[PDF]Antibiotic chemotherapy during pregnancy and lactation period ...
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από I Mylonas - 2011 - Γίνεται αναφορά σε 35 - Σχετικά άρθρα
3 Σεπ 2010 - ing pregnancy, with the exception of cases in which there is a maternal allergy to penicillin. Cephalosporins are another first-line antibiotic used ...
Arch Gynecol Obstet (2011) 283:7–18 DOI 10.1007/s00404-010-1646-3123 MATERNO-FETAL MEDICINE Antibiotic chemotherapy during pregnancy and lactation period: aspects for consideration Ioannis Mylonas
Abstract Background Infections during gestation, delivery and the postnatal period can jeopardise not only the mother, but also the child. Along with chromosomal abnormalities and immunological diseases, infection in early pregnancy represents the most important reason for abortion. During the second and third trimester, infections are the principal cause for preterm labour, premature membrane rupture, premature delivery and the resultant complications in the newborn child. Many pregnant women are very cautious about taking antibiotics due to primarily potentially detrimental eVects on the unborn child. However, there are no contraindications for antibiotic treatment during pregnancy in the event of a serious infectious disease of the mother. Materials and methods In this review the indications and contraindications of the administration of antibiotics during pregnancy are being reviewed. Results Penicillins are a Wrst-line antibiotic treatment during pregnancy, with the exception of cases in which there is a maternal allergy to penicillin. Cephalosporins are another Wrst-line antibiotic used during pregnancy. In principle, more commonly used cephalosporins should be given priority. Owing to associated nephrotoxicity and ototoxicity, aminoglycosides should not be prescribed at any time during pregnancy. Systematic use of aminoglycosides should be considered solely in the event of life-threatening infections with gram-negative pathogens and/or treatment failure of recommended antibiotics during pregnancy. The use of metronidazole is also permitted during pregnancy, provided the indications for its use have been strictly veriWed. Lincosamides should be used only if penicillins, cephalosporins and erythromycin have failed to eradicate infection. Sulfonamides, trimethoprim and cotrimoxazole are second-line agents for the use during pregnancy. Tetracyclines should not be administered to pregnant women after the Wfth week of pregnancy, and are deemed contraindicated. As a precautionary measure, gyrase inhibitors are also contraindicated for pregnant women, children and young adolescents. Conclusion On the basis of our current state of knowledge, the vast majority of antibiotics do not cause serious harm to the unborn child if used properly and at the appropriate doses during pregnancy. The treatment with an antibiotic that is contraindicated does not justify termination of pregnancy. However, ultimately no medicine, including antibiotics, can be described as absolutely safe. Keywords Pregnancy · Antibiotics · Treatment · Contraindication · Adverse outcome Introduction Infections during gestation, delivery and the postnatal period can jeopardise not only the mother, but also the child [1–4]. Along with chromosomal abnormalities and immunological diseases, infection in early pregnancy represents the most important reason for abortion [5]. During the second and third trimester, infections are the principal cause for preterm labour, premature membrane rupture, premature delivery and the resultant complications in the newborn child [3, 5]. Many pregnant women are very cautious about taking antibiotics due to potentially detrimental eVects on the I. Mylonas (&) Division of Infectious Diseases in Gynaecology and Obstetrics, 1st Department of Obstetrics and Gynaecology, Ludwig-Maximilians-University Munich, Maistrasse 11, 80337 Munich, Germany e-mail: ioannis.mylonas@med.uni-muenchen.de 8 Arch Gynecol Obstet (2011) 283:7–18 123 unborn child. However, it is precisely for the protection of the child that antibiotics, particularly suYcient doses of antibiotics, should not be withheld from the mother. Despite this, studies have shown that mothers are more prone to take antibiotics when unaware of a pregnancy when compared with during pregnancy [3, 5, 6]. In this review, the indications and contraindications of the administration of antibiotics during pregnancy are being reviewed. Search strategy and selection criteria for identifying relevant data were by performed by searching Medline, Current Contents, Web of Science, Embase and references from relevant articles. English and German pharmacological, gynaecological and infectious diseases textbooks were also reviewed. In addition, numerous articles were identi- Wed through searches of the extensive Wles of the author. Search terms were “pregnancy”, “antibiotic”, “anti-infective drugs” “infection”, “infectious diseases”, “adverse pregnancy outcome” and “foetal malformation”. English and German language manuscripts were reviewed. Antibiotic therapy during pregnancy The administration of antibiotics during pregnancy harbours several concerns to physicians and patients about the risk of the foetus, since such a treatment should neither jeopardise pregnancy nor causes harm to the unborn child. However, studies on the safety of antibiotic use during pregnancy are based on case–control