Pharmacokinetics and tissue penetration of a single 1,000-milligram, intravenous dose of metronidazole for antibiotic prophylaxis of colorectal surgery

Self Cite

The concentrations of clavulanic acid and amoxicillin were determined in sera and different abdominal tissues of 17 patients who underwent elective colorectal surgery. Patients were randomly allocated to two groups. At the time of induction of anesthesia, patients in group 1 were given 200 mg of clavulanic acid with 2,000 mg of amoxicillin and patients in group 2 received 400 mg of clavulanic acid with 2,000 mg of amoxicillin. In both groups, the initial dose was administered again after 2 h. Blood samples were collected to determine peak and trough antibiotic levels. Serial blood samples were also collected at predetermined periods (opening and closure of the abdominal cavity and surgical anastomosis). Abdominal wall fat, epiploic fat, and colonic wall tissue samples were collected simultaneously. Antibiotic concentrations were determined by high-performance liquid chromatography. Increasing the dose of clavulanic acid to 400 mg resulted in significantly higher peak and trough levels in serum (P < 0.03). Following the injection of 400 mg, mean concentrations of clavulanic acid in the fatty tissues were significantly increased at the time of opening (P < 0.02). The concentrations of clavulanic acid and amoxicillin in fatty tissues were 17 to 52% and 12 to 23% of the levels in sera, respectively. In the colonic wall, the concentrations of clavulanic acid and amoxicillin were 52 to 63% and 49 and 27% of the levels in sera, respectively. In sera, clavulanic acid given at a dose of 200 or 400 mg reached or exceeded the concentrations found to be effective in vitro to reduce the MICs of amoxicillin from the resistant to the susceptible category for 90% of the potential pathogens. In most of the tissues investigated, increasing the dose of clavulanic acid to 400 mg resulted in a significantly higher number of samples with concentrations found to be effective in vitro (72 versus 11%; P < 0.05). In conclusion, increasing the dose of clavulanic acid to 400 mg resulted in higher levels in sera and improved penetration into the abdominal tissues in patients undergoing colorectal surgery.

Section: Discussionmentioning

confidence: 99%

“…It seems clear that during a surgical procedure, adequate antibiotic concentrations should be achieved at all sites of potential infection. Also, antibiotic activity should be maintained throughout the procedure, from incision to closure (4,6,8,13,14,18,19).…”

mentioning

confidence: 99%

Comparison of concentrations of two doses of clavulanic acid (200 and 400 milligrams) administered with amoxicillin (2,000 milligrams) in tissues of patients undergoing colorectal surgery

Martin

Mallet

Sastre

et al. 1995

Self Cite

“…It is distributed widely and reaches 42 to 76% of plasma concentrations in colonic mucosa (9,13). Metronidazole is extensively metabolized by the liver and excreted predominantly in feces, with only 12% excreted unchanged in urine (12).…”

Section: Discussionmentioning

confidence: 99%

Prospective Observational Study Comparing Three Different Treatment Regimes in Patients with Clostridium difficile Infection

Wenisch

Schmid

Kuo

et al. 2012

In a hospital-based, prospective cohort study, the effects of the three standard treatment regimens for mild Clostridium difficile infection (CDI), oral (p.o.) metronidazole at 500 mg three times/day, intravenous (i.v.) metronidazole at 500 mg three times/day, and oral (p.o.) vancomycin at 250 mg four times/day, were compared with respect to the risk of occurrence of complications, sequelae, and all-cause death within 30 days after the date of starting treatment. Differences in the incidence of these outcomes were tested by 2 or Fisher's exact tests. A Poisson regression model was performed to control for possible confounding effects of sex, age, and severity of comorbidity categorized according to the Charlson comorbidity index. The highest mortality was observed in the metronidazole i.v. group, with a mortality rate 38.1% (16/42) compared to mortality rates of 7.4% (9/121) in the metronidazole p.o. group and 9.5% (4/42) in the vancomycin p.o. group (P < 0.001). After adjustment for possible effects of sex, age (>65 years), and severity of comorbidity, the relative risk of a 30-day fatal outcome for patients receiving metronidazole i.v. was 4.3 (95% confidence interval [CI] ‫؍‬ 1.92 to 10; P < 0.0001) compared to patients treated with metronidazole p.o. and 4.0 (95% CI ‫؍‬ 1.31 to 5.0; P < 0.015) compared to patients treated with vancomycin p.o. There were no significant differences in the risk of complications between the three treatment groups. This study generates the hypothesis that treatment with i.v. metronidazole is inferior to the oral alternatives metronidazole and vancomycin.

