Accepted Manuscript

A Comparison of Three Antibiotic Regimens for Prevention of Post-Cesarean

Endometritis: An Historical Cohort Study

Erin Ward, M.D, Patrick Duff, M.D

PII: S0002-9378(16)00337-9
DOI: 10.1016/j.ajog.2016.02.037
Reference: YMOB 10961

To appear in: American Journal of Obstetrics and Gynecology

Received Date: 2 November 2015

Revised Date: 10 February 2016
Accepted Date: 13 February 2016

Please cite this article as: Ward E, Duff P, A Comparison of Three Antibiotic Regimens for Prevention
of Post-Cesarean Endometritis: An Historical Cohort Study, American Journal of Obstetrics and
Gynecology (2016), doi: 10.1016/j.ajog.2016.02.037.

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A Comparison of Three Antibiotic Regimens for Prevention of Post-Cesarean
Endometritis: An Historical Cohort Study

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Erin Ward, M.D.

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Patrick Duff, M.D.
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Division of Maternal-Fetal Medicine

University of Florida College of Medicine

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Gainesville, Florida 32610

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352 273 7971

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duffp@ufl.edu
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Short Title: Antibiotic prophylaxis for prevention of post-cesarean endometritis

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CONDENSATION

Cefazolin plus azithromycin administered preoperatively is significantly more effective

than cefazolin alone administered after cord clamping in preventing post-cesarean

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endometritis.

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ABSTRACT

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BACKGROUND: Prophylactic antibiotics are of proven value in decreasing the

frequency of post-cesarean endometritis. The beneficial effect of prophylaxis is

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enhanced when the antibiotics are administered prior to the surgical incision as

opposed to after clamping of the umbilical cord. However, the optimal antibiotic

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regimen for prophylaxis has not been firmly established.

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OBJECTIVE: To compare three different antibiotic regimens for prevention of post-
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cesarean endometritis.

STUDY DESIGN: This retrospective historical cohort study was conducted at the
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University of Florida, a tertiary care facility that serves a predominantly indigent patient
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population. In the period January 2003 to December 2007, our standard prophylactic
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antibiotic regimen for all women having cesarean delivery was cefazolin, 1 gram,

administered immediately after the babys umbilical cord was clamped. In November
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2008 we began to administer the combined regimen of cefazolin, 1 gram intravenously,

plus azithromycin, 500 mg intravenously, both given 30 to 60 minutes prior to skin

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incision. In the period January December 2014, we continued the dual agent
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regimen but based the dose of cefazolin on the patients BMI 2 grams intravenously if

BMI < 30 and 3 grams if BMI > 30. Surgical technique was consistent throughout all

three time periods. Our primary end point was the frequency of endometritis in each

time period. This diagnosis was based on fever greater than or equal to 37.5 degrees C,

lower abdominal pain and tenderness, the exclusion of other localizing signs of
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infection, and the requirement for administration of therapeutic antibiotics. In the first

year after beginning the new antibiotic regimen, we also monitored the frequency of

neonatal sepsis evaluations and compared it with the frequency recorded during the

year immediately preceding the change in antibiotic regimens.

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RESULTS: During the entire period 20032014, 29,633 women delivered at our

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institution, and 6455 women (22%) had a cesarean delivery. In the period January

2003- December 2007, 1034 women had a primary or repeat cesarean delivery. 170

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women (16.4%, 95% CI, 14.4 18.4%) developed endometritis. In the period November

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2008- December 2013, 4484 women had a primary or repeat cesarean delivery. 59
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patients (1.3%, 95% CI 1.01.7 %) developed endometritis (p<.0001 compared to

period 1). In the year 2014, 937 women had a cesarean delivery; 22 (2.3%, 95% CI
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1.3-3.3 %) developed endometritis (p<.0001 compared to period 1 and p>0.5 and < .10

compared to period 2). The frequency of evaluations for suspected neonatal sepsis in
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infants delivered to mothers having cesarean delivery was 17.6% in the period January
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December 2007 and 19.3% in the period November 2008- November 2009 (RR 1.1,

95% CI 0.7, 1.9). One infant had proven sepsis in the former period; two had proven
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sepsis in the latter period (NS).

