In Vitro Activity of Ceftazidime-Avibactam Against Isolates. in a Phase 3 Open-label Clinical Trial for Complicated

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1 AAC Accepted Manuscript Posted Online 21 November 2016 Antimicrob. Agents Chemother. doi: /aac Copyright 2016, American Society for Microbiology. All Rights Reserved 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 Gregory G. Stone, a# Patricia A. Bradford, a Paul Newell, b Angela Wardman b AstraZeneca Pharmaceuticals, Waltham, MA a ; AstraZeneca Pharmaceuticals, Alderley Park, UK b Running title: Ceftazidime-avibactam MICs against Gram-negative pathogens #corresponding author: Gregory G. Stone, AstraZeneca Pharmaceuticals, 35 Gatehouse Drive, Waltham, MA Phone: ; Fax: ; Gregory.stone@astrazeneca.com

2 12 Abstract 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 (NCT ). 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 µg/ml, respectively. Overall, ceftazidime-avibactam activity against ceftazidime-nonsusceptible isolates was comparable to the activity of ceftazidime-avibactam previously reported against ceftazidime-susceptible isolates. Downloaded from on December 27, 2018 by guest

3 Avibactam is the first in a class of new non-β-lactam β-lactamase inhibitors with a broader-spectrum inhibitory activity than previous generations of inhibitors against Ambler class A and C β-lactamases and some Ambler class D enzymes, including enzymes such as Klebsiella pneumoniae carbapenemase (KPC) and the carbapenem hyrolyzing oxacillinase OXA-48 but with no activity against class B metallo-β-lactamases (1, 2). In combination, ceftazidime and avibactam have a spectrum of activity that includes extended spectrum β-lactamase (ESBL) producing Enterobacteriaceae, derepressed AmpC-positive Enterobacteriaceae, Pseudomonas aeruginosa, as well as isolates expressing serine carbapenemases such as KPC, or OXA-48 (3, 4). An open-label, phase 3 study (The REPRISE study) was conducted to compare the safety and efficacy of ceftazidime-avibactam with that of best available therapy (~97% 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

4 regional) laboratory according to local practices. Bacterial cultures were isolated from patient specimens and submitted to a central laboratory (Covance CLS, Indianapolis, IN) for identification and susceptibility testing. Susceptibility testing was performed using microbroth dilution and interpreted according to Clinical and Laboratory Standards Institute (CLSI) methodologies (6, 7). FDA interpretive criteria were used for tigecycline (8). For ceftazidime-avibactam susceptibility testing, avibactam was tested at a constant concentration of 4 µg/ml in doubling dilutions of ceftazidime. All agents were tested by reference broth microdilution methods using frozen panels according to the manufacturer s recommendations (Trek Diagnostics, Westlake, OH). Phenotypic detection of ESBL enzyme production was performed according to the CLSI guidelines using the screening and confirmatory tests (6). Reference antibiotics included representative agents in relevant classes for comparative purposes. Genetic identification of common β-lactamases and upregulation of AmpC was 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. In total, 341 baseline isolates of Enterobacteriaceae (314 isolates) and P. aeruginosa (27 isolates) from 333 randomized patients were obtained. There were 27 patients with ciai and 306 patients with cuti randomized in the study. Of the Enterobacteriaceae, Escherichia coli (139 isolates) was the most common organism isolated, followed by K. pneumoniae (131 isolates) and Enterobacter cloacae (17 isolates). The analysis

