Objective
The objective of the study was to compare the pharmacokinetics of 2 g and 3 g doses of cefazolin when used for perioperative prophylaxis in obese gravidae undergoing cesarean delivery.
Study Design
We performed a double-blinded, randomized controlled trial from August 2013 to April 2014. Twenty-six obese women were randomized to receive either 2 or 3 g intravenous cefazolin within 30 minutes of a skin incision. Serial maternal plasma samples were obtained at specific time points up to 8 hours after drug administration. Umbilical cord blood was obtained after placental delivery. Maternal adipose samples were obtained prior to fascial entry, after closure of the hysterotomy, and subsequent to fascial closure. Pharmacokinetic parameters were determined via noncompartmental analysis.
Results
The median area under the plasma concentration vs time curve was significantly greater in the 3 g group than in the 2 g group (27204 μg/mL per minute vs 14058 μg/mL per minute; P = .001). Maternal plasma concentrations had an impact by body mass index. For every 1 kg/m 2 increase in body mass index at the time of the cesarean delivery, there was an associated 13.77 μg/mL lower plasma concentration of cefazolin across all time points ( P = .01). By the completion of cesarean delivery, cefazolin concentrations in maternal adipose were consistently above the minimal inhibitory concentration for both Gram-positive and Gram-negative bacteria with both the 2 g and 3 g doses. The median umbilical cord blood concentrations were significantly higher in the 3 g vs the 2 g group (34.5 μg/mL and 21.4 μg/mL; P = .003).
Conclusion
Cefazolin concentrations in maternal adipose both at time of hysterotomy closure and fascial closure were above the minimal inhibitory concentration for both Gram-positive and Gram-negative bacteria when either 2 g or 3 g cefazolin was administered as perioperative surgical prophylaxis. Maternal cefazolin concentrations in plasma and maternal adipose tissue are related to both dose and body mass index.
Currently more than 50% of American pregnancies are complicated by maternal overweight status or obesity. Obesity has been correlated with numerous adverse pregnancy outcomes such as hypertensive disorders of pregnancy, gestational diabetes, and increased rates of operative delivery. Moreover, obesity, irrespective of pregnancy, has been demonstrated to be an independent risk factor for the development of postoperative surgical site infections (SSIs). Development of such infections can have both long-term medical sequelae for patients and economic impacts on the health care system.
The American Congress of Obstetricians and Gynecologists recommends surgical prophylaxis with an appropriate antibiotic regimen within 60 minutes of skin incision to reduce postoperative wound complications. The goal of antibiotic prophylaxis is to prevent skin flora from contaminating the operative field. Common skin organisms include Gram-positive bacteria ( Staphylococcus aureus , Streptococcus species, and enterococci), Gram-negative bacteria ( Escherichia coli, Proteus , Serratia ), and anaerobes.
Currently accepted standards for precesarean delivery antibiotic use involves the administration of 1 g of cefazolin, a first-generation hydrophilic cephalosporin, to patients with a body mass index (BMI) of less than 30 kg/m 2 and, based on bariatric literature, 2 g of cefazolin for those with a BMI of 30 kg/m 2 or greater.
To be an effective surgical prophylaxis, cefazolin concentrations should exceed the minimal inhibitory concentration (MIC) for Gram-positive cocci of 1 μg/g and Gram-negative rods (GNRs) of 4 μg/g. Few studies have examined the pharmacokinetics of cefazolin in pregnant women. Moreover, it is unclear whether current antibiotic recommendations are sufficient to prevent SSIs at the time of cesarean delivery in the obese gravida.
Pevzner et al have suggested that antibiotic concentrations in the adipose tissue of obese women given 2 g of cefazolin at the time of cesarean delivery did not reach the MIC of cefazolin for GNRs, thus making this dose ineffective surgical prophylaxis. By assessing the pharmacokinetic parameters of 2 g vs 3 g of cefazolin administered as perioperative prophylaxis in the obese gravida at the time of cesarean delivery, we aim to determine the impact of BMI and cefazolin dose on cefazolin concentrations in maternal plasma, umbilical cord blood, and maternal adipose tissue.
Materials and Methods
Participants
We conducted a double-blinded, randomized controlled trial at Magee-Womens Hospital of University of Pittsburgh Medical Center (Pittsburgh, PA) from August 2013 to April 2014. Eligible participants were pregnant women aged 18 years or older with a prepregnancy BMI of 30 kg/m 2 or greater who were to be delivered via scheduled cesarean delivery. Potential participants were screened for eligibility via assessment of either the available paper medical record or electronic medical chart. Potential participants were consented at a prenatal appointment, during an encounter while in the obstetrical triage unit, or in the preoperative area on the day of presentation for their scheduled cesarean delivery. At the time of surgery, all participants had intact membranes.
