Journal of Antimicrobial Chemotherapy (1978) 4 (Suppl. C), 75-81
Metronidazole in surgical infections
Susannah J. Eykyn and Ian Phillips
Thirty patients with anaerobic sepsis were treated with intravenous and oral metronidazole. No other antimicrobial agents were given. Mixed growths of anaerobic and aerobic bacteria were isolated from 22 patients and anaerobes alone from 8 patients. Very satisfactory clinical results were seen in most patients, though in many surgical drainage was also essential. Only 2 of the 22 patients from whom both aerobic and anaerobic bacteria were cultured later required specific therapy for the aerobic organisms. Introduction
Metronidazole has been shown to be a highly effective agent for the treatment of anaerobic sepsis (Tally, Sutter & Finegold, 1972, 1975; Study Group, 1974, 1975, 1976, 1977; Ingham et al., 1975; Selkon, Hale & Ingham, 1976; Eykyn & Phillips, 1976; Sharp, Corringham, Nye, Sagor & Noone, 1977); it has also been used successfully in the chemoprophylaxis of infection after hysterectomy (Study Group, 1974), appendicectomy (Study Group, 1976) and elective colonic surgery (Goldring, Scott, McNaught & Gillespie, 1975; Study Group, 1977). Until recently no parenteral preparation of metronidazole was available and this limited the use of the drug, particularly in the early post-operative period. Selkon, Hale & Ingham (1976) first reported on the use of intravenous metronidazole and found it to be clinically effective and safe. We have been using parenteral metronidazole in St. Thomas' Hospital since October 1975 and it has been given to over 200 patients; the results obtained in some of these cases were recently reviewed (Eykyn & Phillips, 1976). Many of the patients treated with metronidazole were seriously ill and the drug was frequently combined with other antimicrobial agents (usually gentamicin and ampicillin) to provide broad spectrum activity. In such a situation, it is difficult to attribute a clinical response solely to metronidazole. This paper reviews the results in patients with surgical infections treated with metronidazole and no other antimicrobial agent. For every patient studied adequate bacteriological specimens were submitted to the laboratory and detailed prospective clinical records kept. Patients and methods
The decision to use metronidazole was made after consultation between clinician and microbiologist. The main indication for its use was sepsis associated with intestinal 75 0305-7453/78/0901-C075S01.00/0
© 1978 The British Society for Antimicrobial Chemotherapy
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Francisco on March 21, 2015
Department of Microbiology, St. Thomas's Hospital Medical School, London, SE1 TEH, England
76
S. J. Eykyn and I. Phillips
Bacteriological methods
Specimens of pus or drainage fluids These were delivered to the laboratory and cultured with minimal delay. Initially, special'gassed out' containers were used to collect specimens but later pus was collected in sterile universal containers. Specimens were held in ultra-violet light to detect the red fluorescence characteristic olBacteroides melaninogenicus (Myers, Cherry, Bomside & Bomside, 1969). If sufficient clinical material was available gas-liquid chromatography was performed on a Pye Unicam Series 104 Chromatograph. This method of enabling a rapid presumptive diagnosis of anaerobic infection to be made was originally described by Gorbach, Mayhew, Bartlett, Thadepalli & Onderdonk (1974). Our method did not involve derivatisation or extraction of the volatile substances from the specimen, which was injected directly on to a column containing Chromosorb 101 (Carlsson, 1973). The medium used for anaerobic culture was brain-heart infusions agar (Oxoid CM 375) with the following additives: 0 0 5 % cysteine hydrochloride, 1% Vitamin K-haemin solution, 0-5 % yeast extract, 100 mg/1 neomycin, 7-5 % whole defibrinated horse blood and 2-5% lysed (by freezing and thawing) defibrinated horse blood. Plates were incubated in an atmosphere of 10% carbon dioxide in nitrogen in an anaerobic jar. Wherever possible anaerobic isolates were fully identified and their susceptibility to metronidazole assessed with a 2-5 jig disc. Aerobic cultures were set up on appropriate media according to routine laboratory procedure. Blood cultures Blood was taken for culture when patients were thought on clinical criteria to be septicaemic. The method was that used routinely for all blood cultures in the laboratory: 10 ml venous blood was added to each of two bottles containing 10 ml digest broth plus 0-1% glucose and 0-06% Liquoid (sodium polyanethol sulphonate, Southern Group Laboratories). One culture was incubated in an atmosphere of carbon dioxide and the other contained a nail for anaerobiosis. Sub-cultures were made on blood agar plates after incubation at 37°C for 24 h, 48 h, and one to 2 weeks. Results
Thirty patients (15 males and 15 females) were treated with metronidazole. Their ages ranged from 6 to 80 years. Four patients received only the intravenous preparation, 10 only the oral preparation, and in 16 intravenous treatment was followed by oral treatment. The total dose of oral metronidazole varied widely with 3 patients receiving 60 to 100 g; the average oral dose was about 10 g. The total dose of intravenous
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Francisco on March 21, 2015
surgery, usually with putrid pus and sometimes with cellulitis. Gas-liquid chromatography often provided useful confirmatory evidence of anaerobic sepsis within a short time of receiving the specimen in the laboratory. Intravenous metronidazole was administered as a buffered, isotonic 0-5 % w/v aqueous solution in 100 ml bottles each containing 500 mg metronidazole and infused every 8 h over 20 min. The two children treated received 250 mg every 8 h. The decision to discontinue intravenous treatment or to change to oral treatment (adult dose 400 mg every 8 h, children 200 mg every 8 h) was made on clinical grounds and in no case was the drug initially prescribed for a specific time.
