Clinical pharmacology of anti-infectives during pregnancy

12.1

Antibacterial therapy

Penicillins are the antibiotics of choice during pregnancy. They cross the placenta and small amounts are excreted in breast milk. Penicillin G and V are 45%–68% and 75%–89% bound to plasma proteins, respectively, are partially metabolized (<30%) to inactive metabolites, and parent drug and metabolites are excreted in the urine via filtration and tubular secretion. One pharmacokinetic study of a dose of one million international units (IU) of penicillin G intravenously (IV) every 4 h in pregnant women concluded that this produced adequate maternal penicillin concentrations for prophylaxis against Group B Streptococcus [ ]. Current guidelines recommend an initial dose of 5 million IU, followed by 2.5–3 million IU every 4 h [ ]. Another study of a single 2.4 million IU intramuscular dose of penicillin G for prevention of congenital syphilis showed high variability and some subtherapeutic concentrations; authors suggested that higher doses may need to be studied [ ]. Current syphilis treatment guidelines in pregnancy recommend use of penicillins, but state optimal doses are unknown [ ]. A study of a single oral dose of penicillin V in both pregnant and nonpregnant (control) women demonstrated significantly decreased area under the concentration time curve (AUC—a measure of overall exposure), shorter half-life, and increased penicillin clearance in pregnant women. The authors concluded shorter dose intervals (1 million IU every 6 h instead of every 8 h) or higher doses of penicillin V may be needed during pregnancy [ ]. Studies of higher than standard doses have not been described. In pregnant women with a penicillin allergy history, desensitization protocols have been safely applied [ ].

Amoxicillin , ampicillin , dicloxacillin , and ticarcillin are all mainly eliminated via renal filtration and tubular secretion, with about 10% metabolized. Oxacillin is about half metabolized and half eliminated unchanged in the urine. Piperacillin is 10%–20% excreted via bile into the feces, with the rest eliminated unchanged in the urine. Nafcillin , unlike all the other penicillins, is 60% metabolized, undergoes enterohepatic recirculation, and both parent and metabolites are excreted in the bile. Plasma protein binding is about 20% for amoxicillin, ampicillin, and piperacillin, is about 50% for ticarcillin, and is 70%–99% for nafcillin, oxacillin, and dicloxacillin. One study of a single oral 500 mg dose of amoxicillin in pregnant women for postexposure prophylaxis against anthrax showed increased clearance during pregnancy compared to postpartum, and concluded that anthrax preventative concentrations will not be feasible in pregnant women [ ]. Studies of IV amoxicillin have recommended a dose during labor or during preterm premature rupture of membranes of 2 g followed by 1 g every 4 h [ ]. Two older reported studies of ampicillin pharmacokinetics following 500 mg doses during pregnancy found decreased exposure and suggested increased loading doses (because of the large increase in distribution volume) were likely needed [ , ]. Finally, two studies of piperacillin–tazobactam in pregnant women found increased clearance and distribution volume during pregnancy, and suggested that higher than standard doses may be needed during pregnancy [ , ].

Cephalosporins can be safely used to treat various infections during pregnancy, and older agents are preferred due to more data and experience in pregnancy. Specific doses depend on the infection site and offending microbe. They are classified by antibacterial activity. Examples of first-generation agents are: cefadroxil , cephalexin , cephradine , and cefazolin ; second-generation agents: cefoxitin , cefotetan , cefaclor , cefprozil , cefuroxime , cefuroxime axetil ; and third/fourth/fifth-generation agents: cefotaxime , ceftazidime , ceftriaxone , ceftizoxime , cefixime , cefditoren , cefdinir , cefpodoxime , ceftibuten , cefepime , and ceftaroline . As a class, they all cross the placenta well [ ], and small amounts are found in breast milk. Many are 60%–90% protein bound in plasma, except for cefaclor, cephalexin, cefadroxil, cefpodoxime, cefotaxime, ceftizoxime, ceftazidime, and cefuroxime, which are less than 50% protein bound.

For first-generation agents, one study of cephalothin in pregnant women concluded that pregnancy alterations in exposure were insignificant and no dose changes were warranted [ ]. Cephalothin is 10%–40% metabolized, with the rest excreted unchanged in urine, while the other first-generation agents are not metabolized and are wholly excreted unchanged in urine. In contrast, studies of cephradine and cefazolin in pregnant women showed increased clearance and distribution volumes, decreased AUCs and shorter half-lives, concluding that doses in pregnancy should be increased, possibly by reducing dose intervals rather than by increasing dose amounts [ , ].

