von Mandach et al, Ceftriaxone for prophylaxis in cesarean section 385

t Med Ceftriaxone (single dose) versus cefoxitin (multiple doses): success

21 (1993) 385-397 an(j fajiure of antibiotic prophylaxis in 1052 cesarean sections

Ursula von Mandach1, Renate Huch1, Raffaele Malinverni2, and Albert Huch1

University Department of Obstetrics and Gynecology, Unit of Perinatal

Physiology, Zurich, Switzerland, 2University Department of Internal Medicine,
Poliklinic, Berne, Switzerland

1 Introduction Curriculum vitae

Cesarean section rates have risen sharply in
recent years with the advance in pregnancy
monitoring techniques and the early identifi-
cation of maternal and fetal risk. In our clinic,
the section rate rose from 15% in 1980 to
22.4% in 1991. Rising section rates necessitate
a thorough and comprehensive analysis of the
problem of postoperative complications. Infec-
tion is the most common postoperative com-
plication in cesarean section [16,18]. Numerous
placebo-controlled studies have shown a sig-
nificant reduction in postoperative morbidity
through the use of perioperative antibiotic pro-
phylaxis; the greatest experience has been with
the cephalosporins [2, 10, 12, 25, 31, 32, 34,
36, 37]. There is little difference in the antibac-
terial activity of the various agents. None is
effective against enterococci; some are more
effective than others against anaerobe organ-
isms. The basic difference however is in the
plasma half-life (t1/2) and in the renal clearance,
respectively, and thus in the duration of suffi-
ciently high concentrations to stem bacteria in
tissues and in urine. Comparative studies be-
tween different cephalosporins or between the
same drug using different doses, i. e. single vs.
multiple or smaller vs. larger doses, have not
shown a significantly higher effectiveness for
any regimen, except in a few cases [8, 12, 13,
15, 19, 27, 28]. This is the reason that, in spite
of many contradictions, unclarified factors and
1993 by Walter de Gruyter & Co. Berlin · New York
URSULA VON MANDACH
was born in Basle,
Switzerland, in 1955
and studied pharmacy.
She worked four years
in the Division of Clin-
ical Pharmacology at
the University of Berne
and received her PhD in
1984. Since 1985 she
has worked in clinical
research (Unit of Per-
inatal Physiology) at the University of Zurich. Her
main interests are the mechanisms and drug therapy
ofpreterm labor and antibiotic prophylaxis in cesarean
section.
the lack of definite data, many authors have
come to the conclusion that in prophylaxis of
cesarean section the duration of sufficient levels
for activity does not play any significant role.
Therefore a single dose of a short-acting ceph-
alosporin of the 1st generation such as cephal-
othin or cefazolin, which is potent but inex-
pensive, is to be recommended for prophylaxis
[1, 9, 20]. For postpartal infections, however,
this argument is only valid for wound infec-
tions. Only for the wound does the time re-
quired for antibacterial protection correspond
approximately to the operation time [24]. Since

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386 von Mandach et al, Ceftriaxone for prophylaxis in cesarean section
all the cephalosporins cover this time with a
single dose, long-acting drugs or multiple doses
of short-acting drugs are not expected to result
in a lower incidence of wound infections. With
all other infections, however, the inoculation
extends for hours or even days after the end of
the operation. Therefore long-acting agents
should reduce both the number and the degree
of severity of these infections, and thus also the
duration of hospitalization and the costs. Sup-
posed differences between the various drugs or
regimens might only be due to the small num-
ber of cases in the studies. KAISER [23] claims
that a clinical study comparing two different
antibiotic regimens must consist of at least 900
cases in order that (e. g.) a 50% reduction in
the infection rate could be brought into a p-
value of 0.05.
In addition to the choice of antibiotic and the
regimen, the indication is also a controversial
theme in the literature. Although some studies
show a clear advantage of general antibiotic
prophylaxis for all patients [11, 14] most au-
thors tended to use such prophylaxis only in
patients at high risk [1]. However, a very diverse
spectrum of criteria is used in the literature to
define patients in a high-risk collective.
Patients at our clinic (a university hospital)
come from widely diverse socio-economic
classes (age, origin, education). This is also a
center with many referred cases of pathological
pregnancies (a premature delivery rate of 15%)
as well as a training center for obstetricians,
meaning that cesarean sections are performed
not only by highly experienced surgeons but
also by those in training. Thus it has been
routine practice for many years to perform
antibiotic prophylaxis in every patient under-
going a cesarean section.
The present study was designed to determine:
1. The effectiveness of a long-acting antibiotic
prophylaxis with a mixed patient population
and the given clinical situation;
2. Whether a single dose of ceftriaxone, a long-
acting cephalosporin of the 3rd generation,
which has not been widely used for prophylaxis
in cesarean section, is just as or more effective
than 3 doses of cefoxitin, a cephalosporin of
the 2nd generation, and why or why not.
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Cefoxitin had been the antibiotic of choice in
our clinic for several years for prophylaxis and
is one of the recommended agents for prophy-
laxis in cesarean section in the United States
[1]. The multiple dose regimen for cefoxitin was
chosen to produce a long-acting prophylaxis.
There are 1052 cases in this study, statistically
the minimum required. Care was taken to ob-
tain a differentiated analysis of the postoper-
ative complications (infections and other prob-
lems).
2 Subjects and methods
2.1 Patients
All patients undergoing cesarean section from
July 1985 up to and including June 1989 were
randomized for antibiotic prophylaxis with ei-
ther a single dose of ceftriaxone (Rocephin®)
l g i. v. immediately after division of the um-
bilical cord or with three doses of cefoxitin
(Mefoxitin®) l g i. v.; the first of which was
also given intraoperatively following division
of the cord, the second at 8 h and the third at
16 h after the first dose. Primary randomization
was based on the first letter of the surname
(A —K: cefoxitin, L —Z: ceftriaxone). The
name of the antibiotic administered had to be
written on the control sheet for the anesthesia.
All these sheets were examined and patients
whose primary randomization did not corre-
spond to the antibiotic written on the control
sheet were excluded from the study. Also ex-
cluded were patients who had received antibi-
otics less than 14 days before section or for
whom antibiotic prophylaxis did not conform
to the study protocol. 135 patients were ex-
cluded. The final study population was com-
prised of 536 patients treated with ceftriaxone
and 516 treated with cefoxitin, i.e. a total of
1052 patients.
As shown in table I, the socio-economic situ-
ation (age, origin, education) was similar in
both groups. The data also indicate the wide
diversity (already mentioned) in origin and ed-
ucation of our patients.
In both treatment groups, the population at
preoperative risk of infection was defined as
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von Mandach et al, Ceftriaxone for prophylaxis in cesarean section 387

