Dose-dependent Synergistic Interactions of #Colistin with #Rifampicin, #Meropenem and #Tigecycline against #Carbapenem-resistant #Klebsiella pneumoniae #Biofilms (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Dose-dependent Synergistic Interactions of Colistin with Rifampicin, Meropenem and Tigecycline against Carbapenem-resistant Klebsiella pneumoniae Biofilms

Anastasia Geladari, Maria Simitsopoulou, Charalampos Antachopoulos, Emmanuel Roilides

DOI: 10.1128/AAC.02357-18

 

ABSTRACT

Carbapenem-resistant Klebsiella pneumoniae (CR-Kp) can cause biofilm-related bloodstream infections associated with significant morbidity and mortality worldwide. We investigated the bactericidal activities of colistin (CST), rifampicin (RIF), meropenem (MEM), gentamicin (GEN) and tigecycline (TGC) alone and that of CST in combination with RIF, MEM, GEN or TGC against CR-Kp mature biofilms. Twenty CR-Kp blood isolates were derived from equal number of bloodstream infections in adult patients. Biofilm formation was assessed by staining with 0.4% crystal violet and measuring optical density spectrophotometrically at 545 nm. Biofilm damage was measured as % reduction of metabolic activity by XTT assay. MIC50 for biofilms was determined as the minimum concentration that caused ≥50% bacterial damage compared to that for untreated controls. Antibacterial drug interactions were analyzed by the Bliss independence model. Four of the twenty CR-Kp isolates were biofilm producers. Biofilm MIC50’s of CST, RIF, MEM, GEN and TGC for these isolates were 64, 8, >256, 128 and 8 mg/L, respectively. Synergistic interactions were observed at 32-64 mg/L of CST combined with 0.25-4 mg/L of RIF, at 32 mg/L of CST combined with 0.007-0.25 mg/L of MEM, and at 16-32 mg/L of CST combined with 16-64 mg/L of TGC. The synergy was highest for CST+RIF, with %ΔE±SE 49.87±9.22 compared to 29.52±4.97 for CST+MEM (p<0.001) and 32.44±6.49 for CST+TGC (p<0.001). Indifferent results were exhibited by CST+GEN. None of the combinations exhibited antagonism. These drug interactive findings, especially that of CST with RIF, may be of importance in the treatment of biofilm-related CR-Kp infections.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Antibiotics; Drugs Resistance; Carbapene; Klebsiella pneumoniae; Colistin; Gentamicin; Tigecycline; Meropenem; Rifampicin.

——

Activity of #nacubactam (RG6080/OP0595) combinations against #MBL-producing #Enterobacteriaceae (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

Activity of nacubactam (RG6080/OP0595) combinations against MBL-producing Enterobacteriaceae

Shazad Mushtaq, Anna Vickers, Neil Woodford, Andreas Haldimann, David M Livermore

Journal of Antimicrobial Chemotherapy, dky522, https://doi.org/10.1093/jac/dky522

Published: 24 December 2018

 

Abstract

Background

Diazabicyclooctanes (DBOs) are promising β-lactamase inhibitors. Some, including nacubactam (OP0595/RG6080), also bind PBP2 and have an enhancer effect, allowing activity against Enterobacteriaceae with MBLs, which DBOs do not inhibit. We tested the activity of nacubactam/β-lactam combinations against MBL-producing Enterobacteriaceae.

Methods

Test panels comprised (i) 210 consecutive Enterobacteriaceae with NDM or VIM MBLs, as referred by UK diagnostic laboratories, and (ii) 99 supplementary MBL-producing Enterobacteriaceae, representing less prevalent phenotypes, species and enzymes. MICs were determined by CLSI agar dilution.

