ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, May 1975, p. 672-675 Copyright 0 1975 American Society for Microbiology
Vol. 7, No. 5 Printed in U.SA.
Treatment of Anaerobic Infections with Metronidazole FRANCIS P. TALLY,* VERA L. SUTTER,
AND
SYDNEY
M.
FINEGOLD
Infectious Disease Section, Veterans Administration Hospital, Sepulveda, California 91343,* and Medical Service and Anaerobic Bacteriology Research Laboratory, Wadsworth Hospital Center, University of California, Los Angeles, California 90073 Received for publication 3 October 1974
The results of treatment of 10 patients with anaerobic infections with metronidazole are presented. Six patients were cured, three showed initial good response but circumstances required a change to another drug, and one patient did not respond. The unique spectrum of the drug, its pharmacology, and limitations are discussed. The results indicate that further clinical trials to determine the efficacy of metronidazole in the treatment of anerobic infections are indicated.
Recent studies have documented the role of anaerobic microorganisms as the etiological agents of serious infections in man. At present there are only two drugs, chloramnphenicol and clindamycin, approved for use in anerobic bacterial infections by the Food and Drug Administration, which are consistently active against most anaerobes including Bacteroides fragilis (10). Metronidazole has excellent in vitro activity against obligately anaerobic microorganisms (14). B3ecause this compound has been used for over a decade without serious adverse reactions and because of its impressive in vitro activity against anaerobes, much interest has been generated in its potential value in the treatment of anaerobic infections. There are limited clinical data on the management of systemic anaerobic infections (11). Accordingly, we wish to report the clinical evaluation of 10 patients with anaerobic infections treated with metronidazole; three have been discussed briefly in an earlier report (17). Limitations of this drug will also be discussed. (This paper was presented in part at the 13th Interscience Conference on Antimicrobial Agents and Chemotherapy, 19-21 September 1973, Washington, D.C.) MATERIALS AND METHODS Patients. All patients were hospitalized at the
the maost frequent isolates, a reflection of the preponderance of pulmonary infections. Seven patients had pure anaerobic infections and three patients had tmixed anaerobic-aerobic infections. Methods. Specimens were obtained in a manner which precluded contamination by normal flora. The specimens were processed and isolates were identified in the Wadsworth Anaerobic Bacteriology Laboratory according to previous published criteria (16). MetronidAzole was given in doses of 250 to 750 mg every 8 h by mouth and was the only antimicrobial agent employed.
RESULTS The clinical and bacteriological features of the cases are briefly summarized in Table 1. Six patients had bacteriological and clinical cures of their infections. One of these patients, with a stable residual scar after 104 days of therapy, returned after 18 months with a recurrence of abscess formation in the same pulmonary segment. Three patients showed initial clinical response to therapy, but metronidazole had to be discontinued. One patient was considered a treatment failure. The three patients in whom therapy had to be discontinued and the one who failed to respond will be discussed. One patient (case 9), a known alcoholic with a pulmonary abscess, had clearing of foul-smelling sputum, defervescence, decreased leukoyte count, and a 50% reduction in the size of the abscess cavity in 10 days when he refused continued hospitalization. Because of metronidazole's disulfiram-like effect and lack of reliability of the patient, therapy was changed to oral clindamycin. A second patient (case 10) had reactivation of chronic osteomyelitis of the tibia with malaise and foulsmelling drainage from a sinus tract. Cultures
Wadsworth Hospital Center, Veterans Administration, Los Angeles, Calif. They had anaerobic infections of mild to moderate severity and were able to take oral medication and to give informed consent. One had septicemia; two, pulmonary abscesses; six necrotizing pneumonia; and one, osteomyelitis. Thirty-three anaerobic organisms were isolated from the 10 patients. Fusobacterium nucleatum, Bacteroides melanogenicus, and the anaerobic cocci were 672
VOL. 7, 1975
METRONIDAZOLE TREATMENT OF ANAEROBIC INFECTIONS
673
TABLE 1. Clinical and bacteriologic summary of cases
Caseno. ifetyof Case n. infction
Bacteriology acterology
Infcto
3
Fusobacterium necrophorum F. russii Necrotizing pneumonia Eubacterium lentum F. nucleatum Necrotizing
4
Pulmonary ab- Bacteroides melani-
1
2
Septicemia
Therapy Response oMetroniduration (Q8H) I(mg) I(days)II dazole dose
250
23
Cured
250
42
Cured
No portal of entry found. Residual pulmonary
250
80
Cured
Residual pulmonary
250
104
Cured
250
21
scar.