Surgical infections
77
Table I. Type of infection in 30 patients treated with metronidazole Intestinal tract (20)
Genital tract (3)
9 sepsis following colonic surgery (1)* 1 tubo-ovarian abscess(l) 8 perforated gangrenous appendix (2) 1 scrotal abscess 2 diverticulitis with abscess
Others (7) 2 chronic osteomyelitis (1) 1 wound sepsis after renal transplant 1 'biliary' septicaemia (1)
1 sepsis following caesarean section
1 sepsis following laparotomy (adhesions)
2 pleuro-pulmonary infection (1) 1 gas gangrene (1)
* Figures in brackets denote infections from which anaerobes only were isolated 8/30. Table II. Clinical response in 30 patients treated with metronidazole Improved Good response Bacteria isolated Anaerobes only Aerobes and anaerobes Total patients
With drainage
Without drainage
6
2
10 16
4 6
With drainage
Without drainage
Poor response
4 4
3 3
1 1
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metronidazole varied from 2 to 15 g. The intravenous preparation was well tolerated and apart from occasional nausea with the oral drug there were no observed side effects. The type of infection in the 30 patients treated is shown in Table I. Cultures from 22 of these 30 patients yielded both anaerobic and aerobic bacteria; anaerobes alone were isolated from 8 patients. The clinical response to treatment, the types of bacteria isolated and the details of surgical drainage are shown in Table II. All eight patients from whom anaerobes alone were cultured did very well on metronidazole though in 6 surgical drainage was also performed. Fourteen of the 22 patients with aerobes and anaerobes on culture had a good and in some cases, quite dramatic response, though 10 also required drainage. Details of the 7 patients who improved initially on metronidazole are given in Table III. In case 4 inadequate drainge at the original operation was thought responsible for the subsequent development of a pelvic abscess and this was probably also true of case 5. In only two patients was specific treatment required for aerobic organisms: in case 6, a deep wound infection developed following a recent renal transplant. Culture of the pus yielded a heavy growth of B. fragilis and a light growth of Staph. aureus. B. fragilis was also isolated from the blood. Although initial definite clinical improvement occured on metronidazole neither the fever nor the wound sepsis resolved until flucloxacillin was added to the treatment. A pus specimen taken after a few days of metronidazole therapy grew Staph. aureus in pure heavy culture; no anaerobes were isolated. Case 7, an alcoholic epileptic, was treated with metronidazole for a lung abscess from which Fusobacterium nucleatum, Peptostreptococcus anaerobius, Streptococcus milleri and Haemophtius influenzae were isolated on direct
S. J. Eykyn and I. Phillips
78
Table in. Type of infection, outcome of treatment and organisms isolated following treatment for patients who 'improved' on metronidazole Case No.
Type of infection
Outcome
Bacteria isolated after metronidazole
Died bronchopneumonia
No further specimen
Died bronchopneumonia
No further specimen
Developed wound infection Aerobes and anaerobes
6.
Perforated appendix, peritonitis Gross diverticular disease with abscess Wound sepsis, renal
7.
transplant Lung abscess
2. 3. 4. 5.
