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Potency of parenteral antimicrobials including ceftolozane/tazobactam against nosocomial respiratory tract pathogens: considerations for empiric and directed therapy.

ABSTRACT: Empiric therapy decisions are predicated on knowledge of both the epidemiology and antimicrobial susceptibility of the probable infecting pathogen(s). The objective of this study was to evaluate the microbial distribution and phenotypic profiles of nosocomial respiratory isolates collected from multiple US hospitals and assess the clinical utility of various monotherapy and combination regimens.Hospitals provided consecutive non-duplicate adult inpatients Gram-negative nosocomial respiratory isolates from cultures received ?48 h after hospital admission. Minimum inhibitory concentrations (MICs) for 12 antimicrobials were determined using broth microdilution methods. An antibiogram was constructed for monotherapy regimens as well as combinations inclusive of either tobramycin (TOB) or ciprofloxacin (CIP).Six hospitals provided 518 nosocomial respiratory isolates. P. aeruginosa (PSA) comprised 28% of the population followed by Klebsiella pneumoniae (13%), Enterobacter spp. (13%), S. maltophilia (9%), S. marcesens (6%), A. baumannii (6%), and others (18%). When considering monotherapy for the Enterobacteriaceae & PSA ceftolozane/tazobactam (C/T) provided the highest (87%) percent susceptibility (%S) followed by meropenem (MEM), CIP, cefepime (FEP), ceftazidime (CAZ) and piperacillin-tazobactam (TZP) at 71-85%S. The addition of TOB > CIP improved the probability that the antimicrobial combination would provide ?1 active agent.PSA was the predominant nosocomial respiratory pathogen; however, the Enterobacteriaceae comprised an additional 53% in this survey. When considering empiric ?-lactam monotherapy therapy for the entire spectrum of pathogens C/T provided the highest (78%) %S followed by MEM, FEP and TZP. The addition of either TOB > CIP to these ?-lactams enhances the likelihood that an active agent would be selected when considering empirical therapy choices for nosocomial respiratory tract infections.

SUBMITTER: Sutherland CA

PROVIDER: S-EPMC5303068 | biostudies-other | 2017 Jan

REPOSITORIES: biostudies-other

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Potency of parenteral antimicrobials including ceftolozane/tazobactam against nosocomial respiratory tract pathogens: considerations for empiric and directed therapy.

Sutherland Christina A CA Nicolau David P DP

Journal of thoracic disease 20170101 1

<h4>Background</h4>Empiric therapy decisions are predicated on knowledge of both the epidemiology and antimicrobial susceptibility of the probable infecting pathogen(s). The objective of this study was to evaluate the microbial distribution and phenotypic profiles of nosocomial respiratory isolates collected from multiple US hospitals and assess the clinical utility of various monotherapy and combination regimens.<h4>Methods</h4>Hospitals provided consecutive non-duplicate adult inpatients Gram- ...[more]

PMID: 28203427

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Project description:The rising frequency of multidrug-resistant and extensively drug-resistant (MDR/XDR) pathogens is making more frequent the inappropriate empirical antimicrobial therapy (IEAT) in nosocomial pneumonia, which is associated with increased mortality. We aim to determine the short-term benefits of appropriate empirical antimicrobial treatment (AEAT) with ceftolozane/tazobactam (C/T) compared with IEAT with piperacillin/tazobactam (TZP) in MDR Pseudomonas aeruginosa pneumonia. Twenty-one pigs with pneumonia caused by an XDR P. aeruginosa strain (susceptible to C/T but resistant to TZP) were ventilated for up to 72 h. Twenty-four hours after bacterial challenge, animals were randomized to receive 2-day treatment with either intravenous saline (untreated) or 25 to 50 mg of C/T per kg body weight (AEAT) or 200 to 225 mg of TZP per kg (IEAT) every 8 h. The primary outcome was the P. aeruginosa burden in lung tissue and the histopathology injury. P. aeruginosa burden in tracheal secretions and bronchoalveolar lavage (BAL) fluid, the development of antibiotic resistance, and inflammatory markers were secondary outcomes. Overall, P. aeruginosa lung burden was 5.30 (range, 4.00 to 6.30), 4.04 (3.64 to 4.51), and 4.04 (3.05 to 4.88) log10CFU/g in the untreated, AEAT, and IEAT groups, respectively (P = 0.299), without histopathological differences (P = 0.556). In contrast, in tracheal secretions (P < 0.001) and BAL fluid (P = 0.002), bactericidal efficacy was higher in the AEAT group. An increased MIC to TZP was found in 3 animals, while resistance to C/T did not develop. Interleukin-1β (IL-1β) was significantly downregulated by AEAT in comparison to other groups (P = 0.031). In a mechanically ventilated swine model of XDR P. aeruginosa pneumonia, appropriate initial treatment with C/T decreased respiratory secretions' bacterial burden, prevented development of resistance, achieved the pharmacodynamic target, and may have reduced systemic inflammation. However, after only 2 days of treatment, P. aeruginosa tissue concentrations were moderately affected.

