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Colistin and Polymyxin B Dosage Regimens against Acinetobacter baumannii: Differences in Activity and the Emergence
Soon-Ee Cheah1, Jian Li1, Brian T Tsuji2
1Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), Parkville, Victoria, Australia.
Abstract:
Infections caused by multidrug-resistant Acinetobacter baumannii are a major public health problem, and polymyxins are often the last line of therapy for recalcitrant infections by such isolates. The pharmacokinetics of the two clinically used polymyxins, polymyxin B and colistin, differ considerably, since colistin is administered as an inactive prodrug that undergoes slow conversion to colistin. However, the impact of these substantial pharmacokinetic differences on bacterial killing and resistance emergence is poorly understood. We assessed clinically relevant polymyxin B and colistin dosage regimens against one reference and three clinical A. baumannii strains in a dynamic one-compartment in vitro model. A new mechanism-based pharmacodynamic model was developed to describe and predict the drug concentrations and viable counts of the total and resistant populations. Rapid attainment of target concentrations was shown to be critical for polymyxin-induced bacterial killing. All polymyxin B regimens achieved peak concentrations of at least 1 mg/liter within 1 h and caused ≥4 log10 killing at 1 h. In contrast, the slow rise of colistin concentrations to 3 mg/liter over 48 h resulted in markedly reduced bacterial killing. A significant (4 to 6 log10 CFU/ml) amplification of resistant bacterial populations was common to all dosage regimens. The developed mechanism-based model explained the observed bacterial killing, regrowth, and resistance. The model also implicated adaptive polymyxin resistance as a key driver of bacterial regrowth and predicted the amplification of preexisting, highly polymyxin-resistant bacterial populations following polymyxin treatment. Antibiotic combination therapies seem the most promising option for minimizing the emergence of polymyxin resistance.
Insights
Polymyxin B demonstrated superior bacterial killing compared to colistin due to faster concentration attainment. Both drugs amplified resistant Acinetobacter baumannii populations, suggesting combination therapy is crucial.
Area of Science:
- Microbiology
- Pharmacology
- Infectious Diseases
Background:
- Multidrug-resistant Acinetobacter baumannii infections pose a significant public health threat.
- Polymyxins are last-resort antibiotics for treating infections caused by these resistant bacteria.
- Clinical use of polymyxin B and colistin is complicated by their differing pharmacokinetics, with colistin administered as a prodrug.
Purpose of the Study:
- To investigate the impact of pharmacokinetic differences between polymyxin B and colistin on bacterial killing and resistance emergence in Acinetobacter baumannii.
- To develop and validate a mechanism-based pharmacodynamic model for predicting drug concentrations, bacterial counts, and resistance dynamics.
- To compare the efficacy of clinically relevant dosage regimens of polymyxin B and colistin against Acinetobacter baumannii in an in vitro model.
Main Methods:
- Utilized a dynamic one-compartment in vitro model to simulate polymyxin B and colistin exposure.
- Tested multiple Acinetobacter baumannii strains, including one reference and three clinical isolates.
- Developed a novel mechanism-based pharmacodynamic model to analyze drug concentrations and bacterial populations (total and resistant).
Main Results:
- Rapid achievement of target drug concentrations was critical for effective bacterial killing by polymyxins.
- Polymyxin B regimens rapidly achieved peak concentrations and demonstrated significant bacterial killing within 1 hour.
- Colistin regimens showed slower concentration increases, leading to markedly reduced bacterial killing and substantial amplification of resistant populations (4-6 log10 CFU/ml) for both drugs.
Conclusions:
- Pharmacokinetic differences significantly impact polymyxin efficacy, with rapid concentration attainment being key.
- Adaptive resistance mechanisms drive bacterial regrowth, and polymyxin treatment amplifies pre-existing resistant populations.
- Antibiotic combination therapies represent the most promising strategy to mitigate the emergence of polymyxin resistance in Acinetobacter baumannii infections.
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