Results

MICs of nacubactam alone were bimodal, clustering at 1–8 mg/L or >32 mg/L; >85% of values for Escherichia coli and Enterobacter spp. fell into the low MIC cluster, whereas Proteeae were universally resistant and the Klebsiella spp. were divided between the two groups. Depending on the prospective breakpoint (4 + 4 or 8 + 4 mg/L), and on whether all isolates were considered or solely the Consecutive Collection, meropenem/nacubactam and cefepime/nacubactam inhibited 80.3%–93.3% of MBL producers, with substantial gains over nacubactam alone. Against the most resistant isolates (comprising 57 organisms with MICs of nacubactam >32 mg/L, cefepime ≥128 mg/L and meropenem ≥128 mg/L), cefepime/nacubactam at 8 + 4 mg/L inhibited 63.2% and meropenem/nacubactam at 8 + 4 mg/L inhibited 43.9%. Aztreonam/nacubactam, incorporating an MBL-stable β-lactam partner, was almost universally active against the MBL producers and, unlike aztreonam/avibactam, had an enhancer effect.

Conclusions

Nacubactam combinations, including those using MBL-labile β-lactams, e.g. meropenem and cefepime, can overcome most MBL-mediated resistance. This behaviour reflects nacubactam’s direct antibacterial and enhancer activity.

Topic: phenotype – cefepime – agar – aztreonam – enterobacter – enterobacteriaceae – klebsiella – laboratory – lactams – diagnosis – enzymes – meropenem – anti-bacterial agents – escherichia coli – enhancer of transcription – dilution technique – dilute (action) – binding (molecular function) – malnutrition-inflammation-cachexia syndrome – avibactam

Issue Section: ORIGINAL RESEARCH

© 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/open_access/funder_policies/chorus/standard_publication_model)

Keywords: Antibiotics; Drugs Resistance; Enterobacteriaceae; Aztreonam; Meropenem; Nacubactam.

——

Averting the #postantibiotic era: successful use of #meropenem/vaborbactam for #carbapenem-resistant #Serratia marcescens and #Enterobacter aerogenes bacteraemia in a haemodialysis patient (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

Averting the post-antibiotic era: successful use of meropenem/vaborbactam for carbapenem-resistant Serratia marcescens and Enterobacter aerogenes bacteraemia in a haemodialysis patient

Sarah C J Jorgensen, Philip McDonald, Ryan P Mynatt, Jason M Pogue, Stephen A Lerner, Sorabh Dhar, Hossein Salimnia, Michael J Rybak

Journal of Antimicrobial Chemotherapy, dky346, https://doi.org/10.1093/jac/dky346

Published: 04 September 2018

Sir,

The prevalence of carbapenem-resistant Enterobacteriaceae (CRE) has increased dramatically over the past two decades, fuelling speculation that we are nearing the ‘post-antibiotic era’ and attesting to the critical need for novel antibiotics with activity against MDR pathogens.1 In 2015 the US FDA approved ceftazidime/avibactam for the treatment of complicated urinary tract infections (cUTIs) and complicated intra-abdominal infections caused by MDR Gram-negative bacteria.2 The introduction of ceftazidime/avibactam represented significant progress in the treatment of CRE, with accumulating real‐world data demonstrating improved efficacy and safety compared with older, more toxic antibiotics.3–5However, treatment failure rates as high as 30%–50% have been…

(…)

___

Issue Section: Research letter

© 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/open_access/funder_policies/chorus/standard_publication_model)

Keywords: Antibiotics; Drugs Resistance; Carbapenem; Serratia marcescens; Enterobacter aerogenes; Bacteremia; Meropenem; Vaborbactam.

……

Various sequence types of #Enterobacteriaceae carrying #blaNDM-5 gene from commercial #chicken #farms in #China (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Various sequence types of Enterobacteriaceae carrying blaNDM-5 gene from commercial chicken farms in China

Rong Xiang, An-Yun Zhang, Xiao-Lan Ye, Zhuang-Zhuang Kang, Chang-Wei Leiand Hong-Ning Wang*

Author Affiliations: Animal Disease Prevention and Food Safety Key Laboratory of Sichuan Province, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610065, Sichuan, P.R.China

 

ABSTRACT

A total of 108 meropenem-resistant Enterobacteriaceae isolates were obtained from 1658 rectal swabs collected from 15 unrelated commercial chicken farms in China between 2014 and 2016. These samples yielded sixteen Escherichia coli and two Klebsiella pneumoniae isolates of diverse sequence types carrying a blaNDM-5-bearing IncX3 plasmid. Klebsiella pneumoniae strain sequence type 709 (ST709) has two blaNDM-5-carrying plasmids that were transferred together to E.coli.