Project description:INTRODUCTION:Hospital-acquired and ventilator-associated bacterial pneumonia (HABP and VABP) are associated with significant healthcare resource utilization (HCRU). This a priori, exploratory, secondary analysis from the ASPECT-NP clinical trial evaluated resource utilization among patients with ventilated HABP (vHABP)/VABP treated with ceftolozane/tazobactam or meropenem. METHODS:This analysis used data from the randomized, double-blind, noninferiority phase 3 ASPECT-NP trial of patients with vHABP/VABP randomized to receive ceftolozane/tazobactam 3 g (ceftolozane 2 g/tazobactam 1 g) or meropenem 1 g for 8-14 days. Day 28 outcomes included hospital length of stay (LOS), intensive care unit (ICU) LOS, and time to mechanical ventilation extubation in the microbiological intention-to-treat (mITT) population and in an HCRU population. The HCRU population, a subset of patients from the mITT population that were alive at day 28, was used to remove resource use bias influenced by mortality rates. RESULTS:Ceftolozane/tazobactam-treated versus meropenem-treated patients, respectively, had fewer deaths (20.1% vs. 25.5%), fewer hospital discharges (30.7% vs. 32.4%), and higher ICU discharges (60.0% vs. 58.3%) and extubations (51.9% vs. 48.2%) by day 28. In the HCRU population, adjusted LOS differences (95% confidence intervals) for ceftolozane/tazobactam compared with meropenem were 0.1 (-?1.4 to 1.6) hospitalization days, -?1.4 (-?2.9 to 0.2) ICU days, and -?0.9 (-?2.4 to 0.7) mechanical ventilation days. Patterns were similar among the VABP and Pseudomonas aeruginosa subgroups. CONCLUSION:Similar 28-day resource utilization outcomes were observed between ceftolozane/tazobactam and meropenem in the mITT population of patients from ASPECT-NP with vHABP/VABP due to gram-negative pathogens. ASPECT-NP was not powered to detect differences in resource utilization outcomes between treatment groups; however, numerical differences in ICU LOS and duration of mechanical ventilation were noted. Further study is needed to assess resource utilization in the real-world practice setting, especially among patients excluded from ASPECT-NP, including those with resistant P. aeruginosa infections. TRIAL REGISTRATIONS:ClinicalTrials.gov: NCT02070757, registered February 25, 2014; EudraCT: 2012-002862-11.

Project description:Guidelines for the treatment of sepsis, febrile neutropenia, and hospital-acquired pneumonia caused by Pseudomonas aeruginosa include empirical regimens incorporating two antibiotics from different classes with activity against P. aeruginosa for select at-risk patients to increase the likelihood that the organism will be susceptible to at least one agent. The activity against P. aeruginosa and the rates of cross-resistance of ceftolozane-tazobactam were compared to those of the ?-lactam comparators cefepime, ceftazidime, piperacillin-tazobactam, and meropenem alone and cumulatively with ciprofloxacin or tobramycin. Nonurine P. aeruginosa isolates were collected from adult inpatients at 44 geographically diverse U.S. hospitals. MICs were determined using reference broth microdilution methods. Of the 1,257 isolates collected, 29% were from patients in intensive care units and 39% were from respiratory sites. The overall rate of susceptibility to ceftolozane-tazobactam was high at 97%, whereas it was 72 to 76% for cefepime, ceftazidime, piperacillin-tazobactam, and meropenem. The rate of nonsusceptibility to all four comparator ?-lactams was 11%; of the isolates nonsusceptible to the four comparator ?-lactams, 80% remained susceptible to ceftolozane-tazobactam. Among the isolates nonsusceptible to the tested ?-lactam comparators, less than half were susceptible to ciprofloxacin. By comparison, approximately 80% of the ?-lactam-nonsusceptible isolates were susceptible to tobramycin, for overall cumulative susceptibility rates of 94 to 95%, nearly 10% higher than that of the ciprofloxacin-?-lactam combinations and approaching that of ceftolozane-tazobactam as a single agent. The rates of susceptibility to ceftolozane-tazobactam were consistently high, with little observable cross-resistance. Ceftolozane-tazobactam monotherapy performed at or above the level of commonly utilized combination therapies on the basis of in vitro susceptibilities. Ceftolozane-tazobactam should be considered for use in patients at high risk for resistant P. aeruginosa infection and as an alternative to empirical combination therapy, especially for patients unable to tolerate aminoglycosides.

Dataset Information

Potency of parenteral antimicrobials including ceftolozane/tazobactam against nosocomial respiratory tract pathogens: considerations for empiric and directed therapy.

Publications

Potency of parenteral antimicrobials including ceftolozane/tazobactam against nosocomial respiratory tract pathogens: considerations for empiric and directed therapy.

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