5 included 31 isolates of Enterobacteriaceae that were susceptible to ceftazidime; however, these came from patients co-infected with a ceftazidime-nonsusceptible isolate. Susceptibility to ceftazidime-avibactam and comparator agents is shown in Table 1. Ceftazidime-avibactam was very active against all the Enterobacteriaceae, with overall MIC 50 and MIC 90 values of 0.25 and 1 µg/ml, respectively. The MIC distributions of ceftazidime and ceftazidime-avibactam are graphically depicted in Fig. 1. The ceftazidime-avibactam MIC distribution was shown to be 8 µg/ml for all isolates except four that produced a class B metallo-β-lactamase (which is not inhibited by avibactam). As expected, ceftazidime-avibactam MICs were high ( 32 µg/ml) for these four isolates, which were K. pneumoniae (2 isolates, 1 with NDM-1 and 1 with VIM-1), E. cloacae (1 isolate, with NDM-1), and Providencia rettgeri (one isolate, with NDM-1). Of the remaining isolates, for which ceftazidime-avibactam MICs were 8 µg/ml, the majority possessed CTX-M and were usually associated with OXA-1/30 or other enzymes such as SHV-12. There were also 9 isolates that possessed the carbapenemases KPC (6 isolates of K. pneumoniae; 1 from a ciai patient and 5 from cuti patients) or OXA-48 (3 isolates of K. pneumoniae, all from cuti patients). The ceftazidime-avibactam MICs ranged from 0.5 to 4 µg/ml (10). MICs of ceftazidime alone were 64 µg/ml for all of these carbapenemase producers. Against 27 isolates of P. aeruginosa, the ceftazidime MIC 50 and MIC 90 values were 64 µg/ml and >64 µg/ml; the ceftazidime-avibactam values were 8 µg/ml and 64 µg/ml. Of the 27 P. aeruginosa isolates, 13 possessed either a class B enzyme (one isolate with VIM-2) or at least one class D enzyme (12 isolates with OXA-2, OXA-10, OXA-17, and/or OXA-74), which

6 most likely contributed to the higher MIC 90 values observed in this analysis relative to those reported in previous studies against P. aeruginosa (11-13). The ceftazidime-avibactam MIC 90 value was 8 µg/ml for the 14 isolates without a class B or class D enzyme. The CLSI-recommended phenotypic test involving reduction of cephalosporin MICs with clavulanic acid showed that 216 Enterobacteriaceae were phenotypically positive for an ESBL (Table 2). The ceftazidime-avibactam MIC 90 values for E. coli and K. pneumoniae were 0.5 and 1 µg/ml. In contrast, the ESBL phenotype-negative isolates of E. coli and K. pneumoniae were associated with higher ceftazidime-avibactam MIC 90 values: 8 and 4 µg/ml. This observation was most likely due to the presence of class B, C, or D β-lactamases that raised the MICs of ceftazidime but are not reduced by clavulanic acid in the ESBL tests. Organisms producing class B and some class D enzymes, which mask the ESBL test, are not inhibited by avibactam, thus resulting in the higher ceftazidime-avibactam MIC 90 values. This highlights a shortcoming of using only phenotypic tests to determine the presence or absence of an ESBL in isolates that carry multiple enzymes of different molecular classes. Twenty-five baseline clinical isolates (Enterobacter spp, 13 isolates; P. aeruginosa, 7 isolates; Citrobacter freundii, 5 isolates) were hyperproducers of AmpC β-lactamase, either as a sole mechanism of resistance (10 isolates) or in combination with other enzymes (15 isolates). Of the 18 Enterobacteriaceae, only 5 isolates (2 E. cloacae and 1 Enterobacter aerogenes) had an upregulated AmpC as the sole mechanism of

7 resistance. The ceftazidime MICs for 4 of these strains were 64 µg/ml while the ceftazidime-avibactam MICs ranged from 0.25 to 1 µg/ml. One isolate of E. aerogenes, shown to be positive for upregulation of AmpC, was fully susceptible to ceftazidime. The ceftazidime MIC was 1 µg/ml whereas the ceftazidime-avibactam MIC was 0.12 µg/ml. Of the 13 Enterobacteriaceae with upregulated AmpC in combination with other enzymes, the ceftazidime MICs ranged from 8 to 64 µg/ml whereas the ceftazidime-avibactam MICs ranged from 0.12 to 4 µg/ml. Five of the seven isolates of P. aeruginosa were hyperproducers of AmpC β-lactamase as the sole β-lactamase responsible for ceftazidime resistance, whereas in two strains it was produced in combination with other acquired enzymes. Regardless of whether AmpC hyperproduction was the sole mechanism for ceftazidime resistance, there was a twoto four-dilution decrease in MICs for ceftazidime-avibactam relative to ceftazidime, except in one strain in which there was only a one-dilution decrease in MIC, from 64 µg/ml for ceftazidime to 32 µg/ml for ceftazidime-avibactam. This strain also possessed an OXA-17. Although no enzymatic inhibitory studies have been performed with avibactam and OXA-17, avibactam has been shown to be variable at inhibiting class D β-lactamases. The MIC for ceftazidime ranged from 16 to >64 µg/ml, whereas the range for ceftazidime-avibactam was 4 to 32 µg/ml. In conclusion, ceftazidime-avibactam was highly active against isolates with the majority of MICs 8 µg/ml in this phase 3 clinical study. This included isolates that were not susceptible to ceftazidime, due to ESBL, carbapenemases (KPC or OXA-48),

