Bacterial Proteins; beta-Lactamase Inhibitors; beta-Lactamases; Carbapenems; Ceftazidime; Cephalosporins; Cystic Fibrosis; Drug Combinations; Drug Resistance, Bacterial; Female; Hospitals; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Piperacillin, Tazobactam Drug Combination; Porins; Pseudomonas aeruginosa; Pseudomonas Infections; Scotland; Tazobactam; Whole Genome Sequencing

Topics: Anti-Bacterial Agents; Carbapenems; Cephalosporins; Cross Infection; Cross-Sectional Studies; Drug Resistance, Multiple, Bacterial; Hospitals; Humans; Intensive Care Units; Microbial Sensitivity Tests; Piperacillin, Tazobactam Drug Combination; Pneumonia, Ventilator-Associated; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies; United States

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

To find the most suitable antibiotic against urinary tract infection caused by Extended Spectrum Beta Lactamase producing uropathogens, and the epidemiology of Extended Spectrum Beta Lactamase producers.. The cross-sectional study was conducted at Pir Mehr Ali Shah University of Arid Agriculture, Rawalpindi, Pakistan, from July 2014 to July 2015, and comprised urine samples of patients suffering from urinary tract infection which were cultured on Cysteine Lactose Electrolyte Deficient agar medium. Analysis was done on Muller- Hintonagar plates and optical density was set as 0.1 at 530nm. Antimicrobial sensitivity was tested using Kirby-Bauer disc diffusion method. Further confirmation was done through gram staining and biochemical tests. Extended Spectrum Beta Lactamase production was confirmed through phenotypic methods, including phenotypic confirmatory disc diffusion test, double disc synergy test and Epsilometer test.. Of the 150 samples, 98(65%) showed growth of a total of 114 pathogenic isolates. Escherichia coli was the commonest organism in 94(82%) samples. Piperacillin Tazocin was the most suitable antimicrobial drug in 88(90%) cases. Overall, 23(20%) isolates were producers of Extended Spectrum Beta Lactamase.. Piperacillin Tazocin was found to be the drug of choice for patient suffering from urinary tract infection.

Topics: Adolescent; Adult; Anti-Bacterial Agents; beta-Lactamases; Cross-Sectional Studies; Escherichia coli; Escherichia coli Infections; Female; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Pakistan; Piperacillin, Tazobactam Drug Combination; Proteus; Proteus Infections; Pseudomonas aeruginosa; Pseudomonas Infections; Urinary Tract Infections; Young Adult

There are several empiric antibiotic treatment options for febrile neutropenia, yet there is no universally-accepted initial protocol. We aimed to assess the performance of a protocol (piperacillin, gentamicin and cefazolin) introduced over 40 years ago and compare its coverage against bacteria isolated from blood of neutropenic patients with that of various commonly used antibiotic treatment protocols.. Adults with neutropenia admitted between 2003 and 2012 to the hemato-oncologic departments and in whom blood cultures were taken on admission were included. Appropriateness of several common antibiotic protocols was assessed based on the susceptibility of the blood isolates. Crude mortality rates were computed by the susceptibility of bacteria isolated from patients' blood to the actual treatment given.. In total, 180 admissions of neutropenic patients (95 in patients who had fever above 38 °C) with positive blood cultures were analyzed. The actual antibiotic regimen prescribed was deemed appropriate in 82% of bacteremia episodes. The recommended institutional protocol was used in 62% of bacteremia episodes in neutropenic patients. This protocol would have been appropriate in 85% of all neutropenic bacteremia episodes and 89% of episodes in febrile neutropenia patients compared with piperacillin/tazobactam (79%, P = 0.13 and 76%, P = 0.002, respectively) and imipenem (93%, P = 0.004 and 92%, P = 0.74, respectively). Isolation of bacteria resistant to the actual antibiotic treatment given was associated with higher mortality at one week and at 30 days.. Common current antibiotic regimens provide similar coverage among febrile neutropenic patients, whereas broad spectrum antibiotic combinations maximize coverage among neutropenic patients.

Topics: Adult; Anti-Bacterial Agents; Bacteremia; Blood Culture; Carbapenem-Resistant Enterobacteriaceae; Cefazolin; Clinical Protocols; Enterobacteriaceae Infections; Gentamicins; Humans; Imipenem; Microbial Sensitivity Tests; Middle Aged; Neoplasms; Neutropenia; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies; Staphylococcal Infections; Staphylococcus aureus; Streptococcal Infections; Streptococcus

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

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

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

This study investigated the resistance of bacteria isolated from diabetic foot ulcers (DFUs) to antibiotics frequently used in the management of the diabetic foot infections, at a range of pH values (pH 6.5, 7.5, and 8.5) known to exist in DFU wound fluid. This study aimed to determine whether changes (or atypical stasis) in wound fluid pH modulate the antibiotic resistance of DFU isolates, with potential implications in relation to the suppression/eradication of bacterial infections in DFUs.. Thirty bacterial isolates were recovered from DFU wound fluid, including Staphylococcus spp, Staphylococcus aureus, Escherichia coli, Streptococcus spp, Pseudomonas spp, and Pseudomonas aeruginosa. The resistances of these isolates to a panel of antibiotics currently used in the treatment of infected or potentially infected DFUs, ie, ciprofloxacin, amoxicillin-clavulanate, doxycycline, and piperacillin-tazobactam, at the previously mentioned pH values were determined by a modification of the Kirby-Bauer assay.. The resistance of DFU isolates to clinically relevant antibiotics was significantly affected by the pH levels in DFU wound fluid.. These findings highlight the importance of a more comprehensive understanding of the conditions in DFUs to inform clinical decision making in the selection and application of antibiotics in treating these difficult-to-heal wounds. The scale of the differences in the efficacies of antibiotics at the different pH values examined is likely to be sufficient to suggest reconsideration of the antibiotics of choice in the treatment of DFU infection.

Topics: Anti-Bacterial Agents; Diabetic Foot; Drug Resistance, Microbial; Humans; Microbial Sensitivity Tests; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Staphylococcal Infections; Wound Healing

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

Topics: Aged; Anti-Bacterial Agents; Azithromycin; Campylobacter Infections; Coinfection; Colitis, Ulcerative; Feces; Female; Fever; Humans; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas Infections; Sigmoidoscopy; Treatment Outcome

Topics: Aged; Amikacin; Anti-Bacterial Agents; Case-Control Studies; Colistin; Drug Resistance, Multiple, Bacterial; Female; Humans; Immunocompromised Host; Intensive Care Units; Male; Microbial Sensitivity Tests; Middle Aged; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pneumonia, Ventilator-Associated; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies; Ventilators, Mechanical

A 31-year-old woman with systemic lupus erythematosus presented to the emergency department with cough for 1 week. Chest radiograph demonstrated cavitating lesion in the right upper zone with surrounding ground-glass change. Blood culture results from the day of hospital presentation grew

Topics: Adult; Anti-Bacterial Agents; Diagnosis, Differential; Female; Humans; Immunocompromised Host; Lung Diseases; Lupus Erythematosus, Systemic; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Tomography, X-Ray Computed

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

Pseudomonas spp are important opportunistic and nosocomial pathogens. One such species is Pseudomonas monteilii (P. monteilii). It has been described as an environmental contaminant and potential pathogen. We identified this organism as the causative agent of an exacerbation of bronchiectasis and an environmental contaminant in our hospital on two separate occasions.. P. monteilii was the cause of an exacerbation of bronchiectasis in a 30-year-old HIV negative male. Patient presented with cough with sputum production and exertional dyspnea. The isolate was recovered from a sputum sample in significant counts and definitively identified by Matrix-Assisted Laser Desorption/Ionisation- Time of Flight Mass Spectrometry (MALDI-TOF MS). He was treated with piperacillin-tazobactam and recovered clinically and microbiologically. Another two isolates of the organism were contaminants from the hospital environment. The three isolates were susceptible to all tested antibiotics. Typing by Random amplification of polymorphic DNA (RAPD) found no clonal relationship between them.. Less common species of Pseudomonas need to be identified accurately. This organism is identified by commonly used phenotypic systems as P. putida which may have contributed to a lower reported prevalence. P. monteilii is a known environmental contaminant and must also be considered as a potential pathogen, particularly in patients with chronic lung disease.

Topics: Adult; Bronchiectasis; Humans; Male; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas; Pseudomonas Infections; Random Amplified Polymorphic DNA Technique; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

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

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

The Clinical and Laboratory Standards Institute (CLSI) recently re-examined Pseudomonas aeruginosa minimum inhibitory concentration (MIC) susceptibility breakpoints for piperacillin/tazobactam (TZP). The objectives of this study were to analyse the impact of elevated TZP MICs (32-64 mg/L) versus lower respective MICs on P. aeruginosa bacteraemia patient outcomes. Data were gathered from a Veterans Health Administration national clinical database on P. aeruginosa bacteraemia episodes from 2007 to 2013. Patients treated with TZP were identified, comprising 53 elevated MIC episodes and 301 low MIC episodes. Propensity score matching (1:2 ratio) utilising independent variables associated with 30-day all-cause mortality was conducted to compare the outcomes of 53 elevated MIC episodes with 106 matched low MIC episodes. Independent baseline variables associated with 30-day all-cause mortality for all 354 episodes were hyperkalaemia, elevated blood urea nitrogen, elevated temperature, hypoglycaemia, lack of urinary source and thrombocytopenia. Similar 30-day all-cause mortality was found between the two propensity-matched TZP groups (elevated MIC 24.5% vs. low MIC 22.6%; P = 0.79).

