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Clinical Infectious Diseases : An... Jul 2016Ceftolozane/tazobactam and ceftazidime/avibactam are 2 novel β-lactam/β-lactamase combination antibiotics. The antimicrobial spectrum of activity of these antibiotics... (Review)
Review
Ceftolozane/tazobactam and ceftazidime/avibactam are 2 novel β-lactam/β-lactamase combination antibiotics. The antimicrobial spectrum of activity of these antibiotics includes multidrug-resistant (MDR) gram-negative bacteria (GNB), including Pseudomonas aeruginosa. Ceftazidime/avibactam is also active against carbapenem-resistant Enterobacteriaceae that produce Klebsiella pneumoniae carbapenemases. However, avibactam does not inactivate metallo-β-lactamases such as New Delhi metallo-β-lactamases. Both ceftolozane/tazobactam and ceftazidime/avibactam are only available as intravenous formulations and are dosed 3 times daily in patients with normal renal function. Clinical trials showed noninferiority to comparators of both agents when used in the treatment of complicated urinary tract infections and complicated intra-abdominal infections (when used with metronidazole). Results from pneumonia studies have not yet been reported. In summary, ceftolozane/tazobactam and ceftazidime/avibactam are 2 new second-generation cephalosporin/β-lactamase inhibitor combinations. After appropriate trials are conducted, they may prove useful in the treatment of MDR GNB infections. Antimicrobial stewardship will be essential to preserve the activity of these agents.
Topics: Azabicyclo Compounds; Ceftazidime; Cephalosporins; Drug Therapy, Combination; Humans; beta-Lactamase Inhibitors
PubMed: 27098166
DOI: 10.1093/cid/ciw243 -
Revista Espanola de Quimioterapia :... Sep 2021Ceftazidime is a 3rd generation cephalosporin active against Pseudomonas aeruginosa. Avibactam is an inhibitor of class A, C and some class D β-lactamases. The... (Review)
Review
Ceftazidime is a 3rd generation cephalosporin active against Pseudomonas aeruginosa. Avibactam is an inhibitor of class A, C and some class D β-lactamases. The antibacterial spectrum of ceftazidime-avibactam covers 95% of P. aeruginosa isolates and >99% of enterobacteria, including strains carrying extended-spectrum β-lactamases (ESBLs). Selection of resistant mutants in Klebsiella pneumoniae and Enterobacter cloacae strains producing KPC-3 or KPC-2 after exposure to ceftazidime-avibactam has been described by the appearance of one or more amino acid changes in the Ω-loop of the β-lactamase. These strains usually regain susceptibility to meropenem. There is evidence of a shorter multidrug-resistant organisms colonization period in patients treated with this antimicrobial, which could be beneficial in the treatment of infections caused by bacteria carrying ESBLs or carbapenemases.
Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Bacterial Proteins; Ceftazidime; Drug Combinations; Humans; Klebsiella pneumoniae; Microbial Sensitivity Tests; beta-Lactamases
PubMed: 34598423
DOI: 10.37201/req/s01.11.2021 -
Journal of Global Antimicrobial... Sep 2020Ceftazidime-avibactam (CAZ-AVI) is a novel synthetic β-lactamase inhibitor combination. Although the combination has been available clinically for only a few years,... (Review)
Review
OBJECTIVE
Ceftazidime-avibactam (CAZ-AVI) is a novel synthetic β-lactamase inhibitor combination. Although the combination has been available clinically for only a few years, cases of resistance to CAZ-AVI have already been reported.
METHODS
In the present review, we summarize the distribution of CAZ-AVI-resistant strains and the possible resistance mechanisms.
RESULTS
There are no significant differences in CAZ-AVI resistance rates across different regions. CAZ-AVI maintains good activity against Gram-negative bacteria, especially Enterobacteriaceae. Pseudomonas aeruginosa is less susceptible to CAZ-AVI compared with Enterobacteriaceae, with a resistance rate ranging from 2.9 to 18%. The resistance to CAZ-AVI exceeds 50% in Acinetobacter baumannii. A higher resistance rate to CAZ-AVI is associated with carbapenem resistance. Moreover, β-lactamase-related amino acid substitutions are the main mechanisms that lead to CAZ-AVI resistance. Membrane protein amino acid substitutions and efflux pumps also play important roles in CAZ-AVI resistance.
