Cefazolin versus cefazolin plus metronidazole for antibiotic prophylaxis at cesarean section.

Background: Although prophylactic antibiotic medications have been shown to reduce the incidence of postoperative infectious morbidity after cesarean delivery, the most effective regimens have not been established. The purpose of this investigation was to compare the efficacy and costs of prophylaxis with cefazolin alone with cefazolin plus metronidazole.

Methods: Women undergoing cesarean delivery were randomized to prophylaxis with 2 g cefazolin (n = 81) or 1 g cefazolin plus 500 mg metronidazole (n = 79). Postoperative infectious morbidity and the duration of hospitalization in the two groups were compared.

Results: Thirty-seven (23%) of 160 patients developed endomyometritis. There was a significant reduction in the number of postoperative infections (14 versus 32%) and hospital days (3.12 versus 4.46) with cefazolin and metronidazole prophylaxis (P = 0.0064 versus P = 0.014) compared with cefazolin alone. The estimated antibiotic prophylaxis cost per person was less with cefazolin and metronidazole than with cefazolin alone ($9.12 versus $26.73).

Conclusion: Antibiotic prophylaxis with metronidazole and cefazolin results in fewer postoperative infections, decreased duration of hospitalization, and lower medication cost than cefazolin alone.

**********

Endometritis is the most common complication associated with cesarean delivery. Without prophylactic antibiotics, infection rates from 5 to 85% (mean, 35-40%) have been reported. (1,2) Numerous studies have shown that perioperative antibiotics significantly reduce the incidence of postpartum endometritis to approximately 5% after cesarean delivery. (2,3) However, controversy exists regarding which antibiotics should be used. (4) According to current recommendations, the literature supports the use of a single dose of a first-generation cephalosporin immediately after clamping the umbilical cord. (5-8) A single 2-g dose of cefazolin is generally recommended for all women undergoing cesarean delivery and has become the standard prophylactic antibiotic at many centers. (5) A recent meta-analysis revealed a similar efficacy in the reduction of postoperative endometritis with first-generation cephalosporins or ampicillin. (9)

Despite the current recommendations, there is a general assumption that newer, extended-spectrum antibiotics such as cefotetan may be more effective as prophylactic agents than the recommended medications, because endometritis is predominately polymicrobial. (8) The combination of cefazolin and metronidazole provides comparable Gram-negative coverage and superior Gram-positive and anaerobic coverage to that of cefotetan. (9) However, no previous studies have evaluated the effectiveness of this combination for cesarean section prophylaxis. This study was designed to address both the effectiveness of this regimen as well as the cost savings compared with cefazolin when used for surgical prophylaxis in a predominately indigent, high-risk obstetric population.

Patients and Methods

This randomized, double-blind study was conducted from December 1996 through November 1998 according to a protocol approved by the University of Tennessee Health Science Center Institutional Review Board. All women undergoing cesarean delivery at The Regional Medical Center at Memphis were considered eligible to participate in this study. Patients were excluded if they had received intrapartum antibiotics; had known sensitivities to penicillins, cephalosporins, or metronidazole; had known ethanol consumption within 24 hours of delivery; or had known liver disease. Standard doses of either 2 g cefazolin IV or 1 g cefazolin plus 500 mg metronidazole IV were used for antibiotic prophylaxis. Randomization was performed with computer-generated random numbers, and assignments were placed in sealed envelopes and shuffled. After informed consent was obtained, the envelopes were opened, and the anesthesiology staff in attendance administered the assigned prophylactic antibiotics after the umbilical cord was clamped at cesarean section. Cesarean delivery was performed in a standardized fashion, and the abdominal cavity was irrigated with 1 L normal saline before fascial closure. Operative delivery was considered to be emergent if performed for fetal distress or a disorder of labor. Elective cesarean deliveries included repeat cesarean section, malpresentation, macrosomia, or other conditions thought to contraindicate vaginal delivery.

Postoperative care was provided by the resident house staff and attending physicians of the obstetrical service. House staff and attending physicians were unaware of antibiotic assignments. Patients were considered to have a diagnosis of postoperative infection if they exhibited standard criteria, including an oral temperature of 38[degrees]C or greater on two occasions at least 6 hours apart after the first postoperative day in conjunction with pelvic pain or uterine tenderness, an elevated white blood cell count, and foul-smelling lochia in the absence of other sources of infectious morbidity. Antibiotic therapy was instituted secondary to these clinical features or on the basis of a strong clinical suspicion by the attending obstetrics service. The obstetrics staff instituted antibiotic therapy at their discretion. Most commonly, antibiotic therapy consisted of the triple IV antibiotic combination of 2 g ampicillin every 6 hours, gentamicin 140 mg load with 100 to 120 mg every 8 hours, and 900 mg clindamycin every 8 hours. Gentamicin peak and trough levels were obtained if there was no response to therapy in 48 hours as per institutional protocol. Patients with postoperative endometritis were treated with intravenous antibiotics until afebrile for 24 to 48 hours with resolution of symptoms. Oral antibiotics were not used after intravenous therapy, and patients were not discharged on antibiotics.

