The Journal of Maternal-Fetal & Neonatal Medicine

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Calculating the appropriate prophylactic dose of

cefazolin in women undergoing cesarean delivery

Yuval Fouks , Eran Ashwal , Yariv Yogev , Sharon Amit , Tali Ben Mayor Bashi ,
Noa Sinai , Anastasia Firsow , Eyal Hasson , Ronni Gamzu & Ariel Many

To cite this article: Yuval Fouks , Eran Ashwal , Yariv Yogev , Sharon Amit , Tali Ben Mayor
Bashi , Noa Sinai , Anastasia Firsow , Eyal Hasson , Ronni Gamzu & Ariel Many (2020):
Calculating the appropriate prophylactic dose of cefazolin in women undergoing cesarean delivery,
The Journal of Maternal-Fetal & Neonatal Medicine, DOI: 10.1080/14767058.2020.1786529

To link to this article: https://doi.org/10.1080/14767058.2020.1786529

Published online: 14 Jul 2020.

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THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE
https://doi.org/10.1080/14767058.2020.1786529

ORIGINAL ARTICLE

Calculating the appropriate prophylactic dose of cefazolin in women

undergoing cesarean delivery
Yuval Fouksa, Eran Ashwala, Yariv Yogeva, Sharon Amitb, Tali Ben Mayor Bashia, Noa Sinaia,
Anastasia Firsowc,d, Eyal Hassonc,d, Ronni Gamzua and Ariel Manya
a
Department of Obstetrics and Gynecology, Lis Maternity Hospital, Tel-Aviv, Israel; bThe Department of Clinical Microbiology and
Infectious Diseases, Hadassah University Hospital, Jerusalem, Israel; cThe Clinical Biochemistry Laboratory, Tel-Aviv Medical Center,
Tel-Aviv, Israel; dSackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel

ABSTRACT ARTICLE HISTORY

Background and Objectives: Surgical site infection and other postoperative complications are Received 8 March 2020
relatively common in obstetrical procedures, and they are associated with morbidity, prolonged Accepted 19 June 2020
hospital stay, and readmissions. Appropriate levels of antimicrobial agents given directly before
KEYWORDS
skin incision can prevent the establishment of surgical-related infection caused by endogenous
Cefazolin; minimal
microorganisms present on the woman’s skin. We aimed to determine serum concentrations of inhibitory concentration;
cefazolin given to pregnant women prior to scheduled cesarean delivery and to compare their cesarean delivery;
drug concentrations and pharmacokinetics in 2 weight groups. antimicrobial prophylaxis
Study Design: We conducted a prospective cohort analysis of the pharmacokinetics of cefazolin
in women undergoing cesarean delivery (August 2017 to September 2018). One or two grams
of intravenous cefazolin was administered within 30 min prior to skin incision to women weigh-
ing <80 kg and
80 kg, respectively. Maternal serum samples were obtained at skin incision
and 30 min later. The serum concentration of cefazolin was measured by high-pressure liquid
chromatography. Antimicrobial coverage was defined as being appropriate when the cefazolin
levels were above the minimal inhibitory concentration. Pharmacokinetic parameters were esti-
mated using a one-compartment model.
Results: A total of 61 women were enrolled, of whom 47 underwent cesarean delivery (study
group). The mean time that had elapsed between drug administration to incision was
13 ± 6.9 min (95% confidence interval 10.6–16.2 min). The drug levels after 30 min in women
who weighed >80 kg and in women who received 2 g cefazolin, after 30 min from incision dif-
fered significantly (87.0 ± 26.0 vs 55.4 ± 16.6 lg/ml, p ¼ .0001).
Conclusion: A single 1- or 2-g dose of cefazolin provides serum concentrations above minimal
inhibitory concentrations for susceptible pathogens in most women undergoing scheduled
cesarean delivery.

