What the evidence says
We conclude that all patients, even those having a scheduled cesarean before the onset of labor or ruptured membranes, should receive prophylactic antibiotics in a single dose administered preoperatively rather than after cord clamping (Level I Evidence, Level 1A Recommendation; TABLE). In high-risk populations (eg, women in labor with ruptured membranes who are having an urgent cesarean), for whom the baseline risk of infection is high, administer the combination of cefazolin plus azithromycin in lieu of cefazolin alone (Level I Evidence, Level 1A Recommendation; TABLE).
If the patient has a history of an immediate hypersensitivity reaction to beta-lactam antibiotics, we recommend the combination of clindamycin (900 mg) plus gentamicin (1.5 mg/kg) as a single infusion prior to surgery. We base this recommendation on the need to provide reasonable coverage against a broad range of pathogens. Clindamycin covers gram-positive aerobes, such as staphylococci species and group B streptococci, and anaerobes; gentamicin covers aerobic gram-negative bacilli. A single agent, such as clindamycin or metronidazole, does not provide the broad-based coverage necessary for effective prophylaxis (Level III Evidence, Level 1C Recommendation; TABLE).
If the patient is overweight or obese, should you modify the antibiotic dose?
The prevalence of obesity in the United States continues to increase. One-third of all US reproductive-aged women are obese, and 6% of women are extremely obese.17 Obesity increases the risk of postcesarean infection 3- to 5- fold.18 Because both pregnancy and obesity increase the total volume of a drug’s distribution, achieving adequate antibiotic tissue concentrations may be hindered by a dilutional effect. Furthermore, pharmacokinetic studies consistently have shown that the tissue concentration of an antibiotic—which, ideally, should be above the minimum inhibitory concentration (MIC) for common bacteria—determines the susceptibility of those tissues to infection, regardless of whether the serum concentration of the antibiotic is in the therapeutic range.19
These concerns have led to several recent investigations evaluating different doses of cefazolin for obese patients. Pevzner and colleagues conducted a prospective cohort study of 29 women having a scheduled cesarean delivery.20 The patients were divided into 3 groups: lean (BMI <30 kg m2), obese (BMI 30.0–39.9 kg m2), and extremely obese (BMI >40 kg m2). All women received a 2-g dose of cefazolin 30 to 60 minutes before surgery. Cefazolin concentrations in adipose tissue obtained at the time of skin incision were inversely proportional to maternal BMI (r, −0.67; P<.001). All specimens demonstrated a therapeutic concentration (>1 µg/g) of cefazolin for gram-positive cocci, but 20% of the obese women and 33% of the extremely obese women did not achieve the MIC (>4 µg/g) for gram-negative bacilli (P = .29 and P = .14, respectively). At the time of skin closure, 20% of obese women and 44% of extremely obese women did not have tissue concentrations that exceeded the MIC for gram-negative bacteria.
Swank and associates conducted a prospective cohort study that included 28 women.18 They demonstrated that, after a 2-g dose of cefazolin, only 20% of the obese women (BMI 30–40 kg m2) and 0% of the extremely obese women (BMI >40 kg m2) achieved an adipose tissue concentration that exceeded the MIC for gram-negative rods (8 µg/mL). However, 100% and 71.4%, respectively, achieved such a tissue concentration after a 3-g dose. When the women were stratified by actual weight, there was a statistically significant difference between those who weighed less than 120 kg and those who weighed more than 120 kg. Seventy-nine percent of the former had a tissue concentration of cefazolin greater than 8 µg/mL compared with 0% of the women who weighed more than 120 kg. Based on these observations, the authors recommended a 3-g dose of cefazolin for women who weigh more than 120 kg.
In a double-blind RCT with 26 obese women (BMI ≥30 kg m2), Young and colleagues demonstrated that, at the time of hysterotomy and fascial closure, significantly higher concentrations of cefazolin were found in the adipose tissue of obese women who received a 3-g dose of antibiotic compared with those who received a 2-g dose.21 However, all concentrations of cefazolin were consistently above the MIC of cefazolin for gram-positive cocci (1 µg/g) and gram-negative bacilli (4 µg/g). Further, Maggio and co-workers conducted a double-blind RCT comparing a 2-g dose of cefazolin versus a 3-g dose in 57 obese women (BMI ≥30 kg m2).22 They found no statistically significant difference in the percentage of women who had tissue concentrations of cefazolin greater than the MIC for gram-positive cocci (8 µg/g). All samples were above the MIC of cefazolin for gram-negative bacilli (2 µg/g). Based on these data, these investigators did not recommend increasing the dose of cefazolin from 2 g to 3 g in obese patients.21,22
The studies discussed above are difficult to compare for 3 reasons. First, each study used a different MIC of cefazolin for both gram-positive and gram-negative bacteria. Second, the authors sampled different maternal tissues or serum at varying times during the cesarean delivery. Third, the studies did not specifically investigate, or were not powered sufficiently to address, the more important clinical outcome of surgical site infection. In a recent historical cohort study, Ward and Duff were unable to show that increasing the dose of cefazolin to 2 g in all women with a BMI <30 kg m2 and to 3 g in all women with a BMI >30 kg m2 reduced the rate of endometritis and wound infection below the level already achieved with combined prophylaxis with cefazolin (1 g) plus azithromycin (500 mg).15
Sutton and colleagues recently assessed the pharmacokinetics of azithromycin when used as prophylaxis for cesarean delivery.23 They studied 30 women who had a scheduled cesarean delivery and who received a 500-mg intravenous dose of azithromycin that was initiated 15, 30, or 60 minutes before the surgical incision and then infused over 1 hour. They obtained maternal plasma samples multiple times during the first 8 hours after surgery. They also obtained samples of amniotic fluid, placenta, myometrium, adipose tissue, and umbilical cord blood intraoperatively. The median concentration of azithromycin in adipose tissue was 102 ng/g, which is below the MIC50 for Ureaplasma species (250 ng/mL). The median concentration in myometrial tissue was 402 ng/g. The concentration in maternal plasma consistently exceeded the MIC50 for Ureaplasma species.