Pharmacokinetics of [18F]fleroxacin in healthy human subjects studied by using positron emission tomography.

Positron emission tomography (PET) with [18F]fleroxacin was used to study the pharmacokinetics of fleroxacin, a new broad-spectrum fluoroquinolone, in 12 healthy volunteers (9 men and 3 women). The subjects were infused with a standard therapeutic dose of fleroxacin (400 mg) supplemented with approximately 20 mCi of [18F]fleroxacin. Serial PET images were made and blood samples were collected for 8 h, starting at the initiation of the infusion. The subjects were then treated with unlabeled drug for 3 days (400 mg/day). On the fifth day, infusion of radiolabeled drug, PET imaging, and blood collection were repeated. In most organs, there was rapid accumulation of radiolabeled drug, with stable levels achieved within 1 h after completion of the infusion. Especially high peak concentrations (in micrograms per gram) were achieved in the kidney (> 34), liver (> 25), lung (> 20), myocardium (> 19), and spleen (> 18). Peak concentrations of drug more than two times the MIC for 90% of Enterobacteriaceae strains tested (> 10-fold for most organisms) were achieved in all tissues except the brain and remained above this level for more than 6 to 8 h. The plateau concentrations in tissues (2 to 8 h, in micrograms per gram +/- standard error of the mean) of drug were as follows: brain, 0.83 +/- 0.032; myocardium, 4.53 +/- 0.24; lung, 5.80 +/- 0.48; liver, 7.31 +/- 0.33; spleen, 6.00 +/- 0.47; bowel, 3.53 +/- 0.74; kidney, 8.85 +/- 0.64; bone, 2.87 +/- 0.29; muscle, 4.60 +/- 0.33; prostate, 4.65 +/- 0.48; uterus, 3.87 +/- 0.39; breast, 2.68 +/- 0.11; and blood, 2.35 +/- 0.09. Concentrations of fleroxacin in tissue were similar in males and females, before and after pretreatment with unlabeled drug.     

Pharmacokinetics of [18F]fleroxacin in patients with acute exacerbations of chronic bronchitis and complicated urinary tract infection studied by positron emission tomography.

The pharmacokinetics of fleroxacin, a new broad-spectrum fluoroquinolone, were measured by positron emission tomography (PET) with [18F]fleroxacin in five patients with acute bacterial exacerbations of chronic bronchitis and in five patients with symptomatic, complicated urinary tract infection. Two studies were performed with each patient, one within 24 h of the initiation and one within 24 h of the completion of a 7-day course of fleroxacin, 400 mg/day. For each study, the patient received an infusion of that day's therapeutic dose of fleroxacin (400 mg) supplemented with approximately 740 MBq of [18F]fleroxacin, and serial PET images and blood samples were collected for 6 to 8 h starting at the initiation of the infusion. Between studies, the drug was administered orally. In all infected tissues, there was rapid accumulation of radiolabeled drug, with stable levels achieved within 1 h after completion of the infusion. In kidneys, accumulation was greater in the presence of active infection (P < 0.01), while in lungs, accumulation was lower (P < 0.02). Infection of the lung or urinary tract had no effect on drug delivery to uninvolved tissues. Also, there was no difference between the results obtained at the beginning and the end of therapy. Overall, peak concentrations of drug many times the MIC at which 90% of the infecting organisms are inhibited (MIC90) were achieved in the kidneys (> 30 micrograms/g), prostate glands (> 11 micrograms/g), and lungs (> 14 micrograms/g). Plateau concentrations (2 to 8 h; given as mean micrograms per gram +/- standard error of the mean) of drug in kidneys (15.11 +/- 0.55), prostate glands (5.08 +/- 0.19), and lungs (5.75 +/- 0.22) were also well above the MIC90 for most relevant pathogens. All patients had a good therapeutic response to fleroxacin.     

The comparative activity of fleroxacin, three other quinolones and eight unrelated antimicrobial agents.

