Plasma drug activity in patients on treatment for multidrug-resistant tuberculosis.

Little is known about plasma drug concentrations relative to quantitative susceptibility in patients with multidrug-resistant tuberculosis (MDR-TB). We previously described a TB drug activity (TDA) assay that determines the ratio of the time to detection of plasma-cocultured Mycobacterium tuberculosis versus control growth in a Bactec MGIT system. Here, we assess the activity of individual drugs in a typical MDR-TB regimen using the TDA assay. We also examined the relationship of the TDA to the drug concentration at 2 h (C2) and the MICs among adults on a MDR-TB regimen in Tanzania. These parameters were also compared to the treatment outcome of sputum culture conversion. Individually, moxifloxacin yielded superior TDA results versus ofloxacin, and only moxifloxacin and amikacin yielded TDAs equivalent to a -2-log killing. In the 25 patients enrolled on a regimen of kanamycin, levofloxacin, ethionamide, pyrazinamide, and cycloserine, the C2 values were found to be below the expected range for levofloxacin in 13 (52%) and kanamycin in 10 (40%). Three subjects with the lowest TDA result (<1.5, a finding indicative of poor killing) had significantly lower kanamycin C2/MIC ratios than subjects with a TDA of ≥1.5 (9.8 ± 8.7 versus 27.0 ± 19.1; P = 0.04). The mean TDAs were 2.52 ± 0.76 in subjects converting to negative in ≤2 months and 1.88 ± 0.57 in subjects converting to negative in >2 months (P = 0.08). In Tanzania, MDR-TB drug concentrations were frequently low, and a wide concentration/MIC range was observed that affected plasma drug activity ex vivo. An opportunity exists for pharmacokinetic optimization in current MDR-TB regimens, which may improve treatment response.

Efficacy of high doses of levofloxacin in experimental foreign-body infection by methicillin-susceptible Staphylococcus aureus.

Antimicrobial efficacy in orthopedic device infections is diminished because of bacterial biofilms which express tolerance to antibiotics. Recently, the use of high doses of levofloxacin with rifampin has been recommended for staphylococcal infections. In the present study, we evaluated the efficacy of levofloxacin at doses of 50 mg/kg/day and 100 mg/kg/day (mimicking the usual and high human doses of 500 mg/day and 750 to 1,000 mg/day, respectively) and compared it to that of to linezolid, cloxacillin, vancomycin, and rifampin in a rat tissue cage model of experimental foreign-body infection by Staphylococcus aureus. The antimicrobial efficacy in vitro (by MIC, minimum bactericidal concentration, and kill curves) for logarithmic- and stationary-phase bacteria was compared with the in vivo efficacy. In vitro bactericidal activity at clinically relevant concentrations was reached by all drugs except rifampin and linezolid in the log-phase studies but only by levofloxacin in the stationary-phase studies. The bacterial count decreases from in vivo tissue cage fluids (means) for levofloxacin at 50 and 100 mg/kg/day, rifampin, cloxacillin, vancomycin, linezolid, and controls, respectively, were: -1.24, -2.26, -2.1, -1.56, -1.47, -1.15, and 0.33 (all groups versus controls, P < 0.05). Levofloxacin at 100 mg/kg/day (area under the concentration-time curve/MIC ratio, 234) was the most active therapy (P = 0.03 versus linezolid). Overall, in vivo efficacy was better predicted by stationary-phase studies, in which it reached a high correlation coefficient even if the rifampin group was excluded (r = 0.96; P < 0.05). Our results, including in vitro studies with nongrowing bacteria, pharmacodynamic parameters, and antimicrobial efficacy in experimental infection, provide good evidence to support the use of levofloxacin at high doses (750 to 1,000 mg/day), as recently recommended for treating patients with orthopedic prosthesis infections.

Pharmacodynamics and bactericidal activity of gatifloxacin in experimental pneumonia caused by penicillin-resistant Streptococcus pneumoniae.

BACKGROUND: Antimicrobial resistance rates for Streptococcus pneumoniae continue to increase worldwide, and resistance to nearly every major class of antimicrobials used to treat pneumococcal infections has been reported. Gatifloxacin (GFLX) is one of the quinolones that have strong activity against S. pneumoniae. METHODS: We compared the bacteriological, pharmacological and histopathological effects of orally administered GFLX with those of levofloxacin (LVFX) and ciprofloxacin (CPFX) in a murine model of pneumonia caused by penicillin-resistant S. pneumoniae (PRSP). RESULTS: Treatment with GFLX resulted in a significant decrease in the number of viable bacteria (control, CPFX, LVFX, and GFLX: 6.48 +/- 0.36, 6.44 +/- 0.27, 5.51 +/- 0.15, and 4.89 +/- 0.28 log10 CFU/lung, respectively, mean +/- SD). A significant decrease in mortality was observed in the GFLX-treated group in comparison with the other groups. Histopathological examination revealed that inflammatory changes in GFLX-treated mice were less marked than in the other mice. CONCLUSION: Our results suggest that orally administered GFLX is effective in PRSP pneumonia. The pharmacokinetic profiles also reflected the effectiveness of GFLX.

