Elizabeth B. Hirsch

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.

Impact of multidrug-resistant Pseudomonas aeruginosa infection on patient outcomes

Rates of antibiotic resistance in Pseudomonas aeruginosa are increasing worldwide. The multidrug-resistant (MDR) phenotype in P. aeruginosa could be mediated by several mechanisms including multidrug efflux systems, enzyme production, outer membrane protein (porin) loss and target mutations. Currently, no international consensus on the definition of multidrug resistance exists, making direct comparison of the literature difficult. Inappropriate empirical therapy has been associated with increased mortality in P. aeruginosa infections; delays in starting appropriate therapy may contribute to increased length of hospital stay and persistence of infection. In addition, worse clinical outcomes may be associated with MDR infections owing to limited effective antimicrobial options. This article aims to summarize the contemporary literature on patient outcomes following infections caused by drug-resistant P. aeruginosa. The impact of antimicrobial therapy on patient outcomes, mortality and morbidity; and the economic impact of MDR P. aeruginosa infections will be examined.

In Vitro Activity of MK-7655, a Novel β-Lactamase Inhibitor, in Combination with Imipenem against Carbapenem-Resistant Gram-Negative Bacteria

ABSTRACT Carbapenem-resistant bacteria represent a significant treatment challenge due to the lack of active antimicrobials available. MK-7655 is a novel β-lactamase inhibitor under clinical development. We investigated the combined killing activity of imipenem and MK-7655 against four imipenem-resistant bacterial strains, using a mathematical model previously evaluated in our laboratory. Time-kill studies (TKS) were conducted with imipenem and MK-7655 against a KPC-2-producing Klebsiella pneumoniae isolate (KP6339) as well as 3 Pseudomonas aeruginosa isolates (PA24226, PA24227, and PA24228) with OprD porin deletions and overexpression of AmpC. TKS were performed using 25 clinically achievable concentration combinations in a 5-by-5 array. Bacterial burden at 24 h was determined in triplicate by quantitative culture and mathematically modeled using a three-dimensional response surface. Mathematical model assessments were evaluated experimentally using clinically relevant dosing regimens of imipenem, with or without MK-7655, in a hollow-fiber infection model (HFIM). The combination of imipenem and MK-7655 was synergistic for all strains. Interaction indices were as follows: for KP6339, 0.50 (95% confidence interval [CI], 0.42 to 0.58); for PA24226, 0.60 (95% CI, 0.58 to 0.62); for PA24227, 0.70 (95% CI, 0.66 to 0.74); and for PA24228, 0.55 (95% CI, 0.49 to 0.61). In the HFIM, imipenem plus MK-7655 considerably reduced the bacterial burden at 24 h, while failure with imipenem alone was seen against all isolates. Sustained suppression of bacterial growth at 72 h was achieved with simulated doses of 500 mg imipenem plus 500 mg MK-7655 in 2 (KP6339 and PA24227) strains, and it was achieved in an additional strain (PA24228) when the imipenem dose was increased to 1,000 mg. Additional studies are being conducted to determine the optimal dose and combinations to be used in clinical investigations.

Ceftolozane/tazobactam and ceftazidime/avibactam: Two novel β-lactam/β-lactamase inhibitor combination agents for the treatment of resistant Gram-negative bacterial infections

The rise in resistant Gram-negative bacteria is a major concern and has led to difficulty in treating multidrug-resistant (MDR) infections. Two recently approved combination antibiotics, ceftolozane/tazobactam and ceftazidime/avibactam, may be effective in treating these resistant infections. Ceftolozane is a novel cephalosporin that has been developed in combination with tazobactam, a recognised β-lactamase inhibitor (BLI). Avibactam is a novel BLI combined with ceftazidime, a cephalosporin with an established history. Both of these β-lactam/BLI combination agents have been shown to retain in vitro activity against selected resistant Gram-negative pathogens, including Enterobacteriaceae and Pseudomonas aeruginosa; notably, ceftazidime/avibactam has demonstrated consistent activity against Klebsiella pneumoniae carbapenemase (KPC)-producing organisms. Both agents have been approved for the indications of complicated intra-abdominal infection (with metronidazole) and complicated urinary tract infection, and have ongoing phase 3 trials for the treatment of ventilator-associated and nosocomial pneumonia. This manuscript will review current data available regarding the spectrum of activity and clinical trials that led to the US Food and Drug Administration (FDA) approval of these agents. Both agents appear to be well tolerated and show promise in the treatment of MDR Gram-negative infections.

Assessment of Antimicrobial Combinations for Klebsiella pneumoniae Carbapenemase–Producing K. pneumoniae

BACKGROUND The prevalence of bla(KPC) among gram-negative bacteria continues to increase worldwide. Limited treatment options exist for this multidrug-resistant phenotype, often necessitating combination therapy. We investigated the in vitro and in vivo efficacy of multiple antimicrobial combinations. METHODS Two clinical strains of Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae were studied. The killing activities of six 2-agent combinations of amikacin, doripenem, levofloxacin, and rifampin were quantitatively assessed using a validated mathematical model. Combination time-kill studies were conducted using clinically relevant concentrations; observed bacterial burdens were modeled using 3-dimensional response surfaces. Selected combinations were further validated in a neutropenic murine pneumonia model, using human-like dosing exposures. RESULTS The most enhanced killing effect in time-kill studies was seen with amikacin plus doripenem. Compared with placebo controls, this combination resulted in significant reduction of the bacterial burden in tissue at 24 hours, along with prolonged animal survival. In contrast, amikacin plus levofloxacin was found to be antagonistic in time-kill studies, showing inferior animal survival, as predicted. CONCLUSIONS Our modeling approach appeared to be robust in assessing the effectiveness of various combinations for KPC-producing isolates. Amikacin plus doripenem was the most effective combination in both in vitro and in vivo infection models. Empirical selection of combinations against KPCs may result in antagonism and should be avoided.