The in vitro activity of fleroxacin, a new trifluorinated quinolone was evaluated against 432 bacterial isolates. Fleroxacin was 1- to 2-fold less active than ciprofloxacin and at least as active as ofloxacin and lomefloxacin against most members of the family Enterobacteriaceae. The MICs of fleroxacin for 90% of strains tested (MIC90) were < or = 0.25 micrograms/ml against all isolates of Enterobacteriaceae except Citrobacter freundii (MIC90, 4 micrograms/ml) and Serratia marcescens (MIC90, 2 micrograms/ml). Fleroxacin was as active as ciprofloxacin, ofloxacin and lomefloxacin against Pseudomonas spp, (MIC90 for all quinolones tested were > 8 micrograms/ml). Acinetobacter and Haemophilus influenzae were very susceptible to fleroxacin; however fleroxacin was 1-fold less active than lomefloxacin against Acinetobacter and at least 1-fold less active than ciprofloxacin or ofloxacin against H. influenzae. Methicillin-susceptible and -resistant strains of Staphylococcus epidermidis and methicillin-susceptible strains of S. aureus were very susceptible to fleroxacin, with an MIC90 < or = 1 microgram/ml (range 0.5-1 microgram/ml). Methicillin-resistant S. aureus and Staphylococcus spp. other than aureus and epidermidis were not susceptible to fleroxacin (MIC90 > 8 micrograms/ml). In addition, fleroxacin as well as ciprofloxacin, ofloxacin and lomefloxacin were inactive against Enterococcus spp. (MIC90 > 8 micrograms/ml). Streptococcus pneumoniae and S. pyogenes were resistant to both fleroxacin and lomefloxacin but were very susceptible to ciprofloxacin and ofloxacin. These results suggest that fleroxacin represents a valid therapeutic option in the treatment of infections caused by most Enterobacteriaceae and some species of staphylococcus.     

A positron emission tomography microdosing study with a potential antiamyloid drug in healthy volunteers and patients with Alzheimer's disease

This work describes a microdosing study with an investigational, carbon 11-labeled antiamyloid drug, 1,1'-methylene-di-(2-naphthol) (ST1859), and positron emission tomography (PET) in healthy volunteers (n = 3) and patients with Alzheimer's disease (n = 6). The study aimed to assess the distribution and local tissue pharmacokinetics of the study drug in its target organ, the human brain. Before PET studies were performed in humans, the toxicologic characteristics of ST1859 were investigated by an extended single-dose toxicity study according to guidelines of the Food and Drug Administration and European Medicines Agency, which are relevant for clinical trials with a single microdose. After intravenous bolus injection of 341 +/- 21 MBq [(11)C]ST1859 (containing <11.4 nmol of unlabeled ST1859), peripheral metabolism was rapid, with less than 20% of total plasma radioactivity being in the form of unchanged parent drug at 10 minutes after administration. In both the control and patient groups, uptake of radioactivity into the brain was relatively fast (time to reach maximum concentration, 9-17 minutes) and pronounced (maximum concentration [standardized uptake value], 1.3-2.2). In both healthy volunteers and patients, there was a rather uniform distribution of radioactivity in the brain, including both amyloid-beta-rich and -poor regions, with slow washout of radioactivity (half-life, 82-185 minutes). In conclusion, these data provide important information on the blood-brain barrier penetration and metabolism of an investigational antiamyloid drug and suggest that the PET microdosing approach is a useful method to describe the target-organ pharmacokinetics of radiolabeled drugs in humans.     

18F]Ciprofloxacin, a new positron emission tomography tracer for noninvasive assessment of the tissue distribution and pharmacokinetics of ciprofloxacin in humans