pneumonia
scess 5
6
Necrotizing pneumonia
Necrotizing pneumonia
7
Necrotizing pneumonia
8
Necrotizing pneumonia with pulmonary abscess
9
10
Comment
scar.
nogenicus
F. nucleatum B. oralis Fusobacterium sp. Peptostreptococcus sp. B. melaninogenicus Eubacterium sp. Haemophilus influenzae F. nucleatum Clostridium butyricum B. melaninogenicus F. nucleatum B. melaninogenicus Eubacterium sp. Veillonella sp. Peptostreptococcus micros a-Streptococcus (aerobic) B. melaninogenicus Propionobacterium acnes F. nucleatum
Pulmonary ab- F. nucleatum scess Peptostreptococcus intermedius B. oralis B. fragilis Peptococcus prevotii Peptococcus sp. E. alactolyticun B. melaninogenicus Osteomyelitis B. fragilis subspecies fragilis P. prevotii B. melaninogenicus P. acnes Pseudomonas aeruginosa Klebsiella pneumonia
Staphylococcus aureus
Relapse
Residual pulmonary scar. Recurrent infection 18 months later. H. influenzae persisted in coughed
sputum.
250
61
Cured
750
15
Initial good Drug stopped because of granulocytopenia. response
750 750
750
31 (lst) 52 (2nd)
10
Bronchiectasis of RUL.
Responded; Patient left hospital cured against advice with persistent infiltrate, Initial
good
response
750
14
Initial
good
response
returned, and was cured. Switched to clindamycin when he refused continued hospitalization.
Switched to clindamycin for therapy dur-
ing surgery.
674
TALLY, SUTTER, AND FINEGOLD
yielded three aerobes and four anaerobes, including B. fragilis. The drainage stopped after metronidazole. After 14 days, therapy was changed to clindamycin because of the need for parenteral medication during a sequestrectomy. A third patient (case 7) had necrotizing pneumonia and was responding to therapy when he developed neutropenia (3,100/cu mm leukocyte count with 11% polymorphonuclear leukocytes). Bone marrow examination was normal and leukocyte count returned to normal 5 days after cessation of metronidazole therapy. The patient who failed on therapy (case 5) had bronchietasis and necrotizing pneumonia, with F. nucleatum, B. melaninogenicus, Peptostreptococcus sp. Eubacterium sp., and Haemophilus influenzae recovered on transtracheal aspiration. He was discharged improved after 2 weeks of hospitalization, but failed to continue metronidazole therapy. He returned in 6 weeks with an infiltrate in the same pulmonary segment but refused another transtracheal aspiration. Metronidazole was restarted, but after 3 weeks of therapy his infection persisted. Ampicillin was substituted because culture of the coughed sputum yielded H. influenzae; the infiltrate cleared entirely over the next 3 weeks. DISCUSSION Penicillin is considered the drug of choice in the treatment of anaerobic infections, except for those involving B. fragilis (due to the resistance of this organism). In the treatment of infections in which B. fragilis is the predominant pathogen, the clinician's armamentarium of effective antimicrobial agents is presently limited to chloramphenicol and clindamycin (2). Recently, clindamycin has been widely advocated for the treatment of anaerobic infections, as an alternative to chloramphenicol, in view of the irreversible bone marrow suppression that may occur with the latter compound. With the widespread use of clindamycin, however, there have been reports of the development of pseudomembranous colitis in patients being treated with this compound (4, 18, 19). Furthermore, some strains of certain species of clostridia and of Fusobacterium varium are resistant to clindamycin (2, 21), and there is no evident to date that clindamycin penetrates the central nervous systems well. Therefore, there is clearly a need for additional antimicrobial compounds active against anaerobic bacteria. Metronidazole, which was introduced into clinical medicine for the treatment of Trichomonas vaginalis infections in 1959, is such an agent (5). It was first reported to be active against a gram-negative anaerobic bacillus in
ANTIMICROB. AGENTS CHEMOTHER.
