Abstract
Question My patient has a urinary tract infection and is currently breastfeeding her 9-week-old son. I would like to prescribe her ciprofloxacin. Should I be concerned about osteoarticular toxicity in the infant?
Answer Although there are concerns about the possible risk of osteoarticular toxicity with ciprofloxacin, the amounts excreted into breast milk are low and studies report no substantial increase in osteoarticular toxicity even with the systemic use of ciprofloxacin in neonates and children. Therefore, interrupting breastfeeding during ciprofloxacin treatment appears unnecessary.
Urinary tract infections (UTIs) occur in 3% of women in the postpartum period.1,2 Ciprofloxacin is a second-generation, broad-spectrum fluoroquinolone antibiotic with bactericidal activity against Gram-positive and Gram-negative organisms, including those resistant to penicillins, cephalosporins, and aminoglycosides.3 Fluoroquinolones interfere with supercoiling of DNA and, therefore, with transcription, by inhibiting the bacterial enzyme DNA gyrase.4
The bioavailability of ciprofloxacin is approximately 70%. It is widely distributed to tissues after oral administration, where it often reaches higher concentrations than in plasma. It is partly metabolized in the liver and excreted as the unchanged drug in the urine to an extent of 40% to 50%, where active tubular secretion also has an important role.5 The spectrum of activity and its high urine-to-plasma concentration ratio make it a useful agent for treating UTI.3
Relative infant dose (RID) is the key parameter when considering the safety of taking medications during breastfeeding. It is calculated by dividing the dose supplied to the infant via milk by the mother’s weight-adjusted dose. An RID of less than 10% of the mother’s weight-adjusted dose is generally considered safe for breastfeeding.6
Animal and human studies on osteoarticular toxicity
The demonstration of toxic effects from fluoroquinolones on diarthrodial joints of immature beagles in the late 1970s suggested that they could pose a risk to the growing cartilage in the human skeletal system and raised concerns about their use in children.7,8 However, several studies have demonstrated the safe use of ciprofloxacin in the pediatric population since then.9–13 A systematic review evaluating the efficacy and safety of ciprofloxacin in neonates found no evidence of osteoarticular toxicity.14 Another systematic review assessing the safety of ciprofloxacin use in more than 16 000 pediatric patients demonstrated an increased but relatively low and reversible risk of arthropathy and concluded that the risk of ciprofloxacin-induced arthropathy should be weighed against the benefits of using ciprofloxacin in children with appropriate indications.15
Ciprofloxacin levels in human breast milk
Ciprofloxacin is excreted in breast milk in both animals and humans.16–19 A study by Giamarellou et al included 10 postpartum women who received 3 oral 750-mg doses of ciprofloxacin every 12 hours.17 The highest average ciprofloxacin level reported in the breast milk of these women was 3.79 mg/L at the second hour. The 12- and 24-hour levels were measured as 0.20 mg/L and 0.02 mg/L, respectively.17 Infants were estimated to receive an average maximum dose of 0.57 mg/kg per day, with an RID of 2.7% if the weight of the mother is assumed to be 70 kg.
Gardner et al detected a breast-milk ciprofloxacin level of 0.98 mg/L at about 11 hours after the last dose in a mother who had been taking 500 mg of oral ciprofloxacin per day for 10 days. The 4-month-old infant (6.1 kg) had no detectable levels of ciprofloxacin in her serum 2.7 hours after nursing, which occurred 1 time 8 hours after the dose.18 No adverse effects were observed. The maximum dose that the infant would receive was estimated at 0.15 mg/kg per day, which would be equal to an RID of 2.1%.
Cover and Mueller reported on a mother with acute renal failure who received a single 500-mg dose of oral ciprofloxacin.19 The 4-hour ciprofloxacin level in her breast milk was 3.02 mg/L. However, the level could have been elevated because of her renal dysfunction. This study estimated the infant would receive a maximum dose of 0.45 mg/kg per day, which is equivalent to an RID of 6.3%, assuming the weight of the mother was 70 kg.
Effects reported in breastfed infants
Clostridium difficile toxin–positive pseudomembranous colitis treated surgically was reported in a 2-month-old infant whose mother used ciprofloxacin during breastfeeding.20 Pseudomembranous colitis in children is also commonly associated with the previous use of other antibiotics.21 Ampicillin, penicillin, amoxicillin, cephalosporins, and clindamycin are frequent causes of pseudomembranous colitis in childhood.22
In long-term follow-up of 3 children who were exposed to ciprofloxacin in utero and during breastfeeding owing to their mothers’ multidrug-resistant tuberculosis treatment, no adverse effects were detected at the ages of 1.25, 1.8, and 3.9 years. One of these children, who had also been diagnosed with multidrug-resistant tuberculosis, presented with poor weight gain and failure to thrive (below the third percentile for his age).23
Greenish discoloration of the teeth was reported in 2 of 5 infants who received intravenous ciprofloxacin for the treatment of severe nosocomial Klebsiella pneumoniae infection.24
Conclusion
Limited evidence suggests that ciprofloxacin is excreted in breast milk; however, the amount of infant exposure is low and the estimated RIDs are between 2.1% and 6.3%. Although the manufacturer and some authorities advise against ciprofloxacin use during breastfeeding, clinical data show no substantial evidence of osteoarticular toxicity in neonates and children who received ciprofloxacin for various indications, including neonatal sepsis, nosocomial Klebsiella pneumoniae infection, and cystic fibrosis with acute pulmonary exacerbations.9–15 Further, it is worth mentioning that neonates and children with these clinical conditions were exposed to much higher doses (5–60 mg/kg/d14 and 3.1–93.8 mg/kg/d15) than the infants who were exposed via breastfeeding (0.15 mg/kg/d18 to 0.57 mg/kg/d17).
Therefore, based on the existing data, interrupting breastfeeding during the treatment of a maternal infection that necessitates ciprofloxacin therapy is highly unjustifiable. Nevertheless, monitoring the breastfed infant for gastrointestinal symptoms such as diarrhea is necessary, as it is with any other antibiotic use during breastfeeding.
Notes
MOTHERISK
Motherisk questions are prepared by the Motherisk Team at the Hospital for Sick Children in Toronto, Ont. Dr Kaplan is a visiting professor of pharmacology in the Motherisk Program from the Terafar-Izmir Katip Celebi University Teratology Information, Training and Research Center in Izmir, Turkey. Dr Koren is Director of the Motherisk Program. Dr Koren is supported by the Research Leadership for Better Pharmacotherapy during Pregnancy and Lactation.
Do you have questions about the effects of drugs, chemicals, radiation, or infections in women who are pregnant or breastfeeding? We invite you to submit them to the Motherisk Program by fax at 416 813-7562; they will be addressed in future Motherisk Updates. Published Motherisk Updates are available on the Canadian Family Physician website (www.cfp.ca) and also on the Motherisk website (www.motherisk.org).
Footnotes
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Competing interests
None declared
- Copyright© the College of Family Physicians of Canada
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