meropenem and Enterobacteriaceae-Infections

In 2010, the Clinical and Laboratory Standards Institute (CLSI) lowered carbapenem breakpoints to reduce the proportion of 'susceptible' organisms that produced carbapenemases. Few studies have evaluated the effect of this change on clinical outcomes. This systematic review aimed to evaluate the effect of carbapenem MICs on 30-day mortality from pooled patient-level data from studies of patients treated with carbapenems across a range of meropenem MICs. PubMed was searched to March 2019 with the terms 'carbapenem', 'meropenem', 'imipenem', 'doripenem', 'ertapenem', 'susceptibility' and 'outcomes'. Studies were included in the analysis if patients had Enterobacteriaceae bacteraemia treated with a carbapenem for ≥48 h and mortality was reported. Studies were excluded if all isolates were either susceptible or resistant to meropenem based on CLSI 2010 breakpoints or if only carbapenemase-producing isolates were included. Authors were contacted for patient-level data. The primary outcome was 30-day mortality, with planned subset analyses of patients treated with meropenem, receiving active combination therapy, treated in the ICU or infected with Klebsiella pneumoniae. Of 157 articles identified, 4 met the inclusion criteria (115 eligible patients). The odds of mortality increased with each increasing meropenem MIC dilution (OR = 1.51, 95% CI 1.06-2.15) as a continuous variable. A similar increase in odds was observed in patients treated with meropenem, treated in the ICU, infected with K. pneumoniae or receiving no other active antimicrobials. Increasing meropenem MICs in Enterobacteriaceae were associated with increased mortality; however, more work is needed to define optimal clinical decision rules for infections within the susceptible range.

Topics: Anti-Bacterial Agents; Bacteremia; Enterobacteriaceae; Enterobacteriaceae Infections; Humans; Meropenem; Microbial Sensitivity Tests

Ceftazidime/avibactam and meropenem/vaborbactam are changing the management of invasive infections due to carbapenem-resistant Enterobacteriaceae (CRE), leading to higher rates of clinical cure, decreased mortality, and decreased rates of acute kidney injury compared with colistin-based regimens. However, these 2 agents are not interchangeable with regard to management of CRE infections, and clinicians need to be aware of their differences. This review focuses on differences in the in vitro activity of these agents as a function of mechanism of carbapenem resistance, the clinical data supporting their superiority over colistin-based therapy, and the differences between agents with regard to propensity for selection of resistance. Furthermore, considerations and recommendations for hospital formularies and antibiotic stewardship programs regarding positioning of these agents are discussed.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; Boronic Acids; Carbapenem-Resistant Enterobacteriaceae; Ceftazidime; Disease Management; Drug Combinations; Enterobacteriaceae Infections; Heterocyclic Compounds, 1-Ring; Humans; Meropenem

Pantoea is a Gram-negative, non-encapsulated, non-spore-forming, ubiquitous straight rod which can be isolated from geographical and ecological sources such as plant surfaces, buckwheat seeds, human feces, and the environment. The genus Pantoea is a rare pathogen in a clinical setting, and is divided into 20 different species such as Pantoea agglomerans, Pantoea ananatis, Pantoea deleyi, Pantoea dispersa, Pantoea septica, Pantoea stewartii or Pantoea rwandensis. Pantoea dispersa has been reported to cause other infections, including respiratory infections, neonatal sepsis, and bloodstream infections. We report a case of Pantoea dispersa bacteremia caused by acute cholangitis. This is the first case report of Pantoea dispersa bacteremia caused by acute cholangitis as far as we had searched.. A 38-year-old Japanese woman suffered from acute cholangitis; a blood culture showed that Gram-negative rod was positive. The treatment was successful with intravenously administered meropenem, and it was switched to orally administered levofloxacin according to microbiological susceptibility. The organism was identified as Pantoea dispersa by both genetic investigation by 16S ribosomal RNA and additional biochemical tests. To the best of our knowledge, this is the first case report of Pantoea dispersa bacteremia caused by acute cholangitis.. The epidemiology and clinical features of Pantoea dispersa are still unknown. More cases of infections caused by Pantoea dispersa might be revealed with advancing technical methods, such as matrix-assisted laser desorption/ionization time-of-flight mass spectrometry or 16S ribosomal RNA analysis. Physicians must know that a variety of infections caused by Pantoea dispersa could occur in immunocompromised as well as immunocompetent patients.

Topics: Acute Disease; Adult; Anti-Bacterial Agents; Bacteremia; Bile Ducts; Cholangitis; Enterobacteriaceae Infections; Female; Humans; Immunocompetence; Immunocompromised Host; Levofloxacin; Meropenem; Pantoea

There is currently a paucity of published literature focused on the treatment of infections caused by NDM-producing organisms.. We describe a case of a bacteraemia caused by an extensively drug-resistant (XDR) New Delhi metallo-β-lactamase (NDM)-producing Serratia marcescens and review the treatment options for XDR NDM-producing Enterobacteriaceae.. Infections caused by New Delhi beta-lactamase (NDM)-producing Enterobacteriaceae are becoming increasingly prevalent worldwide. The presence of the enzyme results in multidrug-resistant and extensively drug-resistant phenotypes which often pose a treatment challenge. Despite this challenge, case reports and series have demonstrated good clinical outcomes with numerous treatment options in comparison to infections due to KPC-producing Enterobacteriaceae.. Further good-quality research focused on the treatment of NDM-producing Enterobacteriaceae is warranted.

Topics: Amikacin; Anti-Bacterial Agents; Bacteremia; beta-Lactamases; Child; Drug Resistance, Multiple, Bacterial; Enterobacteriaceae; Enterobacteriaceae Infections; Female; Humans; Meropenem; Serratia Infections; Serratia marcescens; Thienamycins; Treatment Outcome

Complicated urinary tract infections are increasingly caused by multidrug-resistant organisms. Carbapenem-resistant Enterobacteriaceae (CRE) constitute a rising threat among uropathogens with significant morbidity and mortality. Meropenem-vaborbactam is a novel carbapenem and cyclic boronic acid-based beta-lactamase inhibitor combination with potent activity against subtypes of CRE. Areas covered: This article reviews mechanisms of carbapenem resistance, existing treatment options for CRE, and the current evidence to support the use of meropenem-vaborbactam for the treatment of infections caused by subtypes of CRE including complicated urinary tract infections. Expert commentary: Meropenem-vaborbactam is a superior treatment option for infections secondary to Klebsiella pneumoniae carbapenemase (KPC)-producing CRE. It is associated with higher rates of treatment success and lower rates of toxicity than traditional agents and demonstrates a potentially higher barrier to acquired antimicrobial resistance than ceftazidime-avibactam. At present, meropenem-vaborbactam should be regarded as a preferred treatment option for invasive infections secondary to KPC-producing CRE.

Topics: Adult; Animals; Anti-Bacterial Agents; Boronic Acids; Carbapenem-Resistant Enterobacteriaceae; Drug Combinations; Drug Resistance, Multiple, Bacterial; Enterobacteriaceae Infections; Humans; Klebsiella pneumoniae; Meropenem; Urinary Tract Infections

The increasing prevalence of infections due to multidrug-resistant (MDR) gram-negative bacteria constitutes a serious threat to global public health due to the limited treatment options available and the historically slow pace of development of new antimicrobial agents. Infections due to MDR strains are associated with increased morbidity and mortality and prolonged hospitalization, which translates to a significant burden on healthcare systems. In particular, MDR strains of Enterobacteriaceae (especially Klebsiella pneumoniae and Escherichia coli), Pseudomonas aeruginosa, and Acinetobacter baumannii have emerged as particularly serious concerns. In the United States, MDR strains of these organisms have been reported from hospitals throughout the country and are not limited to a small subset of hospitals. Factors that have contributed to the persistence and spread of MDR gram-negative bacteria include the following: overuse of existing antimicrobial agents, which has led to the development of adaptive resistance mechanisms by bacteria; a lack of good antimicrobial stewardship such that use of multiple broad-spectrum agents has helped perpetuate the cycle of increasing resistance; and a lack of good infection control practices. The rising prevalence of infections due to MDR gram-negative bacteria presents a significant dilemma in selecting empiric antimicrobial therapy in seriously ill hospitalized patients. A prudent initial strategy is to initiate treatment with a broad-spectrum regimen pending the availability of microbiological results allowing for targeted or narrowing of therapy. Empiric therapy with newer agents that exhibit good activity against MDR gram-negative bacterial strains such as tigecycline, ceftolozane-tazobactam, ceftazidime-avibactam, and others in the development pipeline offer promising alternatives to existing agents.

Topics: Acinetobacter baumannii; Anti-Bacterial Agents; Boronic Acids; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Enterobacteriaceae Infections; Escherichia coli; Heterocyclic Compounds, 1-Ring; Hospitals; Humans; Klebsiella pneumoniae; Meropenem; Pseudomonas aeruginosa; Sisomicin; Tetracyclines; Thienamycins

Carbapenem-resistant Enterobacteriaceae (CRE) is a worldwide challenge and associated with a high mortality rate in critically ill patients. This review focused on rapid diagnosis, optimization of antimicrobial therapy, and implication of effective infection control precautions to reduce impact of CRE on vulnerable patients.. Several new diagnostic assays have recently been described for the early diagnosis of CRE. Retrospective studies are supportive for colistin plus meropenem combination for the treatment of CRE infections; however, solid evidence is still lacking. Ceftazidime-avibactam may be an effective therapeutic agent for infections caused by carbapenem-hydrolyzing oxacillinase-48 and Klebsiella pneumoniae carbapenamase-producing Enterobacteriaceae, but not for New Delhi metallo-β-lactamase producers. Gastrointestinal screening may permit early identification of patients with CRE infections. There is not enough evidence to recommend selective digestive decontamination for CRE carriers.. The information for rapid diagnosis of CRE is accumulating. There are new agents with high in-vitro activity against CRE, but clinical experience is limited to case reports. Active surveillance with a high rate of compliance to basic infection control precautions seems to be the best approach to reduce the impact of CRE on vulnerable patients.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactam Resistance; beta-Lactamases; Carbapenems; Ceftazidime; Colistin; Critical Illness; Drug Combinations; Drug Therapy, Combination; Enterobacteriaceae; Enterobacteriaceae Infections; Humans; Meropenem; Retrospective Studies; Thienamycins

The objective of this study was to describe the microbiological characteristics of an extensively drug-resistant (XDR) isolate of Morganella morganii obtained from a patient with sepsis of urinary origin and to describe the patient's clinical characteristics. We further aimed to perform a literature review of the situation in Latin America regarding Gram-negative bacillus (GNB) carriers of New Delhi metallo-β-lactamase (NDM-1) and qnr genes and current reports on the treatment of infections caused by XDR enterobacteria, with particular attention to colistin-resistant isolates.. The patient's clinical data were obtained from his medical history. Microbiological identification and susceptibility testing were done using the VITEK 2 Compact System. Resistance genes were detected by PCR and sequencing.. Blood and urine cultures grew an M. morganii isolate (Mm4232) harboring NDM-1 and qnrD1. The patient was treated successfully with fosfomycin and double doses of meropenem. There are no previous reports of the use of fosfomycin and meropenem to treat infections by XDR enterobacteria harboring NDM-1 carbapenemase.. This is the first report of qnrD1 in South America. We consider that this report could be helpful to physicians implementing treatments for infections caused by XDR GNB, including colistin-carbapenem-resistant GNB.

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Colistin; Drug Resistance, Bacterial; Drug Therapy, Combination; Enterobacteriaceae Infections; Fosfomycin; Humans; Male; Meropenem; Morganella morganii; Sepsis; South America; Thienamycins; Young Adult

Existing clinical studies concerning the impact of therapy with third-generation cephalosporins or cefepime on infections caused by extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae are retrospective, non-randomised, and have been carried out with a small number of patients and low-dosage schedules that lack PK-PD correlations with clinical efficacy. Rates of clinical failure and mortality are higher than those in studies with non-ESBL- producing Enterobacteriaceae. Therefore, in settings with a high prevalence of ESBL-producing Enterobacteriaceae, empirical therapy with advanced cephalosporins should be avoided. Temocillin, an old beta-lactam that is stable in the presence of both ESBLs and AmpC beta-lactamases, seems to deserve revival, although clinical data are limited.

Topics: Anti-Bacterial Agents; beta-Lactams; Cephalosporins; Enterobacteriaceae; Enterobacteriaceae Infections; Humans; Meropenem; Microbial Sensitivity Tests; Penicillins; Thienamycins

The increasing multidrug resistance among gram-negative uropathogens necessitates new treatments for serious infections. Plazomicin is an aminoglycoside with bactericidal activity against multidrug-resistant (including carbapenem-resistant) Enterobacteriaceae.. We randomly assigned 609 patients with complicated urinary tract infections (UTIs), including acute pyelonephritis, in a 1:1 ratio to receive intravenous plazomicin (15 mg per kilogram of body weight once daily) or meropenem (1 g every 8 hours), with optional oral step-down therapy after at least 4 days of intravenous therapy, for a total of 7 to 10 days of therapy. The primary objective was to show the noninferiority of plazomicin to meropenem in the treatment of complicated UTIs, including acute pyelonephritis, with a noninferiority margin of 15 percentage points. The primary end points were composite cure (clinical cure and microbiologic eradication) at day 5 and at the test-of-cure visit (15 to 19 days after initiation of therapy) in the microbiologic modified intention-to-treat population.. Plazomicin was noninferior to meropenem with respect to the primary efficacy end points. At day 5, composite cure was observed in 88.0% of the patients (168 of 191 patients) in the plazomicin group and in 91.4% (180 of 197 patients) in the meropenem group (difference, -3.4 percentage points; 95% confidence interval [CI], -10.0 to 3.1). At the test-of-cure visit, composite cure was observed in 81.7% (156 of 191 patients) and 70.1% (138 of 197 patients), respectively (difference, 11.6 percentage points; 95% CI, 2.7 to 20.3). At the test-of-cure visit, a higher percentage of patients in the plazomicin group than in the meropenem group were found to have microbiologic eradication, including eradication of Enterobacteriaceae that were not susceptible to aminoglycosides (78.8% vs. 68.6%) and Enterobacteriaceae that produce extended-spectrum β-lactamases (82.4% vs. 75.0%). At late follow-up (24 to 32 days after initiation of therapy), fewer patients in the plazomicin group than in the meropenem group had microbiologic recurrence (3.7% vs. 8.1%) or clinical relapse (1.6% vs. 7.1%). Increases in serum creatinine levels of 0.5 mg or more per deciliter (≥40 μmol per liter) above baseline occurred in 7.0% of patients in the plazomicin group and in 4.0% in the meropenem group.. Once-daily plazomicin was noninferior to meropenem for the treatment of complicated UTIs and acute pyelonephritis caused by Enterobacteriaceae, including multidrug-resistant strains. (Funded by Achaogen and the Biomedical Advanced Research and Development Authority; EPIC ClinicalTrials.gov number, NCT02486627.).

Topics: Administration, Intravenous; Administration, Oral; Adult; Aged; Anti-Bacterial Agents; Drug Administration Schedule; Drug Resistance, Multiple, Bacterial; Enterobacteriaceae; Enterobacteriaceae Infections; Female; Humans; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Patient Acuity; Sisomicin; Urinary Tract Infections

Extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae pose a huge threat to human health, especially in the context of complicated urinary tract infections (cUTIs). Carbapenems and piperacillin-tazobactam (PTZ) are two antimicrobial agents commonly used to treat cUTIs.. A monocentric retrospective cohort study focused on the treatment of cUTIs in adults was conducted from January 2019 to November 2021. Patients with a positive urine culture strain yielding ≥ 103 colony-forming units per milliliter (CFU/mL), and sensitive to PTZ and carbapenems, were included. The primary endpoint was clinical success after antibiotic therapy. The secondary endpoint included rehospitalization and 90-day recurrence of cUTIs caused by ESBL-producing Enterobacteriaceae.. Of the 195 patients included in this study, 110 were treated with PTZ while 85 were administered meropenem. The rate of clinical cure was similar between the PTZ and meropenem groups (80% vs. 78.8%, p = 0.84). However, the PTZ group had a lower duration of total antibiotic use (6 vs. 9; p < 0.01), lower duration of effective antibiotic therapy (6 vs. 8; p < 0.01), and lower duration of hospitalization (16 vs. 22; p < 0.01).. In terms of adverse events, the safety of PTZ was higher than that of meropenem in the treatment of cUTIs.

Topics: Adult; Anti-Bacterial Agents; beta-Lactamase Inhibitors; beta-Lactamases; Carbapenems; Enterobacteriaceae; Enterobacteriaceae Infections; Humans; Meropenem; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Pyelonephritis; Retrospective Studies; Urinary Tract Infections

The review aims to review the positioning of meropenem-vaborbactam in clinical practice, taking into consideration the characteristics of other available drugs, namely ceftazidime-avibactam, plazomicin, and colistin.. The search terms 'meropenem-vaborbactam' or RX7009 for the years 2006 until 2021 were used.. Coupling of meropenem with the cyclic boronate derivative varobactam enhances considerably the in vitro intrinsic activity of meropenem against isolates producing KPC (

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Bacterial Proteins; beta-Lactamases; Boronic Acids; Carbapenem-Resistant Enterobacteriaceae; Ceftazidime; Drug Combinations; Enterobacteriaceae Infections; Humans; Klebsiella pneumoniae; Meropenem; Microbial Sensitivity Tests

Fecal carriage of extended-spectrum beta-lactamase and Carbapenemase-producing Enterobacteriaceae is a potential risk for the transmission of infection with resistant strains. Understanding the burden of these resistant strains in asymptomatic people is essential to reduce the chain of infection transmission. However, data on the fecal carriage of Extended-spectrum Beta-lactamase and Carbapenemase-producing Enterobacteriaceae among food handlers were limited in developing countries especially in Ethiopia. The aim of the present study is, therefore, to assess fecal carriage rate, associated factors, and antimicrobial resistance patterns of Extended-spectrum Beta-lactamase and Carbapenemase-producing Enterobacteriaceae among food handlers at the University of Gondar Cafeterias, Northwest Ethiopia.. An institution-based cross-sectional study was conducted from February to June 2021 at the University of Gondar cafeterias. A total of 290 stool samples were collected, transported using Cary Blair transport medium, and processed. All isolates were cultured and identified by using MacConkey agar, and routine biochemical tests. Antimicrobial susceptibility testing was done to each isolate following the Kirby Bauer disk diffusion method. If the zone of inhibition was ≤ 22 mm for ceftazidime, ≤25 mm for ceftriaxone, and ≤27 for cefotaxime they were considered as potential ESBL strain and selected for a further phenotypic confirmatory. Moreover, the double-disc diffusion test and the modified carbapenem inactivation method were used for confirmations of Extended-spectrum β-lactamase and Carbapenemase-producing Enterobacteriaceae respectively. If a ≥5mm difference in zone diameter for either antimicrobial agent in combination with clavulanic acid versus the zone diameter of the agent when tested alone (without B-lactamase inhibitor), was confirmed as ESBL-PE and if the zone of inhibition diameter between 6-15mm and 16- 18mm with a pinpoint colony, it was considered as carbapenem resistance Enterobacteriaceae. Data were entered using Epi-data version 4.6 and then exported to SPSS version 26 for analysis. Potential risk factors were assessed using multivariable logistic regression and a p-value less than 0.05 was considered statistically significant.. Out of 290 stool samples, 63 (21.7%) and 7 (2.4%) were confirmed as Extended-spectrum β-lactamase and Carbapenemase-producing Enterobacteriaceae. The most predominant ESBL-PE was E. coli 43 (14.8%) followed by K. pneumoniae 17 (5.9%). Most of the Extended-spectrum β-lactamase and Carbapenemase-producing isolates were resistant to tetracycline, cefotaxime, ceftazidime, and ceftriaxone (100% each). In contrast, a low resistance level was recorded for Meropenem and cefoxitin. The overall Multi-drug resistant Enterobacteriaceae (MDR) was 147 (42.3%). Antibiotics usage in the last 3 months and drinking unpasteurized milk were associated with the carriage of the Extended-spectrum beta-lactamase-Producing Enterobacteriaceae.. The high fecal carriage rate of Multi-drug resistance isolate, Extended-spectrum β-lactamase, and Carbapenemase-producing Enterobacteriaceae were recorded among food handlers. Therefore, this study gives signals in the spread of drug-resistant bacteria easily to the community. Hence, the need for adjusting and promotion of infection prevention measures to prevent the spread of drug-resistant bacteria should not be underestimated.

