Clinical Outcomes, Drug Toxicity, and Emergence of Ceftazidime-Avibactam Resistance Among Patients Treated for Carbapenem-Resistant Enterobacteriaceae Infections: Table 1.

Abstract

Thirty-seven carbapenem-resistant Enterobacteriaceae (CRE)-infected patients were treated with ceftazidime-avibactam. Clinical success and survival rates at 30 days were 59% (22/37) and 76% (28/37), respectively. In 23% (5/22) of clinical successes, CRE infections recurred within 90 days. Microbiologic failure rate was 27% (10/37). Ceftazidime-avibactam resistance was detected in 30% (3/10) of microbiologic failures.Keywords. ceftazidime-avibactam resistance; carbapenemresistant Enterobacteriaceae; Klebsiella pneumoniae carbapenemase.Ceftazidime-avibactam is a novel β-lactam/β-lactamase inhibitor combination that was recently approved by the US Food and Drug Administration for the treatment of complicated intraabdominal and complicated urinary tract infections [1]. The agent demonstrates in vitro activity against carbapenem-resistant Enterobacteriaceae (CRE) that produce Klebsiella pneumoniae carbapenemase (KPC), but not metallo-β-lactamases such as New Delhi MBL (NDM), Verona integron-encoded MBL (VIM), or imipenemase (IMP) [2]. Ceftazidime-avibactam may offer a significant advance over previously developed antimicrobials with in vitro activity against CRE, such as colistin, gentamicin, and tigecycline, which are limited by concerns over efficacy and/or toxicity. Our objective in this study was to describe our initial clinical experience with ceftazidimeavibactam against CRE infections. METHODSWe conducted a retrospective study of patients with CRE infection who were treated with ceftazidime-avibactam at the University of Pittsburgh Medical Center between April 2015 and February 2016. CRE was defined by current Centers for Disease Control and Prevention criteria as resistance to any carbapenem [3]. A standard dosage of 2.5 g intravenously (IV) every 8 hours was used, with adjustments for renal impairment made according to manufacturer recommendations [1]. Types of CRE infection were classified according to National Healthcare Safety Network criteria [4]. Clinical success was defined as survival and absence of recurrence at 30 days following the onset of infection, resolution of signs and symptoms of infection, and sterilization of site-specific cultures within 7 days of treatment initiation. Microbiologic failure was defined as isolation of CRE following ≥7 days of ceftazidime-avibactam treatment. Recurrences within 90 days of onset were defined by microbiologic failure and concomitant signs of infection. Minimum inhibitory concentrations (MICs) were determined using reference Clinical and Laboratory Standards Institute broth microdilution methods; avibactam was tested at a fixed concentration of 4 µg/mL [2]. Isolates were tested for the presence of β-lactamases as described previously [5,6]. Comparisons between groups were made using Fisher exact test (categorical variables) and Mann-Whitney U (continuous variables). Significance was defined as P ≤ .05 (2-tailed). RESULTSThirty-seven consecutive patients treated for 3 days or longer with ceftazidime-avibactam were evaluated. Median age was 64 years (range, 26-...

In Vitro Selection of Meropenem Resistance among Ceftazidime-Avibactam-Resistant, Meropenem-Susceptible Klebsiella pneumoniae Isolates with Variant KPC-3 Carbapenemases

“…Likewise, our bla KPC data are in keeping with results from numerous studies demonstrating that KPC mutations alter enzyme activity (12,13). The D179Y KPC-3 substitution alone or in combination with other substitutions, such as T243M, is the most common mutation among clinical ceftazidime-avibactamresistant K. pneumoniae isolates at our center (1,2) and in resistant Enterobacteriaceae isolates selected by in vitro drug exposure (14). Substitutions in the KPC ⍀-loop (amino acid positions 165-179) enhance affinity for ceftazidime, which is postulated to prevent subsequent binding of avibactam (15).…”

“…The drug is endorsed as front-line therapy for infection caused by KPC-producing Enterobacteriaceae due to its activity in vitro, its favorable safety profile, and the paucity of other active agents. We recently reported the first 3 cases of ceftazidime-avibactam resistance to emerge among KPC-producing K. pneumoniae isolates during treatment (1). We demonstrated that ceftazidime-avibactam resistance was caused by plasmid-borne bla KPC-3 mutations (2), which also restored carbapenem susceptibility in certain isolates.…”

Ceftazidime/Avibactam: Who Says You Can’t Teach an Old Drug New Tricks?

“…The largest case series described the clinical outcomes associated with ceftazidime/avibactam in patients with CRE infections (50). The most prevalent infection types were pneumonia (32%) and bacteremia (27%).…”

“…However, recent case series have specifically reviewed patients with CRE infections treated with ceftazidime/avibactam (50)(51)(52). While efficacy was obtained in many of the treated patients, the overall success was worrisome (range 45-59%), relapse rates were higher than desired even with combination therapy (up to 23%), and there was development of resistance to ceftazidime/avibactam (MIC >16 mg/L) following relatively short courses of therapy (10-19 days) (50)(51)(52). Although, these case series represent a small sample size, it does give rise to the fear of having only this agent for treatment of CRE infections.…”

De nouveaux antibiotiques : oui mais pour quelles situations en réanimation ?

“…Parmi les associations avec inhibiteurs de β-lactamase, seules celles contenant l'avibactam sont potentiellement utiles. Les premières études cliniques avec ceftazidime-avibactam sur des infections à EPC des groupes A (KPC) et D sont plutôt encourageantes [5,6] mais malheureusement on voit déjà apparaître des souches résistantes avec de nouveaux mécanismes récemment décrits tels que bla KPC-3 [7]. L'association de l'avibactam (inhibiteur de BLSE) avec l'aztréonam (plus stable vis-à-vis de NDM et VIM) pourrait être utilisée pour traiter des infections à EPC du groupe B. Cette association n'étant pas encore disponible, des auteurs ont proposé l'administration combinée de ceftazidime-avibactam + aztréonam [8].…”