Journal of Antimicrobial Chemotherapy (1978) 4 (Suppl. C), 51-54
Metronidazole in obstetrics and gynaecology
S. A. SeUgman
Prophylaxis with metronidazole for patients undergoing hysterectomy eliminates the overt anaerobic infections which otherwise occur in over 20% of these women. Convalescence is much smoother than in patients without clinical infections, where there is a high incidence of minor morbidity due to anaerobes. Anaerobic infection is of relatively minor importance in normal obstetrics, but is more common following caesarean section. A regimen has been established for the minimum totally effective dose of metronidazole for use in prophylaxis. Introduction
Over the last few years we have become increasingly aware of the importance of non-sporing anaerobes in causing post-operative infection in gynaecology. Three years ago we decided to look into this more closely and also to evaluate the use of metronidazole in the prevention of such infections. We had not previously used any prophylactic chemotherapy or antibiotics, but felt justified in using metronidazole in view of the absence of toxicity in the dose employed, the lack of side effects, the complete absence of activity against aerobic and facultative bacteria, and its apparent failure to induce resistant strains of organisms. Gynaecological study
We studied 200 patients, one-half of them as controls, the others receiving prophylactic metronidazole, and our results have been published (Study Group, 1974; 1975); but I would like to elaborate on a few points from our findings. Of the commonly performed gynaecological operations, hysterectomy, where the vagina is cut across, carries the highest risk of post-operative infection. Following operation there is an increase in the anaerobic population of the vagina and in many cases this is followed by clinical infection. In one-third of these the infection is localised in the abdominal wound; in the rest the infection is in the pelvic cellular tissues and, in some cases, the abdominal wound is also affected. The risk of infection appears higher following vaginal, than following abdominal, hysterectomy, although there were only 7 vaginal hysterectomy patients in our control group, 3 of whom became infected. Twenty-one per cent of our abdominal hysterectomy patients developed anaerobic 51 0305-7453A78/O9O1-CO51 $01.00/0
O 1978 The British Society for Antimicrobial Chemotherapy
Downloaded from http://jac.oxfordjournals.org/ at Lakehead University on March 17, 2015
Department of Obstetrics and Gynaecology, Luton and Dunstable Hospital, Luton LU4 ODZ, England
52
°S. A. Seligman
Prophylactic dosage schedule At that time we were giving metronidazole pre-operatively and continuing for 1 week post-operatively, the course being interrupted for the day of operation until oral feeding was resumed. We decided to find the shortest effective course we could give, starting with just one pre-operative dose of 2 g on the evening before the morning of operation, to ensure a bactericidal level in the blood at the time of operation. A group of 50 patients on this regime was compared with 50 on a full course of metronidazole. In no case was there any bacteriologically confirmed infection of the abdominal wound or pelvic tissues. It rapidly became evident, however, that the convalescence of the patients receiving a single pre-operative dose of metronidazole was not as smooth as that to which we had become accustomed with the full regime (Table I). Twenty-three of 50 patients on the full course remained apyrexial as against only 8 on the single dose course. Pyrexia did not continue for more than 3 days in any of the full course patients, whereas 11 of the other patients had a prolonged pyrexia. The clinical comments in the notes are interesting: 'probable urinary infection'?'? respiratory infection'. The difference between the two metronidazole groups was statistically highly significant. The next step was to increase our regime to cover the operation and the 24 h
Table I. Post-operative pyrexia (over 37-2"C) following metronidazole Number of days pyrexia Full course Pre-operative only Pre-operative + 24 h Pre-operative + 48 h
0
1
2
3
23 8 20 28
17 15 19 19
6 9 3 3
4 7 3 0
3+ 0 11 5 0
Total 50 50 50 50
Downloaded from http://jac.oxfordjournals.org/ at Lakehead University on March 17, 2015
infections. Infections from facultative organisms occurred in only 5 % of cases: one half urinary infections and one half wound infections. In those clinical infections found bacteriologically to be due to anaerobes, the infection was almost always associated with a mixture of organisms, whilst in one third of the infections there was a small number of facultative anaerobes, such as Escherichia coli, present. Had we not looked for, or been able to isolate, the anaerobes, we would have grown a pure culture of the facultative organisms, incriminating them as a cause of the infection. In those patients given prophylactic metronidazole, the effect was dramatic. Postoperative anaerobic infection ceased to exist. Instead of 23% of our hysterectomy patients having to spend up to a month in hospital, we were able to transfer them all, together with their bottles of metronidazole tablets, to a convalescent home on the 5 th or 7th post-operative day, increasing our turnover and making much more efficient use of our hospital beds. These figures do not tell the whole story. Patients' convalescence became much more smooth, and many of the complications which we used to see frequently, which we labelled 'wound' or 'pelvic-haematoma', or where we were unable to establish a firm diagnosis for pyrexia, simply disappeared. We discontinued our trial as we believed it was unethical to withhold metronidazole prophylaxis from patients having a hysterectomy.