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacteremia; beta-Lactamase Inhibitors; Female; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Propensity Score; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies; Risk Factors; Survival Analysis

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

Given the inconsistent clinical findings, our goal was to characterize the pharmacodynamics (PDs) of prolonged-infusion piperacillin-tazobactam (TZP) in an in vitro pharmacodynamic model of Pseudomonas aeruginosa. Specifically, the study was designed to investigate the influence of MIC on the activity of prolonged-infusion TZP using pharmacokinetics (PKs) consistent with a non-critically ill patient population. There was no benefit with prolonged- compared with standard-infusion TZP against isolates with susceptible MICs of 8 or 16 mg/L. However, prolonged-infusion TZP produced more than two times the final bacterial kill against less susceptible isolates with an intermediate MIC of 32 mg/L. The PDs of TZP were well described by a sigmoid Emax model (r(2) = 0.84) where %ƒT>MIC thresholds of 27 and 75% were associated with bacteriostatic and bactericidal effects, respectively. However, the well-established PD relationship with %ƒT>MIC was not observed with prolonged-infusion TZP. In conclusion, this study characterizes the targeted benefits of prolong-infusion TZP based on pathogen MIC, and supports the assertion that the benefits are selective and most likely observed in patients with less susceptible pathogens or altered PKs.

Topics: Anti-Bacterial Agents; Humans; In Vitro Techniques; Infusions, Intravenous; Microbial Sensitivity Tests; Monte Carlo Method; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections

The purpose of this study is to evaluate the outcome differences between patients receiving piperacillin-tazobactam pre- and post-implementation of an extended infusion dosing protocol in a community teaching hospital adult intensive care unit.. On December 19th, 2011, extended infusion dosing of piperacillin-tazobactam was implemented at St. John's Hospital's intensive and cardiac care units (ICU/CCU) following IRB-approval. This is a historical case-control cohort study involving review of electronic medical charts of patients who received traditional or extended infusion therapy. Data was collected for patients that received piperacillin-tazobactam in the ICU/CCU from December 19th, 2010 through March 19th, 2011 for traditional infusion and from December 19th, 2011 through March 19th, 2012 for extended infusion. Primary endpoints were ICU/CCU mortality at discharge and length of stay.. The study included 113 patients with 52 in the traditional-infusion group and 61 extended-infusion group. There was no statistically significant difference in the primary end-point of ICU/CCU mortality between the two groups (14.8% vs. 21.1%; p = 0.374). In the extended infusion group, there was a shorter length of ICU and CCU stay (8.32 vs. 12.06 days; p = 0.025) and shorter length of hospital stay (11.32 vs. 19.7 days; p = 0.006). The extended-infusion group showed a decrease in cost of therapy that was statistically significant ($120.21 vs. $155.17; p = 0.035). Adverse drug effects did not differ between the two study groups.. This study showed that treatment with extended-infusion piperacillin-tazobactam therapy improved patient outcomes while maintaining patient safety and decreasing costs.

Topics: Adult; Aged; Aged, 80 and over; Case-Control Studies; Cohort Studies; Delayed-Action Preparations; Female; Hospitals, Community; Hospitals, Teaching; Humans; Intensive Care Units; Male; Middle Aged; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas Infections; Treatment Outcome

The spread of antimicrobial-resistant organisms is a global concern. To stem this tide, an antimicrobial stewardship program at hospitals is essential to optimize the prescription of broad spectrum antibiotics. In this study we examined the impact of computerized pre-authorization for broad spectrum antibiotics for Pseudomonas aeruginosa at a children's hospital.. An antimicrobial stewardship program at Tokyo Metropolitan Children's Medical Center was assessed between March 2010 and March 2015. A paper-based post-prescription audit was switched to computerized pre-authorization for broad antipseudomonal agents in October 2011. The prescriber was required to obtain approval from physicians in the pediatric infectious diseases division before prescribing restricted antimicrobial agents. Approved prescriptions were processed and logged electronically. We evaluated days of therapy per 1000 patient-days, the cost of antibiotics, and the susceptibility of P. aeruginosa to piperacillin, ceftazidime, cefepime, piperacillin/tazobactam, carbapenems, and ciprofloxacin. Also, the average length of admission and infection-related mortality at 30 days were compared pre- and post-intervention.. Administration of carbapenems, piperacillin/tazobactam, and ceftazidime decreased significantly after the introduction of computerized pre-authorization. Antibiotic costs were reduced by JPY2.86 million (USD 26,000) annually. None of the antipseudomonal agents showed decreased sensitivity. The average length of admission was shorter in post-intervention. Infection-related mortality at 30 days showed no difference between the pre- and post-intervention periods.. An antimicrobial stewardship program using computerized pre-authorization decreased the use and cost of broad spectrum antibiotics without significant difference in infection-related mortality at 30 days, although our study did not improve susceptibilities of P. aeruginosa.

Topics: Anti-Bacterial Agents; Anti-Infective Agents; Carbapenems; Cefepime; Ceftazidime; Cephalosporins; Hospitals; Humans; Japan; Microbial Sensitivity Tests; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Tokyo

Gram-negative microorganisms are uncommon pathogens responsible for infective endocarditis. Pseudomonas mendocina, a Gram-negative water-borne and soil-borne bacterium, was first reported to cause human infection in 1992. Since then, it has rarely been reported as a human pathogen in the literature. We describe the first case of native valve infective endocarditis due to P. mendocina in the USA.. A 57-year-old white man presented with bilateral large leg ulcers, fever, and marked leukocytosis. His past medical history included gout and chronic alcohol use. P. mendocina was isolated from his blood cultures. A comprehensive review of P. mendocina infection in the literature was performed. A total of eight cases of P. mendocina infection were reported in the literature. More than two-thirds of the cases of P. mendocina septicemia were associated with native valve infective endocarditis. Thus, an echocardiogram was performed and demonstrated mitral valve endocarditis with mild mitral insufficiency. His leg wounds were debrided and were probably the source of P. mendocina bacteremia. Unlike Pseudomonas aeruginosa, P. mendocina is susceptible to third-generation cephalosporins. Our patient received a 6-week course of antimicrobial therapy with a favorable clinical outcome.. Our reported case and literature review illuminates a rare bacterial cause of infective endocarditis secondary to P. mendocina pathogen. Native cardiac valves were affected in all reported cases of infective endocarditis, and a majority of affected heart valves were left-sided. The antibiotics active against P. mendocina are different from those that are active against P. aeruginosa, and they notably include third-generation cephalosporins. The outcome of all reported cases of P. mendocina was favorable and no mortality was described.

Topics: Anti-Bacterial Agents; Bandages; Debridement; Endocarditis, Bacterial; Heart Valve Diseases; Humans; Leg Ulcer; Male; Middle Aged; Pain; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas Infections; Pseudomonas mendocina; Treatment Outcome

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

Carbapenems have an overall broad antibacterial spectrum and should be protected against from the acquisition of drug resistance. The clinical advantages of carbapenem in cases of pneumonia have not been certified and the need for antipseudomonal antimicrobial agents to treat healthcare-associated pneumonia (HCAP) remains controversial. We introduced an antimicrobial stewardship program for carbapenem and tazobactam/piperacillin use and investigated the effects of this program on the clinical outcomes of 591 pneumonia cases that did not require intensive care unit management, mechanical ventilation or treatment with vasopressor agents [221 patients with community-acquired pneumonia (CAP) and 370 patients with HCAP]. Compared with the pre-intervention period, age, comorbidities and the severity and etiology of pneumonia did not differ during the intervention period. Carbapenems were rarely used during the intervention period in cases of pneumonia (CAP: 12% vs. 1%, HCAP: 13% vs. 1%), while antipseudomonal beta-lactam use was reduced from 33% to 8% among cases with HCAP. This reduction in the rate of carbapenem administration did not have an impact on the prognosis in the cases of CAP, and the in-hospital mortality was lower among the patients with HCAP during the intervention period (15% vs. 5%, p = 0.013). The causes of death in the cases of HCAP were not directly related to pneumonia during the intervention period. The current study shows that carbapenem use can be avoided in cases of CAP or HCAP that are not in a critical condition. The frequent use of antipseudomonal beta-lactams does not improve the clinical outcomes of HCAP.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Carbapenems; Community-Acquired Infections; Cross Infection; Female; Hospital Mortality; Humans; Male; Middle Aged; Needs Assessment; Organizational Policy; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pneumonia, Bacterial; Prognosis; Pseudomonas Infections