8 and/or upregulated AmpC production. In addition, isolates of Enterobacteriaceae that had ceftazidime-avibactam MICs >8 µg/ml produced class B enzymes that are not inhibited by avibactam. The ceftazidime-avibactam MIC 90 against P. aeruginosa isolated in this clinical study, which included a high proportion of strains with class B or D enzymes that avibactam does not inhibit, was 64 µg/ml. Ceftazidime-avibactam was shown to have good efficacy and was well tolerated in this global trial (5), suggesting the utility of ceftazidime-avibactam in treating patients with cuti or ciai caused by Gram-negative pathogens nonsusceptible to ceftazidime but susceptible to ceftazidime-avibactam. Overall, the activity of ceftazidime-avibactam against ceftazidime-nonsusceptible isolates was comparable to the activity of ceftazidime-avibactam previously reported against ceftazidime-susceptible isolates (14). Acknowledgements The authors would like to thank all investigators and patients involved in this clinical trial program. Editorial support was provided by Prime Medica Ltd, Knutsford, Cheshire, UK, funded by AstraZeneca. Funding This work was supported by AstraZeneca and Actavis plc. Ceftazidime-avibactam is being developed by AstraZeneca and Actavis plc, a subsidiary of Allergan Inc. All

9 authors had full access to all trial data and take responsibility for the integrity of the data and the accuracy of the data analysis Transparency declarations GGS, PAB, PN, and AW were employees and shareholders of AstraZeneca at the time the study was conducted. Downloaded from on December 27, 2018 by guest

10 154 References Stachyra T, Levasseur P, Pechereau MC, Girard AM, Claudon M, Miossec C, Black MT In vitro activity of the β-lactamase inhibitor NXL104 against KPC-2 carbapenemase and Enterobacteriaceae expressing KPC carbapenemases. J Antimicrob Chemother 64: Ehmann DE, Jahic H, Ross PL, Gu RF, Hu J, Kern G, Walkup GK, Fisher SL Avibactam is a covalent, reversible, non-β-lactam β-lactamase inhibitor. Proc Natl Acad Sci U S A 109: Zhanel GG, Lawson CD, Adam H, Schweizer F, Zelenitsky S, Lagace-Wiens PR, Denisuik A, Rubinstein E, Gin AS, Hoban DJ, Lynch JP, 3rd, Karlowsky JA Ceftazidime-avibactam: a novel cephalosporin/β-lactamase inhibitor combination. Drugs 73: Li H, Estabrook M, Jacoby GA, Nichols WW, Testa RT, Bush K In vitro susceptibility of characterized β-lactamase-producing strains tested with avibactam combinations. Antimicrob Agents Chemother 59: Carmeli Y, Armstrong J, Laud PJ, Newell P, Stone G, Wardman A, Gasink LB Ceftazidime-avibactam or best available therapy in patients with ceftazidime-resistant Enterobacteriaceae and Pseudomonas aeruginosa