Topics: Anti-Bacterial Agents; beta-Lactamases; Carbapenem-Resistant Enterobacteriaceae; Cefotaxime; Ceftazidime; Ceftriaxone; Cross-Sectional Studies; Enterobacteriaceae; Enterobacteriaceae Infections; Escherichia coli; Ethiopia; Humans; Klebsiella pneumoniae; Meropenem; Microbial Sensitivity Tests; Prevalence

Carbapenem-resistant Enterobacteriaceae (CRE) are an urgent threat to public health requiring the development of novel therapies. TP0586532 is a novel non-hydroxamate LpxC inhibitor that inhibits the synthesis of lipopolysaccharides, which are components of the outer membranes of Gram-negative bacteria. Based on the mechanism of action of TP0586532, we hypothesized that it might enhance the antibacterial activity of other antibiotics by increasing the permeability of the outer bacterial membrane. The combination of TP0586532 with meropenem, amikacin, cefepime, piperacillin, and tigecycline showed synergistic and additive effects against carbapenem-susceptible Klebsiella pneumoniae and Escherichia coli. Checkerboard experiments against 21 carbapenem-resistant K. pneumoniae and E. coli strains (13

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Butanols; Carbapenem-Resistant Enterobacteriaceae; Carbapenems; Enterobacteriaceae Infections; Escherichia coli; Gram-Negative Bacteria; Humans; Imidazoles; Klebsiella pneumoniae; Meropenem; Microbial Sensitivity Tests

Heteroresistance is the phenomenon wherein subpopulations of presumed isogenic bacteria show varied antibiotic susceptibilities, and the current gold standard for the determination of heteroresistance is population analysis profiling (PAP). However, when conducting PAP to confirm carbapenem heteroresistance in Enterobacteriaceae, the authors found some isolates that did not seem to be heteroresistant, despite meeting PAP criteria. This article elaborates on the validity of PAP for the determination of heteroresistance, especially among carbapenemase-producing Enterobacteriaceae (CPE). Bacterial cells that were originally non-viable on selective agar supplemented with a high concentration of meropenem were found to be occasionally viable, likely due to the hydrolysis of carbapenems by carbapenemases produced by dying cells, mimicking the emergence of subpopulations with enhanced resistance. As such, PAP for CPE is highly affected by carbapenemases produced by dying populations, and may not detect heterogeneity in carbapenem resistance appropriately among seemingly isogenic clones.

Topics: Agar; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Carbapenem-Resistant Enterobacteriaceae; Carbapenems; Enterobacteriaceae Infections; Humans; Meropenem; Microbial Sensitivity Tests

The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide. Bacterial co-infections are associated with unfavourable outcomes in respiratory viral infections; however, microbiological and antibiotic data related to COVID-19 are sparse. Adequate use of antibiotics in line with antibiotic stewardship (ABS) principles is warranted during the pandemic. We performed a retrospective study of clinical and microbiological characteristics of 140 COVID-19 patients admitted between February and April 2020 to a German University hospital, with a focus on bacterial co-infections and antimicrobial therapy. The final date of follow-up was 6 May 2020. Clinical data of 140 COVID-19 patients were recorded: The median age was 63.5 (range 17-99) years; 64% were males. According to the implemented local ABS guidelines, the most commonly used antibiotic regimen was ampicillin/sulbactam (41.5%) with a median duration of 6 (range 1-13) days. Urinary antigen tests for Legionella pneumophila and Streptococcus peumoniae were negative in all cases. In critically ill patients admitted to intensive care units (n = 50), co-infections with Enterobacterales (34.0%) and Aspergillus fumigatus (18.0%) were detected. Blood cultures collected at admission showed a diagnostic yield of 4.2%. Bacterial and fungal co-infections are rare in COVID-19 patients and are mainly prevalent in critically ill patients. Further studies are needed to assess the impact of antimicrobial therapy on therapeutic outcome in COVID-19 patients to prevent antimicrobial overuse. ABS guidelines could help in optimising the management of COVID-19. Investigation of microbial patterns of infectious complications in critically ill COVID-19 patients is also required.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Ampicillin; Anti-Bacterial Agents; Antifungal Agents; Antimicrobial Stewardship; Aspergillosis; Azithromycin; Bacterial Infections; Cohort Studies; Coinfection; COVID-19; Enterobacteriaceae Infections; Escherichia coli Infections; Female; Germany; Humans; Klebsiella Infections; Linezolid; Male; Meropenem; Middle Aged; Piperacillin, Tazobactam Drug Combination; Practice Patterns, Physicians'; Retrospective Studies; SARS-CoV-2; Staphylococcal Infections; Streptococcal Infections; Sulbactam; Vancomycin; Young Adult

Topics: Animals; beta-Lactamase Inhibitors; beta-Lactamases; Enterobacteriaceae; Enterobacteriaceae Infections; Meropenem; Mice

Topics: Animals; beta-Lactamase Inhibitors; beta-Lactamases; Enterobacteriaceae; Enterobacteriaceae Infections; Meropenem; Mice

Carbapenem-resistant Enterobacterales (CRE) and carbapenemase-producing Enterobacterales (CPE) are difficult to treat and are a serious public health threat. Nacubactam (NAC) is a novel non-β-lactam diazabicyclooctane β-lactamase inhibitor with in vitro activity against some Enterobacterales expressing classes of β-lactamases.. The antimicrobial efficacy of meropenem (MEM), cefepime (FEP), and aztreonam (ATM), each in combination with NAC, were assessed in vitro and in vivo against Klebsiella pneumoniae and Escherichia coli. Ten isolates, including CRE and/or CPE with β-lactamase genes, were used in this study. The relationship between phenotype and in vivo efficacy was assessed in a murine neutropenic thigh-infection model. Efficacy was determined by the change in bacterial quantity.. The results of the in vitro study showed the minimum inhibitory concentrations of the combination of NAC with either MEM, FEP, or ATM in a 1:1 ratio were 2 to >128-fold lower than those of MEM, FEP, or ATM alone against CRE+ isolates. In addition, combinations of β-lactams and NAC administered in the murine thigh-infection model showed greater efficacy against CRE+/CPE+, CRE+/CPE-, and CRE-/CPE+ isolates harboring various β-lactamase genes (IMP-1, IMP-6, KPC, DHA-1, or OXA-48) compared with MEM, FEP, ATM, and NAC alone.. MEM, FEP, or ATM in combination with NAC showed potent in vivo antimicrobial activity in a murine thigh-infection model caused by K. pneumoniae and E. coli, including CRE and/or CPE isolates. These findings indicate that these combinations of β-lactams and NAC are potential candidates for the treatment of CRE and/or CPE infections.

Topics: Animals; Anti-Bacterial Agents; Azabicyclo Compounds; Aztreonam; Bacterial Proteins; beta-Lactamases; Carbapenem-Resistant Enterobacteriaceae; Cefepime; Dose-Response Relationship, Drug; Drug Resistance, Bacterial; Drug Therapy, Combination; Enterobacteriaceae Infections; Escherichia coli; Humans; Klebsiella pneumoniae; Lactams; Meropenem; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Models, Animal; Specific Pathogen-Free Organisms

The coronavirus disease 2019 causes a wide degree of organ dysfunction and is associated with bacterial secondary infections. We reported lung microbiota dynamics in a critically ill patient with coronavirus disease 2019, who developed severe Hafnia alvei ventilator-associated pneumonia and required extracorporeal membrane oxygenation support.

Topics: Bronchoalveolar Lavage; COVID-19; Dysbiosis; Enterobacteriaceae Infections; Hafnia alvei; Humans; Lung; Male; Meropenem; Microbiota; Middle Aged; Pneumonia, Ventilator-Associated; Respiration, Artificial; Respiratory Distress Syndrome; SARS-CoV-2

Twenty patients with carbapenem-resistant Enterobacteriaceae infections were treated with meropenem-vaborbactam. Thirty-day clinical success and survival rates were 65% (13/20) and 90% (18/20), respectively. Thirty-five percent of patients had microbiologic failures within 90 days. One patient developed a recurrent infection due to meropenem-vaborbactam-nonsusceptible, ompK36 porin mutant Klebsiella pneumoniae.

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Boronic Acids; Carbapenem-Resistant Enterobacteriaceae; Enterobacteriaceae Infections; Humans; Klebsiella pneumoniae; Meropenem; Microbial Sensitivity Tests

Detecting carbapenemase-producing Enterobacteriaceae (CPE) has become increasingly difficult due to the emergence of diverse enzymes. The aim of the study was to evaluate an agar plate-based modified carbapenem inactivation method (p-mCIM) for detection of CPE. Stock strains and clinical isolates of CPE were used to evaluate the p-mCIM. The p-mCIM was performed as described for the mCIM, except that meropenem disks were placed on the lawn of test organisms on Mueller-Hinton agar (MHA) plates. Among 17 stock strains of CPE, six of eight KPC-2-like- and all six NDM-1-like carbapenemase-producing strains were positive by the p-mCIM without incubation in the carbapenem inactivation (CI) step. Among 380 CPE clinical isolates detected, 308 and 38 were KPC-2-like and NDM-1-like enzyme producers, respectively. The required incubation time in the CI step to show all isolates were positive by p-mCIM was 3 h for isolates with KPC-2-like enzyme and 1 h for isolates with metallo-β-lactamases. Twenty-eight of 30 isolates with OXA-48-like enzymes were p-mCIM positive. Sensitivities of both the p-mCIM and the mCIM (based on inhibition zone of ≤15 mm) for detection of CPE were 100%. All 70 ertapenem-nonsusceptible, but carbapenemase gene-negative isolates tested were both p-mCIM (based on inhibition zone of ≥21 mm) and mCIM negative. In conclusion, performance of the p-mCIM, which uses a lawn of bacterial colonies on MHA plate instead of a bacteria-suspended Tryptic soy broth tube in the CI step, is essentially identical to that of the CLSI-recommended mCIM in the detection of clinical isolates of Enterobacteriaceae producing carbapenemases including difficult to detect bla

Topics: Agar; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Carbapenem-Resistant Enterobacteriaceae; Carbapenems; Enterobacteriaceae Infections; Humans; Meropenem; Microbial Sensitivity Tests; Sensitivity and Specificity

Through their action on DNA replication, anticancer chemotherapies could increase the basal mutation rate in bacteria and increase the risk of selecting antibiotic resistant mutants. We investigated the impact of several drugs on a beta-lactamase model using KPC-type carbapenemase-producing Enterobacteriaceae. We studied the impact of anticancer chemotherapies used in pediatric hematologic malignancies on 7 clinical isolates of Enterobacteriaceae producing KPC-type carbapenemases. We compared the mutation rates from cultures with/without chemotherapy on ceftazidime-avibactam, rifampicin and ceftazidime-avibactam combined with meropenem media. Mechanisms of ceftazidime-avibactam resistance were explored on a subset of mutants. After exposure to some cytotoxic molecules, the bacterial mutation rates leading to ceftazidime-avibactam and to rifampicin resistance increased up to 10

Topics: Anti-Bacterial Agents; Antineoplastic Agents; Azabicyclo Compounds; Bacterial Proteins; beta-Lactamases; Carbapenem-Resistant Enterobacteriaceae; Ceftazidime; Drug Combinations; Drug Resistance, Bacterial; Enterobacteriaceae Infections; Genome, Bacterial; Humans; Meropenem; Microbial Sensitivity Tests; Mutation; Rifampin; Whole Genome Sequencing

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; beta-Lactams; Drug Resistance, Bacterial; Enterobacteriaceae; Enterobacteriaceae Infections; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests

Limited treatment options complicate management of infections with New Delhi metallo-β-lactamase (NDM)-producing organisms. The efficacy of combination therapy with meropenem (MEM) and cefmetazole (CMZ) was assessed against NDM-producing Enterobacteriaceae.. MICs of MEM, ERT and CMZ in monotherapy ranged from 8 to 32, 16 to 128, and 32 to 512 µg/mL, respectively. In the checkerboard assay, MEM/ERT resulted in no synergy, whereas MEM/CMZ showed a synergistic effect in all the tested isolates. Furthermore, the MIC of MEM in combination decreased by 2- to 8-fold compared with that of MEM alone. The time-kill study revealed a bactericidal effect in 4 of 13 isolates at 24 h. Scanning electron microscopy showed spheroidisation of the bacterial cell in the MEM/CMZ combination; this was not observed in single antibiotic conditions. Kinetic studies indicated CMZ was a better antagonist for NDM-1 than ERT. Whole-genome sequence analysis did not reveal any explainable differences between isolates susceptible and those non-susceptible to combination therapy.. In vitro studies showed the potential effectiveness of MEM/CMZ combination therapy against NDM-producing organisms.

Topics: Anti-Bacterial Agents; beta-Lactamases; Cefmetazole; Drug Therapy, Combination; Enterobacteriaceae; Enterobacteriaceae Infections; Ertapenem; Humans; Meropenem

The comparative efficacy of ceftazidime-avibactam and meropenem-vaborbactam for treatment of carbapenem-resistant

Topics: Aged; Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; Boronic Acids; Carbapenem-Resistant Enterobacteriaceae; Carbapenems; Ceftazidime; Cohort Studies; Drug Combinations; Drug Resistance, Multiple, Bacterial; Enterobacteriaceae Infections; Female; Humans; Male; Meropenem; Middle Aged; Retrospective Studies; Treatment Outcome; Urinary Tract Infections

Topics: Amines; Aminoglycosides; Anti-Bacterial Agents; Bacterial Proteins; Benzimidazoles; beta-Lactamases; Carbapenem-Resistant Enterobacteriaceae; DNA Replication; Drug Resistance, Multiple, Bacterial; Drug Synergism; Drug Therapy, Combination; Enterobacteriaceae Infections; Escherichia coli; High-Throughput Screening Assays; Meropenem; Microbial Sensitivity Tests; Mutagenesis, Site-Directed; Plasmids; Quinazolines; Repressor Proteins; Triazoles

In recent years, the prevalence of carbapenem-resistant

Topics: Anti-Bacterial Agents; Carbapenem-Resistant Enterobacteriaceae; Carbapenems; Drug Resistance, Multiple, Bacterial; Enterobacteriaceae Infections; Gene Expression Profiling; Genome, Bacterial; Genomics; High-Throughput Nucleotide Sequencing; Humans; Meropenem; Microbial Sensitivity Tests; Oligonucleotides, Antisense; Transcriptome

Enterobacterales resistant to carbapenems, a class of last-resort antimicrobials, are ranked as an "urgent" and "critical" public health hazard by CDC and WHO. IMP-type carbapenemase-containing Enterobacterales are endemic in Japan, and blaIMP-6 is one of the notable carbapenemase genes responsible for the resistance. The gene is plasmid-encoded and confers resistance to meropenem, but not to imipenem. Therefore, IMP-6-producing Enterobacterales isolates are occasionally overlooked in clinical laboratories and are referred to as 'stealth-type'. Since previous reports in Japan were confined only to some geographical regions, their distribution across prefectures and the factors affecting the distribution remain unclear. Here, we revealed the dynamics of the geographical distribution of Enterobacterales with IMP-6 phenotype associated with antimicrobial use in Japan. We utilized comprehensive national surveillance data of all routine bacteriological test results from more than 1,400 hospitals in 2015 and 2016 to enumerate Escherichia coli and Klebsiella pneumoniae isolates with the antimicrobial susceptibility pattern (phenotype) characteristic of IMP-6 (imipenem susceptible, meropenem resistant), and to tabulate the frequency of isolates with the phenotype for each prefecture. Isolates were detected in approximately half of all prefectures, and combined analysis with the national data of antimicrobial usage revealed a statistically significant association between the frequency and usage of not carbapenems but third-generation cephalosporins (p = 0.006, logistic mixed-effect regression) and a weaker association between the frequency and usage of fluoroquinolones (p = 0.043). The usage of third-generation cephalosporins and fluoroquinolones may select the strains with the IMP-6 phenotype, and contribute to their occasional spread. We expect the findings will promote antimicrobial stewardship to reduce the spread of the notable carbapenemase gene.

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Carbapenems; Drug Resistance, Bacterial; Enterobacteriaceae; Enterobacteriaceae Infections; Escherichia coli; Escherichia coli Infections; Humans; Imipenem; Japan; Klebsiella Infections; Klebsiella pneumoniae; Meropenem; Phenotype

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

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

Topics: Amikacin; Anti-Bacterial Agents; Carbapenem-Resistant Enterobacteriaceae; Colistin; Drug Resistance, Multiple, Bacterial; Drug Synergism; Drug Therapy, Combination; Enterobacteriaceae Infections; Humans; Meropenem; Microbial Sensitivity Tests; Multilocus Sequence Typing

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

Little is known regarding the appropriate timing and sequencing of a carbapenem and polymyxin in combination against carbapenem-resistant Enterobacteriaceae. Meropenem and polymyxin B were administered simultaneously or 1 agent 2 h prior to the other, in vitro. The carbapenem should be administered prior to the polymyxin when used in combination.

Topics: Anti-Bacterial Agents; Carbapenem-Resistant Enterobacteriaceae; Drug Synergism; Enterobacteriaceae Infections; Humans; Meropenem; Microbial Sensitivity Tests; Microbial Viability; Polymyxin B

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamase Inhibitors; beta-Lactamases; Boronic Acids; Carbapenem-Resistant Enterobacteriaceae; Drug Combinations; Drug Resistance, Bacterial; Enterobacteriaceae Infections; Humans; Meropenem; Microbial Sensitivity Tests; Tertiary Care Centers; Wisconsin

The clinical effectiveness of carbapenem antibiotics such as meropenem is becoming increasingly compromised by the spread of both metallo-β-lactamase (MBL) and serine-β-lactamase (SBL) enzymes on mobile genetic elements, stimulating research to find new β-lactamase inhibitors to be used in conjunction with carbapenems and other β-lactam antibiotics. Herein, we describe our initial exploration of a novel chemical series of metallo-β-lactamase inhibitors, from concept to efficacy, in a survival model using an advanced tool compound (ANT431) in conjunction with meropenem.