The biodistribution and pharmacokinetics of the fluorine-18-labeled fluoroquinolone antibiotic [(18)F]ciprofloxacin in tissue were studied noninvasively in humans by means of positron emission tomography (PET). Special attention was paid to characterizing the distribution of [(18)F]ciprofloxacin to select target tissues. Healthy volunteers (n = 12) were orally pretreated for 5 days with therapeutic doses of unlabeled ciprofloxacin. On day 6, subjects received a tracer dose (mean injected amount, 700 +/- 55 MBq, which contained about 0.6 mg of unlabeled ciprofloxacin) of [(18)F]ciprofloxacin as an intravenous bolus. Thereafter, PET imaging and venous blood sampling were initiated. Time-radioactivity curves were measured for liver, kidney, lung, heart, spleen, skeletal muscle, and brain tissues for up to 6 h after radiotracer administration. The first application of [(18)F]ciprofloxacin in humans has demonstrated the safety and utility of the newly developed radiotracer for pharmacokinetic PET imaging of the tissue ciprofloxacin distribution. Two different tissue compartments of radiotracer distribution could be identified. The first compartment including the kidney, heart, and spleen, from which the radiotracer was washed out relatively quickly (half-lives [t(1/2)s], 68, 57, and 106 min, respectively). The second compartment comprised liver, muscle, and lung tissue, which displayed prolonged radiotracer retention (t(1/2), >130 min). The highest concentrations of radioactivity were measured in the liver and kidney, the main organs of excretion (standardized uptake values [SUVs], 4.9 +/- 1.0 and 9.9 +/- 4.4, respectively). The brain radioactivity concentrations were very low (<1 kBq. g(-1)) and could therefore not be quantified. Transformation of SUVs into absolute concentrations (in micrograms per milliliter) allowed us to relate the concentrations at the target site to the susceptibilities of bacterial pathogens. In this way, the frequent use of ciprofloxacin for the treatment of a variety of infections could be corroborated.     

Penetration of fleroxacin and ciprofloxacin into skin blister fluid: a comparative study.

The penetration of multiple-dose concentrations of oral fleroxacin (400 mg every 24 h) and ciprofloxacin (500 mg every 12 h) into skin blister fluid in 12 healthy volunteers was determined in a randomized crossover study. Serum, blister fluid, and paper disk samples were analyzed by large-plate microbiologic assay. The mean areas under the concentration-time curve (AUC) for serum were 88.6 and 18.2 micrograms.h/ml/70 kg for fleroxacin and ciprofloxacin, respectively. The mean AUC for blister fluid and paper disks were 71.2 and 15.0 micrograms.h/ml/70 kg and 77.8 and 15.4 micrograms.h/ml/70 kg for fleroxacin and ciprofloxacin, respectively. Calculated penetration into interstitial fluid ranged from 74 to 92% for fleroxacin and 56 to 96% for ciprofloxacin; penetration was calculated by using the ratio of maximum drug concentration or AUC in blister fluid and paper disks to maximum drug concentration or AUC in serum. There was no significant difference between fleroxacin and ciprofloxacin in the percent penetration into skin blister fluid.     

Fleroxacin combined with rifampin

We determined the effect of the combination of rifampin and fleroxacin against Enterobacteriaceae and streptococcal species. None of the 65 isolates tested by checkerboard assay demonstrated synergy, 12% of isolates showed an additive effect; 86.7% were indifferent, and only 1 isolate showed antagonism. The mean FIC was 1.2. When using 2 and 8 micrograms/ml of rifampin, fleroxacin MICs of 285 isolates of Enterobacteriaceae, Pseudomonas aeruginosa, Haemophilus influenzae, staphylococci, streptococci, Bacteroides, and Clostridium were not increased, but synergy was not demonstrated. Time-kill studies against Escherichia coli, P. aeruginosa, Enterobacter cloacae, Staphylococcus aureus, and Enterococcus faecalis failed to show increased killing when the two agents were present at one-half the MBC. The fleroxacin-rifampin interaction is one of indifference but provides coverage for species not adequately inhibited by fleroxacin.     

Fleroxacin pharmacokinetics in patients with liver cirrhosis.

In this open-label study, the disposition of fleroxacin in liver disease in 12 healthy male volunteers, 6 male cirrhotics without ascites (group A), and 6 male cirrhotics with ascites (group B) was evaluated. Fleroxacin (400 mg) was administered orally and intravenously to each subject in a random crossover fashion. Fleroxacin was completely absorbed and achieved similar peak concentrations in plasma in all three study groups (P greater than 0.05). The volume of distribution exceeded 1 liter/kg in healthy controls and was not affected by liver impairment (P greater than 0.05). Only group B demonstrated differences in the pharmacokinetic parameters evaluated: the systemic and renal clearances of fleroxacin and the renal clearances and clearances of the two major metabolites of fleroxacin formed, N-demethyl fleroxacin and fleroxacin N-oxide, were significantly lower and the half-lives of the parent drug and its metabolites were significantly longer in group B than in healthy controls and group A (P less than 0.05). The elimination of the two metabolites appeared to be formation rate limited in all three study groups. It was concluded from this study that a 50% reduction in the fleroxacin maintenance dose in patients with liver disease appears justified only in patients with ascites. However, no change in the fleroxacin loading dose is needed in patients with compromised liver function.     