To evaluate the pharmacokinetic and pharmacodynamic profiles of piperacillin-tazobactam administered as a 4-hour infusion in critically ill patients undergoing continuous renal replacement therapy (CRRT).. Prospective, observational, pharmacokinetic study.. Intensive care unit of a tertiary care hospital in Montréal, Canada.. Twenty critically ill adults who were undergoing continuous venovenous hemodiafiltration and receiving a 4-hour infusion of piperacillin 4 g-tazobactam 0.5 g every 8 hours for a documented or suspected infection.. Blood samples were collected every hour over an 8-hour dosing interval. Prefilter and postfilter blood samples, and effluent and urine samples were also collected.. The primary outcome was the proportion of patients who achieved an unbound piperacillin plasma concentration above a target minimum inhibitory concentration (MIC) of 64 mg/L (MIC that inhibits 90% of isolates for Pseudomonas aeruginosa) for at least 50% of the dosing interval; 18 (90%) of the 20 patients achieved this outcome. In all patients, the free piperacillin concentrations were above the Pseudomonas aeruginosa breakpoint of 16 mg/L for the entire time interval. Regarding piperacillin pharmacokinetic parameters, the median (interquartile range) minimum unbound plasma concentration was 65.15 mg/L (51.30-89.30), maximum unbound plasma concentration was 141.3 mg/L (116.75-173.90), sieving coefficient was 0.809 (0.738-0.938), total clearance was 65.82 ml/minute (53.79-102.87), and renal clearance was 0.16 ml/minute (0.05-3.04). The median CRRT dose was 32.0 ml/kg/h (25.0-39.8).. Administration of a 4-hour infusion of piperacillin-tazobactam was associated with a favorable pharmacodynamic profile in patients undergoing CRRT. Concentrations associated with maximal activity were attained in our patients.

Topics: Aged; Anti-Bacterial Agents; Critical Illness; Female; Hemodiafiltration; Humans; Infusions, Intravenous; Male; Microbial Sensitivity Tests; Middle Aged; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Prospective Studies; Pseudomonas aeruginosa; Pseudomonas Infections; Tertiary Care Centers

Evidence from a recent randomized study of our group suggests that intravenous clarithromycin resulted in earlier resolution of ventilator-associated pneumonia. The need to understand the mechanism of action of clarithromycin guided to the study of a model of experimental empyema by multidrug-resistant Pseudomonas aeruginosa in 40 rabbits. Animals were randomized into controls (group A); treatment with clarithromycin (group B); treatment with piperacillin/tazobactam (group C); and treatment with both agents (group D). Pleural fluid was collected at regular time intervals for quantitative culture, estimation of cell apoptosis and of concentrations of tumour necrosis factor-alpha (TNFα). After 7 days, animals were euthanized for estimation of tissue growth. Bacterial growth in the pleural fluid of group D was significantly decreased compared with the other groups on day 5. Lung growth of group D was lower than group A. That was also the case of cytokine stimulation by pleural fluid samples on U937 monocytes. It is concluded that administration of clarithromycin enhanced the antimicrobial efficacy of piperacillin/tazobactam and decreased bacterial growth in the pleural fluid and in tissues. It also attenuated the pro-inflammatory phenomena induced by the β-lactam.

Topics: Adjuvants, Immunologic; Animals; Anti-Bacterial Agents; Apoptosis; Clarithromycin; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Empyema, Pleural; Humans; Interleukin-6; Male; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pleural Effusion; Pseudomonas aeruginosa; Pseudomonas Infections; Rabbits; Tumor Necrosis Factor-alpha; U937 Cells

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

Bacterial gene islands add to the genetic repertoire of opportunistic pathogens. Here, we perform comparative analyses of three Pseudomonas aeruginosa strains isolated sequentially over a 3-week period from a patient with ventilator-associated pneumonia (VAP) who received clindamycin and piperacillin-tazobactam as part of their treatment regime. While all three strains appeared to be clonal by standard pulsed-field gel electrophoresis, whole-genome sequencing revealed subtle alterations in the chromosomal organization of the last two strains; specifically, an inversion event within a novel 124-kb gene island (PAGI 12) composed of 137 open reading frames [ORFs]. Predicted ORFs in the island included metabolism and virulence genes. Overexpression of a gene island-borne putative β-lactamase gene was observed following piperacillin-tazobactam exposure and only in those strains that had undergone the inversion event, indicating altered gene regulation following genomic remodeling. Examination of a separate cohort of 76 patients with VAP for integration at this tRNA(lys) recombination site demonstrated that patients exhibiting evidence of integration at this site had significantly higher 28-day mortality. These findings provide evidence that P. aeruginosa can integrate, rapidly remodel, and express exogenous genes, which likely contributes to its fitness in a clinical setting.

Topics: Anti-Bacterial Agents; Clindamycin; DNA, Bacterial; Electrophoresis, Gel, Pulsed-Field; Gene Rearrangement; Genetic Variation; Genome, Bacterial; Genomic Islands; Humans; Longitudinal Studies; Molecular Typing; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pneumonia, Ventilator-Associated; Pseudomonas aeruginosa; Pseudomonas Infections; Sequence Analysis, DNA

The aim of this study was to compare ceftolozane with ceftazidime, piperacillin/tazobactam (TZP) and imipenem in an experimental rabbit model of Pseudomonas aeruginosa pneumonia. Efficacy was assessed following 2 days of treatment by total colony counts in different tissues (lung, spleen and blood culture). Mean ± standard deviation pulmonary bacterial loads were 4.9 ± 0.3, 3.6 ± 0.3, 4.8 ± 0.2, 5.5 ± 0.8 and 3.9 ± 0.3 log₁₀CFU/g of lung for ceftolozane (1g), ceftolozane (2g), ceftazidime, TZP and imipenem, respectively, compared with 6.3 ± 0.9 log₁₀CFU/g of lung for control animals. The higher ceftolozane dose [2g three times daily (t.i.d.)] showed significantly better efficacy than the lower dose (1g t.i.d.). In conclusion, in this rabbit model of P. aeruginosa pneumonia, ceftolozane had an efficacy equivalent to that of comparator agents at a dose of 1g t.i.d. and had better efficacy at a higher dose (2g t.i.d.).

Topics: Animal Structures; Animals; Anti-Bacterial Agents; Bacterial Load; Ceftazidime; Cephalosporins; Colony Count, Microbial; Disease Models, Animal; Female; Humans; Imipenem; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pneumonia, Bacterial; Pseudomonas aeruginosa; Pseudomonas Infections; Rabbits; Treatment Outcome

OprD loss and hyperexpression of AmpC, MexAB-OprM, MexCD-OprJ, MexEF-OprN, and MexXY-OprM were evaluated among 120 Pseudomonas aeruginosa isolates collected during 2012 in U.S. hospitals and selected based on ceftazidime MIC values (1 to >32 μg/ml). AmpC derepression (10-fold greater than that with the control) and OprD loss (decreased/no band) were the most prevalent resistance mechanisms: 47.5 and 45.8% of the isolates were considered positive, respectively. Elevated expression of the efflux pumps MexAB-OprM, MexCD-OprJ, MexEF-OprN, and MexXY-OprM was observed in 32.5, 8.3, 0.0, and 28.4% of the isolates, respectively. A total of 21 different combinations of resistance mechanisms were noted, and the most prevalent included AmpC derepression with OprD loss with and without efflux hyperexpression (38 and 10 isolates, respectively). A total of 26 isolates had no changes in the resistance mechanisms tested and had lower MIC values for all β-lactams or β-lactam/β-lactamase inhibitor combinations analyzed. OprD loss had a strong correlation with elevated MIC results for imipenem and meropenem (median MIC values of 8 and 4 μg/ml, respectively), with all combinations displaying OprD loss also displaying elevated median MIC values for these carbapenems (4 to >8 μg/ml). AmpC expression levels were greater in isolates displaying elevated cefepime, ceftazidime, or piperacillin-tazobactam MIC values (≥4, ≥4, and ≥16 μg/ml, respectively). Isolates displaying derepressed AmpC had ceftolozane-tazobactam MIC values ranging from 1 to 16 μg/ml. No strong correlation was noticed with MIC values for this β-lactam/β-lactamase inhibitor combination and OprD loss or hyperexpression of efflux systems. Two KPC-producing isolates were detected among 16 isolates displaying ceftolozane-tazobactam MIC values of ≥8 μg/ml.