and cohort studies, since placebo-controlled randomised trials are considered not ethical. Therefore, due to the existing trials, several problems on the risk assessment and interpretation exist, such as recall bias, adequate indication and statistical power. Moreover, the experience of thalidomide and its intake during pregnancy with subsequent phokomelia in born infants is still a matter of discussion and a negative paradigm in medications used during pregnancy [7]. In addition, several reports have raised some concern on the use of antibiotic treatment during pregnancy. For example, erythromycin was associated with pyloric stenosis in infants [8, 9] or even miscarriage after pivmecillinam use [10]. However, according to our current state of knowledge and experience, the vast majority of antibiotics do not cause serious harm to the unborn child if used and dosed properly [11–15]. However, untreated infections might themselves harbour a substantial risk and treatment might prevent adverse pregnancy outcome. In general, there are no contraindications for antibiotic treatment during pregnancy in the event of a serious infectious disease in the mother. However, there are several classes of antibiotics that are approved and recommended for the use during pregnancy (Table 1), approved with a restrictive use (Table 2) and contraindicated during pregnancy and lactation period (Table 3) [4, 11–15]. In the light of the importance of the beneWcial eVects of breastfeeding, the practice of weaning a child due to antibiotic therapy has largely been abandoned. In terms of obstetric outcomes, early therapy is crucial for success. Knowledge of the most important bacterial pathogens, frequent obstetric infections and the indications for antibiotic therapy during pregnancy will facilitate the selection of a suitable antibiotic and subsequent outpatient or inpatient treatment regimen (Table 4). Penicillins and cephalosporins Currently, penicillins constitute the oldest group of eVective antibiotics that are most widely used. Penicillins belong to the -lactam class of antibiotics and act by speciWcally hindering bacterial cell wall synthesis. Penicillins and -lactam inhibitors can cross the placental barrier and reach the foetus in quantities suYcient to be detected in foetal blood and amniotic Xuid [16]. At therapeutic doses, penicillins have practically no toxicity in humans [5, 16]. Penicillins are eVective against gram-positive streptococcal, staphylococcal, enterococcal and meningococcal strains, and are used primarily for the treatment of syphilis, Table 1 Antibiotics approved for use during pregnancy [2, 4, 5, 11–16, 21] Category Comments Recommendations Penicillins and cephalosporins No indications of foetal impairment Good placental permeability Under certain circumstances, it may be necessary to consider an increase in dosage to achieve the desired therapeutic eVect Penicillins and cephalosporins are Wrst-line antibiotics during pregnancy More established cephalosporins should be given priority Macrolides No detrimental eVects on the fetus or the mother have been identiWed to date More recent erythromycin derivatives such as azithromycin, clarithromycin and roxithromycin should be assessed with caution due to the lack of adequate clinical data Macrolides may be used during pregnancy if mandated by the bacterial spectrum or in cases of penicillin allergy Erythromycin estolate should not be administered during the second and third trimesters due to its hepatotoxicity Spiramycin is the drug of choice for toxoplasmosis during the Wrst trimester Arch Gynecol Obstet (2011) 283:7–18 9 123 gonorrhoea and meningitis [16]. Aminopenicillins are also available in combination with a -lactam inhibitor (clavulanic acid, sulbactam and tazobactam). To date, no malformations or other undesirable eVects of penicillins have been reported in studies of either animals or humans [17–20]. Side eVects associated with penicillin are relatively rare. They include immediate or delayed hypersensitivity reactions, particularly skin rashes (aVecting 5–10% of patients), fever and anaphylactic shock [5]. Gastrointestinal symptoms or interstitial nephritis are occasionally reported. When compared with penicillin G, ampicillin causes more severe side eVects, including nausea, vomiting and diarrhoea [21]. Because of the lack of serious side eVects, penicillins are Wrst-line antibiotics for the use during pregnancy [2, 4, 16, 17]. In fact, maternal allergy to penicillin represents the only potential therapeutic problem with penicillins [16]. Cephalosporins also have a -lactam ring structure. All cephalosporins inhibit the biosynthesis of the bacterial cell wall, thus exerting bactericidal eVects [5, 16]. The pharmacokinetic proWle of cephalosporins is similar to penicillins [5]. Cephalosporins are also capable of passing through the placenta and can be detected in bactericidal concentrations in the amniotic Xuid. Immune haemolytic reactions have been observed in patients treated with second- and thirdgeneration cephalosporins, in particular cefotetan [22]. In rare cases, mothers have experienced oversensitivity reactions, such as skin rash and anaphylactic shock. An increase Table 2 Antibiotics approved for restricted use during pregnancy [2, 4, 5, 11–16, 21] Category Comments Recommendations Aminoglycosides No teratogenic side eVects have been reported to date There is evidence of selective