Penetration of fleroxacin into human and animal tissues.

Fleroxacin concentrations in human and rat tissues were determined by HPLC following extraction with dichloromethane:isopropanol. This method yielded a high recovery of more than 85%. In the investigated tissues the fleroxacin levels were equal to or higher than those concomitantly measured in plasma. The concentration ratios 'tissue/plasma' were 1.6-2.7 for lung, 1.9-2.1 for muscle, 1.1-1.9 for gynaecological tissues and 1.2 for bone. Only in the case of fat and lens/eye lower ratios of 0.05-0.5 were found. The actual measured fleroxacin concentrations in most tissues and in plasma were high. Following oral administration of the recommended therapeutic dose of 400 mg, once daily, peak concentrations of 5-6 mg/l were reached in human plasma at steady state. Even 24 h after drug intake the fleroxacin level was still approximately 1 mg/l and thus in the range of the MIC90 values of susceptible bacteria causative for many types of tissue infections.     

Activity of fleroxacin alone and in combination with clindamycin or metronidazole in experimental intra-abdominal abscesses.

To assess the potential efficacy of fleroxacin in combination with clindamycin or metronidazole in mixed aerobic and anaerobic infections, we used a rat model of intra-abdominal abscesses in which the inoculum consisted of pooled rat feces mixed with BaSO4. Two hours after bacterial challenge, antimicrobial therapy was begun intravenously with regimens designed to stimulate human pharmacokinetics. A combination of clindamycin and gentamicin was included as an established treatment regimen. After 8.5 days of therapy, final bacterial counts in abscesses showed that fleroxacin alone or combined with metronidazole or clindamycin effectively eradicated Escherichia coli, with bacterial densities of < or = 2.84 +/- 0.1, < or = 2.9 +/- 0.1, and < or = 2.9 +/- 0.1 (mean +/- standard error of the mean) log10 CFU/g, respectively. The addition of either clindamycin or metronidazole to fleroxacin substantially enhanced the effectiveness of the regimens against Bacteroides fragilis, with bacterial counts of < or = 3.0 +/- 0.1 or < or = 2.9 +/- 0.1 log10 CFU/g, respectively, versus 9.2 +/- 0.2 log10 CFU/g for fleroxacin alone. The combination of metronidazole and fleroxacin also resulted in a significantly greater reduction of peptostreptococci and Bacteroides thetaiotaomicron than fleroxacin alone (< or = 2.9 +/- 0.1 versus 6.1 +/- 0.9 log10 CFU/g and 3.3 +/- 0.4 versus 8.3 +/- 0.1 log10 CFU/g, respectively). Except for those of B. fragilis, counts of other anaerobes were reduced to a greater extent by metronidazole plus fleroxacin than by clindamycin plus fleroxacin, although differences were not always significant. Metronidazole plus fleroxacin was at least as active a clindamycin plus gentamicin against all species and was significantly more active against Clostridium spp. No regimen effectively eradicated enterococci from the abscesses. These results suggest that the addition of either metronidazole or clindamycin would effectively enhance the spectrum of fleroxacin for treatment of mixed aerobic and anaerobic infections.     

