Journal of Antimicrobial Chemotherapy (1978) 4 (Suppl. C), 55-62

An evaluation of metronidazole in the prophylaxis of anaerobic infections in obstetrical patients*

Groupt

Luton and Dunstable Hospital, Luton LU4 ODZ, England

The frequency of post-delivery non-clostridial anaerobic infection and vaginal carriage rates of non-clostridial anaerobes were studied in 149 obstetrical patients; 79 of these patients received prophylactic metronidazole and the vaginal carriage rate was reduced from 25 to 11 % during the puerperium. In contrast, the vaginal carriage rate in 70 control patients rose from 24 to 90% over the same period. Anaerobic infections developed in 2 of 70 control patients (both caesarean section deliveries) but none developed in metronidazole-treated patients. Introduction

Non-sporing anaerobic bacteria make up a large portion of the normal vaginal flora; bacteroides and anaerobic cocci are the predominant anaerobes, various species of which are encountered in about 70% of high vaginal and cervical swabs. The commonest species are Bacteroides fragilis and B. melaninogenicus (Burdon, 1928; Hare & Polunin, 1960; Gorbach, Menda, Thadepalli & Keith, 1973; Bullen, Willis & Williams, 1973; Study Group, 1974, 1975). There is some evidence to suggest that the incidence of non-sporing anaerobes in the vagina is subject to variations that depend on normal hormonal influences. Thus, Hite, Hesseltine & Goldstein (1947) did not find Bacteroides species in the vaginas of any of 61 normal antenatal patients, and de Louvois and his colleagues (1975a, b) isolated bacteroides from the vaginas of only 5-2% of 265 women during the first half of pregnancy (see also Goplerud, Ohm & Galask, 1976). In a study of the vaginal bacteria in gynaecological patients, Neary, Allen, Okubadejo & Payne (1973) reported the presence of Bacteroides species in 17% of patients who were in the first half of the menstrual cycle, but in only 2-5 % of those in the second half. Anaerobic bacteria that are present in the introitus and lower vagina are representatives of the faecal flora and are more properly regarded as faecal contaminants rather than normal inhabitants. Modern techniques of accouchement ensure that significant post-partum infections of * Requests for reprints should be addressed to A.T.W., Public Health Laboratory, Luton and Dunstable Hospital, Lewsey Road, Luton LU4 ODZ, England. t The Study Group consisted of: A. T. Willis, I. R. Ferguson, P. H. Jones, K. D. Phillips, P. V. Tearle [Department of Clinical Microbiology (Public Health Laboratory)]; G. C. Brentall, G. H. Bancroft-Livingston, S. A. Seligman (Department of Obstetrics and Gynaecology); Irene Sutch, Deborah Edwards (Pharmacy). 55 0305-7453/78/09O1-CO55S01.0O/0 © 1978 The British Society for Antimicrobial Chemotherapy

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Report by a Study

56

Study Group

Patients and methods

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the genital tract are relatively infrequent. However, in view of the common presence of non-clostridial anaerobes in the vagina and introitus, it is not surprising that these organisms are frequently involved in puerperal infections, from many of which multiple bacterial species, both anaerobic and aerobic, may be isolated. Modern experience leaves little room for doubt, however, that obligate anaerobes are the predominant pathogens in most serious, and in many of the more trifling of these post-partum infections. The anaerobic pathogens most commonly implicated are B. melaninogenicus, B. fragilis, B. capillosus, fusobacteria and anaerobic cocci (ThadepaUi, Gorbach & Keith, 1973; Bosio & Taylor, 1973; Sweet, 1975). The clinical picture of puerperal anaerobic sepsis is variable. Commonly there is merely a mild fever and a heavy or offensive lochia; extension of localized infections such as endometritis may lead to the development of pyometra, or adnexal or pelvic abscess. In more severe infections a swinging temperature with peritonitis, pelvic thrombophlebitis or bacteraemia may develop. The more severe forms of bacteroides puerperal sepsis are associated particularly with caesarean section (Pearson & Anderson, 1970; Bosio & Taylor, 1973). Studies at the Luton and Dunstable Hospital (Study Group, 1974,1975,1976,1977) made use of the specific bactericidal activity of metronidazole against anaerobes in the prevention of post-operative sepsis following gastrointestinal and gynaecological surgery. We report here the clinical and bacteriological findings of a double-blind trial of metronidazole that was aimed at assessing the value of the drug in the prophylaxis of genital tract sepsis following delivery.

