β-Lactamase Characterization of Baseline Enterobacteriaceae (ENT) From a Phase 3 Trial of Ceftazidime-Avibactam (CAZ-AVI) for the Treatment of Infections Caused by CAZ-Nonsusceptible (NS) Pathogens

Carbapenem sparing regimens are needed for the treatment of ESBL/AmpC producing Enterobacterales infections. We sought to compare the clinical efficacy of ceftazidime/avibactam and carbapenems against ESBL/AmpC producing Enterobacterales spp. A systematic review and meta-analysis of randomized controlled trials comparing ceftazidime/avibactam with carbapenems for the treatment of ESBL/AmpC producing Enterobacterales was conducted. Five RCTs with ESBLs/AmpC specific outcome data were compiled. Of the 246 patients infected with an ESBL producing microorganism in the ceftazidime/avibactam arm, 224 (91%) had a clinical response at TOC versus 240 of 271 (89%) patients in the carbapenem arm (RR 1.02, 95% CI 0.97–1.08, P=0.45, I2=0%). Clinical response for AmpC producers in the ceftazidime/avibactam and carbapenem arms were 32/40 (80%) and 37/42 (88%), respectively (RR 0.91, 95% CI 0.76–1.10, P=0.35, I2=0%). Microbiological response and mortality rates were not reported specifically for ESBL/AmpC producers. Ceftazidime/avibactam may be a carbapenem-sparing option for the treatment of mild to moderate complicated urinary tract and intraabdominal infections caused by ESBL producing Enterobacterales spp. and the data are limited to provide any conclusive recommendations for the AmpC producers. Care should be taken before extrapolating this to severe infections, given that the representation of this population in the reviewed studies was negligible. Ceftazidime/avibactam is a costly drug active against carbapenem resistant microorganisms, and should be used judiciously to preserve its activity against these.

Section: Resultsmentioning

confidence: 99%

“…(6%). CTX-M-15 plus OXA-1 with or without other ESBLs was the most common ␤-lactamase phenotype (46%), followed by other CTX-M types with or without other ESBLs (26%) and CTX-M-15 alone (11%) (19)(20)(21)(22)(23). Clinical response.…”

Section: Resultsmentioning

confidence: 99%

Is Ceftazidime/Avibactam an Option for Serious Infections Due to Extended-Spectrum-β-Lactamase- and AmpC-Producing Enterobacterales ?: a Systematic Review and Meta-analysis

Isler

Ezure

Romero

et al. 2020

“…In a pathogen-directed open-label phase III trial (the REPRISE trial) comparing CAZ-AVI to the best available therapy for treatment of cUTI and cIAI caused by ceftazidimeresistant Gram-negative organisms (11), few patients with carbapenem-resistant infections met the trial's inclusion criteria. Among the 292 Enterobacteriaceae isolates recovered from 288 patients in the REPRISE trial, only nine harbored non-MBL carbapenemases: six KPC-producing Klebsiella pneumoniae isolates and three OXA-48-producing K. pneumoniae isolates (12). In an effort to amass data about the effectiveness of CAZ-AVI against carbapenem-resistant organisms, we present a case series of patients with infections caused by CRE or CRPa who were treated with CAZ-AVI salvage therapy on a compassionate-use basis.…”

mentioning

confidence: 99%

Ceftazidime-Avibactam as Salvage Therapy for Infections Caused by Carbapenem-Resistant Organisms

Temkin

Torre‐Cisneros

Beović

et al. 2017

172

107

Ceftazidime-avibactam (CAZ-AVI) is a recently approved ␤-lactam-␤-lactamase inhibitor combination with the potential to treat serious infections caused by carbapenem-resistant organisms. Few patients with such infections were included in the CAZ-AVI clinical trials, and clinical experience is lacking. We present a case series of patients with infections caused by carbapenem-resistant Enterobacteriaceae (CRE) or Pseudomonas aeruginosa (CRPa) who were treated with CAZ-AVI salvage therapy on a compassionate-use basis. Physicians who had prescribed CAZ-AVI completed a case report form. We used descriptive statistics to summarize patient characteristics and treatment outcomes. We used the Wilcoxon rank sum test and Fisher's exact test to compare patients by treatment outcome. The sample included 36 patients infected with CRE and two with CRPa. The most common infections were intra-abdominal. Physicians categorized 60.5% of patients as having life-threatening infections. All but two patients received other antibiotics before CAZ-AVI, for a median of 13 days. The median duration of CAZ-AVI treatment was 16 days. Twentyfive patients (65.8%) concurrently received other antibiotics to which their pathogen was nonresistant in vitro. Twenty-eight patients (73.7%, 95% confidence interval [CI], 56.9 to 86.6%) experienced clinical and/or microbiological cure. Five patients (20.8%) with documented microbiological cure died, whereas 10 patients (71.4%) with no documented microbiological cure died (P ϭ 0.01). In three-quarters of cases, CAZ-AVI (alone or combined with other antibiotics) cured infections caused by carbapenemresistant organisms, 95% of which had failed previous therapy. Microbiological cure was associated with improved survival. CAZ-AVI shows promising clinical results for infections for which treatment options are limited.