1964 (1). Prince et al. subsequently have shown that the agent is unique in that it is active against only obligately anaerobic microorganisms, including the protozoa T. vaginalis and Entamoeba histolytica (14). In 1972, Nastro and Finegold described the bactericidal activity of this agent against B. fragilis; this has been confirmed by Whelan and Hale (12, 20). The bactericidal activity would theoretically make the drug useful in endocarditis and perhaps in patients with impaired host defense mechanisms. Metronidazole has shown excellent in vitro activity against gram-negative anaerobic bacilli. The gram-positive cocci and the nonsporing bacilli have demonstrated some resistance. These isolates are usually aerotolerant. The results of the preliminary clinical study with metronidazole reported here indicate that it will be useful in the therapy of certain anaerobic infections. In six patients there was complete clearing of the infectious process, usually with early clinical response to therapy. In three patients there was good clinical response, but definitive cure was not achieved because therapy had to be changed. In one of these patients, there was a side-effect which precluded further use of the medication. The final patient had to be regarded as a treatment failure; the data suggest that involvement of an aerobe (resistant to metronidazole) in the infection may have accounted for this lack of response. The overall results must be considered as good, considering the significant mortality (25%) seen with necrotizing pneumonia in the antimicrobial era (1). Neutropenia, which promptly cleared after discontinuation of the drug, was the only potentially serious side-effect noticed in this limited series. With previous extensive use of this medication in the treatment of Trichomonas infections, amebiasis, and chronic alcoholism, this side-effect has only rarely been reported (3, 8, 13). Other adverse reactions to metronidazole (including minor gastrointestinal disturbances, metallic taste, urticaria, vaginal and urethral burning, and darkening of the urine) have been reported. In addition, central nervous system side-effects of ataxia, vertigo, and headaches have occurred, and when the drug is used in combination with disulfiram there is the hazard of psychotic reactions (15). None of these adverse reactions was noted in our patients. Metronidazole is well absorbed from the gastrointestinal tract and ser.um levels up to 72.0 Ag/ml have been achieved with oral therapy (6, 9). The compound diffuses into all tissues with therapeutic levels achieved in abscesses, bile,
VOL 7, 1975
METRONIDAZOLE TREATMENT OF ANAEROBIC INFECTIONS
675
and cerebrospinal fluid (17). The data is limited 4. Cohen, L. E., L. J. McNeill, and R. F. Wells. 1973. Clindamycin-associated colitis. J. Am. Med. Assoc. on central nervous system levels but when avail223:1379-1380. able have suggested that inhibitory levels may 5. Cosar, C., and L. Julou. 1959. Activite de 1' (hydroxy-2' be achieved. The availability of only an oral 6thyl)-1-methyl-2 nitro-5 imitazole (8.823 R.P.) vis-avis des infections experimentales a 7richomonas vagiform of the medication currently limits its clininalis. Ann. Inst. Pasteur Paris 96:238-241. cal usefulnss because infections which fre- 6. Davies, A. H. 1967. Metronidazole in human infections quently involve B. fragilis usually require parwith syphilis. Br. J. Vener. Dis. 43:197-200. enteral medication. 7. Davies, A. H., J. A. McFadzean, and S. Squires. 