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Emergence of Ceftazidime-Avibactam Resistance: What Have We Learned in the Past 4 Years?

FEB 18, 2019 | RYAN K. SHIELDS, PHARMD, MS
The US Food and Drug Administration (FDA) approved ceftazidime-avibactam for clinical use in February 2015, effectively changing the landscape for treatment of carbapenem-resistant Enterobacteriaceae (CRE) infec­tions. Compared with traditional salvage agents (including aminoglycosides, colistin, and tigecycline), treatment with ceftazidime-avibactam is safer and more effective.1-3 Despite these encouraging findings, the emergence of ceftazidime-avi­bactam resistance has been reported and may pose a serious threat to patients. Over the past 4 years, new insights into the molecular mechanisms and predisposing factors associated with ceftazidime-avibactam resistance have been described.

Avibactam is a novel diazabicyclooctane β-lactamase inhib­itor that reversibly inhibits Ambler classes A, C, and some class D β-lactamases. Avibactam does not inhibit class B metallo-β-lactamases (MBLs). In surveillance studies, the combination of ceftazidime-avibactam demonstrated potent in vitro activity against a wide spectrum of gram-negative pathogens, including multidrug-resistant Enterobacteriaceae and CRE.4-6 Categorized by the FDA-approved susceptibility breakpoint (≤8/4 μg/mL), ceftazidime-avibactam was active against 97.5% of contemporary CRE isolates.6 In a subsequent study, 99.3% of Klebsiella pneumoniae carbapenemase (KPC)- producing CRE were susceptible.5 Against OXA-48 producing CRE, ceftazidime-avibactam was active against 100% of isolates in a recent clinical study.7

In the United States, inherent resistance to ceftazidime-avi­bactam is rare, but has been reported. Against CRE blood­stream isolates, Aitken and colleagues described unusually high rates of resistance; however, 86% of resistant isolates harbored a New Delhi metallo-β-lactamase that is refractory to avibactam inhibition.8 Against a KPC-producing K pneu­moniae isolate, Nelson and colleagues demonstrated that a higher copy number of blaKPC-3 plus decreased outer membrane permeability may manifest in resistance to ceftazidime-avi­bactam.9,10 Decreased outer membrane permeability contrib­uted to a resistant phenotype in one other KPC K pneumoniae identified through surveillance studies.5 Although drug efflux does not appear to be a major contributor to resistance,10,11 a rare 4 amino acid insertion into penicillin binding protein 3 (PBP3) has been implicated in decreased susceptibility against a single KPC Escherichia coli isolate.12 Taken together, the data suggest combinations of increased blaKPC copy number, impaired outer membrane permeability, and/or variant PBP3 may contribute to decreased ceftazidime-avibactam suscepti­bility in a minority of KPC-producing isolates not previously exposed to the agent.

TREATMENT-RELATED RESISTANCE

Of greater concern to clinicians are recent reports describing the emergence of ceftazidime-avibactam resistance following treatment. In a study of 77 patients treated for CRE infections, resistance emerged in 10%, including 14% of patients infected by K pneumoniae and 32% with microbiologic failures.13 Resistant isolates harbored blaKPC-3 Ω-loop mutations that encoded variant KPC-3 enzymes. The most common variant featured a tyrosine for aspartic acid substitution at Ambler amino acid position 179 (D179Y),13,14 which was successfully predicted by prior in vitro passage studies.15 blaKPC-3 Ω-loop mutations have been validated as the cause of ceftazidime-avibactam resistance by targeted gene deletion and laboratory transfer of mutant genes into competent E coli.14 KPC variants demonstrate enhanced ceftazidime affinity that prevents avibactam binding,16-18 and a decreased ability to hydrolyze carbapenems that results in restoration of carbapenem susceptibility in some isolates.14,19,20 These data attest to the significance of mutations within β-lac­tamase genes that lead to substantial changes in the hydrolytic profile of the resulting enzyme.21 KPC-3 evolved from KPC-2 and differs by a single amino acid at Ambler position 273 (H273Y).22 This substitution results in a ~30-fold increase in the catalytic efficiency against ceftazidime,23 and consequently higher ceftazi­dime-avibactam MICs against clinical K pneumoniae isolates harboring KPC-3 compared with KPC-2.24 It is unclear if these factors predispose KPC-3 K pneumoniae to ceftazidime-avi­bactam resistance among patients. Recently, 2 cases of resis­tance were reported among K pneumoniae isolates carrying KPC-2 variants with characteristic D179Y substitutions.25,26