 

FOOTNOTES

*Corresponding author. Mailing address: College of Life science, Sichuan University, NO. 29 Wangjiang Road, Chengdu, Sichuan, China, 610064., Phone: +86-28-8547-1599. Fax: +86-28-8547-1599., E-mail: whongning@163.com

Copyright © 2018 American Society for Microbiology. All Rights Reserved.

Keywords: Antibiotics; Drugs Resistance; Meropenem; Enterobacteriaceae; Poultry; China.

—–

In vitro activity of #ceftazidime / #avibactam against isolates of #Pseudomonas aeruginosa collected in #European countries: INFORM global surveillance 2012–15 (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

In vitro activity of ceftazidime/avibactam against isolates of Pseudomonas aeruginosa collected in European countries: INFORM global surveillance 2012–15

Krystyna M Kazmierczak, Boudewijn L M de Jonge, Gregory G Stone, Daniel F Sahm

Journal of Antimicrobial Chemotherapy, dky267, https://doi.org/10.1093/jac/dky267

Published: 11 July 2018

 

Abstract

Objectives

The activity of ceftazidime/avibactam was assessed against 5716 Pseudomonas aeruginosa isolates collected from 96 medical centres in 18 European countries as part of the International Network for Optimal Resistance Monitoring (INFORM) global surveillance programme from 2012 to 2015. Activity was analysed against subsets of isolates based on resistance phenotypes and β-lactamase content.

Methods

Antimicrobial susceptibility testing was performed by broth microdilution and β-lactamase genes were detected by PCR screening and sequencing.

Results

Ceftazidime/avibactam was highly active in vitro against the overall collection of P. aeruginosa isolates and colistin-resistant isolates (92.4% and 92.9% susceptible, respectively). Although activity was slightly reduced against MBL-negative subsets of ceftazidime-non-susceptible (79.6% susceptible), meropenem-non-susceptible (85.1% susceptible) and MDR (81.6% susceptible) P. aeruginosa, ceftazidime/avibactam remained the second most active entity, after colistin, compared with all other comparator agents tested. At the country level, susceptibility to ceftazidime/avibactam ranged from 74.6% to 99.6%, with decreased susceptibilities only observed in countries where MBLs are more frequently encountered, such as the Czech Republic, Greece, Romania and Russia. Ceftazidime/avibactam was also active in vitro against 87.6% of meropenem-non-susceptible isolates in which no acquired β-lactamases were detected by molecular methods; these isolates were assumed to hyperproduce the chromosomally encoded AmpC in combination with alterations in OprD or drug efflux. As expected, ceftazidime/avibactam was not active against isolates carrying MBLs.

Conclusions

The data show that ceftazidime/avibactam is highly potent in vitro against clinical isolates of P. aeruginosa collected in European countries, including isolates that exhibit resistance to ceftazidime, meropenem and colistin and combined resistance to agents from multiple drug classes.

Issue Section: ORIGINAL RESEARCH

© 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)

Keywords: Antibiotics; Drugs Resistance; Colistin; Meropenem; Avibactam; Ceftazidime; Pseudomonas aeruginosa; European Region.

——

In vitro activity of #ceftazidime / #avibactam against isolates of #Enterobacteriaceae collected in #European countries: #INFORM global surveillance 2012–15 (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

In vitro activity of ceftazidime/avibactam against isolates of Enterobacteriaceae collected in European countries: INFORM global surveillance 2012–15

Krystyna M Kazmierczak, Boudewijn L M de Jonge, Gregory G Stone, Daniel F Sahm

Journal of Antimicrobial Chemotherapy, dky266, https://doi.org/10.1093/jac/dky266

Published: 11 July 2018

 

Abstract

Objectives

The activity of ceftazidime/avibactam was assessed against 24 750 isolates of Enterobacteriaceae collected from 96 medical centres in 18 European countries as part of the International Network for Optimal Resistance Monitoring (INFORM) global surveillance programme from 2012 to 2015. Activity was analysed against subsets of isolates based on resistant phenotypes and β-lactamase content.

