Assessment of mortality stratified by meropenem minimum inhibitory concentration in patients with Enterobacteriaceae bacteraemia: A patient-level analysis of published data.

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.

Activity of minocycline against Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae clinical isolates, with comparison to doxycycline and tigecycline.

We examined the in vitro activity of minocycline against 103 Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae isolates and found approximately half had susceptible (26%) or intermediate (26%) MICs. For a subset of 35 isolates, susceptibility was highest to tigecycline (71% FDA vs. 20% EUCAST) followed by minocycline (14%) and then doxycycline (6%).

Activity of fosfomycin and comparison of several susceptibility testing methods against contemporary urine isolates.

Fosfomycin is recommended as first-line treatment for acute uncomplicated cystitis in women. It has demonstrated in vitro activity against a variety of pathogens; however, a paucity of data are available from the USA. We determined the susceptibility of a collection of urine isolates to fosfomycin and compared multiple methods of susceptibility testing. Consecutive non-duplicate Enterobacteriaceae, enterococci and Pseudomonas aeruginosa isolates were collected from the clinical microbiology laboratory between August 2013 and January 2014. Isolates represented hospitalised or emergency department patients with monomicrobial bacteriuria. Fosfomycin MICs were determined in duplicate, on separate days, by Etest and disk diffusion and results were compared with agar dilution. Nitrofurantoin and ciprofloxacin were used as comparators. MIC results were categorised using Clinical and Laboratory Standards Institute interpretive criteria for Escherichia coli and Enterococcus faecalis. Correlation between the three testing methods was evaluated. Overall susceptibility to fosfomycin was 94.4%, 93.5% and 87.9% by agar dilution, disk diffusion and Etest, respectively. Five fosfomycin-resistant isolates were identified, including two Morganella morganii, one P. aeruginosa, one Proteus mirabilis and one Enterobacter aerogenes. Across all organisms, rates of essential agreement, categorical agreement, minor errors, major errors and very major errors for Etest/disk diffusion compared with agar dilution were 77.3%/NA, 89.5/93.8%, 7.1/5.0%, 3.6/1.3% and 0/0%, respectively. Fosfomycin displayed fairly consistent activity against a majority of isolates collected when using the susceptibility breakpoint of 64 µg/mL. MICs for E. coli were particularly low (≤2 µg/mL). These data lend support to current guidelines that recommend fosfomycin as empirical first-line therapy for uncomplicated UTI.

Cefepime free minimum concentration to minimum inhibitory concentration (fCmin/MIC) ratio predicts clinical failure in patients with Gram-negative bacterial pneumonia.

Cefepime is an antibiotic commonly used in nosocomial infections. The objective of this study was to elucidate the relationship between cefepime exposure and clinical outcome in patients with Gram-negative bacterial pneumonia. A previously published population pharmacokinetic model of cefepime was validated in 12 adult patients with normal renal function by measuring plasma concentrations at steady-state. Additionally, clinical outcomes for 33 patients with Gram-negative bacterial pneumonia who received cefepime monotherapy were determined. The free minimum concentration (fCmin) to MIC ratio for each patient was determined by conditioning the validated pharmacokinetic model using patient-specific creatinine clearance (CLCr), dosing regimen and cefepime MIC of the organism isolated, and was subsequently correlated with clinical failure. Classification and regression tree (CART) analysis was used to determine the most significant drug exposure breakpoint. Mean±S.D. CLCr and cefepime Cmin in the 12 patients were 87.5±21.2mL/min and 6.2±3.8mg/L, respectively. In comparison, the Cmin predicted by the pharmacokinetic model was 5.8mg/L using a CLCr of 90mL/min. MICs of organisms ranged from 0.5mg/L to 8mg/L. Percent time free drug above MIC of 100% was achieved in 32/33 patients, but 12 patients experienced clinical failure. CART analysis determined patients with an fCmin/MIC≥2.1 had a significantly lower risk of clinical failure (OR=0.11, 95% CI 0.02-0.67; P=0.017). The fCmin/MIC ratio is a useful predictor of clinical failure in Gram-negative bacterial pneumonia. The clinical utility of fCmin/MIC in therapeutic drug monitoring should be further explored.

Detection and treatment options for Klebsiella pneumoniae carbapenemases (KPCs): an emerging cause of multidrug-resistant infection.

Bacteria producing Klebsiella pneumoniae carbapenemases (KPCs) are rapidly emerging as a cause of multidrug-resistant infections worldwide. Bacterial isolates harbouring these enzymes are capable of hydrolysing a broad spectrum of beta-lactams including the penicillins, cephalosporins, carbapenems and monobactam. Detection of isolates harbouring carbapenemases can be inconsistent using automated systems, often requiring subsequent confirmatory tests. Phenotypic methods utilizing boronic acid disc tests have demonstrated promising results and appear practical for use in clinical microbiology laboratories. Treatment of infection caused by KPC bacteria is particularly worrisome as the carbapenems are often agents of the last resort for resistant Gram-negative infections. The optimal treatment of infections caused by KPC bacteria is not well established and clinical outcome data remain sparse. We reviewed the current literature regarding clinical outcomes following KPC infections, with a specific effort to summarize the clinical data available for specific antimicrobial agents. A total of 15 papers involving 55 unique patient cases were reviewed. While the total number of patients is relatively small, some useful insights could still be gathered to guide clinicians in the management of KPC infections. Tigecycline and the aminoglycosides were associated with positive outcomes in the majority of cases. Clinical success rates were low when the polymyxins were used as monotherapy, but were much higher when they were used in combination. Studies examining combination therapy and well-controlled clinical trials are needed to ascertain the optimal treatment of infections caused by KPC bacteria.