Metronidazole is often recommended for combination therapy with certain cephalosporins, fluoroquinolones, aminoglycosides, and monobactams for the treatment of mixed aerobic-anaerobic infections (20
). As a result, one potential antimicrobial regimen could be the combination of a fluoroquinolone, such as levofloxacin, and metronidazole. We chose to evaluate the pharmacokinetics, safety, and pharmacodynamics of three different dosages of metronidazole in combination with levofloxacin in healthy adult subjects after the administration of multiple doses.
The observed pharmacokinetic parameters of intravenous levofloxacin at 750 mg administered once daily in our 18 healthy adult subjects were similar to those previously described for healthy subjects with CLCR
values greater than 80 ml/min (6
). The mean (± SD) concentrations in plasma before (Cmin
) and after (Cmax
) the last intravenous dose were 0.7 ± 0.3 and 9.5 ± 3.4 mg/liter, respectively. The AUC0-24
for all available sampling periods was 61.3 ± 14.2 mg
h/liter. For the subjects with a CLCR
greater than 80 ml/min (n
= 4) studied by Chow et al. (6
), mean pharmacokinetic parameters at steady state were as follows: Cmin
, 0.68 ± 0.15 mg/liter; Cmax
, 8.71 ± 0.9 mg/liter; and AUC0-24
, 67.4 ± 1.75 mg
Our study compared the pharmacokinetics after multiple doses of three different intravenous metronidazole regimens (500 mg every 8 h, 1,000 mg once daily, and 1,500 mg once daily) combined with levofloxacin. The mean (± SD) Cmax
after the administration of 1,000 mg once daily was 24.8 ± 6.8 mg/liter. A 50% increase in dose (1,500 mg once daily) resulted in a mean increase in Cmax
of approximately 50% (37.7 ± 10 mg/liter). The mean observed Cmax
was similar between the 500-mg every-8-h and 1,000-mg once-daily regimens (22.5 ± 5 and 24.8 ± 6.8 mg/liter, respectively). This is not unexpected, since the Cmin
was highest after the administration of 500 mg every 8 h (10.4 ± 1.9 mg/liter), and this residual concentration contributes to the Cmax
observed after the administration of multiple doses. Similarly, we observed a proportional increase in the systemic exposure over a dosing interval (AUC0-τ
) as dose was increased from 500 mg (118.7 + 23 mg
h/liter), to 1,000 mg (227 ± 57 mg
h/liter), and to 1,500 mg (338 ± 105 mg
h/liter). Systemic exposure over 24 h (AUC0-24
) was similar between the 500-mg every-8-h (356 ± 68 mg
h/liter) and the 1,500-mg once-daily (338 ± 105 mg
h/liter) regimens, and both were significantly higher than when metronidazole was administered as a 1,000-mg dose once daily (227 ± 57 mg
h/liter). This was expected, since the total daily doses for 500 mg every 8 h and 1,500 mg once daily are the same.
The elimination half-life appeared to be statistically lower during the 500-mg every-8-h regimen (8.0 ± 1.3 h) than during once-daily administration of higher doses. The initial pharmacokinetic analysis compared the concentration-versus-time profile over 8 h for the 500-mg dose to the concentrations over 24 h for the once-daily regimens. We reanalyzed the data and compared the concentration-versus-time profiles of all three regimens over an 8-h time period only. Consequently, no statistically significant difference was observed in plasma half-life among the 500-mg every-8-h (8.0 ± 1.3 h), 1,000-mg once-daily (8.4 ± 1.9 h), and 1,500-mg once-daily (8.7 ± 1.4 h) regimens. The systemic clearance, renal clearance, and percentage of a dose of metronidazole that was recovered in the urine over 25.5 h did not appear to be affected by the dose administered. The pharmacokinetics of metronidazole appear to be linear and proportional to the dose administered after multiple doses of 500 mg every 8 h, 1,000 mg once daily, and 1,500 mg once daily.