Table I. Socio-economic data of patients studied confirmed after section) or an infection of the
urinary tract (midstream urine culture > 104
Ceftriaxone Cefoxitin organisms per milliliter) and/or with any other
(n = 536) (n = 516) clinically diagnosed infection (without antibi-
Age 30.2 ± 5.2 29.8 ± 5.2
otic treatment) (figure 1). Many of these at-
(years; mean ± SD) risk patients belonged to more than one pre-
operative risk subgroup, so that the total num-
Origin (%) ber of risks encountered exceeded the number
— Switzerland 53 55 of patients. Of the total of 1052 patients
— South Europe* 25 26 treated, 689 (66%) were at preoperative risk,
— Other European 12 9 distributed equally between the two groups
countries (347/536 = 65% on ceftriaxone and 342/516
— Asia 3 = 66% on cefoxitin).
- Other 7

Education (%)
— low 37 39 2.2 Study parameteres
— high with practical 55 50 2.2.1 Postoperative infections
training
— university 11 a) Fever
Fever was defined as an axillary temperature
Italy, Spain, Portugal and Yugoslavia > 38 °C sustained for at least two consecutive
days (day of operation excluded) in patients
not satisfying the criteria listed in sections a) —
patients undergoing emergency section, non- d). Concomitant diagnoses other than in sec-
elective section, or whose membranes had rup-
tion a) —d) were noted.
tured prior to the section, or with an amniotic
fluid infection (suspected without antibiotic b) Endometritis
treatment before section, microbiologically The criteria were fever, offensive lochia and a

Ceftriaxone Cefoxitin
347 of 536 Patients (=65%) 342 of 516 Patients (=66%)
with one or more risk factors with one or more risk factors

n = 634 n = 616

Figure 1. Frequency of risk factors (number of risks/risk group) diagnosed preoperatively in the patients
studied.
Risk groups: a = emergency (elective or non-elective) section, b = non-elective section, c = rupture of
membranes prior to section, d = infection of amniotic fluid, e = urine culture > 104 organisms/ml urine,
f = other infections.
Some patients belonged to more than one risk group, meaning that the total number of risks exceeded the
number of patients. There is no significant difference in the frequency of any risk factor between the two
antibiotic groups (χ2 test not significant).

J. Perinat. Med. 21 (1993)

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388 von Mandach et al, Ceftriaxone for prophylaxis in cesarean section
tender uterus. Leukocytosis and/or a shift to
the left was an additional but non-obligatory
criterion.
c) Wound infection
Wound infection was defined as an infection of
the operative incision with a purulent discharge
and positive bacteriology. In the absence of
microbiological confirmation (analysis not per-
formed or laboratory report mislaid), the pu-
rulent discharge had to persist for several days
(with or without additional antibiotic treat-
ment) or the wound had to require exploration.
d) Urinary tract infection
Urinary tract infection was defined as > 104
organisms per milliliter in catheter urine or
> 105 organisms in midstream urine, with pos-
itive identification of a pathogen. The diagnosis
was not admissible in the absence of positive
pathogen identification. If the analysis had not
been performed or the laboratory report had
been mislaid, patients could be classified as
having an urinary tract infection only if they
were symptomatic and/or required additional
therapy with other antibiotics,
been mislaid, patients could be classified as
having an urinary tract infection only if they
were symptomatic and/or required additional
therapy with other antibiotics.
2.2.2 Other postoperative complications
All postoperative complications other than
those classified in postoperative infections were
noted.
2.2.3 Duration of hospitalization
The time is defined as beginning on the day of
operation and ending on the day of discharge.
2.2.4 Microbiology
Wound and urine samples were processed in
the Institute for Medical Microbiology, Uni-
versity of Zurich. We analyzed the microorgan-
isms in the wound and urinary tract infections
on the basis of the results of these routinely
performed investigations.
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Wound swabs from superficial material were
incubated aerobically and those from deep ma-
terial were incubated aerobically and anaero-
bically.
Catheter samples were taken on the 1st post-
operative day before removing the catheter in
situ. Midstream samples were taken on the 6th
postoperative day.
Identification was performed in most cases us-
ing an API strip (API, Bio-Merieux, Balme-les-
Grottes, France), and otherwise by recognized
standard procedures [4]. Pathogen susceptibil-
ity was determined using the agar diffusion
technique according to NCCLS guidelines (Per-
formance Standards for Antimicrobial Disk
Susceptibility Tests, 4th Edition, NCCLS Doc-
ument M2-A4).
Urine sample results were analyzed separately
for catheter and midstream urine.
2.2.5 Tolerance
All side-effects were recorded (non-specific and
hypersensitivity reactions: with an onset less
than 48 hours after section; others: during hos-
pitalization after cesarean section).
2.3 Statistics
The data from each patient's case report form
were entered into D-Base III Plus for further
statistical analysis using the Stat View II™
program on Macintosh.
Data were compared within and between
groups using the chi-2 test or Fisher's exact
test or the Mann-Whitney U test, respectively,
with a p-value < 0.05.
3 Results
3.1 Postoperative infections
a) Overview (tables II and III)
The incidence of fever, endometritis and wound
infection was similar in both groups. By con-
trast, the incidence of urinary tract infection
was significantly lower with ceftriaxone than
with cefoxitin (p < 0.001) (table II). The over-
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von Mandach et al, Ceftriaxone for prophylaxis in cesarean section 389