The rates of postoperative infectious morbidity, length of hospital stay, length of postoperative stay, duration of antibiotic therapy, estimated blood loss at surgery, and operative time were compared between the two groups. The Regional Medical Center Pharmacy provided the average wholesale prices (AWPs) for the antibiotics.

On the basis of approximately a 30% rate of postoperative endomyometritis and wound infection, preliminary power analysis indicated that 62 participants would be required in each group to show a reduction in postoperative infectious morbidity to 10% with 80% power at P = 0.05 significance level. Groups were compared with the use of a two-tailed Student's t test and the [X.sup.2] statistic for continuous and discrete variables as appropriate. Statistical analyses were performed with Stat View 5.0 (SAS Institute, Inc., Cary, NC) and Primer of Biostatistics version 3.0 (McGraw-Hill, New York, NY). P < 0.05 was considered statistically significant.

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Results

Of the 160 patients recruited from a largely indigent, innercity population, 81 were randomized to cefazolin alone and 79 were administered cefazolin plus metronidazole for perioperative prophylaxis. There were 167 neonates delivered in the 160 pregnancies, including 7 sets of twins. Five sets of twins were delivered in the single-antibiotic prophylaxis group, and two sets of twins were delivered in the cefazolin plus metronidazole group. There were no significant differences in the demographics between women in either group participating in the study (Table 1). Although cesarean delivery was performed for emergent indications in 39 (48%) of 81 women administered cefazolin alone versus 28 (35%) of 79 women administered combination prophylactic antibiotics, there was no significant difference (P = 0.14). Elective cesarean section was performed in 42 (52%) of 81 women administered cefazolin alone and 51 (65%) of 79 women administered cefazolin plus metronidazole, but there was no significant difference (P = 0.14). The indications for cesarean delivery are summarized in Table 1. There were 37 cases of postoperative infection, for an overall rate of 23% for postoperative endomyometritis. No adverse reaction or intolerance was reported with either prophylactic antibiotic regimen.

No statistically significant differences between the two groups were observed with regard to length of time from rupture of membranes until delivery, mean operative time, estimated blood loss, or total hospital days (Table 2). There was a significant reduction in the number of postoperative days hospitalized (3.12 [+ or -] 0.8 d versus 4.46 [+ or -] 4.7 d) and the number of days treated with antibiotics postoperatively (0.4 [+ or -] 1.04 d versus 1.98 [+ or -] 5.2 d) among patients in the group that underwent the combination prophylaxis compared with the group that was administered cefazolin alone. The cefazolin plus metronidazole group had an infection rate of 14% (11 of 79 women), and the group that was administered cefazolin alone had an infection rate of 32% (26 of 81 women), representing a significant decrease in postoperative infectious morbidity with the cefazolin and metronidazole combination (P < 0.01) (Table 2).

The 26 patients who developed postpartum endometritis after prophylactic cefazolin were compared with the 11 patients who developed endometritis after prophylactic cefazolin plus metronidazole (Table 3). There were no differences between the two groups with regard to the time from rupture of membranes until delivery, total operative time, or estimated blood loss, nor were there any differences between the two groups with regard to the number of hospital days, postoperative days, or antibiotic days (Table 3).

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The AWP for cefazolin 2 g IV, cefazolin 1 g plus metronidazole 500 mg IV, and triple antibiotic therapy were $5.66/dose, $4.83/dose, and $10.60/d, respectively. Antibiotic costs were estimated by using the formula

(n X prophylactic cost) + [(AD X treatment cost) / n],

where n represents the number of patients and AD represents total antibiotic days. The antibiotic cost, calculated on the basis of AWP, for those patients who underwent prophylaxis with cefazolin alone was $26.73/patient, whereas the antibiotic cost for patients who were administered prophylaxis with cefazolin plus metronidazole was $9.12/patient. This cost difference represents a savings of $17.61/patient with cefazolin plus metronidazole prophylaxis.

Discussion

The use of perioperative antibiotic prophylaxis is a well-established practice that has been shown to decrease the incidence of postcesarean endometritis. (3) Cefazolin traditionally has been recommended as the antibiotic of choice for prophylaxis, (5,6) but because of the polymicrobial nature of postpartum endometritis, the use of new, extended-spectrum agents for cesarean section prophylaxis has been suggested. (10) In a recent study, however, 2 g of the broad-spectrum antibiotic cefotetan was no more effective than the standard 2-g dose of cefazolin in the prevention of postoperative febrile morbidity, and the increase in antibiotic cost did not justify the use of the extended-spectrum antibiotic regimen. (8) In a study comparing 10 prophylactic antibiotic regimens, cefotetan administered as a single 1-g dose was associated with the lowest rate of postoperative endomyometritis in a predominately Hispanic, indigent population. (10) However, this difference was not statistically significant.