Methods

Antimicrobial susceptibility testing was performed using broth microdilution and the presence of β-lactamase genes in isolates of interest was determined using PCR and sequencing.

Results

Ceftazidime/avibactam was the most active agent, compared with all other tested comparator agents, against the overall collection of Enterobacteriaceae isolates (99.4% susceptible) and against subsets of ceftazidime-non-susceptible (97.7% susceptible), colistin-resistant (98.2% susceptible), MDR (96.7% susceptible) and meropenem-non-susceptible, MBL-negative (98.5% susceptible) isolates. At the country level, susceptibility to ceftazidime/avibactam ranged from 96.3% to 100% among Enterobacteriaceae isolates, with decreased susceptibilities only observed in countries where MBLs were more frequently encountered (e.g. Greece and Romania). Ceftazidime/avibactam was active against 99.7% of Enterobacteriaceae isolates that carried serine β-lactamases, including ESBLs, AmpC cephalosporinases and carbapenemases (KPC, GES and OXA-48-like) in all combinations. As expected, ceftazidime/avibactam was not active against isolates carrying MBLs.

Conclusions

The data show that ceftazidime/avibactam is highly potent in vitro against clinical isolates of Enterobacteriaceae collected in European countries, including isolates that exhibit resistance to ceftazidime, meropenem and colistin and combined resistance to agents from multiple drug classes.

Issue Section: ORIGINAL RESEARCH

© 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)

Keywords: Antibiotics; Drugs Resistance; Colistin; Meropenem; Ceftazidime; Avibactam; Enterobacteriaceae; European Region.

—–

#Antibiotic #pressure on the acquisition and loss of antibiotic #resistance genes in #Klebsiella pneumoniae (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

Antibiotic pressure on the acquisition and loss of antibiotic resistance genes in Klebsiella pneumoniae

Patricia J Simner, Annukka A R Antar, Stephanie Hao, James Gurtowski, Pranita D Tamma, Clare Rock, Belita N A Opene, Tsigereda Tekle, Karen C Carroll, Michael C Schatz, Winston Timp

Journal of Antimicrobial Chemotherapy, dky121, https://doi.org/10.1093/jac/dky121

Published: 10 April 2018

 

Abstract

Objectives

In this study, we characterize a concurrent disseminated infection with a virulent hypermucoviscous (HMV) Klebsiella pneumoniae and an OXA-181-producing XDR K. pneumoniae from a patient with recent hospitalization in India. During exposure to meropenem therapy, the highly susceptible HMV K. pneumoniae became resistant to carbapenems, consistent with the acquisition of blaOXA-181.

Methods

Twelve K. pneumoniae isolates were recovered from the patient and the hospital room environment over a 3 month hospitalization. Phenotypic and molecular studies were completed to characterize the isolates. Oxford Nanopore and Illumina MiSeq WGS were performed to study phylogeny (MLST and SNPs), plasmids and virulence genes and demonstrate changes in the organism’s resistome that occurred over time.

Results

WGS revealed that the HMV K. pneumoniae belonged to ST23 and harboured an IncH1B virulence plasmid, while the XDR K. pneumoniae belonged to ST147 and possessed two MDR plasmids (IncR and IncFII), the blaOXA-181-bearing ColKP3 plasmid and chromosomal mutations conferring the XDR phenotype. Sequential isolates demonstrated plasmid diversification (fusion of the IncR and IncFII plasmids), mobilization of resistance elements (ompK35 inactivation by ISEcp1-blaCTX-M-15 mobilization, varying numbers of resistance genes on plasmid scaffolds) and chromosomal mutations (mutations in mgrB) leading to further antibiotic resistance that coincided with antibiotic pressure. Importantly, the HMV strain in this study was unable to preserve the carbapenem-resistant phenotype without the selective pressure of meropenem.

