Shawn H. MacVane

Impact of extended‐spectrum β‐lactamase–producing organisms on clinical and economic outcomes in patients with urinary tract infection

OBJECTIVE To compare clinical and economic outcomes between patients with urinary tract infection (UTI) due to extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella species (ESBL-EK) versus patients with non-ESBL-EK UTI. PATIENTS AND METHODS Eighty-four (3.6%) of 2345 patients admitted between September 1, 2011 and August 31, 2012 with UTI were positive for ESBL-EK. Fifty-five ESBL-EK UTI (cases) and matched controls (non-ESBL-EK UTI) were included in the analysis. Clinical and economic outcomes were compared between cases and controls for statistical significance. RESULTS Cases were more likely to have diabetes mellitus, a history of recurrent UTIs, recently received antibiotics, recently been hospitalized, and had previous isolation of an ESBL-producing organism compared with controls. Failure of initial antibiotic regimen (62% vs 6%; P < 0.001) and time to appropriate antibiotic therapy (51 vs 2.5 hours; P < 0.001) were greater in cases. The median cost of care was greater (additional

Clinical Pharmacodynamics of Antipseudomonal Cephalosporins in Patients with Ventilator-Associated Pneumonia

3658; P = 0.02) and the median length of stay (LOS) prolonged for cases (6 vs 4 days; P = 0.02) despite similar hospital reimbursement (additional

Prolonging β-lactam infusion: A review of the rationale and evidence, and guidance for implementation

469; P = 0.56). Although not significant, infection-related mortality (7.2% vs 1.8%) and 30-day UTI readmission (7.2% vs 3.6%) were higher in ESBL-EK cases. CONCLUSIONS UTI caused by ESBL-EK is associated with significant clinical and economic burden. The cost of care and LOS of patients with ESBL-EK UTI were 1.5 times those caused by non-ESBL-EK. Importantly, the additional cost of care is a liability to the hospital, as this is not offset by reimbursement. Appropriate and timely initial antibiotics may minimize the ESBL-EK impact on outcomes of patients with UTI.OBJECTIVE To compare clinical and economic outcomes between patients with urinary tract infection (UTI) due to extended-spectrum β-lactamase–producing Escherichia coli and Klebsiella species (ESBL-EK) versus patients with non-ESBL-EK UTI. PATIENTS AND METHODS Eighty-four (3.6%) of 2345 patients admitted between September 1, 2011 and August 31, 2012 with UTI were positive for ESBL-EK. Fifty-five ESBL-EK UTI (cases) and matched controls (non–ESBL-EK UTI) were included in the analysis. Clinical and economic outcomes were compared between cases and controls for statistical significance. RESULTS Cases were more likely to have diabetes mellitus, a history of recurrent UTIs, recently received antibiotics, recently been hospitalized, and had previous isolation of an ESBL-producing organism compared with controls. Failure of initial antibiotic regimen (62% vs 6%; P < 0.001) and time to appropriate antibiotic therapy (51 vs 2.5 hours; P < 0.001) were greater in cases. The median cost of care was greater (additional

Discovery of Dap-3 Polymyxin Analogues for the Treatment of Multidrug-Resistant Gram-Negative Nosocomial Infections

3658; P = 0.02) and the median length of stay (LOS) prolonged for cases (6 vs 4 days; P = 0.02) despite similar hospital reimbursement (additional

In Vivo Efficacy of Humanized Exposures of Ceftazidime-Avibactam in Comparison with Ceftazidime against Contemporary Enterobacteriaceae Isolates

469; P = 0.56). Although not significant, infection-related mortality (7.2% vs 1.8%) and 30-day UTI readmission (7.2% vs 3.6%) were higher in ESBL-EK cases. CONCLUSIONS UTI caused by ESBL-EK is associated with significant clinical and economic burden. The cost of care and LOS of patients with ESBL-EK UTI were 1.5 times those caused by non–ESBL-EK. Importantly, the additional cost of care is a liability to the hospital, as this is not offset by reimbursement. Appropriate and timely initial antibiotics may minimize the ESBL-EK impact on outcomes of patients with UTI. Journal of Hospital Medicine 2014;9:232–238.

Unexpected In Vivo Activity of Ceftazidime Alone and in Combination with Avibactam against New Delhi Metallo-β-Lactamase producing Enterobacteriaceae in a Murine Thigh Infection Model

ABSTRACT Advanced-generation cephalosporins are frequently used for empirical coverage of ventilator-associated pneumonia (VAP) due to their activity against a broad spectrum of Gram-positive and Gram-negative aerobic bacteria, including Pseudomonas aeruginosa and Enterobacteriaceae. Providing optimal antibiotic exposure is essential to achieving successful response in patients with VAP. We evaluated exposures of two antipseudomonal cephalosporins, ceftazidime and cefepime, in patients with VAP due to Gram-negative bacilli to identify the pharmacodynamic parameter predictive of microbiological success. Population pharmacokinetic models were used to estimate individual free drug exposures. Pharmacodynamic indices were determined for each patient using the baseline Gram-negative bacilli with the highest drug MIC. Classification and regression tree analysis was utilized to partition exposure breakpoints, and multivariate logistic regression was conducted to identify predictors of microbiological success. A total of 73 patients (18 receiving ceftazidime therapy and 55 receiving cefepime therapy) were included. MICs ranged widely from 0.047 to 96 μg/ml. The microbiological success rate was 58.9%. Predictive breakpoints were identified for all pharmacodynamic parameters, including a serum fT > MIC greater than 53% (P = 0.02). When controlling for APACHE II (odds ratio [OR], 1.01; 95% confidence interval, 0.93 to 1.09; P = 0.85) and combination therapy (OR, 0.74; 95% confidence interval, 0.25 to 2.19; P = 0.59), achieving a greater than 53% fT > MIC remained a significant predictor of success (OR, 10.3; 95% confidence interval, 1.1 to 92.3; P = 0.04). In patients with VAP due to Gram-negative bacilli, serum exposure of greater than 53% fT > MIC was found to be a significant predictor of favorable microbiological response for antipseudomonal cephalosporins. These data are useful when determining dosing regimens for cephalosporin agents under development for pneumonia.

