Bactericidal activity of metronidazole against Bacteroides fragilis

The comparative bactericidal activity of penicillin G, carbenicillin, clindamycin, and metronidazole against eight susceptible strains of Bacteroides fragilis and four strains of Clostridium perfringens was determined by performing colony counts anaerobically of cultures incubated in brucella broth. With the B. fragilis strains, there was a lag phase of growth of approximately 8 h, during which time metronidazole did not reduce the colony counts. However, within 4 h of the onset of exponential growth, metronidazole caused an abrupt decrease in counts to less than 100 colonies per ml in all strains tested. Moreover, in two strains in which the bactericidal rate was followed hourly, a 3-to 6-log decrease occurred over 1 h or less. In contrast, penicillin G and carbenicillin caused a gradual decline in colony counts from the start of approximately 1 log for each 8-h interval and were bactericidal for all strains tested. Clindamycin demonstrated the slowest bactericidal activity and for 25% of the strains was only bacteriostatic. With the C. perfringens strains, after a lag phase of 4 h, an abrupt decrease in colony counts also occurred with metronidazole, whereas penicillin and clindamycin again demonstrated more gradual killing effects. These studies showed a unique, time-related bactericidal action of metronidazole as compared with the other three antimicrobial agents.

Section: Resultssupporting

confidence: 74%

mentioning

confidence: 99%

Unique Bactericidal Action of Metronidazole Against Bacteroides fragilis and Clostridium perfringens

Ralph

Kirby

1975

“…In general, peak blood levels as determined by bioassay with single 250-and 500-mg doses are in the same range as those reported previously with chemical methods (5,16,17), i.e., 5 to 6 jg/ml and 10 to 12 ,g/ml, respectively. As in most previous studies, the rate of absorption was quite variable in our volunteers, with high blood levels occurring in some within 15 min after ingestion, and peaks as late as 2 to 4 h in others.…”

Section: Discussionsupporting

confidence: 67%

“…Maximum blood levels would be about 10 Ag/ml higher for each dose. Thus, since most anaerobic bacteria, including Bacteroides fragilis, have minimum inhibitory concentrations of 6 jg/ml or lower for metronidazole (7,13,17), a 2-g daily dose should give very favorable blood levels even for severe infections.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Metronidazole as Determined by Bioassay

Ralph

Clarke

Libke

et al. 1974

The pharmacokinetics of metronidazole, a drug effective in vitro against most anaerobic bacteria and promising in treating anaerobic infections, are described. Serum and urine levels after single and multiple doses in 10 adult male volunteers were measured by an agar well diffusion bioassay using clostridial species as the test organisms under anaerobic conditions. Peak serum levels averaged 11.5 ,ug/ml and 6.2 ug/ml after single 500-mg and 250-mg doses, respectively. Renal clearance was only 10.2 ml/min per 1.73 M2, and less than 20% of the administered dose was recovered in the urine as active drug in 24 h. The average serum half-life was 8.7 h, and there was no protein binding as determined by an ultrafiltration method. With multiple doses of metronidazole (500 mg four times a day and 250 mg three times a day), blood levels increased progressively for the first few doses and then leveled off, with no significant accumulation occurring between 3 and 7 days. On 250 mg three times a day, serum levels just before the 8 a.m. dose (12 h after the preceding dose) on the third day averaged 3.9 Mg/ml, and before the 8 p.m. dose, 5.7 Mg/ml. For the higher, 500-mg dose (four times a day) regimen, the corresponding minimum serum levels were 13.1 Mig/ml at 8 a.m. and 21.3 Mg/ml at 8 p.m. Peak levels would have been about 10 ,g/ml higher, and since the minimum inhibitory concentrations of most anaerobes including Bacteroides fragilis are less than 6 Mg/ ml, these concentrations should be highly effective therapeutically, even for severe infections.With the increasing awareness of the pathogenicity of anaerobic bacteria, antimicrobial agents which were effective against these organisms are receiving greater attention. Metronidazole [1-(,-hydroxyethyl)-2-methyl-5-nitroimidazole], which has been used effectively for many years against certain protozoal infec-

“…Minocycline was included because it is a derivative of tetracycline, the former drug of choice against Bacteroides fragilis infection (13). Recent encouraging reports on the effectiveness of metronidazole against anaerobes (19,26,29) prompted us to investigate the activity of this antiparasitic drug. Penicillin and carbenicillin were evaluated to determine the possibility of using high doses of penicillin or its derivatives as components of the initial antimicrobial therapy of infections when the cause is unknown but may include anaerobic bacteria.…”

mentioning

confidence: 99%

Antimicrobial Susceptibilities of Anaerobic Bacteria: Recent Clinical Isolates

Staneck

Washington

1974

Minimal inhibitory concentrations of clindamycin, minocycline, metronidazole, penicillin, and carbenicillin were determined by agar dilution against 150 recent clinical isolates of anaerobic bacteria. Ninety-nine percent of Bacteroides fragilis and all B. melaninogenicus, Clostridium perfringens, and Fusobacterium were inhibited by clindamycin at 3.1 Ag/ml. Only 58% of other clostridial species were inhibited by this concentration of clindamycin. Minocycline at 3.1 ,ug/ml inhibited 72%3 of C. perfringens, 81% of other Clostridium species, and 66, 75, and 100% of B. fragilis, B. melaninogenicus, and Fusobacterium, respectively. Metronidazole at 12.5 ug/ml inhibited all bacteria tested. B. fragilis was resistant to both penicillin and carbenicillin at 6.2 sg/ml. Concentrations of 25 ,g/ml for penicillin and 100 ,ug/ml for carbenicillin were needed to inhibit more than 90% of B. fragilis. Organisms other than B. fragilis were moderately or extremely susceptible to the penicillins.