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
Carbapenems are frequently the last line of defence in serious infections due to multidrug-resistant Gram-negative bacteria, but their use is threatened by the growing prevalence of carbapenemase-producing pathogens. Ceftazidime-avibactam is a potential new agent for use in such infections. We aimed to assess the efficacy, safety, and tolerability of ceftazidime-avibactam compared with best available therapyin patients with complicated urinary tract infection or complicated intra-abdominal infection due to ceftazidime-resistant Gram-negative pathogens.
Methods
REPRISE was a pathogen-directed, international, randomised, open-label, phase 3 trial that recruited patients from hospitals across 16 countries worldwide. Eligible patients were aged 18–90 years with complicated urinary tract infection or complicated intra-abdominal infection caused by ceftazidime-resistant Enterobacteriaceae or Pseudomonas aeruginosa. Patients were randomised (1:1) to 5–21 days of treatment with either ceftazidime-avibactam (a combination of 2000 mg ceftazidime plus 500 mg avibactam, administered via a 2-h intravenous infusion every 8 h) or best available therapy. The primary endpoint was clinical response at the test-of-cure visit, 7–10 days after last infusion of study therapy, analysed in all patients who had at least one ceftazidime-resistant Gram-negative pathogen, as confirmed by the central laboratory, and who received at least one dose of study drug. Safety endpoints were assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01644643.
Findings
Between Jan 7, 2013, and Aug 29, 2014, 333 patients were randomly assigned, 165 to ceftazidime-avibactam and 168 to best available therapy. Of these, 154 assigned to ceftazidime-avibactam (144 with complicated urinary tract infection and ten with complicated intra-abdominal infection) and 148 assigned to best available therapy (137 with complicated urinary tract infection and 11 with complicated intra-abdominal infection) were analysed for the primary outcome. 163 (97%) of 168 patients in the best available therapy group received a carbapenem, 161 (96%) as monotherapy. The overall proportions of patients with a clinical cure at the test-of-cure visit were similar with ceftazidime-avibactam (140 [91%; 95% CI 85·6–94·7] of 154 patients) and best available therapy (135 [91%; 85·9–95·0] of 148 patients). 51 (31%) of 164 patients in the ceftazidime-avibactam group and 66 (39%) of 168 in the best available therapy group had an adverse event, most of which were mild or moderate in intensity. Gastrointestinal disorders were the most frequently reported treatment-emergent adverse events with both ceftazidime-avibactam (21 [13%] of 164 patients) and best available therapy (30 [18%] of 168 patients). No new safety concerns were identified for ceftazidime-avibactam.
Interpretation
These results provide evidence of the efficacy of ceftazidime-avibactam as a potential alternative to carbapenems in patients with ceftazidime-resistant Enterobacteriaceae and P aeruginosa.
Funding
AstraZeneca.
Introduction
The prevalence of multidrug-resistant Gram-negative pathogens, including extended-spectrum β-lactamase (ESBL)-producing and carbapenemase-producing Enterobacteriaceae and Pseudomonas aeruginosa, is increasing worldwide.1, 2, 3 Contributing factors are the extensive use of antibiotics, both in human beings and animals, poor infection control, and the greatly increased global mobility of people, allowing the rapid spread of multidrug-resistant pathogens.1, 4, 5 As the prevalence of ESBL-producing pathogens has increased, so has the use of carbapenem antibiotics—frequently the last line of defence against multidrug-resistant Gram-negative bacteria, but now threatened by the growing prevalence of carbapenemase-producing pathogens.6 Therefore, alternative treatment options and carbapenem-sparing regimens for patients with serious infections caused by multidrug-resistant Gram-negative pathogens are urgently needed.
Research in context
Evidence before this study
We searched PubMed with the search terms “ceftazidime-avibactam” AND “randomised”, and the European Congress of Clinical Microbiology and Infectious Diseases 2015 abstracts with the search term “ceftazidime-avibactam”, for articles published on or before July 16, 2015. No other restrictions were applied to the search, but we excluded preclinical and surveillance studies and reviews from the results. PubMed searches using the above terms identified three reports of phase 1 trials assessing the safety, tolerability, and pharmacokinetics of ceftazidime-avibactam, and two phase 2 trials of ceftazidime-avibactam in patients with complicated urinary tract infection and complicated intra-abdominal infection caused by Gram-negative pathogens. The phase 2 trial in patients with complicated urinary tract infection demonstrated clinical response rates with ceftazidime-avibactam similar to those for imipenem-cilastatin. In patients with complicated intra-abdominal infection, ceftazidime-avibactam (in combination with metronidazole) achieved a response that was similar to that achieved with meropenem. Both studies included some patients with ceftazidime-resistant infections, but this was not an inclusion criterion in either trial. The ECCMID 2015 search identified the results of some phase 3 studies of ceftazidime-avibactam: the REPRISE study reported here, and a single report of two identical phase 3 studies in complicated intra-abdominal infection (RECLAIM 1 and 2), which included some patients with ceftazidime-resistant Gram-negative infections. Ceftazidime-avibactam plus metronidazole was shown to be non-inferior to meropenem. Other ongoing or recently completed (but not yet published) phase 3 trials of ceftazidime-avibactam, including patients with complicated urinary tract infection, complicated intra-abdominal infection, or nosocomial pneumonia, also included all-comers rather than specifically recruiting patients with ceftazidime-resistant infections.
