Gentamicin and clindamycin therapy in postpartum

endometritis: The efficacy of daily dosing versus dosing

every 8 hours
Jeffrey C. Livingston, MD,a Eloisa Llata, MD,a Eliza Rinehart, PharmD,b
Colleen Leidwanger, PharmD,b Bill Mabie, MD,a Bassam Haddad, MD,c and Baha Sibai, MDd
Memphis, Tenn, Creteil, France, and Cincinnati, Ohio

OBJECTIVE: The objective of the study was to evaluate the efficacy of gentamicin and clindamycin given
once daily versus the more common 8-hour dosing regimen for the treatment of postpartum endometritis.
STUDY DESIGN: In a prospective, placebo-controlled, double-blinded study, patients who had postpartum
endometritis diagnosed were randomly selected to receive 1.5 mg/kg gentamicin and 900 mg clindamycin
phosphate administered every 8 hours versus gentamicin 5 mg/kg and clindamycin phosphate 2700 mg ad-
ministered as a single-daily dose. The single-dose group received an infusion of gentamicin and clindamycin,
followed by an administration of intravenous placebo 8 and 16 hours later to maintain blinding. Treatment
success was defined as absence of fever 72 hours after initiation of antibiotic therapy.
RESULTS: One hundred ten patients were enrolled. The daily-dose group (n = 55) and the thrice-daily dose
group (n = 55) were similar with respect to age, gravidity, parity, gestational age, and maternal weight. Clini-
cal characteristics (including maximum temperature, presence of predelivery chorioamnionitis, white blood
cell count, and mode of delivery) were also similar. There was no difference in the mean time from initiation
of therapy until becoming afebrile in the daily-dose group (27.4 ± 24.9 hours) compared with the thrice-daily
dose group (32.9 ± 26.3 hours). Forty-five of 56 (82%) patients in the daily-dose group and 38 of 55 (69%)
patients in the thrice-daily dose group had treatment success (P = .12).
CONCLUSION: Once-daily dosing with gentamicin and clindamycin in women with postpartum endometritis
has a similar success rate as the standard every 8-hour dosing schedule. (Am J Obstet Gynecol
2003;188:149-52.)

Key words: Endometritis, gentamicin, clindamycin

Postpartum endometritis remains the most common
infectious complication in the puerperium estimated to
affect 1% to 8% of pregnancies, depending on the popu-
lation studied and the definitions of endometritis used.
The majority of cases of endometritis are polymicrobial
with a mixture of aerobic and anaerobic organisms in-
volved.1
A common treatment for postpartum endometritis in-
volves the use of combination antimicrobial coverage, in-
cluding an aminoglycoside for coverage of gram-negative
From the Division of Maternal Fetal Medicine, Department of Obstetrics
and Gynecology,a and Department of Pharmacy,b University of Tennessee
Health Science Center, the Service de OB/GYN Gynecologie-Obstetrique,
Centre Hospitalier Intercommunal de Creteil,c and the Department of Ob-
stetrics and Gynecology,d University of Cincinnati.
Received for publication April 18, 2002; revised July 11, 2002; accepted
August 19, 2002.
Reprint requests: Jeffrey C. Livingston, MD, Prenatal Diagnostic Center,
Carilion Health System, 102 Highland Ave, Suite 455, Roanoke, VA
24013. E-mail: jlivingston@carilion.com
© 2003, Mosby, Inc. All rights reserved.
0002-9378/2003 $30.00 + 0
doi:10.1067/mob.2003.88
organisms and clindamycin phosphate for coverage of
gram-positive and anaerobic organisms.2 These drugs
have traditionally been given in doses three times daily.3
A recent Cochrane Library review of antibiotic trials of
gentamicin and clindamycin versus other antibiotic regi-
mens showed treatment failures were higher in the other
antibiotic treatment regimen group (relative risk 1.37,
95% CI 1.1-1.7).4 Single-dose gentamicin therapy can be
used with equal efficacy as thrice-daily dosing in the treat-
ment of postpartum endometritis.5,6 There are currently
no published trials using once-daily dosing of clin-
damycin.
The purpose of this study was to evaluate the efficacy of
gentamicin and clindamycin given once daily versus the
more common 8-hour dosing regimen for the treatment
of postpartum endometritis.
Material and methods
The Institutional Review Board at the University of
Tennessee Health Science Center, Memphis approved
this study. Inclusion criteria included at least two of the
following: temperature of 100.4°F on two separate occa-

