IV azithromycin is on shortage. Is there any literature available to support alternative pre-op antibiotics (such as erythromycin) for laboring women undergoing C-sections? Is there a role for PO azithromycin instead of IV azithromycin?

Comment by InpharmD Researcher

There is limited literature describing alternative preoperative antibiotics to IV azithromycin for women undergoing cesarean delivery. The American College of Obstetricians and Gynecologists (ACOG) recommends a single dose of IV azithromycin for unplanned cesarean delivery but does not provide alternatives in cases of allergy, intolerance, or drug shortage. While ACOG and the Society of Obstetricians and Gynaecologists of Canada (SOGC) recommend erythromycin in other obstetric contexts, such as prelabor rupture of membranes (PROM) or as an alternative to cefazolin in patients with penicillin allergy, no literature has specifically evaluated erythromycin for preoperative prophylaxis in cesarean delivery. One study published in 2020 during the COVID-19 pandemic described the successful use of single-dose oral clarithromycin as a substitute for azithromycin during a drug shortage (see Table 1). Two additional studies described oral azithromycin in obstetric settings; however, these are not directly applicable: in one study, patients received IV doxycycline with a cephalosporin and oral azithromycin (1 gram) 6–12 hours postoperatively, and another evaluated oral azithromycin (2 grams) as preoperative prophylaxis in women undergoing vaginal delivery. Overall, evidence supporting alternatives to IV azithromycin in the setting of drug shortage is limited; however, oral clarithromycin may be a reasonable option during azithromycin shortage, based on limited observational evidence demonstrating reduced endometritis rates, though guideline recommendations and comparative trials are lacking.

A targeted literature search was conducted using PubMed and Google Scholar from database inception through February 2026 using combinations of the terms “cesarean section,” “azithromycin,” “clarithromycin,” “erythromycin,” “macrolide,” “antibiotic prophylaxis,” and “drug shortage.” Relevant clinical guidelines (ACOG, SOGC), randomized controlled trials, observational studies, and review articles evaluating alternative macrolides or oral azithromycin for cesarean prophylaxis were included and reviewed for applicability.

Background

The 2018 American College of Obstetricians and Gynecologists (ACOG) guidance on the use of prophylactic antibiotics in labor and delivery recommend that antibiotic prophylaxis is appropriate for all cesarean deliveries, unless the patient is already receiving an antibiotic regimen with equivalent broad-spectrum coverage, such as for chorioamnionitis. Prophylaxis should be administered within 60 minutes before the start of the cesarean delivery, or as soon as possible if emergent circumstances prevent preincision administration. First-line therapy is a single intravenous dose of cefazolin, with 1 g recommended for women weighing ≤80 kg and 2 g for women >80 kg. Single-dose therapy is generally as effective as multidose therapy, while reducing cost, toxicity, and the risk of colonization with resistant organisms. For patients with severe penicillin or cephalosporin allergies (anaphylaxis, angioedema, respiratory distress, or urticaria), a single-dose combination of clindamycin with an aminoglycoside is a reasonable alternative. For nonelective cesarean deliveries, the addition of intravenous (IV) azithromycin 500 mg, infused over 1 hour, to a standard antibiotic prophylaxis regimen may be considered, as it significantly reduces the composite risk of endometritis, wound infection, or other infections without increasing neonatal complications. Notably, the use of alternative antibiotics to IV azithromycin, including other macrolides or oral azithromycin, is not discussed. [1]

In addition to cesarean delivery prophylaxis, ACOG recommends antibiotic prophylaxis for patients with prelabor rupture of membranes (PROM) at less than 34 0/7 weeks of gestation to prolong the latency period between membrane rupture and delivery. The recommended regimen consists of a 2-day course of intravenous ampicillin and erythromycin followed by a 5-day course of oral amoxicillin and erythromycin, which has been shown to prolong pregnancy and reduce short-term neonatal complications. In situations where erythromycin is not available, azithromycin has been substituted; one retrospective cohort study reported no differences in latency or maternal or fetal outcomes with azithromycin substitution, although the dose and route of administration were not specified. Overall, ACOG emphasizes timely, single-dose, weight-appropriate, broad-spectrum antibiotic prophylaxis as the standard of care for cesarean delivery, with adjustments for allergy status or high-risk nonelective procedures. [1]

A 2017 guideline reaffirmed by the Society of Obstetricians and Gynaecologists of Canada (SOGC) reviewed antibiotic prophylaxis for obstetric procedures to prevent infectious complications. Based on evidence from systematic reviews, randomized controlled trials, and observational studies, the guideline recommends universal prophylaxis for all women undergoing elective or emergency cesarean delivery with a single preincision dose of cefazolin administered 15 to 60 minutes before skin incision. Clindamycin or erythromycin are suggested alternatives for patients with penicillin allergy. Notably, the guideline does not discuss the use of azithromycin for cesarean delivery prophylaxis. [2]