uptake of aminoglycosides by the foetal kidney resulting in damage to immature nephrons Although an impairment of the 8th cranial nerve has been proven only for streptomycin, this complication cannot be entirely ruled out for other aminoglycosides All aminoglycosides must be considered potentially nephrotoxic and ototoxic Prescriptions are restricted to vital indications Gentamicin is currently considered the safest choice due to extensive and comprehensive experience with this antibiotic Therapeutic blood concentrations in the mother do not equate with safety for the foetus Metronidazole Animal experiments suggest mutagenic and carcinogenic eVects, but no embryo-toxic/teratogenic eVects have been reported in humans For trichomonas and anaerobic infections Metronidazole may also be used during pregnancy for appropriate indications For precautionary reasons, it is currently recommended not to use metronidazole during the Wrst trimester This also applies to systematic therapy, especially as there are doubts about the eVectiveness of vaginal application Clindamycin No detrimental eVects to the foetus are currently known This antibiotic should only be used speciWcally for anaerobic infections due to potential maternal side eVects (diarrhoea, pseudomembranous colitis). Clindamycin and lincomycin should only be used in the event that penicillins, cephalosporins and macrolides are ineVective, i.e. for infections with Bacteroides fragilis and other anaerobic bacteria Routine prescription of clindamycin after dental procedures is not approved The use of clindamycin or lincomycin is not a suYcient reason for either a termination of pregnancy or additional diagnostics Sulfonamides, trimethoprim and cotrimoxazole If administered shortly before birth, a component of this group of antibiotics (sulfamethoxazole) can cause kernicterus due to the displacement of bilirubin in the newborn Owing to the mode of action of these antibiotics, damage during the Wrst months of pregnancy cannot be ruled out Teratogenic eVects have been observed in animal experiments No toxic eVects to the embryo or foetus have been identiWed for trimethoprim to date Sulfonamides, trimethoprim and cotrimoxazole are second-line antibiotics throughout the pregnancy period Vancomycin and teicoplanin No detrimental eVects on the foetus have been identiWed to date Use only for strictly deWned indications 10 Arch Gynecol Obstet (2011) 283:7–18 123 in transaminase levels, thrombophlebitis at the injection site, haemolysis and bone marrow disorders can also occur [21]. Based on the available data, including the results of a prospective study of cefuroxime use during the Wrst trimester [23], cephalosporin at therapeutic doses is not teratogenic [24]. The results of another study have indicated that children of mothers who received cefuroxime during pregnancy exhibited normal physical and mental development [25]. Increased clearance of cephalosporins during pregnancy has been reported; thus, it may be necessary to change the doses or dosing intervals [16, 26]. Along with penicillins, cephalosporins are Wrst-line antibiotics for the use during pregnancy and more commonly used cephalosporins should be given priority. Macrolides Macrolides are bacteriostatic antibiotics that inhibit protein biosynthesis via reversible binding to the bacterial 50S ribosomal subunit. Because of their size, lower levels of macrolides are able to reach the foetus [5, 16]. The antibacterial spectrum of macrolides includes predominantly gram-positive cocci, but also chlamydia, mycoplasma and legionella, campylobacter as well as coxiella, bartonella, corynebacteria and several mycobacterium species. Macrolides are suitable alternatives for patients who are allergic to penicillin [2, 4]. Erythromycin is a member of the macrolide group and is deemed highly safe for the use during pregnancy. In rare cases, temporary impairment of hearing may occur. Other macrolides include roxithromycin, clarithromycin and azithromycin. These agents are characterised primarily by improved bioavailability and tolerance, fewer side eVects (e.g. gastrointestinal side eVects) and an extended antibacterial spectrum [21]. The activity spectra of these macrolide antibiotics, are similar to erythromycin, but for the most part, these agents have fewer gastrointestinal side eVects. To date, there is no evidence that erythromycin [27] or azithromycin, clarithromycin [28, 29], josamycin, roxithromycin and spiramycin [30] are teratogenic. However, a recent study based on the data from the Swedish Medical Birth Registry reported a slightly signiWcant increase in the rate of malformations in 1,844 children exposed to macrolides during early pregnancy when compared with children who were exposed to phenoxymethylpenicillin [31]. In France, toxoplasmosis is treated with spiramycin throughout pregnancy (from the earliest point of diagnosis until delivery). To date, there have been no indications that this practice is associated with malformations of newborns. Clarithromycin should be used with caution because it has been shown to have teratogenic eVects in animals and to induce cardiovascular defects in rats [5, 32]. There have been several reports of liver toxicity in mothers [33] who were treated with erythromycin estolate during the second half of pregnancy. Cholestatic icterus was reported in some patients during the second week of treatment [5, 16]. The condition