Table II. Postoperative infections In both antibiotic groups the incidence of

wound infection was significantly higher in
Ceftriaxone Cefoxitin patients with than in those without preopera-
(n = 536) (n = 516) tive risk (p < 0.01 & p < 0.001). All other
n (%) n (%) infection rates were not different in patients
1. Fever 14 (2.6) 10 (1.9) with and those without risk (table III).
2. Endometritis 4 (0.8) 3 (0.6) b) Fever
3. Wound infection 17 (3.2) 20 (3.9) Of the patients with fever 3/11 on Ceftriaxone
4. Urinary tract 52 (9.7) 92 17.8)* and 4/10 on cefoxitin also had other compli-
infection
cations (see section "Other complications" and
1.-3. Total 35 (6.5) 33 (6.4) table IV).
1.-4. Total 87 (16.2) 125 (24.2)* c) Endometritis
Endometritis was an isolated complication in
Significance between Ceftriaxone and cefoxitin:
* p < 0.001 (estimated by χ2 test)
six out of seven patients. In the remaining
patient (on cefoxitin), it was associated with
wound and urinary tract infection.
d) Wound infection
all infection rate was 6.5% (a total of 35 infec- Wound infection was associated with urinary
tions) with Ceftriaxone and 6.4% (a total of 33 tract infection in 4/17 patients (24%) on cef-
infections) with cefoxitin, excluding urinary triaxone and in 3/20 patients (15%) on cefox-
tract infection (statistically not significant). In- itin, and additionally with endometritis in one
cluding urinary tract infection, it increased in patient on cefoxitin.
both groups significantly and was significantly In the ceftriaxone group, wound infection was
higher with cefoxitin than with Ceftriaxone treated systemically with antibiotics or locally
(p < 0.001) (table II). with Povidone-Iodine (Betadine®), each in 7/17
Seven patients with a wound infection and 1 patients (41%). With cefoxitin, concomitant
patient with endometritis had additionally an systemic antibiotic therapy (i. v. and/or p. o.)
urinary tract infection, meaning that on cef- was required in 10/20 patients (50%); 4 patients
triaxone a total of 83 patients (15.5%) and on (20%) received purely local treatment with
cefoxitin a total of 121 patients (23.4%) were Povidone-Iodine.
classified as patients with an infection e) Urinary tract infection
(p < 0.001). Systemic oral antibiotic therapy was required

Table III. Postoperative infections in patients with and without preoperative risk of infection

Ceftriaxone Cefoxitin

with risk without risk with risk without risk

(n = 347) (n = 189) (n = 342) (n = 174)

1. Fever 3.2 1.6 2.1 1.7

2. Endometritis 1.2 — 0.6 0.6
3. Wound infection 4.9 0.5* 5.9 _**
4. Urinary tract infection 10.1 9.0 18.4 16.7

Significance between groups with and without risks:

* p < 0.01;
** p < 0.001 (estimated by χ2 test carried out with the actual number of infections)

J. Perinat. Med. 21 (1993)

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390 von Mandach et al, Ceftriaxone for prophylaxis in cesarean section