Topics: Anti-Bacterial Agents; beta-Lactamase Inhibitors; beta-Lactamases; Carbapenem-Resistant Enterobacteriaceae; Carbapenems; Crystallography, X-Ray; Drug Resistance, Multiple, Bacterial; Enterobacteriaceae Infections; Inhibitory Concentration 50; Meropenem; Microbial Sensitivity Tests; Picolinic Acids; Protein Binding; Structure-Activity Relationship

Topics: Aged; Anti-Bacterial Agents; Craniotomy; Drug Resistance, Multiple, Bacterial; Empyema; Enterobacteriaceae Infections; Humans; Male; Meningeal Neoplasms; Meropenem; Piperacillin, Tazobactam Drug Combination; Postoperative Complications; Seizures; Spinal Puncture; Staphylococcal Infections; Surgical Wound Infection; Treatment Outcome; Vancomycin

Here, we evaluated the combinations of antibiotics polymyxin B (PMB), tigecycline (TGC) and meropenem (MEM) by time-kill curves (TKC) against carbapenem-resistant Enterobacter cloacae isolates. Combination of PMB/TGC and PMB/MEM showed promising results in sub-inhibitory concentration of PMB indicating the possibility of reducing the dose of PMB used in the treatment.

Topics: Anti-Bacterial Agents; Carbapenem-Resistant Enterobacteriaceae; Drug Synergism; Enterobacter cloacae; Enterobacteriaceae Infections; Humans; Meropenem; Microbial Sensitivity Tests; Microbial Viability; Polymyxin B; Tigecycline

Carbapenem-resistant Enterobacteriaceae (CREs)-mediated infections remain a huge public health concern. CREs produce enzymes such as metallo-β-lactamases (MBLs), which inactivate β-lactam antibiotics. Hence, developing efficient molecules capable of inhibiting these enzymes remains a way forward to overcoming this phenomenon. In this study, we demonstrate that pyridyl moieties favor the inhibitory activity of cyclic metal-chelating agents through in vitro screening, molecular modeling, and docking assays. Di-(2-picolyl) amine and tris-(2-picolyl) amine exhibited great efficacy against different types of MBLs and strong binding affinity for NDM-1, whereas 2-picolyl amine did not show activity at a concentration of 64 mg/L in combination with meropenem; it further showed the lowest binding affinity from computational molecular analysis, commensurating with the in vitro screening assays. The findings revealed that the pyridyl group plays a vital role in the inhibitory activity of the tested molecules against CREs and should be exploited as potential MBL inhibitors.

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Chelating Agents; Enterobacteriaceae; Enterobacteriaceae Infections; Humans; Meropenem; Metals; Microbial Sensitivity Tests; Models, Molecular

Infections due to Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae are associated with increased morbidity and high mortality. Meropenem-vaborbactam (MV) is a novel β-lactam/β-lactamase inhibitor combination active against KPC-producing Enterobacteriaceae. The aim of this post hoc analysis of the TANGO-II randomized controlled trial was to assess the efficacy of MV versus best available therapy (BAT) in the subgroup of patients without prior antimicrobial failure.. The primary outcome measure was clinical cure at the test of cure (TOC). Secondary outcome measures included (1) clinical cure at the end of therapy (EOT), (2) microbiological cure at TOC, (3) microbiological cure at EOT, and (4) 28-day all-cause mortality.. First-line MV was associated with a 42.9% absolute increase in clinical cure rate at TOC (95% confidence intervals [CI] 13.7-72.1) in comparison with first-line BAT. A 49.3% absolute increase in clinical cure rate at EOT (95% CI 20.8-77.7), a 42.6% absolute increase in microbiological cure rate at EOT (95% CI 13.4-71.8), and a 36.2% absolute increase in microbiologic cure rate at TOC (95% CI 5.9-66.6) were also observed, in addition to a 29.0% absolute reduction in mortality (95% CI - 54.3 to - 3.7). Overall, fewer adverse events were observed in the MV group than in the BAT group.. MV was superior to BAT in the subgroup of patients with serious carbapenem-resistant Enterobacteriaceae (CRE) infections and no prior antimicrobial failure, with very high rates of clinical success, and was well tolerated. Post approval and real-world studies remain essential to clearly define the most appropriate population for early, empirical MV coverage, in accordance with antimicrobial stewardship principles.. The Medicines Company.

Topics: Adult; Anti-Bacterial Agents; Boronic Acids; Carbapenem-Resistant Enterobacteriaceae; Dose-Response Relationship, Drug; Enterobacteriaceae Infections; Female; Humans; Male; Meropenem; Middle Aged

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Enterobacteriaceae; Enterobacteriaceae Infections; Humans; Meropenem; Microbial Sensitivity Tests

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

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

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

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

Accurate and rapid detection of carbapenemases and identification of their types in Enterobacteriaceae are both still major challenges for clinical laboratories in attempting to prevent the intrusion and transmission of carbapenemase-producing Enterobacteriaceae. This study aimed to evaluate the performance of the MASTDISCS combi Carba plus disc system in identification of different carbapenemase types, including OXA-48-type carbapenemase, for which no specific enzyme inhibitors have so far been available. The simple disc system discriminates carbapenemases, including OXA-48-types exhibiting low carbapenem minimum inhibitory concentrations, by targeting Enterobacteriaceae isolates with a EUCAST meropenem screening cut-off of ≥0.25 mg/L.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Bacterial Typing Techniques; beta-Lactamases; Carbapenem-Resistant Enterobacteriaceae; Carbapenems; Disk Diffusion Antimicrobial Tests; Enterobacteriaceae; Enterobacteriaceae Infections; Enzyme Assays; Enzyme Inhibitors; Humans; Meropenem; Sensitivity and Specificity; Thienamycins

BD Phoenix™ is an automated bacterial identification and susceptibility testing system. Here, its performance in screening IMP-producing Enterobacteriaceae was evaluated. The system identified 97.8% of IMP producers as being nonsusceptible to imipenem or meropenem, which was higher than that identified by the broth microdilution method (91.3%, imipenem; 41.3%, meropenem).

Topics: Anti-Bacterial Agents; Automation, Laboratory; Bacterial Proteins; Carbapenems; DNA, Bacterial; Enterobacter cloacae; Enterobacteriaceae Infections; Imipenem; Inosine Monophosphate; Klebsiella pneumoniae; Meropenem; Microbial Sensitivity Tests

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

We hypothesised that treatment with a tigecycline-based antimicrobial regimen for intra-abdominal infection (IAI) could be associated with lower rates of subsequent carbapenem-resistant Enterobacteriaceae (CRE) colonisation or Clostridium difficile infection (CDI) compared with a meropenem-based regimen.. We performed a retrospective, single-centre, matched (1:1) cohort analysis of all patients who received at least 5 days of empirical or targeted tigecycline (TIG)- or meropenem (MER)-based treatment regimens for IAI over a 50-month period. Patients with previous CRE colonisation and CDI were excluded. Risk factors for CRE and CDI were assessed with a Cox regression model that included treatment duration as a time-dependent variable. Thirty-day mortality was assessed with Kaplan-Meier curves.. We identified 168 TIG-treated and 168 MER-treated patients. The cumulative incidence rate ratio of CDI was 10-fold lower in TIG-treated vs. MER-treated patients (incidence rate ratio [IRR] 0.10/1000 patient-days, 95%CI 0.002-0.72, P = 0.007), but similar incidence rates were found for CRE colonisation (IRR 1.39/1000 patient-days, 95%CI 0.68-2.78, P = 0.36). In a multivariate Cox regression model, the receipt of a TIG- vs. MER-based regimen was associated with significantly lower rates of CDI (HR 0.07, 95%CI 0.03-0.71, P = 0.02), but not CRE (HR 1.12, 95% CI 0.45-2.83, P = 0.80). All-cause 30-day mortality was similar in the two groups (P = 0.46).. TIG-based regimens for IAI were associated with a 10-fold lower incidence of CDI compared with MER-based regimens, but there was no difference in the incidence of CRE colonisation.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Carbapenem-Resistant Enterobacteriaceae; Carrier State; Clostridioides difficile; Clostridium Infections; Enterobacteriaceae Infections; Female; Humans; Incidence; Intraabdominal Infections; Male; Meropenem; Middle Aged; Minocycline; Retrospective Studies; Risk Factors; Survival Analysis; Thienamycins; Tigecycline; Young Adult

Antibiotic resistance associated with the clinically significant carbapenemases KPC, NDM and OXA-48 in Enterobacteriaceae is emerging as worldwide. In Australia, IMP-producing Enterobacteriaceae are the most prevalent carbapenemase-producing Enterobacteriaceae (CPE). Genomic characteristics of such CPE are well described, but the corresponding proteome is poorly characterised. We have thus developed a method to analyse dynamic changes in the proteome of CPE under antibiotic pressure. Specifically, we have investigated the effect of meropenem at sub-lethal concentrations to develop a better understanding of how antibiotic pressure leads to resistance. Escherichia coli strains producing either NDM-, IMP- or KPC-type carbapenemases were included in this study, and their proteomes were analysed in growth conditions with or without meropenem. The most significant difference in the bacterial proteomes upon the addition of meropenem was triggered amongst NDM-producers and to a lower extent amongst KPC-producers. In particular, HU DNA-binding proteins, the GroEL/GroES chaperonin complex and GrpE proteins were overexpressed. These proteins may thus contribute to the better adaptability of NDM- and KPC-producers to meropenem. A significant meropenem-induced increase in the expression of the outer membrane protein A was only observed in IMP-producers, thus demonstrating that carbapenemase-mediated resistance relies on far more complex mechanisms than simple inactivation of the antibiotic.

Topics: Anti-Bacterial Agents; Australia; Bacteria; Bacterial Proteins; beta-Lactamases; Carbapenem-Resistant Enterobacteriaceae; Enterobacteriaceae; Enterobacteriaceae Infections; Escherichia coli; Escherichia coli Proteins; Humans; Meropenem; Microbial Sensitivity Tests; Proteome

Raoultella Ornithinolytica (RO) is an encapsulated, Gram- negative, nonmotile aerobic rob which was reclassified from Klepsiella genus belonging in the family of Enterobacteriaceae. It is a rare human infection and few cases have been reported in post thoracotomy patients. Here we present a case of a left lower lobectomy patient that was complicated by pleural effusion and high fever with positive sputum cultures of Raoultella Ornithinolytica and positive pleural fluid cultures of Staphylococcus hominis. It is related with aquatic life poisoning. There are few cases reported and even fewer postoperatively. The infection is rare in human therefore the bacteria is still underreported.

Topics: Aged; Anti-Bacterial Agents; Carcinoma, Non-Small-Cell Lung; Ciprofloxacin; Enterobacteriaceae; Enterobacteriaceae Infections; Humans; Male; Meropenem; Pleural Effusion; Postoperative Complications; Sputum; Staphylococcal Infections; Staphylococcus hominis; Treatment Outcome

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

'Last-line' antimicrobial usage has promoted the emergence of MDR bacteria. Production of Klebsiella pneumoniae carbapenemases (KPCs) is increasingly common and leads to resistance to most antimicrobials. However, ceftazidime/avibactam demonstrates activity against KPC-producing strains. Ceftazidime/avibactam in the empirical setting remains unknown.. Strains underwent genetic analysis evaluating blaKPC presence/production and MICs were determined. Four strains were assessed in an in vitro, one-compartment pharmacokinetic (PK)/pharmacodynamic (PD) model for 96 h. The following bolus dosing exposures were tested: 2.5 g of ceftazidime/avibactam every 8 h, 2 g of meropenem every 8 h, 1.25 mg/kg polymyxin B every 12 h, amikacin 'once-daily dosing' (peak of 70-80 mg/L), tigecycline at 200 mg ×1 dose followed by 100 mg every 12 h, and a drug-free growth control.. Thirty blaKPC-producing strains were evaluated; 97% of strains were ceftazidime/avibactam susceptible with MIC50/MIC90 values of 0.38/1.5 mg/L (range 0.032-16 mg/L). Two K. pneumoniae strains, one Klebsiella oxytoca strain and one Citrobacter freundii strain underwent further analysis in PK/PD models. Ceftazidime/avibactam displayed potent activity with a reduction of 4.23 ± 0.42 cfu/mL from the initial inoculum at 96 h. Against susceptible isolates, amikacin displayed similar activity compared with ceftazidime/avibactam at 96 h, although this was not demonstrated against all strains. Polymyxin B produced comparable activity to ceftazidime/avibactam against two strains. Neither meropenem nor tigecycline produced effective killing and were comparable to the drug-free growth control at 96 h.. blaKPC-producing organisms demonstrated susceptibility to ceftazidime/avibactam and bactericidal activity was observed in the PK/PD model. Based on these data, ceftazidime/avibactam is a valuable agent for treating KPC-producing organisms and should be considered for treatment of infections caused by these pathogens.

Topics: Amikacin; Anti-Bacterial Agents; Azabicyclo Compounds; Bacterial Proteins; beta-Lactamase Inhibitors; beta-Lactamases; Carbapenem-Resistant Enterobacteriaceae; Ceftazidime; Drug Combinations; Enterobacteriaceae Infections; Meropenem; Models, Theoretical; Polymyxin B; Treatment Outcome

The aim of this study was to evaluate the two rapid colorimetric methods (CNPt-Direct and Blue-Carba) for the detection of carbapenemase production directly from blood culture in a routine microbiology laboratory. The methods were initially evaluated on spiked blood cultures with 61 carbapenemase-positive isolates. Afterwards, they were used in blood cultures (314 samples were evaluated) obtained from patients in a routine microbiology laboratory during a period of 6 months. The colorimetric methods were compared to the conventional culture of blood. The results of the spiked blood cultures indicated that both colorimetric methods presented positive results for the vast majority (95%) of the isolates harboring KPC, NDM, and IMP genes. However, the assay failed to detect many GES- and OXA-48-like-positive isolates (65% positive results). In the second part of the study, a total of 314 blood cultures from patients were evaluated, and 33 yielded

Topics: Anti-Bacterial Agents; Bacterial Proteins; Bacteriological Techniques; beta-Lactamases; Blood Culture; Colorimetry; Diagnostic Tests, Routine; Drug Resistance, Bacterial; Enterobacteriaceae; Enterobacteriaceae Infections; False Negative Reactions; Humans; Meropenem; Reagent Kits, Diagnostic; Sensitivity and Specificity

Vaborbactam is a novel inhibitor of serine β-lactamases, including KPCs, which predominate in China. It is being developed in combination with meropenem.. Using the broth microdilution method, the in vitro activity of meropenem/vaborbactam against 128 KPC-producing Enterobacteriaceae from China was investigated.. Meropenem alone showed no activity (MIC50 and MIC90 >64 mg/L), but the addition of vaborbactam potentiated meropenem in a dose-dependent manner with MIC90 decreasing from >64 to 0.5 mg/L in the presence of increasing concentrations of vaborbactam. MIC50 and MIC90 of meropenem with 8 mg/L vaborbactam (MV8) were reduced to 0.5 and 8 mg/L, respectively. MV8 (4 mg/L meropenem) inhibited 76.6% of Klebsiella pneumoniae and 100% of Escherichia coli isolates. Seventy-three (77.7%) of the K. pneumoniae isolates belonged to ST11; the remaining 22.3% of isolates were represented by 12 different STs. Of the ST11 and non-ST11 isolates, 71.2% and 95.2%, respectively, were inhibited by MV8 (4 mg/L meropenem). In 14 strains characterized for intrinsic resistance mechanisms, MV8 MIC was increased in isolates with defects in both OmpK35 and OmpK36. The highest MV8 MIC was observed in the strain that had both non-functional porins and increased expression of blaKPC and acrB.. Our findings suggest that meropenem/vaborbactam has good activity against KPC-producing Enterobacteriaceae from China. However, a higher percentage of K. pneumoniae isolates for which MV8 MIC was elevated compared with other geographical areas is noteworthy. This might be due to clonal dissemination of ST11 KPC-producing isolates that are defective in both major porins, OmpK35 and OmpK36.

Topics: Anti-Bacterial Agents; beta-Lactamase Inhibitors; beta-Lactamases; Boronic Acids; China; Enterobacteriaceae; Enterobacteriaceae Infections; Humans; Meropenem; Microbial Sensitivity Tests

Carbapenem resistant Enterobacteriaceae (CRE) are a growing threat worldwide. Infections caused by these organisms have exhibited high rates of mortality (50%) for which there is no standard of care and a dearth of clinical trials. Most in vitro data on CRE focus on Klebsiella pneumoniae, but it is known that effective therapy may depend on species or even strain. To address this, meropenem, amikacin, and polymyxin B alone and in combination were evaluated by time kill against four carbapenem-producing Enterobacter cloacae clinical isolates representing a range of meropenem nonsusceptibility (2-32 mg/L) and resistance mechanisms (KPC 2 and/or VIM 1). As meropenem minimum inhibitory concentration (MIC) increased, bactericidal activity and synergy were maintained for 48 hours in isolates exposed to meropenem and amikacin, but synergy and bactericidal activity were not maintained in all isolates exposed to meropenem and polymyxin B.

Topics: Amikacin; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Cytoskeletal Proteins; Drug Synergism; Enterobacter cloacae; Enterobacteriaceae Infections; Humans; Meropenem; Microbial Sensitivity Tests; Microbial Viability; Multilocus Sequence Typing; Polymyxin B

Topics: Adult; Anti-Bacterial Agents; Bacteremia; beta-Lactamase Inhibitors; Boronic Acids; Carbapenem-Resistant Enterobacteriaceae; Drug Combinations; Enterobacter aerogenes; Enterobacteriaceae Infections; Heterocyclic Compounds, 1-Ring; Humans; Male; Meropenem; Microbial Sensitivity Tests; Renal Dialysis; Serratia marcescens; Treatment Outcome

The spread of carbapenemase-producing Enterobacteriaceae (CPE) is an increasing global public health concern. The development of simple and reliable methods for CPE detection is required in the clinical setting. This study aimed to establish a dual-wavelength measurement method using an ultraviolet-visible spectrophotometer to rapidly quantify imipenem hydrolysis in bacterial cell suspensions. The hydrolytic activities of 148 strains including various CPE strains (Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, and Enterobacter aerogenes containing the bla

Topics: Absorption, Physicochemical; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactam Resistance; beta-Lactamases; Carbapenem-Resistant Enterobacteriaceae; Enterobacteriaceae Infections; Hydrolysis; Imipenem; Meropenem; ROC Curve; Sensitivity and Specificity; Spectrophotometry, Ultraviolet; Statistics, Nonparametric

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

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

Topics: Anti-Bacterial Agents; beta-Lactamases; Drug Resistance, Bacterial; Enterobacteriaceae; Enterobacteriaceae Infections; Genes, Bacterial; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests

Necrotizing fasciitis is an uncommon soft-tissue infection that involves the superficial fascia, subcutaneous fat, and deep fascia. Herein, we report the first case of Enterobacter cloacae-related necrotizing fasciitis after peritoneal dialysis in delayed graft function.. A 58-year-old man, who was a hepatitis B-viral carrier and had atrial fibrillation, received cadaveric renal transplantation with peritoneal dialysis and encountered delayed graft function. On postoperative day 5, we tried hemodialysis via the right jugular dialysis catheter. However, he was unable to endure the hemodynamic changes during hemodialysis, showing rapid ventricular rhythm on electrocardiography. On postoperative day 7, we changed to peritoneal dialysis. However, he presented with fever and pain on his left flank and lower extremity. His white blood cell count and C-reactive protein levels were suddenly elevated. According to the abdomen computed tomography scan, there were subcutaneous fluid and air in the left flank and anterolateral pelvic wall. We performed peritoneal dialysis catheter removal, debridement, and drainage of the left external oblique muscle fascia. In a culture, Enterobacter cloacae was identified. After receiving meropenem for 2 months, his wound healed and delayed graft function was recovered.. Peritoneal dialysis of delayed graft function seems to be effective in reducing the incidence and severity of delayed recovery of renal function after renal transplantation in some reports. However, it is necessary to be cautious when dealing with a rapidly developing and life-threatening soft-tissue infection, such as necrotizing fasciitis. To reduce mortality rates, early diagnosis, recurrent surgical debridement, and aggressive therapy are mandatory.

