Current Reviews

Use of Antibiotics for Ear, Nose, and Throat Disorders in Pregnancy and Lactation JENNIFER

R. NIEBYL,

MD

Antibiotics are widely used during pregnancy; however, because of the potential for maternal and fetal side effects, they should only be used when the indication is clear and the risk-benefit ratio justifies their use. Pregnant patients should be warned that they are particularly susceptible to vaginal yeast infections, and should symptoms occur, they may need to take antifungal agents. PENICILLINS The penicillins are probably the class of antibiotics most widely used in pregnant women. They have a wide margin of safety and are not toxic for both the pregnant woman and the fetus.’ Ampicillin is one of the most frequently used drugs in the treatment of respiratory infections during pregnancy. However, adverse effects may include nausea, epigastric distress, diarrhea, and candidal vaginitis. Before therapy, it is important to ascertain that the patient is not allergic to penicillin. Should this patient inadvertently receive penicillin, the severity of a reaction may range from a mild rash to anaphylaxis. Kosim observed one patient who had a stillborn infant, which was attributed to an anaphylactic reaction to penicillin.’ There is no evidence that penicillin or its derivatives are teratogenic. In the CollaboraFrom the Department of Obstetrics and Gynecology, University of Iowa Hospitals and Clinics, Iowa Citv, IA. Address reprint requests to Jennifer Ft. Niebyi, MD, Professor and Head, Department of Obstetrics and Gvnecology, University of Iowa Hospitals and Clinics, Iowa City, IA 52242. Copyright 0 1992 by W.B. Saunders Company 0196-0709/92/l 304-0001$5.00/O American

Journal

of Otolaryngology,

tive Perinatal Project, 3,546 mothers took penicillin derivatives in the first trimester of pregnancy, with no increased risk of anoma1ies.l In another controlled study of 110 patients,3 penicillin G was administered for a total of 107 weeks in the first trimester, and the incidence of birth defects was no different from that in the nontreated controls. There is little experience in pregnancy with the new penicillins, such as piperacillin, mezlocillin, and azlocillin; therefore, these drugs should be used only when another antibiotic is not effective. Pharmacology The pharmacokinetics of the penicillin group of antibiotics have been well studied. Several of these studies have shown that the serum levels of these drugs are lower and their renal clearance is higher during pregnancy than when compared with the nonpregnant state.4-6 The increase in maternal renal function, due to an increase in both renal blood flow and glomerular filtration rate, results in a higher renal excretion of drugs, which is the case with the penicillins. The expansion of the maternal intravascular volume during the late stages of pregnancy is another factor that affects antibiotic levels. Thus, if the same dose of penicillin or ampicillin is administered to both nonpregnant and pregnant women, lower serum levels are attained during pregnancy due to the distribution of the drug in a larger intravascular volume. The transplacental passage of penicillin is by simple diffusion. The free-circulating portion of the antibiotic crosses the placenta, resulting in a lower maternal serum level of the

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unbound portion of the drug. Data indicate that the maternal administration of penicillins with high-protein binding, eg, oxacillin, cloxacillin, dicloxacillin, and nafcillin results in lower fetal tissue and amniotic fluid levels than the administration of penicillins, eg, penicillin G, ampicillin, and methicillin, which are poorly bound.7*8 Amoxicillin is similar to ampicillin in its spectrum of activity, but is stable in the presence of gastric acid and may be administered without regard to meals. Most penicillins are primarily excreted unchanged in the urine, with only small amounts being inactivated in the liver. This is significant in patients with impaired renal function, which requires reduction in dosage. Breastfeeding Penicillin G is excreted into breast milk in low concentrations. Milk-plasma ratios vary between 0.2 and 0.13. Although no adverse effects are clearly attributable to penicillin in breast milk, three theoretical problems might be observed in the nursing infant: (1) modification of bowel flora [possible diarrhea, candidiasis], (2) allergic response, and (3) interference with the interpretation of culture results. The benefits of continued breast feeding usually outweigh these potential risks. Ampicillin and amoxicillin are excreted into breast milk in low concentrations. Oxacillin, dicloxacillin, and ticarcillin are highly protein bound and are excreted into breast milk only in very small amounts. CEPHALOSPORINS There is no evidence of teratogenicity of the However, they are sufficephalosporins. ciently new that they are not included in the Collaborative Perinatnal Project; therefore, studies have not been performed in large numbers of patients. First- and secondgeneration agents appear to be safe, but the third-generation agents have had even more limited use during pregnancy.