A number of studies have evaluated the pharmacokinetics of intravenous metronidazole after single-dose administration to patients (5
) and healthy volunteers (4
). 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.
All three combinations of levofloxacin and metronidazole were well tolerated in the 18 healthy adult male subjects. No serious drug-related adverse events were reported over the 54 study periods. The most commonly reported potentially drug-related adverse effects were metallic or unpleasant taste (n
= 28) and irritation at the site of the infusion (n
= 15), followed by headache (n
= 5), diarrhea (n
= 5), and nausea (n
= 2). The scatter plots of the individual concentrations in plasma as well as the mean values of AUC0-24
, and Cmin
were very similar for subjects with and without adverse events within each dosing regimen. These findings are consistent with adverse effects that have been observed in clinical trials (1
Pharmacodynamic analysis was performed to compare pharmacokinetic results with inhibitory and bactericidal activities (AUIC0-24 and AUBC0-24) provided by the three regimens against five clinical isolates. Levofloxacin at 750 mg once daily plus either metronidazole at 500 mg every 8 h or metronidazole at 1,500 mg once daily resulted in similar inhibitory and bactericidal activities against the five clinical isolates tested, with one exception. The AUIC0-24 for the 1,500-mg once-daily regimen against B. thetaiotamicron was significantly higher than those for the other two dosing regimens. However, the 5% difference between the dosing regimens of 1,500 mg once daily (AUIC0-24 = 238) and 500 mg every 8 h (AUIC0-24 = 225) probably does not translate into clinical significance. Although the 1,500-mg once-daily regimen of metronidazole achieved lower trough concentrations in plasma than did the 500-mg every-8-h regimen, both the median reciprocal inhibitory and bactericidal titers of metronidazole at these trough concentrations remained similar to those of the 500-mg every-8-h regimen. Thus, increasing the dose of metronidazole to 1,500 mg once daily provides higher median reciprocal inhibitory and bactericidal titers at peak concentrations in plasma and adequate and excellent bactericidal titers at trough concentrations in plasma.
Overall, the combination of levofloxacin at 750 mg once daily and metronidazole at 500 mg every 8 h or 1,500 mg once daily appeared to have greater bactericidal and inhibitory activity than did the regimen where metronidazole was administered as a dose of 1,000 mg once daily. This might be explained by the fact that the systemic exposure of metronidazole over 24 h (AUC0-24) was not significantly different between the 1,500-mg once-daily regimen and the 500-mg every-8-h regimen (1,500-mg total daily dose), whereas AUC0-24 with the 1,000-mg once-daily regimen was significantly lower. Despite these pharmacokinetic differences in the 1,000-mg once-daily regimen, the median reciprocal inhibitory and bactericidal titers at steady state yielded results within the ranges of 8 to 16 and 4 to 8 at peak and trough concentrations, respectively. In addition, the mean values for AUIC0-24 were greater than 200 for all four anaerobic organisms tested. These data indicate that the regimen of levofloxacin at 750 mg with metronidazole at 1,000 mg once daily will provide coverage for anaerobic pathogens for which MICs are ≤2 μg/ml.
In summary, the intravenous administration of 1,500 mg once daily or 500 mg every 8 h resulted in similar systemic exposure, safety, and AUIC0-24
values. If metronidazole exhibits concentration-dependent activity, the higher Cmax
observed after the administration of 1,500 mg once daily may also be beneficial for the treatment of anaerobic pathogens for which the MICs are higher, such as B. thetaiotaomicron
. Levofloxacin at 750 mg and metronidazole at 1,500 mg may offer a more convenient once-daily treatment option for mixed aerobic-anaerobic infections, compared to the standard administration of metronidazole at 500 mg every 8 h. A small number of studies have evaluated the efficacy of metronidazole at 1,500 mg administered once daily for the treatment of intra-abdominal infections (3
). 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 for the treatment of mixed aerobic-anaerobic infections.