Topics: Anti-Bacterial Agents; Delayed Graft Function; Enterobacter cloacae; Enterobacteriaceae Infections; Fasciitis, Necrotizing; Humans; Kidney Transplantation; Male; Meropenem; Middle Aged; Peritoneal Dialysis; Thienamycins

Infections caused by carbapenemase-producing Enterobacteriaceae (CPE) are becoming increasingly common worldwide. Although CPE infections can be fatal, few reports in the literature have described effective and successful treatments for infectious diseases caused by several types of IMP CPE, and, to our knowledge, no reports have described the successful treatment of IMP-6 CPE infections. We describe two patients who developed bacteremia caused by IMP-6 CPE after surgery for cancer who were successfully treated with amikacin plus high-dose prolonged-infusion meropenem. Both patients were treated over a 2-week period using amikacin 15 mg/kg at various intervals based on therapeutic drug monitoring and meropenem 2000 mg infused over 3 hours every 12 hours. The dosages of amikacin and meropenem were determined based on the creatinine clearance of each patient. Both patients were cured of their bacteremia and did not experience any antibiotic-related adverse effects. Based on the outcomes of these patients, it appears that amikacin plus high-dose prolonged-infusion meropenem may be safe and effective for the treatment of bacteremia caused by IMP-6 CPE.

Topics: Aged; Amikacin; Anti-Bacterial Agents; Bacteremia; Bacterial Proteins; beta-Lactamases; Carbapenem-Resistant Enterobacteriaceae; Drug Therapy, Combination; Enterobacteriaceae Infections; Humans; Male; Meropenem; Microbial Sensitivity Tests; Thienamycins; Treatment Outcome

A 55-year-old man undergoing chemotherapy for recurrent multiple myeloma presented with a 2-day history of bilateral lower leg rash with pain and oedema. On examination, there were numerous non-palpable retiform pruritic patches over both lower legs. Skin pnch biopsy demonstrated a diffuse interstitial neutrophilic infiltrate with necrosis. Peripheral blood and skin tissue cultures both isolated

Topics: Anti-Bacterial Agents; Citrobacter freundii; Debridement; Ecthyma; Enterobacteriaceae Infections; Humans; Immunocompromised Host; Lower Extremity; Male; Meropenem; Middle Aged; Multiple Myeloma; Rare Diseases; Thienamycins; Treatment Outcome

Quinolones are frequently used classes of antimicrobials in hospitals, crucial for the treatment of infections caused by Gram-negative bacteria. The inappropriate use of quinolones and other antimicrobial agents for the treatment of bacterial infections leads to a significant increase of resistant isolates. The acquisition of antimicrobial resistance may be related to achievement of resistance determinant genes mediated by plasmids, transposons and gene cassettes in integrons. The objective of this cross-sectional study, conducted from December 2015 to July 2016 at two teaching hospitals in Ahvaz, southern Iran, was to screen for the presence of class 1 integrons and quinolone resistance genes in clinical isolates of Enterobacter spp. In all, 152 non-duplicated Enterobacter isolates were collected from clinical specimens and identified as Enterobacter spp. using standard microbiological methods. Antimicrobial susceptibility test was determined using the disc diffusion method according to the CLSI recommendation. Determination of class 1 integrons and PMQR genes was assessed by PCR. Analysis of antibiotic susceptibility tests showed that the highest antibiotic resistance was toward ciprofloxacin (55.3%), while the lowest level was observed against meropenem (34.9%). Moreover, 47.4% (72/152) and 29% (44/152) of isolates were positive for class 1 integron and quinolone resistance genes, respectively. The relative frequencies of antibiotic resistance were significantly higher among class 1 integron-positive isolates. In summary, our results highlight the importance of PMQR genes in the emergence of quinolone-resistant Enterobacter isolates. Moreover, it seems that class 1 integrons have a widespread distribution among Enterobacter isolates and have clinical relevance to multiple-drug-resistant isolates.

Topics: Anti-Bacterial Agents; Cross Infection; Cross-Sectional Studies; Drug Resistance, Multiple, Bacterial; Enterobacter; Enterobacteriaceae Infections; Fluoroquinolones; Genes, Bacterial; Humans; Imipenem; Integrons; Iran; Meropenem; Microbial Sensitivity Tests; Plasmids; Thienamycins

The use of sugar for treating wounds which are difficult to heal and positive to resistant pathogens has already been documented. The authors describe the successful treatment by direct instillation of granular sugar in the antibiotic-resistant infected surgical site wound of a child with sarcoma. Sugar instillation in the extended spectrum beta-lactamase (ESBL)-producing Enterobacter cloacae positive wound, in addition to systemic treatment with meropenem and levofloxacin, allowed culture negativization in six days and complete wound healing in 30 days. These results make the use of sugar an attractive option for wounds which are difficult to treat, even in an immunocompromised child.

Topics: Administration, Topical; Child; Combined Modality Therapy; Drug Resistance, Multiple, Bacterial; Enterobacter cloacae; Enterobacteriaceae Infections; Humans; Immunocompromised Host; Levofloxacin; Male; Meropenem; Neurilemmoma; Soft Tissue Neoplasms; Sucrose; Surgical Wound Infection; Thienamycins; Wound Healing

The objective of this study was to test the efficacy of an inhibitor of the New Delhi metallo-β- lactamase (NDM-1). Inhibiting expression of this type of antibiotic-resistance gene has the potential to restore antibiotic susceptibility in all bacteria carrying the gene.. We have constructed a peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO) that selectively inhibits the expression of NDM-1 and examined its ability to restore susceptibility to meropenem in vitro and in vivo .. In vitro , the PPMO reduced the MIC of meropenem for three different genera of pathogens that express NDM-1. In a murine model of lethal E. coli sepsis, the PPMO improved survival (92%) and reduced systemic bacterial burden when given concomitantly with meropenem.. These data show that a PPMO can restore antibiotic susceptibility in vitro and in vivo and that the combination of PPMO and meropenem may have therapeutic potential against certain class B carbapenem-resistant infections in multiple genera of Gram-negative pathogens.

Topics: Animals; Anti-Bacterial Agents; Bacterial Load; beta-Lactamases; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Enterobacteriaceae; Enterobacteriaceae Infections; Escherichia coli; Meropenem; Mice; Microbial Sensitivity Tests; Morpholinos; Sepsis; Thienamycins

Carbapenem-resistant Enterobacteriaceae (CRE) are associated with considerable mortality. As mechanisms of carbapenem resistance are heterogeneous, it is unclear if mortality differs based on resistance mechanisms. We sought to determine whether CRE resistance mechanism determination is prognostically informative.. We conducted an observational study comparing 14-day mortality between patients with carbapenemase-producing (CP)-CRE compared with non-CP-CRE bacteremia. Clinical data were collected on all patients. A comprehensive DNA microarray-based assay was performed on all isolates to identify β-lactamase-encoding genes.. Our findings suggest that CP-CRE may be more virulent than non-CP-CRE and are associated with poorer outcomes. This underscores the added importance of delineating underlying resistance mechanisms of CRE to direct antibiotic treatment decisions.

Topics: Adult; Aged; Anti-Bacterial Agents; Bacteremia; Bacterial Proteins; beta-Lactam Resistance; beta-Lactamases; Carbapenems; Cohort Studies; DNA, Bacterial; Enterobacteriaceae; Enterobacteriaceae Infections; Female; Humans; Male; Meropenem; Middle Aged; Retrospective Studies; Thienamycins; Treatment Outcome

Topics: Anti-Bacterial Agents; Bacterial Load; beta-Lactam Resistance; beta-Lactamases; Dose-Response Relationship, Drug; Enterobacteriaceae; Enterobacteriaceae Infections; Gene Expression; Humans; Meropenem; Microbial Sensitivity Tests; Thienamycins

The aim of this study was the evaluation of the influence of the susceptibility patterns of Escherichia coli and Klebsiella pneumoniae isolates, specifically the presence of extended-spectrum β-lactamases and the geographical area (Europe and USA), on the meropenem dosing requirements in critically ill patients with different degrees of renal function by estimation of the probability of pharmacokinetic/pharmacodynamic (PK/PD) target attainment. Additionally, estimation of the PK/PD breakpoints according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) approach was also an objective. Six dosing regimens were evaluated: 0.5 g, 1 g and 2 g every 8 h given as 0.5-h or 3-h infusions. Pharmacokinetic data were obtained from the literature, and susceptibility data to meropenem for E. coli and K. pneumoniae were collected from the Tigecycline Evaluation and Surveillance Trial (T.E.S.T.) surveillance study. For the same dose level, the 3-h infusion provided a probability of target attainment (PTA) ≥90 % for minimum inhibitory concentration (MIC) values up to two-fold dilution higher than those obtained with the 0.5-h infusion. For E. coli, the cumulative fraction of response (CFR) was 100 % in most cases, and neither the dose nor the infusion length nor the geographical area significantly affected the probability to reach the target. With regards to K. pneumoniae, the CFR increased when increasing the dose and decreasing the creatinine clearance (CLCR). The CFR for Spanish and USA strains was higher than that calculated for European strains. Meropenem PK/PD breakpoints are dependent on the dose, infusion length and CLCR, ranging from 2 to 32 mg/L. Based on our results, meropenem administered as a extended infusion is the best option to treat infections due to E. coli and K. pneumoniae.

Topics: Algorithms; Anti-Bacterial Agents; beta-Lactamases; Critical Illness; Drug Resistance, Bacterial; Enterobacteriaceae; Enterobacteriaceae Infections; Europe; Female; Geography; Humans; Kidney Function Tests; Male; Meropenem; Microbial Sensitivity Tests; Monte Carlo Method; Risk Factors; Thienamycins; United States

A local predominance of carbapenemase producing Enterobacteriaceae with low minimum inhibitory concentrations (MIC) to meropenem prompted a review of methods available for carbapenemase detection. We report on results using two selective media, temocillin discs, CarbaNP test, GeneXpert Carba-R assay and an in-house PCR assay.

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Enterobacteriaceae; Enterobacteriaceae Infections; Enzyme Assays; Humans; Meropenem; Microbial Sensitivity Tests; Polymerase Chain Reaction; Thienamycins

A flow cytometry test was developed to identify carbapenemase production by Enterobacteriaceae and to discriminate between the different types of carbapenemases (classes A, B, and D). It is based on the detection of meropenem activity against bacteria, coupled with different carbapenemase inhibitors, which is assessed by flow cytometry. It represents a convenient, fast, and reliable approach (100% sensitivity and 100% specificity) for the detection and characterization of different carbapenemases.

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Boronic Acids; Cloxacillin; Edetic Acid; Enterobacteriaceae; Enterobacteriaceae Infections; Enzyme Inhibitors; Flow Cytometry; Gene Expression; Humans; Meropenem; Penicillins; Thienamycins

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

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

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

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

To describe the identification of two carbapenem-resistant, NDM-1 and IMP-4, carbapenemases coproducing Enterobacteriaceae isolates recovered from hospitalized patients in China. Both Klebsiella pneumoniae clinical isolates (Kpn922 and Kpn9599) were resistant to meropenem and imipenem and were subjected to additional antibiotic susceptibility testing. Polymerase chain reaction (PCR) and sequence analyses were used to characterize bacterial carbapenemase resistance genes, extended-spectrum β-lactamases, plasmid-mediated AmpC enzymes, quinolone resistance, and 16s RNA methylase. Genetic relatedness was determined using pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). Plasmids were analyzed by S1-PFGE and Southern blot.. PCR analyses revealed that the Kpn922 isolate carried blaNDM-1, blaIMP-4, blaTEM-1, and blaSHV-1 genes, while Kpn9599 carried blaNDM-1, blaIMP-4, blaTEM-1, and blaSHV-12 genes. MLST determined that the two isolates were ST1043 and ST571 sequence types. Southern blot analyses revealed that metallo-β-lactamase genes were plasmid borne in both isolates. Plasmids ∼300 kb simultaneously carried blaNDM-1 and blaIMP-4.. Coexistence of blaNDM-1 and blaIMP-4 in these clinical isolates may herald the emergence of a new pattern of drug resistance. Surveillance of carbapenemases, particularly metallo-β-lactamases, in Enterobacteriaceae is urgently needed to control and prevent the spread of these resistance determinants in China.

Topics: Adolescent; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Carbapenems; China; Drug Resistance, Multiple, Bacterial; Enterobacteriaceae; Enterobacteriaceae Infections; Hospitals; Humans; Imipenem; Klebsiella Infections; Klebsiella pneumoniae; Male; Meropenem; Plasmids; Quinolones; Thienamycins

To investigate the evolutionary trends in non-susceptibility of carbapenems against the isolates of Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae from patients hospitalized in intensive care units (ICUs) of major teaching hospitals throughout Taiwan during 2005-2009, we applied the breakpoints of MICs recommended by Clinical and Laboratory Standards Institute and European Committee on Antimicrobial Susceptibility Testing in 2013. Escalations in imipenem MIC levels for overall E. coli and E. cloacae isolates and extended-spectrum β-lactamase (ESBL)-producing K. pneumoniae isolates were noted during this period. The overall MIC levels against imipenem and meropenem for subgroups of ESBL producers of 3 Enterobacteriaceae species were significantly higher than those of respective overall groups in 2007 and 2009. Compared with meropenem, we found that significant evidence of imipenem MIC creep and evidence of extraordinarily high rates of non-susceptibility to ertapenem among isolates of 3 species in 2009 existed. The prominent rises in rates of ertapenem non-susceptibility for ESBL-producing E. coli and K. pneumoniae during 2005-2009 and rate of ESBL positivity for E. cloacae between 4 years were notably found. Based on our findings, ertapenem should be used cautiously in management of the ICU infections caused by these potentially ESBL-producing Enterobacteriaceae isolates in Taiwan.

Topics: Anti-Bacterial Agents; beta-Lactams; Carbapenems; Enterobacter cloacae; Enterobacteriaceae; Enterobacteriaceae Infections; Ertapenem; Escherichia coli; Hospitals, Teaching; Humans; Imipenem; Intensive Care Units; Klebsiella pneumoniae; Meropenem; Microbial Sensitivity Tests; Taiwan; Thienamycins

We report a case of a frail 82-year-old man with seronegative rheumatoid arthritis and a recent pacemaker insertion, admitted with pulmonary oedema and a symptomatic pericardial effusion. He was treated with diuretics and an urgent pericardiocentesis, a sample from which cultured Enterobacter cloacae. A subsequent abdominal CT scan revealed faecal loading, an abnormal anorectal canal and sigmoid colon and a bowel perforation. Endoscopy, biopsies and histopathology confirmed a diagnosis of cytomegalovirus (CMV) colitis with coexistent fungal infection. The E. cloacae infection was successfully treated with 6 weeks of intravenous meropenem, while the CMV and fungal infections were treated with a combination of valganciclovir and fluconazole. We postulate that the bowel perforation resulted from a combination of CMV colitis, faecal loading and steroid therapy and led to bacterial translocation of E. cloacae and the development of the pericardial effusion. This case represents an unusual pathophysiology for the development of an E. cloacae pericardial effusion.

Topics: Aged, 80 and over; Anti-Bacterial Agents; Arthritis, Rheumatoid; Colitis; Colon, Sigmoid; Cytomegalovirus Infections; Diuretics; Drug Therapy, Combination; Enterobacter cloacae; Enterobacteriaceae Infections; Frail Elderly; Humans; Intestinal Perforation; Male; Meropenem; Pacemaker, Artificial; Pericardial Effusion; Pericardiocentesis; Pulmonary Edema; Radiography; Rectum; Risk Factors; Thienamycins; Treatment Outcome

Increasing numbers of clinical isolates of Enterobacteriaceae that produce carbapenemase are now being detected, with the most common carbapenemase found among Enterobacteriaceae in Japan being IMP-1-type metallo-β-lactamase. Clinical isolates of Enterobacteriaceae harbouring carbapenemases may be resistant to carbapenem antimicrobial agents, despite apparent in vitro susceptibility when tested according to Clinical and Laboratory Standards Institute criteria. We evaluated the prevalence of carbapenemase producers among isolates of Enterobacteriaceae at our hospital and assessed the performance of the modified Hodge test (MHT) for correctly identifying the phenotype. We studied 47 clinical isolates obtained between 2006 and 2010 for which the MIC of imipenem was 2 or 4 μg imipenem ml- 1. Antibacterial susceptibility testing was done for cephalosporins and carbapenems, the MHT was performed with meropenem and detection of the genes encoding IMP-1, VIM-2, KPC-2 and NDM-1-type metallo-β-lactamases was performed by PCR. Twelve isolates showed a positive result in the MHT with meropenem and were classified as carbapenemase producers. Of these 12 isolates, seven carried the gene for IMP-1 type, but not for VIM-2, KPC-2 or NDM-1 types. None of the carbapenemase genes tested were detected in the other five isolates. All five isolates were Enterobacter cloacae showing high resistance to ceftazidime and aztreonam. False-positive results were inhibited when Mueller-Hinton agar supplemented with 200 mg cloxacillin ml- 1 was used for the MHT. Five of 12 MHT-positive isolates were shown to have no carbapenemase genes and these isolates were high AmpC producers. Adding cloxacillin when performing the MHT prevented such false-positive results. The MHT with cloxacillin can overcome most problems related to detection of carbapenemases.

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Cloxacillin; Drug Resistance, Multiple, Bacterial; Enterobacteriaceae; Enterobacteriaceae Infections; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Thienamycins

Invasive infections due to carbapenem-resistant Enterobacteriaceae (CRE) are becoming increasingly more prevalent and provide significant morbidity and mortality. Providing curative therapy and overcoming bacterial resistance are difficult tasks with limited antibiotic options. Alternative antibiotics and approaches to therapy are required, with often a compromise in patient outcome.. To demonstrate the effective use of therapeutic drug monitoring (TDM) in difficult-to-treat infections due to multiresistant gram-negative bacteria.. A case of an elderly woman with an invasive cervical spine infection due to CRE is presented. Her protracted therapeutic course was complicated by multiple treatment failures and severe cervical spine instability. Therapeutic success, as determined by wound healing, cervical spine stability, and continued suppression of inflammatory markers, was obtained by continuous daily ertapenem infusions with TDM guiding the optimal drug dosing.. In this unusual setting, TDM was utilized successfully to achieve favorable serum antibiotic concentrations and lead to control of the infection. TDM may be a useful tool in difficult-to-treat infections caused by multiresistant bacteria.

Topics: Amikacin; Anti-Bacterial Agents; beta-Lactams; C-Reactive Protein; Drug Monitoring; Drug Resistance, Multiple, Bacterial; Enterobacter cloacae; Enterobacteriaceae Infections; Ertapenem; Female; Fosfomycin; Humans; Meropenem; Middle Aged; Osteomyelitis; Staphylococcal Infections; Staphylococcus epidermidis; Thienamycins

Pantoea agglomerans is a plant pathogen which very rarely causes an opportunistic infection. Human beings are usually infected by thorn prick injuries or by contaminated parenteral fluids. Pantoea agglomerans has been reported as a cause of neonatal sepsis very rarely and to the best of our knowledge this is the first reported case from India.. A 4-day-old Asian baby boy from the rural area of Odisha, India, was admitted to our neonatal intensive care unit when he presented with fever, tachypnea and chest retraction. Pantoea species were isolated from his blood culture.. He was treated successfully with meropenem administered intravenously and other supportive measures. Early detection and proper management may cause a favorable outcome.

