Yes (2) Ampicillin 13.32.IV.

Yes (1) Azlocillin 7.3040 IV.

Yes (1) Azlocillin 20.3240 IV.

No Cefazolin 6.1027 PO.

Yes (2) Cefuroxime 7.1135 PO.

Yes (2) Cephradine 12.1027 PO.

Yes (2) Piperacillin 5.3040 IV.

No Source: Little BB. Obstet Gynecol 1999; 93: 858.

EGA, estimated gestational age; AUC, area under the curve; V , volume of distribution; C , peak plasma concentration; C , steady-state concentration; t , half-life; Cl, d max SS.

1/2.

clearance; PPB, plasma protein binding; PO, by mouth; denotes a decrease during pregnancy compared with nonpregnant values; denotes an increase during pregnancy compared with nonpregnant values; = denotes no difference between pregnant and nonpregnant values; IV = intravenous; IM = intramuscular.

aControl groups: 1, nonpregnant women; 2, same individuals studied postpartum; 3, historic adult controls (s.e.x not given); 4, adult male controls; 5, adult male and female controls combined.

Antibiotics 25.Table 2.2 Mean antibiotic concentration ratios for various penicillins Antibiotic cord blood to maternal blood ratio Mean antibiotic concentration ratios for various penicillins Antibiotic cord blood to maternal blood ratio Ampicillin 0.71.

Ampicillin plus sulbactam 1.00.Mezlocillin 0.40.

Ticarcillin plus clavulanic acid 0.80.

From Gilstrap et al., 1988a; Maberry et al., 1990.

levels in the fetus (Gilstrap et al et al., 1988a; Landers et al et al., 1983; Maberry et al et al., 1990).

The ratios of cord blood to maternal blood concentration of several penicillins are shown in Table 2.2.

Although all penicillins (Box 2.1) would appear to cross the placenta readily, there is no evidence to date that they are teratogenic, and they have been used in pregnant women for many years without apparent adverse fetal effects.

Although they are not teratogenic, the penicillins may cause significant adverse effects in the mother, including hypersensitivity reactions, serum sickness, hematologic toxicity, renal toxicity, hypokalemia, gastrointestinal toxicity, and central nervous system toxicity (Box 2.2).

Box 2.1 The penicillins Natural penicillins Bucampicillin Penicillin G Extended-spectrum penicillins Penicillin V Azlocillin Antistaphylococcal penicillins Carbenicillin Cloxacillin Mezlocillin Dicloxacillin Piperacillin Methicillin Ticarcillin Nafcillin Penicillins with beta-lactamase inhibitors Oxacillin Amoxicillin plus clavulanic acid (Augmentin) Derivatives of 6-aminopenicillanic acid Ampicillin plus sulbactam (Unasyn) Amoxicillin Piperacillin plus tazobactam (Zosyn) Ampicillin Ticarcillin plus clavulanic acid (Timentin) Adapted from Faro, 1989; PDR, 2004.

Box 2.2 Potential adverse fetal and maternal effects of penicillin Fetal effects Fetal effects Hematologic toxicity None known, but fetal hypersensitivity is a Renal toxicity theoretical risk Central nervous system toxicity Gastrointestinal toxicity Maternal effects Hypersensitivity reactions From Faro, 1989.

26.Antimicrobials during pregnancy Macrolide antibiotics The macrolide antibiotics as a group are effective against a variety of aerobic organisms and have poor activity against most Gram-negative organisms. The major antibiotics in this group are erythromycin, azithromycin, and clarithromycin.

Erythromycin Erythromycin is a bacteriostatic agent which interferes with bacterial protein synthesis.

Unlike most antibiotics, erythromycin crosses the placenta poorly, achieving very low levels in the fetus. This latter fact is exemplified by the observation that erythromycin provides inadequate treatment for the fetus when given to the mother for the treatment of syphilis, as is discussed in detail later in this chapter. The major preparations are listed in Box 2.3.

Box 2.3 The erythromycins Erythromycin Erythromycin gluceptate Erythromycin estolate Erythromycin lactobionate Erythromycin ethylsuccinate Erythromycin stearate From PDR, 2004 (trade names too numerous to list).

There are no reports linking erythromycin and congenital anomalies or adverse fetal effects. Likewise, there have been few maternal adverse effects (Box 2.4) reported with the use of this antibiotic during pregnancy, with the exception of gastrointestinal upsets (which may be worse in pregnancy), hypersensitivity reactions, and hepat.i.tis (Hautekeete, 1995).