CONCLUSIONS
To maintain its efficacy, CAZ-AVI should not be used for pathogens that are naturally resistant to it. For CAZ-AVI-resistant strains, other effective antibacterial agents or CAZ-AVI in combination with other antibacterial agents should be considered.
Topics: Azabicyclo Compounds; Ceftazidime; Drug Combinations; Microbial Sensitivity Tests
PubMed: 31863899
DOI: 10.1016/j.jgar.2019.12.009 -
Antimicrobial Agents and Chemotherapy Sep 2022First variants of the Klebsiella pneumoniae carbapenemase (KPC), KPC-2 and KPC-3, have encountered a worldwide success, particularly in K. pneumoniae isolates. These... (Review)
Review
First variants of the Klebsiella pneumoniae carbapenemase (KPC), KPC-2 and KPC-3, have encountered a worldwide success, particularly in K. pneumoniae isolates. These beta-lactamases conferred resistance to most beta-lactams including carbapenems but remained susceptible to new beta-lactam/beta-lactamase inhibitors, such as ceftazidime-avibactam. After the marketing of ceftazidime-avibactam, numerous variants of KPC resistant to this association have been described among isolates recovered from clinical samples or derived from experimental studies. In KPC variants resistant to ceftazidime-avibactam, point mutations, insertions and/or deletions have been described in various hot spots. Deciphering the impact of these mutations is crucial, not only from a therapeutic point of view, but also to follow the evolution in time and space of KPC variants resistant to ceftazidime-avibactam. In this review, we describe the mutational landscape of the KPC beta-lactamase toward ceftazidime-avibactam resistance based on a multidisciplinary approach including epidemiology, microbiology, enzymology, and thermodynamics. We show that resistance is associated with three hot spots, with a high representation of insertions and deletions compared with other class A beta-lactamases. Moreover, extension of resistance to ceftazidime-avibactam is associated with a trade-off in the resistance to other beta-lactams and a decrease in enzyme stability. Nevertheless, the high natural stability of KPC could underlay the propensity of this enzyme to acquire mutations conferring resistance to ceftazidime-avibactam (CAZavi), particularly via insertions and deletions.
Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Bacterial Proteins; Carbapenems; Ceftazidime; Drug Combinations; Drug Resistance, Multiple, Bacterial; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; beta-Lactamase Inhibitors; beta-Lactamases
PubMed: 35980232
DOI: 10.1128/aac.00447-22 -
The Lancet. Infectious Diseases Mar 2018Nosocomial pneumonia is commonly associated with antimicrobial-resistant Gram-negative pathogens. We aimed to assess the efficacy and safety of ceftazidime-avibactam in... (Randomized Controlled Trial)
Randomized Controlled Trial
Ceftazidime-avibactam versus meropenem in nosocomial pneumonia, including ventilator-associated pneumonia (REPROVE): a randomised, double-blind, phase 3 non-inferiority trial.
BACKGROUND
Nosocomial pneumonia is commonly associated with antimicrobial-resistant Gram-negative pathogens. We aimed to assess the efficacy and safety of ceftazidime-avibactam in patients with nosocomial pneumonia, including ventilator-associated pneumonia, compared with meropenem in a multinational, phase 3, double-blind, non-inferiority trial (REPROVE).
METHODS
Adults with nosocomial pneumonia (including ventilator-associated pneumonia), enrolled at 136 centres in 23 countries, were randomly assigned (1:1) to 2000 mg ceftazidime and 500 mg avibactam (by 2 h intravenous infusion every 8 h) or 1000 mg meropenem (by 30-min intravenous infusion every 8 h) for 7-14 days; regimens were adjusted for renal function. Computer-generated randomisation codes were stratified by infection type and geographical region with a block size of four. Participants and investigators were masked to treatment assignment. The primary endpoint was clinical cure at the test-of-cure visit (21-25 days after randomisation). Non-inferiority was concluded if the lower limit of the two-sided 95% CI for the treatment difference was greater than -12·5% in the coprimary clinically modified intention-to-treat and clinically evaluable populations. This trial is registered with ClinicalTrials.gov (NCT01808092) and EudraCT (2012-004006-96).
