18.3 Antimicrobial Stewardship & Pharmacotherapy in Pregnancy and Lactation

Principles of Antimicrobial Stewardship in Women's Health

Antimicrobial stewardship optimizes clinical outcomes while minimizing multidrug-resistant organisms (MDROs) and drug toxicities. Core tenets include prescribing the narrowest effective spectrum, utilizing cultures for de-escalation, and limiting therapy to the shortest effective duration.

Distinguishing Asymptomatic Colonization from Infection

• Asymptomatic Bacteriuria (ASB): Isolation of ≥10⁵ CFU/mL of a single uropathogen in a clean-catch midstream urine specimen from an individual without lower urinary symptoms (dysuria, urgency, frequency) or systemic signs (fever, flank pain).
• In Nonpregnant Women: In healthy nonpregnant females, ASB represents benign colonization. Treating ASB provides no clinical benefit, does not prevent cystitis, increases adverse effects, disrupts normal flora, and breeds resistance. IDSA guidelines strictly advise against screening or treating ASB in nonpregnant healthy women.
• In Pregnant Women: In contrast, untreated ASB in pregnancy carries a 20% to 35% risk of progressing to acute maternal pyelonephritis, secondary to progesterone-mediated ureteral dilation, hydronephrosis, and mechanical compression by the gravid uterus. Pyelonephritis triggers maternal sepsis, ARDS, preterm labor, and low birth weight. ACOG and USPSTF mandate universal screening for ASB at the initial prenatal visit (12 to 16 weeks gestation) via urine culture, with prompt treatment (cephalexin, amoxicillin-clavulanate, or nitrofurantoin) and a test-of-cure urine culture 1 to 2 weeks post-treatment.
• Vaginal Colonization: Incidental discovery of Candida, Gardnerella, or Actinomyces on routine Pap smears in asymptomatic patients represents benign colonization and must not be treated.

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Gestational Safety: First-Line Antimicrobial Classes

1. Penicillins

• Mechanism & Safety: Bactericidal inhibition of bacterial cell wall peptidoglycan cross-linking via binding to penicillin-binding proteins (PBPs). Because mammalian cells lack peptidoglycan cell walls, beta-lactams have an exceptional therapeutic index and robust safety across all trimesters.
• Clinical Formulations: Amoxicillin/ampicillin are safe for respiratory, enterococcal urinary, and Listeria monocytogenes infections (IV ampicillin). Penicillin G is first-line for intrapartum Group B Streptococcus (GBS) chemoprophylaxis (5 million units IV loading dose, then 2.5–3.0 million units IV every 4 hours until delivery). Benzathine penicillin G is the only proven curative therapy for syphilis; allergic pregnant patients must undergo desensitization. Caution: Amoxicillin-clavulanate is strictly contraindicated in Preterm Premature Rupture of Membranes (PPROM) due to increased neonatal necrotizing enterocolitis (NEC).

2. Cephalosporins

• Mechanism & Safety: Inhibition of cell wall synthesis (bactericidal) with first-line safety across all trimesters.
• Clinical Formulations: First-generation cephalexin (500 mg PO BID-QID) is first-line for ASB and cystitis in pregnancy; cefazolin is gold standard for cesarean surgical prophylaxis. Second-generation agents (cefoxitin, cefotetan) provide anaerobic coverage for inpatient PID. Third-generation ceftriaxone (500 mg IM) is first-line for N. gonorrhoeae, while IV ceftriaxone treats inpatient antenatal pyelonephritis.

3. Macrolides

• Mechanism & Safety: Reversibly binds the 50S ribosomal subunit, inhibiting protein synthesis. Oral azithromycin (1 g single dose) is first-line for Chlamydia trachomatis in pregnancy. Erythromycin base is safe for PPROM latency protocols. Cautions: Erythromycin estolate is contraindicated due to maternal drug-induced cholestatic jaundice. Clarithromycin is avoided due to animal teratogenicity data; azithromycin is preferred.

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Antimicrobials with Gestational Timing Restrictions

1. Nitrofurantoin (Macrobid)

• Mechanism & Timing: Reduced by bacterial enzymes into reactive intermediates attacking ribosomes and DNA. Concentrates heavily in urine. Safe for cystitis and ASB in the 1st (when alternatives are lacking) and 2nd trimesters.
• Contraindication at Term (38 to 42 Weeks) & Labor: Fetal/neonatal erythrocytes have immature glutathione reductase and low reduced glutathione (GSH). Exposure near delivery triggers acute neonatal hemolytic anemia, severe hyperbilirubinemia, and Heinz body formation.

2. Trimethoprim-Sulfamethoxazole (TMP-SMX, Bactrim)

• Mechanism: Sequential dual inhibition of bacterial folic acid synthesis (trimethoprim inhibits dihydrofolate reductase; sulfamethoxazole inhibits dihydropteroate synthase).
• First-Trimester Restriction (Weeks 1–12): Trimethoprim folate antagonism during organogenesis (weeks 3–8) increases risks of neural tube defects, cardiac malformations, and oral clefts.
• Third-Trimester Near-Term Restriction (≥32–34 Weeks, Especially ≥36 Weeks): Sulfonamides competitively displace unconjugated bilirubin from albumin binding sites. In the newborn with an immature blood-brain barrier and deficient glucuronidation, displaced free bilirubin deposits in the basal ganglia, precipitating kernicterus (chronic bilirubin encephalopathy, choreoathetosis, sensorineural deafness).

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Strictly Contraindicated Classes in Pregnancy

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Antimicrobial Pharmacotherapy During Lactation

Antimicrobial transfer into milk depends on molecular weight (<200 Da diffuses freely; >800 Da crosses poorly), protein binding (>90% bound leaves low free drug to enter milk), and milk pH (7.0–7.2 vs. plasma 7.4; weakly basic drugs undergo ion trapping).

• Relative Infant Dose (RID): Quantitative metric assessing safety:

$$\text{RID} = \left(\frac{\text{Infant dose via milk in mg/kg/day}}{\text{Maternal dose in mg/kg/day}}\right) \times 100\%$$

An RID <10% is widely accepted as clinically safe in healthy term infants.

Class Guidance in Lactation

• Penicillins & Cephalosporins: RID <1% to 2%. Fully compatible with breastfeeding; counsel mothers on potential mild infant loose stools or thrush.
• Macrolides (Azithromycin, Erythromycin): Compatible with lactation (RID <5%).
• Nitrofurantoin: Compatible in healthy term infants >1 month of age; avoid if infant is <1 month or has diagnosed Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency due to hemolysis risk.
• TMP-SMX: Compatible in healthy term infants >2 months; avoid in premature infants, hyperbilirubinemic newborns, or infants with G6PD deficiency.
• Fluoroquinolones: Low concentrations pass into milk; beta-lactams are preferred.
• Chloramphenicol: Strictly contraindicated during lactation due to potential bone marrow suppression and Gray Baby Syndrome.