Slow recovery in poorly No further specimen controlled diabetic Developed pelvic abscess Aerobes and anaerobes
Failed to resolve
Staph. aureus
Failed to resolve
Strep, milleri + H. influenzae
lung aspiration. He responded initially to metronidazole, rapidly becoming afebrile and feeling markedly better. However after 10 weeks treatment the abscess had failed to resolve and a further aspiration yielded Strep, milleri and H. influenzae. Treatment was then changed to amoxycillin which brought about complete resolution. The single patient who responded only poorly to metronidazole was seriously ill with extensive abdominal sepsis following major surgery for widespread bowel carcinoma. Bacteriology Pus or drainage fluid was obtained from all but 2 of the 30 patients studied, and in most but not all cases it was putrid. Anaerobic organisms were isolated from every specimen received and in 22 cases aerobes were also grown. Anaerobes were isolated from the blood of 4 patients, including 2 from whom no local specimen was obtained. Multiple isolates, both of anaerobes and aerobes were commonplace from a single specimen of pus. All anaerobic isolates were sensitive to metronidazole on disc sensitivity testing. Table IV. Bacteria isolated from blood and pus of 22 patients infected with aerobic and anaerobic organisms Aerobes Escherichia coli Proteus mirabilis
Pus 13 4
Anaerobes B. fragilis subsp. fragilis B. fragilis subsp.
Pus
Blood
15 3
3
thetaiotaomicron Klebsiells spp. Staph. aureus Strep, faecalis Strep, milleri Haemolytic streptococcus (not group A)
1 4 5 9 3
B. melaninogenicus Other bacteroides Fusobacterium spp. Peptostreptococci Clostridium perfringens Other clostridia Bifidobacterium
9 4 4 12 2 6 1
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Sepsis following colonic resection Sepsis following resection fistula Scrotal abscess
1.
Surgical infections
79
Table V. Bacteria isolated from pus and blood in 8 patients with anaerobes alone Clinical details 1. 2. 3. 4.
8.
B. melaninogenicus None obtained Clostridium perfringens B. fragilis subsp. fragilis
Blood Not cultured B. fragilis subsp. fragilis Cl. perfringens
Not cultured
B. fragilis subsp. fragilis None obtained Fusobacterium necrophorum Sterile B. fragilis subsp. fragilis Not cultured
B. melaninogenicus Bacteroides spp. Peptostreptoccus anaerobius
Not cultured
Table IV shows the bacteria isolated from the 22 patients with mixed aerobic and anaerobic infections and Table V the organisms isolated and the clinical details for the 8 patients from whom anaerobes only were isolated. Red fluorescence in ultra-violet light Of the 24 specimens of pus investigated, 13 fluoresced bright red in ultra-violet light. B. melaninogenicus was isolated on culture from 9 of these, in each case with other anaerobic organisms and in 7 cases with aerobes as well. B. melaninogenicus was also isolated together with other anaerobes, but only in small numbers, from one specimen of pus that did not fluoresce. Gas-liquid chromatography This was performed on 21 specimens of pus. Seventeen of these produced volatile acids in addition to acetic, propionic and lactic acids. The other 4 specimens, however, produced only small quantities of acetic, propionic and lactic acids. From 3 of these B. fragilis was the only anaerobe isolated, and E. coli was also grown in one case. The fourth specimen of pus that produced only acetic, propionic and lactic acids on chromatography yielded B. melaninogenicus, Peptostrep. anaerobius and a Bacteroides sp. on culture but only in light growth. Discussion Anaerobic organisms are undoubtedly responsible for much of the sepsis associated with surgery to the intestinal tract or the female genital tract. Improved isolation techniques have made microbiologists and clinicians more aware of the pathogenic role of anaerobes and, it is to be hoped, more aware of the need to send specimens of pus (rather than swabs) to the laboratory with minimum delay to obtain the maximal anaerobic recovery rate. Anaerobic sepsis also occurs at sites other than those relating to intestinal or genital tracts but is much less common. Anaerobic organisms are seldom the only microorganisms cultured from infected wounds following operations such as colectomy and appendicectomy: aerobes are almost invariably also present and were found in 22 of our 30 patients. It is nevertheless currently fashionable to attribute the
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Francisco on March 21, 2015
5. 6. 7.
Tubo-ovarian abscess Gangrenous appendix Gas gangrene leg Abscess following removal hip prosthesis 'Biliary* septicaemia Lung abscess and empyema Wound sepsis following appendicectomy Wound sepsis following colectomy
Pus
80
S. J. Eykyn and I. Phillips
References
Carlsson, J. Simplified chromatographic procedure for identification of bacterial metabolic products. Applied Microbiology 25: 287-9 (1973). Eykyn, S. J. & Phillips, I. Metronidazole and anaerobic sepsis. British Medical Journal ii: 1418-21 (1976). Goldring, J., Scott, A., McNaught, W. & Gillespie, G. Prophylactic oral antimicrobial agents in elective colonic. surgery: a controlled trial. Lancet ii: 997-1000 (1975). Gorbach, S. L., Mayhew, J. W., Bartlett, J. G., Thadepalli, H. & Onderdonk, A. B. Rapid diagnosis of Bacteroides fragilis infection by direct gas liquid chromatography of clinical specimens. Clinical Research 22: 442 A (1974). Ingham, H. R., Rich, G. E., Selkon, J. B., Hale, J. H., Roxby, C. M., Betty, M. J., Johnson, R. W. G. & Uldall, R. R. Treatment with metronidazole of three patients with serious infections due to Bacteroidesfragilis.Journal of Antimicrobial Chemotherapy 1: 235-42 (1975).