Topics: Anti-Bacterial Agents; Bacterial Outer Membrane Proteins; Bacterial Proteins; beta-Lactam Resistance; beta-Lactamases; Cefepime; Ceftazidime; Cephalosporins; Cross Infection; Gene Expression Regulation, Bacterial; Humans; Membrane Transport Proteins; Microbial Sensitivity Tests; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Porins; Pseudomonas aeruginosa; Pseudomonas Infections

Pseudomonas aeruginosa (PA) bacteraemia is associated with high morbidity and mortality. We assessed clinical outcomes in patients with PA bacteraemia treated with piperacillin-tazobactam (TZP) versus other antibiotics, and monotherapy versus combination, all with proven activity by disc testing without minimum inhibitory concentration (MIC) data.. All patients with PA bacteraemia in 2007 to 2008 were reviewed for demographic, comorbidity, clinical, laboratory, treatment and outcome data. Primary outcome was 30-day mortality. Secondary outcomes included microbiological clearance, clinical response and length of stay (LOS).. Median age for 91 patients was 65 years. Median Simplified Acute Physiology Score (SAPS) II score was 30. Monotherapy was used in 77 cases: 42 on ceftazidime, 17 on TZP, 10 on carbapenems, and 8 on other antipseudomonal antibiotics. The 30-day mortality was 20.9%, and similar between ceftazidime and TZP versus other antibiotics respectively. More patients in combination versus monotherapy group had cardiovascular diseases, diabetes mellitus and vascular access as source of bacteraemia. Patients on monotherapy had higher 30-day mortality (24.7% vs 0%, P = 0.037). Multivariate analysis identified SAPS II score (OR = 1.097, 95% CI, 1.032 to 1.166, P = 0.003) and cancer (OR = 4.873, 95% CI, 1.235 to 19.223, P = 0.024) as independent predictors of 30-day mortality.. TZP appeared to be an effective culture-guided antibiotic for PA bacteraemia. High 30-day mortality in monotherapy might be confounded by comorbidity, illness severity and sample size. Cancer patients and a high SAPS II score were independent predictors of 30-day mortality.

Topics: Aged; Anti-Bacterial Agents; Bacteremia; Ceftazidime; Drug Therapy, Combination; Female; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies; Treatment Outcome

Dodecapeptide SC4 is a broad-spectrum bactericidal agent that functions by disintegrating bacterial membranes and neutralizing endotoxins. For insight into which SC4 amino acids are functionally important, we assessed Gram-negative bactericidal effects in structure-activity relationship experiments. Subsequently, SC4 was tested in a murine bacteremia model to combine and compare the efficacy with Zosyn, a first-line antibiotic against Pseudomonas aeruginosa (P. aeruginosa).. SC4 alanine-scanning analogs and their activities on were tested on P. aeruginosa. Survival studies in P. aeruginosa challenged mice were executed to monitor overall efficacy of SC4 and Zosyn, as a single modality and also as combination treatment. ELISAs were used to measure blood serum levels of selected inflammatory cytokines during treatment.. Cationic residues were found to play a crucial role in terms of bactericidal activity against P. aeruginosa. In vivo, while only 9% (3/34) of control animals survived to day two and beyond, 44% (12/27) to 41% (14/34) of animals treated with SC4 or Zosyn, respectively, survived beyond one week. Combination treatment of SC4 and Zosyn demonstrated improved survival, i.e. 60% (12/20). The TNFα, IL-1, and IL-6 serum levels were attenuated in each treatment group compared to the control group.. These data show that combination treatment of SC4 and Zosyn is most effective at killing P. aeruginosa and attenuating inflammatory cytokine levels in vivo.. Combination treatment of SC4 and Zosyn may be useful in the clinic as a more effective antibiotic therapy against Gram-negative infectious diseases.

Topics: Animals; Anti-Bacterial Agents; Bacteremia; Cytokines; Disease Models, Animal; Inflammation Mediators; Male; Mice; Penicillanic Acid; Peptide Fragments; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Time Factors

The study through Monte Carlo simulation of β-lactam pharmacokinetic/pharmacodynamic target attainment and determination of subsequent serum concentrations of piperacillin-tazobactam administered through continuous infusion to children treated for fever and neutropenia shows that 400 mg/kg/day has the highest probability of target attainment against Pseudomonas aeurginosa in our oncology ward compared with the standard regimen of 300 mg/kg/day.

Topics: Adolescent; Anti-Bacterial Agents; Child; Female; Fever of Unknown Origin; Humans; Infusions, Intravenous; Male; Neutropenia; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas Infections; Treatment Outcome

Management of nosocomial pneumonia is frequently complicated by bacterial resistance. Extended infusions of beta-lactams are increasingly being used to improve clinical outcomes. However, the impact of this strategy on the emergence of antimicrobial resistance is not known. A hollow-fiber infection model with Pseudomonas aeruginosa (PAO1) was used. Pharmacokinetic (PK) profiles of piperacillin-tazobactam similar to those in humans were simulated over 5 days. Three dosages of piperacillin-tazobactam were administered over 0.5 h or 4 h, with redosing every 8 h. Two initial bacterial densities were investigated (∼10(4) CFU/ml and ∼10(7) CFU/ml). The time courses of the total bacterial population and the resistant subpopulation were determined. All data were described using a mathematical model, which was then used to define the relationship between drug concentrations, bacterial killing, and emergence of piperacillin resistance. There was logarithmic growth in controls in the initial 24 h, reaching a plateau of ∼9 log10 CFU/ml. Bacterial killing following administration of piperacillin via bolus dosing and that after extended infusions were similar. For the lower initial bacterial density, trough total plasma piperacillin concentration/MIC ratios of 3.4 and 10.4 for bolus and extended-infusion regimens, respectively, were able to suppress the emergence of piperacillin resistance. For the higher initial bacterial density, all regimens were associated with progressive growth of a resistant subpopulation. A stratified approach, according to bacterial density, is required to treat patients with nosocomial pneumonia. Antimicrobial monotherapy may be sufficient for some patients. However, for patients with a high bacterial burden, alternative therapeutic strategies are required to maximize bacterial killing and prevent antimicrobial resistance.

Topics: Anti-Bacterial Agents; Colony Count, Microbial; Computer Simulation; Drug Administration Schedule; Drug Resistance, Bacterial; Humans; Infusions, Intravenous; Microbial Sensitivity Tests; Models, Statistical; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections

The pharmacokinetics-pharmacodynamics (PK-PD) breakpoint of piperacillin/tazobactam (PIPC/TAZ) for hospital-acquired pneumonia (HAP) and Pseudomonas aeruginosa-induced bacteremia is controversial, since the susceptibility of P. aeruginosa to PIPC/TAZ is known to be lower than that set by the Clinical Laboratory Standards Institute (CLSI), ≤64 mg/L. The association between MIC levels and bacterial eradication after various PIPC/TAZ treatments was investigated. In all, 61 and 17 Japanese patients from the microbiology laboratory database with HAP and P. aeruginosa-induced bacteremia, respectively, who were treated with PIPC/TAZ (4.5 g, b.i.d., t.i.d., or q.i.d.) between 2008 and 2009 were retrospectively analyzed. Pertinent clinical data were retrieved from medical records. The MIC level was determined using the microdilution method. Appropriate empirical therapy with PIPC/TAZ was selected for all patients within 24 h of positive culture results. The microbiological effect after treatment was used to determine the efficacy of each PIPC/TAZ administration method. In PIPC/TAZ-treated HAP patients (4.5 g, t.i.d.), the microbiological efficacy was 93.3% (28/30) when the MIC was ≤16 mg/L, while it was 50.0 (5/9) and 0% (0/3) with MICs of 32 (p < 0.05) and 64 mg/L, respectively. In PIPC/TAZ-treated bacteremia patients (4.5 g, t.i.d. or q.i.d.), the microbiological efficacy was 100% (11/11) when the MIC was <16 mg/L, while it was 33.3 (1/3) and 0% (0/3) with MICs of 32 (p < 0.05) and ≥64 mg/L, respectively. The present CLSI susceptibility breakpoints do not necessarily predict clinical outcomes. The appropriateness evaluation of the current CLSI resistance breakpoint of PIPC/TAZ and the PK-PD breakpoint determination warrant further studies.

Topics: Anti-Bacterial Agents; Bacteremia; Cross Infection; Humans; Microbial Sensitivity Tests; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pneumonia, Bacterial; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies

CXA-101 is a novel antipseudomonal cephalosporin with enhanced activity against Gram-negative organisms displaying various resistance mechanisms. This study evaluates the efficacy of exposures approximating human percent free time above the MIC (%fT > MIC) of CXA-101 with or without tazobactam and piperacillin-tazobactam (TZP) against target Gram-negative organisms, including those expressing extended-spectrum β-lactamases (ESBLs). Sixteen clinical Gram-negative isolates (6 Pseudomonas aeruginosa isolates [piperacillin-tazobactam MIC range, 8 to 64 μg/ml], 4 Escherichia coli isolates (2 ESBL and 2 non-ESBL expressing), and 4 Klebsiella pneumoniae isolates (3 ESBL and 1 non-ESBL expressing) were used in an immunocompetent murine thigh infection model. After infection, groups of mice were administered doses of CXA-101 with or without tazobactam (2:1) designed to approximate the %fT > MIC observed in humans given 1 g of CXA-101 with or without tazobactam every 8 h as a 1-h infusion. As a comparison, groups of mice were administered piperacillin-tazobactam doses designed to approximate the %fT > MIC observed in humans given 4.5 g piperacillin-tazobactam every 6 h as a 30-min infusion. Predicted piperacillin-tazobactam %fT > MIC exposures of greater than 40% resulted in static to >1 log decreases in CFU in non-ESBL-expressing organisms with MICs of ≤32 μg/ml after 24 h of therapy. Predicted CXA-101 with or without tazobactam %fT > MIC exposures of ≥37.5% resulted in 1- to 3-log-unit decreases in CFU in non-ESBL-expressing organisms, with MICs of ≤16 μg/ml after 24 h of therapy. With regard to the ESBL-expressing organisms, the inhibitor combinations showed enhanced CFU decreases versus CXA-101 alone. Due to enhanced in vitro potency and resultant increased in vivo exposure, CXA-101 produced statistically significant reductions in CFU in 9 isolates compared with piperacillin-tazobactam. The addition of tazobactam to CXA-101 produced significant reductions in CFU for 7 isolates compared with piperacillin-tazobactam. Overall, human simulated exposures of CXA-101 with or without tazobactam demonstrated improved efficacy versus piperacillin-tazobactam.