Clinical laboratory-based assay methodologies may underestimate and increase variability of vancomycin protein binding in hospitalized patients.

Given the sparse antibiotic pipeline and the increasing prevalence of resistant organisms, efforts should be made to optimise the pharmacodynamic exposure of currently available agents. Prolonging the infusion duration is a strategy used to increase the percentage of the dosing interval that free drug concentrations remain above the minimum inhibitory concentration (fT>MIC), the pharmacodynamic efficacy driver for time-dependent antibiotics such as β-lactams. β-Lactams, the most commonly prescribed class of antibiotics owing to their efficacy and safety profile, have been the mainstay of therapy since the discovery of penicillin over 60 years ago. Mounting evidence, including the use of population pharmacokinetic modelling and Monte Carlo simulation, suggests that prolonging the infusion time of β-lactam antibiotics may have advantages over standard infusion techniques, including an enhanced probability of achieving requisite fT>MIC exposures, lower mortality and potentially reductions in infection/antibiotic-related costs. As a result of these favourable attributes, clinical practice guidelines support the use of prolonged-infusion β-lactams in the treatment of many severe infections. This article discusses the rationale and evidence for prolonging the infusion of β-lactam antibiotics and provides guidance for the implementation of a prolonged-infusion programme.

Impact of Loading Doses on the Time to Adequate Predicted Beta-Lactam Concentrations in Prolonged and Continuous Infusion Dosing Schemes

We report novel polymyxin analogues with improved antibacterial in vitro potency against polymyxin resistant recent clinical isolates of Acinetobacter baumannii and Pseudomonas aeruginosa . In addition, a human renal cell in vitro assay (hRPTEC) was used to inform structure-toxicity relationships and further differentiate analogues. Replacement of the Dab-3 residue with a Dap-3 in combination with a relatively polar 6-oxo-1-phenyl-1,6-dihydropyridine-3-carbonyl side chain as a fatty acyl replacement yielded analogue 5x, which demonstrated an improved in vitro antimicrobial and renal cytotoxicity profiles relative to polymyxin B (PMB). However, in vivo PK/PD comparison of 5x and PMB in a murine neutropenic thigh model against P. aeruginosa strains with matched MICs showed that 5x was inferior to PMB in vivo, suggesting a lack of improved therapeutic index in spite of apparent in vitro advantages.

Demography and burden of care associated with patients readmitted for urinary tract infection

ABSTRACT Ceftazidime-avibactam is a β-lactam β-lactamase inhibitor combination under investigation for the treatment of serious Gram-negative infections. When combined with avibactam, a novel non-β-lactam β-lactamase inhibitor, ceftazidime has activity against isolates that produce Ambler class A, class C, and some class D β-lactamases. However, little is known of the in vivo efficacy of the combination against these targeted ceftazidime- and carbapenem-resistant Enterobacteriaceae. Using humanized exposures in the murine thigh model, we evaluated the efficacy of ceftazidime-avibactam against Enterobacteriaceae exhibiting MICs of ≥8 μg/ml to aid in the assignment of interpretive susceptibility criteria. Eighteen clinical Enterobacteriaceae isolates, including nine carbapenem-resistant strains, were evaluated against ceftazidime-avibactam (2,000 mg/500 mg) as a 2-h infusion every 8 h. To highlight the impact of avibactam, 13 select isolates were tested in the neutropenic model against a humanized regimen of 2,000 mg ceftazidime every 8 h (2-h infusion). Additionally, nine isolates were evaluated in immunocompetent animals. The efficacy was evaluated as the change in log10 CFU compared with that of 0-h controls after 24 h. The vast majority (17/18, 94%) of the isolates were resistant to ceftazidime alone. The ceftazidime monotherapy failed to have activity against 10 of 13 isolates, while ceftazidime-avibactam produced reductions in bacterial density against 16 of 18 isolates. Ceftazidime-avibactam (2,000 mg/500 mg) every 8 h (2-h infusion) displayed dependable activity against the Enterobacteriaceae isolates, exhibiting MICs of ≤16 μg/ml (free drug concentration above the MIC [fT>MIC] of ≥62%) and variable activity was noted at an MIC of 32 μg/ml (fT>MIC of 34%). The presence of a functioning immune system enhanced the efficacy for both regimens against all tested isolates. These data support further examination of the use of ceftazidime-avibactam as an effective therapy against infections due to Gram-negative infections, including carbapenem-resistant Enterobacteriaceae.

In Vitro Activity of Human-Simulated Epithelial Lining Fluid Exposures of Ceftaroline, Ceftriaxone, and Vancomycin against Methicillin-Susceptible and -Resistant Staphylococcus aureus

ABSTRACT The emergence of the New Delhi metallo-β-lactamase (NDM) among Enterobacteriaceae has become a global concern because of its high levels of in vitro resistance to nearly all available antibiotics. However, recent in vivo studies demonstrated the efficacies of carbapenems against NDM-1-producing isolates despite high MICs. Herein, we report in vivo findings with ceftazidime and ceftazidime-avibactam against an isogenic pair (wild type and NDM-1) and four clinical NDM-producing isolates that demonstrate discordance between MICs measured in vitro and the in vivo activity of ceftazidime-avibactam against this resistant genotype.