improved within a few weeks of withdrawal of the medication without complications or any signs of harm to the foetus. In conclusion, erythromycin is a safe Wrst-line antibiotic for the use during pregnancy [4, 5, 16]. Caution is advised solely for erythromycin estolate due to its potential hepatotoxicity during pregnancy. More recent erythromycin derivatives, such as azithromycin, clarithromycin and roxithromycin should be used with caution due to the relative lack of experience with these drugs [5]. Spiramycin is indicated for toxoplasmosis during the Wrst trimester. Table 3 Contraindicated antibiotics during pregnancy [2, 4, 5, 11–16, 21] Category Comments Recommendations Tetracyclines Tetracyclines can disturb the development of teeth and bones A link between the use of tetracyclines and lethal liver damage in mothers cannot be ruled out Contraindicated starting from the 16th week of pregnancy until the age of seven due to tooth discoloration All tetracyclines are contraindicated after the 16th week of pregnancy Prior to the 16th week, they are considered second-line antibiotics Accidental administration of tetracycline after the 16th week of pregnancy does not justify termination of pregnancy No additional prenatal diagnostic measures are necessary, especially for doxycycline Chinolones Causes severe cartilage damage in animals Gyrase inhibitors must be avoided during pregnancy In well-founded cases, it is possible to use gyrase inhibitors that have been tested on a large number of pregnant patients (e.g. norXoxacin or ciproXoxacin) Rifampicin and streptomycin Not permitted for the treatment of tuberculosis during the Wrst 3 months of pregnancy Spiramycin is the drug of choice for the treatment of toxoplasmosis during the early stages of pregnancy Arch Gynecol Obstet (2011) 283:7–18 11 123 Lincosamines Lincosomide antibiotics, such as lincomycin and clindamycin are similar to macrolides in their spectrum of activity and mechanism of action [5]. In addition to a high level of eYcacy against gram-positive bacteria [with the exception of methicillin-resistant Staphylococcus aureus (MRSA)], clindamycin is active against all anaerobic bacteria, as well as actinomycetes and nocardia. Cross-resistance to clindamycin and erythromycin is in the range of approximately 20% [16]. There are no known teratogenic eVects of this group of antibiotics in humans [5]. Resorption after oral administration is almost complete and clindamycin can be used during any trimester. Another advantage of clindamycin is its speciWc pharmacokinetic proWle, which includes not only placental permeability, which is important for treating maternal–foetal infections, but also accumulation in granu- Table 4 Frequently occurring diseases and their causes during pregnancy and lactation [1–3] Disease Bacterial causes Primary treatment options Endometritis postpartum Chlamydia trachomatis Gonococci Penicillins Colpitis Streptococci (Group A) Staphylococcus aureus Trichomonas Penicillins and cephalosporins Metronidazole (trichomoniasis) Mastitis Staphylococcus aureus Puerperal sepsis Streptococci (Group A) Penicillins Vulvitis Streptococci (Group A) Staphylococcus aureus Penicillins and cephalosporins Wound infection Staphylococcus aureus Streptococci (Group A) Enterobacteria Anaerobic bacteria Chlamydia trachomatis (perihepatitis) Antibiotic prophylaxis for caesarean section Cephalosporins Ampicillin/amoxicillin Cervicitis Gonococci Chlamydia trachomatis Macrolides Amoxicillin Cystitis and pyelonephritis Mostly Escherichia coli (»80%) Proteus mirabilis (10–15%) Other enterobacteria Staphylococcus saprophyticus (young and sexual active women) Rarely Pseudomonas spp. and Staphylococcus aureus Penicillins and cephalosporins are suYcient in most cases Premature rupture of membranes (PROM) Many bacteria Ampicillin/amoxicillin Macrolides Prevention of premature birth Many bacteria Ampicillin/amoxicillin Cephalosporins Macrolides Asymptomatic vaginal streptococci infection Streptococci (Group B) Penicillins Macrolides Trichomoniasis Trichomonas vaginalis Metronidazole Tinidazole after the 20th week of pregnancy Chorioamnionitis Many bacteria Ampicillin/amoxicillin Cephalosporins Listeriosis Listeria monocytogenes Ampicillin/amoxicillin Lues Treponema pallidum Penicillins Pneumonia Streptococcus pneumoniae (¡30%) Haemophilus inXuenzae (¡5%) Staphylococcus aureus (¡5%) Mycoplasma pneumoniae (¡10%) Chlamydia pneumoniae Klebsiella pneumoniae Penicillins and cephalosporins are suYcient in most cases Toxoplasmosis—primary infection Toxoplasma gondii Spiramycin up to the 15th week of pregnancy Afterwards sulfonamides and pyrimethamine 12 Arch Gynecol Obstet (2011) 283:7–18 123 locytes (e.g. abscess pus). One potential risk that is observed in 2–10% of all cases is the occurrence of pseudomembranous colitis after several weeks of treatment, as well as upon vaginal application [34]. Pregnancy complications as a consequence of bacterial vaginosis cannot be suYciently prevented or treated via vaginal clindamycin therapy [35]. Aminoglycosides Aminoglycosides have a narrow spectrum of activity, targeting gram-negative bacteria. They are bactericidal, and act by inhibiting protein synthesis. This group of antibiotics, includes amikacin, gentamicin, kanamycin, neomycin, netilmicin, paromomycin, spectinomycin, streptomycin and tobramycin [4]. Prenatal streptomycin or kanamycin injections are associated with impaired