Obstetrics and gynaecology
53
following it by giving, in addition to the pre-operative oral dose, suppositories containing 1 g of metronidazole, the first with the pre-medication, then 8-hourly for 24 h. The results showed an improvement over the single dose course, but were still not as satisfactory as the full course. We then extended the course to 48 h post-operatively, changing from suppositories to oral metronidazole when feeding recommenced. This has proved entirely satisfactory. We have also decreased the pre-operative dose to 1200 mg, which we have found gives a bactericidal level at the time of operation in all patients.
We have extended our studies into the field of obstetrics to see the importance of anaerobic sepsis following labour and caesarean section. The full results will be published later (Study Group, 1978). The vaginal flora changes during pregnancy, becoming scanty, and anaerobes are rarely present. Following delivery, a variety of bacterial species appear within 2 to 3 days, with non-sporing anaerobes always present and commonly predominant. In our series, which included 155 patients, there were no infections following normal or forceps deliveries, although we have seen other women who became infected following difficult forceps extractions, or who developed local anaerobic infections associated with episiotomies or perineal tears. Anaerobic sepsis did occur following caesarean section—both emergency and elective—and could be prevented by the prophylactic administration of metronidazole. Metronidazole given to the mother passes the placenta and can be found in the cord blood and amniotic fluid in a concentration similar to that in the mother's blood. This may be important in the prevention of foetal infection, particularly in association with prolonged ruptured membranes. It has been stated that once a foetus becomes infected with bacteroides, its chance of survival is almost nil (Pearson & Anderson, 1967), and I suggest that respiratory infections in the newborn with anaerobes are a far commoner cause of death than is generally recognized.
Management of post-operative anaerobic sepsis
We do not have to treat post-operative anaerobic infections in our patients as we no longer see this complication. However, a few words on this subject from our earlier experience may be pertinent. Although, using gas-liquid chromatography, the laboratory can confirm the presence of anaerobes in pus within 30 min of receiving the specimen (Phillips, Tearle & Willis, 1976), the diagnosis can easily be made clinically from the foul, faeculent odour. This has been wrongly attributed to the presence of E. coli, the pus from which is, however, odourless. Before commencing our investigations, we had believed that anaerobic infections always rapidly resolved following drainage of the abscess. We found that this was not always so. Despite free drainage of stinking pus from an abdominal wound or pelvic abscess, some women remained ill and pyrexial, with cellulitis and parametritis. Encouraged by the prophylactic effectiveness of metronidazole, we began to use it
Downloaded from http://jac.oxfordjournals.org/ at Lakehead University on March 17, 2015
Obstetrical study
54
S. A. Seligman
References
Downloaded from http://jac.oxfordjournals.org/ at Lakehead University on March 17, 2015
therapeutically, again with dramatic results, with rapid resolution of the clinical signs of infection and disappearance of anaerobes from the affected areas. Although a small number of facultative organisms can often be isolated from pus from these wounds, we do not consider them significant and have not found it necessary to treat them. Our policy is—'treat the anaerobes, and the aerobes will look after themselves'. Treatment should be by the oral route, where possible. A loading dose of 2 g can be given initially, although this may not be strictly necessary, and can be followed by 200 mg thrice daily. Metronidazole taken by mouth is rapidly absorbed, reaching a peak concentration in about one hour, although this is considerably delayed if this tablet is taken immediately after a meal. Where oral administration is impossible, suppositories containing 1 g metronidazole can be given 8-hourly. The blood-level rises more slowly than with oral tablets, the peak occurring in 4 to 6 h. Metronidazole can be given intravenously, but our experience with this route is limited.
Pearson, H. E. & Anderson, G. V. Perinatal deaths associated with Bacteroides infections. Obstetrics and Gynecology 30: 486-92 (1967). Phillips, K. D.,Tearle, P. V.& Willis, A.T. Rapid diagnosis of anaerobic infections by gas-liquid chromatography of clinical material. Journal of Clinical Pathology 29: 428-32 (1976). Study Group Metronidazole in the prevention and treatment of Bacteroides infections in gynaecological patients. Lancet ii: 1291-41 (1974). Study Group An evaluation of metronidazole in the prophylaxis and treatment of anaerobic infections in surgical patients. Journal of Antimicrobial Chemotherapy 1: 393-401 (1975). Study Group An evaluation of metronidazole in the prophylaxis of anaerobic infections in obstetrical patients. Journal of Antimicrobial Chemotherapy 4 (Suppl. C): 55-62 (1978).