1964. Treatment of Vincent's stomatitis with metronidazole. Only obligately anaerobic organisms are susBr. Med. J. 1:1149-1150. ceptible to metronidazole; this may be both an 8. Gallant, D. M., M. P. Bishop, E. Camp, and C. Tisdale. advantage (due to its lack of effect on indige1968. A six month controlled evaluation of metronidanous aerobic flora) and a disadvantage (in that zole in chronic alcoholic patients. Curr. Ther. Res. 10:82-87. aerobic and microaerophilic organisms which P. O., J. A. McFadzean, S. Squires, A. J. King, are commonly found in mixed anaerobic infec- 9. Kane, and C. S. Nichol. 1961. Absorption and excretion of tions will not respond to this agent). Certain metronidazole: Part 1, serum concentration and uriorganisms commonly classed with the anaernary excretion after oral administration. Br. J. Vener. Dis. 37:273-275. obes but not obligately anaerobic, such as W. J., M. Gardner, and J. A. Washington II. microaerophilic cocci and Actinomyces, are re- 10. Martin, 1972. In vitro antimicrobial susceptibility of anerobic sistant to metronidazole. bacteria isolated from clinical specimens. Antimicrob. Preliminary data on the effectiveness of metAgents Chemother. 1:148-158. ronidazole in the treatment of certain anaerobic 11. Mitre, R. J., and E. B. Rotheram. 1974. Anaerobic septicemia from thrombophlebitis of the jugular vein. infections are encouraging. Clinical trials have Successful treatment with metronidazole. J. Am. Med. been hampered by the lack of a parenteral Assoc. 230:1168-1169. medication and the drug's limited spectrum. 12. Nastro, L. J., and S. M. Finegold. 1972. Bactericidal activity of five antimicrobial agents against BacterAlthough initial evaluation is promising, there oides fragilis. J. Infect. Dis. 126:104-107. is inadequate data on the treatment of infec- 13. Powell, S. J. 1970. New developments in the therapy of tions with B. fragilis to draw any firm concluamoebiasis. Gut 11:967-968. sions. At this time the compound should be 14. Prince, N. H., E. Brunberg, E. Titsworth, and W. F. DeLorenzo. 1969. Effects of 1-(2-nitro-1-imadazolyl)-3considered only investigational for the treat2-propanol and 2-methyl-5-nitroimidazole-1-ethanol ment of anaerobic infections, and its use reagainst anaerobic and aerobic bacteria and protozoa. trials. clinical to controlled stricted carefully Appl. Microbiol. 18:728-730. Further studies are indicated to determine the 15. Rothstein, E., and D. D. Clancy. 1969. Toxicity of disulfiram combined with metronidazole. N. Engl. J. toxicity and efficacy of metronidazole in the Med. 280:1006-1007. treatment of anaerobic infections. 16. Sutter, V. L., H. R. Atteberry, J. E. Rosenblatt, K. S. Bricknell, and S. M. Finegold. 1972. Anaerobic bacteriology manual. University of California, Los Angeles. This study was supported in part by a grant from G. D. 17. Tally, F. P., V. L. Sutter, and S. M. Finegold. 1972. Metronidazole versul anaerobes: in vitro data and Searle Company. initial clinical observations. Calif. Med. 117:22-26. 18. Tedesco, F. J., R. J. Stanley, and D. H. Alpers. 1974. LITERATURE CITED Diagnostic features of clindamycin-associated pseudomembranous colitis. N. Engl. J. Med. 290:841-843. 1. Bartlett, J. G., and S. M. Finegold. 1972. Anaerobic pleuropulmonary infections. Medicine (Baltimore) 19. Wells, R. F., L. E. Cohen, and C. J. McNeill. 1974. Clindamycin and pseudomembranous colitis. Lancet 51:413-450. 1:66. 2. Bartlett, J. G., V. L. Sutter, and S. M. Finegold. 1973. Treatment of anaerobic infections with lincomycin and 20. Whelan, J. P. F., and J. H. Hale. 1973. Bactericidal activity of metronidazole against Bacteroides fragilis. clindamycin. N. Engl. J. Med. 287:1006-1010. J. Clin. Pathol. 26:393-395. 3. Benazet, F., L. Lacroix, C. Godard, L. Guillaume, and J.-P. Leroy. 1970. Laboratory studies of the chemother- 21. Wilkins, T. D., and T. Thiel. 1973. Resistance of some species of Clostridium to clindamycin. Antimicrob. apeutic activity and toxicity of some nitro heterocycles. Agents Chemother. 3:136-137. Scand. J. Infect. Dis. 2:139-143.