hearing of exposed children, with a particularly sensitive phase up to approximately the fourth month of pregnancy [16, 32]. Thus, aminoglycosides should generally not be administered during the Wrst 4 months of pregnancy due to potential ototoxicity and nephrotoxicity. Although the risk of damage to the eighth cranial nerve has only been described for isolated cases of foetal exposure to kanamycin and streptomycin [5], this complication cannot be entirely ruled out for other aminoglycosides. A retrospective case–controlled study failed to establish an increased rate of malformations after oral neomycin and parenteral gentamycin treatment [36]. In summary, aminoglycosides and in particular kanamycin and streptomycin, should not be administered parenterally during pregnancy due to potential ototoxicity associated with these agents [4, 5, 16]. Aminoglycosides should be used systematically solely for life-threatening infections with gram-negative pathogens when treatment with Wrst-line antibiotics fails to achieve the desired eVect. Serum concentrations must be monitored regularly for the duration of therapy. Overall, the risks associated with the treatment with aminoglycosides do not justify termination of pregnancy. Depending on the extent of parenteral therapy, the hearing ability of the child must be veriWed early during the postpartum period [16]. Metronidazole and derivates Metronidazole and other nitroimidazoles (e.g. ornidazole) act by inhibiting DNA synthesis, thus they are bactericidal in nature. This group of antibiotics targets anaerobic bacteria, including bacteroides fragilis and protozoans (amoebas and lamblia). These agents are used primarily in combination with other antibiotics (e.g. aminoglycosides, amino- or acylureidopenicillin and clindamycin). Metronidazole has a wide therapeutic spectrum. The preferred route of administration is oral or local application for the treatment of trichomonas or anaerobic infections. Several groups have recommended metronidazole for the prevention of premature birth due to bacterial vaginosis [35]. Some of the side eVects to be considered include gastrointestinal disorders and more rarely, changes in blood count and allergies, as well as central nervous system disorders, which aVect predominantly alcoholics and patients with medication withdrawal symptoms [37]. Following oral and intravenous administration, the concentration of metronidazole in the developing embryo frequently reaches higher levels than in the mother [5]. Relevant quantities also reach the foetus upon vaginal application. The results of animal studies have raised some question about the potential mutagenic and carcinogenic eVects of metronidazole, but these have not been conWrmed in humans [16, 38]. The results of a retrospective study of metronidazole during pregnancy showed an association between prenatal exposure to metronidazole and childhood neuroblastoma, but this association was not statistically signiWcant [39]. Another study conducted over a period of more than 20 years yielded no indication of an increased risk of malignancy after metronidazole administration [40]. Based on the results of analysis of over 3,000 pregnancies, it appears that metronidazole is not teratogenic in humans [16, 38, 41, 42]. Although there is insuYcient data to make conclusive statements about nimorazole, ornidazole and tinidazole, which are used for the oral treatment of trichomonas, amoeba and bacterial vaginosis, there are no indications to date that these agents are teratogenic [16, 32]. In summary, the use of metronidazole during pregnancy is permitted only if the indications for use have been strictly veriWed. Trichomonas infection should be treated with a single oral dose of 2 g [5]. Parenteral administration is advisable only for dangerous anaerobic infections. Protracted vaginal application should be avoided, as it is not considered suYciently eVective and may also lead to prolonged exposure of the foetus [5]. Metronidazole should be used over nimorazole and tinidazole. Termination of pregnancy or further diagnostics is not indicated. Sulfonamides and cotrimoxazole Sulfonamides are synthetic, bacteriostatic, broad-spectrum antibiotics that are amongst the oldest anti-infective drugs. Today, sulfadiazin and sulfalen are oVered as single-agent therapies; however, the importance of sulfonamides for the treatment of bacterial infections has diminished signiWcantly over the past several years. This is due in part to the fact that many microorganisms have developed resistance to Arch Gynecol Obstet (2011) 283:7–18 13 123 sulfonamides, and because bactericidal penicillins and cephalosporins are more eVective and have no associated toxicity in the developing embryo or foetus [5, 21]. Sulfonamides are eVective against most gram-positive and many gram-negative bacteria. However, several gram-negative bacteria have developed resistance to sulfonamides and this class of antibiotics is used only in very speciWc cases, i.e. urinary tract infections, treatment of meningococcal strains and as a preventative against rheumatic fever. Side eVects, such as gastrointestinal disorders and oversensitivity may occur [21]. To date, there is no evidence that sulfonamides, trimethoprim and combined preparations have teratogenic potential in humans [5, 6, 16, 43]. A study of the Collaborative Perinatal Project [44] looked at data from 1,455 children born to mothers