FINDINGS
Between April 13, 2013, and Dec 11, 2015, 879 patients were randomly assigned. 808 patients were included in the safety population, 726 were included in the clinically modified intention-to-treat population, and 527 were included in the clinically evaluable population. Predominant Gram-negative baseline pathogens in the microbiologically modified intention-to-treat population (n=355) were Klebsiella pneumoniae (37%) and Pseudomonas aeruginosa (30%); 28% were ceftazidime-non-susceptible. In the clinically modified intention-to-treat population, 245 (68·8%) of 356 patients in the ceftazidime-avibactam group were clinically cured, compared with 270 (73·0%) of 370 patients in the meropenem group (difference -4·2% [95% CI -10·8 to 2·5]). In the clinically evaluable population, 199 (77·4%) of 257 participants were clinically cured in the ceftazidime-avibactam group, compared with 211 (78·1%) of 270 in the meropenem group (difference -0·7% [95% CI -7·9 to 6·4]). Adverse events occurred in 302 (75%) of 405 patients in the ceftazidime-avibactam group versus 299 (74%) of 403 in the meropenem group (safety population), and were mostly mild or moderate in intensity and unrelated to study treatment. Serious adverse events occurred in 75 (19%) patients in the ceftazidime-avibactam group and 54 (13%) patients in the meropenem group. Four serious adverse events (all in the ceftazidime-avibactam group) were judged to be treatment related.
INTERPRETATION
Ceftazidime-avibactam was non-inferior to meropenem in the treatment of nosocomial pneumonia. These results support a role for ceftazidime-avibactam as a potential alternative to carbapenems in patients with nosocomial pneumonia (including ventilator-associated pneumonia) caused by Gram-negative pathogens.
FUNDING
AstraZeneca.
Topics: Adult; Aged; Anti-Bacterial Agents; Azabicyclo Compounds; Ceftazidime; Double-Blind Method; Drug Combinations; Female; Humans; Male; Meropenem; Middle Aged; Pneumonia, Ventilator-Associated
PubMed: 29254862
DOI: 10.1016/S1473-3099(17)30747-8 -
Clinical Infectious Diseases : An... Nov 2021A growing body of observational evidence supports the value of ceftazidime-avibactam (CAZ-AVI) in managing infections caused by carbapenem-resistant Enterobacteriaceae. (Observational Study)
Observational Study
BACKGROUND
A growing body of observational evidence supports the value of ceftazidime-avibactam (CAZ-AVI) in managing infections caused by carbapenem-resistant Enterobacteriaceae.
METHODS
We retrospectively analyzed observational data on use and outcomes of CAZ-AVI therapy for infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp) strains. Multivariate regression analysis was used to identify variables independently associated with 30-day mortality. Results were adjusted for propensity score for receipt of CAZ-AVI combination regimens versus CAZ-AVI monotherapy.
RESULTS
The cohort comprised 577 adults with bloodstream infections (n = 391) or nonbacteremic infections involving mainly the urinary tract, lower respiratory tract, and intra-abdominal structures. All received treatment with CAZ-AVI alone (n = 165) or with ≥1 other active antimicrobials (n = 412). The all-cause mortality rate 30 days after infection onset was 25% (146/577). There was no significant difference in mortality between patients managed with CAZ-AVI alone and those treated with combination regimens (26.1% vs 25.0%, P = .79). In multivariate analysis, mortality was positively associated with presence at infection onset of septic shock (P = .002), neutropenia (P < .001), or an INCREMENT score ≥8 (P = .01); with lower respiratory tract infection (LRTI) (P = .04); and with CAZ-AVI dose adjustment for renal function (P = .01). Mortality was negatively associated with CAZ-AVI administration by prolonged infusion (P = .006). All associations remained significant after propensity score adjustment.
CONCLUSIONS
CAZ-AVI is an important option for treating serious KPC-Kp infections, even when used alone. Further study is needed to explore the drug's seemingly more limited efficacy in LRTIs and potential survival benefits of prolonging CAZ-AVI infusions to ≥3 hours.
Topics: Adult; Anti-Bacterial Agents; Azabicyclo Compounds; Bacterial Proteins; Ceftazidime; Drug Combinations; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Retrospective Studies; beta-Lactamases
PubMed: 33618353
DOI: 10.1093/cid/ciab176 -
Clinical Infectious Diseases : An... Jun 2016When combined with ceftazidime, the novel non-β-lactam β-lactamase inhibitor avibactam provides a carbapenem alternative against multidrug-resistant infections.... (Randomized Controlled Trial)
Randomized Controlled Trial
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.