JENNIFER

R. NIEBYL

receiving equivalent dosages due to a shorter half-life in pregnancy and an increased volume of distribution. This is true not only for well-established cephalosporin drugs, such as cephalothin,l’ cephalexin, and cephazolin, but also for the newer cephalosporins, eg, cephoxitin, cephradine, and cefuroxime.ll-l3 These drugs readily cross the placenta to the fetal blood stream and ultimately to the amniotic fluid. Breast Feeding The cephalosporins are excreted into breast milk in sufficiently low concentrations that the infant receives an insignificant dose. Although the same theoretical concerns exist as with the penicillins, the advantages of continued breast feeding during treatment usually outweigh these risks. SULFONAMIDES No teratogenic effects were noted by Heinonen et al among 1,455 human infants exposed to sulfonamides during the first trimester.l The sulfonamides compete with bilirubin for binding sites on albumin, thus raising the levels of free bilirubin in the serum and increasing the risk of hyperbilirubinemia or kernicterus in the neonate.‘4V’5 For that reason, it has been recommended that an alternate antibiotic be used during the third trimester if possible, although there are no data to support this recommendation, Kernicterus in the neonate following in utero exposure has not been reported, as the fetus can clear the free bilirubin through the placenta. The administration of sulfonamides should be avoided in glucose-6-phosphate dehydrogenase-deficient women, A dose-related toxic reaction may occur in these individuals resulting in red cell hemolysis. There is also a theoretical risk to the fetus if the drug is used near the time of delivery because fetal red cells are deficient in glutathione, although this has not been reported.

Pharmacology

Pharmacology

Maternal serum levels attained with these drugs are lower than in nonpregnant patients

The sulfonamides are easily absorbed orally, and they readily cross the placenta,

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achieving fetal plasma levels of 50% to 90% in the maternal plasma.16 Ylikorkala et al studied the pharmacokinetics of trimethoprimsulfamethoxazole in 10 pregnant women in and found the maternal the first trimesterI serum levels of the drug to be comparable with nonpregnant individuals. The elimination half-life of this combination drug was shorter in the pregnant women, and trimethoprim was cleared faster from the maternal serum than sulfamethoazole.17

Use With Trimethoprim Sulfa is often administered with trimethoprim. Controlled trials have failed to show any increased risk of birth defects after first trimester exposure.‘*,” Although trimethoprim antagonizes folic acid in bacteria, it does not affect the human enzyme system with similar potency.

nancy, but the effect was noted by x-ray to be reversible when the drug was stopped. Alternate antibiotics are currently recommended during pregnancy. Hepatotoxicity from tetracyclines administered in large doses has been reported in pregnant women; usually with intravenous administration. This presumably has been an overdose effect and has not been reported with brief courses of therapy at lower doses. Tetracycline-induced hepatotoxicity differs from acute fatty liver during pregnancy in that it is not unique to pregnant women, and reversal of the disease does not occur with abortion or delivery. First trimester exposure to tetracycline did not have any teratogenic risk in the 341 women in the Collaborative Perinatal Project’ or in the 174 women studied by Aselton et aLz4

Breast Feeding Breast Feeding Sulfonamides are excreted into breast milk in low concentrations. The milk-plasma ratio is approximately .5.” The amount of sulfonamide ingested by an infant would not be toxic, less than 1% of the maternal dose, and so breast feeding is usually continued during administration of these drugs. During the first 5 days of life, or with premature infants when hyperbilirubinemia may be a problem, sulpha drugs are best avoided.‘l

Tetracycline is excreted into breast milk in low concentrations, with milk-plasma ratios varying between .2 and 1.5. Tetracycline was not detectable in the serum of breast feeding infants, and delayed bone growth from tetracycline has not been reported when the drug was taken by breast feeding mothers. This may be due to the high binding of the drug to calcium and protein, limiting absorption from the milk.