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Francisco on March 21, 2015
major pathogenic role to the anaerobes when a mixed infection with aerobes and anaerobes is found. Metronidazole is the only available antimicrobial that can achieve selective anaerobic chemotherapy; by treating patients with mixed infections with metronidazole and no other antimicrobial it has been possible to test this hypothesis. Assessment of the clinical response to metronidazole is frequently difficult because essential surgical drainage is often required as was the case in 20 of our 30 patients. Even if drainage forms the major part of treatment our experience would suggest that metronidazole plays an important if secondary role in such cases. In a few patients, however, quite dramatic clinical improvement occurred that could only be attributed to metronidazole and in four of these patients bacterial cultures yielded both aerobes and anaerobes. Further cultures during metronidazole treatment always yielded aerobic bacteria usually in heavy growth, but these eventually disappeared as the sepsis resolved. No specific treatment was required. In two patients, a renal transplant recipient on immunosuppressive drugs and a man with a lung abscess, specific anaerobic chemotherapy failed, and only when an antimicrobial compound active against the aerobic organism present was given did the infection finally resolve. Although this series is small it seems likely that for sepsis associated with intestinal surgery and perhaps in some other sites, metronidazole can reasonably be used alone in mixed infections with impressive results. More studies are required as it is obviously to the patient's advantage if he can be effectively treated with one drug instead of two or even three, as is frequent current practice. Undoubtedly one of the most useful indications of anaerobic sepsis is the presence of putrid pus. Fluorescence of the specimen under ultra-violet light will often detect the presence of B. melaninogenicus. Gas-liquid chromatography provides useful confirmatory evidence of the presence of anaerobes in that volatile acids other than acetic, propionic and lactic are usually present. It is becoming clear, however, from this series and other unpublished observations in this laboratory that B. fragilis, as the sole anaerobe in pus samples, may produce only acetic, propionic and lactic acids on chromatography and such pus does not have a putrid odour. Whilst gas-liquid chromatography is a useful diagnostic aid it is not essential for the satisfactory diagnosis or treatment of anaerobic sepsis. Our results suggest that metronidazole is a safe and highly effective agent for the treatment not only of sepsis caused solely by anaerobes but for many cases of sepsis where mixed infection with both aerobic and anaerobic bacteria occurs.
Surgical infections
81
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Myers, M. B., Cherry, G., Bornside, B. B. & Bornside, G. H. Ultraviolet red fluorescence of Bacteroides melaninogenicus. Applied Microbiology 17: 760-2 (1969). Selkon, J. B., Hale, J. H. & Ingham, H. R. Metronidazole in the treatment of anaerobic infection in man. Chemotherapy 1: 277-81 (1976). Sharp, D. J., Corringham, R. E. T., Nye, E. B., Sagor, G. R. & Noone, P. Successful treatment of Bacteroides bacteraemia with metronidazole, after failure with clindamycin and lincomycin. Journal of Antimicrobial Chemotherapy 3: 233-7 (1977). Study Group Metronidazole in the prevention and treatment of Bacteroides infection in gynaecological patients. Lancet ii: 1540-3 (1974). Study Group An evaluation of metronidazole in the prophylaxis and treatment of anaerobic infection in surgical patients. Journal ofAntimicrobial Chemotherapy 1: 393-401 (1975). Study Group Metronidazole in prevention and treatment of bacteroides infections after appendicectomy. British Medical Journal i: 318-21 (1976). Study Group Metronidazole in prevention and treatment of bacteroides infections in elective colonic surgery. British Medical Journal i: 607-10 (1977). Tally, F. P., Sutter, V. L. & Finegold, S. M. Metronidazole versus anaerobes. In vitro data and initial clinical observations. California Medicine 117: 22-6 (1972). Tally, F. P., Sutter, V. L. & Finegold, S. M. Treatment of anaerobic infections with metronidazole. Antimicrobial Agents and Chemotherapy 7: 672-5 (1975).