Pharmacology of aztreonam after intravenous infusion

The pharmacokinetics of aztreonam, a monocyclic beta-lactam which inhibits most members of the family Enterobacteriaceae at concentrations of less than 1 microgram/ml and most Pseudomonas aeruginosa isolates at concentrations of less than 16 micrograms/ml, were examined in healthy male volunteers after 30-min intravenous infusions of 0.5, 1, and 2 g of the drug. Mean peak levels of the drug in serum at the end of infusion were 65.5, 164, 255 micrograms/ml after 0.5 1, and 2 g, respectively, with levels of the drug in serum of 1.8, 3, and 8.5 micrograms/ml at 8.5 h for the three doses, respectively. The half-life was approximately 2 h for all three doses. The total serum clearance averaged 1 ml/min per kg. The apparent volume of distribution averaged 0.17 liter/kg for the three doses. Overall excretion of the drug in urine was 61%, with mean levels in urine of 23, 52, and 109 micrograms/ml at 8.5 to 12.5 h after 0.5, 1, and 2 g of aztreonam, respectively. Concentrations of the drug in serum after a 1-g dose exceeded the minimal inhibitory concentration for 90% of the members of the Enterobacteriaceae by four- to eightfold for 8 h and exceeded the minimal inhibitory concentration for P. aeruginosa isolates for 4 h.     

Lomefloxacin, a new fluoroquinolone. Studies on in vitro antimicrobial spectrum, potency, and development of resistance

Lomefloxacin (NY-198; SC-47111), a potent new difluoroquinolone, was studied to compare its in vitro activity with that of other antimicrobials against 2194 clinical isolates. Lomefloxacin showed excellent inhibitory and bactericidal activity against strains of Enterobacteriaceae and inhibited greater than 99% of the isolates at a concentration of 4 micrograms/ml or less. Lomefloxacin exhibited good-to-moderate activity against strains of Acinetobacter (MIC90 4 micrograms/ml) and Pseudomonas aeruginosa (MIC90 8 micrograms/ml), but poor activity for Pseudomonas cepacia (MIC90 greater than 16 micrograms/ml). Staphylococcus aureus, and Staphylococcus epidermidis isolates, both oxacillin-susceptible and -resistant strains, were susceptible (MIC90 1 micrograms/ml) to lomefloxacin and the other fluoroquinolones. Strains of Haemophilus influenzae, (MIC90 less than or equal to 0.13 micrograms/ml) Neisseria gonorrhoeae (MIC90 less than or equal to 0.03 micrograms/ml), and Branhamella catarrhalis (MIC90 less than or equal to 0.03 micrograms/ml) were highly susceptible to lomefloxacin. Streptococcal isolates, especially viridans streptococci, were considerably less susceptible to the fluoroquinolones. Overall, lomefloxacin had comparable activity to norfloxacin, fleroxacin, and ofloxacin, and against many facultative anaerobes lomefloxacin was more active than imipenem, cefotaxime, ceftazidime, ticarcillin/clavulanic acid, aztreonam, trimethoprim/sulfamethoxazole and gentamicin. Development of resistance to lomefloxacin by spontaneous mutation was low and comparable to that of other fluoroquinolones. Growth in subinhibitory concentrations resulted in increased resistance to fluoroquinolones for selected test strains.     

In vitro activity of T-3761, a new fluoroquinolone.

The in vitro activity of T-3761, a new fluoroquinolone antimicrobial agent which has an oxazine ring structure with a cyclopropyl moiety at C-10, was compared with those of other agents against 2,854 clinical isolates. T-3761 had a broad spectrum of activity and had potent activity against gram-positive and -negative bacteria. The MICs of T-3761 against 90% of the methicillin-susceptible Staphylococcus aureus, methicillin-susceptible and -resistant Staphylococcus epidermidis, and Clostridium spp. tested were 0.39 to 6.25 micrograms/ml. Its activity was comparable to those of ciprofloxacin and ofloxacin and four- to eightfold greater than those of norfloxacin and fleroxacin, but its activity was two- to eightfold less than that of tosufloxacin. Some isolates of ciprofloxacin-resistant S. aureus (MIC of ciprofloxacin, greater than or equal to 3.13 micrograms/ml) were still susceptible to T-3761 (MIC of T-3761, less than or equal to 0.78 micrograms/ml). The MICs of T-3761 against 90% of the streptococci and enterococci tested were 3.13 to 100 micrograms/ml. Its activity was equal to or 2- or 4-fold greater than those of norfloxacin and fleroxacin, equal to or 2- or 4-fold less than those of ofloxacin and ciprofloxacin, and 4- to 16-fold less than that of tosufloxacin. The activity of T-3761 against gram-negative bacteria was usually fourfold greater than those of norfloxacin, ofloxacin, and fleroxacin. Many isolates which were resistant to nonfluoroquinolone agents, such as minocycline- or imipenem-resistant S. aureus, ceftazidime-resistant members of the family Enterobacteriaceae, gentamicin- or imipenem-resistant Pseudomonas aeruginosa, and ampicillin-resistant Haemophilus influenzae and Neisseria gonorrhoeae, were susceptible to T-3761. The MBCs of T-3761 were either equal to or twofold greater than the MICs. The number of viable cells decreased rapidly during incubation with T-3761 at one to four times the MIC. At a concentration of four times the MIC, the frequencies of appearance of spontaneous mutants resistant to T-3761 against S. aureus, Escherichia coli, Serratia marcescens, and P. aeruginosa were 2.2 x 10(-8) to less than or equal to 1.2 x 10(-9). The 50% inhibitory concentrations of T-3761 for DNA gyrases isolated from E. coli and P. aeruginosa were 0.88 and 1.9 micrograms/ml, respectively.     

