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CIPROFLOXACIN

Drugs in Pregnancy and Lactation..


Name: CIPROFLOXACIN
Class: Anti-infective (Quinolone)
Risk Factor:    CM

Fetal Risk Summary

Ciprofloxacin is a synthetic, broad-spectrum antibacterial agent. As a fluoro quinolone, it is in the same class as enoxacin, levofloxacin, lomefloxacin, norfloxacin, ofloxacin, and sparfloxacin. Nalidixic acid and Cinoxacin are also quinolone drugs.

Ciprofloxacin did not impair fertility and was not embryotoxic or teratogenic in mice and rats at doses up to 6 times the usual human daily dose (1). A similar lack of embryo and fetal toxicity was observed in rabbits. As with other quinolones, multiple doses of ciprofloxacin produced permanent lesions and erosion of cartilage in weight-bearing joints leading to lameness in immature rats and dogs (1).

A number of reports have described the use of ciprofloxacin during human gestation (2,3,4,5,6,7,8,9 and 10). In a 1993 Reference, data on 103 pregnancies exposed to the drug were released by the manufacturer (2). Of these cases, there were 63 normal live newborns (52 exposed during 1st trimester, 7 during the 2nd or 3rd trimesters, and 4 in which the exposure time was unknown), 18 terminations, 10 spontaneous abortions (all 1st trimester), 4 fetal deaths (3 during 1st trimester, 1 in 3rd trimester), and 8 infants with congenital defects (7 exposed between 2 and 12 weeks postmenstruation and 1 on a single day of her last menstrual period) (these defects are included among those shown in Reference 9 below).

No congenital malformations were observed in the infants of 38 women who received either ciprofloxacin (N=10) or norfloxacin (N=28) during pregnancy (35 in the 1st trimester) (3). Most (N=35) received the drugs for the treatment of urinary tract infections. Matched to a control group, the fluoroquinolone-exposed pregnancies had a significantly higher rate of cesarean section for fetal distress and their infants were significantly heavier. No differences were found between the groups in infant development or in the musculoskeletal system.

A 1995 letter described seven pregnant women with multidrug resistant typhoid fever who were treated with ciprofloxacin during the 2nd and 3rd trimesters (4). All delivered healthy infants who were doing well at 5 years of age without evidence of cartilage damage. The authors also described the healthy outcome of another pregnant woman treated with ciprofloxacin during the 1st trimester. That infant was doing well at 6 months of age. A subsequent letter, also in women with typhoid fever, described three pregnant women in the 2nd and 3rd trimesters who were treated with ciprofloxacin (5). A normal outcome occurred in one patient and the pregnancies of the other two were progressing satisfactory.

A surveillance study on the use of fluoroquinolones during pregnancy was conducted by the Toronto Motherisk Program among members of the Organization of Teratology Information Services and briefly reported in 1995 (6). Pregnancy outcome data were available for 134 cases, of which 68 involved ciprofloxacin, 61 were exposed to norfloxacin, and 5 were exposed to both drugs. Most (90%) were exposed during the first 13 weeks postconception. Fluoroquinolone-exposed pregnancies were compared to matched controls and there were no differences in live births (87% vs. 86%), terminations (3% vs. 5%), miscarriages (10% vs. 9%), abnormal outcomes (7% vs. 4%), cesarean section rate (12% vs. 22%), fetal distress (15% vs. 15%), and pregnancy weight gain (15 kg vs. 16 kg). The mean birth weight of the exposed infants was 162 g higher than those in the control group and their gestations were a mean 1 week longer.

An abstract, published in 1996, described six pregnancies exposed to ciprofloxacin during the 1st trimester (7). Five healthy babies (one set of twins) had been born and two pregnancies were progressing normally. In a 1997 Reference, a pregnant woman with Q fever (Coxiella burnetii) at 28 weeks' gestation was treated with ciprofloxacin for 3 weeks (8). Because her symptoms did not resolve, a cesarean section was performed at 32 weeks' with delivery of a healthy, female infant. No evidence of transplacental spread of the infection, which is known to cause stillbirth and abortion in animals and humans, was found (8).