AMINOGLYCOSIDES TETRACYCLINES The tetracyclines readily cross the placenta and are firmly bound by chelating to calcium in developing bone and tooth structuresz2 This produces brown discoloration of the teeth, hypoplasia of the enamel, inhibition of bone growth,23 and other skeletal abnormalities. The yellowish brown staining of the teeth usually takes place in the second or third trimesters of pregnancy, although bone incorporation can occur earlier. Depression of skeletal growth was particularly common among premature infants treated with tetracycline in the nursery. A 40% inhibition of fibular growth in the second trimester was demonstrated in patients who subsequently aborted the preg-

This group of drugs is commonly used in combination with the penicillins and/or clindamycin. They should be administered during pregnancy only when serious gramnegative infections are suspected. Gentamicin is preferred over tobramycin and amikacin as it has been more extensively studied. Streptomycin and kanamycin have been associated with congenital deafness in the offspring of mothers who took these drugs during pregnancy. Ototoxicity was reported with doses as low as 1 g of streptomycin biweekly for 8 weeks during the first trimester. It is recommended that the dosage be limited to a total of 20 g during the last half of pregnancy.25 Eighth cranial nerve damage has been re-

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ported following in utero exposure to kanamycin. Of 391 children whose mothers had received 50 mglkg of streptomycin for prolonged periods during pregnancy, 9 children were observed to have hearing loss [2.3%].26 Although ototoxicity in the fetus has not been reported with use of aminoglycosides other than kanamycin and streptomycin, it may potentially occur with the other aminoglycosides. The incidence of ototoxicity and nephrotoxicity may be increased with simultaneous use of ethacrynic acid.27 Neuromuscular blockade can be potentiated by the combined use of these drugs and curariform drugs, and therefore the dosages should be reduced appropriately. Other than ototoxicity, there are no known teratogenic effects associated with the use of aminoglycosides in the first trimester. In 135 infants exposed to streptomycin in the Collaborative Perinatal Project,’ no teratogenic effects were observed. In a group of 1,619 newborns whose mothers were treated for tuberculosis with multiple drugs, including streptomycin, during pregnancy, the incidence of congenital defects was the same as the control group.28 Pharmacology These drugs are poorly absorbed after oral administration and are rapidly excreted by the normal kidney. Because the rate of clearance is related to the glomerular filtration rate, dosage must be reduced in the face of abnormal renal function. Due to more rapid elimination, serum aminoglycoside levels are usually lower in pregnant patients versus nonpregnant patients receiving equivalent doses. Thus it is important to monitor levels to prevent subtherapeutic dosing. 2g*30 Wide interpatient variation in gentamicin levels has been observed in obstetric patients, varying with the volume of distribution of the drug.30 Breast Feeding Limited information is available on the excretion of gentamicin into breast milk. Other aminoglycosides, such as amikacin, kanamyand tobramycin, are cin,31 streptomycin,

JENNIFER

R. NIEBYL

known to be excreted in low levels into breast milk. Because oral absorption of these drugs in the infant is poor, ototoxicity or other side effects would not be expected. ERYTHROMYCIN Erythromycin estolate has been associated with subclinical reversible hepatotoxicity during pregnancy.32 Thus, other forms of erythromyin are usually recommended. No teratogenic risk of erythromycin has been reported. In 79 patients in the Collaborative Perinatal Project’ and 260 in another study,24 no increased risk of birth defects was noted. Pharmacology Erythromycin and its salts are not consistently absorbed from the gastrointestinal tract of pregnant women and their transplacental passage is unpredictable. Both maternal and fetal serum levels achieved after the administration of the drug in pregnancy are low and vary considerably.33*34 The usual oral dose is 250 to 500 mg every 6 hours, but the higher dose may not be well tolerated in pregnant women who are susceptible to nausea and gastrointestinal symptoms. Breast Feeding Erythromycin is excreted into breast milk in small amounts with milk-plasma ratios of about .5. No reports of adverse effects have been noted in infants exposed to erythromytin in breast milk. CLINDAMYCIN Clindamycin is used during pregnancy when anaerobic infections are suspected. If diarrhea develops during the administration of this drug, the patient should be evaluated for the possibility of pseudomembranous colitis, which has been reported in up to 10% of patients.35 No reports linking the use of clindamycin with congenital defects have been noted, although this drug is new and was not included in the Collaborative Perinatal Project.*

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Pharmacology Maternal serum levels after dosing at various stages of pregnancy are similar to those of nonpregnant patients.” Clindamycin is almost completely absorbed after oral administration, and a small percent is absorbed after topical application. Most of the drug is metabolized in the liver to products excreted in the urine and bile, and only 10% of the drug is excreted unchanged in the urine.

Breast Feeding Clindamycin is excreted into breast milk in low levels, and nursing is usually continued during administration of this drug. Two bloody stools were observed in one nursing infant whose mother was receiving clindamytin and gentamicin, 36 which cleared when the breast feeding was stopped. Except for this one case, no other adverse effects in nursing infants have been reported.