149
150 Livingston et al January 2003
Am J Obstet Gynecol

Table I. Patient characteristics

Once-daily dosing Thrice-daily dosing

(n = 55) (n = 55) P value

Age (y) 23.3 ± 5.8 22.6 ± 5.2 .54

Weight (kg) 191.3 ± 45.2 193.2 ± 51.5 .84
Gravid (No.) 3* 3* .50
Parity (No.) 1* 1* .50
Gestational age (wk) 37.5 ± 3.6 27.5 ± 4.6 .93
Highest temperature (°F) 101.8 ± 0.82 102.1 ± 1.3 .24
White blood cell count (
103/uL) 13 ± 5.4 13.7 ± 6.4 .64
Serum creatinine (mg/dL) 0.76 ± 0.16 0.74 ± 0.14 .62
Pretreatment chorioamnionitis (No. [%]) 3 (5.5) 5 (9.1) .46
Uterine tenderness (No. [%]) 48 (82.7) 45 (82) .56
Antepartum positive GBS culture (No. [%]) 4 (7.3) 1 (1.8) .17
Cesarean section (No. [%]) 40 (72) 46 (84) .17

Data expressed as mean ± SD. GBS, Group B Streptococcus.

*Median.

Table II. Outcomes in treatment groups

Once-daily dosing Thrice-daily dosing

(n= 55) (n = 55) P value

Time until afebrile (h) 27.4 ± 24.9* 32.9 ± 26.3 .28

Treatment failure (No. [%]) 10 (18.2) 17 (30.1) .12
Length of maternal hospital stay (d) 4.1 ± 2.9 5.1 ± 2.4 .21

*Data expressed as mean ± SD.