Topics: Animals; Anti-Bacterial Agents; beta-Lactamases; Cephalosporins; Colony Count, Microbial; Disease Models, Animal; Drug Combinations; Drug Resistance, Bacterial; Escherichia coli; Escherichia coli Infections; Female; Humans; Klebsiella Infections; Klebsiella pneumoniae; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Penicillanic Acid; Phenotype; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Tazobactam; Thigh

This report describes two subsequent liver-small bowel-pancreas-kidney (multivisceral) transplantations in a child colonized with multidrug-resistant Pseudomonas aeruginosa. We discuss the dilemma concerning the transplantation of patients colonized with multidrug-resistant Pseudomonas spp., its potential consequences, and the peri and postoperative management of these patients.

Topics: Anti-Bacterial Agents; Antifungal Agents; Child, Preschool; Disease Management; Drug Resistance, Multiple, Bacterial; Female; Fluconazole; Humans; Intestine, Small; Kidney Transplantation; Liver Transplantation; Organ Transplantation; Pancreas Transplantation; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections

Topics: Cervical Vertebrae; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Osteomyelitis; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Radiography; Smoking

Six years after initiating a monthly antibiotic cycling protocol in the surgical intensive care unit (SICU), we retrospectively reviewed antibiogram-derived sensitivities of predominant gram-negative pathogens before and after antibiotic cycling. We also examined susceptibility patterns in the medical intensive care unit (MICU) where antibiotic cycling is not practiced.. Antibiotic cycling protocol was implemented in the SICU starting in 2003, with monthly rotation of piperacillin/tazobactam, imipenem/cilastin, and ceftazidime. SICU antibiogram data from positive clinical cultures for years 2000 and 2002 were included in the pre-cycling period, and those from 2004 to 2009 in the cycling period.. Profiles of SICU pseudomonal isolates before (n = 116) and after (n = 205) implementing antibiotic cycling showed statistically significant improvements in susceptibility to ceftazidime (66% versus 81%; P = 0.003) and piperacillin/tazobactam (75% versus 85%; P = 0.021), while susceptibility to imipenem remained unaltered (70% in each case; P = 0.989). Susceptibility of E. coli isolates to piperacillin/tazobactam improved significantly (46% versus 83%; P < 0.0005), trend analysis showing this improvement to persist over the study period (P = 0.025). Similar findings were not observed in the MICU. Review of 2004-2009 antibiotic prescription practices showed monthly heterogeneity in the SICU, and a 2-fold higher prescribing of piperacillin/tazobactam in the MICU (P < 0.0001).. Six years into antibiotic cycling, we found either steady or improved susceptibilities of clinically relevant gram-negative organisms in the SICU. How much of this effect is from cycling is unknown, but the antibiotic heterogeneity provided by this practice justifies its ongoing use.

Topics: Anti-Bacterial Agents; Ceftazidime; Cilastatin; Cilastatin, Imipenem Drug Combination; Critical Care; Cross Infection; Drug Combinations; Drug Resistance, Bacterial; Enterobacter cloacae; Enterobacteriaceae Infections; Escherichia coli; Escherichia coli Infections; Humans; Imipenem; Infection Control; Klebsiella Infections; Klebsiella pneumoniae; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies; Surgical Wound Infection

The Study for Monitoring Antimicrobial Resistance Trends (SMART) is an international surveillance study designed to monitor resistance trends among aerobic and facultative Gram-negative bacilli (GNB) isolated from intra-abdominal infections. During 2003-2010, a total of 20710 GNB isolates were collected at medical centers in China, Hong Kong, Korea, New Zealand, and Taiwan. The susceptibility profiles of 2252 isolates of non-Enterobacteriaceae GNB were determined. At least 10 isolates of a given organism were required for that organism to be included in the analysis. Pseudomonas aeruginosa was the leading organism (49.2% of non-Enterobacteriaceae GNB), followed by Acinetobacter baumannii (21.5%), Aeromonas spp. (11.6%), and Stenotrophomonas maltophilia (9.1%). All the other species/genera made up less than 2%. The rates of susceptibility of the four major organisms were examined for two different time periods and according to whether the isolates had been obtained <48 h after hospitalization or ≥ 48 h after hospital admission. P. aeruginosa, Aeromonas spp., and S. maltophilia showed sustained levels of susceptibility to several antimicrobial agents in the two time periods, whereas A. baumannii exhibited very high rates of resistance to most antimicrobial agents including imipenem. Nosocomial P. aeruginosa and A. baumannii were more resistant than community-acquired pathogens, although this was not the case for Aeromonas spp. and S. maltophilia. Worldwide and regional surveillance is necessary to guide empirical antimicrobial therapy for infections due to non-Enterobacteriaceae GNB.

Topics: Acinetobacter Infections; Aeromonas; Anti-Bacterial Agents; Asia; Australasia; Drug Resistance, Bacterial; Humans; Imipenem; Intraabdominal Infections; Microbial Sensitivity Tests; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Population Surveillance; Prospective Studies; Pseudomonas aeruginosa; Pseudomonas Infections

Antibiotic homogeneity is thought to drive resistance but in vivo data are lacking. In this study, we determined the impact of antibiotic homogeneity per se, and of cefepime versus antipseudomonal penicillin/β-lactamase inhibitor combinations (APP-β), on the likelihood of infection or colonisation with antibiotic resistant bacteria and/or two commonly resistant nosocomial pathogens (methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa). A secondary question was whether antibiotic cycling was associated with adverse outcomes including mortality, length of stay, and antibiotic resistance.. We evaluated clinical and microbiological outcomes in two similar metropolitan ICUs, which both alternated cefepime with APP-β in four-month cycles. All microbiological isolates and commensal samples were analysed for the presence of antibiotic-resistant bacteria including MRSA and P. aeruginosa.. Length of stay, mortality and overall antibiotic resistance were unchanged after sixteen months. However, increased colonisation and infection by antibiotic-resistant bacteria were observed in cefepime cycles, returning to baseline in APP-β cycles. Cefepime was the strongest risk factor for acquisition of antibiotic-resistant infection.. Ecological effects of different β-lactam antibiotics may be more important than specific activity against the causative agents or the effect of antibiotic homogeneity in selection for antibiotic resistance. This has important implications for antibiotic policy.

Topics: Adult; Aged; Anti-Bacterial Agents; Cefepime; Cephalosporins; Drug Prescriptions; Drug Resistance, Bacterial; Female; Humans; Intensive Care Units; Length of Stay; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Middle Aged; Nasopharynx; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Staphylococcal Infections; Survival Rate

This study aimed to evaluate the accuracy of routine systems (Vitek2 cards AST-N022 and AST-N026; Kirby Bauer; Etest) for susceptibility testing of Pseudomonas aeruginosa to piperacillin and piperacillin-tazobactam. Vitek2 (card AST-N022) showed the worst performance; the other three methods (Vitek2 card AST-N026, Kirby-Bauer and E-test) performed comparably but never fulfilled the minimal standard proposed by FDA.

Topics: Anti-Bacterial Agents; Bacteriological Techniques; Humans; Microbial Sensitivity Tests; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Predictive Value of Tests; Pseudomonas aeruginosa; Pseudomonas Infections

Topics: Anti-Bacterial Agents; Anti-Infective Agents; Cefepime; Cephalosporins; Drug Resistance, Multiple, Bacterial; Fluoroquinolones; Formularies, Hospital as Topic; Humans; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Tobramycin

To find out the frequency and susceptibility pattern of multi-drug resistant (MDR) Pseudomonas aeruginosa in clinical specimens.. Cross-sectional observational study.. Department of Microbiology, Army Medical College, National University of Sciences and Technology (NUST), Rawalpindi, from January to September 2010.. Routine clinical specimens were subjected to standard microbiological procedures and the isolates were identified to the species level. The antibiotics susceptibility was determined by Kirby Bauer Disc diffusion method and the results were interpreted according to the Clinical and Laboratory Standards Institute (CLSI) guidelines.. The frequency of MDR Pseudomonas aeruginosa among all the Pseudomonas aeruginosa strains isolated was found to be 22.7%. These isolates were most sensitive to Colistin followed by Piperacillin-Tazobactam and Cefoperazone-Sulbactum.. Increasing fequency of infections due to MDR Pseudomonas aeruginosa is an emerging threat in our set up which an be prevented by prescribing antibiotics judiciously and by adopting proper disinfection measures.