Box 2.4 Potential adverse fetal and maternal effects of erythromycin erythromycin Fetal effects None known Maternal effects Gastrointestinal intolerance Hepat.i.tis Hypersensitivity reactions Hautekeete, 1995.

Azithromycin Azithromycin (Zithromax) belongs to the azalide cla.s.s of antibiotics and is similar to the macrolide erythromycin. It is effective against many of the same organisms as erythromycin and especially useful against Neisseria gonorrhoeae Neisseria gonorrhoeae and and Chlamydia trachomatis Chlamydia trachomatis.

Antibiotics 27.It is well absorbed orally and has the advantage of single-dose therapy for chlamydial infections. Although there are no large epidemiological studies in pregnant women, it is listed as a category B drug by its manufacturer. This antibiotic has been utilized as single-dose therapy for chlamydial infections during pregnancy (Allaire et al et al., 1995; Bush and Rosa, 1994; Rosenn et al et al., 1995, Turrentine et al et al., 1995).

Clarithromycin Clarithromycin (Biaxin) belongs to the macrolide group of antibiotics. Although it is effective against a wide variety of aerobic organisms, it is most commonly used for treatment or prophylaxis against Mycobacterium avium Mycobacterium avium complex (MAC) in patients who are human immunodeficiency virus (HIV)-positive. It also has good activity against complex (MAC) in patients who are human immunodeficiency virus (HIV)-positive. It also has good activity against Ureaplasma urealytic.u.m Ureaplasma urealytic.u.m (Reisner, 1996). There are no large randomized studies of clarithromycin in pregnant women, and it is listed as a category C drug by its manufacturer. (Reisner, 1996). There are no large randomized studies of clarithromycin in pregnant women, and it is listed as a category C drug by its manufacturer.

Cephalosporins As a group, the cephalosporins are probably the most commonly used antibiotics in obstetrics and gynecology. They are very similar in structure to the penicillins, both containing a four-member beta-lactam ring. They are also bactericidal and inhibit cell wall synthesis. Cephalosporins are generally cla.s.sified into first, second, and third generation (Box 2.5).

All of the cephalosporins cross the placenta (Bawdon et al et al., 1982; Dinsmoor and Gibbs, 1988; Giamarellou et al et al., 1983; Gilstrap et al et al., 1988b; Kafetzis et al et al., 1983; Maberry et al et al., 1990; Martens 1989), although their half-lives ( t t ) may be shorter and 1/2 ) may be shorter and 1/2 their serum levels lower than in nonpregnant women (Landers et al et al., 1983). The ratio of cord blood to maternal blood for cefoxitin in one study was 0.35 and for cefotaxime was 1.0 (Gilstrap et al et al., 1988a; Maberry et al et al., 1990). Cephalosporins as a group are Box 2.5 The cephalosporins Box 2.5 The cephalosporins First generation Third generation Cephalothin Cefotaxime Cephaprin Ceftizoxime Cephradine Cefoperazone Cefazolin Ceftriaxone Moxalactam Second generation Cefmenoxime Cefamandole Cefmetazole Cefoxitin Cefuroxime Cefotetan Cefixime Cefuroxime Ceftazidime Cefonicid Cefpodoxime proxetil Cefaclor Cefprozil Adapted from Martens, 1989; PDR, 2004.

28.Antimicrobials during pregnancy apparently not teratogenic in humans, although few scientific studies have been done with these antibiotics during pregnancy. However, animal studies with cephalosporins containing the N N-methylthiotetrazole (MTT) side chain have revealed potential adverse fetal effects (Martens, 1989). When given to rats at doses 1.5 to 8 times the human dose, these types of cephalosporins resulted in testicular toxicity manifested by the failure of seminiferous tubule and spermatozoa development. The consequences of this finding for the human fetus is unknown at this time. Since the majority of second- and third-generation cephalosporins contain the MTT side chain, they should be used with caution during pregnancy. Cefoxitin, a second-generation cephalosporin, does not contain this side chain and at least theoretically would appear to be a better choice when a broad-spectrum cephalosporin is indicated during pregnancy (Martens, 1989).

