CONCISE REVIEWS OF PEDIATRIC INFECTIOUS DISEASES ® Use of Colistin in Children Pranita D. Tamma, MD, and Carlton K. Lee, PharmD, MPH Key Words: Colistimethate, Colistin (Pediatr Infect Dis J 2009;28: 534 –535) Colistin, or Polymixin E, is a cationic polypeptide antibiotic obtained from Bacil- lus spp. It was initially used therapeutically in the United States in 1959 but intravenous formulations were gradually abandoned in the early 1980s due to nephrotoxicity con- cerns. The emergence of bacteria resistant to most classes of commercially available anti- biotics and the shortage of new antimicrobial agents with activity against gram-negative microorganisms have led to the reconsidera- tion of polymixins as valuable therapeutic options. MECHANISM OF ACTION The positively charged peptide ring of colistin binds with the anionic lipopolysac- charide (LPS) molecules by displacing cal- cium and magnesium from the outer mem- brane of gram-negative bacteria, leading to permeability changes in the cell envelope, leakage of cell contents, and cell death. In addition, by association with LPS it exerts an anti-endotoxin activity and subsequently leads to decreased levels of serum endotoxin and TNF-. 1 Studies of polymixin-resistant Pseudomonas aeruginosa strains have sug- gested that alterations of the outer membrane of the bacterial cell (reduction in LPS, re- duced levels of specific outer membrane pro- teins, reduction in cell envelope Mg++ and Ca++ contents, and lipid alterations) are related to the development of resistance. Re- sistance is postulated to be induced by a gene (PmrA), which modifies LPS resulting in reduced binding affinity of colistin and pos- sibly related antimicrobial peptides to the outer membrane. 2 PHARMACOKINETICS/ PHARMACODYNAMICS The commercially available intrave- nous formulation is Colistimethate, a pro- drug that must be hydrolyzed to the bioactive form colistin. Colistimethate can be admin- istered parenterally or via inhalation and is generally not absorbed from the gastrointes- tinal tract. Absorption from the gastrointes- tinal tract, however, has been observed in human infants and thus, the drug should be used cautiously in this age group. 3 Colistin can be administered orally for bowel decon- tamination and topically for treatment of bacterial skin infections. Similar to aminoglycosides, colistin exhibits properties of concentration-depen- dent bactericidal activity with significant postantibiotic effects of greater than 1 hour. The dosage of intravenous colistin recom- mended by United States manufacturers is 2.5–5 mg/kg per day, divided into 2– 4 equal doses, resulting in a half-life of Colistimethate of 2– 4 hours in children with normal renal function. The time interval between injections should be increased in the presence of impaired renal function as per package instructions. Colistin can be administered intramuscularly at the same doses, but is generally not recom- mended because of severe pain at the injection site. Colistimethate and its metabolites are ex- creted mainly by the kidneys through glomer- ular filtration and urinary excretion. The pharmacokinetics of intravenous colistin in adolescents with cystic fibrosis with a dose of 5–7 mg/kg/day in 3 divided doses has demonstrated a half-life of 3.4 hours, volume of distribution of 0.09 L/kg, and total body clearance of 0.35 mL/min/kg. 4 Data are not available to compare these values to humans without cystic fibrosis. SPECTRUM OF ACTIVITY Colistimethate has bactericidal activ- ity against most gram-negative aerobic ba- cilli. The break point for the “susceptible” interpretative category is an MIC 2 mcg/ mL. Using this definition, susceptibility to polymixin B among 54,731 clinical isolates of gram-negative bacilli as reported from the SENTRY antimicrobial surveillance pro- gram (2001–2004) was as follows: 98.7% of P. aeruginosa; 97.9% for Acinetobacter spp.; 98.2% for Klebsiella spp., and 99.5% for Escherichia coli. 5 It is not indicated for infections due to Proteus spp. or Neisseria spp. Colistin has in vitro activity against 83%– 88% of Stenotrophomonas maltophilia strains. 6 It is active against several Mycobac- terial species including Mycobacterium avium- intracellulare and Mycobacterium tu- berculosis. Colistin is not active against gram-positive aerobic organisms, anaerobes, fungi, or parasites. TOXICITIES Recent data indicate that colistin-re- lated nephrotoxicity, may be less prominent From the Department of Pediatrics, Division of Pedi- atric Infectious Diseases, Johns Hopkins Univer- sity School of Medicine, Baltimore, MD. Copyright © 2009 by Lippincott Williams & Wilkins ISSN: 0891-3668/09/2806-0534 DOI: 10.1097/INF.0b013e3181ac4980 CONTENTS Use of Colistin in Children Congenital Syphilis–Persisting Pestilence EDITORIAL BOARD Co-Editors: Margaret C. Fisher, MD, and Gary D. Overturf, MD Editors for this Issue: Charles R. Woods, MD, MS Board Members Michael Cappello, MD Ellen G. Chadwick, MD Janet A. Englund, MD Leonard R. Krilov, MD Charles T. Leach, MD Kathleen McGann, MD Jennifer S. Read, MD Jeffrey R. Starke, MD Geoffrey A. Weinberg, MD Leonard Weiner, MD Charles R. Woods, MD The Concise Reviews of Pediatric Infectious Diseases (CRPIDS) topics, authors, and contents are chosen and approved indepen- dently by the Editorial Board of CRPIDS. The Pediatric Infectious Disease Journal • Volume 28, Number 6, June 2009 534 | www.pidj.com