Topics: Anti-Bacterial Agents; Diagnosis, Differential; Enterobacteriaceae Infections; Humans; India; Infant, Newborn; Male; Meropenem; Pantoea; Sepsis; Thienamycins

Carbapenemase-producing Enterobacteriaceae (CPE) cause serious infections and are associated with high mortality in part due to limited treatment options. The in vitro activities of the new aminoglycoside plazomicin and comparators were evaluated against a collection of 164 CPE (VIM-1, n=125; KPC-2, n=34; OXA-48, n=4; and IMP-22, n=1). MIC90 values of gentamicin, tobramycin and amikacin were 256, 64 and 16 mg/L, respectively. Plazomicin exhibited an MIC range of 0.12-4 mg/L with MIC50 and MIC90 values of 0.25 and 1 mg/L. The MICs of plazomicin did not correlate with the other aminoglycoside MICs, with the resistance phenotype or with the carbapenemase harboured. Chequerboard experiments against 10 carbapenemase-producing Klebsiella pneumoniae isolates showed that combinations of plazomicin with colistin yielded synergy against 60% of the strains. Synergy of plazomicin with meropenem or fosfomycin was detected against 20% and 25% of the isolates, respectively. Using time-kill methodology, the interactions of plazomicin at 2×, 1× and 0.5× MIC with meropenem, colistin, fosfomycin or tigecycline at steady-state concentrations against two K. pneumoniae carrying the VIM-1 enzyme were investigated. Bactericidal activity was evident for both isolates at 2× MIC of plazomicin. Synergy was observed when plazomicin was combined with meropenem, colistin or fosfomycin against both isolates, whilst the combination with tigecycline resulted in indifference. Antagonism was not observed for any of the combinations tested. The results of this study suggest that plazomicin may address the need for new therapeutic options for the treatment of infections due to CPE.

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Colistin; Drug Resistance, Multiple, Bacterial; Drug Synergism; Drug Therapy, Combination; Enterobacter; Enterobacteriaceae Infections; Fosfomycin; Humans; Klebsiella oxytoca; Klebsiella pneumoniae; Meropenem; Microbial Sensitivity Tests; Minocycline; Serratia marcescens; Sisomicin; Thienamycins; Tigecycline

We aimed to describe the in vivo activity of humanized pharmacokinetic exposures of meropenem and comparators against Verona integron-encoded metallo-β-lactamase (MBL) (VIM)-producing Enterobacteriaceae in a murine model. Levofloxacin activity was predicted by its MIC, and cefepime activity displayed variability, whereas meropenem produced a >1 log CFU reduction against all isolates despite high MICs indicative of resistance. Our results suggest that despite in vitro resistance, high-dose meropenem may be a possible option against infections caused by Enterobacteriaceae producing MBL-type carbapenemases.

Topics: Animals; Anti-Infective Agents; Bacterial Proteins; beta-Lactamases; Cefepime; Cephalosporins; Enterobacteriaceae; Enterobacteriaceae Infections; Levofloxacin; Meropenem; Mice; Microbial Sensitivity Tests; Thienamycins; Thigh

We evaluated the analytical performance of a liquid chromatography-tandem mass spectrometry assay to detect carbapenemase activity in a group of carbapenemase-producing Enterobacteriaceae by meropenem hydrolysis. This one-hour method showed a sensitivity of 94% and a specificity of 100%, representing a rapid and reliable option compared to conventional phenotypic assays.

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Biocatalysis; Chromatography, Liquid; Enterobacteriaceae; Enterobacteriaceae Infections; Humans; Meropenem; Tandem Mass Spectrometry; Thienamycins

In 2010, our hospital, in line with National guidance, changed advice on antibiotic prescribing for UTI to reduce use of cephalosporins in favour of penicillins. We hypothesized that this change in policy would have no impact on the pattern of antibiotic resistance of the organisms causing UTI.. Audit review of all urine samples sent to BWH from 2009 to 2013 and positive cultures showing Enterobacteriaceae were then tested for antibiotic susceptibility.. There has been an increase in the resistance of both Co-amoxiclav and Ciprofloxacin since 2009. Co-amoxiclav and trimethoprim now have similar resistance rates. Ciprofloxacin resistance has risen fairly quickly in the last four years from 1% to 8%. Resistance to nitrofurantoin has remained low. Gentamicin resistance remained stable and very low, second best to meroponem.. The results have been fed back to commissioners and internally and are being used as part of the guideline updating process.. Hospital protocols for treating infections should be reviewed and updated based on accurate local data. These data should be used for formulating regional specific protocols. Our results suggest that meroponem and ciprofloxacin should be reserved for microbiologically proven resistance to other antibiotics.

Topics: Amoxicillin-Potassium Clavulanate Combination; Anti-Bacterial Agents; Ciprofloxacin; Clinical Audit; Drug Resistance, Bacterial; England; Enterobacteriaceae; Enterobacteriaceae Infections; Female; Gentamicins; Health Policy; Humans; Meropenem; Microbial Sensitivity Tests; Nitrofurantoin; Practice Guidelines as Topic; Thienamycins; Trimethoprim; Urinary Tract Infections

Infection with carbapenemase-producing Enterobacteriaceae (CPE) has been shown to cause significant illness among hospitalized patients. Given the paucity of treatment options, there is a critical need to stop the spread of CPE. However, screening for the presence of CPE in laboratory settings has been challenging. In order to assess the effectiveness of current CPE detection guidelines, we analyzed the meropenem MIC distribution for a large set of clinical Enterobacteriaceae isolates. A total of 1,022 isolates submitted to the Public Health Ontario Laboratories (PHOL) from January 2011 to March 2014 were examined. Only isolates displaying a meropenem or ertapenem MIC of ≥ 0.25 or ≥ 1 μg/ml, respectively, were included. Carbapenemase-positive isolates were identified by multiplex PCR. We identified 189 isolates positive for carbapenemases, which primarily comprised NDM, KPC, and OXA-48-like carbapenemases, and these isolates were largely Klebsiella spp., Escherichia coli, and Enterobacter spp. Interestingly, 14 to 20% of these isolates displayed meropenem MICs within the susceptible range on the basis of CLSI and EUCAST breakpoint interpretive criteria. While the majority of meropenem-susceptible CPE isolates were observed to be E. coli, meropenem susceptibility was not exclusive to any one species/genus or carbapenemase type. Application of CLSI screening recommendations captured only 86% of carbapenemase-producing isolates, whereas application of EUCAST recommendations detected 98.4% of CPE isolates. In a region with a low carbapenemase prevalence, meropenem-based screening approaches require a cutoff MIC near the epidemiological wild-type threshold in order to achieve nearly optimal CPE identification.

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; beta-Lactams; Enterobacter; Enterobacteriaceae Infections; Ertapenem; Escherichia coli; Escherichia coli Proteins; Humans; Klebsiella; Meropenem; Microbial Sensitivity Tests; Multiplex Polymerase Chain Reaction; Thienamycins

We report the case of using a long-term combination of meropenem and amikacin to treat infective endocarditis caused by Enterobacter cloacae resistant to third- and fourth-generation cephalosporins. Multi-drug resistant Gram-negative bacilli, such as the E. cloacae in our study, may become possible pathogens of infective endocarditis. Our experience with this case indicates that long-term use of a combination of β-lactam and aminoglycosides might represent a suitable management option for future infective endocarditis cases due to non-Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, Kingella spp. (HACEK group) Gram-negative bacilli such as ours.

Topics: Aged; Amikacin; Anti-Bacterial Agents; beta-Lactam Resistance; Cephalosporins; Endocarditis; Enterobacter cloacae; Enterobacteriaceae Infections; Humans; Male; Meropenem; Thienamycins; Treatment Outcome

The purpose of this study was to identify carbapenem-resistant Klebsiella pneumoniae in a tertiary care hospital in Sharjah Emirate, to identify the plasmids carrying the carbapenemase genes and to reveal clonal relationships among the isolates. Two hundred and two clinically relevant isolates collected between September 2011 and October 2012 at Al-Qassimi hospital, Sharjah, were investigated for meropenem resistance. Strains with decreased susceptibility were further tested with the modified Hodge test, by EDTA and phenylboronic acid synergy and by E-test. The genes of New Delhi metallo-β-lactamase (NDM), IMP, VIM, OXA-48, and KPC beta-lactamases were targeted by polymerase chain reaction and the genes were located on plasmids by Southern blotting. Clusters of the isolates were revealed by macrorestriction analysis. Seven percent of the isolates were originally found to be meropenem resistant, one isolate have lost its resistance during storage. All of the 13 resistant isolates were positive for the NDM-1 gene located on plasmids of 125 to >170 kb, while three isolates also carried the blaOXA-48-like genes. Clusters having repeatedly been isolated over the study period were identified. Carbapenem-resistant Klebsiella pneumoniae carrying the blaNDM-1 gene is a fast emerging problem, emphasizing the potential role of the Middle East as a secondary reservoir for these organisms.

Topics: Anti-Bacterial Agents; Bacterial Typing Techniques; beta-Lactam Resistance; beta-Lactamases; Blotting, Southern; Enterobacteriaceae Infections; Gene Expression; Humans; Incidence; Klebsiella pneumoniae; Meropenem; Microbial Sensitivity Tests; Plasmids; Polymerase Chain Reaction; Retrospective Studies; Thienamycins; United Arab Emirates

To investigate control of an outbreak due to orthopedic infections caused by Enterobacteriaceae producing IMP carbapenemases.. The sporadic orthopedic infections with Enterobacteriaceae producing carbapenemase (CPE) were retrospectively analyzed in a Chinese tertiary care hospital from November 2010 to September 2012.. The CPE were isolated from four distinct orthopedic patients, three patients infected with Enterobacter cloacae while the other with Klebsiella oxytoca. All strains were resistant to almost all the conventional antimicrobial. The strains produced IMP-4 type detected in the two early patients, while other strains could produce IMP-8 type. All of the four patients had ever undergoing invasive surgical procedure, and three of them were given fluoroquinolones for anti-infection treatment while the other patients was treated with meropenem. Ultimately, all patients were cured and discharged, without outbreak of nosocomial infection caused by CPE.. Our study shows that strict infection control plays an important role in limiting dissemination of Enterobacteriaceae producing IMP carbapenemase. In addition, reasonable supporting treatment and disinfection protection seems to be more effective for the infection of strains.

Topics: Adolescent; Anti-Bacterial Agents; Arthritis, Infectious; beta-Lactam Resistance; beta-Lactamases; China; Cross Infection; Disease Outbreaks; Drug Resistance, Multiple, Bacterial; Enterobacter cloacae; Enterobacteriaceae Infections; Female; Fluoroquinolones; Fracture Fixation, Internal; Humans; Infection Control; Klebsiella Infections; Klebsiella oxytoca; Levofloxacin; Male; Meropenem; Middle Aged; Osteitis; Patient Isolation; Protective Clothing; Retrospective Studies; Surgical Wound Infection; Thienamycins; Universal Precautions; Wound Infection

IMP-type metallo-β-lactamase enzymes have been reported in different geographical areas and in various Gram-negative bacteria. However, the risk factors and epidemiology pertaining to IMP-type metallo-β-lactamase-producing Enterobacter cloacae (IMP-producing E. cloacae) have not been systematically evaluated. We conducted a retrospective, matched case-control study of patients from whom IMP-producing E. cloacae isolates were obtained, in addition to performing thorough molecular analyses of the clinically obtained IMP-producing E. cloacae isolates. Unique cases with IMP-producing E. cloacae isolation were included. Patients with IMP-producing E. cloacae were matched to uninfected controls at a ratio of 1 to 3. Fifteen IMP-producing E. cloacae cases were identified, with five of the isolates being obtained from blood, and they were matched to 45 uninfected controls. All (100%) patients from whom IMP-producing E. cloacae isolates were obtained had indwelling devices at the time of isolation, compared with one (2.2%) uninfected control. Independent predictors for isolation of IMP-producing E. cloacae were identified as cephalosporin exposure and invasive procedures within 3 months. Although in-hospital mortality rates were similar between cases and controls (14.3% versus 13.3%), the in-hospital mortality of patients with IMP-producing E. cloacae-caused bacteremia was significantly higher (40%) than the rate in controls. IMP-producing E. cloacae isolates were frequently positive for other resistance determinants. The MICs of meropenem and imipenem were not elevated; 10 (67%) and 12 (80%) of the 15 IMP-producing E. cloacae isolates had a MIC of ≤ 1 μg/ml. A phylogenetic tree showed a close relationship among the IMP-producing E. cloacae samples. Indwelling devices, exposure to cephalosporin, and a history of invasive procedures were associated with isolation of IMP-producing E. cloacae. Screening for carbapenemase production is important in order to apply appropriate clinical management and infection control measures.

Topics: Aged; Aged, 80 and over; Bacteremia; Bacterial Proteins; beta-Lactamases; Cephalosporins; Enterobacter cloacae; Enterobacteriaceae Infections; Female; Hospital Mortality; Humans; Imipenem; Infection Control; Inosine Monophosphate; Japan; Male; Meropenem; Middle Aged; Phylogeny; R Factors; Retrospective Studies; Risk Factors; Tertiary Healthcare; Thienamycins

Topics: Anti-Bacterial Agents; beta-Lactamases; beta-Lactams; Carbapenems; Disease Susceptibility; Drug Resistance, Multiple; Enterobacteriaceae Infections; Ertapenem; Humans; Meropenem; Providencia; Thienamycins

Pantoea calida, a recently described environmental Enterobacteriaceae organism, has not yet been associated with human infection.. We report a case of postoperative meningitis caused by P. calida. After pituitary adenoma resection, a 52-year-old Caucasian woman developed febrile meningitis confirmed by cerebrospinal fluid analysis. P. calida was grown in pure culture from this fluid and was firmly identified with partial rpoB gene sequencing. She was cured by a 14-day course of meropenem.. P. calida must be added to the list of opportunistic Enterobacteriaceae pathogens responsible for postsurgical meningitis. It is easily identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.

Topics: Adenoma; Anti-Bacterial Agents; Cross Infection; Enterobacteriaceae; Enterobacteriaceae Infections; Female; Humans; Meningitis, Bacterial; Meropenem; Middle Aged; Pituitary Neoplasms; Thienamycins

The rapid emergence and dissemination of carbapenem resistance in Enterobacteriaceae complicates the treatment of infections caused by these organisms.. We collected clinical isolates with meropenem inhibition zones of ≤ 22 mm from January 1, 2009, through December 31, 2010. We attempted to amplify the NDM-1 gene from these isolates and conducted the modified Hodge test (MHT). The minimal inhibitory concentration (MIC) of the MHT-positive strains was determined by the agar disk dilution method. The carbapenemase-encoding resistance genes of these strains were examined using polymerase chain reaction (PCR) analysis and a sequencing strategy to characterize these enzymes. The clonal relationship among isolates was analyzed by pulsed-field gel electrophoresis (PFGE).. Among the 158 Enterobacteriaceae isolates that were collected, there were no NDM-1-positive strains and 26 MHT-positive strains. Among the latter, 18 strains were IMP-4-positive, and 1 was KPC-2-positive. In addition, 15 of the IMP-4-positive Klebsiella pneumoniae strains belonged to 4 PFGE genotypes, with 8 strains having the same genotype.. These results suggest that nosocomial infections are one of the main reasons for the spread of these resistant strains.

Topics: Adult; Aged; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; China; DNA, Bacterial; Electrophoresis, Gel, Pulsed-Field; Enterobacteriaceae; Enterobacteriaceae Infections; Female; Genes, Bacterial; Genotype; Hospitals; Humans; Infant; Infant, Newborn; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Molecular Epidemiology; Molecular Typing; Polymerase Chain Reaction; Thienamycins; Young Adult

Carbapenem-resistant Enterobacteriaceae (CRE) are a growing problem worldwide. Guidelines focus on carbapenemase-producing organisms, and little is known about whether strict adherence to infection control measures is effective for CRE without carbapenemase. During 2009, CRE increased markedly in a tertiary hospital, and enhanced infection control measures without active surveillance were adopted.. Beginning in April 2010, enhanced antimicrobial stewardship, strict contact precautions, and cohort isolation were adopted. After September 2010, hand hygiene performance was prospectively monitored by active surveillance, and results were monthly fed back to medical personnel. Available carbapenem-resistant Escherichia coli (ECO) and carbapenem-resistant Klebsiella pneumoniae (KPN) isolated during 2008-2010 were characterized. Imipenem and meropenem minimal inhibitory concentrations were confirmed by E-test (AB biodisk, Solna, Sweden). Phenotypic screening assays and polymerase chain reaction (PCR) amplification of known β-lactamase and carbapenemase genes were performed.. From 3,511 ECO and 2,279 KPN, 44 (0.76%) were CRE (3 ECO, 41 KPN). CRE incidence rates rose from 1.61 in 2008 to 5.49 in 2009; they rose further to 9.81 per 100,000 patient days in early 2010. After adoption of strict infection control measures, CRE frequency fell back in 2011 and remained at baseline afterward. Phenotypic screening and PCR showed AmpC β-lactamase and extended spectrum β-lactamases with or without loss of porins; carbapenemases were not detected.. Enhanced infection control measures, even without active surveillance, seem effective to prevent further spread of CRE in a low-prevalence setting with mainly carbapenemase-nonproducing CRE.

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactam Resistance; beta-Lactamases; Carbapenems; Containment of Biohazards; Cross Infection; Enterobacteriaceae; Enterobacteriaceae Infections; Hospitals, Teaching; Humans; Imipenem; Incidence; Infection Control; Klebsiella Infections; Klebsiella pneumoniae; Meropenem; Microbial Sensitivity Tests; Phenotype; Prevalence; Prospective Studies; Republic of Korea; Retrospective Studies; Thienamycins

We investigated the activity of BAL30072, a dihydroxypyridone monosulfactam, against carbapenem-resistant Enterobacteriaceae and non-fermenters (i) alone, (ii) combined with BAL29880 (to inhibit AmpC) and/or clavulanate [to inhibit extended-spectrum β-lactamases (ESBLs)] and (iii) combined 1:1 with meropenem.. Isolates were from multiple UK hospitals. MICs were determined by CLSI agar dilution. Carbapenemases were identified by PCR and sequencing.. BAL30072 inhibited 69% of the carbapenem-resistant Enterobacteriaceae at ≤4 mg/L, including 60%-87% with OXA-48, IMP, NDM and VIM enzymes or combinations of impermeability with AmpC or ESBL, and 40% with KPC enzymes. The proportions susceptible exceeded 90% for BAL30072+BAL29880+clavulanate, except for isolates with KPC carbapenemases, where members of the international sequence type (ST) 258 Klebsiella pneumoniae clone remained resistant. At 4 mg/L, BAL30072 was active against all OprD-deficient Pseudomonas aeruginosa, against 8/12 with efflux-type β-lactam resistance and 19/25 with metallo-carbapenemases; these proportions were little increased if inhibitors were added. Most Acinetobacter baumannii with OXA or NDM carbapenemases were susceptible to BAL30072 alone at ≤4 mg/L, but those with OXA-58 were resistant, probably for reasons other than their β-lactamase. Addition of meropenem to BAL30072 increased activity against some individual isolates, but with little clear relationship to the resistance mechanism, except for consistent potentiation against OprD-deficient P. aeruginosa.. BAL30072 had good activity against many diverse carbapenem resistance types. Adding clavulanate and/or BAL29880 extended activity against carbapenem-resistant Enterobacteriaceae, but not non-fermenters. Adding meropenem resulted in small increases in activity against individual isolates. Resistance remained common in the K. pneumoniae ST258 KPC clone, even with both inhibitors or meropenem added.