A 2026 expert review emphasizes that postcesarean infections are typically polymicrobial, arising from both skin and genital tract sources, thereby supporting the need for broad antimicrobial prophylaxis. Cefazolin remains the standard agent because of its activity against common skin flora and favorable safety profile; however, its limited activity against genital tract organisms, particularly Ureaplasma species, supports the addition of adjunctive azithromycin in nonelective cesarean deliveries, especially in women in labor or with ruptured membranes. Randomized trials and meta-analyses demonstrate that adding azithromycin to cefazolin reduces postoperative wound infections and endometritis by extending antimicrobial coverage, although alternative agents for patients unable to receive azithromycin are not addressed. A 2022 narrative review further notes that azithromycin is widely used during pregnancy due to its favorable oral bioavailability and placental transfer and is prescribed for sexually transmitted infections, toxoplasmosis, malaria, management of preterm prelabor rupture of membranes (PPROM), and cesarean prophylaxis. For PPROM, the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine recommend 48 hours of intravenous ampicillin and erythromycin followed by 5 days of oral amoxicillin and erythromycin, with azithromycin frequently substituted for erythromycin because of ease of administration, improved tolerability, and lower cost; however, the use of oral azithromycin specifically for cesarean delivery prophylaxis is not discussed. [3], [4]

A 2023 multicountry, placebo-controlled, randomized trial assessed the prophylactic use of azithromycin to reduce maternal sepsis or death in women planning a vaginal birth. Conducted across eight sites in seven low- or middle-income countries, this large-scale trial involved 29,278 women who were in labor at 28 weeks’ gestation or more. Participants were randomly assigned to receive a single 2-g oral dose of azithromycin or a placebo. The primary outcomes examined were a composite of maternal sepsis or death and a composite of stillbirth or neonatal death or sepsis. The trial was halted early based on recommendations from the data and safety monitoring committee due to the observed maternal benefits. Results demonstrated a significant reduction in maternal sepsis or death among women receiving azithromycin, with an incidence of 1.6% compared to 2.4% in the placebo group. This outcome was largely influenced by a reduction in maternal sepsis (1.5% versus 2.3%). The relative risk for maternal sepsis or death was 0.67, indicating a substantial risk reduction with a P value of less than 0.001. In contrast, the administration of azithromycin did not significantly affect the incidence of stillbirth or neonatal death or sepsis, which occurred in 10.5% of the azithromycin group and 10.3% of the placebo group. Subgroup analyses revealed a more pronounced maternal benefit in the African cohort. These findings underscore the potential of azithromycin prophylaxis to lower maternal morbidity and mortality due to sepsis in laboring women planning vaginal deliveries, without impacting neonatal outcomes. [5]

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-2 for your response.

Clarithromycin use for adjunct surgical prophylaxis before non-elective cesarean deliveries to adapt to azithromycin shortages in COVID-19 pandemic
Design	Multi-center, prospective observational cohort study N= 240
Objective	To evaluate safety and effectiveness of clarithromycin as adjunctive antibiotic prophylaxis for patients undergoing non-elective cesarean delivery in comparison with no macrolides, to adapt to azithromycin shortages in COVID-19 pandemic
Study Groups	Clarithromycin (n= 133) No macrolide (n= 107)
Inclusion Criteria	All patients undergoing a non-elective cesarean delivery during the study period
Exclusion Criteria	Diagnosed with an intrapartum infection, antibiotics administered in the postpartum period for non-gynecologic infections, allergy or contraindication to clarithromycin, less than 37 weeks gestational age, vomiting following administration of clarithromycin, missing follow up information or incomplete data
Methods	Patients received standard surgical prophylaxis with IV cefazolin. Clarithromycin 500 mg was administered orally 30 minutes before skin incision for adjunct prophylaxis. Decision to administer clarithromycin was based on hospital protocols. Data was collected from institutional electronic medical records
Duration	March 23, 2020 through June 1, 2020
Outcome Measures	Primary: Development of postpartum endometritis Secondary: Meconium-stained amniotic fluid, neonatal sepsis, neonatal intensive care unit admission, neonatal acute respiratory distress syndrome
Baseline Characteristics		Clarithromycin Group (n= 133)	No Macrolide Group (n= 107)
	Maternal age, years	29.4 ± 6.1	31.3 ± 6.8
	BMI, kg/m²	31.7 ± 9.4	34.2 ± 9.2
	Race White Black	55 (41.3%) 48 (36.1%)	58 (54.2%) 24 (22.4%)
	Group β-streptococcus positive	32 (24.1%)	20 (18.7%)
	Rupture of membranes with prior cesarean	8 (13.5%)	20 (18.7%)
Results		Clarithromycin Group (n= 133)	Control Group (n= 107)	p-value
	Postpartum Endometritis	6 (4.5%)	12 (11.2%)	0.025
	Meconium Stained Amniotic Fluid	22 (16.5%)	14 (13.1%)	0.456
	Neonatal ICU Admission	10 (7.5%)	5 (4.7%)	0.365
Adverse Events	No severe side-effects including hepatotoxicity, nephrotoxicity, cardiac arrhythmias, or significant gastrointestinal symptoms were reported in patients receiving clarithromycin.
Study Author Conclusions	Administration of clarithromycin for adjunctive surgical prophylaxis for non-elective cesarean deliveries may be a safe option that provides suitable endometritis prophylaxis when azithromycin is unavailable, especially for Black race women and women ages 18–29 years.
Critique	The study was limited by its observational design and small sample size, which may introduce biases and limit generalizability. The lack of a randomized controlled trial design and the absence of a comparison group receiving azithromycin are notable limitations. Additionally, the study did not track surgical site infections beyond inpatient care, which could have provided a more comprehensive assessment of infectious outcomes.