Metronidazole in surgical infections
Susannah J. Eykyn and Ian Phillips
Thirty patients with anaerobic sepsis were treated with intravenous and oral metronidazole. No other antimicrobial agents were given. Mixed growths of anaerobic and aerobic bacteria were isolated from 22 patients and anaerobes alone from 8 patients. Very satisfactory clinical results were seen in most patients, though in many surgical drainage was also essential. Only 2 of the 22 patients from whom both aerobic and anaerobic bacteria were cultured later required specific therapy for the aerobic organisms. Introduction
Metronidazole has been shown to be a highly effective agent for the treatment of anaerobic sepsis (Tally, Sutter & Finegold, 1972, 1975; Study Group, 1974, 1975, 1976, 1977; Ingham et al., 1975; Selkon, Hale & Ingham, 1976; Eykyn & Phillips, 1976; Sharp, Corringham, Nye, Sagor & Noone, 1977); it has also been used successfully in the chemoprophylaxis of infection after hysterectomy (Study Group, 1974), appendicectomy (Study Group, 1976) and elective colonic surgery (Goldring, Scott, McNaught & Gillespie, 1975; Study Group, 1977). Until recently no parenteral preparation of metronidazole was available and this limited the use of the drug, particularly in the early post-operative period. Selkon, Hale & Ingham (1976) first reported on the use of intravenous metronidazole and found it to be clinically effective and safe. We have been using parenteral metronidazole in St. Thomas' Hospital since October 1975 and it has been given to over 200 patients; the results obtained in some of these cases were recently reviewed (Eykyn & Phillips, 1976). Many of the patients treated with metronidazole were seriously ill and the drug was frequently combined with other antimicrobial agents (usually gentamicin and ampicillin) to provide broad spectrum activity. In such a situation, it is difficult to attribute a clinical response solely to metronidazole. This paper reviews the results in patients with surgical infections treated with metronidazole and no other antimicrobial agent. For every patient studied adequate bacteriological specimens were submitted to the laboratory and detailed prospective clinical records kept. Patients and methods
The decision to use metronidazole was made after consultation between clinician and microbiologist. The main indication for its use was sepsis associated with intestinal 75 0305-7453/78/0901-C075S01.00/0
© 1978 The British Society for Antimicrobial Chemotherapy
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Francisco on March 21, 2015
Department of Microbiology, St. Thomas's Hospital Medical School, London, SE1 TEH, England
76
S. J. Eykyn and I. Phillips
Bacteriological methods
Specimens of pus or drainage fluids These were delivered to the laboratory and cultured with minimal delay. Initially, special'gassed out' containers were used to collect specimens but later pus was collected in sterile universal containers. Specimens were held in ultra-violet light to detect the red fluorescence characteristic olBacteroides melaninogenicus (Myers, Cherry, Bomside & Bomside, 1969). If sufficient clinical material was available gas-liquid chromatography was performed on a Pye Unicam Series 104 Chromatograph. This method of enabling a rapid presumptive diagnosis of anaerobic infection to be made was originally described by Gorbach, Mayhew, Bartlett, Thadepalli & Onderdonk (1974). Our method did not involve derivatisation or extraction of the volatile substances from the specimen, which was injected directly on to a column containing Chromosorb 101 (Carlsson, 1973). The medium used for anaerobic culture was brain-heart infusions agar (Oxoid CM 375) with the following additives: 0 0 5 % cysteine hydrochloride, 1% Vitamin K-haemin solution, 0-5 % yeast extract, 100 mg/1 neomycin, 7-5 % whole defibrinated horse blood and 2-5% lysed (by freezing and thawing) defibrinated horse blood. Plates were incubated in an atmosphere of 10% carbon dioxide in nitrogen in an anaerobic jar. Wherever possible anaerobic isolates were fully identified and their susceptibility to metronidazole assessed with a 2-5 jig disc. Aerobic cultures were set up on appropriate media according to routine laboratory procedure. Blood cultures Blood was taken for culture when patients were thought on clinical criteria to be septicaemic. The method was that used routinely for all blood cultures in the laboratory: 10 ml venous blood was added to each of two bottles containing 10 ml digest broth plus 0-1% glucose and 0-06% Liquoid (sodium polyanethol sulphonate, Southern Group Laboratories). One culture was incubated in an atmosphere of carbon dioxide and the other contained a nail for anaerobiosis. Sub-cultures were made on blood agar plates after incubation at 37°C for 24 h, 48 h, and one to 2 weeks. Results
Thirty patients (15 males and 15 females) were treated with metronidazole. Their ages ranged from 6 to 80 years. Four patients received only the intravenous preparation, 10 only the oral preparation, and in 16 intravenous treatment was followed by oral treatment. The total dose of oral metronidazole varied widely with 3 patients receiving 60 to 100 g; the average oral dose was about 10 g. The total dose of intravenous
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Francisco on March 21, 2015
surgery, usually with putrid pus and sometimes with cellulitis. Gas-liquid chromatography often provided useful confirmatory evidence of anaerobic sepsis within a short time of receiving the specimen in the laboratory. Intravenous metronidazole was administered as a buffered, isotonic 0-5 % w/v aqueous solution in 100 ml bottles each containing 500 mg metronidazole and infused every 8 h over 20 min. The two children treated received 250 mg every 8 h. The decision to discontinue intravenous treatment or to change to oral treatment (adult dose 400 mg every 8 h, children 200 mg every 8 h) was made on clinical grounds and in no case was the drug initially prescribed for a specific time.