Metronidazole in obstetrics and gynaecology
S. A. SeUgman
Prophylaxis with metronidazole for patients undergoing hysterectomy eliminates the overt anaerobic infections which otherwise occur in over 20% of these women. Convalescence is much smoother than in patients without clinical infections, where there is a high incidence of minor morbidity due to anaerobes. Anaerobic infection is of relatively minor importance in normal obstetrics, but is more common following caesarean section. A regimen has been established for the minimum totally effective dose of metronidazole for use in prophylaxis. Introduction
Over the last few years we have become increasingly aware of the importance of non-sporing anaerobes in causing post-operative infection in gynaecology. Three years ago we decided to look into this more closely and also to evaluate the use of metronidazole in the prevention of such infections. We had not previously used any prophylactic chemotherapy or antibiotics, but felt justified in using metronidazole in view of the absence of toxicity in the dose employed, the lack of side effects, the complete absence of activity against aerobic and facultative bacteria, and its apparent failure to induce resistant strains of organisms. Gynaecological study
We studied 200 patients, one-half of them as controls, the others receiving prophylactic metronidazole, and our results have been published (Study Group, 1974; 1975); but I would like to elaborate on a few points from our findings. Of the commonly performed gynaecological operations, hysterectomy, where the vagina is cut across, carries the highest risk of post-operative infection. Following operation there is an increase in the anaerobic population of the vagina and in many cases this is followed by clinical infection. In one-third of these the infection is localised in the abdominal wound; in the rest the infection is in the pelvic cellular tissues and, in some cases, the abdominal wound is also affected. The risk of infection appears higher following vaginal, than following abdominal, hysterectomy, although there were only 7 vaginal hysterectomy patients in our control group, 3 of whom became infected. Twenty-one per cent of our abdominal hysterectomy patients developed anaerobic 51 0305-7453A78/O9O1-CO51 $01.00/0
O 1978 The British Society for Antimicrobial Chemotherapy
Downloaded from http://jac.oxfordjournals.org/ at Lakehead University on March 17, 2015
Department of Obstetrics and Gynaecology, Luton and Dunstable Hospital, Luton LU4 ODZ, England
52
°S. A. Seligman
Prophylactic dosage schedule At that time we were giving metronidazole pre-operatively and continuing for 1 week post-operatively, the course being interrupted for the day of operation until oral feeding was resumed. We decided to find the shortest effective course we could give, starting with just one pre-operative dose of 2 g on the evening before the morning of operation, to ensure a bactericidal level in the blood at the time of operation. A group of 50 patients on this regime was compared with 50 on a full course of metronidazole. In no case was there any bacteriologically confirmed infection of the abdominal wound or pelvic tissues. It rapidly became evident, however, that the convalescence of the patients receiving a single pre-operative dose of metronidazole was not as smooth as that to which we had become accustomed with the full regime (Table I). Twenty-three of 50 patients on the full course remained apyrexial as against only 8 on the single dose course. Pyrexia did not continue for more than 3 days in any of the full course patients, whereas 11 of the other patients had a prolonged pyrexia. The clinical comments in the notes are interesting: 'probable urinary infection'?'? respiratory infection'. The difference between the two metronidazole groups was statistically highly significant. The next step was to increase our regime to cover the operation and the 24 h
Table I. Post-operative pyrexia (over 37-2"C) following metronidazole Number of days pyrexia Full course Pre-operative only Pre-operative + 24 h Pre-operative + 48 h
0
1
2
3
23 8 20 28
17 15 19 19
6 9 3 3
4 7 3 0
3+ 0 11 5 0
Total 50 50 50 50
Downloaded from http://jac.oxfordjournals.org/ at Lakehead University on March 17, 2015
infections. Infections from facultative organisms occurred in only 5 % of cases: one half urinary infections and one half wound infections. In those clinical infections found bacteriologically to be due to anaerobes, the infection was almost always associated with a mixture of organisms, whilst in one third of the infections there was a small number of facultative anaerobes, such as Escherichia coli, present. Had we not looked for, or been able to isolate, the anaerobes, we would have grown a pure culture of the facultative organisms, incriminating them as a cause of the infection. In those patients given prophylactic metronidazole, the effect was dramatic. Postoperative anaerobic infection ceased to exist. Instead of 23% of our hysterectomy patients having to spend up to a month in hospital, we were able to transfer them all, together with their bottles of metronidazole tablets, to a convalescent home on the 5 th or 7th post-operative day, increasing our turnover and making much more efficient use of our hospital beds. These figures do not tell the whole story. Patients' convalescence became much more smooth, and many of the complications which we used to see frequently, which we labelled 'wound' or 'pelvic-haematoma', or where we were unable to establish a firm diagnosis for pyrexia, simply disappeared. We discontinued our trial as we believed it was unethical to withhold metronidazole prophylaxis from patients having a hysterectomy.