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactam Resistance; beta-Lactamases; DNA, Bacterial; Drug Synergism; Enterobacteriaceae; Enterobacteriaceae Infections; Enzyme Inhibitors; Hospitals; Humans; Meropenem; Microbial Sensitivity Tests; Monobactams; Polymerase Chain Reaction; Sequence Analysis, DNA; Thiazoles; Thienamycins; United Kingdom

Liver abscesses are infectious, space occupying lesions in the liver, the two most common abscesses being pyogenic and amoebic. A pyogenic liver abscess (PLA) is a rare condition with a reported incidence of 20 per 100 000 hospital admissions in the western population. The right lobe of the liver is the most common site in both types of liver abscess. Clinical presentation is elusive with complaints of fever, right upper quadrant pain in the abdomen and hepatomegaly with or without jaundice. The aetiology of PLA has changed in the past few decades and may be of biliary, portal, arterial or traumatic origin, but many cases are still cryptogenic. The most common organisms causing PLA are Gram-negative aerobes, especially Escherichia coli and Klebsiella pneumoniae. Studies have shown a high degree of antimicrobial susceptibility of isolated organism resulting in an overall lower mortality in PLA. Here, we present a case of PLA caused by multidrug-resistant Citrobacter freundii, which is an unusual organism to be isolated.

Topics: Anti-Bacterial Agents; Citrobacter; Contrast Media; Enterobacteriaceae Infections; Humans; Liver Abscess; Male; Meropenem; Middle Aged; Radiography, Interventional; Radiography, Thoracic; Thienamycins; Tomography, X-Ray Computed

 AmpC β-lactamase-producing organisms are associated with significant morbidity and mortality. Induction of resistance to third-generation cephalosporins after exposure to these agents complicates treatment options and carbapenems are considered optimal therapy. The role of cefepime, however, remains unclear. Our objective was to compare clinical outcomes for patients receiving cefepime compared with meropenem for invasive infections caused by organisms expressing AmpC β-lactamases..  Hospitalized patients with blood, bronchoalveolar lavage, or intra-abdominal fluid cultures growing Enterobacter spp, Serratia spp, or Citrobacter spp were evaluated using the cefotetan-boronic acid disk test and the cefotetan-cloxacillin Etest to identify organisms with AmpC β-lactamase production from February 2010 to January 2011. In patients with organisms hyperproducing AmpC β-lactamases (positive by both methods), clinical outcomes for patients receiving cefepime or meropenem therapy were compared. To minimize the possibility of treatment selection bias, 1:1 nearest neighbor propensity score matching was performed prior to regression analysis..  Of 399 patients meeting eligibility criteria, 96 (24%) had confirmed infections with AmpC β-lactamase-producing organisms. Propensity score matching of patients infected with AmpC β-lactamase-positive organisms treated with cefepime or meropenem yielded 32 well-balanced patient pairs with no difference in 30-day mortality (odds ratio, 0.63; 95% confidence interval [CI], .23-2.11; P = .36) or length of hospital stay after infection (relative risk, 0.96; 95% CI, .79-1.26; P = .56) between the 2 groups..  Cefepime may be a reasonable option for the treatment of invasive infections due to AmpC β-lactamase-producing organisms, particularly when adequate source control is achieved.

Topics: Adult; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactam Resistance; beta-Lactamases; Cefepime; Cephalosporins; Cohort Studies; Enterobacteriaceae; Enterobacteriaceae Infections; Hospitalization; Humans; Meropenem; Microbial Sensitivity Tests; Middle Aged; Propensity Score; Thienamycins

Resistance to carbapenem, considered to be the drug of last resort for treating serious enterobacterial infections, is a growing problem. Metallo-beta-lactamase (MBL) mediated carbapenem resistance is considered to be clinically most important, since no traditional inhibitors work against them. Hence, we have investigated the changes in drug profile, affinity and binding stability of meropenem with clinically important MBLs viz., IMP, VIM and NDM during the course of molecular evolution. Phylogenetic trees were constructed and amino acids positions, presumed to be exposed to positive selection pressure were analyzed. Based on sequence diversity and selection pressure, IMP-1, IMP-8, IMP-9, IMP-21, IMP-27, IMP-20 and IMP-26 among IMP genes; VIM-1, VIM-2, VIM-13, VIM-29, VIM-18 and VIM-7 among VIM genes and NDM-1 had been selected for in silico analysis. Mode of interaction of selected MBL variants with meropenem were analyzed by Autodock4.0 and LIGPLOT analysis. In all the trajectories, we had found an increase in mouth opening/solvent accessible volume/area of the catalytic pocket and decrease in Gibbs' free energy (ΔG°) for binding with meropenem and Michealis-Menten constant (Km) - indicating an increase in choice of drugs, binding stability and meropenem affinity from primitive to advanced MBL variants, with exceptions of IMP-20, IMP-26, VIM-13 and VIM-18 which might be due to sign epistasis. Intergenic comparison revealed NDM-1 might have greater drug profile and catalytic efficiency than IMP-1 and VIM-2 due to largest pocket opening and least distance between the Zn-I ion and β-lactam oxygen of meropenem.

Topics: Amino Acid Sequence; Anti-Bacterial Agents; beta-Lactam Resistance; beta-Lactamases; Binding Sites; Carbapenems; Enterobacteriaceae Infections; Evolution, Molecular; Humans; Meropenem; Microbial Sensitivity Tests; Molecular Docking Simulation; Phylogeny; Protein Binding; Receptors, Cell Surface; Sequence Alignment; Sequence Analysis, DNA; Thienamycins

Topics: Anti-Bacterial Agents; beta-Lactam Resistance; Enterobacteriaceae; Enterobacteriaceae Infections; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Thienamycins

Limited antimicrobials remain active for treating severe infections due to KPC-producing pathogens, and optimal regimens have not been established. In murine thigh infections caused by nine KPC-producing clinical strains of Enterobacteriaceae (meropenem MICs, 1 to 4 μg/ml), we evaluated the activities of tigecycline, colistin, meropenem, rifampin, and gentamicin in single and combination regimens lasting for 24 h and 48 h. Rifampin, tigecycline, and gentamicin were the most effective monotherapies, reducing significantly the CFU counts yielded from thighs infected by 88.9 to 100%, 77.8 to 88.9%, and 66.7 to 88.9% of strains, respectively; meropenem and colistin alone exhibited considerably lower performance (significant CFU reduction in 33.3% and 22.2 to 33.3% of the strains, respectively). The addition of rifampin or gentamicin to tigecycline produced synergistic effect in most strains, while antagonism was observed in 33.3 to 44.4% of the strains when colistin was added to tigecycline and in 44.4 to 55.5% of the strains for meropenem combination with tigecycline. Tigecycline combinations with gentamicin or with rifampin caused higher CFU reductions than did tigecycline plus colistin or plus meropenem with almost all strains. Furthermore, tigecycline plus gentamicin was significantly more effective than tigecycline plus colistin or tigecycline plus meropenem in 33.3 to 44.4% and 55.5 to 66.7% of the strains, respectively, while tigecycline plus rifampin significantly outperformed tigecycline plus colistin and tigecycline plus meropenem in 33.3% and 66.7 to 77.8% of the strains, respectively. Overall, our in vivo study showed that tigecycline plus rifampin or plus gentamicin is a robust regimen against soft tissue infections caused by KPC-producing strains. The combinations of tigecycline with colistin or meropenem should be considered with caution in clinical practice.

Topics: Animals; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Colistin; Colony Count, Microbial; Drug Synergism; Drug Therapy, Combination; Enterobacteriaceae Infections; Escherichia coli; Female; Gentamicins; Klebsiella pneumoniae; Meropenem; Mice; Microbial Sensitivity Tests; Minocycline; Rifampin; Thienamycins; Thigh; Tigecycline

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacteremia; beta-Lactams; Case-Control Studies; Drug Resistance, Bacterial; Enterobacteriaceae; Enterobacteriaceae Infections; Ertapenem; Escherichia coli; Female; Humans; Klebsiella pneumoniae; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Risk Factors; Thienamycins; Treatment Outcome

Newborns are rarely infected by extended-spectrum β-lactamase (ESBL)-producing members of the Enterobacteriaceae. In a neonatal intensive care unit, 14 newborns were infected or colonized by CTX-M-15-producing Enterobacter cloacae. All seven infected patients had underlying medical conditions, and five of them were treated successfully with meropenem, whilst one untreated patient died. Paediatric infections caused by multidrug-resistant ESBL-producing Enterobacter cloacae constitute a critical clinical and epidemiological issue.

Topics: Anti-Bacterial Agents; beta-Lactamases; Cluster Analysis; Cross Infection; Disease Outbreaks; Drug Resistance, Multiple, Bacterial; Electrophoresis, Gel, Pulsed-Field; Enterobacter cloacae; Enterobacteriaceae Infections; Female; Genotype; Humans; Infant, Newborn; Intensive Care Units, Neonatal; Male; Meropenem; Microbial Sensitivity Tests; Molecular Typing; Thienamycins; Treatment Outcome

A temocillin minimal inhibitory concentration ≥ 128 mg/L combined with the results of meropenem double disc synergy testing was used to (i) discriminate carbapenemase production from other resistance mechanisms leading to decreased carbapenem susceptibility; and (ii) differentiate Ambler classes in carbapenemase-producing enterobacteriaceae (CPE). The suggested test algorithm discriminated all extended spectrum ß-lactamase/AmpC from CPE isolates, which could further be divided correctly into Ambler classes A and B enzymes as well as OXA-48 in all cases. The algorithm is simple to implement as part of the daily routine in a standard microbiology laboratory with limited access to or resources for molecular biological tools.

Topics: Anti-Bacterial Agents; beta-Lactam Resistance; beta-Lactamases; Carbapenems; Enterobacteriaceae; Enterobacteriaceae Infections; Humans; Meropenem; Microbial Sensitivity Tests; Penicillins; Thienamycins

To describe the treatment and outcomes of patients with carbapenemase-producing Enterobacteriaceae and evaluate whether these cases represented active infection requiring antibiotic therapy or colonization.. Adult inpatients with carbapenemase-producing Enterobacteriaceae were retrospectively evaluated. Cases were classified as colonization versus infection by 2 infectious diseases physicians. Multiple cultures that grew in the same patient within a 2-week period were evaluated as a single case.. A total of 42 cases among 35 patients were identified. The mean age of the cohort was 67.7 ± 13.7 y, mean APACHE II score was 17.9 ± 8.6, and 77% of patients were in the intensive care unit when the carbapenem-producing Enterobacteriaceae was isolated. Klebsiella pneumoniae (84%) was the predominant organism; urine (36%), tissue/wound/drainage (25%), and blood (20%) were the most common sites of collection. Though 43% of cases were classified as colonization, 56% of these cases were treated with antibiotics. Only 1 patient characterized as colonized subsequently developed infection, 29 days later. Among infected cases, colistin (55%), meropenem (41%), aminoglycosides (32%), and tigecycline (27%) were used for treatment, and combination antimicrobial therapy was common (55%). Clinical and microbiological success was higher in patients receiving combination therapy (83% vs 60%, p = 0.35). Colistin monotherapy was only successful in urinary infections. All-cause hospital mortality was 29%.. Nearly half of cases represented colonization, yet the majority were treated with broad-spectrum antibiotics. Determining infection versus colonization is a critical first step in managing patients with carbapenemase-producing Enterobacteriaceae. The risk of not treating apparent colonization appears low.

Topics: Aged; Aged, 80 and over; Aminoglycosides; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Colistin; Drug Resistance, Bacterial; Drug Therapy, Combination; Enterobacteriaceae; Enterobacteriaceae Infections; Female; Humans; Klebsiella Infections; Klebsiella pneumoniae; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Thienamycins; Treatment Outcome

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

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

Topics: Anti-Bacterial Agents; beta-Lactam Resistance; Enterobacteriaceae; Enterobacteriaceae Infections; Humans; Meropenem; Microbial Sensitivity Tests; Thienamycins; United Kingdom

Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) is a potentially useful tool for the detection of antimicrobial resistance, especially that conferred by β-lactamases. Here we describe a modification of a previously reported MALDI-TOF MS meropenem hydrolysis assay. The modified method was validated on 108 carbapenemase-producing members of the Enterobacteriaceae, two NDM-1-producing Acinetobacter baumannii isolates, and 35 carbapenem-resistant enterobacteria producing no carbapenemase. The detection of carbapenemases by MALDI-TOF MS seems to be a powerful, quick, and cost-effective method for microbiological laboratories.

Topics: Acinetobacter baumannii; Bacterial Proteins; beta-Lactamases; Enterobacteriaceae; Enterobacteriaceae Infections; Humans; Hydrolysis; Meropenem; Microbial Sensitivity Tests; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Thienamycins

We investigated the trend in resistance to carbapenems among isolates of Enterobacteriaceae that had been collected from patients with intra-abdominal infections at five medical centers in Taiwan from 2006 to 2010 and evaluated the correlation between resistance to carbapenems and consumption of said agents as part of the Study for Monitoring Antimicrobial Resistance Trends (SMART). During the study period, the usage of ertapenem and that of total carbapenems (ertapenem, imipenem, and meropenem) increased significantly from 6.13 to 13.38 defined daily doses per 1000 patient-days for ertapenem and from 20.43 to 34.25 defined daily doses per 1000 patient-days for total carbapenems. The most common species were Escherichia coli (n = 1095), Klebsiella spp. (n = 663), and Enterobacter spp. (n = 202). The susceptibility of all isolates to ertapenem and to imipenem varied during the study period. For ertapenem, the rates of nonsusceptibility ranged from 3.5% to 10.3% and those for imipenem ranged from 3.5% to 10.7%. Although the use of carbapenems increased during the study period, there was no marked increase in resistance to carbapenems. Continuous monitoring of resistance trends is necessary so that antimicrobial prescription policies can be adjusted and infection control intervention programs can be implemented.

Topics: Anti-Bacterial Agents; beta-Lactams; Carbapenems; Drug Resistance, Bacterial; Enterobacteriaceae; Enterobacteriaceae Infections; Ertapenem; Humans; Intraabdominal Infections; Linear Models; Meropenem; Microbial Sensitivity Tests; Prevalence; Prospective Studies; Taiwan; Thienamycins

Carbapenem resistance due to metallo-β-lactamases (MBLs) in Enterobacteriaceae has gained much prominence in recent months. The emergence and subsequent spread of New Delhi metallo-β-lactamase-1 (NDM-1) constitutes a potential threat in terms of the management of affected patients and institutional infection control efforts. We evaluated an in-house prepared meropenem impregnated MacConkey agar versus CHROMagar KPC.. The lowest limit of detection (LLD) was compared for nine clinical isolates of NDM-1 producing Enterobacteriaceae on the above mentioned agar media.. LLD was comparable for all the nine clinical isolates on both media. The cost of the antibiotic impregnated MacConkey agar was considerably lower (US$0.39) as compared to the commercial media, while its performance remained unaltered for a period of at least 8 weeks of storage.. The in-house medium proved to be a suitable and cheap alternative to the CHROMagar KPC.

Topics: Adult; Anti-Bacterial Agents; beta-Lactamases; Carbapenems; Culture Media; Drug Stability; Enterobacteriaceae; Enterobacteriaceae Infections; Escherichia coli; Escherichia coli Infections; Humans; Klebsiella Infections; Klebsiella pneumoniae; Meropenem; Microbial Sensitivity Tests; Middle Aged; Thienamycins

Topics: Adolescent; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Citrobacter freundii; Enterobacteriaceae Infections; Female; Humans; India; Molecular Sequence Data; Young Adult

Enterobacteriaceae producing carbapenemases, such as KPC or metallo-β-lactamases (MBLs), have emerged on several continents. Phenotypic tests are urgently needed for their rapid and accurate detection. A novel carbapenemase detection test, comprising a meropenem disk, and meropenem disks supplemented with 730 μg of EDTA, 1000 μg of dipicolinic acid (DPA), 600 μg of aminophenylboronic acid (APBA), or 750 μg of cloxacillin, was evaluated against Klebsiella pneumoniae isolates with KPC (n = 34), VIM (n = 21), IMP (n = 4) or OXA-48 (n = 9) carbapenemases, and carbapenem-resistant Enterobacteriaceae with porin loss in combination with an extended-spectrum β-lactamase (ESBL) (n = 9) or AmpC hyperproduction (n = 5). Commercially available diagnostics tablets from Rosco containing meropenem and the same inhibitors as described above (except EDTA) were also evaluated. An increased meropenem inhibition zone was sought in the presence of each added β-lactamase inhibitor. APBA had excellent sensitivity for detecting K. pneumoniae with KPC enzymes. Isolates with combined AmpC hyperproduction and porin loss were also positive in the APBA test but, unlike KPC producers, showed cloxacillin synergy. Both DPA and EDTA had excellent sensitivity for detection of MBL-producing K. pneumoniae. However, EDTA showed poor specificity, with positive results noted for 1/9 ESBL-producing isolates, for 4/34 KPC-producing isolates, and for 4/9 OXA-48-producing isolates, whereas all of these were negative when DPA was used. The in-house test distinguished accurately between several different mechanisms mediating reduced susceptibility to carbapenems in Enterobacteriaceae. The commercial combination tablets from Rosco performed similarly to the in-house test, with the exception of one false-positive MBL result and one false-positive KPC result among the OXA-48 producers.

Topics: Anti-Bacterial Agents; beta-Lactamases; Boronic Acids; Cloxacillin; Enterobacteriaceae; Enterobacteriaceae Infections; Humans; Meropenem; Microbial Sensitivity Tests; Picolinic Acids; Sensitivity and Specificity; Thienamycins

The imipenem and meropenem-resistant strains Citrobacter freundii HS70 and Escherichia coli HS510 were isolated from patients in Shanghai, China. By isoelectric focusing, PCR amplification and sequencing, these strains were each found to produce four β-lactamases: TEM-1, KPC-3, SHV-7 and CTX-M-14. A conjugation experiment and plasmid restriction digestion revealed that the bla (KPC-3) gene was located on the same plasmid in both isolates. Bidirectional primer walking sequencing showed that the nucleotide sequence surrounding the 3.8 kb bla(KPC-3) contained a 671-bp insertion similar to that previously characterized in China. The insertion was located between the promoter and the coding region of the bla(KPC-3) gene. Susceptibility testing performed on recombinant strains carrying the bla(KPC-3) gene with or without the insertion revealed that minimum inhibitory concentrations of imipenem, meropenem, cefepime, and cefotaxime for E. coli EMU-KPC3 (without insertion) were four times higher than that of E. coli EKPC3 (with insertion). The 671 bp insertion reduced bla(KPC-3) expression significantly. Taken together, these results suggest that KPC-3-producing C. freundii and E. coli have begun to emerge in our hospital.