Novel Modeling Framework To Guide Design of Optimal Dosing Strategies for β-Lactamase Inhibitors

ABSTRACT The scarcity of new antibiotics against drug-resistant bacteria has led to the development of inhibitors targeting specific resistance mechanisms, which aim to restore the effectiveness of existing agents. However, there are few guidelines for the optimal dosing of inhibitors. Extending the utility of mathematical modeling, which has been used as a decision support tool for antibiotic dosing regimen design, we developed a novel mathematical modeling framework to guide optimal dosing strategies for a beta-lactamase inhibitor. To illustrate our approach, MK-7655 was used in combination with imipenem against a clinical isolate of Klebsiella pneumoniae known to produce KPC-2. A theoretical concept capturing fluctuating susceptibility over time was used to define a novel pharmacodynamic index (time above instantaneous MIC [T>MICi]). The MK-7655 concentration-dependent MIC reduction was characterized by using a modified sigmoid maximum effect (Emax)-type model. Various dosing regimens of MK-7655 were simulated to achieve escalating T>MICi values in the presence of a clinical dose of imipenem (500 mg every 6 h). The effectiveness of these dosing exposures was subsequently validated by using a hollow-fiber infection model (HFIM). An apparent trend in the bacterial response was observed in the HFIM with increasing T>MICi values. In addition, different dosing regimens of MK-7655 achieving a similar T>MICi (69%) resulted in comparable bacterial killing over 48 h. The proposed framework was reasonable in predicting the in vitro activity of a novel beta-lactamase inhibitor, and its utility warrants further investigations.

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.

Clinical Management of an Increasing Threat: Outpatient Urinary Tract Infections Due to Multidrug-Resistant Uropathogens

Urinary tract infections (UTIs) are among the most commonly treated bacterial infections. Over the past decade, antimicrobial resistance has become an increasingly common factor in the management of outpatient UTIs. As treatment options for multidrug-resistant (MDR) uropathogens are limited, clinicians need to be aware of specific clinical and epidemiological risk factors for these infections. Based on available literature, the activity of fosfomycin and nitrofurantoin remain high for most cases of MDR Escherichia coli UTIs. Trimethoprim-sulfamethoxazole retains clinical efficacy, but resistance rates are increasing internationally. Beta-lactam agents have the highest rates of resistance and lowest rates of clinical success. Fluoroquinolones have high resistance rates among MDR uropathogens and are being strongly discouraged as first-line agents for UTIs. In addition to accounting for local resistance rates, consideration of patient risk factors for resistance and pharmacological principles will help guide optimal empiric treatment of outpatient UTIs.

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.

Clinically relevant concentrations of fosfomycin combined with polymyxin B, tobramycin or ciprofloxacin enhance bacterial killing of Pseudomonas aeruginosa, but do not suppress the emergence of fosfomycin resistance

OBJECTIVES Fosfomycin resistance occurs rapidly with monotherapy. This study systematically investigated bacterial killing and emergence of fosfomycin resistance with fosfomycin combinations against Pseudomonas aeruginosa. METHODS Four clinical isolates and a reference strain of P. aeruginosa were employed. Combinations of fosfomycin plus polymyxin B, tobramycin or ciprofloxacin were examined over 24 h using time-kill studies (inocula ∼10(6) cfu/mL) incorporating clinically relevant concentrations (fosfomycin, 30, 150 or 300 mg/L; polymyxin B, 0.5, 1 or 2 mg/L; tobramycin, 0.5, 1.5 or 4 mg/L; ciprofloxacin, 0.5, 1 or 2.5 mg/L). Microbiological response was examined by log changes and population analysis profiles. RESULTS Against susceptible isolates, monotherapy produced varying degrees of initial killing followed by rapid regrowth. Fosfomycin plus polymyxin B or tobramycin produced greater initial killing (up to ∼4 log10 cfu/mL) with many concentrations compared with monotherapy against fosfomycin-susceptible (FOF(S)) isolates. With these combinations, synergy or additivity was observed in 54 (67%) and 49 (60%) of 81 cases (nine combinations across three isolates at three timepoints) for polymyxin B and tobramycin, respectively. Substantial improvements in killing were absent against fosfomycin-resistant (FOF(R)) isolates. For fosfomycin/ciprofloxacin combinations, synergy or additivity was observed against FOF(R) isolates in 33 of 54 (61%) cases (nine combinations across two isolates at three timepoints), while improvements in killing were largely absent against FOF(S) isolates. No combination prevented emergence of fosfomycin resistance. CONCLUSIONS Against P. aeruginosa, fosfomycin in combination with polymyxin B or tobramycin (FOF(S) isolates) or ciprofloxacin (FOF(R) isolates) increased bacterial killing, but did not suppress emergence of fosfomycin resistance.