Cefuroxime, a second-generation cephalosporin, has lower plasma concentrations and a shorter half-life during pregnancy compared to postpartum [ ]. For cefoxitin, at 19–21 weeks gestation, plasma concentrations were similar to those seen in nonpregnant adults [ ], while at term, clearance of cefoxitin is significantly increased [ ]. The second-generation agents are primarily excreted unchanged in the urine.

Several later generation cephalosporins have been studied in pregnant women. Cefoperazone at term showed a larger distribution volume, lower peak concentration, and decreased protein binding (74% vs. 88%) during pregnancy compared to nonpregnant adults, but also showed that pregnancy did not greatly affect clearance, half-life, or trough concentrations (C _trough ) [ ]. Of note, unlike most other cephalosporins, cefoperazone is metabolized in the liver and excreted in the bile. Ceftazidime clearance increases and concentrations decrease throughout pregnancy compared to postpartum; clearance is primarily renal excretion of unchanged drug [ , ]. Ceftazidime readily crosses the placenta [ ]. Cefotaxime is metabolized to an active metabolite, and both parent drug and metabolite are eliminated in urine. All other cephalosporins are not appreciably metabolized, and are primarily excreted unchanged in the urine. While increased dose amounts and more frequent dosing have been proposed to attain adequate drug concentrations for many cephalosporins, pharmacokinetic studies of such increased doses are lacking.

Carbapenems imipenem-cilastatin and meropenem cross the placenta, have low protein binding, and are excreted mainly unchanged in the urine. Little is known about breast milk penetration. A case report of a breast-feeding mother receiving meropenem for treatment of a postpartum urinary tract infection calculated an infant daily exposure from breast milk of 97 μg/kg/d corresponding to an infant weight-adjusted percentage of maternal dosage of 0.18% [ ]. Clearance and distribution volume of imipenem after a single 500 mg IV dose were significantly increased in early and late pregnancy compared to postpartum, and increased doses may be needed in pregnancy [ ]. No pharmacokinetic studies of meropenem, doripenem, and ertapenem in pregnancy are reported. Carbacephems aztreonam and loracarbef pharmacokinetics have not been studied in pregnancy either. Loracarbef is 25% protein bound, is not metabolized, and is excreted unchanged in the urine. Placental and breast milk penetration are unknown. Aztreonam is about 60% protein bound and is mainly eliminated unchanged in the urine, with 6%–16% metabolized. It crosses the placenta well [ ], and breast milk penetration is unknown. Beta-lactamase inhibitors, given in combination with penicillins or cephalosporins, include sulbactam , tazobactam , and clavulanic acid . All are about 30% protein bound. Sulbactam and tazobactam cross the placenta and undergo some metabolism while most drug is excreted unchanged in urine. Both have significantly decreased exposure during pregnancy [ , ]. For clavulanic acid, half is metabolized, half is excreted in urine, and low amounts cross the placenta [ ].

Macrolides, such as erythromycin, azithromycin , and clarithromycin , are used to treat various infections in pregnant women. Placental concentrations are less than 7% of maternal concentrations [ , ]. Erythromycin breast milk concentrations are about 50% of maternal concentrations, and it is compatible with breastfeeding. It is 73%–81% protein bound, is a substrate and inhibitor of both cytochrome P450 (CYP) 3A4 and permeability glycoprotein (Pgp), concentrates in bile and liver, and is excreted in the bile. Clarithromycin is also a substrate and inhibitor of CYP 3A4 and Pgp, while azithromycin is not metabolized and has no effect on CYP enzymes. Limited information is available on penetration of azithromycin and clarithromycin into breast milk, and both have low protein binding. A study on transfer of azithromycin into breast milk estimated an absolute infant dose of 4.5 mg/kg of body weight (95% prediction interval: 0.6–7.0 mg/kg) and a relative cumulative infant dose of 15.7% of the maternal dose (95% prediction interval: 2.0%–27.8%) [ ]. One pharmacokinetic study of azithromycin found increased distribution volume but unchanged AUC and elimination half-life in pregnancy versus nonpregnant women, suggesting standard doses should be appropriate in pregnancy [ ]. No data are available on the clinical pharmacology of fidaxomicin in pregnant women.

Vancomycin is used for gram-positive bacterial infections. It is administered intravenously to treat systemic infections, widely distributed, 55% protein bound, and excreted renally. It crosses the placenta at concentrations similar to maternal concentrations [ ]. It is excreted in breast milk; infants would likely not absorb vancomycin, but their gut flora may be altered. Data in pregnancy are limited, so use should be reserved for serious infections. Other polypeptides, colistin , polymyxin B , and teicoplanin , have even less data regarding use in pregnancy, and should only be used for compelling indications.