METRONIDAZOLE Metronidazole has trichomonacidal and amebocidal activity as well as effectiveness against certain bacteria, especially anaerobes. Several studies have failed to show any increase in the incidence of congenital defects or other adverse pregnancy outcomes among newborns of mothers treated with metronidazole during pregnancy. In one study,37 4 of 55 infants treated in early pregnancy had a variety of minor defects, and in the Collaborative Perinatal Project,l 2 of 31 infants were abnormal, both close to the expected incidence. In an additional study of 880 infants exposed to metronidazole in the three trimesters of pregnancy, no difference in any adverse outcome was noted compared with controls.38 Controversy regarding the use of metronidazole during pregnancy was initiated when the drug was shown to be positive in the Ames test, which correlates with carcinogenicity in animals. However, doses used were much higher than the doses used clinically, and carcinogenicity in humans has not been confirmed.3g Because some have advised against the use of this drug during pregnancy,40 it

should only be used when no other safe drug is available.

Pharmacology The drug crosses the placenta to the fetus throughout gestation with a cord-maternal plasma ratio at term of approximately 1.O.41

Breast Feeding Metronidazole is excreted into breast milk in small amounts with milk-plasma ratios of about 1.0.One infant had diarrhea while the mother was receiving metronidazole, but otherwise no adverse effects in metronidazoleexposed nursing infants have been reported. The American Academy of Pediatrics recommends interrupting breast feeding after a single 2-g oral dose for 12 to 24 hours to allow clearance of the drug.‘l

CONCLUSION Most antibiotics are safe to use during pregnancy. Tetracyclines should be avoided, and fetal ototoxicity has resulted from prolonged exposure to aminoglycosides in utero. As there is potential for fetal effects of any drug that are yet unrecognized, antibiotics should be used during pregnancy only when there is a clear need.

REFERENCES 1. Heinonen PO, Slone D, Shapiro S: Birth Defects and Drugs in Pregnancy. Littleton, MA, Publishing Sciences Group, 1977, pp 296-314 2. Kosim H: Intrauterine fetal death as a result of anaphylactic reaction to penicillin in a pregnant woman. Dapim Refuiim 18:136-137, 1959 3. Ravid R, Toaff R: On the possible teratogenicity of antibiotic drugs administered during pregnancy-a prospective study, in Klingberg M, Abramovici A, Chemki J (eds): Drugs and Fetal Development. New York, NY, Plenum, 1972, p 505 4. Philipson A: Pharmacokinetics of antibiotics in pregnancy and labour. Clin Pharmacokinet 4:297, 1979 5. Bastert G, Muller WG, Wallhauser KH, et al: Pharmacokinetische Untersuchungen zum Ubertritt von Antibiotika in das Fruchtwasser am Ende der Schwagerschaft. 3. Tiel: Oxacillin. Zietschrift fur Geburtshilfe und Perinatologie 179:346, 1975 6. Philipson A: Pharmacokinetics of ampicillin during pregnancy. J Infect Dis 136:370, 1977 7. Kunin CM: Clinical pharmacology of the new penicillins. I. The importance of serum protein binding in

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determining antimicrobial activity and concentration in serum. Clin Pharmacol Ther 7:166, 1966 8. Macaulay MA, Berg SA, Charles D: Placental transfer of dicloxacillin at term. Am J Obstet Gynecol 102:11621168,1968 9. Greene H, Burkhart

