The bactericidal activity of nitrofurantoin and metronidazole against anaerobic bacteria.
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Bacteroides fragilis↗
Biomedical subjects
E D Ralph
Publications and source records attributed to E D Ralph.
Inactivation of metronidazole by anaerobic and aerobic bacteria.
The rate of inactivation of metronidazole in vitro was determined during the course of time-kill curves against anaerobic and aerobic bacteria in the stationary phase of growth. Metronidazole at a concentration of 10 mug/ml, as measured by bioassay, was rapidly inactivated in broth culture by susceptible anaerobic bacteria (minimum bactericidal concentration </= 3 mug/ml), and this correlated closely with its bactericidal activity. In contrast, the drug was neither inactivated nor had any bactericidal activity against a resistant strain of Propionibacteriumacnes (minimum bactericidal concentration > 1,500 mug/ml). Three of four aerobic bacteria also inactivated metronidazole, although at generally slower rates than the anaerobes, but this was not associated with a bactericidal effect against these organisms. The presence of aerobic bacteria in mixed cultures with Bacteroides fragilis did not, moreover, inhibit the bactericidal activity of metronidazole against the latter organism. However, the possibility still remains that, in vivo, aerobic bacteria capable of inactivating metronidazole could inhibit the action of the drug against anaerobes in mixed infections.
Bacteria↗
Anaerobic meningitis and bacteremia caused by Fusobacterium species.
In the two cases of anaerobic meningitis and bacteremia caused by Fusobacterium species described, upper respiratory tract infection preceded the onset of meningitis. Isolation of the causative organism and appropriate antibiotic therapy resulted in cures in both patients. Although extremely rare, these organisms should be considered as possible causative agents in meningitis when routine cultures are negative, and appropriate anaerobic culture techniques should be employed, especially when sinus, otitic, or mastoid symptoms precede or accompany the onset of meningitis. Susceptibility testing of these organisms is necessary to ensure proper therapy because of the resistance of some anaerobes to antibiotics commonly employed in meningitis. In this regard, metronidazole, which provides excellent cerebrospinal fluid levels, may prove to be an effective agent in anaerobic infections of the central nervous system.
Adolescent↗
Clinical pharmacology of cefamandole as compared with cephalothin.
We compared the pharmacology of cefamandole and cephalothin in six healthy adult male volunteers. After a 1-g, 20-min intravenous (i.v.) infusion, the average peak blood level of cefamandole was 87.6 versus 64.1 mug/ml for cephalothin. An i.v. infusion of 500 mg/h for 2 h (after a loading dose of 750 mg) gave an average steady-state blood level of 28.5 mug/ml for cefamandole and 18.2 mug/ml for cephalothin. Mean peak serum levels after 1 g intramuscularly were similar for the two antibiotics (about 21 mug/ml), but with cefamandole they persisted longer, and the area under the blood level curve was about 25% greater. The average t((1/2)) as determined from both i.v. studies was 34 min for cefamandole versus 30 min for cephalothin. The mean serum clearance for cephalothin, due to its partial conversion to a metabolite, was much greater than for cefamandole (425 versus 272 ml/min per 1.73 m(2)), but the renal clearances were similar for the two antibiotics (268 versus 257 ml/min per 1.73 m(2)). Other values for cefamandole and cephalothin were: 24-h urinary excretion, 80 and 66%; serum protein binding, 74 and 70%; and apparent volume of distribution, 12.8 and 18.5 liters/1.73 m(2), respectively. Thus, the pharmacology of the two antibiotics was similar. Blood levels were somewhat higher with cefamandole i.v., but the results suggest that dosage regimens should be the same for the two antibiotics.
Adult↗
Ticarcillin vs carbenicillin: clinical pharmacokinetics.