ACKNOWLEDGMENT
Vol. 7, No. 5 Printed in U.SA.
Treatment of Anaerobic Infections with Metronidazole FRANCIS P. TALLY,* VERA L. SUTTER,
AND
SYDNEY
M.
FINEGOLD
Infectious Disease Section, Veterans Administration Hospital, Sepulveda, California 91343,* and Medical Service and Anaerobic Bacteriology Research Laboratory, Wadsworth Hospital Center, University of California, Los Angeles, California 90073 Received for publication 3 October 1974
The results of treatment of 10 patients with anaerobic infections with metronidazole are presented. Six patients were cured, three showed initial good response but circumstances required a change to another drug, and one patient did not respond. The unique spectrum of the drug, its pharmacology, and limitations are discussed. The results indicate that further clinical trials to determine the efficacy of metronidazole in the treatment of anerobic infections are indicated.
Recent studies have documented the role of anaerobic microorganisms as the etiological agents of serious infections in man. At present there are only two drugs, chloramnphenicol and clindamycin, approved for use in anerobic bacterial infections by the Food and Drug Administration, which are consistently active against most anaerobes including Bacteroides fragilis (10). Metronidazole has excellent in vitro activity against obligately anaerobic microorganisms (14). B3ecause this compound has been used for over a decade without serious adverse reactions and because of its impressive in vitro activity against anaerobes, much interest has been generated in its potential value in the treatment of anaerobic infections. There are limited clinical data on the management of systemic anaerobic infections (11). Accordingly, we wish to report the clinical evaluation of 10 patients with anaerobic infections treated with metronidazole; three have been discussed briefly in an earlier report (17). Limitations of this drug will also be discussed. (This paper was presented in part at the 13th Interscience Conference on Antimicrobial Agents and Chemotherapy, 19-21 September 1973, Washington, D.C.) MATERIALS AND METHODS Patients. All patients were hospitalized at the
the maost frequent isolates, a reflection of the preponderance of pulmonary infections. Seven patients had pure anaerobic infections and three patients had tmixed anaerobic-aerobic infections. Methods. Specimens were obtained in a manner which precluded contamination by normal flora. The specimens were processed and isolates were identified in the Wadsworth Anaerobic Bacteriology Laboratory according to previous published criteria (16). MetronidAzole was given in doses of 250 to 750 mg every 8 h by mouth and was the only antimicrobial agent employed.
RESULTS The clinical and bacteriological features of the cases are briefly summarized in Table 1. Six patients had bacteriological and clinical cures of their infections. One of these patients, with a stable residual scar after 104 days of therapy, returned after 18 months with a recurrence of abscess formation in the same pulmonary segment. Three patients showed initial clinical response to therapy, but metronidazole had to be discontinued. One patient was considered a treatment failure. The three patients in whom therapy had to be discontinued and the one who failed to respond will be discussed. One patient (case 9), a known alcoholic with a pulmonary abscess, had clearing of foul-smelling sputum, defervescence, decreased leukoyte count, and a 50% reduction in the size of the abscess cavity in 10 days when he refused continued hospitalization. Because of metronidazole's disulfiram-like effect and lack of reliability of the patient, therapy was changed to oral clindamycin. A second patient (case 10) had reactivation of chronic osteomyelitis of the tibia with malaise and foulsmelling drainage from a sinus tract. Cultures
Wadsworth Hospital Center, Veterans Administration, Los Angeles, Calif. They had anaerobic infections of mild to moderate severity and were able to take oral medication and to give informed consent. One had septicemia; two, pulmonary abscesses; six necrotizing pneumonia; and one, osteomyelitis. Thirty-three anaerobic organisms were isolated from the 10 patients. Fusobacterium nucleatum, Bacteroides melanogenicus, and the anaerobic cocci were 672
VOL. 7, 1975
METRONIDAZOLE TREATMENT OF ANAEROBIC INFECTIONS
673
TABLE 1. Clinical and bacteriologic summary of cases
Caseno. ifetyof Case n. infction
Bacteriology acterology
Infcto
3
Fusobacterium necrophorum F. russii Necrotizing pneumonia Eubacterium lentum F. nucleatum Necrotizing
4
Pulmonary ab- Bacteroides melani-
1
2
Septicemia
Therapy Response oMetroniduration (Q8H) I(mg) I(days)II dazole dose
250
23
Cured
250
42
Cured
No portal of entry found. Residual pulmonary
250
80
Cured
Residual pulmonary
250
104
Cured
250
21
scar.