PATIENT CHARACTERISTICS AND RISK FACTORS

To date, 16 cases of treatment-related or emergent ceftazi­dime-avibactam resistance have been reported in the litera­ture,3,13,25-29 and at least 4 other cases have been described in preliminary reports at conference proceedings.30-32 Details of 13 available cases are summarized in the Table (see online). All but 1 case has been observed in K pneumoniae, the most common CRE species worldwide.33 Remarkably, ceftazidime-avibactam resistance has emerged within varying clonal backgrounds of KPC K pneumoniae,13,25-27,31 including sequence type (ST) 258, the predominant international clone34; ST307, an emerging clone35; and ST1519, a rare clone in Europe.27 Resistance also emerged in an ST383 K pneumoniae isolate harboring both CTX-M-14 and OXA-48.28 Overall, rates of resistance following ceftazidime-avibactam treatment are not well defined, but have ranged from 2% to 10% of treated patients in KPC-endemic regions.3,13 Notably, no cases of resistance were reported among 57 patients treated with ceftazidime-avibactam for infections caused by OXA-48-producing Enterobacteriaceae.7

Durations of drug exposure preceding the identification of resistance have ranged from 7 to 54 days. Among patients in whom resistance emerged, more than half have been solid-organ transplantation recipients and all had deep-seated sites of CRE infection, including intra-abdominal infections and pneumonia. Fifty percent of patients required renal replace­ment therapy (RRT) during their treatment course, which has been identified as a risk factor for the emergence of ceftazidime-avibactam resistance.13 Unfortunately, there are no ceftazidime-avibactam dosing recommendations for patients receiving continuous RRT, and thus the doses administered to patients have varied (Online Table).36 It is unclear if inad­equate drug exposures promoted the emergence of resistance in these patients or if such patients share underlying host factors that may be contributing.

Ongoing research efforts have focused on the suppression of ceftazidime-avibactam resistance through combination treat­ment strategies. Interestingly, the available evidence would suggest that resistance has emerged despite combination therapy in some patients.25,27-29 Notwithstanding, combination treatment against CRE has historically fared better than monotherapy when salvage agents are used.37-39 In the case of ceftazidime-avibactam, potential partner agents include the aminoglycosides (including plazomicin), carbapenems, tetracyclines (including eravacycline), colistin, and fosfomycin. In vitro colistin does not potentiate the killing of ceftazidime-avibactam against KPC K pneumoniae, and may select for ceftazidime-avibactam resistant subpopula­tions.40 Carbapenem combinations may mitigate the emergence of blaKPC mutations or treat ceftazi­dime-avibactam resistant subpopulations should they arise. Against KPC K pneumoniae, synergy between meropenem and ceftazidime-avibactam has been reported41 and shown to prevent the emergence of resistance in preliminary studies.42 A key factor that may influence the activity of the combination is reverted carbapenem suscep­tibility, which varies by blaKPC mutation and the presence or absence of porin gene mutations.43 Additional studies are needed to define optimized ceftazidime-avibactam combinations in vitro, and subsequently in vivo. Until such data are available, clini­cians should exercise caution when implementing combination approaches in patients.

CLINICIAN AND LABORATORY CONSIDERATIONS

Susceptibility testing should be performed routinely when ceftazidime-avibactam is being considered for treatment. Of the commercially available methods, testing by disk diffu­sion may overcall resistance at the currently proposed cutoff values.44,45 Gradient strip testing, on the other hand, has been shown to reliably correlate with the gold-standard broth microdilution method.44,45 Importantly, clinicians and micro­biologists now have a better understanding of the nuances in detecting ceftazidime-avibactam resistance. Because auto­mated susceptibility testing systems tend to lag behind FDA approval of new antibiotics, routine surveillance for resistance is rarely employed. Testing ceftazidime-avibactam through reflex algorithms or by clinician request may fail to trigger testing against KPC-variant isolates with restored carbapenem susceptibility.20 In such cases, clinicians and laboratories must work collaboratively to recognize relevant phenotypes against isolates collected from patients with a history of CRE infection and recent ceftazidime-avibactam exposure.

In conclusion, clinical development of ceftazidime-avibactam has marked a major advance for treatment of CRE infections. The emergence of resistance following treatment is concerning, but not surprising given the fate of other antibiotics after regulatory approval.46 Clinicians should be particularly vigi­lant in monitoring for resistance among CRE-infected patients with deep-seated sources of infection and other predisposing factors, such as immunosuppression and receipt of RRT. The most common mechanisms by which resistance is mediated are mutations within the blaKPC gene that encodes variant KPC enzymes with altered spectra of activity, that may include reverted susceptibility to carbapenems. As use of ceftazi­dime-avibactam expands, it is likely that other mechanisms of resistance will be identified. Future research efforts are needed to define effective dosing regimens and combination strategies that will preserve the effectiveness of ceftazidime-avibactam and limit resistance. Taking everything into consideration, the real-world experience with ceftazidime-avibactam has helped to shift CRE treatment paradigms away from older, less effective strategies while setting the bar for other new agents to be measured by. Ongoing reporting of the real-world experiences for each of these agents will be essential in further defining their therapeutic niche in the landscape of CRE management.
Dr. Shields serves as an associate professor in the department of medicine at the University of Pittsburgh where he directs a research laboratory to study antimicrobial-resistant bacteria. He is also a clinical pharmacist in infectious diseases at the University of Pittsburgh Medical Center.
References: 

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