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CONCLUSIONS: When administered prior to skin incision, the combination of cefazolin

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plus azithromycin was significantly more effective in preventing endometritis than

administration of cefazolin after cord clamping and reduced the rate of endometritis to a

very low level without increasing the rate of neonatal sepsis evaluations
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INTRODUCTION

As noted in the recent systematic review by Tita et al (1), multiple publications

have conclusively demonstrated that prophylactic antibiotics reduce the frequency of

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endometritis following unscheduled cesarean delivery. The report by Dinsmoor et al (2)

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confirmed that prophylaxis was also effective in reducing the frequency of endometritis

in patients having a scheduled cesarean delivery in the absence of labor. Recent

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reports (3-5) have also confirmed that preoperative administration of antibiotics is

superior to administration of antibiotics after the umbilical cord is clamped and have

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shown that the concern that preoperative administration would increase the number of
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infants who developed proven sepsis or who required evaluations for suspected sepsis

was unfounded.
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What is not so clear is the optimal antibiotic regimen to administer. Prior to 2008,
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the standard of care was to use a limited-spectrum cephalosporin such as cefazolin for
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prophylaxis (1). In that year, two reports by Tita et al (6,7) demonstrated that combining

cefazolin with azithromycin provided additional benefit in reducing the risk of both
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endometritis and surgical wound infection (incisional abscess and cellulitis). In these
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latter reports, the authors administered both drugs after the babys umbilical cord was
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clamped. When we adopted this two-drug regimen as our standard of care in 2008, we

administered the drugs preoperatively. The objective of our present study was to

compare the efficacy of this preoperative two-drug regimen to our previous experience

with single-dose cefazolin administered after cord-clamping.

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MATERIALS AND METHODS

This retrospective historical cohort study was conducted at the University of

Florida, which is a tertiary care facility that serves a predominantly indigent patient

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population in the rural north central portion of the state. Approximately 80% of our

obstetric patients are insured under the Florida Medicaid Program. Approximately 70%

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of the patients are Caucasian, 20% Hispanic, and 10% African-American.

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In the period of January 2003 December 2007, our prophylactic antibiotic

regimen for all women having cesarean delivery was cefazolin, 1 gram, administered

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intravenously, immediately after the babys umbilical cord was clamped. This regimen
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was based upon previous reports by Duff and coauthors (8,9). In November 2008 we

formally implemented the combined regimen of cefazolin, 1 gram intravenously, plus

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azithromycin, 500 mg intravenously, prior to skin incision. Cefazolin was administered

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as a bolus infusion within one hour of the start of surgery. Azithromycin was
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administered as a continuous infusion over 30 to 60 minutes prior to surgery. We based

the decision to use two drugs on the reports of Tita et al (6,7) and the decision to
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administer the drugs preoperatively on the reports by Sullivan and coworkers (3),

Constantine et al (4), and Owens and coauthors (5). During the period January 1
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December 31, 2014, we kept the dose of azithromycin the same, but modified the dose
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of cefazolin based on the patients BMI 2 grams intravenously if the BMI was < 30 and

3 grams intravenously if the BMI was > 30. We based this decision on the report by

Pevzner et al (10) who showed that in, obese and extremely obese patients, even a 2-

gram dose of cefazolin frequently failed to achieve therapeutic adipose tissue

concentrations against gram-negative bacilli at the time of skin incision and skin closure.
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The small number of patients who had a well-documented history of an

immediate hypersensitivity reaction to beta-lactam antibiotics (less than 2% of patients)

received a single dose of clindamycin, 900 mg intravenously, plus gentamicin, 80 mg

intravenously, both administered as rapid infusions 30 to 60 minutes prior to surgery.