Cephalosporins may also cause adverse effects in the mother, such as hypersensitivity reactions, hematologic toxicity, renal toxicity, hepatic toxicity, diarrhea, and pseudomembranous colitis (Box 2.6). In addition, clinically significant bleeding dyscrasias may occur secondary to the MTT side chain, which in turn may cause hypothrombinemia (Agnelli et al et al., 1986; Martens, 1989). This complication has been reported to be more common with moxalactam and very uncommon with other MTT-containing cephalosporins, such as cefamandole, cefoperazone and cefotetan (Martens, 1989).

Box 2.6 Potential fetal and maternal adverse effects with cephalosporins cephalosporins Fetal effects Gastrointestinal Testicular toxicitya Hematologic Hepatic Maternal effects Hypersensitivity reactions Bleeding dyscrasiaa Renal aAnimal studies only; has not been reported in humans.

Tetracyclines The tetracyclines (Box 2.7) inhibit protein synthesis and are bacteriostatic. They cross the placenta readily and, when utilized in the latter half of pregnancy, may cause yellow-brown discoloration of the deciduous teeth (Kline et al et al., 1964; Kutscher et al et al., 1986; Rendle-Short, 1962). Tetracyclines may also be deposited in the long bones of the developing fetus, although there is no scientific evidence that they inhibit fetal or neonatal growth.

The tetracyclines may also cause adverse maternal effects (Box 2.8). Whalley and colleagues (1964) reported an a.s.sociation between tetracycline use during pregnancy and liver toxicity manifested by azotemia, jaundice and acute fatty degeneration. Pancreat.i.tis has also been reported to occur in these patients. As with erythromycin, tetracycline may cause significant gastrointestinal disturbances manifested by severe nausea and vomiting.

Antibiotics 29.Box 2.7 The tetracyclines Demeclocycline (Declomycin) Doxycycline (Vibramycin, Vira-Tabs, Doryx, Doxy Caps or Tabs, Mondox) Minocycline (Minocin, Dynacin) Oxytetracycline (Terramycin, Urobiotic, Bio-Tabs) Tetracycline (Achromycin) From PDR, 2004.

Box 2.8 Potential adverse fetal and maternal effects of the tetracyclines tetracyclines Fetal effects Gastrointestinal intolerance Yellow-brown discoloration of the deciduous Hypersensitivity teetha Pancreat.i.tis Photosensitivity Maternal effects Vestibular disturbancesb Fatty degeneration of the liver aWhen given in the latter half of pregnancy.

bMinocycline only.

Because of potential adverse fetal effects, the tetracyclines are rarely indicated during pregnancy, except for penicillin-allergic patients who need treatment for syphilis and for whom desensitization is not available.

Aminoglycosides The aminoglycosides interfere with protein synthesis but, unlike erythromycin and tetracycline, they are bactericidal. The various antibiotics in the cla.s.s are listed in Box 2.9.

All of the aminoglycosides cross the placenta. Yoshioka and a.s.sociates (1972), as well as Weinstein and coworkers (1976) reported cord levels of gentamicin of 33 and 42 percent, respectively, of maternal levels. Gilstrap and colleagues (1988a) reported a mean concentration ratio between cord blood and maternal blood for gentamicin of 0.62. It is important to note that serum levels of various aminoglycosides may be subtherapeu-tic in the fetus and mother.

Streptomycin was one of the first members of this group and for many years was the primary drug for the treatment of tuberculosis. It has been reported to result in eighth-nerve damage of the fetus with protracted maternal therapy (Conway and Birt, 1965; Donald and Sellars, 1981). However, the risk of ototoxicity with streptomycin or any of Box 2.9 The aminoglycosides Box 2.9 The aminoglycosides Amikacin (Amikin) Netilmicin (Netromycin) Gentamicin (Garamycin) Streptomycin (Streptomycin) Neomycin Tobramycin (Nebcin) 30.Antimicrobials during pregnancy Box 2.10 Potential adverse fetal and maternal effects of aminoglycosides aminoglycosides Fetal effects Maternal effects Eighth cranial nerve damagea Neuromuscular blockage Ototoxicity Renal toxicity aUncommon and not reported for all aminoglycosides.

the other aminoglycosides is extremely low when these agents are used in therapeutic doses over a short period of time. Excluding possible eighth cranial nerve damage, there is no scientific evidence to date that the aminoglycosides as a group are teratogenic.

Aminoglycosides may cause significant adverse effects in the mother, such as neuromuscular blockade, renal toxicity and ototoxicity (Box 2.10). Again, it should be noted that it may be very difficult to maintain therapeutic levels of aminoglycosides in the mother (or fetus) with usual or standard doses.