Topics: Anti-Bacterial Agents; Cefoperazone; Colistin; Cross-Sectional Studies; Disk Diffusion Antimicrobial Tests; Drug Resistance, Multiple, Bacterial; Enzyme Inhibitors; Humans; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Sulbactam

The optimal approach for empirical antibiotic therapy in patients with severe sepsis and septic shock remains controversial. A retrospective cohort study was conducted in the intensive care units of a university hospital. The data from 760 patients with severe sepsis or septic shock associated with Gram-negative bacteremia was analyzed. Among this cohort, 238 (31.3%) patients received inappropriate initial antimicrobial therapy (IIAT). The hospital mortality rate was statistically greater among patients receiving IIAT compared to those initially treated with an appropriate antibiotic regimen (51.7% versus 36.4%; P < 0.001). Patients treated with an empirical combination antibiotic regimen directed against Gram-negative bacteria (i.e., beta-lactam plus aminoglycoside or fluoroquinolone) were less likely to receive IIAT compared to monotherapy (22.2% versus 36.0%; P < 0.001). The addition of an aminoglycoside to a carbapenem would have increased appropriate initial therapy from 89.7 to 94.2%. Similarly, the addition of an aminoglycoside would have increased the appropriate initial therapy for cefepime (83.4 to 89.9%) and piperacillin-tazobactam (79.6 to 91.4%). Logistic regression analysis identified IIAT (adjusted odds ratio [AOR], 2.30; 95% confidence interval [CI] = 1.89 to 2.80) and increasing Apache II scores (1-point increments) (AOR, 1.11; 95% CI = 1.09 to 1.13) as independent predictors for hospital mortality. In conclusion, combination empirical antimicrobial therapy directed against Gram-negative bacteria was associated with greater initial appropriate therapy compared to monotherapy in patients with severe sepsis and septic shock. Our experience suggests that aminoglycosides offer broader coverage than fluoroquinolones as combination agents for patients with this serious infection.

Topics: Acinetobacter Infections; Adult; Aged; Aminoglycosides; Anti-Bacterial Agents; Carbapenems; Cefepime; Cephalosporins; Cohort Studies; Drug Therapy, Combination; Escherichia coli Infections; Female; Fluoroquinolones; Gram-Negative Bacterial Infections; Hospital Mortality; Humans; Logistic Models; Male; Middle Aged; Multivariate Analysis; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies; Sepsis; Shock, Septic

To report the treatment of therapy-resistant Pseudomonas aeruginosa keratitis with topical piperacillin/tazobactam.. Retrospective report of 3 cases.. Three patients with P. aeruginosa keratitis were unresponsive to various antimicrobials. Resolution of all 3 cases of keratitis occurred upon commencement of topical piperacillin/tazobactam.. Therapy-resistant P. aeruginosa keratitis acquired from the community is becoming an increasing problem. Topical piperacillin/tazobactam is an option for the treatment of therapy-resistant P. aeruginosa keratitis.

Topics: Administration, Topical; Adolescent; Adult; Anti-Bacterial Agents; Corneal Ulcer; Drug Resistance; Eye Infections, Bacterial; Humans; Male; Middle Aged; Ophthalmic Solutions; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Prognosis; Pseudomonas Infections; Retrospective Studies

Topics: Anti-Bacterial Agents; Cataract Extraction; Drug Resistance, Multiple, Bacterial; Endophthalmitis; Eye Infections, Bacterial; Humans; Intravitreal Injections; Keratoplasty, Penetrating; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Visual Acuity; Vitreous Body

Bacterial biofilm formation has been implicated in the high rate of persistent otorrhea after tympanostomy tube insertion. It has been suggested that the tube material may be an important factor in the development of otorrhea. Recently we reported the presence of ciprofloxacin-resistant Pseudomonas aeruginosa (CRPA) biofilms on infected tympanostomy tubes following the use of intractable post-tympanostomy tubes and the onset of otorrhea. In this study, we have evaluated the resistance of piperacillin-tazobactam coated with chitosan on a tympanostomy tube to prevent CRPA biofilm formation in vitro.. Three sets each of piperacillin-tazobactam coated silicone tubes (n=5), commercial silver-oxide coated silicone tubes (Activent, Silic) (n=5) and control uncoated tympanostomy tubes (Paparella type 1) (n=5) were processed for evaluation. The piperacillin-tazobactam coated tympanostomy tubes were compared with the silver-oxide coated tubes and the uncoated control tubes for resistance to CRPA biofilm formation after in vitro incubation.. Scanning electron microscopy showed that the surface of the silver-oxide coated tube (Activent) formed a thick biofilm with crusts as well as an uncoated tube. In contrast, the surface of a piperacillin-tazobactam coated tympanostomy tube showed virtually no CRPA biofilm formation.. The piperacillin-tazobactam coated tympanostomy tube showed resistance to CRPA biofilm formation. The piperacillin-tazobactam coating may be useful to reduce CRPA biofilm formation; however, further in vivo studies are necessary.

Topics: Anti-Bacterial Agents; Bacterial Adhesion; Bacteriological Techniques; Biofilms; Ciprofloxacin; Coated Materials, Biocompatible; Drug Resistance, Bacterial; Equipment Contamination; Equipment Design; Humans; Materials Testing; Microscopy, Electron, Scanning; Middle Ear Ventilation; Otitis Media, Suppurative; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Prosthesis-Related Infections; Pseudomonas aeruginosa; Pseudomonas Infections; Silicones; Surface Properties

We evaluated the susceptibility rates for piperacillin/tazobactam tested against Pseudomonas aeruginosa isolates from the Asia-Pacific (APAC), Europe (EU), Latin America (LA), and North America (NA) for 1997 to 2007. A total of 25 460 isolates were tested originating from APAC (4441), EU (7695), LA (4277), and NA (9047). All testing was performed by reference broth microdilution methods. The samples were collected from >110 medical centers and samples averaging >30 nations/year. For this analysis, results from 1997 to 2007, 1997 to 1999, 2005 to 2007, APAC, EU, LA, and NA were assessed against several broad-spectrum beta-lactams, including cefepime, ceftazidime, imipenem, meropenem, and piperacillin alone, for a total of 12 agents overall. Using P. aeruginosa breakpoints (< or =64 microg/mL), piperacillin/tazobactam had the broadest coverage (% susceptible) in 2 regions (EU, LA) and, overall, at 83.6% followed by meropenem (83.0%) > imipenem (79.7%) > piperacillin (79.5%) > cefepime (77.5%) > ceftazidime (75.8%). Other non-beta-lactam activity results were ciprofloxacin at only 71.5% susceptible, but tobramycin and polymyxin B had higher susceptibility rates (81.0% and 99.5%, respectively). Trends toward piperacillin/tazobactam resistance were noted between 1997 to 1999 and 2000 to 2007 in APAC (-11.6% susceptibility), NA (-4.0%), and EU (-2.3%). LA susceptibility rates were lowest overall but actually increased recently by +2.9% (current rate, 79.4% susceptible). For beta-lactamase inhibitor combinations, susceptibility rates were higher for piperacillin/tazobactam when compared in all regions with piperacillin alone (+2.6-7.1%) and greatest for LA isolates. In contrast, ticarcillin/clavulanate susceptibility rates were lower than ticarcillin tested alone in NA (-1.5%, antagonism), and this agent only inhibited 70.3% of isolates worldwide. In conclusion, piperacillin/tazobactam remained a very active beta-lactam when tested in vitro against clinical isolates of P. aeruginosa found in the SENTRY Program (1997-2007). Trends toward slightly decreased susceptibility were noted in all regions over the last decade (except LA); only polymyxins had susceptibility rates at >90%. Resistance surveillance programs should be sustained to document emerging resistance patterns of old and newer agents for difficult-to-treat pathogens such as P. aeruginosa.

Topics: Anti-Bacterial Agents; Global Health; Humans; Microbial Sensitivity Tests; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Sentinel Surveillance

Contemporary literature lacks a definition of prior antibiotic exposure which captures all patients at risk of developing piperacillin-tazobactam-resistant Pseudomonas aeruginosa (PTR-PA). The results indicated that individual antibiotics that are associated with PTR-PA differ depending on the definition of prior antibiotic exposure utilized. When the specific antibiotic used was replaced by the number of prior exposures, the number of exposures was the only variable associated with an increased risk of antibiotic resistance at each time threshold.

Topics: Aged; Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Female; Humans; Male; Middle Aged; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Respiratory Tract Infections; Retrospective Studies; Risk Factors

An experimental study has been performed to compare the in vitro activity and the in vivo efficacy of magainin II and cecropin A with or without rifampicin against control and multidrug-resistant Pseudomonas aeruginosa strains.. In vitro experiments included MIC determinations and synergy studies. For in vivo studies, animals were given an intraperitoneal injection of P. aeruginosa lipopolysaccharide, P. aeruginosa ATCC 27853 and one clinical multiresistant P. aeruginosa strain. Groups of animals received intravenously isotonic sodium chloride solution, 10 mg/kg rifampicin, 1 mg/kg magainin II or 1 mg/kg cecropin A. Two groups of animals received a combined treatment with magainin II + rifampicin or cecropin A + rifampicin at the same dosages as the singly treated groups. In addition, a further group was treated with tazobactam/piperacillin (120 mg/kg). Lethality, bacterial growth in blood and peritoneum, and endotoxin and TNF-alpha concentrations in plasma were evaluated.. Combinations of alpha-helical antimicrobial peptides showed in vitro synergistic interaction. Magainin II and cecropin A exerted strong antimicrobial activity and achieved a significant reduction in plasma endotoxin and TNF-alpha concentrations when compared with control and rifampicin-treated groups. Rifampicin exhibited no anti-P. aeruginosa activity and good substantial impact on endotoxin and TNF-alpha plasma concentrations. Combined treatment groups had significant reductions in bacterial count, positive blood cultures and mortality rates when compared with singly treated and control groups.. Our results highlight the potential usefulness of these combinations that provide future therapeutic alternatives in P. aeruginosa infections.

