Risk Factor: C*
Class: Anti-infectives/ Aminoglycosides
Fetal Risk Summary
Tobramycin is an aminoglycoside antibiotic. Renal toxicity was observed in pregnant rats and their fetuses after maternal administration of high doses of tobramycin, 30 or 60 mg/kg/day for 10 days, during organogenesis (1). The dose-related fetal renal toxicity consisted of granularity and swelling of proximal tubule cells, poor glomerular differentiation, and increased glomerular density (1).
Tobramycin crosses the placenta into the fetal circulation and amniotic fluid (2,3). Studies in patients undergoing elective abortions in the 1st and 2nd trimesters indicate that tobramycin distributes to most fetal tissues except the brain and cerebrospinal fluid (2). Amniotic fluid levels generally did not occur until the 2nd trimester. The highest fetal concentrations were found in the kidneys and urine (2). In a woman undergoing surgical termination of an ovarian gestation in a 22-week heterotopic pregnancy (intrauterine and ovarian), a single 2-mg/kg IV dose of tobramycin was administered for 10 minutes 5.6 hours before cesarean section (3). Tobramycin was found in all fluids and tissues of the 260-g ovarian fetus, with the highest concentrations occurring in the fetal spleen (1.53 g/mL) and kidney (2.98 g/mL). The intrauterine fetus developed normally and a healthy 2900-g girl was eventually delivered at 38 weeks’ gestation. Reports measuring the passage of tobramycin in the 3rd trimester or at term are lacking.
No reports linking the use of tobramycin with congenital defects have been located. The antibiotic is not teratogenic in rats and rabbits (4). Ototoxicity, which is known to occur after tobramycin therapy, has not been reported as an effect of in utero exposure. However, eighth cranial nerve toxicity in the fetus is well known following exposure to other aminoglycosides (see Kanamycin and Streptomycin) and may potentially occur with tobramycin.
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 81 newborns had been exposed to tobramycin during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of three (3.7%) major birth defects were observed (three expected), one of which was a cardiovascular defect (one expected). No anomalies were observed in five other categories of defects (oral clefts, spina bifida, polydactyly, limb-reduction defects, and hypospadias) for which specific data were available.
The population-based dataset of the Hungarian Case-Control Surveillance of Congenital Abnormalities, covering the period of 19801996, was used to evaluate the teratogenicity of aminoglycoside antibiotics (parenteral gentamicin, streptomycin, tobramycin, and oral neomycin) in a study published in 2000 (5). A case group of 22,865 women who had fetuses or newborns with congenital malformations were compared to 38,151 women who had no newborns with structural defects. A total of 38 cases and 42 controls were treated with aminoglycosides. There were 2 cases and 4 controls treated with tobramycin (odds ratio 0.8, 95% confidence interval 0.23.9). The investigators concluded that there was no detectable teratogenic risk for structural defects for any of the aminoglycoside antibiotics (5). They also concluded, although it was not investigated in this study, that the risk of deafness after in utero aminoglycoside exposure was small.
A potentially serious drug interaction may occur in newborns treated with aminoglycosides who were also exposed in utero to magnesium sulfate (see Gentamicin).
[*Risk Factor D according to manufacturerEli Lilly, 2000.]
Breast Feeding Summary
Tobramycin is excreted into breast milk. Following an 80-mg IM dose given to five patients, milk levels varied from a trace to 0.52 g/mL over 8 hours (6). Peak levels occurred at 4 hours after injection. Because oral absorption of this antibiotic is poor, ototoxicity in the infant would not be expected. However, three potential problems exist for the nursing infant: modification of bowel flora, direct effects on the infant, and interference with the interpretation of culture results if a fever workup is required.
- Mantovani A, Macri C, Stazi AV, Ricciardi C, Guastadisegni C, Maranghi F. Tobramycin-induced changes in renal histology of fetal and newborn Sprague-Dawley rats. Teratogenesis Carcinog Mutagen 1992;12:1930.
- Bernard B, Garcia-Cazares S, Ballard C, Thrupp L, Mathies A, Wehrle P. Tobramycin: maternal-fetal pharmacology. Antimicrob Agents Chemother 1977;11:68894.
- Fernandez H, Bourget P, Delouis C. Fetal levels of tobramycin following maternal administration. Obstet Gynecol 1990;76:9924.
- Welles JS, Emmerson JL, Gibson WR, Nickander R, Owen NV, Anderson RC. Preclinical toxicology studies of tobramycin. Toxicol Appl Pharmacol 1973;25:398409. As cited in Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD: Johns Hopkins University Press, 1989;623.
- Czeizel AE, Rockenbauer M, Olsen J, Sorensen HT. A teratological study of aminoglycoside antibiotic treatment during pregnancy. Scand J Infect Dis 2000;32:30913.
- Takase Z. Laboratory and clinical studies on tobramycin in the field of obstetrics and gynecology. Chemotherapy (Tokyo) 1975;23:1402.