Clindamycin Clindamycin is a derivative of lincomycin, and interferes with protein synthesis. It is a bacteriostatic antibiotic and is used primarily for serious anaerobic infections. Thus, it is used infrequently during pregnancy. Clindamycin crosses the placenta readily, with detectable levels in the fetus (Gilstrap et al et al., 1988a; Weinstein et al et al., 1976). In one study, the mean concentration ratios of clindamycin for cord blood versus maternal blood was 0.15 (Gilstrap et al et al., 1988a). In other reports, the serum levels of this antibiotic approached 50 percent of maternal serum levels (Philipson et al et al., 1973; Weinstein et al et al., 1976).

Although clindamycin crosses the placenta readily, it causes no known adverse fetal effects. There are no adequate studies in humans, but clindamycin was not shown to be teratogenic in laboratory animals (Gray et al et al., 1972). However, clindamycin may be a.s.sociated with adverse maternal effects, the most serious of which is pseudomembranous colitis (Box 2.11). This latter complication is a.s.sociated with a toxin produced by Clostridium difficile Clostridium difficile (George (George et al et al., 1980).

Lincomycin Lincomycin is rarely used today in obstetrics and has been mostly replaced by clindamycin, at least in obstetrics and gynecology. However, it has been used in the past on large numbers of pregnant women without apparent adverse fetal effects (Mickal and Panzer, 1975).

Metronidazole Metronidazole is a nitroimidazole that was first introduced as an antiparasitic and utilized primarily for the treatment of trich.o.m.oniasis. Subsequently, it was shown to be Antibiotics Antibiotics 31.Box 2.11 Potential adverse fetal and maternal effects of aminoglycosides aminoglycosides Clindamycin (Cleocin) Hypersensitivity reaction Gastrointestinal intolerance Leukopenia Diarrhea Chloramphenicol (Chloromycetin) Pseudomembranous colitis Aplastic anemia Metronidazole (Flagyl) Hypersensitivity reaction Antabuse-like effects (disulfiram-like) Blood dyscrasias Peripheral neuropathy Neurotoxicity Gastrointestinal intolerance From PDR, 2004.

very useful for the treatment of serious anaerobic infections. Its usage in pregnancy has been limited primarily to the treatment of trich.o.m.onal vaginitis. Metronidazole interferes with nucleic acid synthesis and causes cell death. It is a relatively small molecule and crosses the placenta readily, with levels in cord blood reaching significant concentrations (Heisterberg, 1984). Although this drug crosses the placenta readily, there is no evidence that it is teratogenic in humans. In one study reported by Rosa and colleagues (1987a) of over 1000 women with first-trimester exposure to this drug, the frequency of fetal anomalies was not increased. In addition, the frequency of congenital anomalies has been shown not to be increased in animal reproduction studies in which metronidazole was given in doses five times the human dose (Hammill, 1989).

However, metronidazole has been reported to be carcinogenic in mice and rats (Hammill, 1989) and to be mutagenic in certain bacteria. To date, metronidazole has not been shown to be carcinogenic in humans. Because of the tumorigenic effects in animals, however, metronidazole is not recommended for use in the first trimester.

Unfortunately, this nitroimidazole provides the only effective treatment for trich.o.m.oniasis. Most pregnant women with this infection can be treated with betadine solution or other similar agents until they are past the first trimester, and then started on metronidazole as necessary. In a recent meta-a.n.a.lysis on the use of metronidazole in pregnant women, no increase in malformations was found (Burtin et al et al., 1995).

Metronidazole does concentrate in the breast milk and results in concentrations close to those found in maternal serum (Simms-Cendan, 1996). Potential adverse maternal effects of metronidazole are summarized in Box 2.11, and include central nervous system manifestation, peripheral neuropathy, gastrointestinal intolerance (nausea, vomiting), and a disulfiram-like reaction (Hammill, 1989) a.s.sociated with alcohol use (nausea, abdominal cramps, and headaches). It may also be a.s.sociated with a metallic after-taste.