Surgical infections
77
Table I. Type of infection in 30 patients treated with metronidazole Intestinal tract (20)
Genital tract (3)
9 sepsis following colonic surgery (1)* 1 tubo-ovarian abscess(l) 8 perforated gangrenous appendix (2) 1 scrotal abscess 2 diverticulitis with abscess
Others (7) 2 chronic osteomyelitis (1) 1 wound sepsis after renal transplant 1 'biliary' septicaemia (1)
1 sepsis following caesarean section
1 sepsis following laparotomy (adhesions)
2 pleuro-pulmonary infection (1) 1 gas gangrene (1)
* Figures in brackets denote infections from which anaerobes only were isolated 8/30. Table II. Clinical response in 30 patients treated with metronidazole Improved Good response Bacteria isolated Anaerobes only Aerobes and anaerobes Total patients
With drainage
Without drainage
6
2
10 16
4 6
With drainage
Without drainage
Poor response
4 4
3 3
1 1
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Francisco on March 21, 2015
metronidazole varied from 2 to 15 g. The intravenous preparation was well tolerated and apart from occasional nausea with the oral drug there were no observed side effects. The type of infection in the 30 patients treated is shown in Table I. Cultures from 22 of these 30 patients yielded both anaerobic and aerobic bacteria; anaerobes alone were isolated from 8 patients. The clinical response to treatment, the types of bacteria isolated and the details of surgical drainage are shown in Table II. All eight patients from whom anaerobes alone were cultured did very well on metronidazole though in 6 surgical drainage was also performed. Fourteen of the 22 patients with aerobes and anaerobes on culture had a good and in some cases, quite dramatic response, though 10 also required drainage. Details of the 7 patients who improved initially on metronidazole are given in Table III. In case 4 inadequate drainge at the original operation was thought responsible for the subsequent development of a pelvic abscess and this was probably also true of case 5. In only two patients was specific treatment required for aerobic organisms: in case 6, a deep wound infection developed following a recent renal transplant. Culture of the pus yielded a heavy growth of B. fragilis and a light growth of Staph. aureus. B. fragilis was also isolated from the blood. Although initial definite clinical improvement occured on metronidazole neither the fever nor the wound sepsis resolved until flucloxacillin was added to the treatment. A pus specimen taken after a few days of metronidazole therapy grew Staph. aureus in pure heavy culture; no anaerobes were isolated. Case 7, an alcoholic epileptic, was treated with metronidazole for a lung abscess from which Fusobacterium nucleatum, Peptostreptococcus anaerobius, Streptococcus milleri and Haemophtius influenzae were isolated on direct
S. J. Eykyn and I. Phillips
78
Table in. Type of infection, outcome of treatment and organisms isolated following treatment for patients who 'improved' on metronidazole Case No.
Type of infection
Outcome
Bacteria isolated after metronidazole
Died bronchopneumonia
No further specimen
Died bronchopneumonia
No further specimen
Developed wound infection Aerobes and anaerobes
6.
Perforated appendix, peritonitis Gross diverticular disease with abscess Wound sepsis, renal
7.
transplant Lung abscess
2. 3. 4. 5.