Lack of bioequivalence of levofloxacin when coadministered with a mineral-fortified breakfast of juice and cereal.

Previous studies have demonstrated that the chelation interactions demonstrated between fluoroquinolones and antacids also occur when they are coadministered with mineral-fortified foods. This study was conducted to evaluate the bioequivalence of levofloxacin when administered in a fasting state as compared to when it was administered with a common breakfast of calcium-fortified orange juice and ready-to-eat cereal. Fourteen of 16 healthy volunteers completed this study and received 500 mg of levofloxacin with each of the following: (1) 12 ounces of water, (2) subject-measured portions of juice and cereal, and (3) subject-measured portions of juice and cereal with milk. Plasma samples were collected prior to dosing and for up to 48 hours after. The results demonstrated that neither fed phase was bioequivalent to the fasting arm in terms of Cmax (with milk, 79.2% [72.6%, 85.7%]; without milk, 79.1% [73.3%, 84.9%]). In addition, a weak correlation was identified between the amount of change in 24-hour exposure and mineral fortification. The results of this study further demonstrate a need to require additional fed-fasted bioequivalence studies for drugs that demonstrate no interaction with the FDA meal but have significant interactions with drugs or supplements that contain large amounts of multivalent ions.

Lack of bioequivalence when levofloxacin and calcium-fortified orange juice are coadministered to healthy volunteers.

Chelation interactions between drugs/supplements that contain large amounts of multivalent ions and the fluoroquinolones have been known for quite some time. However, there has been a lack of taking this interaction into account when they may be coadministered with foods that have been fortified with amounts of multiple multivalent ions that equal or exceed many supplement products. A previous study demonstrated that 12 ounces of calcium-fortified orange juice significantly decreased the bioequivalence of a dose of ciprofloxacin. This study examined, in 16 healthy volunteers, whether 12 ounces of orange juice with and without calcium fortification would demonstrate the same chelation interaction with single doses of levofloxacin. The results of the study demonstrated that both types of juice decreased levofloxacin Cmax values by 14% to 18% and prolonged tmax values by approximately 50%, with calcium-fortified orange juice decreasing Cmax enough to lose bioequivalence as compared to the control arm (89% [78.1%, 99.8%]). Due to the lack of change in overall exposure, it is thought that rather than a chelation interaction, levofloxacin and components of the orange juices competed for intestinal transport mechanisms such as P-glycoprotein and organic anion-transporting polypeptides, which resulted in the discovered interaction. These results further confirm the need to adjust regulatory studies to include bioequivalence/bioavailability studies that contain fortified foods more than high-calorie/high-fat foods to better reflect current American consumption habits.

Efficacy and pharmacodynamics of simulated human-like treatment with levofloxacin on experimental pneumonia induced with penicillin-resistant pneumococci with various susceptibilities to fluoroquinolones.

Newer fluoroquinolones, such as levofloxacin, have shown an enhanced in vitro and in vivo activity against penicillin-resistant Streptococcus pneumoniae infections. The frequency of S. pneumoniae with reduced susceptibility to quinolones, although currently low, raises the question of the therapeutic efficacy of levofloxacin on infection due to such strains. We used an animal model of penicillin-resistant pneumococcal pneumonia using six strains with various levels of susceptibility to ciprofloxacin and levofloxacin in rabbits to induce pneumonia, and simulated a human-like treatment of 500 mg twice a day for 48 h. Strains' susceptibility profiles for ciprofloxacin and levofloxaxin were (ciprofloxacin/levofloxacin MIC, mg/L; genotype): 0.5/0.5 (Cip0.5), 2/1 (Cip2), 4/1.75 (Cip4), 8/1.75 (parC mutation) (Cip8), 10/2 (parC mutation) (Cip10), 64/16 (parC and gyrA mutations) (Cip64), respectively. All the strains induced a crude pneumonia in all rabbits. Significant bacterial reductions at the end of treatment in lung and spleen were observed for the four former strains (P < 0.05) but not for the latter two. An AUC/MIC ratio of at least 32 identified 95% of an at least bacteriostatic effect (P = 0.038) and 76% of a bactericidal effect (P = 0.09). Mutants were detected in treated animals infected with strains harbouring parC mutations (Cip8 and Cip10) and when the AUC/MIC ratio was between 13 and 31. We conclude that levofloxacin is effective against experimental pneumonia due to pneumococci with MIC < 1.5 mg/L, ineffective on experimental pneumonia due to pneumococci with MIC > or = 2 mg/L, and could be associated with the appearance of mutants when a parC mutation is pre-existing.