11 complicated urinary tract infections or complicated intra-abdominal infections (REPRISE): a randomised, pathogen-directed, phase 3 study. Lancet Infect Dis 16: Clinical Laboratory Standards Institute Performance standards for antimicrobial susceptibility testing. Twenty-second informational supplement. Wayne, PA: CLSI. 7. Clinical Laboratory Standards Institute Methods of dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard - 8th edition. Wayne, PA: CLSI. 8. US Food and Drug Administration Tygacil prescribing information. l.pdf. Accessed 19 May Mendes RE, Castanheira M, Woolsey LN, Costello SE, Stone GG, Flamm RK, Jones RN β-lactamase characterization of baseline Enterobacteriaceae from a Phase 3 trial of ceftazidime-avibactam for the treatment of infections caused by ceftazidime-non-susceptible pathogens, abstr IDWeek, San Diego, CA, October 7-11.

12 Stone G, Reiszner E, Hackel M, Badal R Activity of ceftazidime-avibactam (CAZ-AVI) against ESBL positive Enterobacteriaceae (Entb) and CAZ-resistant Pseudomonas aeruginosa from urinary tract infections in Asia/South pacific, Europe, Middle East/Africa and Latin America in the 2013 INFORM surveillance program, abstr MONDAY-268. ASM Microbe, Boston, MA, June Levasseur P, Girard AM, Claudon M, Goossens H, Black MT, Coleman K, Miossec C In vitro antibacterial activity of the ceftazidime-avibactam (NXL104) combination against Pseudomonas aeruginosa clinical isolates. Antimicrob Agents Chemother 56: Hackel M, Stone G, DeJonge B, Sahm DF In vitro activity of ceftazidime-avibactam and comparators against Pseudomonas aeruginosa from Europe , abstr P th European Congress on Clinical Microbiology and Infectious Diseases, Amsterdam, the Netherlands, April Sader HS, Castanheira M, Mendes RE, Flamm RK, Farrell DJ, Jones RN Ceftazidime-avibactam activity against multidrug-resistant Pseudomonas aeruginosa isolated in U.S. medical centers in 2012 and Antimicrob Agents Chemother 59:

13 Flamm RK, Stone GG, Sader HS, Jones RN, Nichols WW Avibactam reverts the ceftazidime MIC90 of European Gram-negative bacterial clinical isolates to the epidemiological cut-off value. J Chemother 26: Bush K Proliferation and significance of clinically relevant β-lactamases. Ann N Y Acad Sci 1277: US Food and Drug Administration FDA approves new antibacterial drug Avycaz. Accessed 19 May Downloaded from on December 27, 2018 by guest

14 TABLE 1 In vitro activity of ceftazidime-avibactam and other agents against Gram-negative isolates from patients enrolled in the phase 3 clinical trial (all randomized patients) Total (N = 333) Range (µg/ml) MIC 50 MIC 90 %S Baseline pathogen Agent n (µg/ml) (µg/ml) Enterobacteriaceae All pathogens Ceftazidime-avibactam > Ceftazidime >64 64 > Amikacin >64 4 > Ciprofloxacin >4 >4 > Colistin > a Gentamicin >16 >16 > Imipenem Meropenem >

15 Total (N = 333) Range (µg/ml) MIC 50 Baseline pathogen Agent n (µg/ml) MIC 90 %S (µg/ml) Piperacillin/tazobactam > > Tigecycline b Trimethoprim/sulfamethoxazole >8 >8 > Enterobacter cloacae Ceftazidime-avibactam > Ceftazidime >64 64 >64 0 Amikacin 17 1 >64 2 > Ciprofloxacin >4 >4 > Colistin > Gentamicin >16 >16 > Imipenem Meropenem >

16 Total (N = 333) Range (µg/ml) MIC 50 Baseline pathogen Agent n (µg/ml) MIC 90 %S (µg/ml) Piperacillin/tazobactam 17 2 > > Tigecycline Trimethoprim/sulfamethoxazole >8 <=0.25 > Escherichia coli Ceftazidime-avibactam Ceftazidime >64 32 > Amikacin > Ciprofloxacin >4 >4 >4 7.2 Colistin Gentamicin >16 16 > Imipenem Meropenem