“…A number of studies have evaluated the pharmacokinetics of intravenous metronidazole after single-dose administration to patients (5,19,28,32,34) and healthy volunteers (4,15,17). Pharmacokinetic parameters derived from plasma metronidazole concentrations after multiple doses in our healthy volunteer study were similar to those reported after single-intravenous-dose administration of 500 mg by Loft et al (17), 1,000 mg by Lau et al (15), and 1,500 mg by Bergan et al (4) to healthy volunteers.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of Intravenous Levofloxacin at 750 Milligrams and Various Doses of Metronidazole in Healthy Adult Subjects

Sprandel

Schriever

Pendland

et al. 2004

The purpose of this investigation was to evaluate the steady-state pharmacokinetics, pharmacodynamics, and safety of intravenous levofloxacin at 750 mg administered once daily combined with three different dosages of intravenous metronidazole (500 mg every 8 h [q8h], 1,000 mg q24h, and 1,500 mg q24h). Eighteen healthy adult subjects received all three combinations in a randomized, crossover fashion. Serial blood and urine samples were collected on the third day of each study period. The 24-h areas under the inhibitory (AUIC 0-24 ) and bactericidal (AUBC 0-24 ) curves of these three combination regimens were determined against clinical isolates of Bacteroides fragilis, Bacteroides thetaiotaomicron, Peptostreptococcus asaccharolyticus, and Escherichia coli. The mean concentrations of levofloxacin were not different between study periods and were similar to those previously published. The mean (؎ standard deviation) areas under the metronidazole plasma concentrationtime curve (AUC 0-24 ) for 1,500-mg q24h (338 ؎ 105 mg ⅐ h/liter) and 500-mg q8h (356 ؎ 68 mg ⅐ h/liter) regimens were not different (P > 0.05), but both were significantly higher than the 1,000-mg q24h AUC 0-24 (P < 0.05, 227 ؎ 57 mg ⅐ h/liter). Mean (؎ standard deviation) total body clearance and renal clearance values were similar among the 500-mg q8h, 1,000-mg q24, and 1,500-mg q24h regimens (62 ؎ 7, 67 ؎ 13, and 67 ؎ 14 and 11 ؎ 3, 12 ؎ 2, and 12 ؎ 5 ml/min/1.73 m 2 , respectively). Levofloxacin at 750 mg q24h plus metronidazole at 500 mg q8h or 1,500 mg q24h resulted in similar AUIC 0-24 and AUBC 0-24 values with one exception: the AUIC 0-24 for the 1,500-mg q24h regimen against B. thetaiotamicron was significantly higher (P < 0.05) than those of the other regimens. Overall, the combination of levofloxacin at 750 mg once daily and metronidazole at 500 mg q8h or 1,500 mg q24h appeared to have greater AUIC 0-24 and AUBC 0-24 values than did the 1,000-mg q24h regimen. All combination regimens of levofloxacin and metronidazole were well tolerated, and no serious drug-related adverse effects were reported. The pharmacokinetic, safety, and pharmacodynamic data from our study suggest that a once-daily regimen of intravenous levofloxacin at 750 mg and metronidazole at 1,500 mg warrants further clinical investigation.The spectrum of in vitro activity for metronidazole is against a variety of anaerobic pathogens which includes Bacteroides and Peptostreptococcus species (1). The in vitro activity of levofloxacin is against a broad range of gram-positive and gramnegative organisms, including Escherichia coli and other Enterobacteriaceae (2). The major approach in the treatment of mixed aerobic-anaerobic infections often involves surgical management in addition to antimicrobial therapy (11). Metronidazole is one of the drugs of choice for infections involving anaerobic pathogens. Due to the lack of gram-negative bacterial coverage, metronidazole is often used in combination with other antimicrobial agents for the treatment of mixed aerobicanaerobic infections. ...