LEVOFLOXACIN

Fetal Risk Summary

Levofloxacin is a synthetic, broad-spectrum antibacterial agent that is the optical isomer of ofloxacin. As a fluoroquinolone, it is in the same class as ciprofloxacin, enoxacin, lomefloxacin, norfloxacin, ofloxacin, and sparfloxacin. Nalidixic acid is also a quinolone drug.

Reproduction studies of levofloxacin in rats with oral doses up to 3 or 18 times the maximum recommended human dose (MRHD) based on surface area or body weight, respectively, and with IV doses up to 1 or 5 times the MRHD (in surface area or body weight, respectively) found no evidence of impaired fertility or reproductive performance (1). No teratogenicity was observed in pregnant rats at oral doses of 14 or 82 times the MRHD, respectively, or with IV doses of 2.7 or 16 times the MRHD, respectively (1). However, decreased fetal weight and increased fetal loss were observed at high doses. In pregnant rabbits, oral doses at 1.6 or 5 times the MRHD, respectively, and IV doses at 0.8 or 2.5 times the MRHD, respectively, did not cause teratogenicity (1).

No studies describing the placental transfer of levofloxacin have been located. Because of its relatively low molecular weight (about 370), transfer to the fetus should be expected. In addition, ofloxacin crosses the placenta (see Ofloxacin), and levofloxacin would be expected to possess similar properties.

In a prospective follow-up study conducted by the European Network of Teratology Information Services (ENTIS), data on 549 pregnancies exposed to fluoroquinolones (none to levofloxacin; 93 to ofloxacin) (see also Ofloxacin) were described in a 1996 Reference (2). Data on another 116 prospective and 25 retrospective pregnancy exposures to the antibacterials were also included. Of the 666 cases with known outcome, 32 (4.8%) of the embryos, fetuses, or newborns had congenital malformations. From previous epidemiologic data, the authors concluded that the 4.8% frequency of malformations did not exceed the background rate (2). Finally, 25 retrospective reports of infants with anomalies, who had been exposed in utero to fluoroquinolones, were described, but no specific patterns of major congenital malformations were detected.

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. 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. 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 on limb reduction defects (2).

In summary, although no reports describing the use of levofloxacin during human gestation have been located, the available evidence for other members of this class, including the optical isomer, ofloxacin, indicates that a causal relationship with birth defects cannot be excluded (see Ofloxacin), although the lack of a pattern among the anomalies is reassuring (see Ciprofloxacin). Because of these concerns and the available animal data, the use of levofloxacin during pregnancy, especially during the 1st trimester, should be considered contraindicated. 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 (3). 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 (3). Others have also concluded that fluoroquinolones should be considered contraindicated in pregnancy, because safer alternatives are usually available (2).

Breast Feeding Summary

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

No reports describing the use of levofloxacin in human lactation have been located. Because levofloxacin is the optical isomer of ofloxacin, its passage into milk should be similar, and the milk concentrations of ofloxacin are about the same as those in the maternal serum (see Ofloxacin). Because of the potential for toxicity, the drug should be avoided during breast feeding.

References

1. Product information. Levaquin. Ortho-McNeil Pharmaceutical, 1997.
2. 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.
3. Norrby SR, Lietman PS. Safety and tolerability of fluoroquinolones. Drugs 1993;45(Suppl 3):59–64.