All obstetrical patients (not booked for short stay) entering the Luton and Dunstable Hospital for induction of labour during a SVi-month period were admitted to the trial, provided that there was no recent history of antibiotic or metronidazole therapy. The study was a double-blind trial using active and placebo suppositories and oral tablets. Patients were randomly allocated to the metronidazole and placebo groups. Initially 144 patients were admitted to the study; 73 received prophylactic metronidazole and 71 were controls. During the study period 5 patients ceased to qualify for the trial—one did not wish to take part and 4 others were discharged home early. We therefore analysed 139 patients, 73 of whom received metronidazole, and 66 were controls. During this period a similar study was made of patients having elective caesarean section. There were 10 of these patients, 6 of whom received prophylactic metronidazole, and 4 were controls. Clinical management On admission. Prior to the first pelvic examination after admission a high vaginal swab for bacteriological study was collected under vision. As part of the predelivery medication each patient for surgical induction was given a suppository rectally which contained either metronidazole or a placebo, while patients for elective caesarean section received oral prophylaxis (or placebo) as outlined below. Management of labour. The conduct of labour was along conventional lines. Patients in whom labour failed to become established after artificial rupture of membranes received oytocin infusion. Of the 73 patients who received metronidazole, 52 were

Prophylaxis in obstetrical patients

57

Prophylactic regimen Induction patients. At the time of surgical induction 1 g of metronidazole or placebo was given in a 4-g Witepsol suppository (Study Group, 1975,1976); this was repeated 8-hourly until delivery. After delivery each patient received oral metronidazole or placebo tablets—200 mg immediately, then 200 mg three times daily to the end of the 7th day. Elective caesarean patients. Eighteen hours pre-operatively an oral dose of metronidazole 1 g or placebo was given; then 200 mg three times daily post-operatively for 7 days. Bacteriological studies. High vaginal swabs, samples of lochia, specimens of pus, wound swabs and so on were examined and assessed by conventional aerobic and anaerobic methods. Results Incidence of postpartum infection Among the 73 surgically induced patients who received prophylactic metronidazole there were no post-partum infections due either to aerobes or anaerobes. In contrast, bacteriologically confirmed clinical infections developed in 3 (4-5%) of 66 control patients (Table I). All of these infected patients had been delivered by emergency caesarean section; 2 of the infections involved only the abdominal wound and were due to aerobic bacteria {Staphylococcus aureus and Escherichia coli), and one was an anaerobic infection of the abdominal wound and of the pelvis due to B. fragilis. Among the 6 elective caesarean section patients who received prophylactic metronidazole there were no postoperative infections. One of the 4 control caesarean section patients developed bacteriologically confirmed post-surgical wound anaerobic sepsis due to an anaerobic streptococcus. Pre-delivery and post-delivery vaginal carriage of anaerobes The pre-delivery carriage rates of anaerobes in the two groups of all 149 patients studied were about the same, i.e. about 25% (Figure 1). During the puerperium, however, the

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delivered normally (45 had episiotomy), 12 had forceps deliveries, and 9 came to caesarean section (Table I). Of the 66 control patients, 45 were delivered normaliy (37 had episiotomy), 10 had forceps deliveries and 11 had caesarean section. Samples of meternal and cord blood for metronidazole assay were collected at the time of delivery, and from patients having caesarean section samples of amniotic fluid were also sometimes obtained. Management during the puerperium. Patients received metronidazole or placebo until the end of the 7th day of the puerperium. Daily samples of lochia were obtained on high vaginal swabs for bacteriological study, and a sample of blood for metronidazole assay was collected on the 3rd day. A sample of milk for metronidazole assay was obtained on the 6th day from mothers who were breast feeding their infants. Careful daily clinical records were kept of the patients' and their infants' progress, special attention being paid to any evidence of clinical infection. Additional specimens for bacteriological study (urine, sputum, surgical wound swabs, etc.) were collected as indicated by the patients' clinical condition. When proven anaerobic sepsis developed the double-blind code was broken to find out whether the patient was receiving placebo or metronidazole.

