A Reappraisal of Ciprofloxacin Use in Infants and Children

Marcia L. Buck, PharmD, FCCP, FPPAG, BCPPS

Disclosures

Pediatr Pharm. 2018;24(8) 

In This Article

Fluoroquinolone Resistance in Children

Widespread use of fluoroquinolones has led to the development of resistance worldwide.[12–15] The first gene variant associated with increased fluoroquinolone minimum inhibitory concentrations (MICs) was identified in the 1980s. Resistance is primarily the result of mutations in the quinolone resistance determining region of DNA gyrase (gyrA, gyrB) and the topoisomerase IV (parC, parE) encoding genes which alter the conformation of amino acids within DNA gyrase and topoisomerase IV in the bacteria. Plasmid-mediated quinolone resistance genes were identified in the late 1990s. Expression of these mutations results in a reduction in fluoroquinolone uptake in bacterial cells, increased drug efflux from the cells, or drug inactivation. The March 2018 issue of PLoS Pathogens provides an in-depth review of fluoroquinolone resistance in Conley and colleagues' thought-provoking and entertaining article, "Wicked: the untold story of ciprofloxacin," available on-line at https://doi.org/10.1371/journal.ppat.1006805.[12]

In 2014, Rose and colleagues evaluated the prevalence of fluoroquinolone resistance in a cohort of 1,433 children treated for Gram negative bacterial infections between 2001 and 2009 at the Alfred I. duPont Hospital for Children.[13] The median age of the patients was 4 years (interquartile range 1–11 years). Use of fluoroquinolones increased from 22 doses/1000 patient-days/year in 2001 to 40 doses/1000 patient-days/year in 2008 (p = 0.005), with a similar rise in the length of therapy, from 14 to 23 days of treatment/1000 patient-days/year (p = 0.004). A total of 2,112 Gram negative infections were identified. The most commonly encountered organisms were E. coli (34.5%), Pseudomonas aeruginosa (26.5%), Klebsiella pneumoniae (13.7%), and Enterobacter cloacae (10.6%). Susceptibility to ciprofloxacin decreased from 173 of 180 cultures (96.1%) in 2001 to 341 of 365 (93.4%) in 2009 (p = 0.003). A similar decline was seen with levofloxacin, with susceptibility in 174 of 180 cultures (96.6%) in 2001 and 350 of 365 (95.9%) in 2009 (p = 0.016). Resistant isolates were most often obtained from bronchial lavage (10.4%), tracheal aspirates (6.4%), and urine cultures (5.6%). The authors found a strong correlation between the number of fluoroquinolone doses administered and the prevalence of resistance for both ciprofloxacin and levofloxacin (r = 0.879 and r = 0.874, respectively, p < 0.001) as well as for days of therapy and resistance (r = 0.938 and r = 0.945, p < 0.001).

Two papers released earlier this year highlight the growing risk for fluoroquinolone resistance in the community. In the April 2018 issue of the Journal of Medical Microbiology, Saksena and colleagues assessed the gut flora of antibiotic naïve neonates in New Delhi to study the presence of communal fluoroquinolone resistance.[14] Stool samples from 100 breastfed infants were collected on day of life 1, 2, and 60. A total of 343 Enterobacteriaceae were isolated. The presence of ciprofloxacin-resistant organisms increased from 15% of neonates on day of life 1 to 38% on day 60 (p < 0.001). Last month, Karp and colleagues found an increase in plasmid-mediated quinolone resistance in non-typhoidal Salmonella isolates submitted to the Centers for Disease Control and Prevention between 2008 and 2014. Their paper adds even greater support to the concerns being expressed over the growing loss of fluoroquinolone efficacy.[15]

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