What is the role of azithromycin as surgical prophylaxis for C-section? What pathogens is it supposed to cover and what population(s) should receive it?

Comment by InpharmD Researcher

The American College of Obstetricians and Gynecologists (ACOG) recommends the addition of a single dose of azithromycin infused over one hour to a standard antibiotic prophylaxis regimen in women undergoing a nonelective cesarean delivery (C-section). The rationale for this recommendation is based on the C/SOAP trial (see Table 1) in which use of azithromycin significantly reduced maternal infections and serious maternal adverse events compared to placebo. A secondary analysis of the C/SOAP trial determined azithromycin to be most effective when administered after skin incision or up to 60 minutes before incision. Another randomized controlled trial also found the addition of azithromycin to cefuroxime to reduce the incidence of cesarean scar defect in women undergoing nonelective C-section. In general, antibiotics that are effective against Gram-positive bacteria (i.e., Enterococcus and Streptococcus), Gram-negative bacteria (i.e., Ureaplasma urealyticum and Escherichia coli), and some anaerobic bacteria are used for prophylaxis for C-section. Of note, azithromycin is considered a broad-spectrum agent that also provides coverage of atypical pathogens including Mycoplasma and Chlamydia.

Background

An updated practice bulletin from the American College of Obstetricians and Gynecologists (ACOG) in September 2018 recommends the addition of a single dose of azithromycin infused over one hour to a standard antibiotic prophylaxis regimen in women undergoing a nonelective cesarean delivery. The recommendation comes after the results of one large, multi-center, double-blind, randomized trial (the C/SOAP trial) which demonstrated a decrease in postcesarean surgical site infection with the addition of azithromycin as antimicrobial prophylaxis (see Table 1). Typically, antibiotics that are effective against Gram-positive bacteria, Gram-negative bacteria, and some anaerobic bacteria are used for prophylaxis for cesarean delivery. It is noted that azithromycin has been substituted in situations for which erythromycin is not available. [1]

A secondary analysis of the C/SOAP trial estimated the association between timing of administration of adjunctive azithromycin for prophylaxis at unscheduled cesarean delivery and maternal infection and neonatal morbidity. The administration times evaluated were after skin incision, or 0 to 30 minutes, >30 to 60 minutes, and >60 minutes prior to skin incision. Of 2,013 participants included for analysis, antibiotics were initiated after skin incision (median 3 minutes, range 0 to 229 minutes) in 269 (13.4%), 0 to 30 minutes preceding skin incision in 1,378 (68.5%), >30 to 60 minutes prior to skin incision in 270 (13.4%), and >60 minutes prior in 96 participants (4.8%). The risk of the primary infectious composite (endometritis, wound infection, and other maternal infections occurring up to 6 weeks after cesarean delivery) for azithromycin compared to placebo were significantly lower for groups initiating azithromycin after skin incision (risk ratio [RR] 0.31; 95% confidence interval [CI] 0.13 to 0.76) or within one hour prior to incision (0 to 30 minutes RR 0.62; 95% CI 0.44 to 0.89; >30 to 60 minutes RR 0.31; 95% CI 0.13 to 0.66). The risk of the primary infectious composite was not significantly different in patients receiving azithromycin >60 minutes before incision (RR 0.59; 95% CI 0.10 to 3.36). Neonatal outcomes were similar for azithromycin compared to placebo across all timing groups. The authors suggest that adjunctive azithromycin administration up to 60 minutes before or a median of 3 minutes after skin incision was associated with reduced risks of maternal composite post-operative infection in unscheduled cesarean deliveries. [2]

Older studies from the 1980s have established the most common agents of nosocomial infections in postpartum women to be Ureaplasma urealyticum, Escherichia coli, Enterococcus, and Streptococcus. While second-generation cephalosporins have a more potent anti-bacterial effect against E. coli and Enterobacteraceae compared to first-generation cephalosporins, azithromycin is known to exert stronger antibacterial and bacteriostatic effects against atypical pathogens such as Mycoplasma, Chlamydia, and anaerobic bacteria. Thus, it is postulated that use of adjunctive prophylactic azithromycin with standard single-dose antibiotics (i.e., cefuroxime) for non-elective cesarean delivery could reduce the occurrence of cesarean scar defect (CSD) by extending the antibacterial spectrum and enhancing antibiotic potency. A randomized, double-blind, controlled clinical trial was carried to test this hypothesis (see Table 2). [3]