In a prospective follow-up study conducted by the European Network of Teratology Information Services (ENTIS), data on 549 pregnancies exposed to fluoroquinolones (70 to ciprofloxacin) were described in a 1996 report (9). Data on another 116 prospective and 25 retrospective pregnancy exposures to the antibiotics were also included. From the 549 follow-up cases, 509 were treated during the 1st trimester, 22 after the 1st trimester, and in 18 cases the exposure occurred at an unknown gestational time. The live-born infants were delivered at a mean gestational age of 39.4 ± 1.5 weeks and had a mean birth weight of 3302 ± 495 g, length of 50.3 ± 2.3 cm, and head circumference of 34.9 ± 1.5 cm. Of the 549 pregnancies, there were 415 live-born infants (390 exposed during the 1st trimester), 356 of which were normal term deliveries (including one set of twins), 15 were premature, 6 were small-for-gestational age (IUGR, <10th percentile), 20 had congenital anomalies (19 from mothers exposed during the 1st trimester; 4.9%), and 18 had postnatal disorders unrelated to either prematurity, low birth weight, or malformations (9). Of the remaining 135 pregnancies, there were 56 spontaneous abortions or fetal deaths (none late) (1 malformed fetus), and 79 elective abortions (4 malformed fetuses). A total of 116 (all involving ciprofloxacin) prospective cases were obtained from the manufacturer's registry (9). Among these, there were 91 live-born infants, 6 of whom had malformations. Of the remaining 25 pregnancies, 15 were terminated (no malformations reported), and 10 aborted spontaneously (one embryo with acardia, no data available on a possible twin). Thus, of the 666 cases with known outcome, 32 (4.8%) of the embryos, fetuses or newborns had congenital malformations. Based on previous epidemiologic data, the authors concluded that the 4.8% frequency of malformations did not exceed the background rate (9). Finally, 25 retrospective reports of infants with anomalies, who had been exposed in utero to fluoroquinolones, were analyzed, but no specific patterns of major congenital malformations were detected.

The defects observed in the 10 infants followed prospectively and in the 8 infants reported retrospectively, all with 1st trimester ciprofloxacin exposure, were (9): Source: Prospective ENTIS Angioma right lower leg Hip dysplasia left side Trisomy, unspecified (pregnancy terminated) Source: Prospective Manufacturer's Registry Hypospadias Auricle indentation, hip dysplasia Cerebellum hypoplasia, oculomotor palsy, development retardation Hooded foreskin Amputation right forearm Hypospadias, bilateral hernia inguinalis Acardia (spontaneous abortion) Source: Retrospective Reports Teeth discoloration Hypoplastic auricle, absence external auditory canal Rubinstein-Taybi syndrome Femur aplasia Femur-fibula-ulna complex Ectrodactyly Defects of heart, trachea, esophagus, urethra, anus, gall bladder, skeleton, heterotopic gastric mucosa, mucosa Heart defect The authors of the above study concluded that pregnancy exposure to quinolones was not an indication for termination, but that this class of antibacterials should still be considered contraindicated in pregnant women because safer alternatives are usually available (9). Because of their own and previously published findings, they further recommended that the focus of future studies should be on malformations involving the abdominal wall and urogenital system, and limb reduction defects. Moreover, this study did not address the issue of cartilage damage from quinolone exposure and the authors recognized the need for follow-up studies of this potential toxicity in children exposed in utero.

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 132 newborns had been exposed to ciprofloxacin during the 1st trimester (F. Rosa, personal communication, FDA, 1993). Three (2.3%) major birth defects were observed (six expected), one of which was a case of spina bifida (none expected). No anomalies were observed in five other categories of defects (cardiovascular defects, oral clefts, polydactyly, limb reduction defects, and hypospadias) for which specific data were available. These data do not support an association between the drug and congenital defects.

A 1998 prospective multicenter study reported the pregnancy outcomes of 200 women exposed to fluoroquinolones compared to 200 matched controls (10). Subjects were pregnant women who had called one of four teratogen information services concerning their exposure to fluoroquinolones. The agents, number of subjects, and daily doses were ciprofloxacin, (N=105; 500–1000 mg), norfloxacin (N=93; 400–800 mg), and ofloxacin (N=2; 200–400 mg). The most common infections involved the urinary tract (69.4%) or the respiratory tract (24%). The fewer live births in the fluoroquinolone group (173 vs. 188, p=0.02) was attributable to the greater number of spontaneous abortions (18 vs. 10, p=0.17) and induced abortions (9 vs. 2, p=0.06). There were no differences between the groups in terms of premature birth, fetal distress, method of delivery, low birth weight (<2500 g), or birth weight. Among the live born infants exposed during organogenesis, major malformations were observed in 3 of 133 subjects and 5 of 188 controls (p=0.54). The defects in subject infants were two cases of ventricular septal defect and one case of patent ductus arteriosus, whereas those in controls were two cases of ventricular septal defect, one case of atrial septal defect with pulmonic valve stenosis, one case of hypospadias, and one case of displaced hip. There were also no differences between the children of the groups in gross motor development milestone achievements (musculoskeletal functions: lifting, sitting, crawling, standing, or walking) as measured by the Denver Developmental Scale (10).

