Plasma and Tissue Cefazolin Concentrations in Obese Patients Undergoing Cesarean Delivery and Receiving Differing Pre-Operative Doses of Drug

Abstract

Background:

Patients undergoing cesarean delivery typically receive a 1-g to 2-g dose of cefazolin as pre-operative antibacterial prophylaxis. This traditional dosage may not provide an adequate tissue concentration of cefazolin in obese patients during the peri-operative period. This study compared the tissue concentrations of prophylactic cefazolin administered as a either a 2-g or a 4-g dose prior to cesarean delivery in obese patients.

Methods:

Twenty obese patients (first trimester body mass index [BMI] >35) who underwent cesarean delivery completed this randomized study. Eleven patients received 2 g of cefazolin, and nine received 4 g. Blood and subcutaneous tissues were collected at the times of the incision and closure. Myometrial biopsies were collected at uterine closure. A cefazolin concentration threshold of 4 mcg/g for tissue samples was used as a surrogate adequate concentration. Plasma and tissue cefazolin concentrations were compared for the two doses.

Results:

Mean plasma, umbilical cord, and myometrial cefazolin concentrations were significantly higher in the 4-g treatment group (p<0.05). Subcutaneous incision site tissue obtained at time of incision creation also was significantly higher in the 4-g group than in the 2-g group (40.11±24.10 mcg/g vs. 18.36±6.68 mcg/g; p=0.0005). Subcutaneous tissue concentrations at closure were significantly different in the two dosage groups (34.89±17.42 mcg/g vs. 21.73±16.02 mcg/g; p=0.044). All tissue samples were above the target of 4 mcg/g. Body morphometry did not correlate with the variability in cefazolin tissue concentration. No surgical site infections, endometritis, or other adverse effects were observed.

Conclusions:

Administering a prophylactic dose of 4 g of cefazolin produced blood and tissue cefazolin concentrations that were significantly higher than concentrations obtained from a 2-g dose in patients with BMIs between 35 and 60 kg/m² undergoing cesarean delivery. It is unclear if the larger cefazolin dose produces a more protective anti-infective effect than that obtained with the more traditional 2-g dose for cesarean delivery in obese patients.

Pre-operative administration of prophylactic antibiotics is a well-accepted evidence-based practice worldwide [1]. The efficacy of prophylactic antibiotics for the prevention of endometritis and surgical site infections (SSIs) in cesarean delivery has been established by clinical trials [2,3]. The accepted mechanism for effective antimicrobial prophylaxis involves achieving therapeutic tissue concentrations of the antibiotic at the time of the incision. Cefazolin is the preferred prophylactic agent because of its excellent safety record in pregnancy and its clinical efficacy as a prophylactic agent [2,4]. Cefazolin is recommended by national guidelines in a dose of 1–2 g intravenously within 60 min prior to cesarean delivery [5]. Dosage recommendations from the national guidelines are admittedly less certain for obese patients, as these patients were not represented substantially in clinical or pharmacokinetic studies. Even a working group from the National Surgical Infection Prevention Project published an advisory statement that recommends consideration of patients' weight and body mass index (BMI) to ensure dosing adequacy [1]. Unfortunately, no specific dosage recommendations were included for obese pregnant patients. Obesity has been identified as a risk factor for SSIs, including cesarean deliveries [3,6 –8]. Theoretically, multiple factors may influence the risk of SSI in the obese patient undergoing cesarean delivery. It is known that subcutaneous tissue depth >3 cm increases the risk of SSI after cesarean delivery [9]. Closure of the subcutaneous tissue layer in this population reduces the risk of site complications [10]. Decreased tissue oxygen tension may play a role in the risk of SSI in the obese patient, but the administration of high-concentration supplemental oxygen in the peri-operative period has not decreased the number of SSIs in patients undergoing cesarean delivery [11].

On pharmacokinetic grounds, it is hypothesized that adequate free-antibiotic tissue concentrations are more important than plasma concentrations in determining prophylactic antibiotic efficacy [12]. Multiple factors influence the distribution of antibiotic molecules from the plasma into the tissues. Such factors include simple diffusion rates, plasma protein binding, active transport, and tissue-site metabolism. Studies of antibiotic tissue concentrations in obese patients undergoing bariatric and abdominal operations show that conventional antibiotic dosing may fail to achieve therapeutic tissue concentrations [13 –16]. A recent study by Pevzner et al. showed that a 2-g dose of cefazolin administered 30–60 min prior to cesarean delivery in obese (BMI 30–39.9) or extremely obese (BMI ≥40) patients failed to achieve targeted minimum inhibitory concentrations (MICs) in 20% and 33%, respectively, of patients at the time of skin incision and in 20% and 40% of patients at the time of incision closure [17]. A recent clinical audit of post-cesarean SSI at our university hospital revealed that of ten patients having infections over a seven-month period, nine had a first-trimester BMI ≥30, and eight had a first-trimester BMI >35. This finding led to initiatives to investigate why this subset of patients was at greater risk of SSI after cesarean delivery. Inadequate antibiotic concentration at the incision site was the variable considered most likely to be responsible for the increase in SSIs. Therefore, we developed a study protocol to determine if administering larger doses of cefazolin would be associated with adequate cefazolin tissue concentrations and a lower risk of infections in obese patients undergoing cesarean delivery. The main objective of this study was to assess if the antibiotic tissue concentrations of prophylactic cefazolin administered as a 2-g versus 4-g dose prior to cesarean delivery in patients with a first-trimester BMI ≥35 were above the MIC breakpoint for organisms common in these SSIs.