Conclusions

To the best of our knowledge, we are the first to report a carbapenem-resistant HMV K. pneumoniae strain in the USA. Ultimately, this case demonstrates the role of antibiotic pressure in the acquisition and loss of important genetic elements.

Issue Section: ORIGINAL RESEARCH

Keywords: Antibiotics; Drugs Resistance; Carbapenem; K. Pneumoniae; USA.

——

#Colistin alone versus colistin plus #meropenem for treatment of severe #infections caused by #carbapenem-resistant Gram-negative bacteria: an open-label, randomised controlled trial (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Colistin alone versus colistin plus meropenem for treatment of severe infections caused by carbapenem-resistant Gram-negative bacteria: an open-label, randomised controlled trial

Mical Paul, MD, Prof George L Daikos, MD, Emanuele Durante-Mangoni, MD, Dafna Yahav, MD, Prof Yehuda Carmeli, MD, Yael Dishon Benattar, MA, Anna Skiada, MD, Roberto Andini, MD, Noa Eliakim-Raz, MD, Amir Nutman, MD, Oren Zusman, MD, Anastasia Antoniadou, MD, Pia Clara Pafundi, Amos Adler, MD, Yaakov Dickstein, MD, Ioannis Pavleas, MD, Rosa Zampino, MD, Vered Daitch, MA, Roni Bitterman, MD, Hiba Zayyad, MD, Fidi Koppel, BA, Inbar Levi, MA, Tanya Babich, MA, Prof Lena E Friberg, PhD, Prof Johan W Mouton, MD, Ursula Theuretzbacher, PhD, Prof Leonard Leibovici, MD

Published: 15 February 2018 / DOI: https://doi.org/10.1016/S1473-3099(18)30099-9

© 2018 Elsevier Ltd. All rights reserved.

 

Summary

Background

Colistin–carbapenem combinations are synergistic in vitro against carbapenem-resistant Gram-negative bacteria. We aimed to test whether combination therapy improves clinical outcomes for adults with infections caused by carbapenem-resistant or carbapenemase-producing Gram-negative bacteria.

Methods

A randomised controlled superiority trial was done in six hospitals in Israel, Greece, and Italy. We included adults with bacteraemia, ventilator-associated pneumonia, hospital-acquired pneumonia, or urosepsis caused by carbapenem-non-susceptible Gram-negative bacteria. Patients were randomly assigned (1:1) centrally, by computer-generated permuted blocks stratified by centre, to intravenous colistin (9-million unit loading dose, followed by 4·5 million units twice per day) or colistin with meropenem (2-g prolonged infusion three times per day). The trial was open-label, with blinded outcome assessment. Treatment success was defined as survival, haemodynamic stability, improved or stable Sequential Organ Failure Assessment score, stable or improved ratio of partial pressure of arterial oxygen to fraction of expired oxygen for patients with pneumonia, and microbiological cure for patients with bacteraemia. The primary outcome was clinical failure, defined as not meeting all success criteria by intention-to-treat analysis, at 14 days after randomisation. This trial is registered at ClinicalTrials.gov, number NCT01732250, and is closed to accrual.

Findings

Between Oct 1, 2013, and Dec 31, 2016, we randomly assigned 406 patients to the two treatment groups. Most patients had pneumonia or bacteraemia (355/406, 87%), and most infections were caused by Acinetobacter baumannii (312/406, 77%). No significant difference between colistin monotherapy (156/198, 79%) and combination therapy (152/208, 73%) was observed for clinical failure at 14 days after randomisation (risk difference −5·7%, 95% CI −13·9 to 2·4; risk ratio [RR] 0·93, 95% CI 0·83–1·03). Results were similar among patients with A baumannii infections (RR 0·97, 95% CI 0·87–1·09). Combination therapy increased the incidence of diarrhoea (56 [27%] vs 32 [16%] patients) and decreased the incidence of mild renal failure (37 [30%] of 124 vs 25 [20%] of 125 patients at risk of or with kidney injury).