BACKGROUND
When combined with ceftazidime, the novel non-β-lactam β-lactamase inhibitor avibactam provides a carbapenem alternative against multidrug-resistant infections. Efficacy and safety of ceftazidime-avibactam plus metronidazole were compared with meropenem in 1066 men and women with complicated intra-abdominal infections from 2 identical, randomized, double-blind phase 3 studies (NCT01499290 and NCT01500239).
METHODS
The primary end point was clinical cure at test-of-cure visit 28-35 days after randomization, assessed by noninferiority of ceftazidime-avibactam plus metronidazole to meropenem in the microbiologically modified intention-to-treat (mMITT) population (in accordance with US Food and Drug Administration guidance), and the modified intention-to-treat and clinically evaluable populations (European Medicines Agency guidance). Noninferiority was considered met if the lower limit of the 95% confidence interval for between-group difference was greater than the prespecified noninferiority margin of -12.5%.
RESULTS
Ceftazidime-avibactam plus metronidazole was noninferior to meropenem across all primary analysis populations. Clinical cure rates with ceftazidime-avibactam plus metronidazole and meropenem, respectively, were as follows: mMITT population, 81.6% and 85.1% (between-group difference, -3.5%; 95% confidence interval -8.64 to 1.58); modified intention-to-treat, 82.5% and 84.9% (-2.4%; -6.90 to 2.10); and clinically evaluable, 91.7% and 92.5% (-0.8%; -4.61 to 2.89). The clinical cure rate with ceftazidime-avibactam plus metronidazole for ceftazidime-resistant infections was comparable to that with meropenem (mMITT population, 83.0% and 85.9%, respectively) and similar to the regimen's own efficacy against ceftazidime-susceptible infections (82.0%). Adverse events were similar between groups.
CONCLUSIONS
Ceftazidime-avibactam plus metronidazole was noninferior to meropenem in the treatment of complicated intra-abdominal infections. Efficacy was similar against infections caused by ceftazidime-susceptible and ceftazidime-resistant pathogens. The safety profile of ceftazidime-avibactam plus metronidazole was consistent with that previously observed with ceftazidime alone.
CLINICAL TRIALS REGISTRATION
NCT01499290 and NCT01500239.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Azabicyclo Compounds; Ceftazidime; Drug Combinations; Female; Humans; Intraabdominal Infections; Male; Meropenem; Metronidazole; Middle Aged; Thienamycins; Treatment Outcome; Young Adult
PubMed: 26962078
DOI: 10.1093/cid/ciw133 -
Antimicrobial Agents and Chemotherapy Oct 2022This is a retrospective single-center study of 24 patients who received ceftazidime-avibactam plus aztreonam (CZA/ATM) for the treatment of VIM-type-producing...
This is a retrospective single-center study of 24 patients who received ceftazidime-avibactam plus aztreonam (CZA/ATM) for the treatment of VIM-type-producing Gram-negative bacillus (GNB) infections. The bacteria isolated were in 22 patients and Pseudomonas aeruginosa in 2. Sixteen out of 19 isolates showed synergistic activity. Two patients presented clinical failure at day 14, and the 30-day mortality was 17% (4/24). CZA/ATM could be considered an alternative therapy for VIM-type-producing GNB infections.
Topics: Humans; Aztreonam; Retrospective Studies; beta-Lactamases; Microbial Sensitivity Tests; Anti-Bacterial Agents; Azabicyclo Compounds; Ceftazidime; Gram-Negative Bacteria; Drug Combinations
PubMed: 36102635
DOI: 10.1128/aac.00751-22 -
Journal of Clinical Microbiology May 2023Due to limited therapeutic options, there is a clinical need to assess the activity of the combination of aztreonam (ATM) and ceftazidime-avibactam (CZA) to guide the...
