GENTAMICIN

Fetal Risk Summary

Gentamicin is an aminoglycoside antibiotic. The antibiotic did not impair fertility or cause fetal harm in rats and rabbits (1). Not surprisingly, gentamicin produces dose-related nephrotoxicity in fetal rats (2,3 and 4). High doses (110 mg/kg/day SC) of gentamicin during gestation have also been shown to produce significant and persistent increases in the blood pressure, as well as nephrotoxicity, in exposed rat offspring (5).

Gentamicin rapidly crosses the placenta into the fetal circulation and amniotic fluid (6,7,8,9,10,11,12,13,14 and 15). Following 40–80-mg IM doses given to patients in labor, peak cord serum levels averaging 34%–44% of maternal levels were obtained at 1–2 hours (6,9,13,14). Following a single 80-mg IM injection before delivery, mean peak amniotic fluid concentrations (5.17 µg/mL) occurred at 8 hours (14). No toxicity attributable to gentamicin was seen in any of the newborns. Patients undergoing 1st and 2nd trimester abortions were given 1 mg/kg IM (10). Gentamicin could not be detected in their cord serum before 2 hours. Amniotic fluid levels were undetectable at this dosage up to 9 hours after injection. Doubling the dose to 2 mg/kg allowed detectable levels in the fluid in one of two samples 5 hours after injection.

The pharmacokinetics of gentamicin in 23 women with pyelonephritis at a mean gestational age of 21.8 weeks were described in 1994 (16). Similar to that observed in postpartum women, standard weight-adjusted doses of gentamicin produced low, subtherapeutic serum levels in most of the women.

A brief study published in 2000 compared gentamicin serum levels in infants of women who had received the antibiotic IV (240-mg single daily dose vs. 80 mg 3 times daily) during labor (17). In the single daily dose group (N=11), all of the mothers had received one dose a mean 5.12 hours before delivery, whereas in the divided dose group (N=10), 9 of 10 mothers received one dose a mean 4.72 hours before delivery. The mean serum levels in the newborn infants were 1.94 ± 0.63 and 0.98 ± 0.45 µg/mL, respectively (p=0.01). There was no correlation between the infant's serum level and the time interval from the mother's dose (17). Based on their analysis, the authors concluded that the divided dose regimen was best for women in labor (17).

In an abstract published in 1997, women undergoing midtrimester terminations received gentamicin either as a 10-mg intraamniotic infusion (N=16) or a single 80-mg IV dose (18). Low median gentamicin plasma levels were measured in the mothers and fetuses after the intraamniotic dose; 0.28 µg/mL (mothers) and 0.4 µg/mL (fetuses). In contrast, the median amniotic fluid concentration, 46 µg/mL, was sustained for greater than 24 hours. After IV dosing, amniotic fluid concentrations were low throughout the study (median 0.35 µg/mL). The authors concluded that intraamniotic infusions of gentamicin was a safe method to administer the antibiotic without reaching toxic levels in the mother or the fetus (18).

Intra-amniotic instillations of gentamicin were given to 11 patients with premature rupture of the membranes (19). Ten patients received 25 mg every 12 hours and one received 25 mg every 8 hours, for a total of 1–19 doses per patient. Maternal gentamicin serum levels ranged from 0.063 to 6 µg/mL (all but one were less than 0.6 µg/mL and that one was believed to be caused by error). Cord serum levels varied from 0.063 to 2 µg/mL (all but two were less than 0.6 µg/mL). No harmful effects were seen in the newborns after prolonged exposure to high local concentrations of gentamicin.

Only one report linking the use of gentamicin to congenital defects has been located. A 34-year-old woman, who was not known to be pregnant at the time, received a 10-day course of gentamicin (300 mg/day) in gestational week 7 (20). The appropriateness of this dose cannot be determined because the mother's height and weight and renal function were not given. The mother was also treated with prednisolone (50 mg/day for 5 days) for an “allergic reaction” to the antibiotic. She delivered an apparently healthy 2950-g (6 pounds 8 ounces) male infant at 37 weeks' gestation. His growth after birth was less than the 5th percentile and at 4.5 years of age, the child was evaluated for short stature (<5th percentile). At this time, he was noted to have impaired renal function. Ultrasound examination revealed small kidneys, both <5th centile for age, with increased echotexture, markedly decreased corticomedullary differentiation, and small bilateral cysts. Although the exact cause of the renal cystic dysplasia was unknown, and a potential genetic defect could not be excluded, the authors speculated, on the basis of animal studies, that the combination of gentamicin and prednisolone had induced the abnormal nephrogenesis.

Gentamicin, in combination with ampicillin (N=62), was compared to two groups of women treated with cefazolin (N=58) or ceftriaxone (N=59) in a randomized trial of the treatment of acute pyelonephritis in pregnancy (21). The mean gestational age at the start of therapy was 14 to 15 weeks. There were no significant differences between the three groups in clinical or pregnancy outcomes. The pregnancy outcomes included gestational age at delivery, preterm delivery, birth weight, neonatal intensive care admission, and length of stay in the neonatal intensive care if admitted (21).

