Antibiotic
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest LowRisk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Probably Compatible
PREGNANCY SUMMARY
No reports describing the use of this antibiotic–enzyme inhibitor combination in the 1st trimester of nonterminated human pregnancies have been located. Four sources consider imipenem–cilastatin to be a safe and effective agent during the perinatal period (1–4).
FETAL RISK SUMMARY
Imipenem, a semisynthetic carbapenem related to the β-lactam antibiotics, is only available in the United States in a 1:1 combination with the enzyme inhibitor cilastatin sodium. The latter agent is a specific, reversible inhibitor of dehydropeptidase I, an enzyme that is present in the proximal renal tubular cells and inactivates imipenem. By inhibiting this enzyme, cilastatin results in higher urinary concentrations of imipenem (5).
Reproductive studies in pregnant rabbits and rats with imipenem at doses up to 2 and 30 times, respectively, and with cilastatin sodium at 10 and 33 times, respectively, the maximum recommended human dose showed no evidence of adverse fetal effects. Similar negative findings were found with imipenem–cilastatin sodium in pregnant mice and rats treated with doses up to 11 times the maximum human dose (5).
Adverse effects observed in pregnant monkeys given either 40 mg/kg/day (IV) or 160 mg/kg/day (SC) included loss of appetite, weight loss, emesis, diarrhea, abortion, and death in some animals. No significant toxicity was observed in nonpregnant monkeys given 180 mg/kg/day SC. An IV infusion of 100 mg/kg/day (approximately three times the maximum daily recommended human IM dose) in pregnant monkeys did not produce significant maternal toxicity or teratogenic effects, but it did result in an increase in embryonic loss (5).
Imipenem–cilastatin crosses the placenta to the fetus (1,6). Seven women at a mean gestational age of 8.6 weeks’ gestation (immediately before pregnancy termination) and seven at a mean gestational age of 38.7 weeks were given a single 20-minute IV infusion of 500 mg of imipenem–cilastatin (6). A third, nonpregnant group was also studied. Maternal plasma and amniotic fluid samples were collected at frequent intervals for 8 hours. In comparison with nonpregnant women, imipenem concentrations in maternal plasma were significantly lower in both early and late pregnancy. The mean concentrations in the amniotic fluid in early and late pregnancy were 0.07 and 0.72 mcg/mL, respectively. At delivery, the mean cord venous and arterial blood concentrations were 1.72 and 1.64 mcg/mL, respectively, representing a fetal:maternal mean ratio of 0.33 (venous) and 0.31 (arterial). Transfer of both imipenem and cilastatin across the placenta at term was observed in two Japanese studies (1,2). Peak concentrations of both agents were about 30% of those measured in the maternal blood (2). Both drugs were also transferred to the amniotic fluid, with the highest concentrations occurring, after a single dose, at about 5–6 hours. Peak amniotic fluid:maternal blood ratios for imipenem and cilastatin were approximately 0.30 and 0.45, respectively (2).
In a 2005 study from Japan, the pregnancy outcomes of 100 women who had preterm premature rupture of membranes (PPROM) at 24–31 weeks’ and who received imipenem/cilastatin sodium (plus betamethasone) were compared with a control group of 40 women with PPROM who were treated with other antibiotics, such as penicillins or cephalosporins, but not betamethasone (4). The mean time from PPROM to delivery in the study and control groups were 11 and 6 days, respectively. No infants died within 1 year of birth in the study group compared with five infants in controls (4).
BREASTFEEDING SUMMARY
Small amounts of imipenem–cilastatin are excreted into breast milk. These amounts are comparable to other β-lactam antibiotics (1). The effects, if any, on a nursing infant are unknown.
References
1.Matsuda S, Suzuki M, Oh K, Ishikawa M, Soma A, Takada H, Shimizu T, Makinoda S, Fujimoto S, Chimura T, Morisaki N, Matsuo M, Cho N, Fukunaga K, Kunii K, Tamaya T, Hayasaki M, Ito K, Izumi K, Takagi H, Ninomiya K, Tateno M, Okada H, Yamamoto T, Yasuda J, Kanao M, Hirabayashi K, Okada E. Pharmacokinetic and clinical studies on imipenem/cilastatin sodium in the perinatal period. Jpn J Antibiot 1988;11:1731–41.
2.Hirabayashi K, Okada E. Pharmacokinetic and clinical studies of imipenem/cilastatin sodium in the perinatal period. Jpn J Antibiot 1988;11:1797–804.
3.Cho N, Fukunaga K, Kunii K, Kobayashi I, Tezuka K. Studies on imipenem/cilastatin sodium in the perinatal period. Jpn J Antibiot 1988;11:1758–73.
4.Ryo E, Ikeya M, Sugimoto M. Clinical study of the effectiveness of imipenem/cilastatin sodium as the antibiotics of first choice in the expectant management of patients with preterm premature rupture of membranes. J Infect Chemother 2005;11:32–6.
5.Product information. Primaxin. Merck & Co., 1994.
6.Heikkila A, Renkonen O-V, Erkkola R. Pharmacokinetics and transplacental passage of imipenem during pregnancy. Antimicrob Agents Chemother 1992;36:2652–5.