Anti-infective (Quinolone)
PREGNANCY RECOMMENDATION: Human Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Probably Compatible
PREGNANCY SUMMARY
Although only a few reports describing the use of levofloxacin during human gestation have been located, the available evidence for other members of this class suggests that the risk of major malformations is low. However, 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, levofloxacin should be used cautiously during pregnancy, especially during the 1st trimester. 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 (1). 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 (1). Others have also concluded that fluoroquinolones should be considered contraindicated in pregnancy, because safer alternatives are usually available (2). A 2013 review stated that fluoroquinolones are usually avoided in pregnancy because of concerns for fetal cartilage damage, but there were no human studies to validate this concern (3).
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. Levofloxacin undergoes limited metabolism and plasma protein binding only is 24%–38%. The mean terminal plasma elimination half-life is about 6–8 hours (4).
Reproduction studies have been conducted in rats and rabbits. In rats given oral and IV doses that were ≤4.2 and ≤1.2 times the maximum recommended human dose based on BSA (MRHD), respectively, no evidence of impaired fertility or reproductive performance was noted. No teratogenicity was observed in pregnant rats with oral and IV doses that were ≤9.4 and ≤1.9 times the MRHD, respectively. However, an oral dose 9.4 times the MRHD caused decreased fetal weight and increased fetal mortality. In pregnant rabbits, no teratogenicity was observed with oral and IV doses that were ≤1.1 and ≤0.5 times the MRHD, respectively (4).
A 2005 study measured the amount of three fluoroquinolones (ciprofloxacin, ofloxacin, levofloxacin) that crossed the perfused human placenta (5). All three agents crossed the placenta from the maternal to the fetal compartment, but the amounts crossing were small: 3.2%, 3.7%, and 3.9%, respectively. The transfer of levofloxacin across the placenta is consistent with the molecular weight (about 370). Moreover, in vivo transfer should be expected because of the low metabolism and plasma protein binding, and the moderately long plasma elimination half-life.
In a 2010 study, 12 women scheduled for a cesarean section were given IV levofloxacin 500 mg over 60 minutes (6). The transplacental passage rate calculated as a percentage of fetal venous concentration to maternal blood concentration was about 67%, whereas the transfetal passage rate calculated as a percentage of fetal arterial drug concentration to fetal venous concentration was about 84% (6).
A second study by the same group as above, measured levofloxacin amniotic fluid concentrations in 10 women given a 500-mg oral dose about 2 hours before amniocentesis (7). The study was conducted between the 16th and 20th gestational weeks. The mean concentrations of levofloxacin in maternal blood and amniotic fluid were 3.95 mcg/mL and 0.60 mcg/mL, an amniotic fluid passage rate of about 16% (7).
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. 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 (2).
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).
BREASTFEEDING SUMMARY
When first marketed, the use of levofloxacin during lactation was not recommended because of the potential for arthropathy and other serious toxicity in the nursing infant (4). Phototoxicity has been observed with quinolones when exposure to excessive sunlight (i.e., ultraviolet [UV] light) has occurred. 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 ofloxacin in this manner have not been conducted (4).
Levofloxacin is excreted into breast milk (8). A lactating woman received levofloxacin 500 mg/day during the first 23 days postpartum. Milk samples were collected at various times at steady state. The peak concentration in milk, 8.2 mcg/mL, occurred 5 hours after a dose. The pharmacokinetics in milk was similar to those in the plasma. Minimal levels of the drug were detectable 65 hours after the last dose. The infant was not allowed to breastfeed (8). The effect of this exposure on a nursing infant is unknown, but other fluoroquinolones are classified as compatible with breastfeeding by the American Academy of Pediatrics (see Ofloxacin and Ciprofloxacin).
References
1.Norrby SR, Lietman PS. Safety and tolerability of fluoroquinolones. Drugs 1993;45(Suppl 3):59–64.
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 Biol 1996;69:83–9.
3.Meaney-Delman D, Rasmussen SA, Beigi RH, Zotti ME, Hutchings Y, Bower WA, Treadwell TA, Jamieson DJ. Prophylaxis and treatment of anthrax in pregnant women. Obstet Gynecol 2013;122:885–900.
4.Product information. Levaquin. Ortho-McNeil Pharmaceutical, 2007.
5.Polachek H, Holcberg G, Sapir G, Tsadkin-Tamir M, Polacheck J, Katz M, Ben-Zvi Z. Transfer of ciprofloxacin, ofloxacin and levofloxacin across the perfused human placenta in vitro. Eur J Obstet Gynecol Reprod Biol 2005;122:61–5.
6.Ozyuncu O, Nemutlu E, Katlan D, Kir S, Beksac MS. Maternal and fetal blood levels of moxifloxacin, levofloxacin, cefepime and cefoperazone. Int J Antimicrob Agents 2010;36:175–8.
7.Ozyuncu O, Beksac MS, Nemutlu E, Katlan D, Kir S. Maternal blood and amniotic fluid levels of moxifloxacin, levofloxacin and cefixime. J Obstet Gynecol 2010;36:484–7.
8.Cahill JB Jr, Bailey EM, Chien S, Johnson GM. Levofloxacin secretion in breast milk: a case report. Pharmacotherapy 2005;25:116–8.