B, Hobby G: Excretion of penicillin in human milk followinn uarturition. Am 1 Obstet Gynecol51:732, 1946 - _ 10. Morrow S, Palmisano P, Cassady G: The placental transfer of cephalothin. J Pediatr 73:262, 1968 11. Dubois M, Delapierre II, Deresse A, et al: Transplacental transfer of cefuroxine, 11th International Congress of Chemotherapy and 19th Interscience Conference on Antimicrobial Agents and Chemotherapy. Boston, MA, 1979 12. Dubois M, Delapierre D, Demonty J, et al: Transplacental and mammary transfer of cephoxitin. 11th International Congress of Chemotherapy and 19th Interscience Conference on Antimicrobial Agents and Chemotherapy. Boston, MA, 1979 13. Philipson A, Stiernsted TG: Pharmacokinetics of Cephradine in Pregnancy. 11th International Congress of Chemotherapy and 19th Interscience Conference on Antimicrobial Agents and Chemotherapy. Boston, MA, 1979 14. Harris RC, Lucey JF, MacLean JR: Kernicterus in premature infants associated with low concentration of bilirubin in the plasma. J Pediatr 23:878, 1950 15. Nyhan WL: Toxicity of drugs in the neonatal period. J Pediatr 59:1, 1961 16. Monif GFG: Infectious Diseases in Obstetrics and Gynecology. New York, NY, Harper & Row, 1974, p 26 17. Ylikorkala 0, Sjostedt E, Jarvinen PA, et al: Trimethoprimsulfonamide combination administered orally and intravaginally in the first trimester of pregnancy: Its absorption into serum and transfer to amniotic fluid. Acta Obstet Gynecol Stand 52:229, 1973 18. Ochoa AG: Trimethoprim and sulfamethoxazole in pregnancy. JAMA 217:1244,1971 19. Brumfitt W, Purse11 R: Double-blind trial to compare ampicillin, cephalexin, co-trimoxazole, and trimethoprim in treatment of urinary infection. Br Med J 2:673,-1972 29. Foster FP: Sulfanilamide excretion in breast milk: Report of a case. Proceedings of Staff Meeting of Mayo Clinic 14:153, 1939 21. Committee on Drugs: American Academy of Pediatrics. The Transfer of Drugs and Other Chemicals into Human Milk. Pediatrics 84:924, 1989 22. Kline AH, Blattner RJ, Lunin M: Transplacental effects of tetracycline on teeth. JAMA 118:178, 1964 23. Cohlan SQ, Bevelander G, Tiamsic T: Growth inhi-

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bition of prematures receiving tetracycline. Am J Dis Child 165:453, 1963 24. Aselton P, Jick H, Milunsky A, et al: First-trimester drug use and congenital disorders. Obstet Gynecol 65:451-455, 1985 25. Robinson GC, Cambon KG: Hearing loss in infants of tuberculous mothers treated with streptomycin during pregnancy. N Engl J Med 271:949,1964 26. Nishimura H, Tanimura T: Clinical Aspects of the Teratogenicity of Drugs. Amsterdam, Excerpta Medica, 1976, p 131 27. Jones HC: Intrauterine ototoxicity: A case report and review of literature. J Nat1 Med Assoc 65:201, 1973 28. Marynowski A, Sianozecka E: Comparison of the incidence of congenital malformations in neonates from healthy mothers and from patients treated because of tuberculbsis. Ginekol Pol 43:?13, 1972 29. Weinstein Al. Gibbs RS. Gallaeher M: Placental transfer of clindamycin and gentamiiin in term pregnancy. Am J Obstet Gynecol 124:688-691, 1976 36. Zaske DE, Cipolle RJ, Strate RG, et al: Rapid gentamicin elimination in obstetric patients. Obstet Gynecol 56:559-564, 1980 31. Wilson JT: Milk plasma ratios and contraindicated drugs, in Wilson JT (ed): Drugs in Breast Milk. Balgowlah, Australia, ADIS Press, 1981, p 79 32. McCormack WM, George H, Donner A, et al: Hepatotoxicity of erythromycin estolate during pregnancy. Antimicrob Agents Chemother 12:630, 1977 33. Philpson A, Sabath LD, Charles D: Erythromycin and clindamycin absorption and elimination in pregnant women. Clin Pharmacol Ther 19:68, 1976 34. Philipson A, Sabath LD, Charles D: Transplacental passage of erythromycin and clindamycin. N Engl J Med 288:1219-1221, 1973 35. Tedesco FJ, Stanley RJ, Alpero DH: Diagnostic features of clindamycin-associated pseudomembraneous enterocolitis. N Enal 1 Med 290:841-843, 1974 36. Mann CF: Chndamycin and breast-feeding. Pediatrics 66:1030, 1980 37. Peterson WF, Stauch JE, Ryder CD: Metronidazole in Pregnancy. Am J Obstet Gynecol94:343, 1966 38. Morgan FK: Metronidazole treatment in pregnancy. bit’1 congress and symp series. Roy Sot Med 18:245,1979 39. Beard CM, Noller KL, O’Fallon WM. et al: Lack of evidence for cancer due to use of metronidazole. N Engl J Med 361:519-522, 1979 40. Finegold SM: Metronidazole. Ann Intern Med 93:585, 1980 41. Karhunen M: Placental transfer of metronidazole and tinidazole in early human pregnancy after a single infusion. Br J Clin Pharmacol 18:254, 1984