In a study investigating the pharmacokinetics of ciprofloxacin, 20 pregnant women, between 19–25 weeks' gestation (mean 21.16 weeks), were scheduled for pregnancy termination because the fetuses were affected with b-thalassemia major (11). Two doses of ciprofloxacin, 200 mg IV every 12 hours, were given prior to abortion. Serum and amniotic fluid concentrations were drawn concomitantly at 4, 8, and 12 hours after dosing. Mean maternal serum concentrations at these times were 0.28, 0.09, and 0.01 µg/mL, respectively, compared to mean amniotic fluid levels of 0.12, 0.13, and 0.10 µg/mL, respectively. The amniotic fluid:maternal serum ratios were 0.43, 1.44, and 10.0, respectively.

In summary, the use of ciprofloxacin during human gestation does not appear to be associated with an increased risk of major congenital malformations. Although a number of birth defects have occurred in the offspring of women who had taken this drug during pregnancy, the lack of a pattern among the anomalies is reassuring. However, a causal relationship with some of the birth defects cannot be excluded. Because of this and the available animal data, the use of ciprofloxacin during pregnancy, especially during the 1st trimester, should be used with caution. A 1993 review on the safety of fluoroquinolones concluded that these antibacterials should be avoided during pregnancy because of the difficulty in extrapolating animal mutagenicity results to humans and because interpretation of this toxicity is still controversial (12). The authors of this review were not convinced that fluoroquinolone-induced fetal cartilage damage and subsequent arthropathies were a major concern, even though this effect had been demonstrated in several animal species after administration to both pregnant and immature animals and in occasional human case reports involving children (12). Others have also concluded that fluoroquinolones should be considered contraindicated in pregnancy, because safer alternatives are usually available (9).

Breast Feeding Summary

The administration of ciprofloxacin during breast feeding is not recommended due to the potential for arthropathy (based on animal data) and other serious toxicity in the nursing infant (1). Phototoxicity has been observed with some members of the quinolone class of drugs when exposure to excessive sunlight (i.e., ultraviolet light) has occurred (1). Well-differentiated squamous cell carcinomas of the skin have been produced in mice who were exposed chronically to some quinolones and periodic ultraviolet light (e.g., see Lomefloxacin), but studies to evaluate the carcinogenicity of ciprofloxacin in this manner have not been conducted.

Ciprofloxacin is excreted into human milk (11,13,14). Ten lactating women were given three oral doses of ciprofloxacin, 750 mg each (11). Six simultaneous serum and milk samples were drawn between 2 and 24 hours after the third dose of the antibacterial. The mean peak serum level occurred at 2 hours, 2.06 µg/mL, then steadily fell to 0.02 µg/mL at 24 hours. Milk concentrations exhibited a similar pattern with a mean peak level measured at 2 hours, 3.79 µg/mL, and the lowest amount at 24 hours, 0.02 µg/mL. The mean milk:serum ratio varied from 0.85–2.14 with the highest ratio occurring 4 hours after the last dose.

A 24-year-old woman, 17 days postpartum, was given a single 500-mg dose of the antibacterial to treat a urinary tract infection (13). She was also suffering from acute renal failure and had undergone her final hemodialysis treatment 7 days prior to administration of ciprofloxacin. Her serum creatinine and blood urea nitrogen at the time of the dose were 740 mmol/L and 26.8 mmol/L, respectively. Milk samples, 40 mL each, were collected at 4, 8, 12, and 16 hours. Concentrations of ciprofloxacin at these times were 9.1, 9.1, 9.1, and 6.0 µmol/L, respectively. (Note: 9.1 and 6.0 µmol/L are approximately 3.0 and 2.0 µg/mL, respectively.) Based on the volume of milk and concentrations, the potential cumulative dose for the infant, who was not allowed to breast-feed, was 1.331 µmol.