Chloramphenicol is well absorbed and widely distributed, is 60% bound to plasma proteins, with higher placental than maternal concentrations [ ]. It is hepatically glucuronidated, and is a potent CYP 3A4 and 2C19 inhibitor. Due to neonatal toxicity, “gray baby syndrome” and agranulocytosis, use during pregnancy, especially near term, should be avoided unless absolutely necessary.

Tetracyclines, including tetracycline , demeclocycline , doxycycline , minocycline , omadacycline , eravacycline , and sarecycline , are generally not recommended in pregnancy due to strong binding to developing teeth and bones. Tetracycline and doxycycline are enterohepatically recirculated and eliminated mainly in feces (doxycycline) or urine (tetracycline). Minocycline is partially hepatically metabolized. These agents chelate cations, cross the placenta, and penetrate into breast milk, but are considered compatible with breastfeeding. No pharmacokinetic studies in pregnancy have been reported.

Lincomycin and clindamycin are hepatically metabolized, cross the placenta with 25%–50% of maternal concentrations found in cord blood, and cross into breast milk but are considered compatible with breastfeeding. Clindamycin, given at 900 mg every 8 h for Group B Streptococcus , was evaluated in pregnant women. The authors found that this standard dose may be subtherapeutic [ ]. Higher doses have not been studied in this population. These drugs should be avoided during pregnancy unless other first-line agents are ineffective or not tolerated.

Linezolid and tedizolid are oxazolidinone antibiotics used to treat gram-positive infections. Linezolid is widely distributed, metabolized by both enzymatic (presumably CYP-mediated) and nonenzymatic processes, and about 30% is eliminated unchanged in the urine. Data in pregnancy are very limited. A case report of a pregnant patient with multidrug-resistant TB showed lower linezolid exposure during pregnancy relative to postpartum [ ]. Placental and breast milk penetration in humans are unknown. No pharmacokinetic data in pregnancy are available for tedizolid . Dalfopristin-quinupristin is also used for gram-positive infections. Both agents are metabolized to several active metabolites by non-CYP processes, but these agents potently inhibit CYP 3A4. The parent compounds and metabolites are mainly eliminated in the feces, with 15%–20% of each parent drug eliminated unchanged in the urine. Placental and breast milk transfer are unknown, and no pharmacokinetic studies in pregnancy are available.

Aminoglycosides , including streptomycin , neomycin , kanamycin , amikacin , gentamicin , tobramycin , and plazomicin , are administered intravenously and eliminated unchanged in the urine. They cross the placenta, and may accumulate in the fetus [ , ]. Gentamicin clearance and dose requirements are increased during pregnancy, which corresponded more with increased distribution volumes than increased renal function [ ]. If used, plasma concentration monitoring is necessary to individualize doses. These agents should be avoided in pregnancy unless needed for life-threatening infections because of fetal oto- and nephrotoxicity risks.

Sulfonamides, including sulfisoxazole , sulfadiazine , sulfamethoxazole , sulfasalazine , and sulfadoxine (see malaria section), are generally used in combination with other antibiotics for various infections, and may be used in pregnancy if penicillins and cephalosporins are not effective. Near term, these drugs should be avoided due to increased risk of hyperbilirubinemia in the neonate; likewise, they are contraindicated in nursing. They readily cross the placenta [ , ] and mostly also penetrate into breast milk. Sulfonamides are hepatically acetylated and are substrates and inhibitors of CYP 2C9.

Trimethoprim is used alone or in combination with sulfamethoxazole for various infections. It is extensively distributed, it inhibits CYP 2C8, and is mostly eliminated unchanged in the urine. It is slowly transported in low concentrations across the placenta [ ], but breast milk concentrations are higher than maternal plasma concentrations and caution should be exercised in lactating women. Trimethoprim is a second-line agent that can be used in pregnancy if first-line agents are ineffective. Folic acid supplementation (0.5 mg daily) should be used along with trimethoprim in the first trimester.

Fluoroquinolones include ciprofloxacin , gatifloxacin , levofloxacin , lomefloxacin , moxifloxacin , norfloxacin , ofloxacin , sparfloxacin , delafloxacin , gemifloxacin , cinoxacin , and nalidixic acid. Absorption of fluoroquinolones is decreased with concomitant cation administration, including calcium, magnesium, iron, and zinc. Lomefloxacin, levofloxacin, norfloxacin, and ofloxacin are mainly excreted unchanged in the urine. Sparfloxacin is metabolized by CYP 1A2. Grepafloxacin is glucuronidated by uridine diphosphate glucuronosyltransferase (UGT) enzymes and metabolized by CYP 1A2. Delafloxacin is glucuronidated by UGT 1A1, UGT 1A3, and UGT 2B15 and renally eliminated. Moxifloxacin is glucuronidated and sulfated, but does not undergo CYP metabolism. Ciprofloxacin is partially excreted unchanged, is partially metabolized by CYP 1A2, and is an inhibitor of CYP 1A2. Low amounts of quinolones cross the placenta [ ], while much higher amounts penetrate into breast milk [ ]. No other pharmacokinetic studies in pregnancy are available. Because of arthropathy risks, quinolones should be avoided in pregnancy and lactation unless needed for complicated, resistant infections.

