Anti-infective
PREGNANCY RECOMMENDATION: Compatible
BREASTFEEDING RECOMMENDATION: Compatible
PREGNANCY SUMMARY
Sulbactam is always given in combination with ampicillin. It has caused no harm in animal reproduction studies, but reports of human exposure in early gestation are lacking. However, none of the penicillins has been shown to be teratogenic. Sulbactam readily crosses the human placenta to the fetus. Although no direct adverse effects of this exposure on the fetus or newborn have been reported, use of the antibiotic combination near delivery may result in superinfection with resistant bacteria in the newborn.
FETAL RISK SUMMARY
Sulbactam is a semisynthetic beta-lactamase irreversible inhibitor that is derived from the basic penicillin nucleus. When used alone, sulbactam does not have effective anti-infective activity (accept against the Neisseriaceae). However, sulbactam extends the activity of ampicillin when given in combination with this antibiotic (1).
Reproduction studies reported by the manufacturer involved mice, rats, and rabbits, but only with the combination of sulbactam and ampicillin (1). There was no evidence of impaired fertility or fetal harm in each species at doses up to 10 times the human dose. Pregnant rats given IV sulbactam at doses up to 500 mg/kg/day at various times, including before mating and throughout gestation, showed no evidence of adverse reproductive effects (2).
Sulbactam crosses the human placenta to the fetus at term (3,4). Placental transfer studies early in gestation have not been located. An abstract from a 1983 symposium reported a linear relationship between fetal and maternal serum sulbactam concentrations when sulbactam/ampicillin was given as a single dose (either 0.5 g/1 g or 1 g/1 g) just before cesarean section. The mean peak fetal serum level of sulbactam was <20 mcg/mL (3). In an in vitro experiment with bidirectional perfused human placental lobules, sulbactam was demonstrated to cross by simple diffusion (4). The placental transfer is consistent with its low molecular weight (about 255).
A 1992 study compared the concentration of three antibiotics (sulbactam/ampicillin, ticarcillin/clavulanic acid, and cefotaxime) in maternal blood, placental tissue, and cord blood in 15 laboring women with chorioamnionitis at ≥37 weeks’ gestation (5). Five of the women received the sulbactam/ampicillin combination. The mean concentrations of sulbactam in maternal blood, placental tissue, and cord blood were 7.25, 3.75, and 9.68 mcg/mL. The cord:maternal ratio was 1.3. The time interval between dosing and delivery and the dose used were not specified (5).
The pharmacokinetics of sulbactam at term were described in a 1993 study (6). The kinetics (area under drug vs. time curve, elimination rate constant, half-life, volume of distribution, and clearance) of a 0.5-g dose of sulbactam (combined with 1 g ampicillin) administered IV at cord clamping were not significantly different from those in nonpregnant patients. Changes were noted but did not reach statistical significance (6).
The combination of sulbactam and ampicillin has been used frequently in the 2nd and 3rd trimesters of pregnancy (7–15). These studies involved prophylaxis, as in cases of preterm premature rupture of the membranes, and therapy for established infections. No cases of fetal or newborn direct harm from exposure to the combination were reported. However, indirect harm to the newborn from antibiotic-related superinfection with resistant bacteria is a concern (15).
Inadvertent intrauterine infusion of sulbactam (1 g) plus ampicillin (2 g) was reported in a brief 2000 communication (16). The antibiotic combination was being given for prophylaxis of preterm premature rupture of the membranes at 30 weeks’ gestation. Apparently the error occurred when the antibiotic was infused into an intrauterine catheter instead of the intended IV catheter. A 1690-g infant (sex not specified) was delivered by cesarean section the next day. No adverse effects of the error were observed.
BREASTFEEDING SUMMARY
Sulbactam is excreted into human breast milk. Sulbactam (0.5 or 1.0 g) was infused either with cephalothin or ampicillin in four postpartum women 2 days after cesarean section (17). The milk concentrations obtained 10–21 hours after a dose ranged from 0.13 to 1.2 mcg/mL (mean 0.52 mcg/mL). No sulbactam was found in one sample obtained at 49 hours. The investigators did not state whether the infants were allowed to nurse. The potential effects of exposure to sulbactam on a nursing infant is unknown, but are probably similar to those that might occur with other antibiotics: modification of bowel flora, direct effects on the infant (e.g., allergy or sensitization), and interference with the interpretation of culture results if a fever workup is required. The American Academy of Pediatrics classifies sulbactam as compatible with breastfeeding (18).