References:
[1] [1] Martingano D, Nguyen A, Nkeih C, Singh S, Mitrofanova A. Clarithromycin use for adjunct surgical prophylaxis before non-elective cesarean deliveries to adapt to azithromycin shortages in COVID-19 pandemic. PLoS One. 2020;15(12):e0244266. Published 2020 Dec 21. doi:10.1371/journal.pone.0244266

Randomized Clinical Trial of Extended Spectrum Antibiotic Prophylaxis With Coverage for Ureaplasma urealyticum to Reduce Post–Cesarean Delivery Endometritis
Design	Randomized, double-blind clinical trial N= 597
Objective	To determine if extended spectrum prophylactic antibiotic treatment (with efficacy against Ureaplasma urealyticum) reduces post–cesarean delivery clinical endometritis
Study Groups	Doxycycline/azithromycin group (n= 301) Placebo group (n= 296)
Inclusion Criteria	Women undergoing cesarean delivery at the institution between October 1, 1996, and September 9, 1999
Exclusion Criteria	Allergy to study medications, fever, clinical signs of chorioamnionitis, impaired hepatic or renal function, immunocompromised condition, on medications metabolized by the cytochrome P450 system, language barrier, need for hysterectomy, need for emergent cesarean, prior participation in the trial
Methods	After cord clamping at cesarean delivery, subjects received 2 g of cefotetan intravenously. Subjects were randomized to receive doxycycline 100 mg (initiated simultaneously with the cefotetan) intravenously plus azithromycin 1 g orally 6–12 hours postoperatively or corresponding placebos.
Duration	October 1, 1996, to September 9, 1999
Outcome Measures	Primary: Frequency of post–cesarean delivery endometritis Secondary: Frequency of wound infections, length of hospital stay
Baseline Characteristics		Cefotetan + doxycycline + azithromycin (n= 301)	Cefotetan + placebo (n= 296)
	Ethnicity White Black	55.5% 41.9%	57.4% 39.5%
	Maternal age, years	25.5 ± 6.2	25.5 ± 6.2
	Nulliparous	42.9%	42.6%
	Multiple gestations	5.3%	6.1%
	Prevalence of STDs	17.9%	16.6%
	Prior cesareans	33.2%	33.8%
	Diabetes mellitus	13.0%	8.8%
	Chronic hypertension	8.3%	6.8%
	Preeclampsia	16.6%	18.9%
	Abbreviations: STDs, sexually transmitted diseases.
Results		Cefotetan + doxycycline + azithromycin (n= 301)	Cefotetan + placebo (n= 296)	p-value
	Endometritis	16.9%	24.7%	0.020
	Wound infections	0.8%	3.6%	0.030
	Endometritis or wound infection	19.0%	27.8%	0.019
	Length of postoperative stay, hours Overall In endometritis cases	95 ± 32 127 ± 46	104 ± 56 146 ± 52	0.016 0.047
Adverse Events	Maternal leukocytosis was more common in the doxycycline/azithromycin group (24.9% vs. 12.5%, P = 0.042)
Study Author Conclusions	Extended spectrum prophylactic antibiotic treatment with efficacy against U.urealyticum reduces the frequency of post–cesarean delivery endometritis and wound infections, and shortens hospital stay.
Critique	The study's strengths include its randomized, double-blind design and significant findings in reducing post-cesarean infections. However, the absence of chorioamnion cultures limits the ability to attribute results specifically to U.urealyticum coverage. The study's applicability to low-risk populations remains uncertain.

References:
[1] [1] Andrews WW, Hauth JC, Cliver SP, Savage K, Goldenberg RL. Randomized clinical trial of extended spectrum antibiotic prophylaxis with coverage for Ureaplasma urealyticum to reduce post-cesarean delivery endometritis. Obstet Gynecol. 2003;101(6):1183-1189. doi:10.1016/s0029-7844(03)00016-4