Patients and Methods

Patients and data sources

This randomized study was conducted at the West Virginia University Hospitals. The protocol was reviewed and approved by the University's Institutional Review Board. Written informed consent was obtained from all enrolled subjects.

Eligible subjects were adults with a BMI ≥35 as measured at the first prenatal (first-trimester) visit who were undergoing cesarean delivery. Exclusion criteria included allergy to cephalosporins, a history of anaphylactic reaction to penicillin, established infection, chronic kidney disease, or emergency cesarean delivery. Patients also were excluded if not all of the planned blood and tissue samples were available. Subjects were randomized using a simple scheme employing computer-generated random numbers, with the allocation concealed until randomization using sequentially numbered opaque envelopes. Subjects, medical personnel, investigators, and laboratory personnel were not blinded to allocation once randomization was complete. The patient care team and the patient likewise were not blinded to treatment group allocation.

The time for patients to enter the operating room and have the surgery is a small window. The administration of prophylactic cefazolin was part of the pre-operative “time out” checklist. Therefore, the usual practice is to administer the antibiotic during the timeout period, which occurs just prior to the start of the procedure. In many cases, the cefazolin was not infused over 15 min but rather given by intravenous push. Thus, delivery of the antibiotic dose was completed before the start of surgery.

Maternal factors that could affect drug distribution were recorded. These were baseline BMI (first antenatal clinic visit), BMI at the time of delivery, weight at delivery, blood loss, number of previous cesarean deliveries, number of prior deliveries, and subcutaneous tissue depth. Times of cefazolin administration and time of surgery start, surgery end, and collection of samples were recorded. Patient outcomes were assessed to identify post-operative infection. For patients without documented post-operative visits, telephone contact was made to obtain the information. Patient records were reviewed six to eight weeks after delivery to assess for SSI. Surgical site infections were identified using the National Healthcare Safety Network criteria [18].

A targeted cefazolin concentration threshold of 4 mcg/mL for plasma and 4 mcg/g for tissue samples was used as a surrogate measure of adequate treatment. This figure was chosen because it is the breakpoint for susceptibility of Staphylococcus aureus and would be above the MICs for most of the commonly encountered organisms, including methicillin-susceptible S. aureus, Streptococcus spp., and Enterobacteriaceae. This same surrogate target was used by Pevzner et al. in related studies [17,19].

Plasma and Tissue Sample Collection and Analysis

Blood was drawn at the time of the skin incision and also at the time of incision closure. Subcutaneous tissue biopsies were harvested at the time of opening and closing of the incision. Myometrial tissue biopsies were obtained at the time of uterine closure by excising a portion of the myometrium at the superior margin of the uterine incision. Umbilical cord blood was collected at the time of cord clamping. Blood samples were centrifuged and the plasma frozen until analysis. Tissue samples were frozen at −20°C until needed. High-performance liquid chromatography was used for analysis of the cefazolin concentrations in both the plasma and the tissue samples using validated methods [20]. The combined intra-day and inter-day accuracy ranged from 2.0% to 7.9% (relative standard deviation).

Statistical Analysis

A convenience sample of 20–24 subjects was chosen for this study in the absence of data to use for a priori sample size calculation. Statistical analysis was performed using JMP 7.0 (SAS Institute Inc., Cary, NC) and Excel 2007 statistics package add-in (Microsoft, Redmond, WA). Continuous data were analyzed using paired and unpaired t-tests as appropriate, and categorical data were analyzed by the Fisher exact test. In situations where data failed a test of normality (Kolmogorov–Smirnov test), a non-parametric (Mann–Whitney U) test was used. Linear regression analysis was performed to assess correlation of concentration measures with body size metrics. A significance of p=0.05 was used for all calculations.

