Activity of cephalosporin CXA-101 (FR264205) and comparators against extended-spectrum- -lactamase-producing Pseudomonas aeruginosa

Sir, Extended-spectrum β-lactamases (ESBLs), belonging to Ambler classes A and D, or ESBLA and ESBLM-D according to the recently suggested novel classification,1 are sometimes encountered in Pseudomonas aeruginosa.2 Although the consequences of the emergence of metallo-β-lactamases (MBLs; ESBLCARBA-B) are even more devastating, the emergence of ESBLA and ESBLM-D (oxacillinases) in P. aeruginosa still poses a substantial therapeutic challenge. Also, piperacillin/tazobactam has been found to have limited activity against ESBLA-producing P. aeruginosa.2 Recently, the cephalosporin CXA-101 (Calixa Therapeutics Inc., San Diego, CA, USA) has completed Phase I trials and in vitro this agent has been found to have excellent antipseudomonal activity,3 but no data are currently available on the activity of this agent, with and without β-lactamase inhibitors, against characterized clinical isolates of ESBL-producing P. aeruginosa. A collection of previously characterized ESBLA-producing (n = 9) and ESBLM-D-producing (n = 1) P. aeruginosa was obtained from Hôpital de Bicêtre, Paris, France. The collection consisted of 10 clinical isolates of P. aeruginosa producing the β-lactamases GES-2, GES-9, VEB-1, VEB-1-A, PER-1, BEL-1, SHV-2a, SHV-5, TEM-4 and OXA-32.2,4–6 The clinical isolates were subjected to antimicrobial susceptibility testing by broth microdilution (Sensititre; Trek Diagnostic Systems, Cleveland, OH, USA). The following antimicrobial agents were tested: CXA-101; CXA-101 with a fixed tazobactam concentration of 4 mg/L; CXA-101 with a fixed tazobactam concentration of 8 mg/L; ceftazidime; ceftazidime with a fixed tazobactam concentration of 4 mg/L; ceftazidime with a fixed clavulanate concentration of 2 mg/L; piperacillin; piperacillin with a fixed tazobactam concentration of 4 mg/L; cefepime; and imipenem. European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints were used for piperacillin with and without tazobactam, ceftazidime, cefepime and imipenem.7 For CXA-101 with and without tazobactam and for ceftazidime with tazobactam or clavulanate, ceftazidime breakpoints were used tentatively due to the similarities in pharmacokinetic properties.3 Whereas all except one isolate (TEM-4) were resistant to ceftazidime, four isolates (producing SHV-2a, SHV-5, TEM-4 and BEL-1) had CXA-101 MICs of ≤4 mg/L (Table 1). Only one of these isolates was susceptible to piperacillin/tazobactam (producing TEM-4) and one isolate to cefepime (producing BEL-1) when EUCAST breakpoints were applied (for piperacillin/tazobactam: susceptible, ≤16 mg/L; and resistant, >16 mg/L). In one of these isolates (producing SHV-5) the MIC of CXA-101 was reduced from 4 to 1 mg/L upon the addition of tazobactam. The addition of tazobactam was of no benefit in strains producing GES, VEB and PER β-lactamases, which all had CXA-101 MICs >64 mg/L. In the only isolate producing an ESBLM-D β-lactamase (OXA-32), the MIC was reduced from >64 to 8 mg/L. The OXA-32-producing isolate was also susceptible to piperacillin/tazobactam. Susceptibility to piperacillin/tazobactam was additionally seen in one isolate (producing PER-1), which was resistant to all β-lactams except imipenem and ceftazidime plus clavulanate. The latter combination was found to have activity against four isolates (producing PER-1, BEL-1, SHV-5 and TEM-4). MICs (mg/L) of CXA-101 plus tazobactam versus comparators for clinical isolates of P. aeruginosa Abbreviations of antimicrobial agents with susceptibility breakpoints derived from EUCAST in brackets (susceptible ≤ /resistant > ): CXA, CXA-101 (tentative breakpoint 8/8); CXT4, CXA-101 with a fixed tazobactam concentration of 4 mg/L (tentative breakpoint 8/8); CXT8, CXA-101 with a fixed tazobactam concentration of 8 mg/L (tentative breakpoint 8/8); CAZ, ceftazidime (8/8); CAT, ceftazidime with a fixed tazobactam concentration of 4 mg/L (tentative breakpoint 8/8); CAC, ceftazidime with a fixed clavulanate concentration of 2 mg/L (tentative breakpoint 8/8); PIP, piperacillin (16/16); TZP, piperacillin with a fixed tazobactam concentration of 4 mg/L (16/16); FEP, cefepime (8/8); and IPM, imipenem (4/8). MICs (mg/L) of CXA-101 plus tazobactam versus comparators for clinical isolates of P. aeruginosa Abbreviations of antimicrobial agents with susceptibility breakpoints derived from EUCAST in brackets (susceptible ≤ /resistant > ): CXA, CXA-101 (tentative breakpoint 8/8); CXT4, CXA-101 with a fixed tazobactam concentration of 4 mg/L (tentative breakpoint 8/8); CXT8, CXA-101 with a fixed tazobactam concentration of 8 mg/L (tentative breakpoint 8/8); CAZ, ceftazidime (8/8); CAT, ceftazidime with a fixed tazobactam concentration of 4 mg/L (tentative breakpoint 8/8); CAC, ceftazidime with a fixed clavulanate concentration of 2 mg/L (tentative breakpoint 8/8); PIP, piperacillin (16/16); TZP, piperacillin with a fixed tazobactam concentration of 4 mg/L (16/16); FEP, cefepime (8/8); and IPM, imipenem (4/8). In conclusion, CXA-101 was found to have good in vitro activity against 4/9 ESBLA-producing P. aeruginosa. The addition of tazobactam extended the activity to the one ESBLM-D-producing isolate tested. Hence, CXA-101 plus tazobactam had good in vitro activity against half of the ESBL-producing P. aeruginosa isolates investigated. In comparison, imipenem had activity against 9/10 isolates, ceftazidime plus clavulanate against 4/10 isolates, piperacillin/tazobactam against 3/10 isolates, cefepime against 2/10 isolates and ceftazidime or ceftazidime plus tazobactam against 1/10 isolates. This study was funded by Calixa Therapeutics Inc. J. G. is the CSO of Calixa Therapeutics Inc. He is also a stockholder in the same company. C. G. G. and P. N.: none to declare.