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The choice of this regimen was based upon an earlier study by Gibbs and Weinstein

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(11) and upon empirical considerations of trying to provide coverage against a

reasonably broad spectrum of microorganisms, including aerobic gram-positive cocci

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(clindamycin), aerobic gram-negative bacilli (gentamicin), and anaerobes(clindamycin).

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Patients who had chorioamnionitis were the only patients specifically excluded
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from the study. Chorioamnionitis was diagnosed using the criteria of Gibbs et al (12):

temperature greater than or equal to 37.8 degrees C plus two or more of the following:
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maternal tachycardia, fetal tachycardia, uterine tenderness, four odor of the amniotic

fluid, or maternal leukocytosis. Patients with chorioamnionitis were treated intrapartum

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with therapeutic antibiotics, usually ampicillin plus gentamicin. If they required cesarean
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delivery, they also received either clindamycin or metronidazole postoperatively in

accordance with the recommendations of Edwards and Duff (13).

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All procedures were performed by resident physicians, assisted by faculty

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members, or by faculty members themselves. Surgical technique was relatively

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consistent throughout the three time periods (14). The hair in the incision line was

clipped, rather than shaved, just prior to the start of surgery, and chlorhexidine was

used to wash the skin. Most procedures were performed through a transverse

abdominal incision. With very few exceptions, all the uterine incisions were low

transverse. Whenever possible, the placenta was extracted by exerting traction on the
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umbilical cord (15). The uterus was usually closed in two layers with continuous sutures

of 0-Vicryl. The visceral and parietal peritoneum were not routinely closed. The fascia

was closed with one or two continuous sutures of 0-Vicryl, and the deep subcutaneous

layer was closed with a single continuous suture of 3-0 Vicryl if this layer was > 2 cm in

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thickness. In the vast majority of cases the skin was reappoximated with a single

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continuous subcuticular suture of 3-0 Monocryl or 4-0 Vicryl. The remaining patients

had skin closure with stainless steel staples.

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Our primary endpoint was the frequency of endometritis. The diagnosis of

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endometritis was based on the clinical findings of fever greater than 37.5 degrees C,
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tachycardia, and uterine pain and tenderness, in the absence of any other localizing

sign of infection (16). A peripheral white blood cell count greater than 15,000/mm3 was
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considered corroborating evidence of endometritis but was not absolutely required to

make the diagnosis. In the opinion of the attending physician, all patients had an
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indication for therapeutic antibiotics and were usually treated with clindamycin plus
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gentamicin.
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Uninfected patients were routinely discharged on the second postoperative day.

Patients with endometritis were treated with parenteral antibiotics until they were
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afebrile and asymptomatic for 24 hours. They were usually discharged on the fourth
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postoperative day.

During the period November 2008 through November 2009, we also monitored

the frequency of sepsis evaluations in neonates delivered to mothers having cesarean

delivery to be certain that preoperative administration of antibiotics was not adversely

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affecting the care of the neonates. We compared the frequency of sepsis evaluations in

this period to the frequency in the year immediately preceding the adoption of the new

prophylaxis regimen. Sepsis was suspected if an infant demonstrated respiratory

distress, lethargy, poor feeding, poor tone, hemodynamic instability, or thermal

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instability (temperature < 36 degrees C or > 38 degrees C). The neonate then had the

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following laboratory tests: complete blood count; C-reactive protein; immature to total

neutrophil ratio; blood, urine, and cerebrospinal fluid culture; and a chest x-ray. The

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diagnosis of proven sepsis required a positive culture or abnormal chest x-ray.

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De-identified data for the first time period were obtained from the departments
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computerized perinatal data base, including information about neonatal sepsis

evaluations. Data for the second and third time periods were obtained from our
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electronic medical record research functionality. The investigation was conducted

under an exempt protocol approved by the Institutional Review Board.

