Review articlePolymyxins:: Pharmacology, pharmacokinetics, pharmacodynamics, and clinical applications
Section snippets
Historical perspective
The polymyxins, a group of basic polypeptide antibiotics with activity versus most gram-negative pathogens, were first isolated from a Bacillus spp. in 1947 [2], [7]. Five different chemical compounds (polymyxins A, B, C, D, and E) are included in this group of antibiotics. Polymyxin B and polymyxin E (colistin) are the two polymyxins that have been used therapeutically. Polymyxin B was isolated from Bacillus polymyxa in 1947, and polymyxin E, or colistin, was isolated from Bacillus colistinus
Toxicity issues
The polymyxins are known to be nephrotoxic, causing damage to the convoluted tubule epithelium. Acute tubular necrosis caused by the polymyxins is manifested by albuminuria, decreased urine output, and increased serum creatinine and blood urea nitrogen [2]. Additionally, the polymyxins can cause neurologic complications, such as dizziness, weakness, perioral paresthesia, and ataxia. The neuromuscular blockade produced by the polymyxins can be severe enough to cause apnea or respiratory failure,
Susceptibility testing
Many issues exist surrounding susceptibility testing for polymyxin B and colistin. The National Committee for Clinical Laboratory Standards does not publish any interpretative guidelines for polymyxin B or colistin susceptibility testing. The last published National Committee for Clinical Laboratory Standards resistance breakpoint criteria for the polymyxins was in 1981, but the recommendation was later removed because of the lack of use of these antibiotics [9]. The Working Party on Antibiotic
Pharmacokinetics
Contemporary pharmacokinetic studies evaluating polymyxin B and colistin are lacking. Most of the data stem from studies done in the 1960s and 1970s. Moreover, most of the pharmacokinetic data for polymyxin B involve intramuscular injection, which is no longer a recommended route of administration because of severe pain on injection. Furthermore, much of the data for colistin involve a specific patient population, namely cystic fibrosis patients. These data were obtained from a young, most
Pharmacodynamics
Polymyxin dosing strategies were developed before the introduction of pharmacodynamic concepts. These dosing strategies were developed without the understanding as to whether polymyxin B or colistin killed bacteria in a concentration-dependent or -independent fashion and without a linkage to pharmacodynamic outcome parameters. Little has changed regarding the understanding of polymyxin B or colistin pharmacodynamics over the last 50 years.
Considering that polymyxins may need to play a vital
Clinical uses
Because of the spectrum of activity of the polymyxins, polymyxin B and colistin have been used primarily for the treatment of gram-negative infections. The polymyxins have been used to treat urinary tract infections; superficial wounds and burns (topical); meningitis; ventriculitis; pneumonia; bacteremia; peritonitis; osteomyelitis; and endocarditis [2], [5], [7], [21], [22], [23]. Most of the clinical data in humans consist of small studies and case reports.
Levin et al [5] evaluated the use of
Emerging resistance
Resistance to the polymyxins can develop by mutation or adaptation. Mutational resistance is inherited and is considered low-level, whereas adaptation requires continuous presence of the antibiotic and is considered high-level [2]. The likely mechanisms of resistance are alterations in the composition of lipopolysaccharide molecules or the substitution of H1 protein for magnesium in the outer membrane [2]. The H1 protein is less likely to be displaced from the outer membrane by the polymyxins
Summary
Although the polymyxins seem attractive because of their unique structure and mechanism of action, relatively little is known about this group of antibiotics. Much of the available information is from a different era of medical practice when the manipulation of dosing strategies, or optimization of pharmacodynamic parameters, was not commonplace. Moreover, the more recent information that is available is limited in scope with regards to patient populations and microorganisms.
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