Added value of this study
The REPRISE study was specifically designed to assess the efficacy of ceftazidime-avibactam and best available therapy in patients with ceftazidime-resistant Gram-negative complicated urinary tract infection or complicated intra-abdominal infection. The proportion of patients who were clinically cured were similar in both treatment groups, with a numerically higher proportion of patients achieving a favourable microbiological response in the ceftazidime-avibactam group. The observed safety and tolerability ceftazidime-avibactam was similar to the recognised profile of ceftazidime alone.
Implications of all the available evidence
These results support the further development of ceftazidime-avibactam as a potential alternative to carbapenems in patients with resistant Gram-negative infections.
Ceftazidime-avibactam could be an important new option for such cases, consisting of ceftazidime, a widely used expanded-spectrum anti-pseudomonal cephalosporin, and avibactam, a novel non-β-lactam β-lactamase inhibitor.7, 8 Avibactam has a broader spectrum of activity than available β-lactamase inhibitors, and has been shown in vitro to restore the activity of ceftazidime against most multidrug-resistant Enterobacteriaceae and P aeruginosa by inhibiting a wide variety of β-lactamases, including class A (such as ESBLs, Klebsiella pneumoniae carbapenemases), class C (AmpC), and some class D enzymes (eg, OXA 48).9
Two phase 3 studies of ceftazidime-avibactam in patients with complicated intra-abdominal infection (RECLAIM 1 and 2 [NCT01499290 and NCT01500239]) have recently been reported,10 and other phase 3 trials are ongoing, including patients with complicated urinary tract infections (RECAPTURE 1 and 2 [NCT01595438 and NCT01599806]), complicated intra-abdominal infection (RECLAIM 3 [NCT01726023]), and nosocomial pneumonia (REPROVE [NCT01808092]). However, on the basis of data from phase 2 trials,7, 8 the US Food and Drug Administration recently approved ceftazidime-avibactam for use in the treatment of adults with complicated intra-abdominal infection, in combination with metronidazole, and complicated urinary tract infection, including kidney infections (pyelonephritis), who have limited or no alternative treatment options.11
The phase 3 studies listed above enrolled patients with or without drug-resistant pathogens. Thus, although they can provide valuable information about safety, tolerability, and efficacy, they might not provide extensive information about efficacy against resistant pathogens. Given the need for new therapies to treat patients with drug-resistant infections, pathogen-directed studies have been recommended.12 The international, randomised, phase 3 study (REPRISE; NCT01644643) reported here is the first multidrug-resistant Gram-negative pathogen-directed study for ceftazidime-avibactam, focusing specifically on the efficacy, safety, and tolerability in patients with complicated urinary tract infection or complicated intra-abdominal infection due to ceftazidime-resistant Gram-negative pathogens.
Section snippets
Study design and participants
REPRISE was an international, randomised, open-label, phase 3 trial that recruited patients from hospitals worldwide. Male and female patients aged 18–90 years with complicated urinary tract infection or complicated intra-abdominal infection caused by ceftazidime-resistant Gram-negative pathogens were eligible for inclusion in the trial. Specified diagnoses for patients with complicated urinary tract infection were either confirmed acute pyelonephritis or complicated lower urinary tract
Results
Between Jan 7, 2013, and Aug 29, 2014, 333 patients were enrolled and randomised at 53 hospitals in 16 countries worldwide: 165 to ceftazidime-avibactam (153 with complicated urinary tract infection and 12 with complicated intra-abdominal infection), and 168 to best available therapy (153 with complicated urinary tract infection and 15 with complicated intra-abdominal infection; figure 1). Although we had planned to include 400 patients, recruitment was ended early because the funder considered
Discussion
The REPRISE study is the first pathogen-directed clinical trial for ceftazidime-avibactam examining its efficacy against ceftazidime-resistant Gram-negative pathogens. Therefore, this study provides valuable information for clinicians and represents an important addition to the ceftazidime-avibactam trial programme, providing supporting data for the pivotal phase 3 trials in complicated intra-abdominal infection and complicated urinary tract infection.