Efficacies of ofloxacin, rifampin, and clindamycin in treatment of Staphylococcus aureus abscesses and correlation with results of an in vitro assay of intracellular bacterial killing.

We studied the efficacies of ofloxacin, rifampin, and clindamycin in a Staphylococcus aureus abscess model and seven antimicrobial regimens in an intracellular killing assay. Ofloxacin plus rifampin was the most effective regimen in the abscess model, and rifampin and ofloxacin were the most active regimens in the intracellular killing assay.

Effects of traditional Chinese medicines on pharmacokinetics of levofloxacin.

The effects of single coadministrations of one of three traditional Chinese medicines, Hotyu-ekki-to, Rikkunshi-to, and Juzen-taiho-to, on the pharmacokinetics of levofloxacin (LVFX) were investigated with eight healthy volunteers in an open, random crossover fashion. Subjects each received a single oral dose of LVFX (200 mg) alone and then with a single coadministration of each Chinese medicine. There were no significant differences in any pharmacokinetic parameters of LVFX between the groups. Also, no significant changes in the urinary recovery (> 80%) and renal clearance of LVFX were observed. These results indicate that the Chinese medicines tested have no significant effect on the rate and extent of bioavailability or renal excretion of LVFX.

Comparative prophylactic efficacies of ciprofloxacin, ofloxacin, cefazolin, and vancomycin in experimental model of staphylococcal wound infection.

Recent shifts in the species and antibiotic resistance patterns of bacteria causing nosocomial infections present new challenges for providing effective prophylaxis in surgery. Traditional regimens lack activity against methicillin-resistant staphylococci and many gram-negative species causing nosocomial infections. The new fluoroquinolones exhibit in vitro activity against many emerging surgical wound pathogens. To determine the potential of this class of antimicrobial agents for use in surgery, we compared the prophylactic efficacies of ciprofloxacin and ofloxacin with those of cefazolin and vancomycin in a guinea pig model of abscess formation. Four Staphylococcus aureus strains, one Staphylococcus epidermidis strain, and one Staphylococcus haemolyticus strain were evaluated. Vancomycin was the most effective prophylactic agent, exhibiting in vivo activity against all strains which was superior or equivalent to those of all other agents tested. Cefazolin was the least effective agent and surpassed the two quinolones in prophylactic efficacy against only one organism, a quinolone- and methicillin-resistant strain of S. aureus. The two quinolones provided excellent protection against infection with all but the quinolone-resistant isolate. The in vivo emergence of quinolone resistance among quinolone-susceptible isolates was not detected. The methicillin-resistant, quinolone-susceptible S. epidermidis and S. haemolyticus isolates were extremely susceptible to prophylaxis, exhibiting 50% infective doses above 4 x 10(6) CFU for seven of the eight antibiotic-strain combinations. We conclude that ciprofloxacin and ofloxacin may be effective antistaphylococcal agents in surgery. The role of these agents remains to be defined, and the definition should include consideration of an adverse effect upon antibiotic resistance patterns of organisms causing nosocomial infections.

Lack of effect of Chinese medicines on bioavailability of ofloxacin in healthy volunteers.

Recently, Chinese medicines have become available as OTC drugs and are frequently prescribed with Western medicine for the treatment of various chronic diseases. In this study, the effect of the Chinese medicines Sho-saiko-to (TJ-9), Rikkunshi-to (TJ-43) and Sairei-to (TJ-114) on the bioavailability of ofloxacin (OFLX) was investigated in seven volunteers in an open, random crossover fashion. Subjects received a single oral dose of OFLX (200 mg) alone and with coadministrations of each Chinese medicine, at one-week intervals. Plasma and urine samples were analyzed by high-performance liquid chromatography. No significant differences in any estimated bioavailability parameters of OFLX were observed between the two phases. The urinary recovery of OFLX excreted within 24 h after the administration of OFLX alone, 80.6 +/- 3.9% (mean +/- SEM), was not significantly different from those after the coadministrations of the Chinese medicines (79.7 +/- 5.1% for TJ-9, 76.8 +/- 2.3% for TJ-43 and 80.3 +/- 5.3% for TJ-114), suggesting that there was no difference in the systemic availability of the four doses. These findings indicate that the Chinese medicines studied have no significant effect on the rate and extent of bioavailability of OFLX.

