Efficacy and safety of ceftazidime/avibactam: a systematic review and meta-analysis

Efficacy and safety of ceftazidime/avibactam: a systematic review and meta-analysis Abstract Background Ceftazidime/avibactam is approved for complicated intra-abdominal and urinary tract infections (UTIs) based on results from randomized controlled trials (RCTs). Data regarding its effectiveness in treating hospital-acquired infections or resistant pathogens have not been systematically compiled. Methods A systematic review and meta-analysis including RCTs evaluating ceftazidime/avibactam versus comparator for the treatment of any infection. Primary outcome was 30 day all-cause mortality. Subgroups of hospital-acquired infections and specific resistance phenotypes were planned. Results Seven publications (eight trials, 4093 patients) were included, reporting a baseline ∼25% of ESBL-carrying Enterobacteriaceae. No significant difference between ceftazidime/avibactam and comparator (mostly carbapenem) was demonstrated for 30 day all-cause mortality, late follow-up mortality and clinical response [relative risk (RR) 1.10, 95% CI 0.70–1.72, P = 0.69; RR 1.23, 95% CI 0.87–1.76, P = 0.25; RR 0.98, 95% CI 0.96–1.01, P = 0.21, respectively, without significant heterogeneity]. Higher microbiological response rate was demonstrated with ceftazidime/avibactam in patients with UTI (RR 1.14, 1.0–1.29, P = 0.05, I2 = 51%). No significant difference in clinical response was demonstrated for patients with ceftazidime-resistant pathogens (RR 1.02, 95% CI 0.94–1.10, P = 0.66, I2 = 0%). Results for other subgroups of resistant pathogens or hospital-acquired infection were not available. Serious adverse events (SAEs) were significantly more common with ceftazidime/avibactam (RR 1.24, 95% CI 1.00–1.54, P = 0.05, I2 = 0%). Conclusions Ceftazidime/avibactam is clinically and microbiologically as effective as carbapenems for treatment of infections in a setting of ∼25% ESBL-carrying Enterobacteriaceae. Safety of the drug should be further evaluated owing to a higher rate of SAEs compared with carbapenems. Further studies should assess the drug’s effectiveness in the treatment of carbapenemase-producing Enterobacteriaceae. Introduction The prevalence of MDR Gram-negative bacteria, including ESBL-producing Enterobacteriaceae and carbapenem-resistant Enterobacteriaceae (CRE) is increasing globally with a high risk of morbidity and mortality from these infections.1 Carbapenems are considered by some to be the treatment of choice in serious infections caused by ESBL-producing bacteria;2 however, carbapenem resistance is now emerging and carbapenem-sparing regimens are warranted.3–5 Ceftazidime/avibactam has in vitro activity against Ambler class A, class C and some class D β-lactamase-producing bacteria, including Enterobacteriaceae and Pseudomonas aeruginosa. It has no activity against metallo-β-lactamase-producing organisms.6–8 Based on several randomized control trials (RCTs), ceftazidime/avibactam was approved by the US FDA and EMA for the treatment of complicated urinary tract infection (cUTI) and complicated intra-abdominal infection (cIAI) in adults with limited or no alternative treatment options.8 Small series have also demonstrated the effectiveness of this drug for the treatment of CRE infections.9,10 In an era of increasing resistance, a β-lactam drug with a broad spectrum may have the potential to be used as empirical therapy for various hospital-acquired infections in locations with high resistance rates. We aimed to evaluate whether the existing evidence supports ceftazidime/avibactam as empirical therapy in such conditions. We performed a systemic review and meta-analysis compiling all RCTs assessing the efficacy and safety of ceftazidime/avibactam for the treatment of various bacterial infections. We planned to assess the efficacy of this drug for the treatment of complicated infections and specifically for subgroups of patients infected with resistant pathogens. Methods This systematic review and meta-analysis was conducted according to the PRISMA guidelines.11 Inclusion criteria and outcomes We included RCTs that compared ceftazidime/avibactam, with or without metronidazole, versus any other antibiotic regimen for the treatment of any infection among adult patients. The primary outcome was 30 day all-cause mortality and if that was unavailable, mortality at the end of follow-up. Secondary outcomes included: clinical response, as defined in individual studies; microbiological response (per patient and per pathogen, as available); superinfections; development of resistance; any adverse events (AEs) and serious AEs (SAEs), AEs requiring discontinuation, renal and liver AEs, and Clostridium difficile-associated diarrhoea. Search strategy and selection criteria We searched the PubMed, Cochrane Central Register of Controlled Trials (Central) and LILACS databases. The search term ‘ceftazidime/avibactam’ OR ‘avibactam’ OR ‘NXL104’ OR ‘AVE1330A’ was combined with the Cochrane filter for RCTs for the PubMed search.12 For the Cochrane library and LILACS databases search, the term ‘ceftazidime/avibactam’ OR ‘avibactam’ OR ‘NXL104’ OR ‘AVE1330A’ was used. Unpublished trials were sought in references of all selected studies, relevant conference proceedings, trial registries and ongoing trial databases and through personal contact with the investigators of the included studies. No language or date restrictions were imposed. The last search was conducted in December 2017. Study selection and data extraction Two reviewers (N. S. and D. Y.) independently conducted the search and decided on publications for inclusion. Extraction of data was conducted by two independent reviewers for each study (N. S., Y. L. W. or D. Y.). For all outcomes we extracted data on the largest patient population available. Intention-to-treat data were mostly unavailable from the included trials, thus data were extracted by modified or microbiologically modified intention-to-treat population if available, and otherwise by clinically or microbiologically evaluated population, as defined in individual trials. We planned to address antibiotic resistance data as suggested by Leibovici et al.13 Risk of bias was assessed using the following domains recommended by the Cochrane handbook:12 allocation sequence generation and allocation concealment, blinding, incomplete outcome data assessment, selective outcome reporting and early termination of the trial. These were graded as low, high or unknown risk of bias according to the criteria suggested by the Cochrane handbook.12 In order to assess the effect of risk of bias on outcomes, we planned to perform sensitivity analyses by the above elaborated domains. For all included studies we recorded the type of infection assessed, pathogens, race, gender, mean age, BMI, CLCR, mean APACHE II score and proportion of the study population with monomicrobial infection, bacteraemia, APACHE II score >10, prior antibiotic use/failure and a baseline resistant pathogen. Statistical analysis We compiled relative risks (RRs) and 95% CIs of individual trials using a Mantel–Haenszel fixed or random effects model. Heterogeneity in the results of the trials was assessed using the χ2 test for heterogeneity and the I2 measure of inconsistency.14 For results with substantial heterogeneity (I2 > 50%) we used the random effects model, otherwise the fixed effects model was used. Data were analysed using Review Manager 5.2 software (RevMan). For the outcomes of mortality and AEs, RRs <1 favour ceftazidime/avibactam. For the outcomes of clinical or microbiological success, RRs <1 favour comparators. Comparisons were subcategorized by the type of infection. Subgroup analyses for mortality and clinical response were planned for bacteraemic patients, patients with APACHE II score >10, patients with P. aeruginosa infection, patients with ceftazidime-resistant pathogens, patients with CRE infection and patients with hospital-acquired infections. Owing to the small number of included studies we did not use a funnel plot to assess small-studies effects. Results A flow chart of the trials is presented in Figure 1. Seven publications representing eight trials (4093 patients) that compared ceftazidime/avibactam ± metronidazole versus any other antibiotic regimen for treatment of cUTI, cIAI and nosocomial pneumonia were included in this review.15–21 The main comparator was a carbapenem (Table 1). Place of infection acquisition was explicitly described as hospital-acquired in only one trial.19 Table 1. Characteristics of included trials Randomizationa Study ID Type of infection Comparator drug Patients randomized (n) generation concealment Blinding MTZ added to CAZ/AVI? Additional antibiotic coverage allowed Vazquez et al.20 cUTI IPM/cilastatin 137 A A double-blind Qin et al.18 cIAI MEM 441 A A double-blind yes Gram-positive Carmeli et al.15 cUTI, cIAI best available therapy, mostly carbapenemb 333 A A open-label yes for cIAI Torres et al.19 nosocomial pneumonia MEM 879 A A double-blind Gram-positive and amikacinc Lucasti et al.16 cIAI MEM 204 A A double-blind yes Gram-positive Mazuski et al.17 cIAI MEM 1066 A A double-blind yes Gram-positive Wagenlehner et al.21 cUTI DOR 1033 A A double-blind Randomizationa Study ID Type of infection Comparator drug Patients randomized (n) generation