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Comparable Efficacy and Better Safety of Double β-Lactam Combination Therapy versus β‑Lactam plus Aminoglycoside in
Yuanyuan Jiao1, Bartolome Moya2, Mong-Jen Chen2
1Departments of Pharmaceutics and Pharmacotherapy & Translational Research, College of Pharmacy, University of Florida, Orlando, Florida, USA yyjiao@cop.ufl.edu jbulitta@cop.ufl.edu.
Abstract:
There is a great need for efficacious therapies against Gram-negative bacteria. Double β-lactam combination(s) (DBL) are relatively safe, and preclinical data are promising; however, their clinical role has not been well defined. We conducted a metaanalysis 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 database were searched through July 2018. We included randomized controlled clinical trials that compared DBL with BLAG combinations. Clinical response was used as the primary outcome and microbiological response in Gram-negative bacteria as the 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; 95% confidence interval [CI], 0.99 to 1.11) and microbiological response in Gram-negatives (risk ratio, 1.11; 95% CI, 0.99 to 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% versus 8.8%, P = 0.0338) and ototoxicity (0.7 versus 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 the latest translational approaches, leveraging mechanistic insights and newer β-lactams for future evaluation in clinical trials.
Insights
Double beta-lactam (DBL) combinations show comparable efficacy to beta-lactam plus aminoglycoside (BLAG) treatments against Gram-negative bacteria. DBL therapies are significantly safer, with reduced renal and ototoxicity, warranting further clinical investigation.
Area of Science:
- Infectious Diseases
- Pharmacology
- Clinical Microbiology
Background:
- Growing need for effective therapies against Gram-negative bacterial infections.
- Double beta-lactam (DBL) combinations show promise but lack defined clinical roles.
- Comparison with established beta-lactam plus aminoglycoside (BLAG) combinations is necessary.
Purpose of the Study:
- To conduct a meta-analysis comparing the clinical and microbiological efficacy of DBL versus BLAG combinations.
- To assess the safety profiles of DBL and BLAG treatments.
- To evaluate specific pathogen responses, including *Pseudomonas aeruginosa*, *Klebsiella* spp., and *Escherichia coli*.
Main Methods:
- Systematic search of PubMed, Embase, ISI Web of Knowledge, and Cochrane Controlled Trials Register through July 2018.
- Inclusion of randomized controlled clinical trials comparing DBL with BLAG.
- Primary outcome: clinical response; Secondary outcome: microbiological response. Safety and heterogeneity assessed.
Main Results:
- Thirteen studies involving 2,771 patients for clinical and 665 for microbiological response were analyzed.
- DBL demonstrated comparable clinical (RR 1.05, 95% CI 0.99-1.11) and microbiological (RR 1.11, 95% CI 0.99-1.25) efficacy to BLAG.
- DBL showed significantly lower renal (6.6% vs 8.8%, P=0.0338) and ototoxicity (0.7% vs 3.1%, P=0.0137) compared to BLAG.
Conclusions:
- Empirically designed DBL combinations offer comparable clinical and microbiological efficacy against Gram-negative bacteria.
- DBL combinations are significantly safer than BLAG, with reduced renal and ototoxicity.
- DBL should be further optimized using translational approaches and newer beta-lactams for future clinical trials.
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