Exclusion criteria included type 1 and type 2 insulin-dependent diabetes mellitus, autoimmune disease including systemic lupus erythematosus or discoid lupus, chronic renal disease, chronic corticosteroid use, history of a previous wound breakdown from a cesarean delivery or any other abdominal surgical procedure, allergy to cephalosporins (eg, anaphylaxis, urticaria, or any other systemic consequences), or receipt of antibiotics within 2 weeks of delivery.
Interventions
Subsequent to enrollment, women were randomized to receive either 2 g or 3 g cefazolin, which was ordered from the Magee Central Pharmacy, as their preoperative antibiotic prophylaxis. Randomization was performed by the pharmacy (using www.randomizer.org ), using a 1:1 simple randomization. All investigators and participants were blinded to the dose assignment. This study was conducted with approval of the University of Pittsburgh Institutional Review Board.
Preoperatively, all women had an initial 18-gauge intravenous line (IV) placed for fluid administration and intraoperative resuscitation. Following consent to randomization, women received a second 18-gauge IV line placed in the opposite arm to obtain necessary maternal blood samples. A 5 mL sample of maternal blood was obtained with placement of this IV line as a baseline maternal blood sample. Ringer’s lactate was infused through the secondary IV line at a rate of 30 mL/h to maintain venous patency.
Women were taken to the operating room in which neuraxial anesthesia was administered. After proper anesthesia administration, cefazolin was infused rapidly over 3 minutes via the initial IV line. The primary surgeon performed an abdominal preparation with 4% chlorhexidine gluconate solution per hospital protocol with subsequent sterile draping of the operative field. All patients received Ringer’s lactate through their standard IV line for surgical resuscitation.
Pharmaceutical preparation
Once a patient agreed to enrollment, a research pharmacist dispensed a 150 mL bag of 0.9% normal saline containing either 2 g or 3 g of cefazolin according to a computer-generated randomization list. Bags containing either cefazolin dosage were identically labeled with the term, Cefazolin Study, along with their respective date of pharmaceutical preparation to ensure allocation concealment. Thus, all operating room personnel were blinded to the administered dose. The principal investigator was unblinded to subject allocation only after recruitment was completed.
Sample collection
Maternal blood
A baseline blood sample was obtained from each patient prior to cefazolin infusion. After a 3 minute infusion of either dosage of cefazolin was completed, a 5 mL blood sample was obtained from the secondary IV site (time zero). This blood sample and all further samples were obtained by discontinuing the infusion of Ringer’s lactate, drawing off 5 mL of fluid before obtaining the actual blood sample for analysis. Samples were collected in a 6 mL pink top K2 EDTA vacutainer blood collection tube.
The secondary IV line was then flushed and the Ringer’s lactate infusion restarted. Subsequent maternal blood samples were similarly obtained at the following times after completion of the infusion: 15 minutes, 30 minutes, 60 minutes, 2 hours, 4 hours, 6 hours, and 8 hours. After the last sample, the secondary IV site was discontinued. All blood samples were centrifuged at 4000 × g for 5 minutes within 10 minutes of obtaining the sample or placed on ice for later centrifugation if it could not occur within that time span. Three 1 mL aliquots of the supernatant plasma from each sample were placed into 2 mL microfuge tubes and stored at –80°C for future analysis.
Umbilical cord blood
After delivery of the fetus, the primary surgeon provided investigators with an isolated segment of umbilical cord from the remaining placenta. A 5 mL sample of blood was obtained from the umbilical vein and subsequently centrifuged at 4000 × g for 5 minutes. Three 1 mL aliquots of the supernatant from each sample were placed into 2 mL microfuge tubes and stored at –80°C until future analysis. No direct venipuncture of any neonate was performed.
Maternal adipose tissue
Quarter-sized (25 mm) samples of maternal subcutaneous adipose tissue were obtained at three separate time points during surgery: prior to rectus fascial entry, after hysterotomy closure, and after fascial closure. Samples were removed via use of Mayo scissors or electrocautery. Once obtained, adipose samples were placed into individually labeled sterile sampling bags. Once sealed, all bags were immediately flash frozen in liquid nitrogen and then stored at –80°C for future analysis.
Maternal urine
Cumulative maternal urine was obtained after 2 hours, 4 hours and 8 hours after the cefazolin administration to aid in the calculation of maternal cefazolin clearance. Total urine produced was collected and recorded at each interval, with 30 mL being aliquoted into 2 separate 15 mL conical tubes. Samples were sealed in biohazard bags and stored at –80°C for future analysis.
Sample processing, preparation, and analysis
Cefazolin concentrations in maternal plasma and umbilical cord blood samples were analyzed using a validated liquid chromatography–mass spectrometry method. The maternal adipose tissue samples were homogenized in a 3:1 ratio of deionized water to adipose tissue and were subsequently analyzed in accordance with a previously established method by Dudley et al.
Statistical analysis
Use of 2 g cefazolin in women with a BMI greater than 40 kg/m 2 vs those with a BMI less than 30 kg/m 2 by Pevzner et al revealed an almost 50% difference in cefazolin adipose concentrations at the end of cesarean delivery (4.35 μg/g vs 9.37 μg/g; P < .001). In using a 2 g vs a 3 g 2-tailed strategy and assuming a 50% increase in tissue concentrations in the 3 g group over the 2 g group, with an alpha error 0.05 and power of 80%, approximately 26 total patients would be needed for this study.