pneumonia
scess 5
6
Necrotizing pneumonia
Necrotizing pneumonia
7
Necrotizing pneumonia
8
Necrotizing pneumonia with pulmonary abscess
9
10
Comment
scar.
nogenicus
F. nucleatum B. oralis Fusobacterium sp. Peptostreptococcus sp. B. melaninogenicus Eubacterium sp. Haemophilus influenzae F. nucleatum Clostridium butyricum B. melaninogenicus F. nucleatum B. melaninogenicus Eubacterium sp. Veillonella sp. Peptostreptococcus micros a-Streptococcus (aerobic) B. melaninogenicus Propionobacterium acnes F. nucleatum
Pulmonary ab- F. nucleatum scess Peptostreptococcus intermedius B. oralis B. fragilis Peptococcus prevotii Peptococcus sp. E. alactolyticun B. melaninogenicus Osteomyelitis B. fragilis subspecies fragilis P. prevotii B. melaninogenicus P. acnes Pseudomonas aeruginosa Klebsiella pneumonia
Staphylococcus aureus
Relapse
Residual pulmonary scar. Recurrent infection 18 months later. H. influenzae persisted in coughed
sputum.
250
61
Cured
750
15
Initial good Drug stopped because of granulocytopenia. response
750 750
750
31 (lst) 52 (2nd)
10
Bronchiectasis of RUL.
Responded; Patient left hospital cured against advice with persistent infiltrate, Initial
good
response
750
14
Initial
good
response
returned, and was cured. Switched to clindamycin when he refused continued hospitalization.
Switched to clindamycin for therapy dur-
ing surgery.
674
TALLY, SUTTER, AND FINEGOLD
yielded three aerobes and four anaerobes, including B. fragilis. The drainage stopped after metronidazole. After 14 days, therapy was changed to clindamycin because of the need for parenteral medication during a sequestrectomy. A third patient (case 7) had necrotizing pneumonia and was responding to therapy when he developed neutropenia (3,100/cu mm leukocyte count with 11% polymorphonuclear leukocytes). Bone marrow examination was normal and leukocyte count returned to normal 5 days after cessation of metronidazole therapy. The patient who failed on therapy (case 5) had bronchietasis and necrotizing pneumonia, with F. nucleatum, B. melaninogenicus, Peptostreptococcus sp. Eubacterium sp., and Haemophilus influenzae recovered on transtracheal aspiration. He was discharged improved after 2 weeks of hospitalization, but failed to continue metronidazole therapy. He returned in 6 weeks with an infiltrate in the same pulmonary segment but refused another transtracheal aspiration. Metronidazole was restarted, but after 3 weeks of therapy his infection persisted. Ampicillin was substituted because culture of the coughed sputum yielded H. influenzae; the infiltrate cleared entirely over the next 3 weeks. DISCUSSION Penicillin is considered the drug of choice in the treatment of anaerobic infections, except for those involving B. fragilis (due to the resistance of this organism). In the treatment of infections in which B. fragilis is the predominant pathogen, the clinician's armamentarium of effective antimicrobial agents is presently limited to chloramphenicol and clindamycin (2). Recently, clindamycin has been widely advocated for the treatment of anaerobic infections, as an alternative to chloramphenicol, in view of the irreversible bone marrow suppression that may occur with the latter compound. With the widespread use of clindamycin, however, there have been reports of the development of pseudomembranous colitis in patients being treated with this compound (4, 18, 19). Furthermore, some strains of certain species of clostridia and of Fusobacterium varium are resistant to clindamycin (2, 21), and there is no evident to date that clindamycin penetrates the central nervous systems well. Therefore, there is clearly a need for additional antimicrobial compounds active against anaerobic bacteria. Metronidazole, which was introduced into clinical medicine for the treatment of Trichomonas vaginalis infections in 1959, is such an agent (5). It was first reported to be active against a gram-negative anaerobic bacillus in
ANTIMICROB. AGENTS CHEMOTHER.
