does pre- and postoperative metronidazole treatment lower...

Does pre- and postoperative metronidazole treatment lowervaginal cuff infection rate after abdominal hysterectomy

among women with bacterial vaginosis?

Per-Göran Larsson1 and Bodil Carlsson2

1Department of Obstetrics and Gynecology, Central Hospital, Skövde (Kärnsjukhuset), and2Department of Obstetrics and Gynecology, Linköpings Universitet and Division of Clinical Microbiology,

Linköpings Universitet, Linköping, Sweden

Objective: Bacterial vaginosis (BV) is a known risk factor for postoperative infection following abdominal hyster-ectomy. Vaginal bacterial flora scored as intermediate has been shown to have the same risk of postoperativeinfection as BV.Methods: Women undergoing total abdominal hysterectomy for benign diseases were open-randomized accord-ing to Zelen to either treatment with metronidazole rectally for at least 4 days or no treatment. At the preoperativegynecological examination a vaginal smear was collected and Gram stained. Women with BV or intermediate florawere merged to one group called abnormal vaginal flora.Results: In total 213 women were randomized to treatment or no treatment. After exclusion of 71 women, 142women were eligible for analysis. Among the 59 women diagnosed with abnormal vaginal flora there were novaginal cuff infections in the treated arm, compared with 27% in the ‘no treatment’ arm (p < 0.01). Treatment alsoreduced the vaginal cuff infection rate from 9.5 to 2% among the 83 women with lactobacilli flora. However,this difference was not statistically significant. Treatment had no effect on the rate of wound infections.Intention-to-treat analysis showed a significant reduction in vaginal cuff infections among women randomizedto treatment.Conclusion: Pre- and postoperative treatment for at least 4 days with metronidazole rectally reducessignificantly vaginal cuff infection among women with abnormal vaginal flora.

Key words: BACTERIAL VAGINOSIS; ABDOMINAL HYSTERECTOMY; POSTOPERATIVE INFECTION;TREATMENT; INTERMEDIATE FLORA

Total abdominal hysterectomy is the mostcommon procedure for removing the uterus. Pre-operative administration of antibiotics has beenrecommended for vaginal hysterectomy, but notalways for abdominal hysterectomy1. Results froma meta-analysis2, published in 1993, showed that21.1% of patients who did not receive antibioticprophylaxis had a serious infection after abdominal

hysterectomy, whereas only 9% of women givenpreoperative antibiotics prior to abdominal hyster-ectomy had serious postoperative infection. Thispractice of preoperative antibiotic administrationhas not been accepted as good clinical practicein Scandinavia, due to the fact that severalScandinavian studies showed little effect of pre-operative antibiotic prophylaxis on postoperative

Infect Dis Obstet Gynecol 2002;10:133–140

Correspondence to: P-G. Larsson, MD, PhD, Department of Obstetrics and Gynecology, Kärnsjukhuset, S-541 85 Skövde,Sweden. Email: [email protected]

133

morbidity3–6. Mittendorf 2 showed that metroni-dazole was the drug of choice for prophylacticantibiotics, but other authors have suggestedsecond-generation cephalosporins as a betterchoice.

Bacterial vaginosis (BV) is a condition in whichthe vaginal flora is characterized by a 1000–10 000-fold increase in concentration of variousbacteria, including anaerobic bacteria, Gardnerellavaginalis, mycoplasmas and Mobiluncus, whichprimarily affect menstruating women. However,the vaginal flora of women without BV differsconsiderably, from a lactobacilli-dominated florato having no identifiable lactobacilli. Women withno or few lactobacilli seen by microscopy, and nothaving a diagnosis of BV, are said to have ‘inter-mediate flora’, i.e. a flora between normal andBV7. Diagnostic difficulties regarding vaginosisarise when trying to differentiate BV from inter-mediate flora and not so much when differentia-ting between normal lactobacilli flora and BV orintermediate flora. Intermediate flora seems to beof similar clinical significance as BV8–10. Thus, ithas been suggested that intermediate flora andBV should be merged to one single group called‘abnormal vaginal flora’11.