References:

[1] ACOG Practice Bulletin No. 199: Use of Prophylactic Antibiotics in Labor and Delivery. Obstet Gynecol. 2018;132(3):e103-e119.
[2] Sanusi A, Ye Y, Boggess K, et al. Timing of Adjunctive Azithromycin for Unscheduled Cesarean Delivery and Postdelivery Infection. Obstet Gynecol. 2022;139(6):1043-1049. doi:10.1097/AOG.0000000000004788
[3] Huang D, Chen S, Cai Y, et al. Adjunctive azithromycin prophylaxis protects women from uterine cesarean scar defect: A randomized controlled trial. Acta Obstet Gynecol Scand. 2022;101(8):889-900. doi:10.1111/aogs.14387
Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

What is the role of azithromycin as surgical prophylaxis for C-section? What pathogens is it supposed to cover and what population(s) should receive it?

Please see Tables 1-3 for your response.

Adjunctive Azithromycin Prophylaxis for Cesarean Delivery (C/SOAP trial)

Design

Double-blind, multicenter, randomized clinical trial

N= 2,013

Objective

To evaluate the benefits and safety of azithromycin-based extended-spectrum prophylaxis in women undergoing nonelective cesarean section

Study Groups

Azithromycin (n= 1,019)

Placebo (n= 994)

Inclusion Criteria

Women with a singleton pregnancy, gestation of 24 weeks or more, undergoing nonelective cesarean delivery

Exclusion Criteria

Allergy to azithromycin or used azithromycin within 7 days before randomization, liver disease, cardiomyopathy, pulmonary edema, chorioamnionitis or other infections

Methods

All eligible patients received cefazolin according to standard prophylaxis protocol. Patients were randomized to receive a single dose of azithromycin 500 mg in 250 ml or saline infused over one hour.

Duration

Follow-up: six weeks 

Outcome Measures

Composite of endometritis, wound infection, or other infections

Baseline Characteristics

  

Azithromycin (n= 1,019) 

Placebo (n= 994)

    

Age, years

28.2 ± 6.1

28.4 ± 6.5

    

Race 

Non-Hispanic black

Hispanic

Non-Hispanic white

Other

351 (34.4%)

203 (19.9%)

356 (34.9%)

109 (10.7%)

 

341 (34.3%)

208 (20.9%)

342 (34.4%)

103 (10.4%)

    

Gestational age, weeks

 

38.9 ± 2.3

39.0 ± 2.3

    

Previous pregnancy

552 (54.2%)

560 (56.3%)

    

Results

 

Azithromycin (n= 1,019)

Placebo (n= 994)

Relative Risk (95% CI) 

p-value 

Composite infections

62 (6.1%)

 119 (12.0%) 0.51 (0.38–0.68)

<0.001

Endometritis

39 (3.8%)

61 (6.1%)

0.62 (0.42–0.92)

0.02

Wound infection

Necrotizing fasciitis

Deep wound infection

24 (2.4%)

0

6 (0.6%)

66 (6.6%)

4 (0.4%)

8 (0.8%)

0.35 (0.22–0.56)

NA

0.73 (0.25–2.10)

<0.001

0.06

0.56

Other infections

3 (0.3%)

6 (0.6%)

0.49 (0.12–1.94)

0.34

Maternal outcomes 

Postpartum fever

Any postpartum readmission

Infection-related

 

51 (5.0%)

83 (8.1%)

23 (2.3%)

 

81 (8.1%)

123 (12.4%)

62 (6.2%)

 

0.61 (0.44–0.86)

0.66 (0.51–0.86)

0.36(0.23-0.58)

 

0.004

0.002

<0.001

Adverse Events

Maternal adverse events: 1.5% vs 2.9%

Neonatal adverse events: 0.7% vs 0.5%

Study Author Conclusions

Among women undergoing nonelective cesarean delivery who were all receiving standard antibiotic prophylaxis, extended-spectrum prophylaxis with adjunctive azithromycin was more effective than placebo in reducing the risk of postoperative infection.