The population-based dataset of the Hungarian Case-Control Surveillance of Congenital Abnormalities, covering the period of 1980–1996, was used to evaluate the teratogenicity of aminoglycoside antibiotics (parenteral gentamicin, streptomycin, tobramycin, and oral neomycin) in a study published in 2000 (22). 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 19 women in the case and control groups, 0.08% and 0.05%, respectively, treated with gentamicin (odds ratio 1.7, 95% confidence interval 0.9–3.2). A case-control pair analysis for the 2nd and 3rd months of gestation also failed to show a risk for teratogenicity. The investigators concluded that there was no detectable teratogenic risk for structural defects for any of the aminoglycoside antibiotics (22). They also concluded, although it was not investigated in this study, that the risk of deafness after in utero aminoglycoside exposure was small.

Ototoxicity, which is known to occur after gentamicin 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 gentamicin. Gentamicin and vancomycin, both of which can cause ototoxicity and nephrotoxicity, have been used together during pregnancy without apparent harm to the fetus or newborn (see Vancomycin).

Potentiation of MgSO4-induced neuromuscular weakness has been reported in a neonate exposed during the last 32 hours of pregnancy to 24 g of MgSO4 (23). The depressed infant was treated with gentamicin for sepsis at 12 hours of age. After the second dose, the infant's condition worsened with rapid onset of respiratory arrest. Emergency treatment was successful, and no lasting effects of the toxic interaction were noted.

Breast Feeding Summary

Small amounts of gentamicin are excreted into breast milk and absorbed by the nursing infant. In a Reference published in 1994, 10 women, who had just delivered term infants, were administered antibiotic prophylaxis with gentamicin, 80 mg IM 3 times daily (24). On the 4th day of a 5-day therapy course, milk and serum samples were obtained. The mean maternal serum levels of gentamicin at 1 and 7 hours after a dose were 3.94 and 1.02 µg/mL, respectively. Mean milk levels at 1, 3, 5, and 7 hours after a dose were 0.42, 0.48, 0.49, and 0.41 µg/mL, respectively, providing mean milk:plasma ratios at 1 and 7 hours of 0.11 and 0.44, respectively. The infants were allowed to breast-feed 1 hour after a dose and serum samples were collected 1 hour later. Five of the 10 infants had detectable (above 0.27 µg/mL) gentamicin serum levels with a mean level of 0.41 µg/mL.

In a case report, a nursing infant developed two grossly bloody stools while his mother was receiving gentamicin and clindamycin (25). The condition cleared rapidly when breast feeding was discontinued. Although both antibiotics are known to be excreted into milk, the cause of the infant's diarrhea cannot be determined with certainty.

References

1. Product information. Garamycin. Schering, 1997.
2. Mallie J-P, Coulon G, Billerey C, Faucourt A, Morin J-P. In utero aminoglycosides-induced nephrotoxicity in rat neonates. Kidney Int 1988;33:36–44.
3. Smaoui H, Mallie J-P, Schaeverbeke M, Robert A, Schaeverbeke J. Gentamicin administered during gestation alters glomerular basement membrane development. Antimicrob Agents Chemother 1993;37:1510–7.
4. Lelievre-Pegorier M, Euzet S, Merlet-Benichou C. Effect of fetal exposure to gentamicin on phosphate transport in young rat kidney. Am J Physiol 1993;265:F807–12.
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17. Regev RH, Litmanowitz I, Arnon S, Shiff J, Dolfin T. Gentamicin serum concentrations in neonates born to gentamicin-treated mothers. Pediatr Infect Dis J 2000;19:890–1.
18. Barak J, Mankuta D, Pak I, Glezerman M, Katz M, Danon A. Transabdominal amnioinfusion of gentamicin: a pharmacokinetic study of maternal plasma and intraamniotic levels (abstract). Am J Obstet Gynecol 1997;176:S59.
19. Freeman D, Matsen J, Arnold N. Amniotic fluid and maternal and cord serum levels of gentamicin after intra-amniotic instillation in patients with premature rupture of the membranes. Am J Obstet Gynecol 1972;113:1138–41.
20. Hulton S-A, Kaplan BS. Renal dysplasia associated with in utero exposure to gentamicin and corticosteroids. Am J Med Genet 1995;58:91–3.
21. Wing DA, Hendershott CM, Debuque L, Millar LK. A randomized trial of three antibiotic regimens for the treatment of pyelonephritis in pregnancy. Obstet Gynecol 1998;92:249–53.
22. Czeizel AE, Rockenbauer M, Olsen J, Sorensen HT. A teratological study of aminoglycoside antibiotic treatment during pregnancy. Scand J Infect Dis 2000;32:309–13.
23. L'Hommedieu CS, Nicholas D, Armes DA, Jones P, Nelson T, Pickering LK. Potentiation of magnesium sulfate-induced neuromuscular weakness by gentamicin, tobramycin, and amikacin. J Pediatr 1983;102:629–31.
24. Celiloglu M, Celiker S, Guven H, Tuncok Y, Demir N, Erten O. Gentamicin excretion and uptake from breast milk by nursing infants. Obstet Gynecol 1994;84:263–5.
25. Mann CF. Clindamycin and breast-feeding. Pediatrics 1980;66:1030–1.