Four studies are available concerning the riskof postoperative pelvic infection after abdominalhysterectomy among women with BV12–15. Thefirst study12 comprised 161 women scheduled forabdominal hysterectomy for benign reasons.Women with BV had a relative risk (RR) of 3.4(95% confidence interval (CI) 1.5–6.7) for cuffcellulitis compared with women who had a nega-tive preoperative diagnosis of BV. In the secondstudy13, 70 women undergoing abdominal hyster-ectomy for benign reasons with exclusion ofpostmenopausal women showed a RR of 4.4 (95%CI 1.4–13.3) for developing postoperative infec-tion if the women had BV. A nation-wide studyfrom Sweden14 found a RR of 3 (95% CI 1.3–7)for postoperative infection after abdominal hyster-ectomy for benign reasons among women withBV compared to women without BV. In a recentlypublished study Lin and co-workers15 found anincreased risk of postoperative infection after allmajor gynecological surgery if the patients had apreoperative diagnosis of BV. In that study women

diagnosed with an intermediate flora had noincreased risk of postoperative infections.

The aims of this study are to investigate theeffect of pre- and postoperative metronidazoletreatment regarding the postoperative infectionrate among women with abnormal vaginal floracompared to women with lactobacilli flora.

SUBJECTS AND METHODS

Study population

The current study included women undergoing anelective total abdominal hysterectomy for benignreasons from 1992 to 1996, less than 50 years of ageor if over 50 still menstruating. We enrolled 213patients into the study. Seventy-one of these wereexcluded (Table 1). Exclusion criteria were pre-operative antibiotic use within one month prior tosurgery, surgery for malignant disease and opera-tions that for other reasons required preoperativeantibiotics. Twenty-two patients were excludedfor missing or inadequate vaginal smears, mostly

Metronidazole treatment and abdominal hysterectomy Larsson and Carlsson

134 INFECTIOUS DISEASES IN OBSTETRICS AND GYNECOLOGY

Wrong randomization n

Supra vaginal hysterectomyPostmenopausalDeclined study entryPreoperative antibioticsMalignant surgeryTotal

101

1553

34

Operative complications n

Preoperative antibioticsRe-operationOther intestinal surgery that required antibioticsTotal

6129

Postoperative complications n

Antibiotics for pneumonia, cholecystis, ileusAllergic reaction to metronidazoleTotal

426

Smear problems n

Missing or uninterrupted smear, treatmentMissing or uninterrupted smear, no treatmentTotal

139

22

Table 1 Excluded patients (n = 71)

due to interfering menstrual blood. We limited thestudy to menstruating women, as the concept ofBV and intermediate flora are poorly understoodregarding postmenopausal women. No consider-ation was taken as to whether the women weremenstruating due to sequential hormone replace-ment therapy (HRT) or endogenous hormoneproduction.

Patient evaluation

Randomization was done according to Zelen16,using sealed envelopes in blocks of ten patients andcarried out before informed consent. The nurseasked patients at preoperative registration if theywanted to join the study, before the patients metthe operating doctor at the final examination.Thus, women randomized to the non-treatmentgroup were not asked to join the study, as no anti-biotic treatment is the normal procedure at theclinic. Women randomized to the treatment groupwere asked to join the study and receive treatment.In some cases the operation method was changedfrom the original planned total abdominal hyster-ectomy to other types of hysterectomies afterrandomization and the women were thenexcluded from the study. The normal preoperativeprocedure included a pelvic examination by theattending physician where vaginal fluid wasobtained from the posterior fornix, placed on amicroscope slide, air-dried and stored at roomtemperature. Demographic data, medical historyand physical findings were recorded on standard-ized study forms. The vaginal slide was Gramstained and analyzed according to Nugents scoringsystem17 by one trained examiner without knowl-edge of the postoperative outcome and all slideswere blindly batch analyzed after the study wasfinished. No evaluation of the vaginal flora wasdone preoperatively and the doctor had no knowl-edge of the vaginal status of the patient duringoperation or at postoperative care. If postoperativeinfection occurred this was recorded by the attend-ing physician on the special form for the study.

Definitions

BV was defined according to Nugent’s criteria17 asabsence of lactobacilli and presence of a Gardnerella

morphotype flora, with a Nugent’s score of7–10. Women with a score of 0–3 were regardedas normal and women with a score of 4–6 asintermediate. Women with a diagnosis of BV orintermediate flora were merged to a group calledabnormal vaginal flora.