1964 (1). Prince et al. subsequently have shown that the agent is unique in that it is active against only obligately anaerobic microorganisms, including the protozoa T. vaginalis and Entamoeba histolytica (14). In 1972, Nastro and Finegold described the bactericidal activity of this agent against B. fragilis; this has been confirmed by Whelan and Hale (12, 20). The bactericidal activity would theoretically make the drug useful in endocarditis and perhaps in patients with impaired host defense mechanisms. Metronidazole has shown excellent in vitro activity against gram-negative anaerobic bacilli. The gram-positive cocci and the nonsporing bacilli have demonstrated some resistance. These isolates are usually aerotolerant. The results of the preliminary clinical study with metronidazole reported here indicate that it will be useful in the therapy of certain anaerobic infections. In six patients there was complete clearing of the infectious process, usually with early clinical response to therapy. In three patients there was good clinical response, but definitive cure was not achieved because therapy had to be changed. In one of these patients, there was a side-effect which precluded further use of the medication. The final patient had to be regarded as a treatment failure; the data suggest that involvement of an aerobe (resistant to metronidazole) in the infection may have accounted for this lack of response. The overall results must be considered as good, considering the significant mortality (25%) seen with necrotizing pneumonia in the antimicrobial era (1). Neutropenia, which promptly cleared after discontinuation of the drug, was the only potentially serious side-effect noticed in this limited series. With previous extensive use of this medication in the treatment of Trichomonas infections, amebiasis, and chronic alcoholism, this side-effect has only rarely been reported (3, 8, 13). Other adverse reactions to metronidazole (including minor gastrointestinal disturbances, metallic taste, urticaria, vaginal and urethral burning, and darkening of the urine) have been reported. In addition, central nervous system side-effects of ataxia, vertigo, and headaches have occurred, and when the drug is used in combination with disulfiram there is the hazard of psychotic reactions (15). None of these adverse reactions was noted in our patients. Metronidazole is well absorbed from the gastrointestinal tract and ser.um levels up to 72.0 Ag/ml have been achieved with oral therapy (6, 9). The compound diffuses into all tissues with therapeutic levels achieved in abscesses, bile,
VOL 7, 1975
METRONIDAZOLE TREATMENT OF ANAEROBIC INFECTIONS
675
and cerebrospinal fluid (17). The data is limited 4. Cohen, L. E., L. J. McNeill, and R. F. Wells. 1973. Clindamycin-associated colitis. J. Am. Med. Assoc. on central nervous system levels but when avail223:1379-1380. able have suggested that inhibitory levels may 5. Cosar, C., and L. Julou. 1959. Activite de 1' (hydroxy-2' be achieved. The availability of only an oral 6thyl)-1-methyl-2 nitro-5 imitazole (8.823 R.P.) vis-avis des infections experimentales a 7richomonas vagiform of the medication currently limits its clininalis. Ann. Inst. Pasteur Paris 96:238-241. cal usefulnss because infections which fre- 6. Davies, A. H. 1967. Metronidazole in human infections quently involve B. fragilis usually require parwith syphilis. Br. J. Vener. Dis. 43:197-200. enteral medication. 7. Davies, A. H., J. A. McFadzean, and S. Squires. 