in all cases. Antibiotics were chosen according
to the in-vitro susceptibility results. Due to the
higher rate of urinary tract infections in the
cefoxitin compared to the ceftriaxone group
(17.8% vs. 9.7%), antibiotic therapy was ad-
ministered more frequently in the cefoxitin
group (p < 0.001).
3.2 Other complications (table IV)
Thirty-nine of all patients with (15 cases) or
without (24 cases) concomitant postoperative
infections had one or more additional compli-
cations: 17 patients on ceftriaxone (3.2%) ver-
sus 22 patients on cefoxitin (4.3%) (statistically
not significant). The most frequent complica-
tions were problems with the wound (not clas-
sified as wound infections): in 10 cases on cef-
triaxone and in 14 cases ofl cefoxitin. Fever
(classified as in section "Postoperative infec-
tions") was another concomitant problem: in
the ceftriaxone group, 2 patients with fever also
had a wound hematoma, 1 patient had a sec-
ondary closure of the wound, 1 patient had
influenza and 1 patient a pericardial effusion;
in the cefoxitin group, 1 patient with fever also
had a wound hematoma, 1 a wound dehiscence,
in 1 patient Escherichia coli sepsis was sus-
pected and 1 had influenza. With ceftriaxone 1
patient was suspected to have pneumonia with-
out fever (clinical auscultation and X-ray).
Other complications, all without fever, oc-
curred isolated.
3.3 Duration of hospifalization
The number of days (mean ± SE) spent in the
hospital were the same for all patients, whether
in the ceftriaxone or in the cefoxitin group:
11.33 ± 0.14 (n = 527; 9 cases missing) versus
11.47 ± 0.15 (n = 511; 25 cases missing).
However, in the subgroup of patients with uri-
nary tract infections, those on ceftriaxone had
a significantly shorter duration of hospitaliza-
tion than those on cefoxitin: 10.76 + 0.39
(n = 51; 1 case missing) versus 11.82 + 0.34
(n = 90; 2 cases missing), p < 0.05 (Mann-
Whitney U test).

Table IV. Other complications

3.4 Microbiological results
Ceftriaxone Cefoxitin
(n = 536) (n = 516) a) Wound infection (table V)
n n Enterococci and coagulase-negative staphylo-
cocci were the main aerobic organisms identi-
Revision of abdomen 2 1* fied by aerobic or anaerobic cultures in both
Protracted wound 10 (-,3) 14(2,2) treatment groups. Of the 14 microbiologically
healing (*, **) confirmed wound infections with ceftriaxone,
Mastitis 1 1 Enterococcus spp. was isolated in 6 cases (43%)
Vulval infection 1 —
(Candida alb.)
and staphylococci in 9 cases (64%). The cor-
Sepsis (E. coli) — 1** responding figures for the 17 wound infections
Pneumonia 1 — with cefoxitin were 6 (35%) and 8 (47%). Other
Influenza (*, **) 2(-,l) 2(1,1) cases with gram-positive cocci included in each
Pos. throat swab — 1 group 1 case with group B ß-hemolytic Strep-
(Streptococc. tococcus and in the cefoxitin group 1 case with
Group A) Streptococcus milleri and 1 case with Staphy-
Pericardial effusion !** — lococcus aureus. In the ceftriaxone group Co-
Cholecystitis — 1*** rynebacterium spp. was isolated in 1 case and
Nephrolithiasis — 1* in the cefoxitin group, Escherichia coli was
Total (%) 17(3.2) 22(4.3)
isolated in 2 cases. 14 anaerobic cultures were
Concomitantly with performed, 5 in the ceftriaxone and 9 in the
* urinary tract infection; cefoxitin group. In 2 cases, both from the ce-
** fever; foxitin group (22%), Peptostreptococcus as-
*** wound infection accharolyticus was identified.

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von Mandach et al, Ceftriaxone for prophylaxis in cesarean section 391

Table V. Wound infections: microorganisms involved

Ceftriaxone Cefoxitin
(14 cultures; (17 cultures;
aerobic n = 9, aerobic n = 8,
anaerobic n = 5) anaerobic n = 9)
(n) (n)

Aerobic growth from all cultures

Gram-pos. cocci
— Enterococcus spp.*
— Coag.-neg. Staph.*
Others

Anaerobic growth from anaerobic cultures

— Peptostreptococc. asaccharolyticus

undifferentiated

Table VI. Urinary tract infections: microorganisms involved

Cultures Ceftriaxone Cefoxitin

Total Catheter Midstream Total Catheter Midstream

urine* urine** urine* urine**
(n = 50) (n = 15) (n = 35) (n = 91) (n = 58) (n = 33)
n n n n n n

Gram-pos. cocci
— Enterococcus spp.*** 37 13 24 69 51 18
— Coag.-neg. Staph.*** 18 18 7 1 6
- Others 2 2 8 2 6
Gram-neg. cocci 1 1 1 1
Gram-pos. rods - 1 1

Gram-neg. rods
— E. coli 3 1 2 13 3 10
— Pseudomonas aerug. 3 1 2 4 1 3
— Citrobacter freundii 2 2 1 1
- Others — — — 4 1 3

Concentration of pathogens:
* > 104 organisms/ml;
** > 105 organisms/ml;
*** undifferentiated

b) Urinary tract infection (table VI) 24 as a mixed culture), and in 69 cases on

Enterococcus spp. was the primary urinary
pathogen in both groups, being isolated in 37
cases on Ceftriaxone (catheter urine: 13 cases
[35%], all as a monoculture; midstream urine:
24 cases [65%], 9/24 as a monoculture and 15/
cefoxitin (catheter urine: 51 cases [71 %], mostly
as a monoculture; midstream urine: 18 cases
[29%], 7/18 as a monoculture, and 11/18 as a
mixed culture). Coagulase-negative staphylo-
cocci were the second most common pathogen