concealment Blinding MTZ added to CAZ/AVI? Additional antibiotic coverage allowed Vazquez et al.20 cUTI IPM/cilastatin 137 A A double-blind Qin et al.18 cIAI MEM 441 A A double-blind yes Gram-positive Carmeli et al.15 cUTI, cIAI best available therapy, mostly carbapenemb 333 A A open-label yes for cIAI Torres et al.19 nosocomial pneumonia MEM 879 A A double-blind Gram-positive and amikacinc Lucasti et al.16 cIAI MEM 204 A A double-blind yes Gram-positive Mazuski et al.17 cIAI MEM 1066 A A double-blind yes Gram-positive Wagenlehner et al.21 cUTI DOR 1033 A A double-blind CAZ/AVI, ceftazidime/avibactam; DOR, doripenem; MEM, meropenem; IPM, imipenem; MTZ, metronidazole. a Randomization generation and concealment: ‘A’ represents low risk of bias. b Only 7/168 patients assigned to best available therapy in this publication were reported to receive a regimen other than carbapenem monotherapy. c 80% of patients in the CAZ/AVI arm and 82% in the comparator arm were given amikacin. Table 1. Characteristics of included trials Randomizationa Study ID Type of infection Comparator drug Patients randomized (n) generation concealment Blinding MTZ added to CAZ/AVI? Additional antibiotic coverage allowed Vazquez et al.20 cUTI IPM/cilastatin 137 A A double-blind Qin et al.18 cIAI MEM 441 A A double-blind yes Gram-positive Carmeli et al.15 cUTI, cIAI best available therapy, mostly carbapenemb 333 A A open-label yes for cIAI Torres et al.19 nosocomial pneumonia MEM 879 A A double-blind Gram-positive and amikacinc Lucasti et al.16 cIAI MEM 204 A A double-blind yes Gram-positive Mazuski et al.17 cIAI MEM 1066 A A double-blind yes Gram-positive Wagenlehner et al.21 cUTI DOR 1033 A A double-blind Randomizationa Study ID Type of infection Comparator drug Patients randomized (n) generation concealment Blinding MTZ added to CAZ/AVI? Additional antibiotic coverage allowed Vazquez et al.20 cUTI IPM/cilastatin 137 A A double-blind Qin et al.18 cIAI MEM 441 A A double-blind yes Gram-positive Carmeli et al.15 cUTI, cIAI best available therapy, mostly carbapenemb 333 A A open-label yes for cIAI Torres et al.19 nosocomial pneumonia MEM 879 A A double-blind Gram-positive and amikacinc Lucasti et al.16 cIAI MEM 204 A A double-blind yes Gram-positive Mazuski et al.17 cIAI MEM 1066 A A double-blind yes Gram-positive Wagenlehner et al.21 cUTI DOR 1033 A A double-blind CAZ/AVI, ceftazidime/avibactam; DOR, doripenem; MEM, meropenem; IPM, imipenem; MTZ, metronidazole. a Randomization generation and concealment: ‘A’ represents low risk of bias. b Only 7/168 patients assigned to best available therapy in this publication were reported to receive a regimen other than carbapenem monotherapy. c 80% of patients in the CAZ/AVI arm and 82% in the comparator arm were given amikacin. Figure 1. View largeDownload slide Trial selection flow chart. Figure 1. View largeDownload slide Trial selection flow chart. All included trials were industry-sponsored multicentre trials. All but three publications15,16,20 were designed as non-inferiority trials using a non-inferiority margin of 10%–12.5%. All trials had low risk of bias for allocation generation, allocation concealment, selective outcome reporting and incomplete outcome assessment. One publication15 was open-label whereas all others were double-blinded. This publication also reported on early discontinuation of recruitment because the funder considered that a sufficient number of patients had been recruited by that time. Dosing and route of administration of study drugs are presented in Table S1 (available as Supplementary data at JAC Online). Planned duration of therapy ranged between 5 and 21 days. Additional antibiotics permitted are shown in Table 1. Follow-up in all trials was performed at end-of-treatment (EOT), test-of-cure (TOC) and late-follow-up (LFU) visits (see Table S2 for definitions in individual trials). Primary outcome: 30 day all-cause mortality (Figure 2) Overall, 36/610 (5.9%) patients died within 30 days in the ceftazidime/avibactam arm and 34/629 (5.4%) in the comparator arm. Mortality for long-term follow-up was 64/1956 (3.3%) in the ceftazidime/avibactam arm and 52/1957 (2.7%) in the comparator arm. All-cause 30 day mortality was reported in four trials including 1239 patients (one UTI,15 two IAI15,16 and one pneumonia trial19). No significant difference in mortality was demonstrated between ceftazidime/avibactam and the comparator (RR 1.1, 95% CI 0.7–1.72, P = 0.69, I2 = 0). Seven trials including 3915 patients reported all-cause mortality at LFU with no significant difference between study arms (RR 1.23, 95% CI 0.87–1.76, P = 0.25, I2 = 0). Among subcategories of type of infection, no statistically significant difference in mortality was demonstrated (Figure 2). Figure 2. View largeDownload slide All-cause mortality at late follow-up. M-H, Mantel–Haenszel. Figure 2. View largeDownload slide All-cause mortality at late follow-up. M-H, Mantel–Haenszel. Data on mortality in the pre-specified subgroups were not available in any of the trials. Sensitivity analysis separating trials by blinding demonstrated no significant difference in mortality at LFU between study arms among studies that were double-blinded (RR 1.27, 95% CI 0.88–1.84, 5 trials, P = 0.20, I2 = 0%). Clinical response Clinical response in the included trials was evaluated at EOT, TOC and LFU (definitions of timepoints of evaluation are summarized in Table S2). At all of these timepoints no significant difference was demonstrated between study arms. Eight trials reported clinical response at the TOC visit (3292 patients) with no difference between study arms (RR 0.98, 95% CI 0.96–1.01, P = 0.21, I2 = 0) (Table 2). Table 2. Clinical responsea Response rate Time of follow-up No. of trials No. of patients RR 95% CI CAZ/AVI comparator EOT 7 2591 0.99 0.98–1.01 1214/1276 (95%) 1261/1315 (96%)  UTI 3 1155 0.99 0.97–1.01  IAI 4 1436 1.00 0.97–1.02 TOC 8 3292 0.98 0.96–1.01 1390/1619 (86%) 1460/1673 (87%)  UTI 3 1155 1.00 0.96–1.03  IAI 4 1411 0.99 0.96–1.02  pneumonia 1 726 0.94 0.86–1.04 LFU 7 2551 1.00 0.97–1.03 1096/1253 (87%) 1131/1298 (87%)  UTI 3 1154 1.01 0.96–1.07  IAI 4 1397 0.99 0.96–1.03 Response rate Time of follow-up No. of trials No. of patients RR 95% CI CAZ/AVI comparator EOT 7 2591 0.99 0.98–1.01 1214/1276 (95%) 1261/1315 (96%)  UTI 3 1155 0.99 0.97–1.01  IAI 4 1436 1.00 0.97–1.02 TOC 8 3292 0.98 0.96–1.01 1390/1619 (86%) 1460/1673 (87%)  UTI 3 1155 1.00 0.96–1.03  IAI 4 1411 0.99 0.96–1.02  pneumonia 1 726 0.94 0.86–1.04 LFU 7 2551 1.00 0.97–1.03 1096/1253 (87%) 1131/1298 (87%)  UTI 3 1154 1.01 0.96–1.07  IAI 4 1397 0.99 0.96–1.03 CAZ/AVI, ceftazidime/avibactam. a There was no heterogeneity (I2 = 0%) for all these outcomes. Table 2. Clinical responsea Response rate Time of follow-up No. of trials No. of patients RR 95% CI CAZ/AVI comparator EOT 7 2591 0.99 0.98–1.01 1214/1276 (95%) 1261/1315 (96%)  UTI 3 1155 0.99 0.97–1.01  IAI 4 1436 1.00 0.97–1.02 TOC 8 3292 0.98 0.96–1.01 1390/1619 (86%) 1460/1673 (87%)  UTI 3 1155 1.00 0.96–1.03  IAI 4 1411 0.99 0.96–1.02  pneumonia 1 726 0.94 0.86–1.04 LFU 7 2551 1.00 0.97–1.03 1096/1253 (87%) 1131/1298 (87%)  UTI 3 1154 1.01 0.96–1.07  IAI 4 1397 0.99 0.96–1.03 Response rate Time of follow-up No. of trials No. of patients RR 95% CI CAZ/AVI comparator EOT 7 2591 0.99 0.98–1.01 1214/1276 (95%) 1261/1315 (96%)  UTI 3 1155 0.99 0.97–1.01  IAI 4 1436 1.00 0.97–1.02 TOC 8 3292 0.98 0.96–1.01 1390/1619 (86%) 1460/1673 (87%)  UTI 3 1155 1.00 0.96–1.03  IAI 4 1411 0.99 0.96–1.02  pneumonia 1 726 0.94 0.86–1.04 LFU 7 2551 1.00 0.97–1.03 1096/1253 (87%) 1131/1298 (87%)  UTI 3 1154 1.01 0.96–1.07  IAI 4 1397 0.99 0.96–1.03 CAZ/AVI, ceftazidime/avibactam. a There was no heterogeneity (I2 = 0%) for all these outcomes. Microbiological response (Figure 3) We evaluated microbiological response at both patient level and isolate level. Most of the results for microbiological response stemmed from cUTI trials, as expected considering the complexity of repeating cultures in cIAIs. Microbiological response per patient at the EOT was reported in four trials (1506 patients, 1151 of them cUTI) with no significant difference between study arms (RR 0.99, 95% CI 0.96–1.02, P = 0.36, I2 = 0). Similar results were reported at the TOC visit (5 trials, 1652 patients, RR 1.04, 95% CI 0.93–1.17, P = 0.51, I2 = 73%), (Figure 3). Compiling only trials including patients with UTI, a significantly higher rate of microbiological response was demonstrated among the ceftazidime/avibactam arm (three trials, 1153 patients, RR 1.14, 95% CI 1.0–1.29, P = 0.05, I2 = 51%). The significant heterogeneity was eliminated by excluding the study of Carmeli et al.15 without changing the results. At LFU, three UTI trials (1147 patients) also demonstrated a statistically significant advantage of ceftazidime/avibactam in terms of microbiological response (RR 1.15, 95% CI 1.05–1.26, P = 0.002, I2 = 12%). Figure 3. View largeDownload slide Microbiological response per patient at test of cure. M-H, Mantel–Haenszel. Figure 3. View largeDownload slide Microbiological response per patient at test of cure. M-H, Mantel–Haenszel. Microbiological response per isolate at TOC was reported from four trials (1419 patients) with significantly higher microbiological response in the ceftazidime/avibactam arm, stemming from two UTI trials (RR 