InpharmD Researcher Critique

 Criticisms of the C/SOAP trial include the fact that the study population was a high-risk group likely to benefit from azithromycin therapy due to obesity and a frequent use of staples.
References:

Tita AT, Szychowski JM, Boggess K, et al. Adjunctive Azithromycin Prophylaxis for Cesarean Delivery. N Engl J Med. 2016;375(13):1231-1241. doi:10.1056/NEJMoa1602044

 

Adjunctive azithromycin prophylaxis protects women from uterine cesarean scar defect: A randomized controlled trial

Design

Randomized, single-center, double-blind, placebo-controlled clinical trial

N= 242

Objective

To investigate the effect of adjunctive azithromycin on cesarean scar defect (CSD) occurrence in women undergoing non-elective cesarean delivery who were already receiving a standard single dose of cefuroxime sodium

Study Groups

Cefuroxime + azithromycin (n= 121)

Cefuroxime + placebo (n= 121)

Inclusion Criteria

Pregnant women with singleton pregnancies who had rupture of membranes (ROM) or in labor; underwent primary, non-elective cesarean section (CS); 18 years or older; at least 37 weeks of gestation

Exclusion Criteria

Fibrinogen <2 g/L, platelet count <100 x 109/L, or hemoglobin <90 g/L before CS; known allergy to cefuroxime sodium or azithromycin; received azithromycin within 7 days before randomization; positive for Group B streptococci at 36 weeks gestation; diagnosed with infection requiring additional antibiotic treatment; severe maternal diseases; preoperative diagnosis of uterine abnormalities; previously undergone CS

Methods

Patients in a hospital in China were randomized (1:1) to receive 1,500 mg cefuroxime sodium plus 500 mg intravenous (IV) azithromycin or 1,500 mg cefuroxime sodium plus placebo within 30 minutes before skin incision. Women and newborns underwent postpartum observation and were given medical treatment at the hospital before discharge, if necessary. Other necessary antibiotics (except azithromycin) were given to patients according to medical indications.

Duration

Enrollment: May 2018 to May 2021

Follow-up: 6 months after CS

Outcome Measures

Primary: CSD 6 weeks post-CS, CSD measurements, residual myometrium thickness (RMT), adjacent myometrium thickness (AMT)

Baseline Characteristics

  

Cefuroxime + azithromycin (n= 121)

Cefuroxime + placebo (n= 121)

  

Age, years

 30 30.4  

Body mass index, kg/m2

 27.4 27.7  

Gestational age

 39.5 39.5  

Lab values post-CS

Hemoglobin, g/L

WBC, x 109/L

Neutrophils, %

hypersensitive C-reactive protein, mg/L

CRP ratio, post/pre-CS

Procalcitonin, mcg/L

Procalcitonin ratio, post/pre-CS

 

113

12.8

80.9

48

5.8

0.14

2.2

 

112.8

12.9

81.5

50

6.1

0.11

2.0

  

Labor duration, hours

5.4

5.8

  

Operation duration, minutes

35.3

35.1

  

Vagional secretion culture pre-CS, n

Negative

Mycoplasma

Others

 

56

40

7

 

57

46

5

  

Uterine cavity culture in-CS, n

Negative

Mycoplasma

Escherichia coli, etc.

 

87

8

8

 

94

9

4

  

Antibiotic doses before randomization

1.8

1.9

  

Antibiotic doses after CS

1.0

1.4

  

Days from CS to follow-up

75.4

75.4

  

Results

Endpoint

Cefuroxime + azithromycin (n= 121)

Cefuroxime + placebo (n= 121)

p-value

CSD between 42-59 days post-CS

n= 50

18 (36%)

n= 55

26 (47.3%)

 0.76

CSD ≥66 days post-CS

n= 54

16 (29.6%)

n= 53

24 (45.3%)

 0.094

Pooled CSD measurements, mm

Width

Length

Depth


10.18 ± 4.63

7.14 ± 3.71

10.18 ± 4.63


9.87 ± 5.15

6.86 ± 3.74

9.87 ± 5.15


0.284

0.734

0.777

Pooled RMT, mm

5.51 ± 2.59

5.05 ± 3.16

0.479

Pooled AMT, mm

10.88 ± 2.83

11.17 ± 3.84

0.706

Single-dose standard cefuroxime was found to be a significant risk factor for CSD compared to adjunctive azithromycin with standard cefuroxime (adjusted odds ratio 2.1; 95% confidence interval 1.1 to 3.8; p= 0.023).