Interpretation

Combination therapy was not superior to monotherapy. The addition of meropenem to colistin did not improve clinical failure in severe A baumannii infections. The trial was unpowered to specifically address other bacteria.

Funding

EU AIDA grant Health-F3-2011-278348.

Keywords: Antibiotics; Drugs Resistance; Italy; Greece; Israel; Colistin; Carbapenem; Meropenem.

——

#Meropenem potentiation of #aminoglycoside activity against #Pseudomonas aeruginosa: involvement of the MexXY-OprM multidrug efflux system (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

Meropenem potentiation of aminoglycoside activity against Pseudomonas aeruginosa: involvement of the MexXY-OprM multidrug efflux system

Keith Poole, Christie Gilmour, Maya A Farha, Michael D Parkins, Rachael Klinoski, Eric D Brown

Journal of Antimicrobial Chemotherapy, dkx539,https://doi.org/10.1093/jac/dkx539

Published: 06 February 2018

 

Abstract

Objectives

To assess the ability of meropenem to potentiate aminoglycoside (AG) activity against laboratory and AG-resistant cystic fibrosis (CF) isolates of Pseudomonas aeruginosa and to elucidate its mechanism of action.

Methods

AG resistance gene deletions were engineered into P. aeruginosa laboratory and CF isolates using standard gene replacement technology. Susceptibility to AGs ± meropenem (at ½ MIC) was assessed using a serial 2-fold dilution assay. mexXY expression and MexXY-OprM efflux activity were quantified using quantitative PCR and an ethidium bromide accumulation assay, respectively.

Results

A screen for agents that rendered WT P. aeruginosa susceptible to a sub-MIC concentration of the AG paromomycin identified the carbapenem meropenem, which potentiated several additional AGs. Meropenem potentiation of AG activity was largely lost in a mutant lacking the MexXY-OprM multidrug efflux system, an indication that it was targeting this efflux system in enhancing P. aeruginosa susceptibility to AGs. Meropenem failed to block AG induction of mexXY expression or MexXY-OprM efflux activity, suggesting that it may be interfering with some MexXY-dependent process linked to AG susceptibility. Meropenem potentiated AG activity versus AG-resistant CF isolates, enhancing susceptibility to at least one AG in all isolates and susceptibility to all tested AGs in 50% of the isolates. Notably, meropenem potentiation of AG activity was linked to MexXY in some but not all CF isolates in which this was examined.

Conclusions

Meropenem potentiates AG activity against laboratory and CF strains of P. aeruginosa, both dependent on and independent of MexXY, highlighting the complexity of AG resistance in this organism.

Issue Section:  ORIGINAL RESEARCH

Keywords: Antibiotics; Drugs Resistance; Meropenem; Aminoglycosides; Pseudomonas aeruginosa.

——

#Ceftazidime – #avibactam versus #meropenem in #nosocomial #pneumonia, including ventilator-associated pneumonia (REPROVE): a randomised, double-blind, phase 3 non-inferiority trial (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Ceftazidime-avibactam versus meropenem in nosocomial pneumonia, including ventilator-associated pneumonia (REPROVE): a randomised, double-blind, phase 3 non-inferiority trial

Prof Antoni Torres, Prof Nanshan Zhong, MD, Prof Jan Pachl, MD, Prof Jean-François Timsit, MD, Prof Marin Kollef, MD, Zhangjing Chen, MD, Jie Song, MD, Dianna Taylor, BSc, Peter J Laud, MSc, Gregory G Stone, PhD, Joseph W Chow, MD

Published: 15 December 2017 / DOI: http://dx.doi.org/10.1016/S1473-3099(17)30747-8

© 2017 Elsevier Ltd. All rights reserved.

 

Summary

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.

Keywords: Antibiotics; Avibactam; Meropenem; Ceftazidime; Pneumonia; Nosocomial Outbreraks.

——-