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392 von Mandach et al, Ceftriaxone for prophylaxis in cesarean section

in the ceftriaxone group, being isolated in 18 4 Discussion

cases all from midstream urine, 14/18 as a
mixed culture. With cefoxitin, coagulase-nega-
tive staphylococci were isolated in 7 cases,
mostly (in 6 cases) from midstream urine, both
as monocultures (3/6) and mixed cultures (3/6).
In both groups other cocci including Staphy-
lococcus saprophyticus, Staphylococcus aureus
(both gram-positive) and Acinetobacter cal-
coaceticus (gram-negative) occurred in isola-
tion. In the cefoxitin group, the second most
common pathogen was E. coli, isolated in 13
cases, mostly from midstream urine (10/13) and
as a mixed culture (8/13). Pseudomonas aeru-
ginosa and Citrobacter freundii occurred in
isolation in both groups.
Group B -hemolytic Streptococcus (gram-pos.
coccus), Corynebacterium spp. (gram-positive
rod), Klebsiella pneumoniae, Proteus mirabilis
and Enterobacter cloacae (all gram-negative
rods) occurred isolated only in the cefoxitin
group. From the patients on ceftriaxone with
enterococci cultivated in the catheter urine, the
midstream urine 5 days later was examined:
75% of the patients had an enterococci con-
centration of > 105/ml, 12.5% had < 105/ml
and 12.5% were sterile. For those in the cefox-
itin group, enterococci concentrations in the
midstream urine were > 105/mlin25%, < 105/
ml in 50% and no findings in 25%.
This randomized controlled study with a high
statistical power shows the efficacy of a long-
acting antibiotic prophylaxis performed in
every patient undergoing cesarean section. The
results are representative for a wide spectrum
of clinical circumstances, i. e. of both patients
and operators.
An infection rate in terms of fever, endometritis
and wound infection (each < 4%) of 6.5% was
achieved with a single dose of l g ceftriaxone
and of 6.4% with 3 doses of l g cefoxitin. These
findings are lower than those of SALTZMAN et
al. [34] with 1 χ 2 g ceftizoxime in a placebo-
controlled study of 108 patients and of HAR-
TERT et al. [19] with l x l g cefonicid and
1 χ 2 g cefoxitin respectively in 139 patients
and of CARLSON and DUFF [8] with 1 χ 2 g
cefazolin and 1 χ 2 g cefotetan respectively in
377 women. Results similar to ours were
achieved by POLK et al. [31] with 3 χ 2 g ce-
foxitin and by MANCUSO and OLIVA [26] with
1 χ l g ceftriaxone in 175 women patients.
Comparison of our data with the meta-analysis
Table VII. Side-effects occurring after cesarean sec-
tion
Ceftriaxone Cefoxitin
(n = 536) (n = 516)
n (%) n (%)

3.5 Safety and tolerance (table VII) Within 48 hours:

— Non-specific reactions
The incidence of non-specific side-effects such Dizziness 18 25
as dizziness, headache and vomiting, which are Headache 14 16
often associated with peridural anesthesia, was Vomiting 14 22
lower in the ceftriaxone than in the cefoxitin Total 46 (8.6) 63* (12.2)
group (p < 0.05). Hypersensitivity reactions
such as rash and/or pruritus were observed in — Hypersensitivity
reactions
2% of patients from each group. Pseudomem-
branous colitis was suspected in 3 patients in Rash 5 7
Pruritus 6 3
the ceftriaxone group on the basis of diarrhea Total 11 (2.1) 10(1.9)
and the isolation of Clostridium difficile toxin.
The diagnosis was confirmed by colonoscopy During hospitalization:
in one patient. Two patients were treated with Diarrhea with
vancomycine hydrochloride orally (4 χ 125 Clostridium difficile
mg/day) over 4 days. One patient was treated
with ornidazole orally (3 χ 500 mg/day) over Difference between ceftriaxone and cefoxitin:
5 days. * p < 0.05 (estimated by χ2 test)