The pharmacokinetic characteristics of ticarcillin, a semisynthetic penicillin more active than carbenicillin against Pseudomonas, were compared to those of carbenicillin in 12 healthy volunteers. Following an intravenous infusion of 2 gm in 5 min, there was a lower average serum level for ticarcillin (218 mug/ml) than for carbenicillin (301 mug/ml), but after 2 hr the differences were not significant. The biologic half-life of ticarcillin was slightly longer than that of carbenicillin (72 and 65 min, P smaller than 0.01) and its volume of distribution was larger (15.7 and 12.3 l, P smaller than 0.01). Eighty-six per cent of the dose of ticarcillin and 99 percent of the dose of carbenicillin was recovered in the urine in 24 hr. Similar but much less marked blood level differences were noted with 2 gm, 30-min infusions. An intravenous infusion of 1 gm/hr gave average steady-state blood levels of about 124 mug/ml for both antibiotics. Probenecid, administered 1 hr before the infusion, caused significant and similar increases in blood levels, half-lives, and volumes of distribution of the 2 antibiotics. Protein binding in 100 percent human serum was 50 percent and 65 percent for carbenicillin and ticarcillin, respectively. These relatively small but definite differences in the pharmacokinetics of ticarcillin and carbenicillin are not likely to be of clinical significance.
Carbenicillin↗
Bioassay of metronidazole with either anaerobic or aerobic incubation.
In a bioassay for metronidazole, a modified agar well diffusion technique was used. Two clostridial species were used as the test organisms, and, with minor variations, the method was as effective with aerobic as with anaerobic incubation. Serum and urine levels of 0.25-128 mug/ml were measurable by this method without dilution of the specimens being assayed. The principal acid and alcohol metabolites of metronidazole were found to possess only approximately 5% and 30%, respectively, of the activity of the parent compound.
Biological Assay↗
Unique bactericidal action of metronidazole against Bacteroides fragilis and Clostridium perfringens.
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.
Bacteroides fragilis↗
Pharmacokinetics of metronidazole as determined by bioassay.
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 mug/ml and 6.2 mug/ml after single 500-mg and 250-mg doses, respectively. Renal clearance was only 10.2 ml/min per 1.73 m(2), 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 mug/ml, and before the 8 p.m. dose, 5.7 mug/ml. For the higher, 500-mg dose (four times a day) regimen, the corresponding minimum serum levels were 13.1 mug/ml at 8 a.m. and 21.3 mug/ml at 8 p.m. Peak levels would have been about 10 mug/ml higher, and since the minimum inhibitory concentrations of most anaerobes including Bacteroides fragilis are less than 6 mug/ml, these concentrations should be highly effective therapeutically, even for severe infections.
Administration, Oral↗
Human pharmacokinetics of BL-P1654 compared with ampicillin.
BL-P1654 is a new ureido-penicillin which has significant activity against both pseudomonas and klebsiella. Its pharmacokinetics were evaluated in five studies in four healthy adult male volunteers after 1-g doses given as: 5- and 30-min intravenous infusions, a 30-min infusion 1 h after the oral administration of 1 g of probenecid, and an intramuscular injection. For comparison, volunteers also received a 30-min infusion of 1 g of ampicillin. Serum levels of the antibiotic were found to fit a two-compartment open model using a Burroughs-5500 computer. After a 30-min infusion, peak serum levels of BL-P1654 (72.8 mug/ml [standard deviation] +/- 5.9) were 50% greater than those of ampicillin (53.6 +/- 8.9). Six hours later, the relative difference was even greater (4.58 +/- 0.25 versus 0.35 +/- 0.09). At 75 min after the 1-g intramuscular injection of BL-P1654, peak serum levels averaged 28.4 +/- 10.3 mug/ml. The half-life of BL-P1654 (2.04 h) was significantly longer than for ampicillin (1.15 h), and the renal clearances of BL-P1654 and ampicillin were 79 versus 244 ml/min per 1.73 m(2), respectively. Probenecid produced no significant change in blood levels, volume of distribution, half-life, or renal clearance, indicating that there is no net tubular secretion of this antibiotic.
Ampicillin↗
Effects of chronic hypoxia on lipolysis in brown adipose tissue in the fetal rabbit.