Topics: Anti-Bacterial Agents; beta-Lactam Resistance; beta-Lactamases; Carbapenems; China; Citrobacter freundii; Enterobacteriaceae Infections; Escherichia coli; Escherichia coli Infections; Female; Humans; Imipenem; Isoelectric Focusing; Meropenem; Microbial Sensitivity Tests; Middle Aged; Plasmids; Polymerase Chain Reaction; Sequence Analysis, DNA; Thienamycins

Antibiotic combinations including tigecycline have not been studied against Klebsiella pneumoniae carbapenemase (KPC)-producing pathogens. Tigecycline alone and combined with colistin and meropenem was tested against eight genetically unrelated KPC-producing clinical strains of Enterobacteriaceae (four K. pneumoniae, two Escherichia coli, one Enterobacter cloacae and one Serratia marcescens) by time-kill assay. Tigecycline displayed a concentration-independent bacteriostatic activity in seven strains and bactericidal activity in one strain. Colistin showed bactericidal activity at 4× the minimum inhibitory concentration (MIC) in three strains and was bacteriostatic for the remaining strains and concentrations. Meropenem was bactericidal in three strains and bacteriostatic in five strains. The tigecycline+meropenem combination was not bactericidal against the four K. pneumoniae strains and was non-synergistic against all eight strains. Tigecycline+colistin was bactericidal against all strains at most time intervals and concentrations and was also synergistic at 1× and 2× MIC against most strains up to 4-8h and at 4× MIC up to 24 h against all strains. These findings suggest that, at most drug concentrations, tigecycline, colistin and meropenem as single agents do not exhibit efficient bactericidal activity against most of the KPC-producing strains. Tigecycline alone might be a therapeutic option for infections caused by KPC-producers when bacteriostatic activity is adequate or combined with colistin when bactericidal activity is necessary. Additional in vivo tests are warranted to assess better the killing kinetics of tigecycline combinations against KPC-producers.

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Colistin; Drug Combinations; Drug Resistance, Bacterial; Enterobacter cloacae; Enterobacteriaceae; Enterobacteriaceae Infections; Escherichia coli; Humans; Klebsiella pneumoniae; Meropenem; Microbial Sensitivity Tests; Minocycline; Serratia marcescens; Thienamycins; Tigecycline

Despite the increasing incidence of carbapenem-intermediate or -resistant Enterobacteriaceae (CIRE), risk factors associated with CIRE infections have not been well defined. This study characterizes factors associated with CIRE among two different source populations.. A case-control study was performed at a tertiary care medical centre between January 2005 and December 2009. Cases were adults with a culture-confirmed Enterobacteriaceae infection with reduced susceptibility to meropenem or ertapenem. The CIRE cases were matched 1:1 to patients from two different control series: (i) those with carbapenem-susceptible Enterobacteriaceae (CSE) infections; and (ii) inpatients residing on the same ward within 30 days of CIRE culture date. Logistic regression was used to identify variables independently associated with CIRE among each source population. Restricted multivariate analyses were performed to determine if covariates predictive of CIRE varied by infecting organism or presence of the bla(KPC) gene.. There were 102 cases of CIRE during the study period. The only covariate independently associated with CIRE in all multivariate analyses was the cumulative number of prior antibiotic exposures. Compared with CSE controls, the odds ratios (95% confidence interval) were 1.43 (1.19-1.72), 2.05 (1.70-2.47) and 2.93 (2.43-3.53) for 1, 2 and ≥ 3 antibiotic exposures, respectively. The strength of this association was comparable for the hospitalized control group and analyses stratified by organism and presence of the bla(KPC) gene.. A patient's cumulative antibiotic exposure history is likely to be more important than any one specific exposure when determining the likelihood of developing a CIRE infection.

Topics: Academic Medical Centers; Adult; Aged; Anti-Bacterial Agents; beta-Lactam Resistance; beta-Lactams; Carbapenems; Case-Control Studies; Drug Utilization; Enterobacteriaceae; Enterobacteriaceae Infections; Ertapenem; Female; Humans; Male; Meropenem; Middle Aged; Risk Factors; Thienamycins

The accurate phenotypic detection of Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae is an increasing necessity worldwide. We evaluated the performance of boronic acid combined-disk tests using as substrate imipenem or meropenem and as inhibitor of KPC production 300 μg aminophenylboronic acid (APBA), 600 μg APBA, or 400 μg phenylboronic acid (PBA). Tests were considered positive when an increase in the growth-inhibitory zone around a carbapenem disk with KPC inhibitor was 5 mm or greater of the growth-inhibitory zone diameter around the disk containing carbapenem alone. The comparison of the combined-disk tests was performed with 112 genotypically confirmed KPC-possessing Enterobacteriaceae isolates. To measure the specificity of the tests, 127 genotypically confirmed KPC-negative Enterobacteriaceae isolates that were nonsusceptible to at least one carbapenem were chosen for testing. Using disks containing imipenem without and with 300 μg APBA, 600 μg APBA, or 400 μg PBA, 72, 92, and 112 of the KPC producers, respectively, gave positive results (sensitivities, 64.3%, 82.1%, and 100%, respectively). Using disks containing meropenem without and with 300 μg APBA, 600 μg APBA, or 400 μg PBA, 87, 108, and 112 of the KPC producers, respectively, gave positive results (sensitivities, 77.7%, 96.4%, and 100%, respectively). Among KPC producers, the disk potentiation tests using meropenem and PBA demonstrated the largest differences in inhibition zones (P < 0.001). All combined-disk tests correctly identified 124 of the 127 non-KPC producers (specificity, 97.6%). This comparative study showed that PBA is the most effective inhibitor of KPC enzymes, and its use in combined-disk tests with meropenem may give the most easily interpreted results.

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; beta-Lactams; Boronic Acids; Enterobacteriaceae; Enterobacteriaceae Infections; Genotype; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Phenotype; Sensitivity and Specificity; Thienamycins

Multidrug-resistant clinical isolates of Providentia carrying bla (PER-1) and bla (VIM-2) were evaluated for the abilities to form biofilm and high biofilm forming capacity was demonstrated in them. Minimum biofilm inhibitory concentrations (MBICs), minimum biofilm eradication concentrations (MBECs), and minimum inhibitory concentrations (MICs) for imipenem and meropenem were also determined. In all tested strains, the MBICs were higher than the MICs for both drugs. Interestingly, the MBICs and the MBEC(50) for meropenem were lower than those for imipenem in the isolates producing high amounts of biofilm, suggesting that meropenem is superior to imipenem in the growth inhibition and eradication of biofilm forming Providentia strains.

Topics: Anti-Bacterial Agents; beta-Lactamases; Biofilms; Carbapenems; Enterobacteriaceae Infections; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Providencia; Thienamycins

Topics: Anti-Bacterial Agents; Anticonvulsants; Drug Interactions; Enterobacteriaceae Infections; Epilepsy, Tonic-Clonic; Female; Humans; Liver Cirrhosis; Meropenem; Middle Aged; Pneumonia, Bacterial; Thienamycins; Valproic Acid

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

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

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

The resistance mechanism of 49 Enterobacteriaceae isolates with decreased susceptibility to carbapenems collected from 2004 to 2008 at 16 teaching hospitals in China was investigated. Moderate- to high-level carbapenem resistance in most isolates was more closely associated with loss or decreased expression of both major porins combined with production of AmpC or extended-spectrum beta-lactamase enzymes, while KPC-2, IMP-4, and IMP-8 carbapenemase production may lead to a low to moderate level of carbapenem resistance in Enterobacteriaceae in China.

Topics: Anti-Bacterial Agents; Bacterial Outer Membrane Proteins; Bacterial Proteins; beta-Lactamases; Carbapenems; China; Cross Infection; Drug Resistance, Bacterial; Electrophoresis, Gel, Pulsed-Field; Enterobacteriaceae; Enterobacteriaceae Infections; Genotype; Integrons; Microbial Sensitivity Tests; Phenotype; Population Surveillance; Porins; Reverse Transcriptase Polymerase Chain Reaction

Five different strains of bacteria belonging to the family Enterobacteriaceae were isolated from two patients hospitalized in the intensive care unit of the Central Military Hospital of Algiers, Algeria. All five strains, one Providencia stuartii strain, two Escherichia coli strains, and two Klebsiella pneumoniae strains, were intermediate or resistant to all beta-lactams, including carbapenems. Synergy between imipenem and EDTA was observed for all five strains. The results of the PCR experiment confirmed the presence of a bla(VIM) gene in all five strains. The bla(VIM) genes were located as part of a class 1 integron on a 180-kb conjugative plasmid. They encoded a novel metallo-beta-lactamase designated VIM-19, which differed from the parental enzyme VIM-1 by only two substitutions: Ser228Arg, previously observed in the closely related enzyme VIM-4, and Asn215Lys, not previously observed in other VIM-type carbapenemases. VIM-19 was further characterized after purification through determination of its kinetic constants. This enzyme was inhibited by EDTA and hydrolyzed penicillins, cephalosporins, and carbapenems, as observed for other VIM-type carbapenemases but with greater catalytic efficiency against penicillins than VIM-1. VIM-19 is the first carbapenemase enzyme identified from an isolate from Algeria. These results confirm the emergence of VIM-4-like enzymes in members of the family Enterobacteriaceae from Mediterranean countries.

Topics: Algeria; Anti-Bacterial Agents; Base Sequence; beta-Lactamases; beta-Lactams; Carbapenems; DNA, Bacterial; Drug Resistance, Bacterial; Enterobacteriaceae; Enterobacteriaceae Infections; Genome, Bacterial; Hospitals, Military; Imipenem; Isoelectric Focusing; Kinetics; Microbial Sensitivity Tests; Molecular Sequence Data; Penicillins; Phenotype

Eighteen carbapenem-resistant, OXA-48-positive enterobacterial isolates recovered from Turkey, Lebanon, Egypt, France, and Belgium were analyzed. In most isolates, similar 70-kb plasmids carrying the carbapenemase gene bla(OXA-48) were identified. That gene was located within either transposon Tn1999 or transposon Tn1999.2, which was always inserted within the same gene. This work highlights the current plasmid-mediated dissemination of the OXA-48 carbapenemase worldwide.

Topics: Anti-Bacterial Agents; Belgium; beta-Lactam Resistance; beta-Lactamases; Carbapenems; DNA Transposable Elements; Egypt; Enterobacteriaceae; Enterobacteriaceae Infections; France; Humans; Lebanon; Microbial Sensitivity Tests; Plasmids; Turkey

The worldwide increase in fluoroquinolone-resistant and extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae pathogens has led to doripenem and other carbapenems assuming a greater role in the treatment of serious infections. We analyzed data from 6 phase 3 multinational doripenem clinical trials on ciprofloxacin-resistant Enterobacteriaceae isolates consisting of all genera (CIPRE) and ESBL-producing Enterobacteriaceae isolates consisting of Escherichia coli, Klebsiella spp., and Proteus spp. with ceftazidime MICs of >or=2 microg/ml (ESBLE) for prevalence by geographic region and disease type, in vitro activities of doripenem and comparator agents, and clinical or microbiologic outcomes in doripenem- and comparator-treated patients across disease types (complicated intra-abdominal infection [cIAI], complicated urinary tract infection [cUTI], and nosocomial pneumonia [NP]). Of 1,830 baseline Enterobacteriaceae isolates, 88 (4.8%) were ESBLE and 238 (13.0%) were CIPRE. The incidence of ESBLE was greatest in Europe (7.8%); that of CIPRE was higher in South America (15.9%) and Europe (14.4%). ESBLE incidence was highest in NP (12.9%) cases; that of CIPRE was higher in cUTI (18.3%) and NP (14.9%) cases. Against ESBLE and CIPRE, carbapenems appeared more active than other antibiotic classes. Among carbapenems, doripenem and meropenem were most potent. Doripenem had low MIC(90)s for CIPRE (0.5 microg/ml) and ESBLE (0.25 microg/ml). Doripenem and comparators were highly clinically effective in infections caused by Enterobacteriaceae, irrespective of their ESBL statuses. The overall cure rates were the same for doripenem (82%; 564/685) and the comparators (82%; 535/652) and similar for ESBLE (73% [16/22] versus 72% [21/29]) and CIPRE (68% [47/69] versus 52% [33/64]). These findings indicate that doripenem is an important therapeutic option for treating serious infections caused by ESBLE and CIPRE.

Topics: Anti-Bacterial Agents; beta-Lactam Resistance; Carbapenems; Ciprofloxacin; Clinical Trials, Phase III as Topic; Doripenem; Enterobacteriaceae; Enterobacteriaceae Infections; Global Health; Microbial Sensitivity Tests; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Prevalence

Enterobacteriaceae clinical isolates harboring KPC-(178 strains) or CTX-M-encoding (67 strains) genes were collected during surveillance programs in the 2000-2007 period; and susceptibility was tested by broth microdilution methods. Organisms were dominantly collected in U.S. hospitals (93%). CTX-M-15 and -14 were the most prevalent CTX-M types (97%), all collected from the United States. KPC producers were isolated in the United States (160/178), Israel, China, and Argentina. bla(CTX-M)-carrying isolates were 95.5 and 98.5%, susceptible to Imipenem and meropenem respectively, and were all susceptible to tigecycline, whereas KPC-producing isolates were highly resistant to all antimicrobials tested except polymyxin B and tigecycline (90.6% and 99.4% susceptibility, respectively). The occurrence of KPC-producing and CTX-M-producing isolates has rapidly increased especially in U.S. hospitals, and expanded therapeutic options are needed to treat infections caused by these emerging organisms.

Topics: Anti-Bacterial Agents; Argentina; beta-Lactamases; China; Drug Resistance, Multiple, Bacterial; Enterobacteriaceae; Enterobacteriaceae Infections; Genes, Bacterial; Hospitals; Humans; Imipenem; Israel; Meropenem; Microbial Sensitivity Tests; Minocycline; Polymyxin B; Thienamycins; Tigecycline; United States

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

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

In this report, we present a case of postneurosurgical meningitis due to Providencia stuartii, which was treated successfully with meropenem therapy lasting 21 days.

Topics: Adult; Anti-Bacterial Agents; Enterobacteriaceae Infections; Humans; Male; Meningitis, Bacterial; Meropenem; Postoperative Complications; Providencia; Thienamycins; Treatment Outcome

A total of 104 carbapenemase (serine- and metallo-beta-lactamase [MbetaL])-producing strains of the Enterobacteriaceae family collected from 2000 to 2005 in medical centers distributed worldwide were tested against tigecycline and 25 comparators by reference broth microdilution methods. The most frequent carbapenemase was KPC-2 or -3 (73 strains), followed by VIM-1 (14), IMP-1 (11), SME-2 (5), and NMC-A (1). All serine carbapenemases were detected in the United States, while MbetaL-producing strains were isolated in Europe. Carbapenemase-producing Enterobacteriaceae showed high rates of resistance to most antimicrobial agents tested. The rank order of in vitro activity against these strains was as follows: tigecycline (100.0% susceptible) > polymyxin B (88.1%) > amikacin (73.0%) > imipenem (37.5%). Tigecycline was very active (MIC(90), 1 microg/ml) against this significant, contemporary collection of well-characterized strains and appears to be an excellent option compared to the polymyxins for treatment of infections caused by these multidrug-resistant Enterobacteriaceae.

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Drug Resistance, Multiple, Bacterial; Enterobacteriaceae; Enterobacteriaceae Infections; Europe; Humans; Latin America; Microbial Sensitivity Tests; Minocycline; North America; Population Surveillance; Tigecycline

A novel gene, bla(KHM-1), encoding a metallo-beta-lactamase, KHM-1, was cloned from a clinical isolate of Citrobacter freundii resistant to most beta-lactam antibiotics. Escherichia coli expressing bla(KHM-1) was resistant to all broad-spectrum beta-lactams except for monobactams and showed reduced susceptibility to carbapenems. Recombinant KHM-1 exhibited EDTA-inhibitable hydrolytic activity against most beta-lactams, with an overall preference for cephalosporins.

Topics: Amino Acid Sequence; Base Sequence; beta-Lactam Resistance; beta-Lactamases; Citrobacter freundii; Conjugation, Genetic; DNA Primers; DNA, Bacterial; Enterobacteriaceae Infections; Escherichia coli K12; Genes, Bacterial; Humans; Microbial Sensitivity Tests; Molecular Sequence Data; Phylogeny; Plasmids; Recombinant Proteins; Sequence Homology, Amino Acid

Quinolone resistance is an emerging problem in China. To investigate the prevalence of the plasmid-mediated quinolone resistance genes qnr and aac(6')-Ib-cr, a total of 265 clinical isolates of Escherichia coli, Klebsiella pneumoniae, Citrobacter freundii, and Enterobacter cloacae with ciprofloxacin MICs of > or =0.25 microg/ml were screened at nine teaching hospitals in China. The qnrA, qnrB, qnrS, and aac(6')-Ib genes were detected by PCR. The aac(6')-Ib-cr gene was further identified by digestion with BtsCI and/or direct sequencing. The qnr gene was present in significantly smaller numbers of isolates with cefotaxime MICs of <2 microg/ml than isolates with higher MICs (> or =2.0 microg/ml) (20.6% and 42.1%, respectively; P < 0.05). aac(6')-Ib-cr was present in 17.0% of the isolates tested, and 7.9% of the isolates carried both the qnr and the aac(6')-Ib-cr genes. Among the isolates with cefotaxime MICs of > or =2.0 microg/ml, qnr and aac(6')-Ib-cr were present in 65.7% and 8.6% of E. cloacae isolates, respectively; 65.5% and 21.8% of K. pneumoniae isolates, respectively; 63.3% and 26.7% of C. freundii isolates, respectively; and 6.5% and 16.9% of E. coli isolates, respectively. The 20 transconjugants showed 16- to 128-fold increases in ciprofloxacin MICs, 14 showed 16- to 2,000-fold increases in cefotaxime MICs, and 5 showed 8- to 32-fold increases in cefoxitin MICs relative to those of the recipient due to the cotransmission of bla(CTX-M-14), bla(CTX-M-3), bla(DHA-1), bla(SHV-2), and bla(SHV-12) with the qnr and aac(6')-Ib-cr genes. Southern hybridization analysis showed that these genes were located on large plasmids of different sizes (53 to 193 kb). These findings indicate the high prevalence of qnr and aac(6')-Ib-cr in members of the family Enterobacteriaceae and the widespread dissemination of multidrug resistance in China.

Topics: Acetyltransferases; Anti-Bacterial Agents; Bacterial Proteins; China; Conjugation, Genetic; Drug Resistance, Bacterial; Enterobacteriaceae; Enterobacteriaceae Infections; Hospitals, Teaching; Humans; Microbial Sensitivity Tests; Plasmids; Polymerase Chain Reaction; Prevalence; Quinolones

Four clinical strains of extended-spectrum beta-lactamase- and AmpC-producing Enterobacter aerogenes were isolated successively from a liver transplantation patient. Isolates C(1) and C(2) were isolated prior to carbapenem therapy, whilst isolates C(3) and C(4) were recovered after 40 days of carbapenem therapy. The homology of these strains was analysed by pulsed-field gel electrophoresis (PFGE). beta-Lactamases were analysed by isoelectric focusing, polymerase chain reaction (PCR) and sequencing. Outer membrane proteins were analysed by PCR, sequencing, sodium dodecyl sulphate-polyacrylamide gel electrophoresis and Western blot. Disruption of OmpE36 in C(1) in vitro was also performed by homologous gene recombination. The isolates demonstrated an indistinguishable PFGE pattern. Molecular characterisation revealed that, in addition to the pre-existing multiple beta-lactamases (DHA-1, TEM-1, SHV-5, CTX-M-3 and CTX-M-14) found in C(1) and C(2), isolates C(3) and C(4) failed to express OmpE36 owing to insertional inactivation by an IS903-like insertion sequence. Other resistance mechanisms, such as production of carbapenem-hydrolysing enzymes or expression of chromosomal efflux, were apparently not involved. Completely replacing OmpE36 by the kanamycin resistance gene (kan) resulted in a significant increase in carbapenem minimum inhibitory concentrations of an ompE36 mutant. Thus, C(3) and C(4) were apparently derived from the previously imipenem-susceptible isolates C(1) and C(2). Following carbapenem exposure, depletion of OmpE36 expression resulted in the collateral effect of carbapenem resistance.