Due to limited therapeutic options, there is a clinical need to assess the activity of the combination of aztreonam (ATM) and ceftazidime-avibactam (CZA) to guide the therapeutic management of multidrug-resistant (MDR) Gram-negative organism infections. We set out to develop a practical MIC-based broth disk elution (BDE) method to determine the activity of the combination ATM-CZA using readily available supplies and compare it to reference broth microdilution (BMD). For the BDE method, a 30-μg ATM disk, a 30/20-μg CZA disk, both disks in combination, and no disks were added to 4 separate 5-mL cation-adjusted Mueller-Hinton broth (CA-MHB) tubes, using various manufacturers. Three testing sites performed both BDE and reference BMD testing of bacterial isolates in parallel from a single 0.5 McFarland standard inoculum and after overnight incubation, assessed them for growth (not susceptible) or no growth (susceptible) at a final concentration of 6/6/4 μg/mL ATM-CZA. During the first phase, the precision and accuracy of the BDE were analyzed by testing 61 isolates at all sites. This testing yielded 98.3% precision between sites, with 98.3% categorical agreement and 1.8% major errors (ME). During the second phase, at each site, we evaluated unique, clinical isolates of metallo-β-lactamase (MBL)-producing ( = 75), carbapenem-resistant Pseudomonas aeruginosa ( = 25), Stenotrophomonas maltophilia ( = 46), and sp. ( = 1). This testing resulted in 97.9% categorical agreement, with 2.4% ME. Different results were observed for different disk and CA-MHB manufacturers, requiring a supplemental ATM-CZA-not-susceptible quality control organism to ensure the accuracy of results. The BDE is a precise and effective methodology for determining susceptibility to the combination ATM-CZA.
Topics: Humans; Aztreonam; Anti-Bacterial Agents; Microbial Sensitivity Tests; Ceftazidime; Drug Combinations; Gram-Negative Bacteria; Pseudomonas aeruginosa; beta-Lactamases
PubMed: 37070979
DOI: 10.1128/jcm.01647-22 -
Clinical Infectious Diseases : An... Sep 2016The global emergence of carbapenem-resistant Enterobacteriaceae highlights the urgent need to reduce carbapenem dependence. The phase 3 RECAPTURE program compared the... (Randomized Controlled Trial)
Randomized Controlled Trial
Ceftazidime-avibactam Versus Doripenem for the Treatment of Complicated Urinary Tract Infections, Including Acute Pyelonephritis: RECAPTURE, a Phase 3 Randomized Trial Program.
BACKGROUND
The global emergence of carbapenem-resistant Enterobacteriaceae highlights the urgent need to reduce carbapenem dependence. The phase 3 RECAPTURE program compared the efficacy and safety of ceftazidime-avibactam and doripenem in patients with complicated urinary tract infection (cUTI), including acute pyelonephritis.
METHODS
Hospitalized adults with suspected or microbiologically confirmed cUTI/acute pyelonephritis were randomized 1:1 to ceftazidime-avibactam 2000 mg/500 mg every 8 hours or doripenem 500 mg every 8 hours (doses adjusted for renal function), with possible oral antibiotic switch after ≥5 days (total treatment duration up to 10 days or 14 days for patients with bacteremia).
RESULTS
Of 1033 randomized patients, 393 and 417 treated with ceftazidime-avibactam and doripenem, respectively, were eligible for the primary efficacy analyses; 19.6% had ceftazidime-nonsusceptible baseline pathogens. Noninferiority of ceftazidime-avibactam vs doripenem was demonstrated for the US Food and Drug Administration co-primary endpoints of (1) patient-reported symptomatic resolution at day 5: 276 of 393 (70.2%) vs 276 of 417 (66.2%) patients (difference, 4.0% [95% confidence interval {CI}, -2.39% to 10.42%]); and (2) combined symptomatic resolution/microbiological eradication at test of cure (TOC): 280 of 393 (71.2%) vs 269 of 417 (64.5%) patients (difference, 6.7% [95% CI, .30% to 13.12%]). Microbiological eradication at TOC (European Medicines Agency primary endpoint) occurred in 304 of 393 (77.4%) ceftazidime-avibactam vs 296 of 417 (71.0%) doripenem patients (difference, 6.4% [95% CI, .33% to 12.36%]), demonstrating superiority at the 5% significance level. Both treatments showed similar efficacy against ceftazidime-nonsusceptible pathogens. Ceftazidime-avibactam had a safety profile consistent with that of ceftazidime alone.
CONCLUSIONS
Ceftazidime-avibactam was highly effective for the empiric treatment of cUTI (including acute pyelonephritis), and may offer an alternative to carbapenems in this setting.
CLINICAL TRIALS REGISTRATION
NCT01595438; NCT01599806.
Topics: Adult; Aged; Anti-Bacterial Agents; Azabicyclo Compounds; Carbapenems; Ceftazidime; Doripenem; Drug Combinations; Female; Humans; Male; Middle Aged; Pyelonephritis; Urinary Tract Infections
PubMed: 27313268
DOI: 10.1093/cid/ciw378