58

Study Group

Table I. Summary of 139 surgically induced obstetrical patients Number of patients with post-partum infections Aerobic

Anaerobic

Prophylactic metronidazole (73): (52) Normal delivery (12) Forceps delivery (9) Caesarean section Controls (66): Normal delivery (45) Forceps delivery (10) Caesarean section (11)

0 0 0 0 2 0 0 2

0 0 0 0 1 0 0 1

(abdominal wound)

(abdominal wound+ pelvic abscess)

100

£ 80 o

g. 60

_o

o •

S 40

o Control • Metronidazole

a> .£3

e

(

S 20

0

1

2

3

4

5

6

7

Days Figure 1. Vaginal carriage rates of anaerobes among 79 metronidazole patients and 70 controls. Day 0 is the last pre-delivery day; days 1 to 7 are post-delivery days.

carriage rates in the 2 groups were widely different. That of patients receiving prophylactic metronidazole remained low throughout the period of study, falling from 25% to nil carriage on day 1, and rising to only 11 % on day 7. The control patients showed early and rapid post-partum colonization of the vagina with anaerobes, the carriage rate rising from 24% to 39% on day 1, and to 90% by day 7. The broad varieties of non-sporing anaerobes isolated from the 149 patients are summarized in Table II. Before deliver B. melaninogenicus was isolated from 13 patients, B. fragilis and other bacteroides from 23 patients, and anaerobic cocci were recovered from 19. During the puerperium these organisms were isolated from 30, 61 and 31 patients respectively. Metronidazole levels Maternal and cord blood samples were collected from most patients in the test and control groups at the time of delivery; maternal blood was also collected on the 3rd day of the puerperium. In addition, milk samples were obtained from 18 mothers who were receiving metronidazole, and blood-free samples of amniotic fluid were obtained from

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Group

Prophylaxis in obstetrical patients

59

Table n. Broad varieties of non-sporing anaerobes isolated from the vaginas of 149 patients before and after delivery Metronidazole group

Control group

Pre-delivery Post-delivery Pre-delivery Post-delivery

Organisms

7 1

1 3

2 11

0 0 6

2 0 5

6 3 27

1 4 60 79

3 5 51 70

9 8 4 70

3 patients at delivery. Assays were performed by May and Baker by the polarographic method. Metronidazole was absent from all samples collected from control patients. The results for the metronidazole group are summarized in Table III. Metronidazole levels in the 3 samples of amniotic fluid examined were 5-3 Mg/ml, 6-7 £ig/ml and 120 /i.g/ml which corresponded with maternal blood levels of 9-5 fig/m], 4-8 pig/ml and 12.0 fj.g/n\\ respectively. We were concerned only with obtaining adequate metronidazole levels, no close attention being paid to the pharmacokinetics of the drug. This matter has been considered by Houghton & Templeton (1978). No adverse side effects of the drug were encountered. Table III. Metronidazole levels in maternal and cord blood at delivery, in maternal blood on the 3rd day, and in maternal milk on the 6th day Metronidazole level (jig/ml) Specimen Maternal blood at delivery Cord blood Maternal blood at 3rd day Maternal milk at 6th day

Range

Mean

(56)

0-1-36-7

111

(56) (51)

0-43-3 2-0-14-6

11-5

(17)

1-1-15-2

4-7

7-8

Discussion

Although earlier experience had led us to expect postpartum anaerobic infections of perineal wounds or of the uterus in about 5 % of vaginal deliveries, there was no sepsis among 55 control and 64 metronidazole patients in the present study. Consequently, no

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B. melaninogenicus only 5 B. melaninogenicus and other bacteroides 0 B. melaninogenicus with other bacteroides 1 and anaerobic cocci 1 B. melaninogenicus and anaerobic cocci 6 Other bacteroides (mainly B. fragilis) only 3 B. fragilis and anaerobic cocci 4 Anaerobic cocci only 59 No anaerobes isolated Totals 79

60

Study Group

Table IV. Post-operative infections among 30 caesarean section patients

Number of patients post-operatively Infected Group Prophylactic metronidazole Control

(15) (15)

Not infected

Aerobic

Anaerobic

15 11

0 2

0 2

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conclusions can be drawn about the activity of prophylactic metronidazole. This low incidence of sepsis (

An evaluation of metronidazole in the prophylaxis of anaerobic infections in obstetrical patients.

Journal of Antimicrobial Chemotherapy (1978) 4 (Suppl. C), 55-62 An evaluation of metronidazole in the prophylaxis of anaerobic infections in obstetr...
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