who were treated with sulfonamides during the Wrst trimester. Data from an additional 5,689 children whose mothers received sulfonamide at various times during pregnancy were also analysed. No reliable association between sulfonamide treatment and foetal malformations was established in either of these settings; thus, sulfonamides should be considered non-teratogenic, and termination of pregnancy after sulfonamide intake during gestation is not supported [4, 16]. Nonetheless, potential toxicity to embryos remains to be a topic of discussion, because folic acid antagonists have been shown to have teratogenic eVects in animal experiments. However, human folic acid reductase is much less sensitive to trimethoprim than the bacterial homologues [5]. The increased risk of kernicterus in newborns associated with sulfonamide therapy is also frequently addressed, since unfavourable eVects on bilirubin concentration in newborns due to sulfonamide treatment up to delivery cannot be completely ruled out. Despite the possibility, the risk of kernicterus should be considered low [1, 5]. Sulfasalazine, a combination of the sulfonamide sulfapyridine and 5-aminosalicylic acid, is often prescribed during pregnancy. It is a proven remedy for chronic inXammatory bowel diseases, such as morbus crohn and colitis ulcerosa [1]. 5-aminosalicylic acid (also known as mesalazine) is also used alone as an antiphlogistic. Toxoplasmosis [45, 46], nocardiosis and pneumocystis carinii pneumonia are other important indications for sulfonamide treatment during pregnancy. In summary, sulfonamide, trimethoprim and cotrimoxazole are second-line agents for the use throughout pregnancy [5]. When there is a relevant indication, for example, urinary tract infection, treatment with cotrimoxazol is supported, even during the Wrst trimester. For patients with acquired immunodeWciency syndrome (AIDS) who need to undergo high-dose antibiotic therapy for pneumocystis carinii pneumonia during the Wrst trimester, folic acid supplements should be incorporated into treatment, due to theoretical considerations [16]. If there is a risk of preterm delivery, sulfonamides should be avoided due to concerns about the bilirubin concentration of the newborn. Glycopeptides Glycopeptide antibiotics inhibit the synthesis of peptidoglycans involved in stabilizing the bacterial cell wall. Their spectrum of the activity includes all gram-positive pathogens, with problematic pathogens frequently being susceptible as well. The two currently available representatives of this class of antibiotic, vancomycin and teicoplanin, are used predominantly for infections with MRSA and enterococcal infections [5, 16, 21]. Glycopeptides should always be regarded as a reserve antibiotic and used accordingly during the pregnancy [5]. Limited data on the side eVect proWle (including nephrotoxicity and neurotoxicity) and teratogenic potential of glycopeptides supports the cautious use of these agents during pregnancy. Tetracyclines Tetracyclines inhibit protein synthesis through inhibition of the bacterial ribosome; hence, they are bacteriostatic. Tetracyclines are a broad-spectrum class of antibiotics [1, 16] used for the treatment of acne, pelvic infections, urinary tract infections, bronchitis and borreliosis [1, 21]. During the 1950s, tetracyclines were some of the more commonly used antibiotics. At the time, numerous publications reported a yellowing of the teeth of children who were exposed prenatally to tetracyclines, a side eVect that stands as the only proven pre-birth side eVect of this class of antibiotics in humans. Tetracyclines cross the placental barrier and can accumulate in developing long tubular bones and teeth [5, 6, 16, 21]. This can lead to tooth discoloration, ranging from yellow to dark brown. In addition, there have been reports of tooth enamel defects, increased susceptibility to dental caries, growth inhibition of the long tubular bones, particularly the Wbula after long-term treatment and premature birth, as well as cataracts due to the accumulation of the antibiotic in eye lenses [5, 6, 16]. There have also been several reports of additional maternal risks, such as fatty liver and nephropathies following tetracycline treatment during pregnancy [47, 48]. Several reports have documented severe and sometimes even fatal tetracyclineconditioned liver damage in the mother [33]. Owing to the reported risks associated with tetracycline treatment during pregnancy, this class of antibiotics must never be administered to pregnant women after the Wfth week of pregnancy [4, 5, 11]. That being said, termination of pregnancy due to treatment with tetracyclines is not 14 Arch Gynecol Obstet (2011) 283:7–18 123 supported, given that an increased risk of malformations of the child has not been deWnitively proven [5]. One case– controlled study reported an increased rate of malformations after administration of oxytetracycline during the second month of pregnancy [49]. These results, however, have yet to be veriWed in other settings by other investigators. Young women who are being treated with extended tetracycline therapy for acne are particularly at risk, and should use reliable contraception methods [5]. Chinolones (gyrase inhibitors) Chinolones (4-chinolones) are gyrase antagonists that act by inhibiting bacterial topoisomerase (gyrase), which is essential for nucleic acid metabolism. Human topoisomerase is not aVected