High-pressure liquid chromatography and microbiological assay of serum ofloxacin levels in adults receiving intravenous and oral therapy for skin infections.

Thirty-two adults hospitalized with skin and skin structure infections received intravenous ofloxacin followed by oral ofloxacin. The standard treatment was 400 mg every 12 h. One patient with renal failure received 400 mg every 24 h. Serum ofloxacin levels were measured (1.5 h postdose and 1 h predose) during intravenous (32 patients) and oral (30 patients) therapy. Levels were assayed by high-pressure liquid chromatography (HPLC) and microbiological assay (MBA). Mean levels +/- standard deviation (in micrograms per milliliter) when measured by MBA after intravenous dosing were (postdose versus predose) 6.23 +/- 2.49 versus 2.42 +/- 1.56, and those after oral dosing were 6.17 +/- 3.25 versus 3.49 +/- 2.77. When measured by HPLC, mean levels +/- standard deviation after intravenous dosing were 5.81 +/- 2.08 versus 2.14 +/- 1.26 and those after oral dosing were 5.63 +/- 2.92 versus 3.41 +/- 2.98. There were no significant differences between levels achieved with oral or intravenous dosing when measured by either MBA or HPLC. Levels in serum did not correlate with side effects. The MICs for 50 and 90% of the 40 aerobic pathogens isolated from 21 patients were 0.5 and 2.0 micrograms/ml, respectively. Cure or improvement was achieved in 30 patients. Intravenous and oral administration of ofloxacin yielded similar levels in serum which were safe and effective in the therapy of skin infections in adult patients.

Activity of temafloxacin against respiratory pathogens.

The activity of the quinolone temafloxacin against respiratory pathogens was compared with those of ciprofloxacin and ofloxacin. MICs for 90% of strains tested indicated that temafloxacin was at least two- to fourfold more potent than the other two quinolones against Staphylococcus aureus, Streptococcus pneumoniae, and Legionella pneumophila. Temafloxacin had potency equal to that of ciprofloxacin and was twofold more active than ofloxacin against Streptococcus pyogenes. Moraxella catarrhalis, and Bordetella pertussis. Against Haemophilus influenzae and Klebsiella pneumoniae, temafloxacin was four- and twofold less potent than ciprofloxacin, respectively. When administered orally in mouse protection tests against S. aureus, S. pneumoniae, and S. pyogenes, temafloxacin was at least eight times more potent than ciprofloxacin and was two to four times more active than ofloxacin. Against H. influenzae, temafloxacin was as active as ofloxacin and was two times less active than ciprofloxacin following oral administration in mice. In treating L. pneumophila in guinea pigs and H. influenzae otitis media in gerbils, temafloxacin and ofloxacin were more effective than ciprofloxacin. Against S. pneumoniae otitis media in gerbils, temafloxacin and ciprofloxacin were more active than ofloxacin. Following subcutaneous administration in mice, temafloxacin achieved higher lung levels than ciprofloxacin or ofloxacin did.

Oral ofloxacin therapy of Pseudomonas aeruginosa sepsis in mice after irradiation.

Death subsequent to whole-body irradiation is associated with gram-negative bacterial sepsis. The effect of oral therapy with the new quinolone ofloxacin for orally acquired Pseudomonas aeruginosa infection was tested in B6D2F1 mice exposed to 7.0 Gy of bilateral radiation from 60Co. A dose of 10(7) organisms was given orally 2 days after irradiation, and therapy was started 1 day later. Only 4 of 20 untreated mice (20%) survived for at least 30 days compared with 19 of 20 mice (95%) treated with ofloxacin (P less than 0.005). P. aeruginosa was isolated from the livers of 21 to 28 untreated mice (75%), compared with only 2 of 30 treated mice (P less than 0.005). Ofloxacin reduced colonization of the ileum by P. aeruginosa; 24 of 28 untreated mice (86%) harbored the organisms, compared with only 5 of 30 (17%) with ofloxacin (P less than 0.005). This experiment was replicated twice, and similar results were obtained. These data illustrate the efficacy of the quinolone ofloxacin for oral therapy of orally acquired P. aeruginosa infection in irradiated hosts.