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We used the uncorrected chi-square test to assess differences in the frequency

of endometritis between the groups. P < .05 was considered statistically significant.
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RESULTS
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During the three time periods of this study, 29,633 women delivered at our

medical center. 6455 women (22%) had a cesarean delivery, and they are the subjects

of this investigation. In each of the three time periods, approximately 65% of patients

had a cesarean during labor, and approximately 35% had a planned cesarean prior to

the onset of labor. In the period January 2003- December 2007, 1034 patients had a
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cesarean delivery. Of note, for three years of this interval, our medical center

experienced a dramatic, but temporary, decrease (40%) in our delivery volume due to

changes in the states Medicaid insurance program, which altered the usual patterns of

referral to our institution. Of these 1034 patients, 170 (16.4%, 95% CI 14.4-18.4%)

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developed endometritis and required treatment with therapeutic antibiotics. In the

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period November 2008- December 2013, when the standard of care was administration

of cefazolin plus azithromycin prior to surgery, 4484 women had a cesarean delivery.

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Fifty-nine patients (1.3%, 95% CI 1.0-1.7%) developed endometritis (p<.0001 compared

to period 1). In the period January December 2014, when we modified the dose of

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cefazolin based on the patients weight, 937 women had an abdominal delivery.
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Twenty-two of these patients (2.3%, 95% CI 1.3-3.3%) developed endometritis (p <

.0001 compared to period 1 and p > .05 and < .10 compared to period 2).
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In the period November 2008- November 2009, 19.3% of infants had evaluations
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for sepsis. In the period January December 2007, the final year in which a single
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dose of cefazolin was routinely administered after cord clamping, 17.6% of infants had

evaluations for sepsis (RR 1.1, 95% CI 0.7, 1.9). Two infants in the former period had
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proven sepsis compared to one infant in the latter period (NS). In light of these
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reassuring observations, which are consistent with the reports of other investigators
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(3,5), we discontinued our specific surveillance of neonatal sepsis evaluations.

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COMMENT

Prophylactic antibiotics for cesarean delivery were adopted on a widespread

basis in the mid-1970s. At that time, the standard of care was to administer the

antibiotics after the babys umbilical cord was clamped because of concern that

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preoperative exposure to antibiotics might increase the neonates risk of infection or

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interfere with the pediatricians ability to assess a newborn for infection (17,18).

Interestingly, this approach was at variance with the unique laboratory experiments of

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Burke (19). Using a guinea pig model, he demonstrated that prophylactic antibiotics

were most effective when present in tissue before surgery began and before bacterial

contamination occurred.
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Sullivan and colleagues (3) were among the first to challenge the practice of
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delaying prophylaxis until after the babys umbilical cord was clamped. In a landmark

investigation, they demonstrated that preoperative administration of cefazolin, 1 gram

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intravenously, was more effective than administration after cord clamping in reducing
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the risk of endometritis, wound infection, and total infection-related morbidity. Other

authors (4,5) subsequently confirmed the observations of Sullivan et al (3).

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More recently, Tita and coworkers (6,7) challenged another commonly-held

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tenant of prophylaxis by suggesting that broadening the spectrum of the antibiotics

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could further enhance the beneficial effects of prophylaxis. In two separate

investigations, they demonstrated that the combination of cefazolin plus azithromycin

significantly decreased the rate of both endometritis and wound infection compared to

administration of cefazolin alone. In the years after adoption of the new combination

regimen, the authors noted that the rate of endometritis at their institution decreased
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from 23% to 2.1%, and the rate of wound infection fell from 4% to 0%. Although

azithromycin provides coverage against many gram-positive organisms, some gram-

negative organisms (e.g., Hemophilus influenzae and Neisseria gonorrheae), and

Chlamydia trachomatis, the authors concluded that the enhanced effect of the

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combination regimen was most likely due to azithromycins excellent activity against

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ureaplasmas.

Interestingly, these organisms rarely are present as single pathogens in patients

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with endometritis; they usually are associated with a complex bacteriological flora that

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includes aerobic and anaerobic gram-positive cocci and aerobic and anaerobic gram-
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negative bacilli (16). Nevertheless, ureaplasmas certainly have been identified as

important in the pathogenesis of chorioamnionitis. In the elegant experimental primate

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model of Grigsby et al (20), azithromycin was remarkably effective in eradicating

ureaplasma infection from the amniotic cavity.