Adverse Events

Not disclosed

Study Author Conclusions

A single dose of intravenous 500 mg azithromycin adjunctive to single‐dose cefuroxime prophylaxis significantly reduced the incidence of CSD in women undergoing non‐elective CS.

InpharmD Researcher Critique

 The adjunctive use of azithromycin did not significantly reduce the incidence of CSD when evaluating patients within 6 weeks of CS and after 66 days. However, the pooled population of both follow-up periods showed a significant reduction when azithromycin was added to cefuroxime.
References:

Huang D, Chen S, Cai Y, et al. Adjunctive azithromycin prophylaxis protects women from uterine cesarean scar defect: A randomized controlled trial. Acta Obstet Gynecol Scand. 2022;101(8):889-900. doi:10.1111/aogs.14387

 

Adjunctive Azithromycin Prophylaxis for Prelabor Cesarean Birth

Design

Retrospective cohort study

N= 2,867

Objective

 To evaluate maternal postoperative infections before and after the addition of adjunctive azithromycin (AZI) to standard antibiotic prophylaxis for pre-labor cesarean births

Study Groups

Pre-AZI (n= 1,391)

Post-AZI (n= 1,476)

Inclusion Criteria

 Underwent pre-labor cesarean birth (performed without evidence of labor) of a liveborn singleton neonate at or after 23 0/7 weeks of gestation during the study period

Exclusion Criteria

 Clinically laboring or underwent induction, augmentation of spontaneous labor, and cesarean births from October to December 2015

Methods

Patient data were collected from a single tertiary care center. Deliveries were categorized into two groups: those that occurred before the implementation of adjunctive 500 mg intravenous azithromycin in addition to standard preoperative cephalosporin antibiotic prophylaxis (the "pre-AZI group" from January 2013 to September 2015), and those that occurred after the implementation of adjunctive azithromycin (the "post-AZI group" from January 2016 to December 2018).

Results were reported as both adjusted and unadjusted outcomes to prevent overfitting a certain model. The specific parameters adjusted varied by outcomes.

Duration

 Data collection: January 1, 2013 to December 31, 2018

Outcome Measures

Primary: Composite of postcesarean infections (endometritis, superficial or deep wound infections, intra-abdominal abscess, urinary tract infections)

Secondary: other wound or postoperative complications, select neonatal morbidities

Baseline Characteristics

  

Pre-AZI

(n= 1,391)

Post-AZI

(n= 1,476)

    

Age, years

 29.2 ± 5.8 30.4 ± 5.9    

Body mass index, kg/m2

 32.6 ± 9.7 32.4 ± 8.8    

Race and ethnicity

Black

White

Hispanic

None of the above

 

42.8%

40.2%

13.5%

3.5%

 

43.1%

40.8%

12.1%

4.0%

    

Nulliparity

 17.0% 18.6%    

Tobacco use

Alcohol use

Illicit drug use

14.0%

1.9%

5.0%

15.7%

3.9%

5.9%

    

Chronic medical conditions

Systemic lupus erythematosus

Chronic hypertension

Chronic kidney disease

Pregestational diabetes mellitus

 

0.8%

14.1%

0.7%

7.1%

 

1.2%

15.7%

1.4%

7.0%

    

Pregnancy characteristics

Pre-eclampsia

Severe pre-eclampsia

Medication-controlled diabetes

Predelivery antibiotics within 2 weeks

Gestational age delivery, week

 

19.9%

15.5%

4.5%

9.6%

36.8

 

26.4%

20.8%

6.4%

20.7%

36.7

    

Primary cesarean indication

Any labor arrest

Nonreassuring fetal status

Malpresentation

Repeat cesarean

Maternal indication

Other

 