Women were defined as having a post-operative vaginal cuff infection if they had three orall of the following four signs during gynecologicalexamination: (1) increased abdominal pain afterthe second day of operation; (2) temperature morethan 38°C rectally after the third day; (3) malo-dorous discharge; and (4) induration or pain in thevaginal vault.

Wound infection was defined as induration andincreased redness around the wound where anti-biotic treatment or debridement where needed. Ifa woman had both vaginal cuff and wound infec-tion she was recorded as a vaginal cuff infection.Urinary tract infection (UTI) was positive urinaryculture with more than 100 000 bacteria/ml.

Unexplained fever was defined as temperatureabove 38°C after the third day of operation with-out any other known diagnosis. All medicalrecords were scrutinized before the vaginal smearswere investigated.

Treatment and follow-up

On the evening before the operation the womenwere given 1 g metronidazole rectally (FlagylÔsuppositories 1 g, Rhône-Poulenc, Rorer,Helsingborg) and the treatment was continuedevery evening until the patient was dischargedfrom the gynecological ward or until any side-effects were noticed. The most common treatmentfor BV is 7-day treatment with oral metronidazolewith a dose of 500 mg BID. Because nausea is awell known side-effect of orally administratedmetronidazole, we chose rectal administrationwhich has a slower reabsorption rate than oraladministration, but the dose of 1 g will give thesame serum concentration as oral treatment. Thegynecologist on duty in the ward performed theoperation. All the surgeons were specialists ingynecology or were supervised by a senior doctor.Total abdominal hysterectomy was performedeither by a low Cohen incision or low longitudinalincision and the vaginal cuff was closed. All other


INFECTIOUS DISEASES IN OBSTETRICS AND GYNECOLOGY 135

surgical procedures done at the same time wererecorded, i.e. bilateral salpingooophorectomy(BSO) or incontinence surgery such as Burchprocedure.

Women over 50 years of age received anti-thrombotic prophylaxis with low molecularheparin. At the operating room the operatingnurse routinely cleaned the vagina preoperativelywith chlorhexidine solution just before the start ofthe operation. A catheter (KAD) was left in thebladder until the second day postoperatively.Patients were free to eat as soon as they felt able. Allwomen were offered a follow-up visit 4–6 weeksafter the operation in the gynecological outpatientclinic. All medical records from the follow-upvisits were scrutinized before the results from thevaginal examinations were added.

Statistics

The Fisher exact test was used when less then 100observations, otherwise the chi square (c2) test wasused, together with RR with 95 % CI. A logisticregression analysis and variance analysis wasperformed.

Ethics

The study was approved by the regional ethicscommittee at the University of Gothenburg andthe ‘Svenska läkemedelsverket’ (Swedish MedicalProducts Agency). Women gave verbal informedconsent to participate in the study.

RESULTS

The study population included 142 patients. Therewere no differences in the demographic factors

between the treated and not treated group(Table 2). There were no differences in operatingtime, preoperative bleeding or preoperative bloodhemoglobin, and a logistic regression was per-formed using these variables which showed thatpreoperative hemoglobin, weight, operating timeand bleeding had no influence on the post-operative infection rate for all three groups ofwomen (all women, non-treatment group andtreatment group). The indication for the hyster-ectomy was dysfunctional uterine bleeding (DUB)or fibroids in more than 80% of cases.

The treatment consisted of metronidazolerectally from the night before operation until dis-charge from the hospital or at minimum 4 days oftreatment. Side-effects such as nausea were noticedamong eight (12%) of the 67 treated women.These eight women discontinued the treatment inadvance but still after the required 4 days of treat-ment. The mean treatment time was 5.8 days witha range of 4–13 days. Two patients had an allergicreaction after the first dose of treatment and wereexcluded from the study (Table 1).

The microscopy of the vaginal flora showed that41.5% of the women had abnormal vaginal flora(17.6% of women with BV and 23.9% with inter-mediate flora) and 58.5% had normal lactobacilliflora.