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von Mandach et al, Ceftriaxone for prophylaxis in cesarean section
by HIRSCH and NEESER [21] of 53 placebo-
controlled trials until 1983 of antibiotic pro-
phylaxis in cesarean section — reported in Eur-
opean and American literature — shows that
our postoperative infection rates in both
groups (excluding urinary tract infection) were
lower than those reported in the treated groups
and highly significantly lower than in the un-
treated controls.
The rates — except for the wound infection —
were similar in patients with a preoperative risk
of infection and those without a risk. These
results support our policy to perform antibiotic
prophylaxis in every patient undergoing cesa-
rean section. Each hospital needs to carefully
analyze the risk factors of its patient population
and then choose the appropriate antibiotic pro-
phylaxis procedure.
The spectrum and incidence of the organisms
responsible for wound infections were similar
in both groups. The primary pathogens were
aerobes such as enterococci and coagulase-neg-
ative staphylococci. Anaerobes were rarely
found, because anaerobic cultures were only
performed in samples taken of deep wounds.
However, no pathogens were found with cef-
triaxone patients, whereas with cefoxitin two
cases (of 9 cultures = 22%) of Peptostrepto-
coccus asaccharolyticus were found, though in
principle both antibiotics are equally effective
in-vitro against these organisms. Me CLOSKEY
[29] showed in a study of ceftriaxone efficacy
in wound infection that gram-positive cocci
were also the most common pathogens, but
that anaerobes accounted for some 30% of the
cases.
Urinary tract infections are more frequent than
the other infections in both antibiotic groups,
and in the cefoxitin group 84% more frequent
than in the ceftriaxone group. These data con-
firm that postoperative urinary tract infections
have little or no association with the surgical
procedure itself. An important factor is the
duration of the urinary catheter in situ. In our
patients the catheter was removed 48 hours
after the section. So at least for this time an-
tibiotic concentrations in urine should be over
the minimum inhibitory concentration (MIC)
for most of the bacterias causing infection in
J. Perinat. Med. 21 (1993)
393
the urinary tract. For ceftriaxone these condi-
tions are fulfilled. Following single i. v. admin-
istration, ceftriaxone is dose-independently
cleared from plasma with a t i/2 of 8 hours [33].
Ceftriaxone is eliminated slowly in urine. After
24 hours, a maximum of 50% of the adminis-
tered dose is excreted in the urine, and only an
insignificant further proportion, to a maximum
of 65%, after 48 hours [6, 30, 35]. Following a
single dose of 1 g, urine levels of 40 μg/ml are
sustained for 24 to 48 hours, thus exceeding
the MIC of most of the pathogens susceptible
to ceftriaxone (MIC90 = 16 μg/ml) [33]. How-
ever, for cefoxitin the conditions mentioned
above are not satisfactorily fulfilled. Cefoxitin
has a ten-fold shorter t1/2: 0.8 hours [17]. It is
rapidly excreted in the urine: the kidney clears
80% of an administered dose within 12 hours.
Its concentration in urine for the first 4 to 6
hours remains approximately 100 μg/ml [7],
meaning that effective levels can be demon-
strated in urine until 12 hours after the last
dose; in our case that is for 28 hours (last dose:
16 hours after cesarean section). These differ-
ences between the pharmacokinetics of the two
antibiotics may explain the higher incidence of
urinary tract infections with cefoxitin than with
ceftriaxone, which is based on the higher fre-
quency of enterococci and E. cqli with cefoxi-
tin:
With cefoxitin the majority of enterococci were
identified in catheter urine specimens as single
isolates on the 1st postoperative day. In con-
trast, with ceftriaxone, half the enterococci
were isolated on postoperative day 1 and the
other half on postoperative day 6. Since both
antibiotics are inactive against enterococci, the
question arises as to the overgrowth of enter-
ococci. ISMAIL et al. [22] show in a study with
3 χ 2 g cefoxitin for prophylaxis in cesarean
section an overgrowth of enterococci in the
flora of the endocervix. No data from literature
are known for ceftriaxone in prophylactic
doses. Based on our data comparing urine cul-
tures after ceftriaxone with those after cefoxi-
tin, we conclude that overgrowth of enterococci
does not occur after 1 χ l g of ceftriaxone but
might occur after 3 χ l g of cefoxitin.
Against E. coli, cefoxitin should have the same
activity as ceftriaxone. Only one case was not
Unauthenticated
Download Date | 5/17/16 6:43 PM
394 von Mandach et al, Ceftriaxone for prophylaxis in cesarean section
susceptible to cefoxitin. We assume that the
cefoxitin concentration in the urine was not
sustained long enough over the MIC to protect
the urine from a late E. coli inoculation.
The lower incidence of urinary tract infections
in the ceftriaxone than in the cefoxitin group
means that treatment costs can be decreased:
a) Patients with postoperative urinary tract in-
fections on ceftriaxone spent one day less in
hospital than those on cefoxitin. However, the
duration of hospitalization of the whole cef-
triaxone group is not lower than that of the
cefoxitin group. This could be due to a statis-
tical problem. Since the subgroup with urinary
tract infections is only a small part of the whole
collective (9.7% of ceftriaxone and 17.8% of
cefoxitin), no statistical significance can be
shown, b) Since every patient with an urinary
tract infection required oral antibiotic therapy,
significantly fewer antibiotics were needed with
ceftriaxone than with cefoxitin. c) Fewer ad-
ditional controls by the physician in discharged
patients and d) fewer cultures of the urine were
needed with ceftriaxone.
Complications other than infections were
equally rare in both groups.
Non-specific side-effects were lower with cef-
triaxone than with cefoxitin (p < 0.05). The
Abstract
The efficacy of perioperative antibiotic prophylaxis
in cesarean section with a single dose of ceftriaxone,
a long-acting cephalosporin not widely used for pro-
phylaxis, was tested. Ceftriaxone as a single dose of
l g i. v. versus three doses of cefoxitin l g i. v. re-
spectively were used in a prospective, randomized,
controlled study consisting of 1052 patients under-
going cesarean section. Postoperative infection rate
as measured by fever, endometritis and wound infec-
tion was 6.5% with ceftriaxone and 6.4% with ce-
foxitin. Urinary tract infections were significantly
more frequent in the cefoxitin than in the ceftriaxone
group (17.8% vs. 9.7%, p < 0.001). Enterococci and
Escherichia coli accounted for urinary tract infec-
Keywords: Antibiotic prophylaxis, ceftriaxone, cesarean section, single dosing.
Download Date | 5/17/16 6:43 PM
fact that the three patients with diarrhea and
Clostridium difficile positive stools all belonged
to the ceftriaxone group was probably a coin-
cidence, because it is well known that growth