1.14, 95% CI 1.04–1.24, P = 0.004, I2 = 68% for UTI trials). Subgroup analyses For patients with bacteraemia, four trials evaluating 152 patients demonstrated no significant difference in clinical response among study arms (RR 1.00, 95% CI 0.82–1.13, P = 0.97, I2 = 0%). No statistically significant difference in clinical response was demonstrated among patients with APACHE II score >10 (RR 0.93, 95% CI 0.86–1.01, P = 0.07, five trials, 995 patients, I2 = 0%). Eight trials (241 patients) reported on clinical response among patients with Pseudomonas aeruginosa infection without significant differences between study arms (RR 0.93, 95% CI 0.83–1.05, P = 0.24, I2 = 0%). Clinical response among patients with ceftazidime-resistant pathogens was also without significant difference between study arms (RR 1.02, 95% CI 0.94–1.10, P = 0.66, I2 = 0%, 6 trials, 480 patients). Several duplicate publications characterized β-lactamases in isolates from included patients22–26 (not described for the trial by Qin et al.18). Resistance profiles of isolates were determined according to the CLSI guidelines using the screening and confirmatory tests.27 Enterobacteriaceae displaying ceftriaxone and/or ceftazidime MIC ≥2 mg/L were further tested for narrow and extended β-lactamases genes. Among a total of 2327 Enterobacteriaceae isolated from all included trials, 613 (26%) were characterized as ESBL positive with variability across trials (highest rates of >60% in two trials).15,19 Clinical response at TOC was reported among patients with a positive screen in three trials (196 patients) with a response rate of 86% and without significant difference between study arms (RR 1.02, 95% CI 0.91–1.14, P = 0.76, without heterogeneity).16,17,20 The number of carbapenemase-producing Enterobacteriaceae (CPE) was highest in two trials: Carmeli et al.15 (including patients with ceftazidime-resistant bacteria) reported carbapenemases in 13/314 isolates (4%); and Torres et al.19 (including patients with nosocomial pneumonia) with 11/171 (6%). In the study of Carmeli et al.,15 13/27 Pseudomonas isolates were reported as harbouring class B or D β-lactamases. Other studies reported between zero and five carbapenemase-producing isolates. Response rates of patients with ESBL-, AmpC- or carbapenemase-producing organisms were reported from only one trial and thus were not compiled. Adverse events (Figure 4) Any AEs were reported in eight trials including 3988 patients. These included 974/1993 (49%) AEs in the ceftazidime/avibactam group and 943/1995 (47%) in the comparator group (RR 1.03, 95% CI 0.97–1.10, P = 0.28, I2 = 14%). AEs requiring discontinuation were without significant difference between arms (RR 1.55, 95% CI 0.98–2.46, P = 0.06, I2 = 0%). Among two trials evaluating cIAI a significantly higher rate of discontinuation was demonstrated for the ceftazidime/avibactam group (RR 2.11, 95% CI 1.00–4.44, P = 0.05, I2 = 0%). SAEs were statistically significantly more common in the ceftazidime/avibactam arm (RR 1.24, 95% CI 1.00–1.54, P = 0.05, I2 = 0%) (Figure 4). More detailed data concerning the nature of these SAEs were not available. Gastrointestinal AEs were significantly more common in the ceftazidime/avibactam group in trials evaluating cIAI (RR 1.61, 95% CI 1.31–1.97, P < 0.01, I2 = 31%). C. difficile-associated diarrhoea was reported in three trials with rates of 3/1255 patients in the ceftazidime/avibactam group and 1/1255 patients in the comparator group. Creatinine increase was significantly more common in the ceftazidime/avibactam group (RR 3.00, 95% CI 1.09–8.20, P = 0.03, I2 = 0%), though this result stemmed from one study.17 Other AEs had no significant difference between study arms, including liver function abnormalities, pyrexia, peripheral oedema, hypersensitivity reactions and neurological AEs. Figure 4. View largeDownload slide Serious adverse events. M-H, Mantel–Haenszel. Figure 4. View largeDownload slide Serious adverse events. M-H, Mantel–Haenszel. Development of resistance Resistance to study drugs at baseline is summarized in Table S3. Two trials reported at least a 4-fold increase in MIC at TOC: Torres et al.19 reported such an increase in 2/125 (1.6%) pathogens in the ceftazidime/avibactam group and 11/131 (8.4%) in the comparator group; and Wagenlehner et al.21 reported 8/393 (2.0%) and 3/317 (0.9%), respectively. Other outcomes Superinfections were documented in three studies: two studies described surgical site infections in a total of 16/630 (2.5%) patients in the ceftazidime/avibactam arm and 17/631 (2.7%) patients in the comparator arm.16,17 Another study reported 0/125 and 3/131 superinfections among ceftazidime/avibactam and comparator, respectively, in patients with nosocomial pneumonia.19 Duration of hospitalization and number of re-admissions were not reported in any of the trials. Discussion We conducted a systematic review and meta-analysis of RCTs comparing ceftazidime/avibactam with any other comparator, mainly carbapenems. We found no significant difference in 30 day mortality and mortality at the end of follow-up between study arms. Clinical response rates were also similar between ceftazidime/avibactam and comparators. Microbiological response was significantly higher for the ceftazidime/avibactam arm in cUTI trials. In trials assessing patients with cIAIs, gastrointestinal AEs and AEs requiring drug discontinuation were significantly more common in the ceftazidime/avibactam arm. SAEs were significantly more common with ceftazidime/avibactam. No significant difference in clinical response was documented for patients with bacteraemia or patients with ceftazidime-resistant pathogens. Data were not available for the pre-planned subgroups of patients with hospital-acquired infections and CRE infections. However, approximately a quarter of baseline isolates in the included trials possessed ESBLs, making the meta-analysis results valid in the setting of hospital-acquired infections in a centre with similar rates of ESBL infections. The comparator in the vast majority of cases was a carbapenem. Use of carbapenems is described to be associated with development of CRE and thus, carbapenems are usually used as last-resort drugs.28,29 Owing to the limited data regarding resistance development in our review we cannot draw conclusions on the association between any of the studied drugs and CRE development. In addition, in a previous systematic review and meta-analysis, higher rates of C. difficile-associated diarrhoea were reported with carbapenems compared with β-lactam/β-lactamase inhibitor combinations.30 This could also not be supported by the current review owing to limited reporting on C. difficile in the included trials. The data presented in this review are from recent RCTs with high methodological quality conducted in various geographical locations. However, there are several limitations for this review. Mortality in the included trials was ∼6% at 30 days. This rate is lower than that described for similar infections in non-randomized studies, for example 12.1% 30 day mortality for complicated diverticulitis,31 10.1% for cIAI in general32 and above 20% for nosocomial pneumonia.33 Lower mortality in RCTs involving antibiotics compared with non-randomized studies has been previously discussed by Paul et al.,34 raising concerns regarding the limited external validity of RCTs in infectious diseases. Exclusion criteria in the trials included in our review were severe renal or liver impairment, immunocompromised and no expected response to antibiotics within 5–21 days. It is possible that excluding patients fulfilling these criteria had an influence on the lower mortality rate compared with non-randomized studies. In addition, conclusions on the drug effectiveness and safety in such patients cannot be drawn. The higher microbiological response rate demonstrated for ceftazidime/avibactam in cUTI studies, stemming mainly from the study by Carmeli et al.,15 might be because of a better response of carbapenemase-producing pathogens included in this study to ceftazidime/avibactam. Most trials used the maximum approved dose of ceftazidime/avibactam in an extended infusion, as opposed to the comparator used in most trials, which was at a low dose and with non-extended administration. We assume that dosage and route of administration have no significant influence in cUTI studies; however, it may bias the results in favour of ceftazidime/avibactam in other infections, as suggested by Kalil and Klompas35 reviewing the RCT by Torres et al.19 including nosocomial pneumonia patients. In conclusion, ceftazidime/avibactam is clinically as effective as carbapenems for the treatment of cUTI, cIAI and nosocomial pneumonia in a setting in which ∼25% of Enterobacteriaceae are ESBL positive. Microbiological response in patients with cUTI is superior with ceftazidime/avibactam. Safety of the drug should be further evaluated due to the higher rate of SAEs compared with carbapenems. Data are too scarce to draw conclusions regarding effectiveness of the drug in CRE infections. Ceftazidime/avibactam may probably be used as a carbapenem-sparing drug, though studies evaluating the drug’s effectiveness specifically for ESBL infections are needed. In addition, individual patient data meta-analysis compiling ESBL infections from the included trials