Metronidazole is used in pregnancy for treatment of symptomatic bacterial vaginosis or asymptomatic disease in women at high risk for preterm delivery. It is effective for eradication of infection, but does not decrease risk of preterm birth [ , ]. It is well absorbed, widely distributed including fetal [ ] and breast milk concentrations as high as maternal concentrations [ ], and is both oxidized and glucuronidated in the liver by unknown enzymes. Pharmacokinetic studies in early pregnancy and at term showed 15%–30% reductions in AUC compared to historical controls [ , ], but a study in 20 pregnant women taking 500 mg twice daily for 3 days showed weight-corrected exposure was similar in different stages of pregnancy and to reported values in nonpregnant adults [ ]. Nimorazole , tinidazole , and ornidazole do not have enough data in human pregnancy to assess appropriate use.

Nitrofurantoin has been used in pregnancy for decades for urinary tract infections. It undergoes some hepatic metabolism, but is mostly concentrated unchanged in urine. Less than 1% crosses into breast milk [ ], and placental exposure is also low. It is contraindicated near term due to risk of hemolytic reactions, particularly in glucose-6-phosphatase dehydrogenase (G6PD) deficiency. Fosfomycin is used as a single 3 g dose for uncomplicated urinary tract infections. It is not metabolized, and is excreted unchanged in urine and feces. No pharmacokinetic studies in pregnancy have been reported, though an observational cohort study did not find an increased risk of an adverse pregnancy outcome after first-trimester fosfomycin exposure [ ]. Methenamine mandelate and methenamine hippurate are antiseptics used for urinary tract infections. They cross the placenta, into breast milk, and are excreted unchanged in urine. Experience in pregnancy is very limited, and they should be avoided.

Atovaquone (see malaria section) and pentamidine are used for Pneumocystis jirovecii infections. Pentamidine crosses the placenta in animals; breast milk penetration is unknown. Elimination is mainly renal, but several metabolites formed by unknown pathways are also present. The half-life is 2–4 weeks. Pharmacokinetic studies of atovaquone in pregnancy have shown more than 50% lower exposure in pregnant women compared to healthy volunteers [ , ]. Higher doses of atovaquone during pregnancy have been suggested [ ].

12.2

Antifungal therapy

For treatment of fungal infections, topical therapy with older agents is considered safe in pregnancy. For topical and mucosal use, nystatin , clotrimazole , and miconazole are drugs of choice, with negligible systemic absorption. Other topical “-azoles” are second line, and other topical antifungals should be avoided due to lack of data in pregnancy. Systemic treatment with fluconazole, ketoconazole, itraconazole , and miconazole should be avoided unless the indication is compelling. No pregnancy pharmacokinetic studies are available. Voriconazole , posaconazole , and isavuconazonium are teratogenic in rodents. A case report is available describing a pregnant woman who received voriconazole for life-threatening refractory invasive aspergillosis in the second and third trimesters. No adverse fetal outcome was noted at birth or at 6-month follow-up [ ]. However, voriconazole remains contraindicated in pregnancy, and should be considered only in life-threatening cases when no alternatives are available. For treatment of vaginal candidiasis after local treatment has failed, low-dose oral fluconazole (150 mg once daily) may be tried. For serious, disseminated fungal infections, amphotericin B is preferred.

Amphotericin B is poorly absorbed and administered intravenously for systemic fungal infections. Its metabolism is unknown, and it is eliminated slowly with a 1–15 day half-life. It crosses the placenta and may be retained in placental and other tissues. Pharmacokinetics of the original or the liposomal formulations in pregnancy have not been studied. Use should be limited in pregnancy to dangerous systemic mycoses.

Flucytosine is active against Cryptococcus neoformans and candida species. It is widely distributed, and mostly eliminated unchanged in the urine. No pregnancy studies are available. Use during pregnancy should be reserved for severe disseminated fungal infection. Griseofulvin and terbinafine should not be used orally during pregnancy because data for systemic therapy during pregnancy with these agents are limited and skin mycoses do not require urgent oral treatment.