Slow recovery in poorly No further specimen controlled diabetic Developed pelvic abscess Aerobes and anaerobes
Failed to resolve
Staph. aureus
Failed to resolve
Strep, milleri + H. influenzae
lung aspiration. He responded initially to metronidazole, rapidly becoming afebrile and feeling markedly better. However after 10 weeks treatment the abscess had failed to resolve and a further aspiration yielded Strep, milleri and H. influenzae. Treatment was then changed to amoxycillin which brought about complete resolution. The single patient who responded only poorly to metronidazole was seriously ill with extensive abdominal sepsis following major surgery for widespread bowel carcinoma. Bacteriology Pus or drainage fluid was obtained from all but 2 of the 30 patients studied, and in most but not all cases it was putrid. Anaerobic organisms were isolated from every specimen received and in 22 cases aerobes were also grown. Anaerobes were isolated from the blood of 4 patients, including 2 from whom no local specimen was obtained. Multiple isolates, both of anaerobes and aerobes were commonplace from a single specimen of pus. All anaerobic isolates were sensitive to metronidazole on disc sensitivity testing. Table IV. Bacteria isolated from blood and pus of 22 patients infected with aerobic and anaerobic organisms Aerobes Escherichia coli Proteus mirabilis
Pus 13 4
Anaerobes B. fragilis subsp. fragilis B. fragilis subsp.
Pus
Blood
15 3
3
thetaiotaomicron Klebsiells spp. Staph. aureus Strep, faecalis Strep, milleri Haemolytic streptococcus (not group A)
1 4 5 9 3
B. melaninogenicus Other bacteroides Fusobacterium spp. Peptostreptococci Clostridium perfringens Other clostridia Bifidobacterium
9 4 4 12 2 6 1
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Sepsis following colonic resection Sepsis following resection fistula Scrotal abscess
1.
Surgical infections
79
Table V. Bacteria isolated from pus and blood in 8 patients with anaerobes alone Clinical details 1. 2. 3. 4.
8.
B. melaninogenicus None obtained Clostridium perfringens B. fragilis subsp. fragilis
Blood Not cultured B. fragilis subsp. fragilis Cl. perfringens
Not cultured
B. fragilis subsp. fragilis None obtained Fusobacterium necrophorum Sterile B. fragilis subsp. fragilis Not cultured
B. melaninogenicus Bacteroides spp. Peptostreptoccus anaerobius
Not cultured
Table IV shows the bacteria isolated from the 22 patients with mixed aerobic and anaerobic infections and Table V the organisms isolated and the clinical details for the 8 patients from whom anaerobes only were isolated. Red fluorescence in ultra-violet light Of the 24 specimens of pus investigated, 13 fluoresced bright red in ultra-violet light. B. melaninogenicus was isolated on culture from 9 of these, in each case with other anaerobic organisms and in 7 cases with aerobes as well. B. melaninogenicus was also isolated together with other anaerobes, but only in small numbers, from one specimen of pus that did not fluoresce. Gas-liquid chromatography This was performed on 21 specimens of pus. Seventeen of these produced volatile acids in addition to acetic, propionic and lactic acids. The other 4 specimens, however, produced only small quantities of acetic, propionic and lactic acids. From 3 of these B. fragilis was the only anaerobe isolated, and E. coli was also grown in one case. The fourth specimen of pus that produced only acetic, propionic and lactic acids on chromatography yielded B. melaninogenicus, Peptostrep. anaerobius and a Bacteroides sp. on culture but only in light growth. Discussion Anaerobic organisms are undoubtedly responsible for much of the sepsis associated with surgery to the intestinal tract or the female genital tract. Improved isolation techniques have made microbiologists and clinicians more aware of the pathogenic role of anaerobes and, it is to be hoped, more aware of the need to send specimens of pus (rather than swabs) to the laboratory with minimum delay to obtain the maximal anaerobic recovery rate. Anaerobic sepsis also occurs at sites other than those relating to intestinal or genital tracts but is much less common. Anaerobic organisms are seldom the only microorganisms cultured from infected wounds following operations such as colectomy and appendicectomy: aerobes are almost invariably also present and were found in 22 of our 30 patients. It is nevertheless currently fashionable to attribute the
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Francisco on March 21, 2015
5. 6. 7.
Tubo-ovarian abscess Gangrenous appendix Gas gangrene leg Abscess following removal hip prosthesis 'Biliary* septicaemia Lung abscess and empyema Wound sepsis following appendicectomy Wound sepsis following colectomy
Pus
80
S. J. Eykyn and I. Phillips
References
Carlsson, J. Simplified chromatographic procedure for identification of bacterial metabolic products. Applied Microbiology 25: 287-9 (1973). Eykyn, S. J. & Phillips, I. Metronidazole and anaerobic sepsis. British Medical Journal ii: 1418-21 (1976). Goldring, J., Scott, A., McNaught, W. & Gillespie, G. Prophylactic oral antimicrobial agents in elective colonic. surgery: a controlled trial. Lancet ii: 997-1000 (1975). Gorbach, S. L., Mayhew, J. W., Bartlett, J. G., Thadepalli, H. & Onderdonk, A. B. Rapid diagnosis of Bacteroides fragilis infection by direct gas liquid chromatography of clinical specimens. Clinical Research 22: 442 A (1974). Ingham, H. R., Rich, G. E., Selkon, J. B., Hale, J. H., Roxby, C. M., Betty, M. J., Johnson, R. W. G. & Uldall, R. R. Treatment with metronidazole of three patients with serious infections due to Bacteroidesfragilis.Journal of Antimicrobial Chemotherapy 1: 235-42 (1975).