may also be helpful. Funding This study was carried out as part of our routine work. Transparency declarations None to declare. Supplementary data Tables S1 to S3 are available as Supplementary data at JAC Online. References 1 Carlet J , Jarlier V , Harbarth S et al. Ready for a world without antibiotics? The Pensières Antibiotic Resistance Call to Action . Antimicrob Resist Infect Control 2012 ; 1 : 11 . Google Scholar CrossRef Search ADS PubMed 2 Pitout JD. Infections with extended-spectrum β-lactamase-producing Enterobacteriaceae: changing epidemiology and drug treatment choices . Drugs 2010 ; 70 : 313 – 33 . Google Scholar CrossRef Search ADS PubMed 3 Kanj SS , Kanafani ZA. Current concepts in antimicrobial therapy against resistant gram-negative organisms: extended-spectrum β-lactamase-producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, and multidrug-resistant Pseudomonas aeruginosa . Mayo Clin Proc 2011 ; 86 : 250 – 9 . Google Scholar CrossRef Search ADS PubMed 4 Nordmann P , Cuzon G , Naas T. The real threat of Klebsiella pneumoniae carbapenemase-producing bacteria . Lancet Infect Dis 2009 ; 9 : 228 – 36 . Google Scholar CrossRef Search ADS PubMed 5 Pfeifer Y , Cullik A , Witte W. Resistance to cephalosporins and carbapenems in Gram-negative bacterial pathogens . Int J Med Microbiol 2010 ; 300 : 371 – 9 . Google Scholar CrossRef Search ADS PubMed 6 Livermore DM , Meunier D , Hopkins KL et al. Activity of ceftazidime/avibactam against problem Enterobacteriaceae and Pseudomonas aeruginosa in the UK, 2015-16 . J Antimicrob Chemother 2018 ; 73 : 648 – 57 . Google Scholar CrossRef Search ADS 7 Tuon FF , Rocha JL , Formigoni-Pinto MR. Pharmacological aspects and spectrum of action of ceftazidime-avibactam: a systematic review . Infection 2017 ; doi:10.1007/s15010-017-1096-y. 8 Wright H , Bonomo RA , Paterson DL. New agents for the treatment of infections with Gram-negative bacteria: restoring the miracle or false dawn? Clin Microbiol Infect 2017 ; 23 : 704 – 12 . Google Scholar CrossRef Search ADS PubMed 9 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 : pii: e00883-17. 10 van Duin D , Lok JJ , Earley M et al. Colistin versus ceftazidime-avibactam in the treatment of infections due to carbapenem-resistant Enterobacteriaceae . Clin Infect Dis 2018 ; 66 : 163 – 71 . Google Scholar CrossRef Search ADS PubMed 11 Liberati A , Altman DG , Tetzlaff J et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration . PLoS Med 2009 ; 6 : e1000100 . Google Scholar CrossRef Search ADS PubMed 12 Higgins JG. Cochrane Handbook for Systematic Reviews of Interventions. 2011 . http://handbook-5-1.cochrane.org/. 13 Leibovici L , Paul M , Garner P et al. Addressing resistance to antibiotics in systematic reviews of antibiotic interventions . J Antimicrob Chemother 2016 ; 71 : 2367 – 9 . Google Scholar CrossRef Search ADS PubMed 14 Higgins JP , Thompson SG , Deeks JJ et al. Measuring inconsistency in meta-analyses . BMJ 2003 ; 327 : 557 – 60 . Google Scholar CrossRef Search ADS PubMed 15 Carmeli Y , Armstrong J , Laud PJ et al. Ceftazidime-avibactam or best available therapy in patients with ceftazidime-resistant Enterobacteriaceae and Pseudomonas aeruginosa complicated urinary tract infections or complicated intra-abdominal infections (REPRISE): a randomised, pathogen-directed, phase 3 study . Lancet Infect Dis 2016 ; 16 : 661 – 73 . Google Scholar CrossRef Search ADS PubMed 16 Lucasti C , Popescu I , Ramesh MK et al. Comparative study of the efficacy and safety of ceftazidime/avibactam plus metronidazole versus meropenem in the treatment of complicated intra-abdominal infections in hospitalized adults: results of a randomized, double-blind, Phase II trial . J Antimicrob Chemother 2013 ; 68 : 1183 – 92 . Google Scholar CrossRef Search ADS PubMed 17 Mazuski JE , Gasink LB , Armstrong J et al. Efficacy and safety of ceftazidime-avibactam plus metronidazole versus meropenem in the treatment of complicated intra-abdominal infection: results from a randomized, controlled, double-blind, phase 3 program . Clin Infect Dis 2016 ; 62 : 1380 – 9 . Google Scholar CrossRef Search ADS PubMed 18 Qin X , Tran BG , Kim MJ et al. A randomised, double-blind, phase 3 study comparing the efficacy and safety of ceftazidime/avibactam plus metronidazole versus meropenem for complicated intra-abdominal infections in hospitalised adults in Asia . Int J Antimicrob Agents 2017 ; 49 : 579 – 88 . Google Scholar CrossRef Search ADS PubMed 19 Torres A , Zhong N , Pachl J et al. Ceftazidime-avibactam versus meropenem in nosocomial pneumonia, including ventilator-associated pneumonia (REPROVE): a randomised, double-blind, phase 3 non-inferiority trial . Lancet Infect Dis 2018 ; 18 : 285 – 95 . Google Scholar CrossRef Search ADS PubMed 20 Vazquez JA , González Patzán LD , Stricklin D et al. Efficacy and safety of ceftazidime-avibactam versus imipenem-cilastatin in the treatment of complicated urinary tract infections, including acute pyelonephritis, in hospitalized adults: results of a prospective, investigator-blinded, randomized study . Curr Med Res Opin 2012 ; 28 : 1921 – 31 . Google Scholar CrossRef Search ADS PubMed 21 Wagenlehner FM , Sobel JD , Newell P et al. Ceftazidime-avibactam versus doripenem for the treatment of complicated urinary tract infections, including acute pyelonephritis: rECAPTURE, a phase 3 randomized trial program . Clin Infect Dis 2016 ; 63 : 754 – 62 . Google Scholar CrossRef Search ADS PubMed 22 Mendes RC , Woosley M , Doyle LN et al. β-lactamase characterization of baseline Gram-negative pathogens from a phase 3 trial of ceftazidime-avibactam (CAZ-AVI) for the treatment of nosocomial pneumonia. Abstract P0408. In: Abstracts of the Twenty-seventh ECCMID, Vienna, Austria, 2017. European Society for Clinical Microbiology and Infectious Diseases. 23 Mendes RE , Castanheira M , Gasink L et al. β-lactamase characterization of Gram-negative pathogens recovered from patients enrolled in the phase 2 trials for ceftazidime-avibactam: clinical efficacies analyzed against subsets of molecularly characterized isolates . Antimicrob Agents Chemother 2015 ; 60 : 1328 – 35 . Google Scholar CrossRef Search ADS PubMed 24 Mendes RE , Castanheira M , Woosley LN et al. Molecular β-lactamase characterization of aerobic Gram-negative pathogens recovered from patients enrolled in the ceftazidime-avibactam phase 3 trials for complicated intra-abdominal infections, with efficacies analyzed against susceptible and resistant subsets . Antimicrob Agents Chemother 2017 ; 61 : pii: e02447 – 16 . Google Scholar CrossRef Search ADS PubMed 25 Stone GG , Bradford PA , Newell P et al. 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 . Antimicrob Agents Chemother 2017 ; 61 : pii: e02447-16. 26 Stone GG , Bradford PA , Yates K et al. In vitro activity of ceftazidime/avibactam against urinary isolates from patients in a Phase 3 clinical trial programme for the treatment of complicated urinary tract infections . J Antimicrob Chemother 2017 ; 72 : 1396 – 9 . Google Scholar PubMed 27 Clinical and Laboratory Standards Institute . Performance Standards for Antimicrobial Susceptibility Testing: Twenty-Second Informational Supplement M100-S22 . CLSI , Wayne, PA, USA , 2012 . 28 Kwak YG , Choi SH , Choo EJ et al. Risk factors for the acquisition of carbapenem-resistant Klebsiella pneumoniae among hospitalized patients . Microb Drug Resist 2005 ; 11 : 165 – 9 . Google Scholar CrossRef Search ADS PubMed 29 Schwaber MJ , Klarfeld-Lidji S , Navon-Venezia S et al. Predictors of carbapenem-resistant Klebsiella pneumoniae acquisition among hospitalized adults and effect of acquisition on mortality . Antimicrob Agents Chemother 2008 ; 52 : 1028 – 33 . Google Scholar CrossRef Search ADS PubMed 30 Shiber S , Yahav D , Avni T et al. β-Lactam/β-lactamase inhibitors versus carbapenems for the treatment of sepsis: systematic review and meta-analysis of randomized controlled trials . J Antimicrob Chemother 2015 ; 70 : 41 – 7 . Google Scholar CrossRef Search ADS PubMed 31 Coccolini F , Trevisan M , Montori G et al. Mortality rate and antibiotic resistance in complicated diverticulitis: report of 272 consecutive patients worldwide: a prospective cohort study . Surg Infect (Larchmt) 2017 ; doi:10.1089/sur.2016.283. 32 Sartelli M , Catena F , Ansaloni L et al. Complicated intra-abdominal infections in a worldwide context: an observational prospective study (CIAOW Study) . World J Emerg Surg 2013 ; 8 : 1 . Google Scholar CrossRef Search ADS PubMed 33 Kalil AC , Metersky ML , Klompas M et al. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society . Clin Infect Dis 2016 ; 63 : e61 – 111 . Google Scholar CrossRef Search ADS PubMed 34 Paul M , Bronstein E , Yahav D et al. External validity of a randomised controlled trial on the treatment of severe infections caused by MRSA . BMJ Open 2015 ; 5 : e008838 . Google Scholar CrossRef Search ADS PubMed 35 Kalil AC , Klompas M. Ceftazidime-avibactam versus meropenem for the treatment of nosocomial pneumonia . Lancet Infect Dis 2017 ; 18 : 229 – 31 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Antimicrobial Chemotherapy Oxford University Press

Efficacy and safety of ceftazidime/avibactam: a systematic review and meta-analysis

Journal of Antimicrobial Chemotherapy , Volume Advance Article (8) – Apr 6, 2018

Loading next page...