The mean time for the postoperative follow-upvisit for non-infected women was 6.4 weeks with arange of 4–12 weeks, except for two patients whodid not come to the scheduled visit. These twopatients were interviewed by telephone. Fourteenwomen had a vaginal cuff infection, 13 of whomwere diagnosed before discharge from the hospital.Only five of the ten wound infections had beendetected before leaving the hospital. Of 25 UTI,21 were known before the patients left the



All women(n = 142)

Treatment group(n = 67)

Non-treatment group(n = 75)

Mean Range Mean Range Mean Range

Age (years)Weight (kg)Operating time (minutes)Preoperative bleeding (ml)Preoperative hemoglobin (g/l)

4671

100578127

33–5844–11043–21075–240083–154

467399

580127

33–5844–11043–210

100–240083–146

4570

102576127

33–5751–9350–19075–230089–154

Table 2 Background factors

hospital. Fifteen patients left the hospital with aslight increase in body temperature, howeverwithout a specific diagnosis i.e. unexplained feverand with no treatment. Four (26%) of thesepatients came back with a UTI but none ofthese patients had an undetected wound or cuffinfection.

There was no significant difference in woundinfection rate among the treated or non-treatedwomen (Table 3). The frequency of cuff infectiondecreased from 27 to 0% in women with an abnor-mal vaginal flora that were treated withmetronidazole (p < 0.05). This finding was evenmore pronounced among women with BV as thevaginal cuff infection decreased from 35.7 to 0% inthe metronidazole group (p < 0.05). The vaginalcuff infection rate only decreased from 9.5 to 2%for women with normal lactobacilli flora (notsignificant) (Table 3). There were no differences inUTI rate between the various vaginal flora groups,and treatment with metronidazole did not reducethe incidence of postoperative UTI.

This study was performed when long post-operative hospital care after abdominal hysterecto-mies was common clinical practice. The mean

time for hospital care was 5.8 days (standard devia-tion, SD 1.7) for women with no infection and6.8 days (SD 3.5) for women with wound infec-tion. Women with UTI stayed in hospital for6.7 days (SD 1.7). Women with cuff infections hada mean hospital stay of 8.8 days (SD 2.4). Varianceanalysis with Tukey’s pairwise comparisonsshowed statistically significant longer hospital careonly for vaginal cuff infection (p < 0.01).

Intention-to-treat analysis for all 142 womenshowed a significant difference regarding cuffinfections: one cuff infection (1.5%) in the treatedgroup versus 14 cuff infections (17%) in thenon-treated group (p < 0.05, c2 test). The relativerisk of postoperative cuff infection was signifi-cantly lower in the treated group versus thenon-treated group (RR 0.1, 95% CI 0.01–0.6).No difference was seen regarding the woundinfections or UTI.

DISCUSSION

Bacterial vaginosis (BV) is a condition in which thevaginal flora is characterized by a 1000–10 000-fold increase in concentrations of various



Wound infectionTreatment group

n (%)Non-treatment group

n (%) Fisher’s exact test Relative risk

Abnormal, n = 59Lactobacilli, n = 83All women, n = 142

3 (12)3 (7)6 (9)

1 (3)3 (7)4 (5.3)

nsnsns*

-3.8 (0.4–34.5) ns1 (0.2–4.6) ns

1.7 (0.5–5.7) ns

Cuff infectionTreatment group


n (%)


0 (0)1 (2)1 (1.5)

9 (27)4 (9.5)

13 (17.3)

0.003ns

0.016*

Not possible0.3 (0.03–2.2) ns

0.1 (0.01–0.6) p < 0.05

Urinary tract infectionsTreatment group


n (%)


7 (27)5 (12)

12 (17.9)

4 (12)9 (21)

13 (17.3)

nsnsns*

1.8 (0.6–4.8) ns0.6 (0.2–1.6) ns

1 (0.5–2.1) ns

*Fisher’s exact test except for ‘all women’: c2 test was used as there were more than 100 observations; ns, not significant

Table 3 Infection rate among women after abdominal hysterectomy and treatment with pre- and postoperativemetronidazole 1 g rectally for a minimum of 4 days