Introduction pH, body temperature, and patient comorbid-

Antimicrobial prophylaxis prior to surgical procedures
is essential for the reduction of surgical site infections
and other postoperative complications [1,2]. These
complications are relatively common in the cesarean
section [3], and they are associated with profound
morbidity, prolonged hospital stay, and re-admissions.
The administration of an appropriate level of an anti-
microbial agent at the time of skin incision decreases
the establishment of surgery-related infection by
endogenous microorganisms present on the patient’s
skin [3–6]. An adequate antimicrobial prophylactic
serum level depends upon several factors, such as the
patient’s weight, fat distribution, renal function, body
ities [7–9].
Cefazolin is one of the most tested antimicrobial
prophylactic agents. Several recent studies have tried
to assess their intraoperative serum and tissue levels
[10–12]. The serum half-life for cefazolin is estimated
to be approximately 1.8 h following intravenous (IV)
administration in the general surgical population [13],
however, it is believed to vary in gravid women due
to the unique hemodynamic changes in pregnancy
[14]. There are limited data on the half-life of cefazolin
during the third trimester in women undergoing
cesarean delivery. The ACOG recommends the admin-
istration of 1 g of IV cefazolin as prophylaxis prior to

CONTACT Yariv Yogev Fouksi@gmail.com Department of Obstetrics and Gynecology, Lis Maternity Hospital, 6 Weizmann Street, Tel Aviv
6423906, Israel
ß 2020 Informa UK Limited, trading as Taylor & Francis Group
2 Y. FOUKS ET AL.
cesarean delivery in women weighing 80 kg, and
increasing the dose to 2 g for women weighing

80 kg [14].
Recent studies that assessed cefazolin levels in
women scheduled for cesarean delivery were mostly
aimed to determine serum and tissue levels at the
time of delivery [10–12,15], and focused primarily on
obese and morbidly obese subjects and not on those
of normal weight. Thus, in this study, we aimed to
determine the cefazolin elimination rate in women
undergoing cesarean delivery and to calculate the
appropriate prophylactic dose of cefazolin in women
undergoing cesarean delivery by maternal weight.
Materials and methods
Study population
We conducted a prospective cohort study at a single
University-affiliated tertiary medical center from
August 2017 to April 2018. Eligibility was limited to
pregnant (more than 37 completed weeks of gesta-
tion) women aged
19 years at the time of study
recruitment who underwent scheduled elective cesar-
ean sections. All the women were assessed for eligibil-
ity by a questionnaire they filled in at the time of
hospital admission. Exclusion criteria included a history
of renal failure (acute or chronic), chronic hyperten-
sion, diabetes, and autoimmune diseases, as well as
exposure to antibiotics (within 14 d) or known allergy
to penicillin and/or to cephalosporins. The study was
approved by the local institutional review board and
all participants provided written informed consent.
Interventions
Pregnant women at term who were undergoing
scheduled cesarean delivery and who weighed <80 kg
received 1 g of IV cefazolin, and those who weighed
>80 kg received 2 g of IV cefazolin.
All participants underwent neuraxial anesthesia. A
bolus of 1 or 2 g of cefazolin was administered IV no
longer than 45 min prior to skin incision. The first
serum samples were taken at the time of skin incision
(time 0), and the second serum samples were taken
30 min from skin incision (time 30).
Sample collection and processing
Blood samples were collected in a 6 ml yellow
top vacutainer tube which was transported to the
laboratory within 3 h and centrifuged for 10 min at
1500 rpm. The specimens were stored at 80  C.
High-performance liquid chromatography (HPLC) was
used to separate the mixture of compounds [16]. It is
accepted that in order to provide an effective level of
cefazolin serum levels should exceed the minimal
inhibitory concentration (MIC) for gram-negative rods
of 8 mg/g [17].
Data collection
The following data were collected: patient’s age, body
weight, and height, antimicrobial dose and time of
infusion, the overall duration of surgery, hemoglobin
concentration and hematocrit level (prior to and after
surgery), basal creatinine level, intraoperative fluid
intake, intraoperative estimated blood loss, and phar-
macokinetic parameters (drug elimination rate and
half-life).
Statistical and pharmacokinetic analysis
The pharmacokinetic analysis was performed accord-
ing to a one-compartment model using the first-order
kinetics, the elimination rate constants (ke), and the
elimination half-lives (t1/2). A p value <.05 was consid-
ered statistically significant. Linear regression models
were assessed for differences between groups across
the entire period during which plasma samples were
obtained. Statistical analysis was performed using
SPSS 25 (St. Louis, MO). Calculations for post hoc
power analysis were based on the estimated differ-
ence in half-life between the 2 groups which received
1 g cefazolin (i.e. the study women weighing <80 kg
and the controls), with an alpha of 0.05 and a power
of 0.8.
Results
Overall, 61 women were recruited for this study, of
whom 47 women underwent scheduled cesarean sec-
tion and 42 were found suitable for analysis after
exclusion (Figure 1). Patients demographics and clin-
ical data are presented in Table 1. All baseline charac-
teristics in both groups such as patient age at the
time of delivery, gestational age, and mean blood loss,
did not differ significantly between the groups. None
of the women who participated in the study had
infectious complications, such as surgical site infection
or metritis, either during postoperative hospitalization
or following discharge.
 THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 3