 
/lp/ou_press/efficacy-and-safety-of-ceftazidime-avibactam-a-systematic-review-and-m0dtASeV8a
Publisher
Oxford University Press
Copyright
© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.
ISSN
0305-7453
eISSN
1460-2091
D.O.I.
10.1093/jac/dky124
Publisher site
See Article on Publisher Site

Abstract

Abstract Background Ceftazidime/avibactam is approved for complicated intra-abdominal and urinary tract infections (UTIs) based on results from randomized controlled trials (RCTs). Data regarding its effectiveness in treating hospital-acquired infections or resistant pathogens have not been systematically compiled. Methods A systematic review and meta-analysis including RCTs evaluating ceftazidime/avibactam versus comparator for the treatment of any infection. Primary outcome was 30 day all-cause mortality. Subgroups of hospital-acquired infections and specific resistance phenotypes were planned. Results Seven publications (eight trials, 4093 patients) were included, reporting a baseline ∼25% of ESBL-carrying Enterobacteriaceae. No significant difference between ceftazidime/avibactam and comparator (mostly carbapenem) was demonstrated for 30 day all-cause mortality, late follow-up mortality and clinical response [relative risk (RR) 1.10, 95% CI 0.70–1.72, P = 0.69; RR 1.23, 95% CI 0.87–1.76, P = 0.25; RR 0.98, 95% CI 0.96–1.01, P = 0.21, respectively, without significant heterogeneity]. Higher microbiological response rate was demonstrated with ceftazidime/avibactam in patients with UTI (RR 1.14, 1.0–1.29, P = 0.05, I2 = 51%). No significant difference in clinical response was demonstrated for patients with ceftazidime-resistant pathogens (RR 1.02, 95% CI 0.94–1.10, P = 0.66, I2 = 0%). Results for other subgroups of resistant pathogens or hospital-acquired infection were not available. Serious adverse events (SAEs) were significantly more common with ceftazidime/avibactam (RR 1.24, 95% CI 1.00–1.54, P = 0.05, I2 = 0%). Conclusions Ceftazidime/avibactam is clinically and microbiologically as effective as carbapenems for treatment of infections in a setting of ∼25% ESBL-carrying Enterobacteriaceae. Safety of the drug should be further evaluated owing to a higher rate of SAEs compared with carbapenems. Further studies should assess the drug’s effectiveness in the treatment of carbapenemase-producing Enterobacteriaceae. Introduction The prevalence of MDR Gram-negative bacteria, including ESBL-producing Enterobacteriaceae and carbapenem-resistant Enterobacteriaceae (CRE) is increasing globally with a high risk of morbidity and mortality from these infections.1 Carbapenems are considered by some to be the treatment of choice in serious infections caused by ESBL-producing bacteria;2 however, carbapenem resistance is now emerging and carbapenem-sparing regimens are warranted.3–5 Ceftazidime/avibactam has in vitro activity against Ambler class A, class C and some class D β-lactamase-producing bacteria, including Enterobacteriaceae and Pseudomonas aeruginosa. It has no activity against metallo-β-lactamase-producing organisms.6–8 Based on several randomized control trials (RCTs), ceftazidime/avibactam was approved by the US FDA and EMA for the treatment of complicated urinary tract infection (cUTI) and complicated intra-abdominal infection (cIAI) in adults with limited or no alternative treatment options.8 Small series have also demonstrated the effectiveness of this drug for the treatment of CRE infections.9,10 In an era of increasing resistance, a β-lactam drug with a broad spectrum may have the potential to be used as empirical therapy for various hospital-acquired infections in locations with high resistance rates. We aimed to evaluate whether the existing evidence supports ceftazidime/avibactam as empirical therapy in such conditions. We performed a systemic review and meta-analysis compiling all RCTs assessing the efficacy and safety of ceftazidime/avibactam for the treatment of various bacterial infections. We planned to assess the efficacy of this drug for the treatment of complicated infections and specifically for subgroups of patients infected with resistant pathogens. Methods This systematic review and meta-analysis was conducted according to the PRISMA guidelines.11 Inclusion criteria and outcomes We included RCTs that compared ceftazidime/avibactam, with or without metronidazole, versus any other antibiotic regimen for the treatment of any infection among adult patients. The primary outcome was 30 day all-cause mortality and if that was unavailable, mortality at the end of follow-up. Secondary outcomes included: clinical response, as defined in individual studies; microbiological response (per patient and per pathogen, as available); superinfections; development of resistance; any adverse events (AEs) and serious AEs (SAEs), AEs requiring discontinuation, renal and liver AEs, and Clostridium difficile-associated diarrhoea. Search strategy and selection criteria We searched the PubMed, Cochrane Central Register of Controlled Trials (Central) and LILACS databases. The search term ‘ceftazidime/avibactam’ OR ‘avibactam’ OR ‘NXL104’ OR ‘AVE1330A’ was combined with the Cochrane filter for RCTs for the PubMed search.12 For the Cochrane library and LILACS databases search, the term ‘ceftazidime/avibactam’ OR ‘avibactam’ OR ‘NXL104’ OR ‘AVE1330A’ was used. Unpublished trials were sought in references of all selected studies, relevant conference proceedings, trial registries and ongoing trial databases and through personal contact with the investigators of the included studies. No language or date restrictions were imposed. The last search was conducted in December 2017. Study selection and data extraction Two reviewers (N. S. and D. Y.) independently conducted the search and decided on publications for inclusion. Extraction of data was conducted by two independent reviewers for each study (N. S., Y. L. W. or D. Y.). For all outcomes we extracted data on the largest patient population available. Intention-to-treat data were mostly unavailable from the included trials, thus data were extracted by modified or microbiologically modified intention-to-treat population if available, and otherwise by clinically or microbiologically evaluated population, as defined in individual trials. We planned to address antibiotic resistance data as suggested by Leibovici et al.13 Risk of bias was assessed using the following domains recommended by the Cochrane handbook:12 allocation sequence generation and allocation concealment, blinding, incomplete outcome data assessment, selective outcome reporting and early termination of the trial. These were graded as low, high or unknown risk of bias according to the criteria suggested by the Cochrane handbook.12 In order to assess the effect of risk of bias on outcomes, we planned to perform sensitivity analyses by the above elaborated domains. For all included studies we recorded the type of infection assessed, pathogens, race, gender, mean age, BMI, CLCR, mean APACHE II score and proportion of the study population with monomicrobial infection, bacteraemia, APACHE II score >10, prior antibiotic use/failure and a baseline resistant pathogen. Statistical analysis We compiled relative risks (RRs) and 95% CIs of individual trials using a Mantel–Haenszel fixed or random effects model. Heterogeneity in the results of the trials was assessed using the χ2 test for heterogeneity and the I2 measure of inconsistency.14 For results with substantial heterogeneity (I2 > 50%) we used the random effects model, otherwise the fixed effects model was used. Data were analysed using Review Manager 5.2 software (RevMan). For the outcomes of mortality and AEs, RRs <1 favour ceftazidime/avibactam. For the outcomes of clinical or microbiological success, RRs <1 favour comparators. Comparisons were subcategorized by the type of infection. Subgroup analyses for mortality and clinical response were planned for bacteraemic patients, patients with APACHE II score >10, patients with P. aeruginosa infection, patients with ceftazidime-resistant pathogens, patients with CRE infection and patients with hospital-acquired infections. Owing to the small number of included studies we did not use a funnel plot to assess small-studies effects. Results A flow chart of the trials is presented in Figure 1. Seven publications representing eight trials (4093 patients) that compared ceftazidime/avibactam ± metronidazole versus any other antibiotic regimen for treatment of cUTI, cIAI and nosocomial pneumonia were included in this review.15–21 The main comparator was a carbapenem (Table 1). Place of infection acquisition was explicitly described as hospital-acquired in only one trial.19 Table 1. Characteristics of included trials Randomizationa Study ID Type of infection Comparator drug Patients randomized (n) generation concealment Blinding MTZ added to CAZ/AVI? Additional antibiotic coverage allowed Vazquez et al.20 cUTI IPM/cilastatin 137 A A double-blind Qin et al.18 cIAI MEM 441 A A double-blind yes Gram-positive Carmeli et al.15 cUTI, cIAI best available therapy, mostly carbapenemb 333 A A open-label yes for cIAI Torres et al.19 nosocomial pneumonia MEM 879 A A double-blind Gram-positive and amikacinc Lucasti et al.16 cIAI MEM 204 A A double-blind yes Gram-positive Mazuski et al.17 cIAI MEM 1066 A A double-blind yes Gram-positive Wagenlehner et al.21 