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Colistin: Its role in pediatrics
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Colistimethate is an antibiotic that has been available for more than 50 years, and yet only recently has interest in its use increased.
Although commercially introduced in the 1950s, use of colistimethate (Coly-Mycin M, JHP Pharmaceuticals) decreased during the 1970s through the 1990s due to concerns over nephrotoxicity and neurotoxicity. With fewer new antibiotics becoming available, and increasing resistance by gram-negative bacterial pathogens to currently available antibiotics, interest in colistin has renewed.
Edward A. Bell
Colistimethate is a polymyxin antibiotic and is also known as polymyxin E. It is pharmacologically similar to polymyxin B, which is commonly available in ophthalmic and topical dosage forms. In its commercial form, colistimethate sodium is not microbiologically active and must be hydrolyzed to the active form, colistin. Colistin has antibacterial activity against many gram-negative pathogens, including Enterobacter aerogenes, Escherichia coli, Klebsiella pneumoniae, Acinetobacter species, and Pseudomonas aeruginosa. It is not active against gram-positive bacterial pathogens.
Colistin’s activity against these pathogens is bactericidal and concentration-dependent. It also displays anti-endotoxin activity, as it can neutralize lipopolysaccharide. Colistin is indicated by the FDA for use in all ages of the pediatric population, including infants.
Although interest in colistin has increased recently, very few efficacy data from controlled trials of its systemic use in infants and children without cystic fibrosis are available because of its relative nonuse during the past 20 to 30 years. Few pharmacokinetic data are available to describe the drug’s behavior and action in the pediatric population. As such, optimal dosing in children is unknown. Despite this, its antimicrobial activity against common gram-negative pathogens, especially multidrug-resistant pathogens, has resulted in renewed interest in its therapeutic use. Most published clinical data in pediatrics describes colistin’s use (systemically and inhaled) in patients with cystic fibrosis, which will not be discussed here.
Case studies
Published reports on the use of colistin in children describe its use as case series and case reports. Falagas reviewed the literature on the systemic use of colistin in children without cystic fibrosis. Included in this review were 326 children from 10 case series and 15 case reports, of which only 17 children were evaluated in reports published after 1977. Of these children, 271 were evaluable for clinical outcome — more than 90% were cured of infection or improved. Nephrotoxicity occurred in 2.8% (10/355) of evaluable children, and no neurotoxicity was reported. Clinical indications in these case reports included sepsis, meningitis, pneumonia and pyelonephritis.
Other smaller case reports on colistin’s use in infants and children have recently been published. Two small reports (Iosifidis and Jajoo) describe the successful use of colistin in infants (including term and preterm neonates) with infections from drug-resistant pathogens. Clinical uses described were pneumonia, meningitis, sepsis and complicated soft tissue infection. Pathogens treated in these reports were resistant to other commonly used antibiotics and included A. baumannii, K. pneumonia, P. aeruginosa and Enterobacter.
Other small case reports on the use of colistin for treatment of nosocomial infection in children (Celebi) and infection in critically ill children (Falagas) caused by these same pathogens also assessed colistin as effective. Most of these case reports describe the IV use of colistin; several patients, however, were treated with colistin given intrathecally or intraventricularly for central nervous system infection.
Fear over the potential for colistin to result in nephrotoxicity resulted in its decreased use during the past several decades. Although renal toxicity continues to be reported, some recent reports suggest that nephrotoxicity may not be as common or serious as once believed, with estimates of nephrotoxicity occurring in up to approximately 20% of patients. Colistin-induced nephrotoxicity manifests as rising serum creatinine and decreased creatinine clearance. There is some evidence that colistin-induced nephrotoxicity is reversible. Other evidence suggests that nephrotoxicity is dose- and duration-dependent.
A recently published retrospective review (Pogue) described adults assigned to colistin for 48 hours or more during a 5-year period and assessed rates of nephrotoxicity. Of 126 patients reviewed, 43% developed nephrotoxicity, which was significantly related to dose and duration. Neurotoxicity has also been reported with colistin use, although less frequently. Neurotoxicity may manifest as circumoral paresthesias, tingling of extremities, dizziness, pruritus or numbness. Neuromuscular blockade and respiratory arrest have been reported and may be more likely in children with neuromuscular conditions.
Confusion with dosing
An important and potentially confusing characteristic to consider when using colistin for systemic infection in children is units of dosage expression. Dosing in the United States is expressed as milligrams of colistin base activity. Pediatric doses (neonatal, infants and children) for IV or intramuscular use are 2.5 mg/kg/day to 5 mg/kg/day, divided every 6 to 12 hours. Doses are often expressed in European studies as international units (IU) of colistimethate sodium or as milligrams of colistimethate sodium.
It is important to consider that dosing by these different expressions is not equivalent. Specifically, 1 mg colistin base equals 2.67 mg colistimethate sodium, which equals 33,333 IU colistimethate sodium. It is believed that this potential for confusion of dosing has led to differing reports of nephrotoxicity, as inappropriately high doses may have been given to some children. Colistin dosing as used in Europe and expressed differently (as IU) are often comparatively lower than doses recommended in the United States. Some have expressed concern that rates of nephrotoxicity may be higher when US doses are used.
Conclusions
As few new antibiotics have been introduced in recent years, and as drug-resistant bacterial pathogens are increasingly complicating treatment options for infectious diseases, renewed interest in colistin has occurred. Some evidence indicates that this relatively “old” antibiotic may not be as toxic as once believed. Because colistin has not been used extensively in recent years, its activity against common gram-negative pathogens may be relatively good. Certainly, more controlled studies are needed in infants and children to better define effective and safe doses.
Currently, colistin use is often described as “salvage therapy,” to be used when resistant pathogens are responsible for clinical disease. This use seems reasonable, given our relatively diminishing supply of useful antibiotics for serious infections. As colistin may not be listed in many clinical microbiological laboratory susceptibility routine tests, clinicians may need to request its evaluation for specific pathogens. When colistin is used, clinicians should consider the potential for dosing errors and its adverse effects of nephrotoxicity and neurotoxicity.
For more information:
- Celebi S. Pediatr Int. 2010;52:410-414.
- Falagas ME. Int J Antimicrob Agents. 2009;33;503.e1-503.e13.
- Falagas ME. Pediatr Infect Dis J. 2009;28:123-127.
- Iosifidis E. Eur J Pediatr. 2010;169:867-874.
- Jajoo M. Pediatr Infect Dis J. 2011;30:218-221.
- Pogue JM. Clin Infect Dis. 2011;53:879-884.
- Tamma PD. Pediatr Infect Dis J. 2009;28:534-535.