Figure 1. Flowchart.

Table 1. Patients’ clinical characteristics.

CS received CS received CS received
1 g cefazolin GYN received 1 g p 1 g cefazolin 2 g cefazolin p
n ¼ 21 n ¼ 17 n ¼ 21 n ¼ 21
Age (years) 34 (±1.1) 53 (±15.8) .001 34 (±1.1) 34.6 (±7.1) .8
Height (m) 1.6 1.6 ns 1.6 1.6 ns
Weight (kg) 67.3 (±6.1) 61.8 (±6.1) .01 67.3 (±6.1) 92.4 (±8.2) .001
BMI 26.1 22.2 .01 26.1 33.6 .0001
Gestational age (weeks) 38 þ 2 nr nr 38 þ 2 38 þ 0 .07
(37 þ 5 – 40 þ 6) (37 þ 5 – 40 þ 6) (37 þ 4 – 40 þ 3)
Hemoglobin at admission (g) 11.9 12.3 11.9 12.1
Hemoglobin (first at maternity) (g) 11 11.1 11 11.4
Hemoglobin (delta) 1.0 (±0.5) 0.97 (±0.6) .4 1.0 (±0.5) 0.9 (±0.7) .3
Hematocrit at admission (%) 35.7 34.8 35.7 35.7
Hematocrit (first at maternity) (%) 34.7 33.2 34.7 34.7
Hematocrit (delta) 1.2 1.5 .7 1.2 1.2 .2
Administrationto incision interval of 13.0 (±4.2) 17.1 (±11.2) .3 13.0 (±4.2) 13.0 (±3.5) .1
cefazolin (min)
First prenatal visit.
Data are mean standard deviation or n (%) unless otherwise specified.

Plasma drug concentrations
Women undergoing cesarean delivery who received
either 1 or 2 g cefazolin had comparable administration-
to-incision time intervals (13 ± 3.5 and 13 ± 4.2 min,
p ¼ .10) (Table 2). All women received prophylactic
boluses within 45 min from skin incision.
Figure 2 demonstrates the linear regression of the
time which elapsed from prophylactic bolus adminis-
tration until skin incision in correlation with serum lev-
els of cefazolin. The rate of decrease in cefazolin level
until incision was higher among women undergoing
cesarean delivery who received 1 g cefazolin compared
to the group received 2 g.
Drug levels following cefazolin administration
Women who weighed <80 kg and received 1 gm cefa-
zolin had lower drug levels at the time of incision
(time 0) than women undergoing cesarean delivery
who weighed >80 kg and received 2 g cefazolin but
4 Y. FOUKS ET AL.

Table 2. Plasma concentrations of cefazolin in cesarean and non-pregnant patients.

CS received 1 g cefazolin GYN received 1g p CS received 1 g cefazolin CS received 2 g cefazolin p
Cefazolin time 0 (lg/ml) 91.0 (±30.8) 112.7 (±32.2) .06 91.0 (±30.8) 128.6.0 (±41.8) .08
Cefazolin time 30 (lg/ml) 55.4 (±16.6) 75.2 (±20.3) .02 55.4 (±16.6) 87.0 (±26.0) .0001
Cefazolin average decrease rate (%) 36.4 (±13.6) 31.1 (±10.7) .2 36.4 (±13.6) 28.8 (±14.8) .07
Half life of cefazolin 1.2 (±0.6) 1.7 (±1.1) .1 1.2 (±0.6) 2.6 (±2.1) .04
Data are mean standard deviation or n (%) unless otherwise specified.