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Adipose Tissue↗
Inhibition of Haemophilus vaginalis (Corynebacterium vaginale) by metronidazole, tetracycline, and ampicillin.
The minimal inhibitory concentrations (MICs) of ampicillin, tetracycline, and metronidazole for 71 strains of Haemophilus vaginalis (Corynebacterium vaginale) were compared by use of an agar-dilution method and an inoculum of 10(6) organisms/ml. All strains were sensitive to 1 microgram of ampicillin/ml, 70% to 4 micrograms of tetracycline/ml, and only 13% of the strains to 8 micrograms of metronidazole/ml. Under anaerobic conditions the susceptibility to metronidazole increased markedly, and 48% of the strains were inhibited by 8 micrograms/ml. In determinations of MICs in broth cultures, reduction of the inoculum size to 10(4) organisms/ml increased susceptibilities to metronidazole and tetracycline, whereas incubation of 48 hr instead of 24 hr decreased susceptibilities to these two drugs. Minimal bactericidal concentrations (MBCs) were generally two- to fourfold greater than the MICs for the three drugs. The results demonstrate that anaerobic conditions, inoculum size, and duration of incubation influence the susceptibility of H. vaginalis to antibiotics in vitro.
Ampicillin↗
Relative susceptibilities of Gardnerella vaginalis (Haemophilus vaginalis), Neisseria gonorrhoeae, and Bacteroides fragilis to Metronidazole and its two major metabolites.
The susceptibilities of strains of Gardnerella vaginalis (Haemophilus vaginalis), Neisseria gonorrhoeae, and Bacteroides fragilis to metronidazole and its principal oxidative metabolites (1-[2-hydroxyethyl]-2-hydroxymethyl-5-nitroimidazole) ("hydroxy" metabolite) and 1-acetic acid-2-methyl-5-nitroimidazole ("acid" metabolite), were compared by determinations of the minimal inhibitory concentrations (MICs) of these compounds. Against ten strains of G. vaginalis, the hydroxy metabolite was the most active (median MIC, 2 microgram/ml); the median MICs of metronidazole and of the acid metabolite were 8 and 64 microgram/ml, respectively. The hydroxy metabolite was also the most active against 15 strains of N. gonorrhoeae (median MIC, 32 microgram/ml). In contrast, metronidazole was the most active against ten strains of B. fragilis (median MIC, 1 microgram/ml); the hydroxy and acid metabolites had median MICs of 2 and 64 micrograms/ml, respectively. These results indicate that in the treatment of G. vaginalis-associated vaginitis with metronidazole, the hydroxy metabolite may contribute a significant antimicrobial effect, in view of its excellent activity in vitro.
Bacteroides fragilis↗
Susceptibility of Trichomonas vaginalis strains to metronidazole: response to treatment.
The effect of the susceptibility of Trichomonas vaginalis strains to metronidazole on response to treatment was determined from minimal inhibitory concentrations (MICs) for organisms isolated during a clinical trial in which single 1- and 2-g doses of metronidazole were compared. Fifty-seven strains were isolated from patients receiving 1 g of metronidazole, and 75 from those receiving 2 g. The mean MIC for all strains was 1.50 microgram/ml (range, 0.5-4.5 microgram/ml) and was similar in both groups. The mean MICs for isolates from patients who were cured were significantly less than the mean MICs of isolates from those who were treatment failures. The cure rates, compared to the MICs for the strains isolated, varied from 84% (MIC, 0.5 microgram/ml) to 16% (MIC, greater than or equal to 3.0 microgram/ml) for the group given the single 1-g dose and from 94% (MIC, 0.5 microgram/ml) to 43% (MIC, greater than or equal to 3.0 micrograms/ml) for those given the 2-g dose. The data demonstrate a direct relationship between susceptibility of T. vaginalis isolates and response to treatment with single-dose regimens of metronidazole.
Clinical Trials as Topic↗
Clinical pharmacokinetics of metronidazole.
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Administration, Oral↗