sions at least 6 hours apart post partum (excluding the
first 12 hours post partum) or a temperature greater than
101.5°F at any point in puerperium, no evidence of infec-
tion from other sources, presence of uterine tenderness,
or a diagnosis of chorioamnionitis in labor thought to re-
quire postpartum prophylactic antibiotic therapy. Not all
patients consented to participate; hence, enrollment was
not consecutive. Before enrollment, each patient had a
physical examination, complete blood cell count with dif-
ferential, urinalysis with culture, and a serum creatinine.
Exclusion criteria for the study included known hyper-
sensitivity reactions to gentamicin or clindamycin, ex-
trapelvic sources of fever, gastrointestinal disorders such
as colitis, treatment with clindamycin or gentamicin
within the previous 12 hours and patients with renal dis-
ease. Renal disease was defined as a creatinine value
greater than 1.5 mg/dL.
Patients were randomly selected in a double-blinded
fashion to receive either (1) clindamycin 2700 mg and
gentamicin 5 mg/kg given once per day or (2) standard
clindamycin 900 mg and gentamicin approximately 1.5
mg/kg every 8 hours. The 8-hour standard gentamicin
dosing regimen for treatment of endometritis was started
with a loading dose of gentamicin of 140 mg, followed by
120 mg every 8 hours of therapy if the patient weighed
less than 90 kg. If the patient weighed more than 90 kg,
the loading dose was 160 mg, followed by 140 mg every 8
hours. Patients who were randomly selected to the once-
daily treatment group received a dose of intravenous
placebo 8 and 16 hours after the initial dose of gentam-
icin and clindamycin to maintain blinding. Gentamicin
and clindamycin were combined and each dose of drug
or placebo was given intravenously over 1 hour. Ran-
domly selected patients were continued on antibiotics
until afebrile for at least 24 hours, at which time they were
discharged at the discretion of the house staff and at-
tending physician. Patient sublingual temperatures were
recorded every 4 hours during treatment.
Treatment success was defined as having no tempera-
ture greater than 100°F by 72 hours after initiation of an-
tibiotic therapy. Patients with rapid clinical deterioration
who needed additional therapy before 72 hours were
considered treatment failures. A self-administered ques-
tionnaire was given to patients before discharge to assess
for possible adverse drug reactions. Data were compared
with the Statview statistical program (SAS Institute, Cary,
NC) or Epistat 6 (Centers for Disease Control and Pre-
vention, Atlanta, Ga). Parametric data were compared
with the use of the Student t test. Nominal data were com-
pared with the χ2 test. A P value of < .05 was considered
significant.
Results
During the period from December 1998 through De-
cember 2000, 112 postpartum women were enrolled in
the study and randomly selected to the once daily or
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Am J Obstet Gynecol
every 8-hour dosing regimens. Patient characteristics are
listed in Table I. There were no differences between the
two study groups regarding any of the categories studied.
Table II demonstrates the cure rates in the two treat-
ment groups. A treatment success was seen in 45 of 55
(82%) patients in the daily-dosing group and 38 of 55
(69%) patients in the thrice-daily dosing group. The
mean duration of therapy was 3 days in both groups.
There were 10 failures in the once-daily dosing group: 3
failures occurred because of persistent fevers for greater
than 72 hours, and 7 required intervention because of
rapid clinical deterioration. There were 17 failures in the
8-hour daily-dosing group: 6 failures occurred because of
persistent fevers for greater than 72 hours, and 11 re-
quired antibiotic change or the addition of heparin be-
cause of rapid clinical deterioration. No patient required
abscess drainage or hysterectomy for uncontrolled pelvic
infection. There were no patients in either treatment
group that were readmitted after discharge. Two patients
in the daily-dose group and three patients in the thrice-
daily dose group had human immunodeficiency virus
(HIV) infection.
No patient reported any rash, gastrointestinal symp-
toms, hearing loss, tinnitus, or vertigo on questionnaire.
This study had a power of 33% to demonstrate a relative
risk of 0.45 from 17% treatment failure in the once-daily
group to 7.7% in the thrice-daily group (α = .1).
Comment
In this age of cost containment, various strategies
have been proposed for the treatment of endometritis
while maintaining clinical efficacy. The gold standard
for treating endometritis in the lower genital tract re-
mains gentamicin and clindamycin. A study by Mitra et
al5 compared once-daily gentamicin versus thrice-daily
gentamicin along with twice-daily clindamycin dosing
in both study arms in the treatment of puerperal in-
fection. They concluded that once-daily gentamicin–
twice-daily clindamycin was safe, efficacious, and cost-
effective. A second study by Del Priore et al6 concluded
that once-daily gentamicin dosing provides high-peak
serum levels and low trough levels so as not to increase
toxicity and reduced cost and is as effective as the stan-
dard 8-hour dosing.
There are several theoretic advantages of high-dose,
longer-interval dosing regimens. The higher serum peak
levels allow for superior bactericidal effect. Aminoglyco-
sides work mostly by killing the offending organisms in a
concentration-dependent fashion.5 Hence, the higher
serum peak levels allow for superior bactericidal effect.
Bacteria that survive the initial dose of medicine become
temporarily insensitive secondary to down-regulation of
the drug uptake. This phenomenon (called adaptive re-
sistance) can last as long as 16 hours. Subsequently, when
low trough levels combine with the longer interval be-
Livingston et al 151
tween dosing, recovery of bacterial sensitivity is regained
for promoting bacterial killing. The lower trough levels
result in lower accumulation of the drug in the renal-
cochlear system, the target organs of aminoglyside toxic-
ity. Although both nephrotoxicity and ototoxicity may
occur with excessive serum gentamicin concentrations,
these toxicities are related to accumulation rather than
peak concentration. This is rarely a problem during the
usual short-term therapy required for postpartum en-
dometritis.8 Consequently, serum peak and trough gen-
tamicin concentrations were not obtained.
Clindamycin has been associated with hypersensitivity
in fewer than 1% of cases.9 Other reported adverse reac-
tions include neuromuscular blockade and pseudomem-
branous colitis.7
The rate of treatment success was similar in both
groups. A similar number of women for each group were
considered to have a treatment failure because of rapid
clinical deterioration. The definition of rapid clinical de-
terioration was left up to the determination of the mater-
nal fetal medicine attending physician. For safety
concerns, patients considered to have rapid clinical de-
terioration were unblinded and subsequently received
ampicillin, gentamicin, and clindamycin by traditional
dosing regimens. One patient in the thrice-daily group
and two in the once-daily group were diagnosed with sep-
tic thrombophlebitis by a single attending physician and
received intravenous heparin. This low threshold for di-
agnosis of rapid clinical deterioration accounts for the
high rate of treatment failures seen in both groups. How-
ever, our treatment success rate for both groups was
within the usual success rates quoted by studies using the
gentamicin and clindamycin regimens.4 Although the
time from initial dosing to afebrile was lower in the once-
daily group, this comparison did not achieve statistical
significance.
As in all studies, ours has some limitations. First, we did
not measure drug levels and cannot comment on the
pharmacokinetics of gentamicin or clindamycin. Second,
the low rate of group B Streptococcus-positive cultures in
both groups is more a reflection of practice patterns than
the true incidence. Third, a type II error may exist. With
the sample size of this study, our study has a power of
33.3%.
Our study has significant implications for the treat-
ment of postpartum endometritis. The single-dose regi-
men is less expensive to administer with respect to drug
cost and especially when nurse-tasking time is taken into
consideration. Once-daily dosing further reduces the
cost, if drug levels are traditionally obtained with thrice-
daily dosing. Other possibilities offered by the use of this
therapy include outpatient therapy for mild postpartum
endometritis. Once-daily gentamicin and clindamycin
regimens for the treatment of pelvic infections warrant
additional study.
152 Livingston et al
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