Obstetrics and gynaecology
53
following it by giving, in addition to the pre-operative oral dose, suppositories containing 1 g of metronidazole, the first with the pre-medication, then 8-hourly for 24 h. The results showed an improvement over the single dose course, but were still not as satisfactory as the full course. We then extended the course to 48 h post-operatively, changing from suppositories to oral metronidazole when feeding recommenced. This has proved entirely satisfactory. We have also decreased the pre-operative dose to 1200 mg, which we have found gives a bactericidal level at the time of operation in all patients.
We have extended our studies into the field of obstetrics to see the importance of anaerobic sepsis following labour and caesarean section. The full results will be published later (Study Group, 1978). The vaginal flora changes during pregnancy, becoming scanty, and anaerobes are rarely present. Following delivery, a variety of bacterial species appear within 2 to 3 days, with non-sporing anaerobes always present and commonly predominant. In our series, which included 155 patients, there were no infections following normal or forceps deliveries, although we have seen other women who became infected following difficult forceps extractions, or who developed local anaerobic infections associated with episiotomies or perineal tears. Anaerobic sepsis did occur following caesarean section—both emergency and elective—and could be prevented by the prophylactic administration of metronidazole. Metronidazole given to the mother passes the placenta and can be found in the cord blood and amniotic fluid in a concentration similar to that in the mother's blood. This may be important in the prevention of foetal infection, particularly in association with prolonged ruptured membranes. It has been stated that once a foetus becomes infected with bacteroides, its chance of survival is almost nil (Pearson & Anderson, 1967), and I suggest that respiratory infections in the newborn with anaerobes are a far commoner cause of death than is generally recognized.
Management of post-operative anaerobic sepsis
We do not have to treat post-operative anaerobic infections in our patients as we no longer see this complication. However, a few words on this subject from our earlier experience may be pertinent. Although, using gas-liquid chromatography, the laboratory can confirm the presence of anaerobes in pus within 30 min of receiving the specimen (Phillips, Tearle & Willis, 1976), the diagnosis can easily be made clinically from the foul, faeculent odour. This has been wrongly attributed to the presence of E. coli, the pus from which is, however, odourless. Before commencing our investigations, we had believed that anaerobic infections always rapidly resolved following drainage of the abscess. We found that this was not always so. Despite free drainage of stinking pus from an abdominal wound or pelvic abscess, some women remained ill and pyrexial, with cellulitis and parametritis. Encouraged by the prophylactic effectiveness of metronidazole, we began to use it
Downloaded from http://jac.oxfordjournals.org/ at Lakehead University on March 17, 2015
Obstetrical study
54
S. A. Seligman
References
Downloaded from http://jac.oxfordjournals.org/ at Lakehead University on March 17, 2015
therapeutically, again with dramatic results, with rapid resolution of the clinical signs of infection and disappearance of anaerobes from the affected areas. Although a small number of facultative organisms can often be isolated from pus from these wounds, we do not consider them significant and have not found it necessary to treat them. Our policy is—'treat the anaerobes, and the aerobes will look after themselves'. Treatment should be by the oral route, where possible. A loading dose of 2 g can be given initially, although this may not be strictly necessary, and can be followed by 200 mg thrice daily. Metronidazole taken by mouth is rapidly absorbed, reaching a peak concentration in about one hour, although this is considerably delayed if this tablet is taken immediately after a meal. Where oral administration is impossible, suppositories containing 1 g metronidazole can be given 8-hourly. The blood-level rises more slowly than with oral tablets, the peak occurring in 4 to 6 h. Metronidazole can be given intravenously, but our experience with this route is limited.
Pearson, H. E. & Anderson, G. V. Perinatal deaths associated with Bacteroides infections. Obstetrics and Gynecology 30: 486-92 (1967). Phillips, K. D.,Tearle, P. V.& Willis, A.T. Rapid diagnosis of anaerobic infections by gas-liquid chromatography of clinical material. Journal of Clinical Pathology 29: 428-32 (1976). Study Group Metronidazole in the prevention and treatment of Bacteroides infections in gynaecological patients. Lancet ii: 1291-41 (1974). Study Group An evaluation of metronidazole in the prophylaxis and treatment of anaerobic infections in surgical patients. Journal of Antimicrobial Chemotherapy 1: 393-401 (1975). Study Group An evaluation of metronidazole in the prophylaxis of anaerobic infections in obstetrical patients. Journal of Antimicrobial Chemotherapy 4 (Suppl. C): 55-62 (1978).