“…Reference antibiotics included representative agents in relevant classes for comparative purposes. Genetic identification of common ␤-lactamases and upregulation of AmpC were provided as previously described (JMI Laboratories, Inc., North Liberty, IA) (9). Only baseline pathogens from all randomized patients were included in the analysis of susceptibility testing to ceftazidime-avibactam and comparators in this report.…”

mentioning

confidence: 99%

“…For bacteremic patients, multiple isolates of the same species from the same patient are counted only once using the isolate with the highest MIC to the study drug received across the culture source (urine or blood). b Genetic identification of ␤-lactamases was provided as previously described (JMI Laboratories, Inc., North Liberty, IA) (9 …”

mentioning

confidence: 99%

In Vitro Activity of Ceftazidime-Avibactam against Isolates in a Phase 3 Open-Label Clinical Trial for Complicated Intra-Abdominal and Urinary Tract Infections Caused by Ceftazidime-Nonsusceptible Gram-Negative Pathogens

Stone

Bradford

Newell

et al. 2017

Self Cite

The in vitro activity of ceftazidime-avibactam was evaluated against 341 Gram-negative isolates from 333 patients in a randomized, phase 3 clinical trial of patients with complicated urinary tract or intra-abdominal infections caused by ceftazidime-nonsusceptible pathogens (NCT01644643). Ceftazidime-avibactam MIC 90 values against Enterobacteriaceae and Pseudomonas aeruginosa (including several class B or D enzyme producers that avibactam does not inhibit) were 1 and 64 g/ ml, respectively. Overall, the ceftazidime-avibactam activity against ceftazidimenonsusceptible isolates was comparable to the activity of ceftazidime-avibactam previously reported against ceftazidime-susceptible isolates. (This study has been registered at ClinicalTrials.gov under identifier NCT01644643.) KEYWORDS ceftazidime nonsusceptible, ceftazidime-avibactam, in vitro activity Avibactam is the first in a class of new non-␤-lactam ␤-lactamase inhibitors with a broader spectrum of inhibitory activity than previous generations of inhibitors against Ambler class A and C ␤-lactamases and some Ambler class D enzymes, including enzymes such as Klebsiella pneumoniae carbapenemase (KPC) and the carbapenemhydrolyzing oxacillinase OXA-48 but with no activity against class B metallo-␤-lactamases (1, 2). In combination, ceftazidime and avibactam have a spectrum of activity that includes extended-spectrum ␤-lactamase (ESBL)-producing Enterobacteriaceae, derepressed AmpC-positive Enterobacteriaceae, Pseudomonas aeruginosa, and isolates expressing serine carbapenemases such as KPC or 4).An open-label, phase 3 study (The REPRISE study [ClinicalTrials registration no. NCT01644643]) was conducted to compare the safety and efficacy of ceftazidimeavibactam (CAZ-AVI) with that of the best available therapy (ϳ97% received a carbapenem; the majority received this as monotherapy), as determined and documented prior to randomization by the treating physician, in complicated urinary tract infections (cUTI) and complicated intra-abdominal infections (cIAI) caused by Gram-negative pathogens nonsusceptible to ceftazidime (5). Patients were eligible for entry into the trial after the identification of at least one ceftazidime-nonsusceptible Gram-negative pathogen isolated from the site of infection. If the pathogen was susceptible to prior antibiotics, the protocol required that patients have either worsening signs and symptoms of cIAI/cUTI or a lack of improvement to be eligible for study entry. Specimens obtained from patients were processed at the local (or regional) laboratory according