17 Total (N = 333) Range (µg/ml) MIC 50 Baseline pathogen Agent n (µg/ml) MIC 90 %S (µg/ml) Piperacillin/tazobactam >128 8 > Tigecycline Trimethoprim/sulfamethoxazole >8 >8 > Klebsiella pneumoniae Ceftazidime-avibactam > Ceftazidime >64 >64 > Amikacin >64 4 > Ciprofloxacin >4 >4 >4 3.8 Colistin Gentamicin >16 >16 > Imipenem Meropenem >

18 Total (N = 333) Range (µg/ml) MIC 50 Baseline pathogen Agent n (µg/ml) MIC 90 %S (µg/ml) Piperacillin/tazobactam > > Tigecycline Trimethoprim/sulfamethoxazole >8 >8 > Other Ceftazidime-avibactam Enterobacteriaceae* Ceftazidime >64 64 > Amikacin >64 4 > Ciprofloxacin >4 >4 > Colistin >128 >128 > b Gentamicin >16 >16 >

19 Non-fermenters Total (N = 333) Range (µg/ml) MIC 50 Baseline pathogen Agent n (µg/ml) MIC 90 %S (µg/ml) Imipenem Meropenem > Piperacilin/tazobactam > > Tigecycline b Trimethoprim/sulfamethoxazole >8 >8 > Pseudomonas Ceftazidime-avibactam aeruginosa Ceftazidime 27 1 >64 64 > Amikacin > Cefepime 27 1 >16 16 > Ciprofloxacin >4 >4 >4 18.5

20 Total (N = 333) Range (µg/ml) MIC 50 Baseline pathogen Agent n (µg/ml) MIC 90 %S (µg/ml) Colistin Gentamicin 27 1 >16 >16 > Imipenem > Meropenem >8 1 > Piperacillin/tazobactam > > a The %S is based on EUCAST breakpoints and includes species with intrinsic resistance to colistin b The %S is based on EUCAST breakpoints and includes species with reduced susceptibility to tigecycline MIC50 and MIC90 were not calculated for pathogens with N < 10 patients. A patient can have more than one pathogen. Multiple isolates of the same species from the same patient are counted only once using the isolate with the highest MIC to study drug received. 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 study drug received across culture source (urine or blood).

21 N Number of patients in treatment group. n Number of pathogens tested. *Other Enterobacteriaceae include: Citrobacter freundii (7), Enterobacter aerogenes (2), Klebsiella oxytoca (1), Morganella morganii (15), Proteus mirabilis (16), Providencia rettgeri (15), Providencia stuartii (15), Raoultella terrigena (15), and Serratia marcescens (1) Downloaded from on December 27, 2018 by guest

22 TABLE 2 In vitro activity of ceftazidime-avibactam against Gram-negative isolates from patients enrolled in the phase 3 clinical trial by ESBL phenotype (all randomized patients) Total (N = 333) MIC 50 MIC 90 %S Baseline Pathogen ESBL status a n Range (µg/ml) (µg/ml) (µg/ml) Enterobacteriaceae Escherichia coli ESBL phenotype positive ESBL phenotype negative Klebsiella pneumoniae ESBL phenotype positive ESBL phenotype negative > Proteus mirabilis ESBL phenotype positive NA b NA 100 ESBL phenotype negative NA NA 100 a Genetic identification β-lactamases was provided as previously described (JMI Laboratories, Inc., North Liberty, IA) (9). b NA: Not Applicable. A MIC50 and MIC90 values were not calculated for pathogens with N < 10 patients.

23 A patient could have more than one pathogen. Multiple isolates of the same species from the same patient are counted only once using the isolate with the highest MIC to study drug received. 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 study drug received across culture source (urine or blood). N Number of patients in treatment group. n Number of pathogens tested. Downloaded from on December 27, 2018 by guest

24 FIG 1. MIC frequency distribution of ceftazidime-avibactam and ceftazidime against ceftazidime-resistant Enterobacteriaceae isolated from patients enrolled in the phase 3 clinical trial. frequency ceftazidime CAZ-AVI Downloaded from <= >64 MIC (ug/ml) on December 27, 2018 by guest

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