cUTI DOR 1033 A A double-blind Randomizationa Study ID Type of infection Comparator drug Patients randomized (n) generation concealment Blinding MTZ added to CAZ/AVI? Additional antibiotic coverage allowed Vazquez et al.20 cUTI IPM/cilastatin 137 A A double-blind Qin et al.18 cIAI MEM 441 A A double-blind yes Gram-positive Carmeli et al.15 cUTI, cIAI best available therapy, mostly carbapenemb 333 A A open-label yes for cIAI Torres et al.19 nosocomial pneumonia MEM 879 A A double-blind Gram-positive and amikacinc Lucasti et al.16 cIAI MEM 204 A A double-blind yes Gram-positive Mazuski et al.17 cIAI MEM 1066 A A double-blind yes Gram-positive Wagenlehner et al.21 cUTI DOR 1033 A A double-blind CAZ/AVI, ceftazidime/avibactam; DOR, doripenem; MEM, meropenem; IPM, imipenem; MTZ, metronidazole. a Randomization generation and concealment: ‘A’ represents low risk of bias. b Only 7/168 patients assigned to best available therapy in this publication were reported to receive a regimen other than carbapenem monotherapy. c 80% of patients in the CAZ/AVI arm and 82% in the comparator arm were given amikacin. Table 1. Characteristics of included trials Randomizationa Study ID Type of infection Comparator drug Patients randomized (n) generation concealment Blinding MTZ added to CAZ/AVI? Additional antibiotic coverage allowed Vazquez et al.20 cUTI IPM/cilastatin 137 A A double-blind Qin et al.18 cIAI MEM 441 A A double-blind yes Gram-positive Carmeli et al.15 cUTI, cIAI best available therapy, mostly carbapenemb 333 A A open-label yes for cIAI Torres et al.19 nosocomial pneumonia MEM 879 A A double-blind Gram-positive and amikacinc Lucasti et al.16 cIAI MEM 204 A A double-blind yes Gram-positive Mazuski et al.17 cIAI MEM 1066 A A double-blind yes Gram-positive Wagenlehner et al.21 cUTI DOR 1033 A A double-blind Randomizationa Study ID Type of infection Comparator drug Patients randomized (n) generation concealment Blinding MTZ added to CAZ/AVI? Additional antibiotic coverage allowed Vazquez et al.20 cUTI IPM/cilastatin 137 A A double-blind Qin et al.18 cIAI MEM 441 A A double-blind yes Gram-positive Carmeli et al.15 cUTI, cIAI best available therapy, mostly carbapenemb 333 A A open-label yes for cIAI Torres et al.19 nosocomial pneumonia MEM 879 A A double-blind Gram-positive and amikacinc Lucasti et al.16 cIAI MEM 204 A A double-blind yes Gram-positive Mazuski et al.17 cIAI MEM 1066 A A double-blind yes Gram-positive Wagenlehner et al.21 cUTI DOR 1033 A A double-blind CAZ/AVI, ceftazidime/avibactam; DOR, doripenem; MEM, meropenem; IPM, imipenem; MTZ, metronidazole. a Randomization generation and concealment: ‘A’ represents low risk of bias. b Only 7/168 patients assigned to best available therapy in this publication were reported to receive a regimen other than carbapenem monotherapy. c 80% of patients in the CAZ/AVI arm and 82% in the comparator arm were given amikacin. Figure 1. View largeDownload slide Trial selection flow chart. Figure 1. View largeDownload slide Trial selection flow chart. All included trials were industry-sponsored multicentre trials. All but three publications15,16,20 were designed as non-inferiority trials using a non-inferiority margin of 10%–12.5%. All trials had low risk of bias for allocation generation, allocation concealment, selective outcome reporting and incomplete outcome assessment. One publication15 was open-label whereas all others were double-blinded. This publication also reported on early discontinuation of recruitment because the funder considered that a sufficient number of patients had been recruited by that time. Dosing and route of administration of study drugs are presented in Table S1 (available as Supplementary data at JAC Online). Planned duration of therapy ranged between 5 and 21 days. Additional antibiotics permitted are shown in Table 1. Follow-up in all trials was performed at end-of-treatment (EOT), test-of-cure (TOC) and late-follow-up (LFU) visits (see Table S2 for definitions in individual trials). Primary outcome: 30 day all-cause mortality (Figure 2) Overall, 36/610 (5.9%) patients died within 30 days in the ceftazidime/avibactam arm and 34/629 (5.4%) in the comparator arm. Mortality for long-term follow-up was 64/1956 (3.3%) in the ceftazidime/avibactam arm and 52/1957 (2.7%) in the comparator arm. All-cause 30 day mortality was reported in four trials including 1239 patients (one UTI,15 two IAI15,16 and one pneumonia trial19). No significant difference in mortality was demonstrated between ceftazidime/avibactam and the comparator (RR 1.1, 95% CI 0.7–1.72, P = 0.69, I2 = 0). Seven trials including 3915 patients reported all-cause mortality at LFU with no significant difference between study arms (RR 1.23, 95% CI 0.87–1.76, P = 0.25, I2 = 0). Among subcategories of type of infection, no statistically significant difference in mortality was demonstrated (Figure 2). Figure 2. View largeDownload slide All-cause mortality at late follow-up. M-H, Mantel–Haenszel. Figure 2. View largeDownload slide All-cause mortality at late follow-up. M-H, Mantel–Haenszel. Data on mortality in the pre-specified subgroups were not available in any of the trials. Sensitivity analysis separating trials by blinding demonstrated no significant difference in mortality at LFU between study arms among studies that were double-blinded (RR 1.27, 95% CI 0.88–1.84, 5 trials, P = 0.20, I2 = 0%). Clinical response Clinical response in the included trials was evaluated at EOT, TOC and LFU (definitions of timepoints of evaluation are summarized in Table S2). At all of these timepoints no significant difference was demonstrated between study arms. Eight trials reported clinical response at the TOC visit (3292 patients) with no difference between study arms (RR 0.98, 95% CI 0.96–1.01, P = 0.21, I2 = 0) (Table 2). Table 2. Clinical responsea Response rate Time of follow-up No. of trials No. of patients RR 95% CI CAZ/AVI comparator EOT 7 2591 0.99 0.98–1.01 1214/1276 (95%) 1261/1315 (96%)  UTI 3 1155 0.99 0.97–1.01  IAI 4 1436 1.00 0.97–1.02 TOC 8 3292 0.98 0.96–1.01 1390/1619 (86%) 1460/1673 (87%)  UTI 3 1155 1.00 0.96–1.03  IAI 4 1411 0.99 0.96–1.02  pneumonia 1 726 0.94 0.86–1.04 LFU 7 2551 1.00 0.97–1.03 1096/1253 (87%) 1131/1298 (87%)  UTI 3 1154 1.01 0.96–1.07  IAI 4 1397 0.99 0.96–1.03 Response rate Time of follow-up No. of trials No. of patients RR 95% CI CAZ/AVI comparator EOT 7 2591 0.99 0.98–1.01 1214/1276 (95%) 1261/1315 (96%)  UTI 3 1155 0.99 0.97–1.01  IAI 4 1436 1.00 0.97–1.02 TOC 8 3292 0.98 0.96–1.01 1390/1619 (86%) 1460/1673 (87%)  UTI 3 1155 1.00 0.96–1.03  IAI 4 1411 0.99 0.96–1.02  pneumonia 1 726 0.94 0.86–1.04 LFU 7 2551 1.00 0.97–1.03 1096/1253 (87%) 1131/1298 (87%)  UTI 3 1154 1.01 0.96–1.07  IAI 4 1397 0.99 0.96–1.03 CAZ/AVI, ceftazidime/avibactam. a There was no heterogeneity (I2 = 0%) for all these outcomes. Table 2. Clinical responsea Response rate Time of follow-up No. of trials No. of patients RR 95% CI CAZ/AVI comparator EOT 7 2591 0.99 0.98–1.01 1214/1276 (95%) 1261/1315 (96%)  UTI 3 1155 0.99 0.97–1.01  IAI 4 1436 1.00 0.97–1.02 TOC 8 3292 0.98 0.96–1.01 1390/1619 (86%) 1460/1673 (87%)  UTI 3 1155 1.00 0.96–1.03  IAI 4 1411 0.99 0.96–1.02  pneumonia 1 726 0.94 0.86–1.04 LFU 7 2551 1.00 0.97–1.03 1096/1253 (87%) 1131/1298 (87%)  UTI 3 1154 1.01 0.96–1.07  IAI 4 1397 0.99 0.96–1.03 Response rate Time of follow-up No. of trials No. of patients RR 95% CI CAZ/AVI comparator EOT 7 2591 0.99 0.98–1.01 1214/1276 (95%) 1261/1315 (96%)  UTI 3 1155 0.99 0.97–1.01  IAI 4 1436 1.00 0.97–1.02 TOC 8 3292 0.98 0.96–1.01 1390/1619 (86%) 1460/1673 (87%)  UTI 3 1155 1.00 0.96–1.03  IAI 4 1411 0.99 0.96–1.02  pneumonia 1 726 0.94 0.86–1.04 LFU 7 2551 1.00 0.97–1.03 1096/1253 (87%) 1131/1298 (87%)  UTI 3 1154 1.01 0.96–1.07  IAI 4 1397 0.99 0.96–1.03 CAZ/AVI, ceftazidime/avibactam. a There was no heterogeneity (I2 = 0%) for all these outcomes. Microbiological response (Figure 3) We evaluated microbiological response at both patient level and isolate level. Most of the results for microbiological response stemmed from cUTI trials, as expected considering the complexity of repeating cultures in cIAIs. Microbiological response per patient at the EOT was reported in four trials (1506 patients, 1151 of them cUTI) with no significant difference between study arms (RR 0.99, 95% CI 0.96–1.02, P = 0.36, I2 = 0). Similar results were reported at the TOC visit (5 trials, 1652 patients, RR 1.04, 95% CI 0.93–1.17, P = 0.51, I2 = 73%), (Figure 3). Compiling only trials including patients with UTI, a significantly higher rate of microbiological response was demonstrated among the ceftazidime/avibactam arm (three trials, 1153 patients, RR 1.14, 95% CI 1.0–1.29, P = 0.05, I2 = 51%). The significant heterogeneity was eliminated by excluding the study of Carmeli et al.15 without changing the results. At LFU, three UTI trials (1147 patients) also demonstrated a statistically significant advantage of ceftazidime/avibactam in terms of microbiological response (RR 1.15, 95% CI 1.05–1.26, P = 0.002, I2 = 12%). Figure 3. View largeDownload slide Microbiological response per patient at test of cure. M-H, Mantel–Haenszel. Figure 3. View largeDownload slide Microbiological response per patient at test of cure. M-H, Mantel–Haenszel. Microbiological response per isolate at TOC was reported from four trials (1419 patients) with significantly