Since 1991, the Baptist Hospital System of Birmingham has recommended the cost-effective combination of 1 g cefazolin and 500 mg metronidazole for perioperative prophylaxis in surgical procedures that may involve anaerobic organisms. (11) Although the combination of these two antibiotics provides better Gram-positive and anaerobic antibacterial coverage than does second-generation cephalosporins, no study has evaluated the combination of metronidazole and cefazolin for cesarean section prophylaxis. (9) This study was designed to address both the effectiveness of this regimen and the potential cost savings compared with cefazolin when used for surgical prophylaxis in a high-risk obstetric population.

The results of this study demonstrate a significant reduction in the rate of postoperative infection, the number of postoperative hospital days, and the duration of antibiotic therapy when cefazolin plus metronidazole was used for prophylaxis instead of cefazolin alone. Because postoperative endomyometritis was diagnosed on the basis of standard criteria or strong clinical suspicion among attending obstetrics service staff, this may represent a potential confounding factor. Because the diagnosis of postoperative infectious morbidity was left in part to the discretion of the attending obstetrics service, we think that the results reflect the actual clinical practice at a large teaching hospital. Although prophylactic cefazolin plus metronidazole was associated with a decrease in the rate of postoperative infectious morbidity, the combination did not seem to influence the duration of infections that developed in the postoperative period, as demonstrated in Table 3. It is possible that the treating physicians may have been aware of the prophylactic antibiotic regimen through review of the anesthesia records. This potentially may have influenced their decision regarding the initiation of therapeutic antibiotics and could represent a confounding factor, although this was thought to be unlikely on the basis of practice patterns at this institution.

We found a substantial difference in antibiotic costs, estimated at $17.61/patient, between the 2-g cefazolin prophylaxis group and the group that underwent prophylaxis with 1 g cefazolin plus 500 mg metronidazole. Based on an average rate of $265.00/d, hospital room charges for postoperative days were estimated to be $1,184.32/patient for the group that underwent prophylaxis with cefazolin alone. The patients in the metronidazole plus cefazolin prophylaxis group were estimated to have incurred a cost of $828.54/patient. This difference represents a $355.78/patient cost savings in the latter group.

When the differences in antibiotic and estimated postoperative room charges were calculated, the metronidazole plus cefazolin prophylaxis group was estimated to have incurred overall costs that were $372.39/patient less than in the cefazolin-alone group. This savings could represent a significant difference in total health care costs. These estimates are based on only a rudimentary analysis of comparative costs incurred and do not include additional charges, such as diagnostic or therapeutic radiographic evaluations and additional laboratory investigations.

The results of this study suggest that cefazolin plus metronidazole may be superior to cefazolin alone for antibiotic prophylaxis at cesarean section. The potential reductions in postoperative infectious morbidity and estimated hospital costs warrant consideration of changing from cefazolin-alone to the cefazolin plus metronidazole combination for perioperative prophylaxis at cesarean delivery.

Faith is like love: it cannot be forced.

--Arthur Schopenhauer

Table 1.  Patient characteristics (a)

                      Cefazolin                Cefazolin plus
                      alone                    metronidazole
Characteristic        (n = 81)                 (n = 79)              P

Maternal age (yr)     24.8 [+ or -] 6.7       25.4 [+ or -] 7.0    0.62

Maternal weight (kg)  90.1 [+ or -] 24.1      92 [+ or -] 25.3     0.62

Maternal body         34.6 [+ or -] 8.8       34.4 [+ or -] 9.21   0.88
mass index

Gestational           37.5 [+ or -] 3.3       37.5 [+ or -] 3.6    0.9
 age (wk)

Birthweight (g)       2,883.8 [+ or -] 864.6  2,972 [+ or -]879.2  0.5

Indication for cesarean section

Repeat                              29 (36%)          31 (39%)     0.7

Arrest disorder                     30 (37%)          19 (24%)     0.1

Distress                             9 (11%)           8 (10%)     0.9

Other                               13 (16%)          21 (27%)     0.2

Parity

Nulliparous                         31 (38%)          29 (37%)     0.9

>1                                  50 (62%)          50 (63%)     0.9

(a) Data are expressed as mean [+ or -] standard deviation or number %).