The only published case involving a woman consuming ciprofloxacin who was breast feeding appeared in 1992 (14). The 4-month-old female infant was being exclusively breast-fed six times/day. The mother had taken a single nighttime dose (500 mg) of the antibacterial for 10 days prior to the collection of simultaneous samples of milk, maternal serum and infant serum, approximately 11 hours after a dose. On the day of sampling breast feeding occurred 8 hours after the mother's dose. Maternal serum, milk, and infant serum ciprofloxacin concentrations were 0.21 µg/mL, 0.98 µg/mL, and undetectable (<0.03 µg/mL), respectively. The authors estimated the infant was consuming 0.92 mg/day (0.15 mg/kg/day) of ciprofloxacin (14). No adverse effects were observed in the infant.

In unpublished studies available to the manufacturer, peak milk levels occurred approximately 4 hours after a ciprofloxacin dose and were about the same as serum levels (personal communication, Miles Pharmaceutical, June 1990). Levels of the antibacterial were undetectable 36–48 hours after a dose. Based on these data, the manufacturer recommends that 48 hours elapse after the last dose of ciprofloxacin before breast feeding is resumed (personal communication, Miles Pharmaceutical, June 1990).

In an unusual report, follow-up of infants who had been treated as neonates with ciprofloxacin for severe Klebsiella pneumoniae revealed two of five infants with greenish colored teeth on eruption (15). The teeth were stained uniformly with dyscalcification at the cervical part. The investigators could not determine the cause of the condition. Other reports of this condition have not been located and the clinical significance of this to a nursing infant exposed to fluoroquinolones via the milk is unknown.

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References

1. Product information. Cipro. Miles Pharmaceutical, 1993.
2. Bomford JAL, Ledger JC, O'Keeffe BJ, Reiter CH. Ciprofloxacin use during pregnancy. Drugs 1993;45 (Suppl 3):461–2.
3. Berkovitch M, Pastuszak A, Gazarian M, Lewis M, Koren G. Safety of the new quinolones in pregnancy. Obstet Gynecol 1994;84:535–8.
4. Koul PA, Wani JI, Wahid A. Ciprofloxacin for multiresistant enteric fever in pregnancy. Lancet 1995; 346:307–8.
5. Leung D, Venkatesan P, Boswell T, Innes JA, Wood MJ. Treatment of typhoid in pregnancy. Lancet 1995; 346:648.
6. Pastuszak A, Andreou R, Schick B, Sage S, Cook L, Donnenfeld A, Koren G. New postmarketing surveillance data supports a lack of association between quinolone use in pregnancy and fetal and neonatal complications. Reprod Toxicol 1995;9:584.
7. Baroncini A, Calzolari E, Calabrese O, Zanetti A. First-trimester exposure to ciprofloxacin (abstract). Teratology 1996;53:24A.
8. Ludlam H, Wreghitt TG, Thornton S, Thomson BJ, Bishop NJ, Coomber S, Cunniffe J. Q fever in pregnancy. J Infect 1997;34:75–8.
9. Schaefer C, Amoura-Elefant E, Vial T, Ornoy A, Garbis H, Robert E, Rodriguez-Pinilla E, Pexieder T, Prapas N, Merlob P. Pregnancy outcome after prenatal quinolone exposure. Evaluation of a case registry of the European Network of Teratology Information Services (ENTIS). Eur J Obstet Gynecol Reprod Bio 1996;69:83–9.
10. Loebstein R, Addis A, Ho E, Andreou R, Sage S, Donnenfeld AE, Schick B, Bonati M, Mortetti M, Lalkin A, Pastuszak A, Koren G. Pregnancy outcome following gestational exposure to fluoroquinolones: a multicenter prospective controlled study. Antimicrob Ag Chemother 1998;42:1336–9.
11. Giamarellou H, Kolokythas E, Petrikkos G, Gazis J, Aravantinos D, Sfikakis P. Pharmacokinetics of three newer quinolones in pregnant and lactating women. Am J Med 1989;87(Suppl 5A):49S– 51S.
12. Norrby SR, Lietman PS. Safety and tolerability of fluoroquinolones. Drugs 1993;45(Suppl 3):59–64.
13. Cover DL, Mueller BA. Ciprofloxacin penetration into human breast milk: a case report. Ann Pharmacother 1990;24:703–4.
14. Gardner DK, Gabbe SG, Harter C. Simultaneous concentrations of ciprofloxacin in breast milk and in serum in mother and breast-fed infant. Clin Pharm 1992;11:352–4.
15. Lumbiganon P, Pengsaa K, Sookpranee T. Ciprofloxacin in neonates and its possible effect on the teeth. Pediatr Infect Dis J 1991;10:619–20.
    
    

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