anaerobic bacteria. However, the vaginal flora ofwomen with ‘intermediate flora’ has an increasedconcentration of bacteria of up to 1000 times7.Houang and co-workers18 showed that the magni-tude of bacteria contamination during operation isan important determinant in the development ofpostoperative infection after abdominal hyster-ectomy. This might be the theoretical explanationof the increased risk of postoperative infection inwomen with either BV or intermediate flora8–10 asit might be the increased concentration of bacteriarather than the pathogenic potential of the bacteriathat causes the postoperative infection. Whendiagnosing BV it is often most difficult to make aclear distinction between full-blown BV and theintermediate flora. This is apparent when usingNugent scoring. According to Nugent’s scoringsystem a score of six is given if there are one–fourlactobacilli per high power field even if there arehundreds or thousands of small bacteria in the samehigh power field. A slide with that many smallbacteria will also often have clue cells but this issomething that Nugent’s scoring system does nottake into account. This is the reason why inter-mediate flora and BV in this study are merged intoone group called abnormal vaginal flora. Thismerging was successful in an earlier study wherewomen with lactobacilli flora did not benefit frompreoperative clindamycin treatment before legalabortion, in contrast to women with abnormalvaginal flora defined as BV or intermediate flora10.To simplify the diagnosis in a practical clinicalaspect it might be helpful to focus on the presenceof lactobacilli. Women with a microscopic findingof vaginal flora of normal lactobacilli will receiveno treatment whereas women in absence ofnormal lactobacilli flora will receive preoperativetreatment.

Lin and co-workers15 did not find any effect ofpreoperative antibiotic treatment in the inter-mediate group. This could be due to the fact thatthey did not exclude postmenopausal women.Postmenopausal women lack lactobacilli in thevaginal flora and will score as intermediate floraaccording to Nugent. An earlier nationwide studyshowed that postmenopausal women have a lowerrisk of postoperative infection than youngerwomen14. In this study we have therefore deliber-ately restricted menstruating or estrogen-replaced

women as the concept of BV and intermediateflora are poorly understood in postmenopausalwomen.

Today, hospital care has shortened in mostplaces and patients are discharged much earlierfrom hospital. In addition, a higher degree ofhysterectomies today are done either laparo-scopically or vaginally, both with considerablyshorter hospital care than abdominal hyster-ectomies. This is important to bear in mind whenpostoperative infection rates are reported andcompared, as many postoperative infections donot arise until after discharge from hospital andtherefore will alter documented infection rates.

In an open randomized trial there are alwayssome methodological weaknesses. When thedoctor in charge of the patient knows whether ornot the patient is treated it might influence theresults: if a patient with a suspected mild infectionreceived metronidazole preoperatively, the doctormay wait one day before diagnosis. And patientsknown to have not been given metronidazolepreoperatively might be given other antibioticssooner. It could therefore be easier to diagnose apostoperative infection if the women had no treat-ment. However this would have affected the infec-tion rates in the treated and not-treated groups, andnot the difference between lactobacilli or abnor-mal vaginal flora group as the diagnosis of thevaginal flora was unknown to the doctor. Thedefinition of postoperative infection is subjective,as always in open clinical studies, and our fre-quency of postoperative infection could only becompared with other hospitals with caution. Thesubjective definition of postoperative infectionwould only reduce any difference in the treatmentgroups and would therefore weaken our resultsbut not affect the conclusion of the study.

There are many different treatment regimensfor BV. One commonly seen is 4 g metronidazolegiven as a single 2 g dose on day one and three.Because of this we required at least 4 days oftreatment for evaluation of efficacy, i.e. 4 gmetronidazole. Treatment with oral metro-nidazole is known to cause nausea, a well-knowneffect even of general anesthesia. Therefore wedecided to administer metronidazole rectallyinstead of orally, to minimize exclusions due tomedical events.



Our study is the first intervention study of BVand intermediate flora among women operatedwith abdominal hysterectomy. We showed thatwomen with BV or intermediate flora benefit fromantibiotic treatment and should be offered treat-ment starting the day before operation. Althoughour intention-to-treat analysis showed that allwomen, even those with normal lactobacilli flora,would benefit from treatment to some degree, itis questionable whether women with normallactobacilli flora should be given antibiotic treat-ment for four days. We found no effect on thefrequency of wound infections or UTI. These

results were expected as UTI and wound infec-tions are mostly caused by aerobic bacteria resistantto metronidazole.

ACKNOWLEDGMENTS

This study was supported by the Rhône–PoulencRorer and grants from the ‘FoU – Skaraborg’ and‘FoU – VästraGötalands regionen’. We thank alldoctors and nurses from the gynecological ward atthe Central Hospital of Skövde (Kärnsjukhuset) fortheir support during the study.

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RECEIVED 10/16/01; ACCEPTED 02/22/02



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