Topics: Animals; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Blood; Drug Synergism; Drug Therapy, Combination; Endotoxins; Injections, Intravenous; Magainins; Microbial Sensitivity Tests; Penicillanic Acid; Peritoneum; Piperacillin; Piperacillin, Tazobactam Drug Combination; Plasma; Pseudomonas aeruginosa; Pseudomonas Infections; Rats; Rats, Wistar; Rifampin; Survival Analysis; Treatment Outcome; Tumor Necrosis Factor-alpha; Xenopus Proteins

To conduct a multicentre observational study to describe management of foot infections in diabetes in the out-patient setting in Italy.. Ten centres equally distributed nationwide were asked to collect, by means of a spreadsheet (Access/Excel Microsoft program), data concerning 30 consecutive diabetic patients with foot infections deemed suitable for antibiotic treatment in the out-patient setting. Centres with > or = 5 years' experience of out-patient management were selected. Data from 271 consecutive patients treated as out-patients were collected and analysed by the central coordinator. Statistical analysis was performed using the SPSS statistical software package.. Lesions were mainly located at the toes and midfoot (33.6 and 30.2%, respectively); 63 (23.2%) patients had multiple ulcers. Seventy (25.8%) patients also had concomitant osteomyelitis. Three hundred and four pathogens, including Gram-positive and Gram-negative aerobes and anaerobes, were isolated in 219/271 patients (80.8%) by culturing debrided tissue (71.2%) or purulent material (28.8%). Infections were polymicrobial in 33.8% of patients. The most common pathogens were Staphylococcus aureus (27.3%) and Pseudomonas spp. (20.4%); enterobacteriaceae, enterococci, streptococci and anaerobes accounted for 11.5, 7.6, 6.9 and 1.9%, respectively. Antibiotics were frequently administered by parenteral route and frequently in combination. Piperacillin/tazobactam was the parenteral antibiotic most frequently utilized (21.1%). Cure/improvement was observed in 93.4% of patients.. Foot ulcers in diabetes are common and serious; the aetiology is often polymicrobial, often including S. aureus and Pseudomonas spp. Treatment in the out-patient setting is safe and effective, and penicillins together with beta-lactamase inhibitors and fluoroquinolones are the most frequent choice.

Topics: Adult; Aged; Aged, 80 and over; Ambulatory Care; Anti-Bacterial Agents; Bacterial Infections; Diabetic Foot; Female; Humans; Italy; Male; Middle Aged; Outpatient Clinics, Hospital; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas Infections; Staphylococcal Infections; Young Adult

The aim of this study was to determine the risk factors for nosocomial infections of imipenem-resistant Pseudomonas aeruginosa (IRPA). A prospective case-control study was performed at a tertiary care hospital in Ankara from January to December 2004. The patients with nosocomial P. aeruginosa infection were included in the study. The features of the patients with IRPA infections were compared to those with imipenem-sensitive P. aeruginosa (ISPA) infections. Only the first isolation of P. aeruginosa was considered. Nosocomial infections were defined according to Center for Disease Control (CDC) criteria. IRPA was isolated from 75 (44.1%) patients, and ISPA was isolated from 95 (55.9%) patients during the study period. IRPA were most frequently isolated from endotracheal aspirate (19%) cultures (p=0.048), whereas ISPA were most frequently isolated from urine (28%) cultures (p=0.023). In multivariate analysis, a longer duration of hospital stay until P. aeruginosa isolation (odds ratio [OR], 1.027; 95% confidence interval [CI], 1.002-1.054, p=0.034), arterial catheter administration (OR, 2.508; 95% CI, 1.062-5.920, p=0.036), vancomycin (OR, 2.882; 95% CI, 1.130-7.349, p=0.027), piperacillin-tazobactam (OR, 6.425; 95% CI, 2.187-18.875, p=0.001), and imipenem (OR, 3.580; 95% CI, 1.252-10.245, p=0.017) treatment within the 14 days before isolation of IRPA were independently associated with imipenem resistance. It was concluded that treatment with imipenem, vancomycin and piperacillin-tazobactam were major risk factors for IRPA infections in hospitalized patients. The nosocomial occurrence of IRPA was also strongly related to the duration of hospital stay, arterial catheter administration.

Topics: Adult; Aged; Anti-Bacterial Agents; Case-Control Studies; Cross Infection; Drug Resistance, Multiple, Bacterial; Female; Humans; Imipenem; Length of Stay; Male; Microbial Sensitivity Tests; Middle Aged; Multivariate Analysis; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Prospective Studies; Pseudomonas aeruginosa; Pseudomonas Infections; Risk Factors; Vancomycin

Bacteremia due to Pseudomonas aeruginosa is associated with grave clinical outcomes. Recent studies have emphasized the importance of appropriate empirical therapy, but controversy arises when piperacillin-tazobactam is used against isolates with reduced susceptibility.. We performed a retrospective cohort study of pseudomonal bacteremia from 2002 to 2006. Patients were identified by the microbiology laboratory database, and pertinent clinical data (demographic characteristics, baseline Acute Physiology and Chronic Health Evaluation [APACHE] II scores, source of bacteremia, and therapy) were retrieved from the electronic medical records. All patients received appropriate empirical therapy within 24 h of positive culture results. Patients receiving piperacillin-tazobactam were compared with those receiving other agents (control subjects). The primary outcome was 30-day mortality from the first day of bacteremia.. A total of 34 bacteremia episodes were identified involving isolates with reduced susceptibility to piperacillin-tazobactam (minimum inhibitory concentration, 32 or 64 mg/L, reported as susceptible); piperacillin-tazobactam was empirically given in 7 episodes. There was no significant difference in baseline characteristics between the 2 groups. Thirty-day mortality was found to be 85.7% in the piperacillin-tazobactam group and 22.2% in the control group (P = .004). Time to hospital mortality was also found to be shorter in the piperacillin-tazobactam group (P < .001). In the multivariate analysis, 30-day mortality was found to be associated with empirical piperacillin-tazobactam therapy (odds ratio, 220.5; 95% confidence interval, 3.8-12707.4; P = .009), after adjustment for differences in age and APACHE II score.. In P. aeruginosa bacteremia due to isolates with reduced piperacillin-tazobactam susceptibility, empirical piperacillin-tazobactam therapy was associated with increased mortality. Additional studies are warranted to examine the appropriateness of the current Clinical Laboratory Standards Institute resistance breakpoint of piperacillin-tazobactam.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacteremia; Cohort Studies; Drug Resistance, Bacterial; Female; Hospital Mortality; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Treatment Outcome

Piperacillin-tazobactam is frequently used to treat Pseudomonas aeruginosa infections in critically ill patients. In an effort to improve clinical outcomes, an extended-infusion dosing scheme for piperacillin-tazobactam therapy was devised using a Monte Carlo simulation and was adopted into clinical practice at Albany Medical Center (Albany, New York). This study evaluates the clinical implications of extended infusion of piperacillin-tazobactam therapy for critically ill patients with P. aeruginosa infection.. We performed a cohort study of patients who received piperacillin-tazobactam therapy for a P. aeruginosa infection that was susceptible to piperacillin-tazobactam during the period January 2000-June 2004. Prior to February 2002, all patients received intermittent infusions of piperacillin-tazobactam (3.375 g intravenously for 30 min every 4 or 6 h); after this time, all patients received extended infusions of piperacillin-tazobactam (3.375 g intravenously for 4 h every 8 h). Data on demographic characteristics, disease severity, and microbiology were collected, and outcomes were compared between groups.. A total of 194 patients comprised the 2 study groups: 102 patients received extended infusions of piperacillin-tazobactam, and 92 patients received intermittent infusions of piperacillin-tazobactam. No differences in baseline clinical characteristics were noted between the 2 groups. Among patients with Acute Physiological and Chronic Health Evaluation-II scores > or =17, 14-day mortality rate was significantly lower among patients who received extended-infusion therapy than among patients who received intermittent-infusion therapy (12.2% vs. 31.6%, respectively; P=.04), and median duration of hospital stay after collection of samples for culture was significantly shorter for patients who received extended-infusion therapy than for patients who received intermittent-infusion therapy (21 days vs. 38 days; P=.02).Conclusions. These results indicate that extended-infusion piperacillin-tazobactam therapy is a suitable alternative to intermittent-infusion piperacillin-tazobactam therapy, and they strongly suggest that improved outcomes may be realized by administering extended-infusion piperacillin-tazobactam therapy to critically ill patients with P. aeruginosa infection.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; APACHE; beta-Lactams; Cohort Studies; Critical Illness; Cross Infection; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Infusions, Intravenous; Male; Microbial Sensitivity Tests; Middle Aged; Models, Biological; Monte Carlo Method; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas Infections; Retrospective Studies