Chloramphenicol Chloramphenicol interferes with protein synthesis and is bacteriostatic. It is rarely used today and generally is not recommended for use in pregnant women, although there is 32 32 Antimicrobials during pregnancy little or no scientific evidence to suggest that it is teratogenic. In a review from the Collaborative Perinatal Project of approximately 100 infants exposed to chloramphenicol in the first trimester, there was no evidence of an increased frequency of congenital malformations (Heinonen et al et al., 1977). It has been a.s.sociated with the 'gray baby syndrome' (cyanosis, vascular collapse, and death) in the premature neonate given large doses of this drug. Although chloramphenicol does cross the placenta readily (Scott and Warner, 1950), transplacental pa.s.sage of the drug rarely, if ever, causes gray baby syndrome in the fetus or newborn (Landers et al et al., 1983). The most significant potential adverse maternal effect is aplastic anemia, which has been reported in approximately one of 100 000 cases. Other potential maternal side effects are summarized in Box 2.11.

Sulfonamides The sulfonamides inhibit folate synthesis and are a.n.a.logs of para-amin.o.benzoic acid, which is necessary for production of folic acid by bacteria (Landers et al et al., 1983). As a group, they are bacteriostatic. The most common sulfonamides are listed in Box 2.12.

Box 2.12 Sulfonamides, trimethoprim, and nitrofurantoin Sulfonamides Sulfonamides Trimethoprim Sulfisoxazole (Gantrisin) Trimethoprim (Proloprim, Trimpex) Sulfamethoxazole (Gantanol) Trimethoprim plus sulfamethoxazole (Bactrim, Sulfacytine (Renoquid) Septra, plus many others) Sulfamethizole (Thiosulfil) Nitrofurantoin Nitrofurantoin macrocrystals (Macrodantin) The sulfonamides cross the placenta readily and reach significant levels in the fetus, although the levels may be lower in the fetus than in the mother (Reid et al et al., 1975).

There are no scientific reports of an a.s.sociation between congenital malformations and the use of sulfonamides during pregnancy. Although the sulfonamides are not teratogenic, they do compete for bilirubin binding sites and, if used near delivery, may cause hyperbilirubinemia, especially in the premature infant (Landers et al et al., 1983). Maternal side effects include hypersensitivity, photosensitivity, blood dyscrasias, and gastrointestinal intolerance.

Trimethoprim Although trimethoprim crosses the placenta, it has not been shown to cause adverse fetal effects. In one report of over 100 women treated with a combination of trimethoprim and sulfamethoxazole, there was no increase in the frequency of fetal anomalies (Williams et al et al., 1969). In another study of 186 pregnant women receiving either a placebo (66 patients) or trimethoprim plus sulfamethoxazole (120 patients), the incidence of fetal malformations was actually lower in the group receiving the antibiotics (3.3 versus 4.5 percent) (Brumfitt and Pursell, 1973). However, because trimethoprim is a folate antagonist (at least in bacteria!), it is generally not recommended for use in Antibiotics Antibiotics 33.pregnancy. Like sulfonamides, trimethoprim is a.s.sociated with few adverse maternal effects (skin rash, gastrointestinal intolerance, and possible hematologic abnormalities).

Nitrofurantoin Nitrofurantoin macrocrystals, commonly used for urinary tract infections during pregnancy, have not been reported to be a.s.sociated with adverse fetal effects. In a randomized prospective study of 100 women treated with nitrofurantoin versus 100 controls, there were no significant differences in birth weight, head circ.u.mference, or body length of the offspring (Lenke et al et al., 1983). The incidence of congenital malformations was not reported. Nitrofurantoin has been reported to cause hemolytic anemia in women with glucose-6-phosphate dehydrogenase deficiency (Powell et al et al., 1963), and because this drug crosses the placenta, this side effect could theoretically also occur in the fetus with this enzyme deficiency. However, in the authors' experience of approximately 1000 pregnant women receiving this medication for urinary tract infections, hemolytic anemia has not occurred in either the mother or the fetus. A pneumonitis has also been reported with this antibiotic. However, this is rare.

Vancomycin Vancomycin is an antibiotic which does not belong to any other cla.s.s of antimicrobial agents. It is both bactericidal and bacteriostatic, and is effective against a wide variety of Gram-positive organisms, including the Enterococci Enterococci (Hermans and Wilhelm, 1987). (Hermans and Wilhelm, 1987).

It is the drug of choice for Clostridium-difficile Clostridium-difficile-a.s.sociated pseudomembranous colitis. It is also used in penicillin-allergic pregnant women for bacterial endocarditis prophylaxis.

There is no available scientific information linking this agent with adverse pregnancy outcomes, including congenital malformations. However, vancomycin may be a.s.sociated with significant maternal side effects, such as nephrotoxicity and ototoxicity.