by therapeutic gyrase inhibitors. To avoid the build-up of resistance, this group of agents should be used exclusively for enterobacterial infections, including infection by Pseudomonas that cannot be treated with classical antibiotics [16]. When administered to young experimental animals (beagle dogs), chinolones caused arthropathy, the pathogenesis of which remains unclear. Doses that substantially exceed the therapeutic range can result in abortion, retardation and reduced ossiWcation in experimental animal models [50]. No such teratogenic eVects are associated with typical therapeutic doses. In humans, irreversible joint cartilage defects have not been detected among prepartally exposed children [51]. A study from the European Network of Teratology Information Services examining data on over 700 exposed pregnant women did not identify any notable risk of malformation associated with chinolones [16, 52]. Similar results were obtained in two other studies that examined a smaller number of patients [53, 54]. The data notwithstanding, administration of gyrase inhibitors to pregnant women, children and young adolescents is deemed contraindicated as a precautionary measure [5, 11, 16]. In well-founded and life-threatening cases, where other common antibiotics are ineVective, it is advisable to use only norXoxacin or ciproXoxacin, which have been tested in a large number of pregnant patients [16]. The intake of gyrase antagonists does not justify either a riskbased pregnancy termination or invasive diagnostics [5]. Tuberculostatics Tuberculostatics are agents that are used selectively for the treatment of tuberculosis. This class of antibiotics includes isoniazid, pyrazinamide, ethambutol, rifampicin and streptomycin, with isoniazid and ethambutol being considered the safest for use during pregnancy [4, 5, 16, 55]. Rifampicin, a partially synthetic reserve antibiotic that is bactericidal and acts by inhibiting bacterial RNA synthesis, is contraindicated in patients with liver disease and those that are breast feeding. Indications for the use during pregnancy must be strictly deWned. Since treatment with these antibiotics stimulates liver activity, weakening of the eVects of a number of other drugs (including -blockers, cyclosporin, glucocorticoids and phenytoin) must be considered. Novel antibiotics—linezolid, daptomycin, tigecycline, doripenem Linezolid is eVective in vitro against multi-resistant grampositive bacteria (especially MRSA and glycopeptide-resistant enterococci). It is suitable for targeted therapy of infections caused by methicillin-resistant or glycopeptide-grampositive cocci and is also an alternative for the treatment of nocardiosis and listeriosis. As there are still insuYcient data regarding administration during pregnancy, this antibiotic is not recommended during pregnancy. Daptomycin is a cyclic lipopeptide, which is only eVective against gram-positive bacteria. In contrast to the glycopeptides, daptomycin is bactericidal and shows a synergism in vitro with aminoglycosides and rifampicin. As there are still insuYcient data regarding administration during pregnancy, this antibiotic is not recommended during pregnancy. Tigecycline is a derivative of minocycline, a tetracycline. It is eVective against gram-positive and gram-negative pathogens, even against those that are resistant to tetracycline. Tigecycline has bacteriostatic properties and shows no activity against Pseudomonas, Serratia, Proteus and Morganella. There are still insuYcient data regarding pregnancy. However, this antibiotic, like other tetracyclins, is contraindicated during pregnancy. Doripenem is a new carbapenem with greater stability against renal dehydropeptidasen. The spectrum of activity similar to that of imipenem and meropenem, and is eVective against Pseudomonas unlike other carbapenems. As there are still insuYcient data regarding administration during pregnancy, this antibiotic is not recommended during pregnancy. Practical points When there are compelling reasons for the prescription of antibiotics to a pregnant patient, the following considerations should be taken into consideration [2, 4, 5]: • No medication should be prescribed without a compelling indication (adequate risk/beneWt assessment). • During the selection of an antibiotic, it is important to choose the drug with the best proven tolerance. Arch Gynecol Obstet (2011) 283:7–18 15 123 Table 5 Overview of antibiotic and their approved usage during pregnancy and lactation period [2, 4, 5, 11–15] Pregnancy Lactation period Crossing placental barrier FDA ADEC German classiWcation DiVusion breast milk German classiWcation Amikacin + C/D D CI + CI Amoxicillin ++ B A AM + SI Amoxicillin/clavulanic acid ? B B1 AM + SI Ampicillin +++ B A AM + SI Ampicillin/sulbactam ? B - SI + SI Azithromycin + B B1 SI + SI Aztreonam + B B1 CI + CI Benzylpenicillin +++ B A AM + SI Cefaclor ? B B1 SI + SI Cefadroxil +++ B ¡ SI + SI Cefalexin +++ B ¡ SI + SI Cefazolin +++ B B1 SI + SI Cefepim ++ B ¡ SI + SI CeWxim +++ B ¡ SI + SI Cefotaxim + B B1 SI + SI Cefotiam ? ¡ ¡ SI + SI Cefoxitin +++ B B1 SI + SI Cefpodoxim–proxetil ? B B1 SI + SI Ceftazidim ++ B B1 SI + SI Ceftibuten ? B ¡ SI + SI Ceftriaxon + B B1 SI + SI Cefuroxime ? B ¡ SI + SI Cefuroximaxetil + B ¡ SI + SI Chloramphenicol +++ C A CI + CI CiproXoxacin +++ C B3 CI ? CI Clarithromycin ? C B3 SI + SI Clindamycin ++ B A CI + CI Cotrimoxazole +++ C C SI + SI Doxycycline ++ D D CI + CI Ertapenem ? B ¡ SI + CI Erythromycin ? B A SI + SI Ethambutol +++ B A SI + SI Flucloxacillin ++ B B1 AM + SI Fosfomycin ++ B ¡ SI + SI Gentamicin ++ C D CI + CI Imipenem/cilastatin +++ C B3 CI ? CI Isoniazid +++ B/C A SI ? SI Josamycin ? ¡ ¡ SI ++ SI LevoXoxacin +++ C B3 CI + CI Linezolid ? C ¡ CI SI Loracarbef + B ¡ SI + SI Meropenem ? B B2 SI + SI Metronidazole +++ B B2 CI/SI + CI/SI Mezlocillin +++ B B1 AM + SI Minocycline ? D D CI + CI 16 Arch Gynecol Obstet (2011) 283:7–18 123 • Groups of antibiotics that have been on the market for a long time and for which there are adequate empirical data should be given priority. • Priority should be given to antibiotics that are not associated with risks to the mother or foetus (i.e. those with no or minimal potential toxic side eVects) based on the latest scientiWc knowledge. • Treatment should be monitored and doses adjusted as needed. • Monotherapy is preferable to combination therapy. Table 5 continued + denotes minor crossing of the placental barrier/diVusion into breast milk ++ denotes moderate crossing of the placental barrier/diVusion into breast milk +++ denotes distinct crossing of the placental barrier/diVusion into breast milk ? denotes unknown FDA classiWcation [Food and Drug Administration (FDA); http://www.fda.gov]: A controlled human studies show no foetal risks; these drugs are the safest, B animal studies show no risk to the foetus and no controlled human studies have been conducted, or animal studies show a risk to the foetus but well-controlled human studies do not, C no adequate animal or human studies have been conducted, or adverse foetal eVects have been shown in animals but no human data are available, D evidence of human foetal risk exists, but beneWts may outweigh risks in certain situations (e.g., life-threatening disorders, serious disorders for which safer drugs cannot be used or are ineVective), X proven foetal risks outweigh any possible beneWt ADEC classiWcation (Australian Drug Evaluation Committee; http://www.tga.gov.au/docs/html/adec/adec.htm): Category A drugs which have been taken by a large number of pregnant women and women of childbearing age without any proven increase in the frequency of malformations or other direct or indirect harmful eVects on the foetus having been observed, Category B1 drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful eVects on the human foetus having been observed, Studies in animals have not shown evidence of an increased occurrence of foetal damage, Category B2 drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful eVects on the human foetus having been observed. Studies in animals are inadequate or may be lacking, but available data show no evidence of an increased occurrence of foetal damage, Category B3 drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful eVects on the human foetus having been observed. Studies in animals have shown evidence of an increased occurrence of foetal damage, the signiWcance of which is considered uncertain in humans, Category C drugs which, owing to their pharmacological eVects, have caused or may be suspected of causing, harmful eVects on the human foetus or neonate without causing malformations. These eVects may be reversible. Accompanying texts should be consulted for further details, Category D drugs which have caused and are suspected to have caused or may be expected to cause, an increased incidence of human foetal malformations or irreversible damage. These drugs may also have adverse pharmacological eVects. Accompanying texts should be consulted for further details, Category X drugs which have such a high risk of causing permanent damage to the foetus that they should not be used in pregnancy or when there is a possibility of pregnancy German classiWcation (,,Rote Liste”;http://www.rote-liste.de): SI strict indication, CI contraindication, AM approved medication Pregnancy Lactation period Crossing placental barrier FDA ADEC German classiWcation DiVusion breast milk German classiWcation MoxiXoxacin ? C ¡ CI + CI Netilmicin + C/D D CI ? CI NorXoxacin ? C B3 CI ? CI OXoxacin ? C B3 CI ? Oxacillin + B B3 AM + SI Phenoxymethylpenicillin ? B A AM + SI Piperacillin + B B1 AM + SI Piperacillin/tazobactam ? B B1 SI ? SI Pyrazinamide ? C B2 SI + SI Quinupristin/dalfopristin ? B ¡ SI ? CI Rifabutin ? C C SI ? SI Rifampicin ++ B/C C CI + SI Roxithromycin ? B B1 SI + SI Teicoplanin ? C B3 CI ? CI Telithromycin ? ¡ ¡ CI ? CI Tobramycin +++ C/D D CI + CI Trimethoprim +++ C B3 CI + CI Vancomycin +++ C B2 SI + SI Arch Gynecol Obstet (2011) 283:7–18 17 123 • Whenever possible, oral therapy should be given priority over infusion therapy. • Placental permeability and elimination of the antibiotic should be taken into consideration (Table 5). According to our current state of knowledge, the vast majority of antibiotics do not cause serious harm to the unborn child if used and dosed properly. Even in cases in which a contraindicated antibiotic has been administered, the risks do not justify termination of the pregnancy. That being said, no medicine, including antibiotics, can be described as absolutely safe during pregnancy [4, 5, 16]. Acknowledgments The author would like to thank Prof. Dr. E.-R. Weissenbacher and Prof. Dr. K. Friese for their helpful discussion regarding antibiotic treatment during pregnancy and lactation period. 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