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

Pseudomonas aeruginosa isolates carrying IMP- or VIM-type metallo-beta-lactamase (MBL) have been increasingly reported in hospitals worldwide. One hundred P. aeruginosa clinical isolates from unrelated inpatients hospitalized at a Turkish university hospital were screened for the presence of bla(IMP) and bla(VIM) genes by polymerase chain reaction (PCR). One (1%) isolate was found to carry a VIM-type MBL gene, whereas nine (9%) carried an IMP-1 MBL gene carried on a cassette inserted into a class 1 integron. Only four of the IMP producers were detected as MBL producers according to E-test MBL. Minimum inhibitory concentrations (MICs) of imipenem for the IMP-1 and VIM-type MBL-producers were highly variable (MIC values, 8-128 mug/ml). Imipenem resistance was not plasmid-mediated according to the transformation assays. Piperacillin/tazobactam was the only effective drug in antimicrobial susceptibility testing. No aztreonam-resistant IMP and VIM producers were detected to produce an extended-spectrum beta-lactamase (ESBL). Three class 1 integrons of approximately 2,300 bp, 1,800 bp, and 1,500 bp in size were detected in each of the nine IMP-positive isolates. Sequencing revealed three novel gene cassette arrays, aac(3)-1c-cmlA5, bla(IMP-1)-aadA7-like, and aacA7-smr-2-orfD. Enterobacterial repetitive intergenic consensus PCR (ERIC-PCR) indicated that a clonal spread of IMP-1-producers had occurred in this hospital.

Topics: Anti-Bacterial Agents; Aztreonam; beta-Lactamases; Drug Resistance, Multiple, Bacterial; Genes, Bacterial; Hospitals, University; Humans; Imipenem; Integrons; Microbial Sensitivity Tests; Molecular Epidemiology; Molecular Sequence Data; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Plasmids; Polymerase Chain Reaction; Pseudomonas aeruginosa; Pseudomonas Infections; Turkey

To compare conventional intermittent dosing regimens of piperacillin-tazobactam with prolonged and continuous infusions to determine the optimal dosing scheme against a local Pseudomonas aeruginosa population.. Pharmacodynamic Monte Carlo simulation model.. Microbiologic data from 470 consecutive non duplicate P. aeruginosa isolates collected from a single institution over 6 months in 2006.. Five thousand simulated surgical patients and patients with neutropenia.. We simulated serum concentration-time profiles at steady state for several piperacillin-tazobactam dosing regimens, including intermittent, prolonged, and continuous infusions. The probability of achieving 50% free time above the MIC against 470 P. aeruginosa isolates was calculated. The cumulative fractions of response for the intermittent-infusion regimens were 74.7% (3.375 g every 6 hrs), 79.9% (4.5 g every 6 hrs), and 85.6% (3.375 g every 4 hrs). For prolonged infusion regimens, the cumulative fractions of response were 83.3% (3.375 g every 8 hrs, 4-hr infusion), 87.1% (4.5 g every 8 hrs, 4-hr infusion), and 89.6% (4.5 g every 6 hrs, 3-hr infusion). For continuous-infusion regimens, the cumulative fractions of response were 82.3% (10.125 g), 86.5% (13.5 g), 89.2% (18 g), 90.0% (20.25 g), and 90.6% (22.5 g).. Both prolonged- and continuous-infusion strategies improved the pharmacodynamics of piperacillin-tazobactam over those of traditional 30-minute intermittent-infusion regimens. Prolonged- and continuous infusion regimens that contained the same daily doses of piperacillin had similar likelihoods of bactericidal exposure. Thus, the selection of dosing strategy depends on the availability of intravenous access versus the convenience of once-daily administration.

Topics: Anti-Bacterial Agents; Computer Simulation; Drug Administration Schedule; Drug Resistance, Bacterial; Hospitals; Humans; Infusions, Intravenous; Microbial Sensitivity Tests; Monte Carlo Method; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Time Factors

We investigated the efficacy of Tachyplesin III alone or combined with piperacillin-tazobactam (TZP) to prevent biofilm formation in vitro and in a rat model of Pseudomonas aeruginosa ureteral stent infection. We have observed that in vitro TZP, in presence of Tachyplesin III, showed minimal inhibitory concentrations (MIC)s twofold and minimal bactericidal concentrations (MBC)s eightfold lower. The in vivo study showed that rats that received intraperitoneal TZP showed the lowest bacterial numbers. Tachyplesin III combined with TZP showed efficacies higher than that of each single compound. Coating ureteral stents with Tachyplesin III is able to inhibit bacterial growth up to 1,000 times.

Topics: Animals; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Bacterial Adhesion; Biofilms; Colony Count, Microbial; Disease Models, Animal; DNA-Binding Proteins; Drug-Eluting Stents; In Vitro Techniques; Male; Penicillanic Acid; Peptides, Cyclic; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Rats; Rats, Wistar; Ureteral Diseases

From 2001 to 2003, rates of susceptibility to piperacillin-tazobactam (86%), ceftazidime (80%), ciprofloxacin (68%), and levofloxacin (67%) did not decrease or decreased by <1.5%, whereas the rate of susceptibility to gentamicin decreased by 3.2% (from 75.5% to 72.3%) and the rate of susceptibility to imipenem decreased by 5.6% (from 84.4% to 78.8%), for 2394 clinical isolates of Pseudomonas aeruginosa collected in the Tracking Resistance in the United States Today surveillance studies. Rates of multidrug resistance (i.e., resistance to > or =3 antimicrobial agents) increased from 7.2% in 2001 to 9.9% in 2003 and were significantly higher for isolates from the East North Central and Mid-Atlantic regions of the United States than for isolates from other regions. Analysis of minimum inhibitory concentrations (MICs) suggested that combining an antipseudomonal beta -lactam with ciprofloxacin or levofloxacin would yield a 3.4%-7.1% increase in the percentage of isolates susceptible to the combination, compared with the beta -lactam alone. Ratios of the area under the serum concentration-time curve values for free drug to modal MICs for ciprofloxacin and levofloxacin were similar and were >125 (target ratio), whereas those ratios for gatifloxacin and moxifloxacin were significantly lower. Ongoing surveillance of P. aeruginosa is essential.

Topics: beta-Lactams; Ceftazidime; Ciprofloxacin; Drug Resistance, Multiple, Bacterial; Fluoroquinolones; Gatifloxacin; Gentamicins; Humans; Microbial Sensitivity Tests; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; United States

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

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

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

Topics: Anti-Bacterial Agents; Diagnosis, Differential; Drug Therapy, Combination; Ecthyma; Female; Gentamicins; Humans; Infant; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections

The antibacterial activity of imipenem, cefepime and piperacillin-tazobactam alone or in combination with amikacin against a Pseudomonas aeruginosa strain producing an extended-spectrum beta-lactamase (PER-1) were compared using an experimental model of pneumonia in non-leucopenic rats. Animals were infected intratracheally with 8.0 +/- 0.4 log10 cfu of P. aeruginosa, and therapy was initiated 3 h later, by which time animal lungs showed bilateral pneumonia containing >7 log10 P. aeruginosa cfu/g of tissue. Since rats eliminate antibiotics much more rapidly than humans, renal impairment was induced in all animals to simulate the pharmacokinetic parameters of humans. MICs determined using an inoculum of 4 log10 cfu/mL were as follows: imipenem, 1 mg/L; cefepime, 8 mg/L; piperacillin-tazobactam, 32 mg/L; and amikacin, 16 mg/L. A noticeable inoculum effect was observed with the four antimicrobial agents tested, which was greatest for cefepime and piperacillin-tazobactam. In-vitro studies indicated that imipenem was the beta-lactam with the greatest bactericidal effect and that amikacin was synergic only in combination with cefepime and imipenem. Cefepime and piperacillin-tazobactam alone failed to decrease bacterial counts in the rats' lungs 60 h after therapy onset, whereas imipenem and, to a lesser extent, amikacin significantly reduced the number of viable microorganisms. Combination of amikacin with any of the three beta-lactams tested was synergic, despite a high amikacin MIC for the infecting strain. These results paralleled our in-vitro data showing a marked inoculum effect for cefepime and piperacillin-tazobactam. Based on the results of this study, the best treatment for infections caused by this type of extended-spectrum beta-lactamase-possessing strain would be imipenem plus amikacin.

Topics: Amikacin; Animals; Anti-Bacterial Agents; beta-Lactamases; Cefepime; Cephalosporins; Colony Count, Microbial; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Imipenem; Lung; Male; Microbial Sensitivity Tests; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pneumonia, Bacterial; Pseudomonas aeruginosa; Pseudomonas Infections; Rats; Rats, Wistar

Topics: Adult; Drug Therapy, Combination; Humans; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pseudomonas Infections