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Combination therapy for carbapenem-resistant Gram-negative bacteria
Alexandre P Zavascki1, Jurgen B Bulitta, Cornelia B Landersdorfer
1Infectious Diseases Service, Hospital de Clínicas de Porto Alegre, 2350 Ramiro Barcelos St, Porto Alegre, 90.035-903, Brazil.
Abstract:
The emergence of resistant to carbapenems Gram-negative bacteria (CR GNB) has severely challenged antimicrobial therapy. Many CR GNB isolates are only susceptible to polymyxins; however, therapy with polymyxins and other potentially active antibiotics presents some drawbacks, which have discouraged their use in monotherapy. In this context, along with strong pre-clinical evidence of benefit in combining antimicrobials against CR GNB, the clinical use of combination therapy has been raised as an interesting strategy to overcome these potential limitations of a single agent. Polymyxins, tigecycline and even carbapenems are usually the cornerstone agents in combination schemes. Optimization of the probability to attain the pharmacokinetic/pharmacodynamic targets by both cornerstone drug and adjuvant drug is of paramount importance to achieve better clinical and microbiological outcomes. Clinical evidence of the major drugs utilized in combination schemes and how they should be prescribed considering pharmacokinetic/pharmacodynamic characteristics against CR GNB will be reviewed in this article.
Insights
Combination therapy is crucial for treating carbapenem-resistant Gram-negative bacteria (CR GNB) when single agents fail. Optimizing drug combinations ensures better clinical outcomes against these challenging infections.
Area of Science:
- Infectious Diseases
- Microbiology
- Pharmacology
Background:
- Emergence of carbapenem-resistant Gram-negative bacteria (CR GNB) poses a significant threat to antimicrobial therapy.
- Polymyxins are often the last resort, but monotherapy has drawbacks, necessitating alternative strategies.
- Pre-clinical data support antimicrobial combinations against CR GNB.
Purpose of the Study:
- To review the clinical evidence for combination therapy against CR GNB.
- To discuss the optimization of pharmacokinetic/pharmacodynamic (PK/PD) targets for cornerstone and adjuvant drugs.
- To guide the clinical prescription of combination therapies based on PK/PD characteristics.
Main Methods:
- Review of clinical evidence for major drugs used in combination schemes against CR GNB.
- Analysis of pharmacokinetic/pharmacodynamic principles relevant to combination therapy.
- Discussion on optimizing drug dosing and combinations for improved outcomes.
Main Results:
- Combination therapy is a viable strategy to overcome limitations of single-agent therapy for CR GNB.
- Polymyxins, tigecycline, and carbapenems are key components in combination regimens.
- Achieving PK/PD targets for both cornerstone and adjuvant drugs is critical for success.
Conclusions:
- Combination therapy offers a promising approach to manage infections caused by CR GNB.
- Careful consideration of PK/PD properties is essential for effective drug selection and dosing.
- Further clinical research is needed to refine optimal combination strategies.
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