Table 2.  Hospital course of all patients according to prophylactic
regimen (a)

Parameter                              Cefazolin alone
                                        (n = 81)

Membrane rupture until delivery     848.8 [+ or -] 3,305.7
interval (min)

Operative time (min)                 61.6 [+ or -] 31.5

Estimated blood loss (ml)           753.1 [+ or -] 316.7

Postoperative days in hospital        4.46 [+ or -] 4.7

Postoperative infectious morbidity   26 (32%)

Parameter                           Cefazolin plus          P
                                    metronidazole (n = 79)

Membrane rupture until delivery     500.5 [+ or -] 1,824.3  0.41
interval (min)

Operative time (min)                 56.9 [+ or -] 28.3     0.32

Estimated blood loss (ml)           837.3 [+ or -] 493.6    0.19

Postoperative days in hospital        3.12 [+ or -] 0.8     0.014

Postoperative infectious morbidity   11 (14%)               0.0064

(a) Data are expressed as mean [+ or -] standard deviation or number
(%).

Table 3.  Hospital course of patients who developed postoperative
endometritis after undergoing prophylaxis with cefazolin alone or
cefazolin plus metronidazole (a)

Parameter           Cefazolin alone (n =       Cefazolin plus       P
                       (n = 26)                metronidazole
                                               (n = 11)

Time from membrane  1,621.4 [+ or -]5,669.8  362.2 [+ or -] 409.5  0.47
rupture until
delivery interval
(min)

Operative time         54.35 [+ or -] 21.1    52.3 [+ or -] 21.9   0.79
(min)

Estimated blood       867.3 [+ or -] 408.9   772.7 [+ or -] 290.1  0.5
loss (ml)

Total hospital          8.69 [+ or -] 7.7      5.1 [+ or -] 1.4    0.14
days

Postoperative days      7.03 [+ or -] 7.6      4.0 [+ or -] 1.5    0.2
in hospital

Antibiotic days         6.08 [+ or -] 7.8      2.9 [+ or -] 0.7    0.19

(a) Data are expressed as mean [+ or -] standard deviation.

From the Department of Obstetrics and Gynecology, University of Tennessee Health Science Center, Memphis, TN.

Reprint requests to Norman L. Meyer. MD, PhD, Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Tennessee Health Science Center, E102 Rout Center for Women and Infants, 853 Jefferson Avenue. Memphis, TN 38103-2896. Email: [e-mail]

Accepted January 9, 2003.

Copyright [c] 2003 by The Southern Medical Association 0038-4348/03/9610-0992

References

1. Anstey JT, Sheldon GW, Blythe JG. Infectious morbidity after primary cesarean sections in a private institution. Am J Obstet Gynecol 1980;136:205-210.

2. Smaill F, Hofmeyr GJ. Antibiotic prophylaxis for cesarean section. Cochrane Database Syst Rev 2002;3:CD000933.

3. Sweet RL, Gibbs RS. Infectious Diseases of the Female Genital Tract, Philadelphia, Lippincott Williams & Wilkins, 2002, ed 4.

4. ASHP Commission on Therapeutics. ASHP therapeutic guidelines on antimicrobial prophylaxis in surgery. Clin Pharm 1992;11:483-513.

5. Crombleholme WR. Use of prophylactic antibiotics in obstetrics and gynecology. Clin Obstet Gynecol 1988;31:466-472.

6. Jakobi P, Weissman A, Zimmer EZ, et al. Single-dose cefazolin prophylaxis for cesarean section. Am J Obstet Gynecol 1988;158:1049-1052.

7. Hopkins L, Smaill F. Antibiotic prophylaxis regimens and drugs for cesarean section. Cochrane Database Syst Rev 2000;2:CD001136.

8. Carlson C, Duff P. Antibiotic prophylaxis for cesarean delivery: Is an extended-spectrum agent necessary? Obstet Gynecol 1990;76:343-346.

9. Rivers TE. Considerations for surgical prophylaxis and perioperative antibiotic therapy, in Pharmacotherapeutics Update. Birmingham, AL, Baptist Medical Center Princeton, 1995, vol 10, p 6.

10. Faro S, Martens MG, Hammill HA, et al. Antibiotic prophylaxis: Is there a difference? Am J Obstet Gynecol 1990;162:900-909.

11. Rivers TE. Considerations in the treatment of anaerobic infections, in Pharmacotherapeutics Update. Birmingham, AL, Baptist Medical Center Princeton, 1991, vol 6, p 1.

RELATED ARTICLE: Key Points

* Administering prophylactic antibiotics at cesarean delivery reduces the incidence of infectious postoperative morbidity.

* The optimal regimen for prophylactic antibiotics in this population has not been established.

* Patients who undergo the cost-effective prophylactic regimen of cefazolin and metronidazole have significantly fewer postoperative infections, shorter duration of hospitalization, and decreased duration of antibiotic therapy than do patients who undergo prophylaxis with cefazolin alone.

Norman L. Meyer, MD, PHD, Keehn V. Hosier, MD, Kim Scott, MD, and Gary H. Lipscomb, MD