higher microbiological response in the ceftazidime/avibactam arm, stemming from two UTI trials (RR 1.14, 95% CI 1.04–1.24, P = 0.004, I2 = 68% for UTI trials). Subgroup analyses For patients with bacteraemia, four trials evaluating 152 patients demonstrated no significant difference in clinical response among study arms (RR 1.00, 95% CI 0.82–1.13, P = 0.97, I2 = 0%). No statistically significant difference in clinical response was demonstrated among patients with APACHE II score >10 (RR 0.93, 95% CI 0.86–1.01, P = 0.07, five trials, 995 patients, I2 = 0%). Eight trials (241 patients) reported on clinical response among patients with Pseudomonas aeruginosa infection without significant differences between study arms (RR 0.93, 95% CI 0.83–1.05, P = 0.24, I2 = 0%). Clinical response among patients with ceftazidime-resistant pathogens was also without significant difference between study arms (RR 1.02, 95% CI 0.94–1.10, P = 0.66, I2 = 0%, 6 trials, 480 patients). Several duplicate publications characterized β-lactamases in isolates from included patients22–26 (not described for the trial by Qin et al.18). Resistance profiles of isolates were determined according to the CLSI guidelines using the screening and confirmatory tests.27 Enterobacteriaceae displaying ceftriaxone and/or ceftazidime MIC ≥2 mg/L were further tested for narrow and extended β-lactamases genes. Among a total of 2327 Enterobacteriaceae isolated from all included trials, 613 (26%) were characterized as ESBL positive with variability across trials (highest rates of >60% in two trials).15,19 Clinical response at TOC was reported among patients with a positive screen in three trials (196 patients) with a response rate of 86% and without significant difference between study arms (RR 1.02, 95% CI 0.91–1.14, P = 0.76, without heterogeneity).16,17,20 The number of carbapenemase-producing Enterobacteriaceae (CPE) was highest in two trials: Carmeli et al.15 (including patients with ceftazidime-resistant bacteria) reported carbapenemases in 13/314 isolates (4%); and Torres et al.19 (including patients with nosocomial pneumonia) with 11/171 (6%). In the study of Carmeli et al.,15 13/27 Pseudomonas isolates were reported as harbouring class B or D β-lactamases. Other studies reported between zero and five carbapenemase-producing isolates. Response rates of patients with ESBL-, AmpC- or carbapenemase-producing organisms were reported from only one trial and thus were not compiled. Adverse events (Figure 4) Any AEs were reported in eight trials including 3988 patients. These included 974/1993 (49%) AEs in the ceftazidime/avibactam group and 943/1995 (47%) in the comparator group (RR 1.03, 95% CI 0.97–1.10, P = 0.28, I2 = 14%). AEs requiring discontinuation were without significant difference between arms (RR 1.55, 95% CI 0.98–2.46, P = 0.06, I2 = 0%). Among two trials evaluating cIAI a significantly higher rate of discontinuation was demonstrated for the ceftazidime/avibactam group (RR 2.11, 95% CI 1.00–4.44, P = 0.05, I2 = 0%). SAEs were statistically significantly more common in the ceftazidime/avibactam arm (RR 1.24, 95% CI 1.00–1.54, P = 0.05, I2 = 0%) (Figure 4). More detailed data concerning the nature of these SAEs were not available. Gastrointestinal AEs were significantly more common in the ceftazidime/avibactam group in trials evaluating cIAI (RR 1.61, 95% CI 1.31–1.97, P < 0.01, I2 = 31%). C. difficile-associated diarrhoea was reported in three trials with rates of 3/1255 patients in the ceftazidime/avibactam group and 1/1255 patients in the comparator group. Creatinine increase was significantly more common in the ceftazidime/avibactam group (RR 3.00, 95% CI 1.09–8.20, P = 0.03, I2 = 0%), though this result stemmed from one study.17 Other AEs had no significant difference between study arms, including liver function abnormalities, pyrexia, peripheral oedema, hypersensitivity reactions and neurological AEs. Figure 4. View largeDownload slide Serious adverse events. M-H, Mantel–Haenszel. Figure 4. View largeDownload slide Serious adverse events. M-H, Mantel–Haenszel. Development of resistance Resistance to study drugs at baseline is summarized in Table S3. Two trials reported at least a 4-fold increase in MIC at TOC: Torres et al.19 reported such an increase in 2/125 (1.6%) pathogens in the ceftazidime/avibactam group and 11/131 (8.4%) in the comparator group; and Wagenlehner et al.21 reported 8/393 (2.0%) and 3/317 (0.9%), respectively. Other outcomes Superinfections were documented in three studies: two studies described surgical site infections in a total of 16/630 (2.5%) patients in the ceftazidime/avibactam arm and 17/631 (2.7%) patients in the comparator arm.16,17 Another study reported 0/125 and 3/131 superinfections among ceftazidime/avibactam and comparator, respectively, in patients with nosocomial pneumonia.19 Duration of hospitalization and number of re-admissions were not reported in any of the trials. Discussion We conducted a systematic review and meta-analysis of RCTs comparing ceftazidime/avibactam with any other comparator, mainly carbapenems. We found no significant difference in 30 day mortality and mortality at the end of follow-up between study arms. Clinical response rates were also similar between ceftazidime/avibactam and comparators. Microbiological response was significantly higher for the ceftazidime/avibactam arm in cUTI trials. In trials assessing patients with cIAIs, gastrointestinal AEs and AEs requiring drug discontinuation were significantly more common in the ceftazidime/avibactam arm. SAEs were significantly more common with ceftazidime/avibactam. No significant difference in clinical response was documented for patients with bacteraemia or patients with ceftazidime-resistant pathogens. Data were not available for the pre-planned subgroups of patients with hospital-acquired infections and CRE infections. However, approximately a quarter of baseline isolates in the included trials possessed ESBLs, making the meta-analysis results valid in the setting of hospital-acquired infections in a centre with similar rates of ESBL infections. The comparator in the vast majority of cases was a carbapenem. Use of carbapenems is described to be associated with development of CRE and thus, carbapenems are usually used as last-resort drugs.28,29 Owing to the limited data regarding resistance development in our review we cannot draw conclusions on the association between any of the studied drugs and CRE development. In addition, in a previous systematic review and meta-analysis, higher rates of C. difficile-associated diarrhoea were reported with carbapenems compared with β-lactam/β-lactamase inhibitor combinations.30 This could also not be supported by the current review owing to limited reporting on C. difficile in the included trials. The data presented in this review are from recent RCTs with high methodological quality conducted in various geographical locations. However, there are several limitations for this review. Mortality in the included trials was ∼6% at 30 days. This rate is lower than that described for similar infections in non-randomized studies, for example 12.1% 30 day mortality for complicated diverticulitis,31 10.1% for cIAI in general32 and above 20% for nosocomial pneumonia.33 Lower mortality in RCTs involving antibiotics compared with non-randomized studies has been previously discussed by Paul et al.,34 raising concerns regarding the limited external validity of RCTs in infectious diseases. Exclusion criteria in the trials included in our review were severe renal or liver impairment, immunocompromised and no expected response to antibiotics within 5–21 days. It is possible that excluding patients fulfilling these criteria had an influence on the lower mortality rate compared with non-randomized studies. In addition, conclusions on the drug effectiveness and safety in such patients cannot be drawn. The higher microbiological response rate demonstrated for ceftazidime/avibactam in cUTI studies, stemming mainly from the study by Carmeli et al.,15 might be because of a better response of carbapenemase-producing pathogens included in this study to ceftazidime/avibactam. Most trials used the maximum approved dose of ceftazidime/avibactam in an extended infusion, as opposed to the comparator used in most trials, which was at a low dose and with non-extended administration. We assume that dosage and route of administration have no significant influence in cUTI studies; however, it may bias the results in favour of ceftazidime/avibactam in other infections, as suggested by Kalil and Klompas35 reviewing the RCT by Torres et al.19 including nosocomial pneumonia patients. In conclusion, ceftazidime/avibactam is clinically as effective as carbapenems for the treatment of cUTI, cIAI and nosocomial pneumonia in a setting in which ∼25% of Enterobacteriaceae are ESBL positive. Microbiological response in patients with cUTI is superior with ceftazidime/avibactam. Safety of the drug should be further evaluated due to the higher rate of SAEs compared with carbapenems. Data are too scarce to draw conclusions regarding effectiveness of the drug in CRE infections. Ceftazidime/avibactam may probably be used as a carbapenem-sparing drug, though studies evaluating the drug’s effectiveness specifically for ESBL infections are needed. In addition, individual