Results

Twenty-three patients were randomized to receive either a 2-g (n=11) or a 4-g (n=9) dose of cefazolin. The other three patients were excluded from the study because of an allergic reaction to cefazolin early in the infusion; inadequate blood draws because of lack of access; and insufficient tissue specimens. Patient demographic and baseline characteristics were similar in the two treatment groups (Table 1). Using the World Health Organization (WHO) definitions of obesity (www.who.int), four patients in the 2-g group and two patients in the 4-g group were extremely obese (BMI>40) according to their baseline BMIs. The mean baseline BMI and delivery BMI values were not significantly different in the two dosage groups. The operational parameters—operative time, blood loss, and subcutaneous incision depth—were similar in the two groups. The timing of myometrial and cord blood collection also was similar.

Table 1.

Demographic and Baseline Characteristics of Patients ^a

	Cefazolin 2 g (n=11)	Cefalozin 4 g (n=9)
Maternal age (years)	31.09±6.46	30.33±4.64
Gestational age (weeks)	38.75±1.28	36.94±3.39
Height (cm)	167.18±7.60	160.90±7.30
Weight (kg)	117.81±23.35	107.78±28.33
Body mass index (BMI; kg/m²)	41.98±6.85	41.01±8.04
BMI at time of delivery	46.02±5.96	43.23±8.44
No. of previous births	1.36±1.12	1.44±0.88
Previous cesarean deliveries	0.91±0.83	1.00±0.71
Mean operative time (min)	68.09±13.53	56.22±14.82
Estimated blood loss (L)	1.054±0.365	0.872±0.182

None of the differences is statistically significant.

The mean cefazolin plasma, umbilical cord, and myometrial concentrations were significantly higher in the 4-g treatment group (Table 2; p<0.05). The concentration in the subcutaneous incision-site tissue obtained at the time of incision also was significantly higher in the 4-g treatment group, 40.11±24.10 mcg/g versus 18.36±6.68 mcg/g (p=0.0005). At the time of incision closure, subcutaneous tissue concentrations remained significantly different in the two dosage groups, 34.89±17.42 mcg/g versus. 21.73±16.02 mcg/g (p=0.044).

Table 2.

Plasma and Tissue Concentrations of Cefazolin

Site	2-g dose (n=11)	4-g dose (n=9)	P value
Plasma concentration at incision (mcg/mL)	155.45±50.97	346.16±166.01	0.0004
Plasma concentration at closure (mcg/mL)	83.49±34.97	150.12±55.54	0.0125
Subcutaneous concentration at incision (mcg/g)	18.36±6.68	40.11±24.10	0.0005
Subcutaneous concentration at closure (mcg/g)	21.73±16.02	34.89±17.42	0.044
Myometrium (mcg/g)	67.18±13.89	146.22±60.99	0.004
Umbilical cord blood (mc/mL)	25.01±12.03	82.23±43.03	0.0001

Plasma concentrations decreased significantly from the time of incision to the time of closure in both treatment groups. In the 2-g group, the mean cefazolin concentrations decreased from 155.45±50.97 to 83.49±34.97 mcg/g (p=0.0002), whereas in the 4-g group, the mean concentrations decreased from 346.16±166.01 to 150.12±55.54 mcg/g (p=0.0008). Subcutaneous tissue concentrations obtained from incision sites did not change significantly during the operative procedure in either dosage group. In the 2-g group, the mean cefazolin subcutaneous tissue concentrations increased slightly, from 18.36±6.68 to 21.73±16.02, whereas in the 4-g group, the mean tissue concentrations decreased from 40.11±24.10 to 34.89±17.42 (p=not significant for either group).

Body size metrics (BMI and weight) appeared to be poor predictors of delivery of cefazolin to the subcutaneous tissue (Table 3). The highest correlation coefficient of determination (R²) was 0.210 (p=0.215), which was seen with patient body weight at delivery and cefazolin tissue concentrations at incision closure. The variability of body size metrics appeared to explain less than 15% of the variability in cefazolin tissue concentrations in all other assessments. Cefazolin concentrations were not significantly lower in patients who were classified as extremely obese.

Table 3.

Assessment of Body Weight and Body Mass Index (BMI) with Cefazolin Subcutaneous Tissue Concentration

Correlation pairing	R²	p value
2-g dose
Baseline BMI–tissue at incision	0.120	0.295
Delivery body weight–tissue at incision	0.061	0.462
Delivery BMI–tissue at incision	0.073	0.421
Baseline BMI–tissue at incision closure	0.005	0.843
Delivery body weight–tissue at incision closure	0.008	0.798
Delivery BMI–tissue at incision closure	0.015	0.722
4-g dose
Baseline BMI–tissue at incision	0.126	0.348
Delivery body weight–tissue at incision	0.140	0.321
Delivery BMI–tissue at incision	0.091	0.431
Baseline BMI–tissue at incision closure	0.061	0.521
Delivery body weight–tissue at incision closure	0.210	0.215
Delivery BMI–tissue at incision closure	0.100	0.406

No patient in either group experienced an SSI or endometritis. Both doses of cefazolin appeared to provide adequate delivery of the drug to the blood and tissue, as no cefazolin concentrations were below the surrogate target MIC of 4 mcg/mL or 4 mcg/g. Lastly, no maternal or neonatal adverse reactions were attributed to cefazolin beyond the one subject who developed an allergic reaction and thus was excluded from the study.

