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The Multidrug-Resistant Gram-negative Superbugs Threat Require Intelligent Use of the Last Weapon
1Department of Medical Microbiology and Parasitology, School of Medical Sciences, Universiti Sains Malaysia Health Campus, 16150 Kubang Kerian, Kelantan, Malaysia; Infection Control and Hospital Epidemiology Unit, Hospital Universiti Sains Malaysia, Universiti Sains Malaysia Health Campus, 16150 Kubang Kerian, Kelantan, Malaysia.
Abstract:
The global emergence and dissemination of multidrug-resistant Gram-negative superbugs, particularly carbapenem-resistant Acinetobacter baumannii and Klebsiella pneumoniae, lead to the limited effectiveness of antibiotics for treating nosocomial infections. In most cases, polymyxins are the last resort therapy, and these antibiotics must be used intelligently to prolong their efficacy in clinical practice. Polymyxin B and colistin (polymyxin E) were introduced prior to modern drug regulation, and the majority of the 'old' drug information is unreliable. Recent pharmacokinetic data do not support the renal dose adjustment of intravenous (IV) polymyxin B as suggested by the manufacturer, and this drug must be scaled by the total body weight. Whereas IV colistin is formulated as an inactive prodrug, colistin methanesulfonate (CMS) has different pharmacokinetic profiles than polymyxin B. To achieve maximum efficacy, CMS should be administered as a loading dose scaled to body weight and a maintenance dose according to the renal profiles. Polymyxin combination therapy is suggested due to a sub-therapeutic plasma concentration in a significant proportion of patients and a high incidence of polymyxin hetero-resistance among Gram-negative superbugs. In conclusion, polymyxins must be reserved as a last resort and should be wisely used when truly indicated.
Insights
Polymyxins are last-resort antibiotics against multidrug-resistant Gram-negative bacteria. Proper dosing of polymyxin B and colistin (polymyxin E) is crucial for efficacy and to combat resistance.
Area of Science:
- Infectious Diseases
- Pharmacology
- Microbiology
Background:
- The rise of multidrug-resistant Gram-negative superbugs, like carbapenem-resistant *Acinetobacter baumannii* and *Klebsiella pneumoniae*, necessitates careful antibiotic stewardship.
- Polymyxins (polymyxin B and colistin/polymyxin E) are critical last-resort treatments for infections caused by these challenging pathogens.
Discussion:
- Current dosing guidelines for intravenous polymyxin B may be unreliable; weight-based dosing is recommended over manufacturer-suggested renal adjustments.
- Intravenous colistin, administered as the prodrug colistin methanesulfonate (CMS), requires specific dosing strategies, including weight-based loading and renally adjusted maintenance doses, due to its distinct pharmacokinetic profile.
- Polymyxin combination therapy may be beneficial to address sub-therapeutic drug concentrations and high rates of polymyxin hetero-resistance.
Key Insights:
- Pharmacokinetic data suggest intravenous polymyxin B should be dosed by total body weight.
- Colistin methanesulfonate (CMS) requires a weight-based loading dose and renal-based maintenance dosing for optimal therapeutic effect.
- Addressing polymyxin hetero-resistance and sub-therapeutic concentrations may warrant combination therapies.
Outlook:
- Judicious use of polymyxins is essential to preserve their clinical utility against emerging superbugs.
- Further research into polymyxin pharmacokinetics and pharmacodynamics is needed to optimize treatment strategies.
- Developing novel antibiotics and alternative therapies remains a priority to combat the growing threat of antimicrobial resistance.