patient data meta-analysis compiling ESBL infections from the included trials may also be helpful. Funding This study was carried out as part of our routine work. Transparency declarations None to declare. Supplementary data Tables S1 to S3 are available as Supplementary data at JAC Online. References 1 Carlet J , Jarlier V , Harbarth S et al. Ready for a world without antibiotics? The Pensières Antibiotic Resistance Call to Action . Antimicrob Resist Infect Control 2012 ; 1 : 11 . Google Scholar CrossRef Search ADS PubMed 2 Pitout JD. Infections with extended-spectrum β-lactamase-producing Enterobacteriaceae: changing epidemiology and drug treatment choices . Drugs 2010 ; 70 : 313 – 33 . Google Scholar CrossRef Search ADS PubMed 3 Kanj SS , Kanafani ZA. Current concepts in antimicrobial therapy against resistant gram-negative organisms: extended-spectrum β-lactamase-producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, and multidrug-resistant Pseudomonas aeruginosa . Mayo Clin Proc 2011 ; 86 : 250 – 9 . Google Scholar CrossRef Search ADS PubMed 4 Nordmann P , Cuzon G , Naas T. The real threat of Klebsiella pneumoniae carbapenemase-producing bacteria . Lancet Infect Dis 2009 ; 9 : 228 – 36 . Google Scholar CrossRef Search ADS PubMed 5 Pfeifer Y , Cullik A , Witte W. Resistance to cephalosporins and carbapenems in Gram-negative bacterial pathogens . Int J Med Microbiol 2010 ; 300 : 371 – 9 . Google Scholar CrossRef Search ADS PubMed 6 Livermore DM , Meunier D , Hopkins KL et al. Activity of ceftazidime/avibactam against problem Enterobacteriaceae and Pseudomonas aeruginosa in the UK, 2015-16 . J Antimicrob Chemother 2018 ; 73 : 648 – 57 . Google Scholar CrossRef Search ADS 7 Tuon FF , Rocha JL , Formigoni-Pinto MR. Pharmacological aspects and spectrum of action of ceftazidime-avibactam: a systematic review . Infection 2017 ; doi:10.1007/s15010-017-1096-y. 8 Wright H , Bonomo RA , Paterson DL. New agents for the treatment of infections with Gram-negative bacteria: restoring the miracle or false dawn? Clin Microbiol Infect 2017 ; 23 : 704 – 12 . Google Scholar CrossRef Search ADS PubMed 9 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 : pii: e00883-17. 10 van Duin D , Lok JJ , Earley M et al. Colistin versus ceftazidime-avibactam in the treatment of infections due to carbapenem-resistant Enterobacteriaceae . Clin Infect Dis 2018 ; 66 : 163 – 71 . Google Scholar CrossRef Search ADS PubMed 11 Liberati A , Altman DG , Tetzlaff J et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration . PLoS Med 2009 ; 6 : e1000100 . Google Scholar CrossRef Search ADS PubMed 12 Higgins JG. Cochrane Handbook for Systematic Reviews of Interventions. 2011 . http://handbook-5-1.cochrane.org/. 13 Leibovici L , Paul M , Garner P et al. Addressing resistance to antibiotics in systematic reviews of antibiotic interventions . J Antimicrob Chemother 2016 ; 71 : 2367 – 9 . Google Scholar CrossRef Search ADS PubMed 14 Higgins JP , Thompson SG , Deeks JJ et al. Measuring inconsistency in meta-analyses . BMJ 2003 ; 327 : 557 – 60 . Google Scholar CrossRef Search ADS PubMed 15 Carmeli Y , Armstrong J , Laud PJ et al. Ceftazidime-avibactam or best available therapy in patients with ceftazidime-resistant Enterobacteriaceae and Pseudomonas aeruginosa complicated urinary tract infections or complicated intra-abdominal infections (REPRISE): a randomised, pathogen-directed, phase 3 study . Lancet Infect Dis 2016 ; 16 : 661 – 73 . Google Scholar CrossRef Search ADS PubMed 16 Lucasti C , Popescu I , Ramesh MK et al. Comparative study of the efficacy and safety of ceftazidime/avibactam plus metronidazole versus meropenem in the treatment of complicated intra-abdominal infections in hospitalized adults: results of a randomized, double-blind, Phase II trial . J Antimicrob Chemother 2013 ; 68 : 1183 – 92 . Google Scholar CrossRef Search ADS PubMed 17 Mazuski JE , Gasink LB , Armstrong J et al. Efficacy and safety of ceftazidime-avibactam plus metronidazole versus meropenem in the treatment of complicated intra-abdominal infection: results from a randomized, controlled, double-blind, phase 3 program . Clin Infect Dis 2016 ; 62 : 1380 – 9 . Google Scholar CrossRef Search ADS PubMed 18 Qin X , Tran BG , Kim MJ et al. A randomised, double-blind, phase 3 study comparing the efficacy and safety of ceftazidime/avibactam plus metronidazole versus meropenem for complicated intra-abdominal infections in hospitalised adults in Asia . Int J Antimicrob Agents 2017 ; 49 : 579 – 88 . Google Scholar CrossRef Search ADS PubMed 19 Torres A , Zhong N , Pachl J et al. Ceftazidime-avibactam versus meropenem in nosocomial pneumonia, including ventilator-associated pneumonia (REPROVE): a randomised, double-blind, phase 3 non-inferiority trial . Lancet Infect Dis 2018 ; 18 : 285 – 95 . Google Scholar CrossRef Search ADS PubMed 20 Vazquez JA , González Patzán LD , Stricklin D et al. Efficacy and safety of ceftazidime-avibactam versus imipenem-cilastatin in the treatment of complicated urinary tract infections, including acute pyelonephritis, in hospitalized adults: results of a prospective, investigator-blinded, randomized study . Curr Med Res Opin 2012 ; 28 : 1921 – 31 . Google Scholar CrossRef Search ADS PubMed 21 Wagenlehner FM , Sobel JD , Newell P et al. Ceftazidime-avibactam versus doripenem for the treatment of complicated urinary tract infections, including acute pyelonephritis: rECAPTURE, a phase 3 randomized trial program . Clin Infect Dis 2016 ; 63 : 754 – 62 . Google Scholar CrossRef Search ADS PubMed 22 Mendes RC , Woosley M , Doyle LN et al. β-lactamase characterization of baseline Gram-negative pathogens from a phase 3 trial of ceftazidime-avibactam (CAZ-AVI) for the treatment of nosocomial pneumonia. Abstract P0408. In: Abstracts of the Twenty-seventh ECCMID, Vienna, Austria, 2017. European Society for Clinical Microbiology and Infectious Diseases. 23 Mendes RE , Castanheira M , Gasink L et al. β-lactamase characterization of Gram-negative pathogens recovered from patients enrolled in the phase 2 trials for ceftazidime-avibactam: clinical efficacies analyzed against subsets of molecularly characterized isolates . Antimicrob Agents Chemother 2015 ; 60 : 1328 – 35 . Google Scholar CrossRef Search ADS PubMed 24 Mendes RE , Castanheira M , Woosley LN et al. Molecular β-lactamase characterization of aerobic Gram-negative pathogens recovered from patients enrolled in the ceftazidime-avibactam phase 3 trials for complicated intra-abdominal infections, with efficacies analyzed against susceptible and resistant subsets . Antimicrob Agents Chemother 2017 ; 61 : pii: e02447 – 16 . Google Scholar CrossRef Search ADS PubMed 25 Stone GG , Bradford PA , Newell P et al. 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 . Antimicrob Agents Chemother 2017 ; 61 : pii: e02447-16. 26 Stone GG , Bradford PA , Yates K et al. In vitro activity of ceftazidime/avibactam against urinary isolates from patients in a Phase 3 clinical trial programme for the treatment of complicated urinary tract infections . J Antimicrob Chemother 2017 ; 72 : 1396 – 9 . Google Scholar PubMed 27 Clinical and Laboratory Standards Institute . Performance Standards for Antimicrobial Susceptibility Testing: Twenty-Second Informational Supplement M100-S22 . CLSI , Wayne, PA, USA , 2012 . 28 Kwak YG , Choi SH , Choo EJ et al. Risk factors for the acquisition of carbapenem-resistant Klebsiella pneumoniae among hospitalized patients . Microb Drug Resist 2005 ; 11 : 165 – 9 . Google Scholar CrossRef Search ADS PubMed 29 Schwaber MJ , Klarfeld-Lidji S , Navon-Venezia S et al. Predictors of carbapenem-resistant Klebsiella pneumoniae acquisition among hospitalized adults and effect of acquisition on mortality . Antimicrob Agents Chemother 2008 ; 52 : 1028 – 33 . Google Scholar CrossRef Search ADS PubMed 30 Shiber S , Yahav D , Avni T et al. β-Lactam/β-lactamase inhibitors versus carbapenems for the treatment of sepsis: systematic review and meta-analysis of randomized controlled trials . J Antimicrob Chemother 2015 ; 70 : 41 – 7 . Google Scholar CrossRef Search ADS PubMed 31 Coccolini F , Trevisan M , Montori G et al. Mortality rate and antibiotic resistance in complicated diverticulitis: report of 272 consecutive patients worldwide: a prospective cohort study . Surg Infect (Larchmt) 2017 ; doi:10.1089/sur.2016.283. 32 Sartelli M , Catena F , Ansaloni L et al. Complicated intra-abdominal infections in a worldwide context: an observational prospective study (CIAOW Study) . World J Emerg Surg 2013 ; 8 : 1 . Google Scholar CrossRef Search ADS PubMed 33 Kalil AC , Metersky ML , Klompas M et al. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society . Clin Infect Dis 2016 ; 63 : e61 – 111 . Google Scholar CrossRef Search ADS PubMed 34 Paul M , Bronstein E , Yahav D et al. External validity of a randomised controlled trial on the treatment of severe infections caused by MRSA . BMJ Open 2015 ; 5 : e008838 . Google Scholar CrossRef Search ADS PubMed 35 Kalil AC , Klompas M. Ceftazidime-avibactam versus meropenem for the treatment of nosocomial pneumonia . Lancet Infect Dis 2017 ; 18 : 229 – 31 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

Journal of Antimicrobial ChemotherapyOxford University Press

Published: Apr 6, 2018

There are no references for this article.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off