References
1.Product information. Unasyn. Pfizer, 2002.
2.Horimoto M, Sakai T, Ohtsuki I, Noguchi Y. Reproduction studies with sulbactam and combinations of sulbactam and cefoperazone in rats. Chemotherapy 1984;32:108–15. As cited in Shepard TH. Catalog of Teratogenic Agents. 10th ed. Baltimore, MD: The Johns Hopkins University Press, 2001:469.
3.Dubois M, Coibion M, Deco J, Delapierre D, Lambotte R, Dresse A. The transplacental transfer of sulbactam sodium when co-administered with ampicillin to healthy pregnant women in labor (abstract). In: Spitzy KH, Karrer K, Breyer S, Lenzhofer R, Moser K, Pichler H, Rainer H, eds. 13th International Congress of Chemotherapy: Vienna, 28th August to 2 September, 1983. TOM 1, Antimicrobial Symposia. Verlag H. Egermann, Publ. Vienna, 1983.
4.Fortunato SJ, Bawdon RE, Baum M. Placental transfer of cefoperazone and sulbactam in the isolated in vitro perfused human placenta. Am J Obstet Gynecol 1988;159:1002–6.
5.Maberry MC, Trimmer KJ, Bawdon RE, Sobhi S, Dax JB, Gilstrap LC III. Antibiotic concentration in maternal blood, cord blood and placental tissue in women with chorioamnionitis. Gynecol Obstet Invest 1992;33:185–6.
6.Chamberlain A, White S, Bawdon R, Thomas S, Larsen B. Pharmacokinetics of ampicillin and sulbactam in pregnancy. Am J Obstet Gynecol 1993;168:667–73.
7.Smith LG Jr, Summers PR, Miles RW, Biswas MK, Pernoll ML. Gonococcal chorioamnionitis associated with sepsis: a case report. Am J Obstet Gynecol 1989;160:573–4.
8.Newton ER, Shields L, Ridgway LE III, Berkus MD, Elliott BD. Combination antibiotics and indomethacin in idiopathic preterm labor: a randomized double-blind clinical trial. Am J Obstet Gynecol 1991; 165:1753–9.
9.Lewis DF, Fontenot MT, Brooks GG, Wise R, Perkins MB, Heyman AR. Latency period after preterm premature rupture of membranes: a comparison of ampicillin with and without sulbactam. Obstet Gynecol 1995;86:392–5.
10.Adair CD, Ernest JM, Sanchez-Ramos L, Burrus DR, Boles ML, Veille JC. Meconium-stained amniotic fluid-associated infectious morbidity: a randomized, double-blind trial of ampicillin-sulbactam prophylaxis. Obstet Gynecol 1996;88:216–20.
11.Lewis DF, Brody K, Edwards MS, Brouillette RM, Burlison S, London SN. Preterm premature ruptured membranes: a randomized trial of steroids after treatment with antibiotics. Obstet Gynecol 1996; 88:801–5.
12.Cox SM, Bohman VR, Sherman ML, Leveno KJ. Randomized investigation of antimicrobials for the prevention of preterm birth. Am J Obstet Gynecol 1996;174:206–10.
13.Lovett SM, Weiss JD, Diogo MJ, Williams PT, Garite TJ. A prospective, double-blind, randomized, controlled clinical trial of ampicillin-sulbactam for preterm premature rupture of membranes in women receiving antenatal corticosteroid therapy. Am J Obstet Gynecol 1997;176:1030–8.
14.Perry KG Jr, Gebhart LD III, Turner KY, Martin RW. Ampicillin/sulbactam and corticosteroids in the management of preterm premature rupture of membranes (abstract). Am J Obstet Gynecol 1998; 178:S201.
15.Carroll EM, Heywood PA, Besinger RE, Muraskas JK, Fisher SG, Gianopoulos JG. A prospective randomized double-blind trial of ampicillin with and without sulbactam in preterm premature rupture of the membranes (abstract). Am J Obstet Gynecol 2000;182:S61.
16.Sigg TR, Kuhn BR. Inadvertent intrauterine infusion of ampicillin-sulbactam. Am J Health-Syst Pharm 2000;57:215.
17.Foulds G, Miller RD, Knirsch AK, Thrupp LD. Sulbactam kinetics and excretion into breast milk in postpartum women. Clin Pharmacol Ther 1985;38:692–6.
18.Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001; 108:776–89.