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

AAC Accepted Manuscript Posted Online 21 November 2016 Antimicrob. Agents Chemother. doi:10.1128/aac.01820-16 Copyright 2016, American Society for Microbiology. All Rights Reserved. 1 2 3 4 5 6 7 8 9 10 11 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 02451 Phone: 781-839-4425; Fax: 781-839-4630; Email: Gregory.stone@astrazeneca.com

12 Abstract 13 14 15 16 17 18 19 20 21 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 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 http://aac.asm.org/ on December 27, 2018 by guest

22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 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

43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 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

64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 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

86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 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

107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 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),

128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 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

148 149 authors had full access to all trial data and take responsibility for the integrity of the data and the accuracy of the data analysis. 150 151 152 153 Transparency declarations GGS, PAB, PN, and AW were employees and shareholders of AstraZeneca at the time the study was conducted. Downloaded from http://aac.asm.org/ on December 27, 2018 by guest

154 References 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 1. Stachyra T, Levasseur P, Pechereau MC, Girard AM, Claudon M, Miossec C, Black MT. 2009. In vitro activity of the β-lactamase inhibitor NXL104 against KPC-2 carbapenemase and Enterobacteriaceae expressing KPC carbapenemases. J Antimicrob Chemother 64:326-329. 2. Ehmann DE, Jahic H, Ross PL, Gu RF, Hu J, Kern G, Walkup GK, Fisher SL. 2012. Avibactam is a covalent, reversible, non-β-lactam β-lactamase inhibitor. Proc Natl Acad Sci U S A 109:11663-11668. 3. 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. 2013. Ceftazidime-avibactam: a novel cephalosporin/β-lactamase inhibitor combination. Drugs 73:159-177. 4. Li H, Estabrook M, Jacoby GA, Nichols WW, Testa RT, Bush K. 2015. In vitro susceptibility of characterized β-lactamase-producing strains tested with avibactam combinations. Antimicrob Agents Chemother 59:1789-1793. 5. Carmeli Y, Armstrong J, Laud PJ, Newell P, Stone G, Wardman A, Gasink LB. 2016. Ceftazidime-avibactam or best available therapy in patients with ceftazidime-resistant Enterobacteriaceae and Pseudomonas aeruginosa

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207 208 209 14. Flamm RK, Stone GG, Sader HS, Jones RN, Nichols WW. 2014. Avibactam reverts the ceftazidime MIC90 of European Gram-negative bacterial clinical isolates to the epidemiological cut-off value. J Chemother 26:333-338. 210 211 212 213 214 215 216 15. Bush K. 2013. Proliferation and significance of clinically relevant β-lactamases. Ann N Y Acad Sci 1277:84-90. 16. US Food and Drug Administration. 2015. FDA approves new antibacterial drug Avycaz. http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm435629.htm. Accessed 19 May 2016. Downloaded from http://aac.asm.org/ on December 27, 2018 by guest

217 218 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 314 0.008 >256 0.25 1 98.7 Ceftazidime 314 0.06 >64 64 >64 9.9 Amikacin 314 0.25 >64 4 >64 86.6 Ciprofloxacin 314 0.015 >4 >4 >4 10.8 Colistin 314 0.12 >128 1 2 91.4 a Gentamicin 314 0.12 >16 >16 >16 40.1 Imipenem 314 0.06 64 0.12 0.5 93.9 Meropenem 314 0.015 >8 0.03 0.25 95.9

Total (N = 333) Range (µg/ml) MIC 50 Baseline pathogen Agent n (µg/ml) MIC 90 %S (µg/ml) Piperacillin/tazobactam 314 0.12 >128 16 >128 52.5 Tigecycline 314 0.12 8 0.5 2 81.8 b Trimethoprim/sulfamethoxazole 314 0.25 >8 >8 >8 34.7 Enterobacter cloacae Ceftazidime-avibactam 17 0.25 >256 0.5 4 94.1 Ceftazidime 17 16 >64 64 >64 0 Amikacin 17 1 >64 2 >64 76.5 Ciprofloxacin 17 0.015 >4 >4 >4 41.2 Colistin 17 0.5 >128 1 2 94.1 Gentamicin 17 0.25 >16 >16 >16 41.2 Imipenem 17 0.12 16 0.25 0.5 94.1 Meropenem 17 0.03 >8 0.06 0.25 94.1