A noncompartmental analysis was performed to determine the following pharmacokinetic parameters: area under the plasma concentration vs time (AUC) curve, volume of distribution, plasma clearance, and half-life. All data were assumed to be nonnormally distributed. The Wilcoxon sign-rank test was used to assess the medians of point-wise comparisons between the 2 randomized groups. Generalized linear models (GLM) assessed for differences between groups across the entire period in which plasma samples were obtained while simultaneously controlling for correlation of repeated measures within subjects, accounting for interactions of BMI and dose over a period of time. Differences in cefazolin concentrations in adipose tissue were analyzed via the Wilcoxon rank-sum test under the assumption of a nonparametric distribution of concentrations.
Statistical analysis was performed using STATA 13.0 (StataCorp, College Station, TX). Values of P < .05 were considered statistically significant.
Results
Figure 1 describes the randomization scheme. A total of 28 total women were recruited into the study between August 2013 and April 2014 with 26 available for analysis. Demographics of the study participants are outlined in Table 1 . The median estimated blood loss for all participants was 800 mL in both groups (2 g, interquartile range, 700–800 mL vs 3 g interquartile range, 800–800 mL; P = .54). Both the 2 g and 3 g groups were well matched for demographic parameters; however, women in the 3 g group exhibited a statistically significant greater gestational weight gain as compared with their 2g counterparts, although the BMI at the time of surgery was similar.
| Variable | 2 g dose (n = 13) | 3 g dose (n = 13) | P value |
|---|---|---|---|
| Gestational age at delivery, wks | 39.3 (39.0–39.4) | 39 (38.0–39.0) | .24 |
| Maternal age, y | 29.0 (23.5–34.0) | 31 (30.0–35.0) | .21 |
| Race | |||
| Caucasian | 7 (53.85%) | 6 (46.15%) | |
| African-American | 5 (38.46%) | 4 (30.77%) | |
| Hispanic/Latino | 0 (0%) | 3 (23.08%) | |
| Asian/Pacific Islander | 1 (7.69%) | 0 (0%) | |
| Prepregnancy BMI, kg/m 2 | 39.6 (34.37–42.2) | 36.1 (32.8–40.6) | .19 |
| BMI at time of surgery, kg/m 2 | 42.9 (39.1–46.2) | 41.8 (37.3–44.6) | .63 |
| Gestational weight gain, kg | 7.18 (4.40–10.44) | 11.27 (8.17–16.33) | .04 |
| Total operative time, min | 59.77 (50.0–65.0) | 67.38 (56.0–72.0) | .17 |
| Intravenous fluids administered in operating room, mL | 1600 (1300–2000) | 1500 (1300–2000) | .96 |
| Hemoglobin value, g/dL | |||
| Preoperative | 12.3 (11.5–12.6) | 11.8 (11.2–12.2) | .29 |
| Postoperative | 10.9 (10.15–11.9) | 10.4 (10.2–10.9) | .29 |
Maternal plasma and umbilical cord blood
Table 2 displays the individual pharmacokinetic parameters in the 2 randomized groups. Compared with the 2 g group, the median area under the cefazolin plasma concentration vs the time curve from time zero to 8 hours (AUC 0→8 ) in maternal plasma was significantly greater in the 3 g group (14058 μg/mL per minute vs 27204 μg/mL per minute, respectively; P = .001). Maternal plasma clearances and the volumes of distribution of cefazolin were similar in both the 2 g and 3 g group. Across the entirety of the sampling period of 8 hours, cefazolin concentrations were lower in the 2 g group at each time point ( P < .001) ( Figure 2 ).
| Pharmacokinetic parameter a | 2 g group | 3 g group | P value |
|---|---|---|---|
| Area under the plasma concentration vs time curve, μg/mL per minute | 14058 ± 1342.8 | 27204 ± 2365.8 | .001 |
| Half-life of cefazolin, min | 107.8 ± 6.26 | 123.3 ± 8.2 | .13 |
| Plasma clearance rate, L/min | 0.14 ± 0.01 | 0.11 ± 0.01 | .21 |
| Plasma volume of distribution, L/kg | 13.36 ± 1.11 | 13.45 ± 1.48 | .48 |
| Umbilical cord blood clearance rate, μg/mL | 21.4 ± 1.49 | 34.5 ± 5.77 | < .001 |
| Plasma volume of distribution at steady state, L/kg | 19.8 ± 1.15 | 18.6 ± 1.4 | .48 |
| Umbilical cord plasma concentration to maternal plasma concentration ratio | 0.18 ± 0.02 | 0.22 ± 0.06 | .37 |
| Maternal renal clearance, mL/min | 18.8 ± 4.8 | 22.5 ± 2.8 | .83 |
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