Discussion

This is the first study to describe the use and tissue delivery of a 4-g dose of cefazolin in obese women undergoing cesarean section delivery. Our original hypothesis, that there would be insufficient cefazolin at the site of surgery in the 2-g group in relation to common MIC breakpoints, appears not to be the case. Despite the higher blood and opening incision tissue concentrations in the 4-g treatment group, we were unable to find any compelling data suggesting a clinical benefit from using the larger dose. However, this conclusion may be limited by the study's modest sample size. A previous study with 29 obese subjects receiving a 2-g pre-cesarean dose did identify five patients with subcutaneous adipose tissue concentrations lower than the 4 mcg/g target and two patients who developed SSIs [17]. Those investigators administered cefazolin over 30–60 min prior to the incision for the cesarean delivery. The findings of our internal audit served as the impetus for our current study. Surprisingly, of our 11 patients receiving 2 g of cefazolin, none had tissue concentrations below 4 mcg/g, nor did any patient develop post-operative infection. Our poor body size–cefazolin tissue concentration correlation may reflect the small number of data points in each dosage group. Nonetheless, our data do suggest that 2 g is adequate for the majority of patients undergoing cesarean delivery.

The cefazolin concentrations reported by Pevzner et al. are lower than those in our patients who were given 2 g of cefazolin [17]. Patient characteristics appeared to be similar in the two studies. However, the previous investigators did wait at least 30 min (but not more than 60 min) from antibiotic to incision. They did not describe the procedure for administering cefazolin, which may or may not have included a longer infusion time (standard 15–30 min). Our cefazolin administration was by intravenous push over 30–60 sec, which may have allowed more rapid cefazolin distribution to the subcutaneous tissue. The obstetric surgeons in our study performed the incision fairly soon after cefazolin was given (on average, 12 min from antibiotic to incision and 74 min from antibiotic to surgery completion). In addition, our study analyzed cefazolin in plasma, whereas the previous study used serum. These factors could explain some of the differences between the two studies.

The absence of SSIs and cases of endometritis may be associated with the excellent delivery of cefazolin to the subcutaneous incisional tissue and myometrial tissue in both dosage groups. Blood and tissue concentrations were well above the targeted MIC of 4 mcg/mL. Essentially all methicillin-susceptible S. aureus have cefazolin MIC values<2 mcg/mL and would be susceptible in vitro [21]. Cefazolin susceptibility patterns among gram-negative pathogens are more variable. Recent MIC distribution data for the common Enterobacteriaceae Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis suggests that a 4 mcg/mL cefazolin in vitro dilution would be effective against 91.0%, 84.1%, and 75.3% of isolates, respectively [22]. The same data set shows that a cefazolin concentration of 16 mcg/mL may be required to achieve >90% susceptibility in all three species. The mean cefazolin concentration delivered to the subcutaneous tissue by our 2-g dose was 18.40±6.68 mcg/g. The subcutaneous tissue concentrations delivered by the 4-g dose were considerably higher (40.11±24.10 mcg/g) and could potentially confer greater protection against organisms with MICs of 16 mcg/mL. What is not known, of course, is what concentration of cefazolin is needed in the tissue in relation to specific bacterial MICs to prevent the development of an infection. We did not witness any SSIs in either dosage group. Our study was not powered to assess differences in infection rate but rather to compare pharmacokinetic differences. Because our patients underwent relatively quick elective cesarean deliveries, we caution against extrapolating our findings to more complicated emergency operations.

Cefazolin generally is well-tolerated with minimal maternal and neonatal risk, with the exclusion of hypersensitivity reactions. The safety of single 4-g doses of cefazolin in non-obese adults has been examined [23]. Our results demonstrated an absence of dose-related toxicities to mother or neonatal infant. Given the findings of this study, it is unclear whether the larger cefazolin dose produces a more protective anti-infective effect over the more traditional 2-g dose in obese patients undergoing cesarean section.

Footnotes

Acknowledgment

The authors are grateful to Dr. Jay Bringman, Department of Obstetrics and Gynecology, Geisinger Health System, Danville, PA, for referring patients and to the Virginia Commonwealth University Analytical Research Laboratory (Dr. Todd Gehr, Dr. Don Farthing, Christine Farthing, and Terri Larus) for performing the analytical work on the plasma and tissue samples.

Author Disclosure Statement

None of the authors has potential conflicts of interest to disclose. Funding for this study was provided by West Virginia University Center for Quality Outcomes.

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