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 bla
KPC-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
Taken together, the data suggest combinations of increased bla
KPC 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.
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 bla
KPC-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 bla
KPC-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
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
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
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 bla
KPC 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 bla
KPC 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 bla
KPC 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.
1. Shields RK, Nguyen MH, Chen L, et al. Ceftazidime-avibactam is superior to other treatment regimens against carbapenem-resistant Klebsiella pneumoniae bacteremia. Antimicrob Agents Chemother. 2017;61(8). doi: 10.1128/AAC.00883-17.
2. van Duin D, Lok JJ, Earley M, et al; Antibacterial Resistance Leadership Group. Colistin vs ceftazidime-avibactam in the treatment of infections due to carbapenem-resistant enterobacteriaceae. Clin Infect Dis. 2018;66(2):163-171. doi: 10.1093/cid/cix783.
3. Tumbarello M, Trecarichi EM, Corona A, et al. Efficacy of ceftazidime-avibactam salvage therapy in patients with infections caused by KPC-producing Klebsiella pneumoniae [published online June 9, 2018]. Clin Infect Dis. doi: 10.1093/cid/ciy492.
4. Sader HS, Castanheira M, Flamm RK, Farrell DJ, Jones RN. Antimicrobial activity of ceftazidime-avibactam against gram-negative organisms collected from US medical centers in 2012. Antimicrob Agents Chemother. 2014;58(3):1684-92. doi: 10.1128/AAC.02429-13.
5. Castanheira M, Mendes RE, Sader HS. Low frequency of ceftazidime-avibactam resistance among Enterobacteriaceae isolates carrying blaKPC collected in US hospitals from 2012 to 2015. Antimicrob Agents Chemother. 2017 Feb 23;61(3). pii: e02369-16. doi: 10.1128/AAC.02369-16.
6. Sader HS, Castanheira M, Shortridge D, Mendes RE, Flamm RK. Antimicrobial activity of ceftazidime-avibactam tested against multidrug-resistant Enterobacteriaceae and Pseudomonas aeruginosa isolates from US medical centers, 2013 to 2016. Antimicrob Agents Chemother. 2017 Oct 24;61(11). pii: e01045-17. doi: 10.1128/AAC.01045-17.
7. Sousa A, Perez-Rodriguez MT, Soto A, et al. Effectiveness of ceftazidime/avibactam as salvage therapy for treatment of infections due to OXA-48 carbapenemase-producing Enterobacteriaceae. J Antimicrob Chemother. 2018 Nov 1;73(11):3170-3175. doi: 10.1093/jac/dky295.
8. Aitken SL, Tarrand JJ, Deshpande LM, et al. High rates of non-susceptibility to ceftazidime-avibactam and identification of New Delhi metallo-beta-lactamase production in Enterobacteriaceae bloodstream infections at a major cancer center. Clin Infect Dis. 2016 Oct 1;63(7):954-958. doi: 10.1093/cid/ciw398.
9. Humphries RM, Yang S, Hemarajata P, et al. First report of ceftazidime-avibactam resistance in a KPC-3 expressing Klebsiella pneumoniae. Antimicrob Agents Chemother. 2015 Oct;59(10):6605-7. doi: 10.1128/AAC.01165-15.
10. Nelson K, Hemarajata P, Sun D, et al. Resistance to ceftazidime-avibactam is due to transposition of KPC in a porin-deficient strain of Klebsiella pneumoniae with increased efflux activity. Antimicrob Agents Chemother. 2017 Sep 22;61(10). pii: e00989-17. doi: 10.1128/AAC.00989-17.
11. Shen Z, Ding B, Ye M, et al. High ceftazidime hydrolysis activity and porin OmpK35 deficiency contribute to the decreased susceptibility to ceftazidime/avibactam in KPC-producing Klebsiella pneumoniae. J Antimicrob Chemother. 2017 Jul 1;72(7):1930-1936. doi: 10.1093/jac/dkx066.