0

9.6%

14.4%

62.0%

8.1%

5.9%

 

0

10.8%

16.2%

56.2%

10.6%

6.1%

    

Delivery anesthesia

General

Neuraxial

Other

 

9.4%

90.2%

0.4%

 

10.5%

89.4%

0.1%

    

Results

Endpoint

Pre-AZI

(n= 1,391)

Post-AZI

(n= 1,476)

Unadjusted odds ratio

(95% confidence interval [CI])

Adjusted odds ratio

(95% CI)

Composite of postcesarean infection

Endometritis

Wound infection

Urinary tract infection

67 (4.8%)

3 (0.2%)

49 (3.5%)

17 (1.2%)

48 (3.3%)

3 (0.2%)

36 (2.4%)

10 (0.7%)

0.66 (0.46 to 0.97)

0.94 (0.19 to 4.68)

0.68 (0.44 to 1.06)

0.55 (0.25 to 1.21)

0.60 (0.40 to 0.89)

0.86 (0.16 to 4.60)

0.61 (0.39 to 0.98)

0.46 (0.20 to 1.06)

Noninfectious wound complication

Seroma

Hematoma

Dehiscence

43 (3.1%)

13 (0.9%)

21 (1.5%)

17 (1.2%)

47 (3.2%)

8 (0.5%)

38 (2.6%)

8 (0.5%)

1.03 (0.68 to 1.57)

0.58 (0.24 to 1.40)

1.72 (1.01 to 2.95)

0.44 (0.19 to 1.02)

0.76 (0.48 to 1.21)

0.34 (0.13 to 0.90)

1.20 (0.67 to 2.15)

0.32 (0.13 to 0.79)

Any wound or postoperative complication

 81 (5.8%) 73 (4.9%) 0.84 (0.61 to 1.16) 0.69 (0.49 to 0.98)

Antibiotics within 6 weeks of delivery

182 (13.1%)

 205 (13.9%) 1.07 (0.86 to 1.33) 0.89 (0.71 to 1.12)

Postpartum fever higher than 100.4°F

 40 (2.9%) 40 (2.7%) 0.94 (0.60 to 1.47) 0.69 (0.43 to 1.12)

Intensive care unit (ICU) admission

 18 (1.3%) 32 (2.2%) 1.13 (0.75 to 1.71) 1.48 (0.80 to 2.76)

Death

 2 (0.1%) 3 (0.2%) 0.93 (0.19 to 4.59) 0.89 (0.14 to 5.66)

Composite neonat al morbidity

5-min Apgar score less than 4

Base excess less than -12

Arterial pH less than 7.0

NICU admission

Death

464 (66.6%)

37 (2.7%)

12 (1.7%)

18 (1.5%)

455 (32.7%)

26 (1.9%)

577 (39.1%)

36 (2.5%)

21 (1.6%)

18 (1.4%)

567 (38.4%)

28 (1.9%)

1.28 (1.10 to 1.49)

0.91 (0.57 to 1.45)

0.98 (0.48 to 2.00)

0.93 (0.48 to 2.00)

0.93 (0.48 to 1.80)

1.28 (1.10 to 1.50)

1.10 (0.91 to 1.33)

0.79 (0.48 to 1.32)

1.15 (0.54 to 2.44)

0.88 (0.44 to 1.77)

1.10 (0.90 to 1.33)

0.74 (0.41 to 1.35)

Adverse Events

 N/A

Study Author Conclusions

 Adopting adjunctive azithromycin for pre-labor cesarean deliveries was associated with lower odds of postpartum infection.

InpharmD Researcher Critique

The study is limited due to its retrospective nature and inability to ensure all patients received the correct antibiotics. Changes to skin and vaginal preparation protocols occurred concurrently with the switch to azithromycin, so results could be exaggerated by the protocol alterations in addition to the antibiotic exposure.



References:

Ruzic MF, Blanchard CT, Cozzi GD, et al. Adjunctive Azithromycin Prophylaxis for Prelabor Cesarean Birth. Obstet Gynecol. 2023;141(2):403-413. doi:10.1097/AOG.0000000000005037