Figure 2. A Linear regression analysis comparing cefazolin concentrations at incision time by interval from administration.

this difference did not reach statistical significance
(128.6 ± 41.8 vs 91.0 ± 30.8 lg/ml, p ¼ .08).
The mean drug levels 30 min from the incision was
significantly higher in the women weighing >80 kg
who received 2 g cefazolin compared to the women
weighing <80 kg who received 1 g cefazolin
(87.0 ± 26.0 vs 55.4 ± 16.6 lg/ml, p ¼ .0001) (Figure 3).
The calculated half-life of cefazolin in pregnancy,
assuming for 1 compartment model, following the
administration of 1 gm cefazolin was 1.1 (0.8–1.8
IQR) hours.
Discussion
The currently available data on pregnancy-related
pharmacokinetic and dosing for cesarean delivery
prophylaxis are incomplete, which may result in sub-
optimal prophylactic antibiotic regimens for women
undergoing cesarean delivery. In this study, we aimed
to determine serum levels of cefazolin among normal
weight and overweight women who underwent
scheduled cesarean deliveries.
In order to evaluate the current antimicrobial regi-
men guidelines, we used the prophylactic doses rec-
ommended by the ACOG [1,2]. Women weighing
>80 kg who underwent cesarean delivery and received
2 g cefazolin had significantly higher serum levels at
both time intervals compared to women who under-
went cesarean delivery who weighed <80 kg and
received 1 g cefazolin. The elimination curve of the lat-
ter group was considerably more acute (Figure 3). The
serum cefazolin levels measured in all study partici-
pants were above the desirable MIC for both intervals.
Although our study did not aim to assess adipose or
tissue levels of cefazolin, we observed initial
serum levels that were comparable [10] and better
[11] than those reported in earlier studies whose
authors concluded that cefazolin adipose concentra-
tions of women with similar weights were
adequate [3,4].

Figure 3. Analysis comparing cefazolin concentrations after 30 min among study groups.
Our objective in calculating the half-life of cefazolin
in pregnant women at term was to assess the impact
of pregnancy on drug pharmacokinetics. We set the
sampling intervals at specific time points, unlike other
studies that assessed cefazolin levels at the time of
fascial incision and intervals after fascial closure [3,5].
The reported half-life of cefazolin in the nonpregnant
population is estimated to be 1.8–2.2 h [1,2]. Our cal-
culated half-life time of cefazolin in women under-
going cesarean delivery who received 1 g cefazolin
was 1.1 h, this difference correlates with a 33.3% vari-
ance in half-life mean value of non-pregnant group
[6]. The calculated half-life, supports the notion that
pregnancy is associated with changes such as
increased glomerular filtration rate, augmented plasma
volume, and relative hypoalbuminemia which may
contribute to significantly lower serum levels com-
pared to the nonpregnant state [7]. Despite these
marked differences that apparently cause increased
drug elimination in pregnant women, the ACOG
guidelines for anti-microbial prophylaxis for cesarean
delivery are largely based on the prevention of surgi-
cal site infection in the general surgical population,
without dose adjustments accounting for differences
between pregnant and non-pregnant women [18].
We found a limited number of studies that used a
comparative model to assess the pharmacokinetics of
cefazolin in pregnant and non-pregnant women [19,20].
THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 5
The design of the current study allowed a com-
parison of cefazolin serum concentrations in obstet-
rical women undergoing scheduled procedures. In
addition, it allowed a comparison of the effect of
pregnancy on cefazolin distribution. Nevertheless, the
current study has some limitations: The relatively low
number of participants may limit the accuracy of the
estimation of individual variability of the pharmacoki-
netic parameters. Second, the study was not suffi-
ciently powered to show differences in surgical site
infection rates. Third, since we recruited only healthy
women with no known comorbidities who underwent
scheduled cesarean deliveries at term, we cannot
generalize our results to high-risk women with
comorbidities or those who undergo urgent cesar-
ean deliveries.
Conclusions
The results of this study demonstrated that cefazolin
serum levels measured after a 30-min interval from
the incision are significantly reduced in pregnant
women undergoing cesarean delivery received lower
doses. Further studies on the time taken to achieve
steady-state conditions in the pregnant state, assess-
ing post-operative complications need to
be undertaken.
6 Y. FOUKS ET AL.
Disclosure statement
No potential conflict of interest was reported by the author(s).
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