12. Zhang Y, Kashikar A, Brown CA, Denys G, Bush K. Unusual Escherichia coli PBP 3 insertion sequence identified from a collection of carbapenem-resistant Enterobacteriaceae tested in vitro with a combination of ceftazidime-, ceftaroline-, or aztreonam-avibactam. Antimicrob Agents Chemother. 2017 Jul 25;61(8). pii: e00389-17. doi: 10.1128/AAC.00389-17.
13. Shields RK, Nguyen MH, Chen L, Press EG, Kreiswirth BN, Clancy CJ. Pneumonia and renal replacement therapy are risk factors for ceftazidime-avibactam treatment failures and resistance among patients with carbapenem-resistant Enterobacteriaceae infections. Antimicrob Agents Chemother. 2018 Apr 26;62(5). pii: e02497-17. doi: 10.1128/AAC.02497-17.
14. Shields RK, Chen L, Cheng S, et al. Emergence of ceftazidime-avibactam resistance due to plasmid-borne blaKPC-3 mutations during treatment of carbapenem-resistant Klebsiella pneumoniae infections. Antimicrob Agents Chemother. 2017 Feb 23;61(3). pii: e02097-16. doi: 10.1128/AAC.02097-16.
15. Livermore DM, Warner M, Jamrozy D, et al. In vitro selection of ceftazidime-avibactam resistance in Enterobacteriaceae with KPC-3 carbapenemase. Antimicrob Agents Chemother. 2015 Sep;59(9):5324-30. doi: 10.1128/AAC.00678-15.
16. Winkler ML, Papp-Wallace KM, Bonomo RA. Activity of ceftazidime/avibactam against isogenic strains of Escherichia coli containing KPC and SHV beta-lactamases with single amino acid substitutions in the Omega-loop. J Antimicrob Chemother. 2015 Aug;70(8):2279-86. doi: 10.1093/jac/dkv094.
17. Barnes MD, Winkler ML, Taracila MA, et al. Klebsiella pneumoniae carbapenemase-2 (KPC-2), substitutions at ambler position Asp179, and resistance to ceftazidime-avibactam: unique antibiotic-resistant phenotypes emerge from beta-lactamase protein engineering. MBio. 2017 Oct 31;8(5). pii: e00528-17. doi: 10.1128/mBio.00528-17.
18. Compain F, Arthur M. Impaired inhibition by avibactam and resistance to the ceftazidime-avibactam combination due to the D(179)Y substitution in the KPC-2 beta-lactamase. Antimicrob Agents Chemother. 2017 Jun 27;61(7). pii: e00451-17. doi: 10.1128/AAC.00451-17.
19. Wolter DJ, Kurpiel PM, Woodford N, Palepou MF, Goering RV, Hanson ND. Phenotypic and enzymatic comparative analysis of the novel KPC variant KPC-5 and its evolutionary variants, KPC-2 and KPC-4. Antimicrob Agents Chemother. 2009 Feb;53(2):557-62. doi: 10.1128/AAC.00734-08.
20. Chen L, Mediavilla JR, Endimiani A, et al. Multiplex real-time PCR assay for detection and classification of Klebsiella pneumoniae carbapenemase gene (bla KPC) variants. J Clin Microbiol. 2011 Feb;49(2):579-85. doi: 10.1128/JCM.01588-10.
21. Alba J, Ishii Y, Thomson K, Moland ES, Yamaguchi K. Kinetics study of KPC-3, a plasmid-encoded class A carbapenem-hydrolyzing beta-lactamase. Antimicrob Agents Chemother. 2005 Nov;49(11):4760-2.
22. Shields RK, Clancy CJ, Hao B, et al. Effects of Klebsiella pneumoniae carbapenemase subtypes, extended-spectrum beta-lactamases and porin mutations on the in vitro activity of ceftazidime-avibactam against carbapenem-resistant Klebsiella pneumoniae. Antimicrob Agents Chemother. 2015 Sep;59(9):5793-7. doi: 10.1128/AAC.00548-15.