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2024, International Journal of Antimicrobial Agents
To understand the global changes in the nonsusceptibility rates of Escherichia coli to meropenem and ceftazidime-avibactam (CZA), we conducted a study using the Antimicrobial Testing Leadership and Surveillance database.
A total of 49 394 E. coli isolates were collected during the 8-year study period.
The countries with the highest nonsusceptible rates for meropenem were India (16.6%), followed by Pakistan (6.7%), Ukraine (5.4%), Qatar (5.3%), and Guatemala (3.2%). For CZA, the nonsusceptible rate was highest in India (15.6%), followed by Qatar (4.0%), Guatemala (3.9%), China (2.6%), and Thailand (2.5%). During the study period, the nonsusceptible rates of meropenem and CZA in E. coli increased in Asia, Latin America, and Africa/Middle East. Isolates from the medical ICU (odds ratio [OR], 4.62) and surgical ICU (OR, 3.98) were associated with a higher risk of CZA nonsusceptible rates. Compared to intestinal specimens, respiratory and genitourinary specimens had the highest OR (2.32 and 2.17) associated with CZA resistance. Further analysis of carbapenemase distribution showed an increase in the percentage of blaNDM-positive isolates and a decrease in blaKPC-positive isolates worldwide, especially in Latin America. Additionally, we observed a gradual decline in the prevalence of blaOXA-positive E. coli without concomitant carriage of metallo-β-lactamase genes in the worldwide surveillance.
Further surveillance is necessary to determine whether blaNDM -positive E. coli (i.e., CZA-resistant isolates) is increasing and leading to more superbugs spreading worldwide.
2024, International Journal of Antimicrobial Agents
This retrospective study aimed to identify the effectiveness of ceftazidime/avibactam (CAZ/AVI) and its optimisation programs for severe hospital-acquired pulmonary infections (sHAPi) caused by carbapenem-resistant and difficult-to-treat Pseudomonas aeruginosa (CRPA and DTR–P. aeruginosa).
We retrospectively analysed observational data on treatment and outcomes of CAZ/AVI for sHAPi caused by CRPA or DTR–P. aeruginosa. The primary study outcomes were to evaluate the clinical and microbiology efficacy of CAZ/AVI.
The cohort consisted of 84 in-patients with sHAPi caused by CRPA (n = 39) and DTR-P. aeruginosa (n = 45) who received at least 72 h of CAZ/AVI therapy. The clinical cure rate was 63.1% in total. There was no significant difference in study outcomes between patients treated with CAZ/AVI monotherapy and those managed with combination regimens. CAZ/AVI as first-line therapy possessed prominent clinical benefits regarding infections caused by DTR–P. aeruginosa. The clinical cure rate was positively relevant with loading dose for CAZ/AVI (odds ratio [OR] 0.03; 95% confidence interval [CI] 0.004–0.19; P < 0.001) and with CAZ/AVI administration by prolonged infusion (odds ratio 0.15; 95% confidence interval 0.03–0.77; P = 0.002). APACHE II score>15 (P = 0.013), septic shock at infection onset (P = 0.001), and CAZ/AVI dose adjustment for renal dysfunction (P = 0.003) were negative predictors of clinical cure.
CAZ/AVI is a valid alternative for sHAPi caused by CPRA and DTR–P. aeruginosa, even when used alone. Optimisations of the treatment with CAZ/AVI in critically ill patients, including loading dose, adequate maintenance dose and prolonged infusion, were positively associated with potential clinical benefits.
The aim of this study was to characterize the blaKPC-33 in a ST15-K19 ceftazidime-avibactam (CAZ-AVI)-resistant Klebsiella pneumoniae strain after the antibiotic CAZ-AVI was approved for use in Wuxi No. 2 People's Hospital, China.
Antimicrobial susceptibility testing was performed by the microdilution broth method. Whole genome sequencing (WGS) was performed using PacBio II and MiSeq sequencers. High-quality reads were assembled using the SOAPdenovo and GapCloser v1.12, and genome annotation was performed using the NCBI Prokaryotic Genome Annotation Pipeline (PGAP). Genomic characteristics were analysed by using bioinformatics methods.