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In the two investigations by Tita et al (6,7), the authors administered the

antibiotics after the babys umbilical cord was clamped. When we adopted the
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expanded spectrum regimen, we administered the drugs prior to surgery, in keeping

with the recent recommendations of Sullivan and coworkers (3), Constantine et al (4),
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and Owens et al (5). Our rate of endometritis subsequently decreased significantly,

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from 16.4% to 1.3% (p<.0001), a figure slightly lower than reported by Tita et al (7).

Sullivan and coworkers (3) noted a frequency of endometritis of 1% in patients who

received preoperative cefazolin. Owens et al (5) observed a rate of endometritis of

2.2% in women who received a single dose of cefazolin preoperatively. In light of these

reports, although we think that both the preoperative timing of antibiotic administration
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and choice of antibiotics played a role in reducing the frequency of infection, we think

that the former was of greatest importance.

In the reports by Tita and colleagues (6,7), there was no evidence that the

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addition of azithromycin created any selective pressures for the emergence of drug-

resistant organisms. Similarly, after adoption of the new antibiotic regimen, we noted no

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temporal increase in the number of unusual complications of endometritis such as pelvic

abscess, septic shock, and septic pelvic vein thrombophlebitis. The rate of all these

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complications, combined, was less than 1% in the final two time periods of the study.

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In addition, because azithromycin is now available in a generic formulation, we
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incurred only modest increase in expense compared to our former regimen of cefazolin

alone. Overall, because of the marked reduction in the frequency of post-cesarean

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endometritis and the reduction in the need for administration of therapeutic antibiotics,
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we experienced a net cost savings.

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In the final year of our investigation, we modified the dose of cefazolin in

accordance with the patients weight. We made this decision in light of the publication
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by Pevzner and coworkers (21) who showed that even a 2 gram dose of cefazolin

sometimes failed to achieve therapeutic tissue concentrations in obese and extremely

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obese patients. Our dose modification did not further decrease the rate of infection. In
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fact, the rate of infection increased slightly (p> .05 and < .10). We acknowledge that our

failure to detect a difference in outcome may be due to a type 2 statistical error. Given

the very low rate of endometritis (1.3%), we would have required a sample size in

excess of 1000 patients in each group to detect a 30% difference in the rate of infection
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with the increased dose of cefazolin. (22) Even a larger sample size would have been

necessary to detect a more pronounced difference in treatment outcome.

Of note, a recent report by Swank et al (23) supported the observations of

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Pevzner and coworkers. (21) However, the subsequent investigation by Young et al (24)

confirmed that adipose tissue concentrations of cefazolin exceeded the MIC for key

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wound pathogens with either a 2 gram or 3 gram dose.

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We acknowledge two major weaknesses in our study. First, we were unable to

reliably follow all patients after discharge from the hospital because they returned to

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many different rural health departments for their postpartum appointments. Therefore,
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we were not able to accurately document the frequency of surgical wound infection

(incisional abscess or cellulitis), given that most such infections occur several days after
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hospital discharge. Second, because of the peculiarities of the research functionality in

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our electronic medical record, we were not able to separate individual patients into
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those who had a cesarean delivery before labor or during labor. However, given the

very low rate of endometritis in the entire group of patients (1.3%), it is doubtful that,
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even with our relatively large sample size, we would have been able to demonstrate a

significant difference in infection rates in patients having a scheduled versus an

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unscheduled cesarean delivery.

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We conclude that administration of cefazolin plus azithromycin prior to skin

incision was significantly more effective than administration of cefazolin alone after cord

clamping. This antibiotic regimen reduced the rate of endometritis to a low level and
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did not increase the rate of neonatal sepsis evaluations compared to administration of

cefazolin alone after cord clamping.

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