23. Giddins MJ, Macesic N, Annavajhala MK, et al. Successive emergence of ceftazidime-avibactam resistance through distinct genomic adaptations in blaKPC-2-harboring Klebsiella pneumoniae ST307. Antimicrob Agents Chemother. 2018 Feb 23;62(3). pii: e02101-17. doi: 10.1128/AAC.02101-17.
24. Athans V, Neuner EA, Hassouna H, et al. Meropenem-vaborbactam as salvage therapy for ceftazidime-avibactam-resistant Klebsiella pneumoniae bacteremia and abscess in a liver transplant recipient. Antimicrob Agents Chemother. 2018 Dec 21;63(1). pii: e01551-18. doi: 10.1128/AAC.01551-18.
25. Shields RK, Nguyen MH, Press EG, Chen L, Kreiswirth BN, Clancy CJ. Emergence of ceftazidime-avibactam resistance and restoration of carbapenem susceptibility in Klebsiella pneumoniae carbapenemase-producing K pneumoniae: a case report and review of literature. Open Forum Infect Dis. 2017 Jul 1;4(3):ofx101. doi: 10.1093/ofid/ofx101.
26. Haidar G, Clancy CJ, Shields RK, Hao B, Cheng S, Nguyen MH. Mutations in blaKPC-3 that confer ceftazidime-avibactam resistance encode novel KPC-3 variants that function as extended-spectrum beta-lactamases. Antimicrob Agents Chemother. 2017 Apr 24;61(5). pii: e02534-16. doi: 10.1128/AAC.02534-16.
27. Gaibani P, Campoli C, Lewis RE, et al. In vivo evolution of resistant subpopulations of KPC-producing Klebsiella pneumoniae during ceftazidime/avibactam treatment. J Antimicrob Chemother. 2018 Jun 1;73(6):1525-1529. doi: 10.1093/jac/dky082.
28. Both A, Buttner H, Huang J, et al. Emergence of ceftazidime/avibactam non-susceptibility in an MDR Klebsiella pneumoniae isolate. J Antimicrob Chemother. 2017 Sep 1;72(9):2483-2488. doi: 10.1093/jac/dkx179.
29. Castanheira M, Arends SJR, Davis AP, Woosley LN, Bhalodi AA, MacVane SH. Analyses of a ceftazidime-avibactam-resistant citrobacter freundii isolate carrying bla KPC-2 reveals a heterogenous population and reversible genotype. mSphere. 2018 Sep 26;3(5). pii: e00408-18. doi: 10.1128/mSphere.00408-18.
30. Lomovskaya O, Castanheira M, Vazquez J, et al. Assessment of MIC increases with meropenem-vaborbactam (Vabomere) and ceftazidime-avibactam in TANGO II (a phase 3 study of the treatment of CRE infections). Presented at: IDWeek 2017; October 7, 2017; San Diego, CA. Abstract 1874. idsa.confex.com/idsa/2017/webprogram/Paper65046.html.
31. Guzman-Puche J, Perez-Nadales E, Causse del Rio M, et al. Selection of mutants of Klebsiella pneumoniae producing KPC-3 ressitant to ceftazidime-avibactam and susceptible to carbapenems in patients treated with ceftazidime-avibactam. Presented at: 28th European Congress of Clinical Microbiology and Infectious Diseases; April 21-24, 2018; Madrid, Spain. Abstract O0931
32. Hemarajata P, Humphries RM. Mechanisms of resistance to ceftazidime-avibactam. Presented at: 28th European Congress of Clinical Microbiology and Infectious Diseases; April 21-24, 2018; Madrid, Spain. Oral presentation #S0386.
33. van Duin D, Doi Y. The global epidemiology of carbapenemase-producing Enterobacteriaceae. Virulence. 2017 May 19;8(4):460-469. doi: 10.1080/21505594.2016.1222343.
34. Chen L, Mathema B, Chavda KD, DeLeo FR, Bonomo RA, Kreiswirth BN. Carbapenemase-producing Klebsiella pneumoniae: molecular and genetic decoding. Trends Microbiol. 2014 Dec;22(12):686-96. doi: 10.1016/j.tim.2014.09.003.
