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Antimicrob Agents Chemother. 2019 Apr 15. pii: AAC.00425-19. doi: 10.1128/AAC.00425-19. [Epub ahead of print]

Comparable Efficacy and Better Safety of Double β-Lactam Combination Therapy versus β-Lactam plus Aminoglycoside in Gram-negatives: A Meta-analysis of Randomized, Controlled Trials.

Author information

1
Departments of Pharmaceutics and Pharmacotherapy & Translational Research, College of Pharmacy, University of Florida, Orlando, FL yyjiao@cop.ufl.edu.
2
Departments of Pharmaceutics and Pharmacotherapy & Translational Research, College of Pharmacy, University of Florida, Orlando, FL.
3
Department of Internal Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
4
Institute for Therapeutic Innovation, College of Medicine, University of Florida, Orlando, FL.
5
Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Microbiology, Monash University, Victoria, Australia.
6
College of Pharmacy, Daegu Catholic University, Gyeongsan, Gyeongbuk, Republic of Korea.
7
Department of Pharmacy Practice, University at Buffalo, Buffalo, New York.
8
Medical Service and GRECC, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH.
9
Departments of Medicine, Pharmacology, Molecular Biology and Microbiology, Biochemistry, Proteomics and Bioinformatics, Case Western Reserve University School of Medicine, Cleveland, OH.
10
CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology (Case VA CARES), Cleveland, OH.
11
Departments of Pharmaceutics and Pharmacotherapy & Translational Research, College of Pharmacy, University of Florida, Orlando, FL jbulitta@cop.ufl.edu.

Abstract

There is a great need for efficacious therapies against Gram-negative bacteria. Double β-lactam combinations (DBL) are relatively safe and preclinical data are promising; however, their clinical role has not been well defined. We conducted a meta-analysis of the clinical and microbiological efficacy of DBL compared to β-lactam plus aminoglycoside combinations (BLAG). PubMed, Embase, ISI Web of Knowledge and Cochrane Controlled Trials Register were searched until July 2018. We included randomized controlled clinical trials which compared DBL with BLAG combinations. Clinical response was used as the primary outcome and microbiological response of Gram-negative bacteria as secondary outcome; sensitivity analyses were performed for Pseudomonas aeruginosa, Klebsiella spp. and Escherichia coli Heterogeneity and risk of bias were assessed. Safety results were classified by systems and organs. Thirteen studies evaluated 2,771 cases for clinical response and 665 cases for microbiological response in various Gram-negative species. DBL achieved slightly, but not significantly better clinical response (risk ratio 1.05, CI [0.99-1.11]) and microbiological response in Gram-negatives (risk ratio 1.11, CI [0.99-1.25]) compared with BLAG. Sensitivity analyses by pathogen showed the same trend. No significant heterogeneity across studies was found. DBL was significantly safer than BLAG regarding renal toxicity (6.6% vs. 8.8%, p=0.0338) and ototoxicity (0.7 vs. 3.1%, p=0.0137). Other adverse events were largely comparable. Overall, empirically-designed DBL showed comparable clinical and microbiological responses across different Gram-negative species, and were significantly safer than BLAG. Therefore, DBL should be rationally optimized via latest translational approaches leveraging mechanistic insights and newer β-lactams for future evaluation in clinical trials.

PMID:
30988147
DOI:
10.1128/AAC.00425-19

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