of Clostridium difficile can occur on treatment
with ß-lactamase-stable penicillins as well as
with every cephalosporin [5]. However, ARONS-
SON et al. [3] showed in a 2-year study in Swe-
den that Clostridium difficile occurs in 1.9%
of healthy adults (> 12 years) and in 1% of
adults with non-antibiotic associated diarrhea.
In our study of antibiotic prophylaxis, the in-
cidence was 0.3% in the total population and
0.8% in the ceftriaxone group, which is dis-
tinctly lower than the levels found by Aronsson
in adults with and without prior antibiotic ther-
apy.
Conclusion:
A single dose of ceftriaxone l g i. v. is simple,
reliable (compliance), well tolerated, inexpen-
sive (fewer urinary tract infections and there-
fore lower treatment costs than with cefoxitin)
and safe (in urine no overgrowth of enterococci
was seen with ceftriaxone, but in contrast, with
cefoxitin). Ceftriaxone can be recommended as
an effective antibiotic for prophylaxis in cesa-
rean section for the described clinical circum-
stances.
tions 1.86-, respectively, 4.3-fold more frequently
with cefoxitin than with ceftriaxone. The time of
hospitalization in patients with urinary tract infec-
tions was significantly lower with ceftriaxone than
with cefoxitin (11 vs. 12 days, p < 0.05). The toler-
ance in both groups was equally satisfactory. A single
dose of ceftriaxone, which is simple, reliable (com-
pliance), well tolerated, inexpensive (fewer urinary
tract infections and therefore fewer treatment costs
than with cefoxitin) and safe (no overgrowth of path-
ogens) in our opinion is the antibiotic regimen of
choice for prophylaxis in cesarean section in the
described circumstances.
J. Perinat. Med. 21 (1993)
Unauthenticated
von Mandach et al, Ceftriaxone for prophylaxis in cesarean section
Zusammenfassung
Ceftriaxon (Einmalgabe) versus Cefoxitin (Mehrfach-
applikation): Erfolg und Mißerfolg der antibiotischen
Prophylaxe bei 1052 Patientinnen mit Sectio caesarea
Ceftriaxon ist ein lang wirksames Breitspektrumce-
phalosporin der 3. Generation, das bisher mit Erfolg
zur therapeutischen Antibiose in- und außerhalb des
geburtshilflich-gynäkologischen Bereichs eingesetzt
wurde. Die vorliegende Untersuchung beinhaltet
erstmals Erfahrungen mit der prophylaktischen An-
wendung einer Einmalgabe von Ceftriaxon an einem
größeren Kollektiv von Patientinnen mit nicht-selek-
tivem oder selektivem Kaiserschnitt. In einer pro-
spektiven, randomisierten, kontrollierten Studie wur-
den bei 1052 Patientinnen die Wirksamkeit und Ver-
träglichkeit der perioperativen Antibiotikumprophy-
laxe von l I g i.v. Ceftriaxon (Rocephin®) mit
derjenigen von Cefoxitin (Mefoxitin®) in einer Do-
sierung von 3 l g i. v. verglichen. In beiden Grup-
pen betrug der Anteil der Patientinnen mit einem
definierten präoperativen Infektrisiko (Notfallsektio,
sekundäre Sektio, vorzeitiger Blasensprung, Verdacht
auf Amnioninfekt, Urikult > l O4 Keime/ml Urin
und andere Infektionen) je 66%. Nach Ceftriaxon
traten im Vergleich zu Cefoxitin fieberhafte Verläufe
(2,6 vs. 1,9%), eine Endometritis (0,8 vs. 0,6%) und
ein Wundinfekt (3,2 vs. 3,9%) gleich häufig auf (Ta-
belle II). Entsprechend war die postoperative Infek-
trate unter Berücksichtigung dieser drei Parameter
in beiden Gruppen gleich hoch (Ceftriaxon: 6,5%,
Cefoxitin: 6,4%). Harnwegsinfekte traten hingegen
in beiden Gruppen häufiger als die anderen Infekt-
parameter auf und zudem in der Cefoxitingruppe
signifikant häufiger als nach Ceftriaxon (17,8 vs.
Schlüsselwörter: Antibiotische Prophylaxe, Ceftriaxon, Einmalgabe, Sectio caesarea.
Resume
Ceftriaxone (dose unique) versus cefoxitine (doses mul-
tiples): succes et echec de la prophylaxie antibiotique
chez 1052 patients ayant subi une cesarienne
La ceftriaxone est une cephalosporine de 3e genera-
tion a large spectre. Cet antibiotique ä longue duree
d'action a ete utilise jusqu'a present avec succes
comme agent anti-infectieux en gynecologie-obste-
trique de meme que dans d'autres domaines. La
presente recherche expose Fexperience acquise avec
{'administration prophylactique d'une dose unique
de ceftriaxone lors de cesariennes qu'elles soient elec-
tives ou non. Elle est la premiere de ce type ä porter
sur un collectif consequent de patientes. Au cours
d'une etude prospective controlee et randomisee chez
1052 femmes, Fefflcacite et la tolerance ä la prophy-
laxie antibiotique perioperatoire de l l g de cef-
J. Perinat. Med. 21 (1993)
395
9,7%, p < 0,001) (Tabelle II). In beiden Antibioti-
kagruppen hatten die Patientinnen ohne und die-
jenigen mit präoperativem Risiko mit Ausnahme des
Wundinfektes keine unterschiedlichen postoperati-
ven Infektraten (Tabelle III). Die mikrobiologische
Untersuchung der Urinproben zeigte bei den Harn-
wegsinfekten ein Überwiegen von Enterokokken.
Trotz Resistenz gegenüber beiden Antibiotika waren
sie jedoch nach Cefoxitin knapp zweimal häufiger
als nach Ceftriaxon. In der Cefoxitingruppe fiel zu-
dem die Besiedelung des Urins mit Escherichia coli
auf, die viermal häufiger vertreten waren als nach
Ceftriaxon (Tabelle VI). Bei den Patientinnen mit
Harnwegsinfekten lag die Hospitalisationsdauer
nach Ceftriaxon tiefer als nach Cefoxitin (11 vs. 12
Tage, p < 0,05). Die Verträglichkeit bezogen auf die
unspeziflschen Nebenwirkungen und allergischen Re-
aktionen war in beiden Antibiotikagruppen gleich
gut (Tabelle VII). Unsere Ergebnisse zeigen, daß nach
der Prophylaxe mit den gewählten Antibiotika fie-
berhafte Verläufe, Endometritiden und Wundinfekte
nach Kaiserschnitt in nur sehr geringer Häufigkeit
auftreten (max. 4%). Harnwegsinfekte bleiben im
Gegensatz dazu problematischer, doch zeigt sich bei
Ceftriaxon eindeutig der Vorteil eines lang wirksa-
men antibiotischen Schutzes im Urin. Berücksichtigt
man bei Ceftriaxon zudem die niedrigeren durch die
geringeren Harnwegsinfekte bedingten Therapieko-
sten (Hospitalisationsdauer, Antibiotika) und die bei
einer Einmalapplikation hundertprozentige Com-
pliance, darf Ceftriaxon zur Prophylaxe bei Sectio
caesarea bevorzugt empfohlen werden.
triaxone (Rocephin®) i. v. ont ete comparees ä celles
de la cefoxitine (MefoxitinR) a un dosage de 3 l g
i. v. Dans les deux groupes, la proportion de patientes
presentant un risque infectieux preoperatoire deflni
(cesarienne d'urgence, cesarienne secondaire, rupture
prematuree des membranes, suspicion d'amnionite,
uricult > 4 germes/ml d'urine et autres infections)
se montait ä 66%. La comparaison entre la cef-
triaxone et la cefoxitine a montre un taux semblable
Revolution febrile (2,6 vs. 1,9%), d'endometrite (0,8
vs. 0,6%) et d'infection de plaie (3,2 vs. 3,9%) (tabelle
II). Ainsi, en considerant ces trois parametres, le taux
d'infections postoperatoires a ete equivalent dans les
deux groupes (ceftriaxone: 6,5%, cefoxitine: 6,4%).
Les infections urinaires, quant a celles, ont ete glo-
balement plus frequentes que les autres parametres
Unauthenticated
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396 von Mandach et al, Ceftriaxone for prophylaxis in cesarean section