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major pathogenic role to the anaerobes when a mixed infection with aerobes and anaerobes is found. Metronidazole is the only available antimicrobial that can achieve selective anaerobic chemotherapy; by treating patients with mixed infections with metronidazole and no other antimicrobial it has been possible to test this hypothesis. Assessment of the clinical response to metronidazole is frequently difficult because essential surgical drainage is often required as was the case in 20 of our 30 patients. Even if drainage forms the major part of treatment our experience would suggest that metronidazole plays an important if secondary role in such cases. In a few patients, however, quite dramatic clinical improvement occurred that could only be attributed to metronidazole and in four of these patients bacterial cultures yielded both aerobes and anaerobes. Further cultures during metronidazole treatment always yielded aerobic bacteria usually in heavy growth, but these eventually disappeared as the sepsis resolved. No specific treatment was required. In two patients, a renal transplant recipient on immunosuppressive drugs and a man with a lung abscess, specific anaerobic chemotherapy failed, and only when an antimicrobial compound active against the aerobic organism present was given did the infection finally resolve. Although this series is small it seems likely that for sepsis associated with intestinal surgery and perhaps in some other sites, metronidazole can reasonably be used alone in mixed infections with impressive results. More studies are required as it is obviously to the patient's advantage if he can be effectively treated with one drug instead of two or even three, as is frequent current practice. Undoubtedly one of the most useful indications of anaerobic sepsis is the presence of putrid pus. Fluorescence of the specimen under ultra-violet light will often detect the presence of B. melaninogenicus. Gas-liquid chromatography provides useful confirmatory evidence of the presence of anaerobes in that volatile acids other than acetic, propionic and lactic are usually present. It is becoming clear, however, from this series and other unpublished observations in this laboratory that B. fragilis, as the sole anaerobe in pus samples, may produce only acetic, propionic and lactic acids on chromatography and such pus does not have a putrid odour. Whilst gas-liquid chromatography is a useful diagnostic aid it is not essential for the satisfactory diagnosis or treatment of anaerobic sepsis. Our results suggest that metronidazole is a safe and highly effective agent for the treatment not only of sepsis caused solely by anaerobes but for many cases of sepsis where mixed infection with both aerobic and anaerobic bacteria occurs.
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Myers, M. B., Cherry, G., Bornside, B. B. & Bornside, G. H. Ultraviolet red fluorescence of Bacteroides melaninogenicus. Applied Microbiology 17: 760-2 (1969). Selkon, J. B., Hale, J. H. & Ingham, H. R. Metronidazole in the treatment of anaerobic infection in man. Chemotherapy 1: 277-81 (1976). Sharp, D. J., Corringham, R. E. T., Nye, E. B., Sagor, G. R. & Noone, P. Successful treatment of Bacteroides bacteraemia with metronidazole, after failure with clindamycin and lincomycin. Journal of Antimicrobial Chemotherapy 3: 233-7 (1977). Study Group Metronidazole in the prevention and treatment of Bacteroides infection in gynaecological patients. Lancet ii: 1540-3 (1974). Study Group An evaluation of metronidazole in the prophylaxis and treatment of anaerobic infection in surgical patients. Journal ofAntimicrobial Chemotherapy 1: 393-401 (1975). Study Group Metronidazole in prevention and treatment of bacteroides infections after appendicectomy. British Medical Journal i: 318-21 (1976). Study Group Metronidazole in prevention and treatment of bacteroides infections in elective colonic surgery. British Medical Journal i: 607-10 (1977). Tally, F. P., Sutter, V. L. & Finegold, S. M. Metronidazole versus anaerobes. In vitro data and initial clinical observations. California Medicine 117: 22-6 (1972). Tally, F. P., Sutter, V. L. & Finegold, S. M. Treatment of anaerobic infections with metronidazole. Antimicrobial Agents and Chemotherapy 7: 672-5 (1975).