K. pneumoniae strain KPHRJ showed resistance to CAZ-AVI. WGS analysis showed that strain KPHRJ had one 5 536 506 bp chromosome (57.25% G+C content) and one plasmid (133 451 bp, G+C 54.29%). KPHRJ was classified as ST15 and K19 serotype. Resistome analysis showed that KPHRJ carries seven antimicrobial resistance genes (ARGs). WGS analysis and conjugation experiments demonstrated that the blaKPC-33 gene was carried by plasmid pKPHRJ, flanked by two copies of IS26 mobile elements (IS26-ISKpn27-blaKPC-33-ISKpn6-korC-TnAs1-tetR-tetA-Tn3-IS26). Besides these acquired resistance genes, mutations in porin protein-coding genes, such as OmpK36 and OmpK37, which may reduce susceptibility to the CAZ-AVI, were also identified from the genome.
Here, we present the WGS of a CAZ-AVI resistant K. pneumoniae isolate, strain KPHRJ, with capsular serotype K19 and belonging to ST15. CAZ-AVI resistance is likely conferred by a KPC-2 variant, blaKPC-33 and mutations in porin-coding genes. We speculate that the approval of the CAZ-AVI in hospital could contribute to the emergence of these genomic features by providing a selective pressure leading to the emergence of CAZ-AVI resistant bacteria.
Ceftazidime-avibactam (CAZ-AVI) combines ceftazidime and a reversible β-lactamase inhibitor that has shown activity against multidrug-resistant (MDR) Enterobacterales and P. aeruginosa. Using data from the Antimicrobial Testing Leadership and Surveillance program (ATLAS), this study examined the in vitro antimicrobial activity of CAZ-AVI and other antibiotics against Gram-negative bacteria collected from Chilean hospitals between 2015 and 2021.
Clinical isolates of Enterobacterales and P. aeruginosa were collected from three medical centres in Chile. Blood, abdominal fluid, urine, soft tissues, and respiratory tract samples were obtained from infected patients. Minimum inhibitory concentrations using the broth microdilution method were determined for susceptibility testing, and the Clinical and Laboratory Standards Institute (CLSI) breakpoints were used for interpreting the results. Extended-spectrum β-lactamases (ESBL) and carbapenemase genes were also detected through polymerase chain reaction.
A total of 2600 Enterobacterales and 836 P. aeruginosa were analysed. CAZ-AVI was the antibiotic with the highest in vitro activity against Enterobacterales (99.72%). The incidence of carbapenem-resistant Enterobacterales (CRE) was 1.5% (n = 39), and the antibiotics with the best in vitro activity were tigecycline (92.31%), CAZ-AVI (88.57%), and amikacin (79.49%). CAZ-AVI was the antibiotic with the best activity against ESBL-producing Enterobacterales (99.34%) and MDR Enterobacterales (99.31%). For KPC-producing Enterobacterales, susceptibility to amikacin was 100%, whereas susceptibility to CAZ-AVI was 91.67%. Regarding MDR and difficult-to-treat resistance P. aeruginosa, 44.83% and 38.99% were susceptible to CAZ-AVI, respectively.
CAZ-AVI shows excellent in vitro activity against Enterobacterales in general, CRE, ESBL-producing Enterobacterales, and KPC-producing Enterobacterales. CAZ-AVI is also an option against MDR P. aeruginosa.
2023, Interdisciplinary Neurosurgery: Advanced Techniques and Case Management
To share the treatment experience of patients with post neurosurgical ventriculitis and meningitis due to Carbapenem resistance Klebsiella pneumonia.
Post neurosurgical ventriculitis and meningitis due to Carbapenem resistance Klebsiella pneumonia is rare and extremely difficult to treat. Increasing resistance to the available antimicrobials has restricted the treatment strategies as a last resort or, unfortunately, none, sometimes.
Data of patients with post neurosurgical ventriculitis due to Carbapenem resistance Klebsiella pneumonia were collected retrospectively. The isolated organisms were treated based on the sensitivity report of the cerebrospinal fluid analysis with intravenous and intraventricular antimicrobials. The outcome was assessed based on the clinical, imaging and lab parameters.
We identified eight patients (two females) with post neurosurgical ventriculitis and meningitis due to Carbapenem resistance Klebsiella pneumonia. Their age ranged from 6 to 65 years. The CSF analysis showed sensitivity to Colistin and newer antimicrobial Ceftazidime-Avibactam. Based on our prior experience, 5/8 patients were initially started on intravenous and intraventricular Colistin. Later, they were switched to intravenous Ceftazidime and Avibactam due to nonresponse to the initial combined intravenous and intraventricular Colistin therapy. The rest of the 3 patients were given straight IV Ceftazidime and Avibactam as a first-line antimicrobial following the sensitivity report. Though, patients showed improved responses to the newer combination of antimicrobial Ceftazidime and Avibactam; only 5/8 were cured.
Intravenous CZA-AVI can be considered first line or as a sequential, targeted treatment to prior intravenous and intraventricular, colistin for post neurosurgical ventriculitis and meningitis due to Carbapenem resistance organisms.