1964. Treatment of Vincent's stomatitis with metronidazole. Only obligately anaerobic organisms are susBr. Med. J. 1:1149-1150. ceptible to metronidazole; this may be both an 8. Gallant, D. M., M. P. Bishop, E. Camp, and C. Tisdale. advantage (due to its lack of effect on indige1968. A six month controlled evaluation of metronidanous aerobic flora) and a disadvantage (in that zole in chronic alcoholic patients. Curr. Ther. Res. 10:82-87. aerobic and microaerophilic organisms which P. O., J. A. McFadzean, S. Squires, A. J. King, are commonly found in mixed anaerobic infec- 9. Kane, and C. S. Nichol. 1961. Absorption and excretion of tions will not respond to this agent). Certain metronidazole: Part 1, serum concentration and uriorganisms commonly classed with the anaernary excretion after oral administration. Br. J. Vener. Dis. 37:273-275. obes but not obligately anaerobic, such as W. J., M. Gardner, and J. A. Washington II. microaerophilic cocci and Actinomyces, are re- 10. Martin, 1972. In vitro antimicrobial susceptibility of anerobic sistant to metronidazole. bacteria isolated from clinical specimens. Antimicrob. Preliminary data on the effectiveness of metAgents Chemother. 1:148-158. ronidazole in the treatment of certain anaerobic 11. Mitre, R. J., and E. B. Rotheram. 1974. Anaerobic septicemia from thrombophlebitis of the jugular vein. infections are encouraging. Clinical trials have Successful treatment with metronidazole. J. Am. Med. been hampered by the lack of a parenteral Assoc. 230:1168-1169. medication and the drug's limited spectrum. 12. Nastro, L. J., and S. M. Finegold. 1972. Bactericidal activity of five antimicrobial agents against BacterAlthough initial evaluation is promising, there oides fragilis. J. Infect. Dis. 126:104-107. is inadequate data on the treatment of infec- 13. Powell, S. J. 1970. New developments in the therapy of tions with B. fragilis to draw any firm concluamoebiasis. Gut 11:967-968. sions. At this time the compound should be 14. Prince, N. H., E. Brunberg, E. Titsworth, and W. F. DeLorenzo. 1969. Effects of 1-(2-nitro-1-imadazolyl)-3considered only investigational for the treat2-propanol and 2-methyl-5-nitroimidazole-1-ethanol ment of anaerobic infections, and its use reagainst anaerobic and aerobic bacteria and protozoa. trials. clinical to controlled stricted carefully Appl. Microbiol. 18:728-730. Further studies are indicated to determine the 15. Rothstein, E., and D. D. Clancy. 1969. Toxicity of disulfiram combined with metronidazole. N. Engl. J. toxicity and efficacy of metronidazole in the Med. 280:1006-1007. treatment of anaerobic infections. 16. Sutter, V. L., H. R. Atteberry, J. E. Rosenblatt, K. S. Bricknell, and S. M. Finegold. 1972. Anaerobic bacteriology manual. University of California, Los Angeles. This study was supported in part by a grant from G. D. 17. Tally, F. P., V. L. Sutter, and S. M. Finegold. 1972. Metronidazole versul anaerobes: in vitro data and Searle Company. initial clinical observations. Calif. Med. 117:22-26. 18. Tedesco, F. J., R. J. Stanley, and D. H. Alpers. 1974. LITERATURE CITED Diagnostic features of clindamycin-associated pseudomembranous colitis. N. Engl. J. Med. 290:841-843. 1. Bartlett, J. G., and S. M. Finegold. 1972. Anaerobic pleuropulmonary infections. Medicine (Baltimore) 19. Wells, R. F., L. E. Cohen, and C. J. McNeill. 1974. Clindamycin and pseudomembranous colitis. Lancet 51:413-450. 1:66. 2. Bartlett, J. G., V. L. Sutter, and S. M. Finegold. 1973. Treatment of anaerobic infections with lincomycin and 20. Whelan, J. P. F., and J. H. Hale. 1973. Bactericidal activity of metronidazole against Bacteroides fragilis. clindamycin. N. Engl. J. Med. 287:1006-1010. J. Clin. Pathol. 26:393-395. 3. Benazet, F., L. Lacroix, C. Godard, L. Guillaume, and J.-P. Leroy. 1970. Laboratory studies of the chemother- 21. Wilkins, T. D., and T. Thiel. 1973. Resistance of some species of Clostridium to clindamycin. Antimicrob. apeutic activity and toxicity of some nitro heterocycles. Agents Chemother. 3:136-137. Scand. J. Infect. Dis. 2:139-143.
ACKNOWLEDGMENT