infectieux. Elles ont de surcroit ete statistiquement
plus nombreuses dans le groupe cefoxitine que dans
le groupe ceftriaxone (17,8 vs. 9,7%, p < 0,001) (ta-
belle II). Aucune difference de taux d'infections pos-
toperatoires, ä Pexception des infections de plaie,
n'est apparue entre les deux groupes d'antibiotiques,
que les patientes aient presente un risque preopera-
toire ou non (tabelle III). L'analyse bacteriologique
des echantillons d'urine infectee a montre une pre-
dominance d'enterocoques. En depit de leur resis-
tance aux deux antibiotiques, ces germes ont ete
cependant presque deux fois plus frequents apres
traitement ä la cefoxitine qu'apres traitement ä la
ceftriaxone. De plus, par rapport au groupe cef-
triaxone, la colonisation de Turine par Escherichia
coli a ete quatre fois plus frequente dans le groupe
cefoxitine (tabelle VI). Chez les patientes avec une
infection urinaire, la duree d'hospitalisation a ete
plus faible apres traitement par ceftriaxone que par
cefoxitine (11 vs. 12 jours, p < 0,05). Par rapport
aux effets secondaires non specifiques et aux reac-
tions allergiques, la tolerance a ete aussi bonne dans
un cas que dans Fautre (tabelle VII).
Nos resultats montrent qu'apres prophylaxie avec les
antibiotiques testes, les evolutions febriles, les en-
dometrites et les infections de plaie suite ä une ce-
sarienne sont demeurees rares (max. 4%). Les infec-
tions urinaires restent en revanche plus problema-
tiques. Cependant l'usage de la ceftriaxone a claire-
ment mis en evidence Favantage que represente une
protection antibiotique a longue duree d'action dans
l'urine. Si Fön tient en outre compte du fait que la
ceftriaxone engendre des coüts therapeutiques infe-
rieurs ä cause du plus faible taux d'infections uri-
naires (duree d'hospitalisation, antibiotiques), et
qu'elle garantit une compliance totale en raison de
son application en dose unique, on peut sans autre
recommander cet antibiotique pour la prophylaxie
lor s des cesariennes.

Mots-cles: Ceftriaxone, cesarienne, dose unique, prophylaxie antibiotique.

Acknowledgements: Particular thanks to DORIS BREITENMOSER from our Research Division for her expert
computer processing. We also thank Prof. Dr. A. VON GRAEVENITZ, Institute of Medical
Microbiology, University of Zurich, for his valuable advice on the analysis of the
microbiological results.

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Received January 8, 1993. Accepted February
4, 1993.
Ursula von Mandach, Pharm. D.
Department of Obstetrics
University of Zurich
Frauenklinikstrasse 10
CH-8091 Zurich
Switzerland
Unauthenticated
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