Polymyxin Antibiotics

Book excerpt: It is our wish that readers discover the importance of polymyxin structure in relation to the mechanisms of activity, resistance and toxicity. We emphasized that reliable analytic methods for polymyxins are critical when investigating their pharmacokinetics (PK) and pharmacodynamics (PD). The complicated dose definitions and different pharmacopoeial standards have already compromised the safe use of polymyxins in patients. Therefore, informed by the latest pharmacological information, scientifically-based dosing recommendations have been proposed for intravenous polymyxins. Considering the PK/PD limitations and potential development of resistance, polymyxin combinations are encouraged; however, the current literature has not shown definite microbiological benefits, possibly because most clinical studies to date overlooked key PK/PD principles. Nephrotoxicity is the major dose-limiting factor and it is imperative to elucidate the mechanisms and develop novel approaches to minimize polymyxin-associated toxicities. In addition, the anti-endotoxin effect of polymyxins supports their clinical use to treat Gram-negative sepsis. Fortunately, the discovery of new-generation polymyxins with wider therapeutic windows has benefited from the latest achievements in polymyxin research.