Total (N = 333) Range (µg/ml) MIC 50 Baseline pathogen Agent n (µg/ml) MIC 90 %S (µg/ml) Piperacillin/tazobactam 17 2 >128 128 >128 23.5 Tigecycline 17 0.25 8 1 4 58.8 Trimethoprim/sulfamethoxazole 17 0.25 >8 <=0.25 >8 70.6 Escherichia coli Ceftazidime-avibactam 139 0.008 8 0.12 1 100 Ceftazidime 139 0.12 >64 32 >64 13.7 Amikacin 139 0.5 >64 4 8 95.7 Ciprofloxacin 139 0.015 >4 >4 >4 7.2 Colistin 139 0.12 4 1 2 97.1 Gentamicin 139 0.25 >16 16 >16 48.2 Imipenem 139 0.06 1 0.12 0.25 100 Meropenem 139 0.015 1 0.03 0.06 100

Total (N = 333) Range (µg/ml) MIC 50 Baseline pathogen Agent n (µg/ml) MIC 90 %S (µg/ml) Piperacillin/tazobactam 139 1 >128 8 >128 75.5 Tigecycline 139 0.12 1 0.25 0.5 100 Trimethoprim/sulfamethoxazole 139 0.25 >8 >8 >8 62.6 Klebsiella pneumoniae Ceftazidime-avibactam 131 0.06 >256 0.5 1 98.5 Ceftazidime 131 0.06 >64 >64 >64 5.3 Amikacin 131 0.25 >64 4 >64 81.0 Ciprofloxacin 131 0.03 >4 >4 >4 3.8 Colistin 131 0.25 64 1 2 94.0 Gentamicin 131 0.12 >16 >16 >16 32.1 Imipenem 131 0.06 64 0.12 1 90.8 Meropenem 131 0.015 >8 0.06 1 91.6

Total (N = 333) Range (µg/ml) MIC 50 Baseline pathogen Agent n (µg/ml) MIC 90 %S (µg/ml) Piperacillin/tazobactam 131 1 >128 128 >128 31.3 Tigecycline 131 0.25 8 1 2 74.0 Trimethoprim/sulfamethoxazole 131 0.25 >8 >8 >8 27.5 Other Ceftazidime-avibactam 27 0.03 256 0.5 2 96.3 Enterobacteriaceae* Ceftazidime 27 0.12 >64 64 >64 18.5 Amikacin 27 0.5 >64 4 >64 74.1 Ciprofloxacin 27 0.015 >4 >4 >4 18.5 Colistin 27 0.5 >128 >128 >128 48.1 100 b Gentamicin 27 0.25 >16 >16 >16 37.0

Non-fermenters Total (N = 333) Range (µg/ml) MIC 50 Baseline pathogen Agent n (µg/ml) MIC 90 %S (µg/ml) Imipenem 27 0.12 16 0.5 4 77.8 Meropenem 27 0.015 >8 0.06 0.25 96.3 Piperacilin/tazobactam 27 0.12 >128 16 >128 55.6 Tigecycline 27 0.25 8 2 8 40.7 b Trimethoprim/sulfamethoxazole 27 0.25 >8 >8 >8 33.3 Pseudomonas Ceftazidime-avibactam 27 1 256 8 64 55.6 aeruginosa Ceftazidime 27 1 >64 64 >64 29.6 Amikacin 27 0.5 >64 16 64 55.6 Cefepime 27 1 >16 16 >16 29.6 Ciprofloxacin 27 0.06 >4 >4 >4 18.5

219 220 221 222 223 224 Total (N = 333) Range (µg/ml) MIC 50 Baseline pathogen Agent n (µg/ml) MIC 90 %S (µg/ml) Colistin 27 0.5 4 2 4 100 Gentamicin 27 1 >16 >16 >16 33.3 Imipenem 27 0.5 >64 2 16 55.6 Meropenem 27 0.06 >8 1 >8 59.3 Piperacillin/tazobactam 27 0.5 >128 64 >128 33.3 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).

225 226 227 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 http://aac.asm.org/ on December 27, 2018 by guest

228 229 230 231 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 108 0.008 2 0.12 0.5 100 ESBL phenotype negative 31 0.06 8 0.25 8 100 Klebsiella pneumoniae ESBL phenotype positive 106 0.12 2 0.5 1 100 ESBL phenotype negative 25 0.06 >256 0.5 4 92.0 Proteus mirabilis ESBL phenotype positive 2 0.06 0.5 NA b NA 100 ESBL phenotype negative 7 0.03 2 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.

232 233 234 235 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 http://aac.asm.org/ on December 27, 2018 by guest

236 237 238 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 140 120 100 80 60 40 20 ceftazidime CAZ-AVI Downloaded from http://aac.asm.org/ 239 240 0 <=0.06 0.12 0.25 0.5 1 2 4 8 16 32 64 >64 MIC (ug/ml) on December 27, 2018 by guest