Topics: Adult; Amino Acid Sequence; Bacterial Outer Membrane Proteins; Bacterial Proteins; beta-Lactam Resistance; beta-Lactamases; Carbapenems; Drug Resistance, Multiple, Bacterial; Enterobacter aerogenes; Enterobacteriaceae Infections; Fatal Outcome; Humans; Imipenem; Liver Transplantation; Male; Meropenem; Microbial Sensitivity Tests; Molecular Sequence Data; Sequence Analysis, DNA; Thienamycins

Topics: Acetamides; Acidosis, Lactic; Anti-Infective Agents; Citrobacter freundii; Enterobacteriaceae Infections; Female; Humans; Immunocompromised Host; Kidney Transplantation; Linezolid; Meropenem; Middle Aged; Oxazolidinones; Thienamycins; Urinary Tract Infections

The clinical course of a patient on continuous ambulatory peritoneal dialysis who developed peritonitis and tunnel infection due to an unusual pathogen, Citrobacter freundii, is described. The patient did not respond well to antibiogram-based therapy (intravenous meropenem and intraperitoneal gentamicin) and removal of the catheter was required.

Topics: Adult; Anti-Bacterial Agents; Catheterization; Citrobacter freundii; Device Removal; Enterobacteriaceae Infections; Female; Gentamicins; Humans; Meropenem; Peritoneal Dialysis, Continuous Ambulatory; Peritonitis; Thienamycins

Bloodstream infections (BSI) caused by extended-spectrum beta-lactamase (ESBL)-producing organisms markedly increase the rates of treatment failure and death. We conducted a retrospective cohort analysis to identify risk factors for mortality in adult in-patients with BSI caused by ESBL-producing Enterobacteriaceae (ESBL-BSI). Particular attention was focused on defining the impact on the mortality of inadequate initial antimicrobial therapy (defined as the initiation of treatment with active antimicrobial agents >72 h after collection of the first positive blood culture). A total of 186 patients with ESBL-BSI caused by Escherichia coli (n = 104), Klebsiella pneumoniae (n = 58), or Proteus mirabilis (n = 24) were identified by our microbiology laboratory from 1 January 1999 through 31 December 2004. The overall 21-day mortality rate was 38.2% (71 of 186). In multivariate analysis, significant predictors of mortality were inadequate initial antimicrobial therapy (odds ratio [OR] = 6.28; 95% confidence interval [CI] = 3.18 to 12.42; P < 0.001) and unidentified primary infection site (OR = 2.69; 95% CI = 1.38 to 5.27; P = 0.004). The inadequately treated patients (89 of 186 [47.8%]) had a threefold increase in mortality compared to the adequately treated group (59.5% versus 18.5%; OR = 2.38; 95% CI = 1.76 to 3.22; P < 0.001). The regimens most commonly classified as inadequate were based on oxyimino cephalosporin or fluoroquinolone therapy. Prompt initiation of effective antimicrobial treatment is essential in patients with ESBL-BSI, and empirical decisions must be based on a sound knowledge of the local distribution of pathogens and their susceptibility patterns.

Topics: Adult; Aged; Anti-Bacterial Agents; Bacteremia; beta-Lactamases; Cross Infection; Drug Resistance, Bacterial; Enterobacteriaceae; Enterobacteriaceae Infections; Escherichia coli; Female; Humans; Klebsiella pneumoniae; Male; Microbial Sensitivity Tests; Middle Aged; Predictive Value of Tests; Proteus mirabilis; Risk Factors; Survival Analysis; Treatment Outcome

A prospective observational study was conducted to identify factors associated with bloodstream infections (BSIs) caused by integron-carrying Enterobacteriaceae and to evaluate the clinical significance of integron carriage. Consecutive patients with Enterobacteriaceae BSIs were identified and followed up until discharge or death. Identification of blood isolates and susceptibility testing were performed by the Wider I automated system. int-1-specific PCR, conserved-segment PCR, and DNA sequencing were used to determine the presence, length, and content of integrons. The relatedness among the isolates was examined by pulsed-field gel electrophoresis. Two hundred fifty episodes of Enterobacteriaceae BSI occurred in 233 patients; 109 (43.6%) were nosocomial, 82 (32.8%) were community acquired, and 59 (23.6%) were health care associated. Integrons were detected in 11 (13.4%) community-acquired, 24 (40.7%) health care-associated, and 46 (42.2%) nosocomial isolates. Integron-carrying organisms were more likely to exhibit resistance to three or more classes of antimicrobials (odds ratio [OR], 9.84; 95% confidence interval [95% CI], 5.31 to 18.23; P < 0.001) or to produce extended-spectrum beta-lactamases (OR, 5.75; 95% CI, 2.38 to 13.89; P < 0.001) or a VIM-type metallo-beta-lactamase (P, 0.003). Inter- or intraspecies integron transfer and cross-transmission of integron-carrying clones were observed. Use of cotrimoxazole (OR, 4.77; 95% CI, 1.81 to 12.54; P < 0.001) and a nosocomial or other health care setting (OR, 3.07; 95% CI, 1.30 to 7.22; P, 0.01) were independently associated with BSIs caused by integron-carrying Enterobacteriaceae. Patients with a nonurinary source of bacteremia (OR, 9.46; 95% CI, 2.77 to 32.32; P < 0.001) and a Pitt bacteremia score of > or =4 (OR, 23.36; 95% CI, 7.97 to 68.44; P < 0.001) had a significantly higher 14-day mortality rate, whereas integron carriage did not affect clinical outcomes. These findings may have implications affecting antibiotic policies and infection control measures.

Topics: Bacteremia; Community-Acquired Infections; Cross Infection; DNA, Bacterial; Drug Resistance, Multiple, Bacterial; Electrophoresis, Gel, Pulsed-Field; Enterobacteriaceae Infections; Gene Transfer, Horizontal; Humans; Infectious Disease Transmission, Professional-to-Patient; Integrons; Microbial Sensitivity Tests; Nucleic Acid Amplification Techniques; Polymerase Chain Reaction; Prospective Studies; Risk Factors; Sequence Analysis, DNA; Treatment Outcome

Enterobacter cloacae is an emerging clinical pathogen that may be responsible for nosocomial infections. Management of these infections is often difficult, owing to the high frequency of strains that are resistant to disinfectants and antimicrobial agents in the clinical setting. Multidrug efflux pumps, especially those belonging to the resistance-nodulation-division family, play a major role as a mechanism of antimicrobial resistance in gram-negative pathogens. In the present study, we cloned and sequenced the genes encoding an AcrAcB-TolC-like efflux pump from an E. cloacae clinical isolate (isolate EcDC64) showing a broad antibiotic resistance profile. Sequence analysis showed that the acrR, acrA, acrB, and tolC genes encode proteins that display 79.8%, 84%, 88%, and 82% amino acid identities with the respective homologues of Enterobacter aerogenes and are arranged in a similar pattern. Deletion of the acrA gene to yield an AcrA-deficient EcDC64 mutant (EcDeltaacrA) showed the involvement of AcrAB-TolC in multidrug resistance in E. cloacae. However, experiments with an efflux pump inhibitor suggested that additional efflux systems also play a role in antibiotic resistance. Investigation of several unrelated isolates of E. cloacae by PCR analysis revealed that the AcrAB system is apparently ubiquitous in this species.

Topics: Bacterial Proteins; Base Sequence; beta-Lactamases; Carrier Proteins; Cloning, Molecular; DNA, Bacterial; Drug Resistance, Bacterial; Enterobacter cloacae; Enterobacteriaceae Infections; Genes, MDR; Genetic Vectors; Humans; Microbial Sensitivity Tests; Molecular Sequence Data; Plasmids; Porins

We report a case of pyogenic spondylitis caused by Enterobacter cloacae as a rare complication of transurethral resection of the prostate (TURP). A 79-year-old man underwent TURP. Immediate after removal of urethral catheter on postoperative day (POD) 7, he developed high fever > 40 degrees C with increased acute inflammatory reaction. Urine and blood culture detected E. cloacae and methicillin-resistant Staplylococcus aureus. He complained of lumbago since POD 9. Two-week administration of imipenem and teicoplanin resulted in resolution of fever as well as laboratory data, so intravenous antibiotics were changed to oral gatifloxacin. However, his lumbago worsened and gait disturbance appeared. On POD 39, diagnosis of pyogenic spondylitis was finally obtained by Ga-scintigraphy and magnetic resonance imaging. Aspiration of the intervertebral disk (L4-5) revealed E. cloacae as the causative organism of pyogenic spondylitis. His condition improved after conservative treatment with teicoplanin, meropenem and ciplofloxacin for 9 weeks.

Topics: Aged; Anti-Bacterial Agents; Anti-Infective Agents; Ciprofloxacin; Enterobacter cloacae; Enterobacteriaceae Infections; Humans; Male; Meropenem; Postoperative Complications; Spondylitis; Suppuration; Teicoplanin; Thienamycins; Transurethral Resection of Prostate

Among 8885 Enterobacteriaceae tested in the 1999 to 2005 period as part of the USA Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) Program, 51 strains with increased imipenem and meropenem MIC values (> or =2 microg/mL) were detected. bla(KPC) was identified from 28 Klebsiella pneumoniae from 3 medical centers in the New York City area (8 ribotypes), 2 Klebsiella oxytoca from Arkansas (same ribotype), 7 Citrobacter freundii (6 from New York [5 ribotypes] and 1 from Delaware), 4 Enterobacter spp. from New York (2 species, different ribotypes), 3 Escherichia coli (2 from New York and 1 from Ohio, same ribotype), and 1 Serratia marcescens (New York). Sequencing confirmed KPC-2 or -3 in all of the strains. S. marcescens strains harboring SME-1 (2 isolates, same ribotype) and SME-2 (1 isolate) were identified from medical centers in Illinois and Washington state, respectively. Our results indicate that bla(KPC-2/3) has emerged widely (New York City area, Arkansas, Delaware, and Ohio) among Enterobacteriaceae isolated in the MYSTIC Program participant sites (2000-2005) and continues to be isolated from multiple species, as a result of clonal expansion and horizontal gene transfer. The escalating occurrence (0.35%) of serine carbapenemases could compromise the role of carbapenems and other beta-lactams in USA clinical practice although observed in only a few locations to date.

Topics: Academic Medical Centers; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Enterobacteriaceae; Enterobacteriaceae Infections; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Population Surveillance; Serine; Species Specificity; Thienamycins; United States

Between March and July 2002, total of 612 clinical isolates of Serratia marcescens, Enterobacter cloacae, and Citrobacter freundii (201 S. marcescens, 228 E. cloacae, and 183 C. freundii) were collected from 13 clinical laboratories in a nationwide distribution. Imipenem and meropenem minimum inhibitory concentrations (MICs) were determined using the agar dilution method according to the National Committee for Clinical Laboratory Standards guidelines. For the isolates with a decreased susceptibility to carbapenems (MICs of >or=2 microg/mL), isoelectric focusing, polymerase chain reaction (PCR) amplification of the carbapenemase genes (bla(IMP-1), bla(VIM-2), bla(SME-1), bla(OXA-23), bla(OXA-25), bla(KPC-1)), and sequencing were performed. The prevalence of S. marcescens, E. cloacae, and C. freundii with a decreased susceptibility to imipenem was 17.9% (36/201), 0.4% (1/228), and 0.5% (1/183), respectively, and to meropenem, it was 11.4% (23/201), 0% (0/228), and 0.5% (1/183), respectively. The bla(VIM-2) was the only carbapenemase detected, and was found in 0.5% (1/201) of S. marcescens and 0.5% (1/183) of C. freundii isolate.

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Carbapenems; Citrobacter freundii; Drug Resistance, Bacterial; Enterobacter cloacae; Enterobacteriaceae Infections; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Prevalence; Serratia marcescens; Thienamycins

This is the second report of a Citrobacter-associated brain abscess in an adult and the first report of its association with an intradural tumor. Excluding those associated with trauma, neurosurgical procedures, and proximity to the skull base, only seven other cases of abscesses associated with intracranial tumors have been published. Five of seven tumor-associated abscesses with a microbiological diagnosis involved gram-negative bacteria, a finding that may indicate a predilection of these microorganisms for intracranial tumors.. A 78-year-old female patient presented with a 6-month history of confusion and personality changes. Her medical history included paroxysmal atrial fibrillation and a 10-day course of high-dose dexamethasone but no other predisposing conditions for sepsis. She was afebrile, had no focal neurological deficits, and had no systemic abnormalities on examination. Computed tomographic imaging revealed a noncalcified, homogeneously enhancing, 3-cm-diameter, extra-axial tumor associated with the right anterior falx cerebri. The tumor did not extend to the skull base.. At craniotomy, 10 to 20 ml of thick pus was found around the posteroinferior surface of the tumor. On extended culture, this material demonstrated Citrobacter koseri growth, which was effectively treated with ceftriaxone followed by meropenem and one repeated abscess aspiration. No systemic source of the infection was found.. The characteristic endothelial invasiveness of Citrobacter and related gram-negative bacteria may predispose to the formation of abscesses in association with intracranial tumors.

Topics: Aged; Brain Abscess; Ceftriaxone; Citrobacter koseri; Craniotomy; Enterobacteriaceae Infections; Female; Frontal Bone; Humans; Magnetic Resonance Imaging; Meningeal Neoplasms; Meningioma; Meropenem; Thienamycins

Topics: Anti-Bacterial Agents; Ascitic Fluid; Child, Preschool; Enterobacter cloacae; Enterobacteriaceae Infections; Humans; Imipenem; Infusions, Parenteral; Kidney Failure, Chronic; Male; Medication Errors; Meropenem; Myoclonus; Peritoneal Dialysis, Continuous Ambulatory; Peritonitis; Thienamycins; Tobramycin

The antimicrobial susceptibility of 103 clinical isolates of Enterobacteriaceae to 11 antibiotics, was investigated, using a conventional inoculum size (5 x 10(5) CFU) and a higher inoculum size (5 x 10(8) CFU). All the isolates produced complex beta-lactamase patterns, including an extended-spectrum beta-lactamase (ESBL) of the TEM- or SHV-type plus other enzymes (a TEM-type or an SHV-type non-ESBL and/or a class C enzyme). The following repertoire of ESBLs was produced by the isolates: TEM-15, TEM-19, TEM-26, TEM-52, TEM-72, TEM-87, TEM-92, SHV-2a, SHV-5 and SHV-12, as assessed by sequencing. Production of the other enzymes was showed by analytical isoelectric focusing. Overall, meropenem was the most active agent and less influenced by inoculum size, while other beta-lactams showed a lower activity and a significant inoculum size effect. In conclusion, from its in vitro performance, meropenem could be considered as the last resource drug against strains producing complex beta-lactamase patterns including an ESBL.

Topics: Anti-Bacterial Agents; beta-Lactam Resistance; beta-Lactamases; beta-Lactams; Colony Count, Microbial; Cross Infection; DNA, Bacterial; Enterobacteriaceae; Enterobacteriaceae Infections; Genes, Bacterial; Humans; Italy; Meropenem; Microbial Sensitivity Tests; Sequence Analysis, DNA; Thienamycins

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

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

The antibacterial activities of imipenem-cilastatin, meropenem-cilastatin, cefepime and ceftazidime against Enterobacter cloacae NOR-1, which produces the carbapenem-hydrolyzing beta-lactamase NmcA and a cephalosporinase, and against one of its in vitro-obtained ceftazidime-resistant mutant were compared by using an experimental model of pneumonia with immunocompetent rats. The MICs of the beta-lactams with an inoculum of 5 log(10) CFU/ml were as follows for E. cloacae NOR-1 and its ceftazidime-resistant mutant, respectively: imipenem, 16 and 128 microg/ml, meropenem, 4 and 32 microg/ml, cefepime, <0.03 and 1 microg/ml, and ceftazidime, 1 and 512 microg/ml. The chromosomally located cephalosporinase and carbapenem-hydrolyzing beta-lactamase NmcA were inducible by cefoxitin and meropenem in E. cloacae NOR-1, and both were stably overproduced in the ceftazidime-resistant mutant. Renal impairment was induced (uranyl nitrate, 1 mg/kg of body weight) in rats to simulate the human pharmacokinetic parameters for the beta-lactams studied. Animals were intratracheally inoculated with 8.5 log(10) CFU of E. cloacae, and therapy was initiated 3 h later. At that time, animal lungs showed bilateral pneumonia containing more than 6 log(10) CFU of E. cloacae per g of tissue. Despite the relative low MIC of meropenem for E. cloacae NOR-1, the carbapenem-treated rats had no decrease in bacterial counts in their lungs 60 h after therapy onset compared to the counts for the controls, regardless of whether E. cloacae NOR-1 or its ceftazidime-resistant mutant was inoculated. A significant decrease in bacterial titers was observed for the ceftazidime-treated rats infected with E. cloacae NOR-1 only. Cefepime was the only beta-lactam tested effective as treatment against infections due to E. cloacae NOR-1 or its ceftazidime-resistant mutant.

Topics: Animals; Anti-Bacterial Agents; Area Under Curve; beta-Lactamases; Carbapenems; Cefepime; Ceftazidime; Cephalosporins; Creatinine; Drug Resistance, Microbial; Enterobacter cloacae; Enterobacteriaceae Infections; Half-Life; Imipenem; Kidney Diseases; Male; Meropenem; Penicillinase; Pneumonia, Bacterial; Protein Binding; Rats; Rats, Wistar; Thienamycins; Uranyl Nitrate

Topics: Anti-Infective Agents; Ciprofloxacin; Drug Resistance, Microbial; Drug Utilization; Enterobacteriaceae; Enterobacteriaceae Infections; Hematology; Hospital Units; Humans; Meropenem; Neurology; Thienamycins

Topics: Brain Abscess; Child; Enterobacter cloacae; Enterobacteriaceae Infections; Humans; Male; Meropenem; Thienamycins

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

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

Meropenem, a new parenteral carbapenem, was tested in vitro by an agar-dilution method against 373 standard strains (aerobes and anaerobes) and against nine expanded-spectrum beta-lactamase-producing strains and their transconjugants (5 CTX-1, 2 CAZ-1, 2 CAZ-2). Meropenem was compared with methicillin, imipenem, piperacillin, cefoxitin, cefotaxime, ceftazidime, gentamicin, chloramphenicol, clindamycin, ciprofloxacin, vancomycin and metronidazole. Meropenem and imipenem exhibited an extended spectrum of activity, with low MICs. Only methicillin-resistant staphylococci, and Pseudomonas (Xanthomonas) maltophilia were resistant. Of the carbapenems, imipenem was more active against methicillin-susceptible staphylococci, streptococci and Enterococcus faecalis, but meropenem was markedly more active against all the Enterobacteriaceae and some pseudomonads. Both had similar activity against Ps. aeruginosa, Acinetobacter spp. and anaerobes. The carbapenem MICs were very low for Enterol acteriaceae producing the expanded-spectrum beta-lactamases. Against CTX-1-producing strains resistant to cefotaxime and ceftazidime and against CAZ-1 or CAZ-2-producers highly resistant to ceftazidime meropenem was the most active, with MICs lower (0.03-0.12 mg/l) than those of imipenem (0.06-0.5 mg/l), for wild type producers and their transconjugants.

Topics: Bacteria; Bacteria, Anaerobic; Bacterial Infections; beta-Lactamases; Carbapenems; Enterobacteriaceae; Enterobacteriaceae Infections; Gram-Positive Bacteria; Humans; Meropenem; Microbial Sensitivity Tests; Thienamycins