35. Villa L, Feudi C, Fortini D, et al. Diversity, virulence, and antimicrobial resistance of the KPC-producing Klebsiella pneumoniae ST307 clone. Microb Genom. 2017 Apr 26;3(4):e000110. doi: 10.1099/mgen.0.000110.
36. Wenzler E, Bunnell KL, Bleasdale SC, Benken S, Danziger LH, Rodvold KA. Pharmacokinetics and dialytic clearance of ceftazidime-avibactam in a critically ill patient on continuous venovenous hemofiltration. Antimicrob Agents Chemother. 2017 Jun 27;61(7). pii: e00464-17. doi: 10.1128/AAC.00464-17.
37. Qureshi ZA, Paterson DL, Potoski BA, et al. Treatment outcome of bacteremia due to KPC-producing Klebsiella pneumoniae: superiority of combination antimicrobial regimens. Antimicrob Agents Chemother. 2012 Apr;56(4):2108-13. doi: 10.1128/AAC.06268-11.
38. Tumbarello M, Viale P, Viscoli C, et al. Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae: importance of combination therapy. Clin Infect Dis. 2012 Oct;55(7):943-50. doi: 10.1093/cid/cis588
39. Tzouvelekis LS, Markogiannakis A, Piperaki E, Souli M, Daikos GL. Treating infections caused by carbapenemase-producing Enterobacteriaceae. Clin Microbiol Infect. 2014 Sep;20(9):862-72. doi: 10.1111/1469-0691.12697.
40. Shields RK, Nguyen MH, Hao B, Kline EG, Clancy CJ. Colistin does not potentiate ceftazidime-avibactam killing of carbapenem-resistant Enterobacteriaceae in vitro or suppress emergence of ceftazidime-avibactam resistance. Antimicrob Agents Chemother. 2018 Jul 27;62(8). pii: e01018-18. doi: 10.1128/AAC.01018-18.
41. Nath S, Moussavi F, Abraham D, Landman D, Quale J. In vitro and in vivo activity of single and dual antimicrobial agents against KPC-producing Klebsiella pneumoniae. J Antimicrob Chemother. 2018 Feb 1;73(2):431-436. doi: 10.1093/jac/dkx419.
42. Jones CE, Kline EG, Morder K, Clancy C, Nguyen MH, Shields RK. Ceftazidime-avibactam and meropenem are synergistic and bactericidal against genetically-diverse KPC-producing Klebsiella pneumoniae. Open Forum Infect Dis. 2018 Nov; 5(Suppl 1): S254. doi: 10.1093/ofid/ofy210.713.
43. Wilson WR, Kline EG, Jones CE, et al. Effects of KPC variant and porin genotype on the in vitro activity of meropenem-vaborbactam against carbapenem-resistant Enterobacteriaceae. Antimicrob Agents Chemother. 2019 Jan 7. pii: AAC.02048-18. doi: 10.1128/AAC.02048-18.
44. Shields RK, Nguyen MH, Press EG, Chen L, Kreiswirth BN, Clancy CJ. In vitro selection of meropenem resistance among ceftazidime-avibactam-resistant, meropenem-susceptible Klebsiella pneumoniae isolates with variant KPC-3 carbapenemases. Antimicrob Agents Chemother. 2017 Apr 24;61(5). pii: e00079-17. doi: 10.1128/AAC.00079-17.
45. Shields RK, Clancy CJ, Pasculle AW, et al. Verification of ceftazidime-avibactam and ceftolozane-tazobactam susceptibility testing methods against carbapenem-resistant Enterobacteriaceae and Pseudomonas aeruginosa. J Clin Microbiol. 2018 Jan 24;56(2). pii: e01093-17. doi: 10.1128/JCM.01093-17.
46. Wenzler E, Lee M, Wu TJ, et al. Performance of ceftazidime/avibactam susceptibility testing methods against clinically relevant Gram-negative organisms. J Antimicrob Chemother. 2018 Dec 10. doi: 10.1093/jac/dky483.