Iontophoretic application of tobramycin to uninfected and Pseudomonas aeruginosa-infected rabbit corneas.

Pseudomonas aeruginosa keratitis was induced in rabbits to study the effects of corneal infection on the delivery of tobramycin by iontophoresis. Some rabbits were treated by use of an eye cup with no current as a control for iontophoresis, and others were treated with fortified drops (1.36%) delivered topically for comparison with results of earlier studies. One hour after treatment with tobramycin, the concentration of drug in the infected corneas was compared with that achieved in mock-infected and uninfected eyes. Iontophoresis of 25 mg of tobramycin per ml at 0.8 mA for 10 min delivered significantly more drug (P = 0.0001) to corneal tissue than did drops or use of an eye cup without current in P. aeruginosa-infected eyes mock-infected eyes, or uninfected eyes. Tobramycin concentrations in the infected corneas (605.9 micrograms/g) were not significantly different (P = 0.815) from the concentrations in mock-infected eyes (641.4 micrograms/g), but were lower (P = 0.007) than those obtained by iontophoresis in uninfected corneas (853.6 micrograms/g). Use of an eye cup without current delivered tobramycin equally to infected, mock-infected, and normal eyes, i.e., 176.5, 171.0, and 163.1 micrograms/g, respectively (P greater than 0.709). Tobramycin delivered by use of fortified drops delivered topically was detectable in mock-infected corneas (20 micrograms/g) and P. aeruginosa-infected corneas (6.0 micrograms/g). These results suggest that iontophoresis has value as an ocular drug delivery system and that an eye cup could also be useful in a therapeutic regimen for ocular infections.     

In vitro activities of sparfloxacin, tosufloxacin, ciprofloxacin, and fleroxacin.

The in vitro activity of sparfloxacin was compared with those of tosufloxacin, ciprofloxacin, and fleroxacin against 730 bacterial isolates representing 49 different species. Sparfloxacin and ciprofloxacin had similar spectra of activity, but sparfloxacin was less active against Pseudomonas aeruginosa and more active against many gram-positive cocci and anaerobic bacteria. Tosufloxacin MICs were generally 8- to 16-fold lower than those for sparfloxacin or ciprofloxacin. All four fluoroquinolones were active against nalidixic acid-susceptible strains of the family Enterobacteriaceae (MIC for 90% of the isolates [MIC90], less than or equal to 0.25 micrograms/ml) but nalidixic acid-resistant strains were less susceptible (MIC90, greater than or equal to 4.0 micrograms/ml). Against Pseudomonas aeruginosa isolates, MIC90s were 1.0 micrograms/ml for tosufloxacin, 2.0 micrograms/ml for ciprofloxacin, and 4.0 micrograms/ml for sparfloxacin. Against Enterococcus faecalis, sparfloxacin and ciprofloxacin MIC90s were 1.0 and 2.0 micrograms/ml, respectively. MIC90s for ciprofloxacin-susceptible Staphylococcus aureus were 0.016 micrograms/ml for tosufloxacin, 0.06 micrograms/ml for sparfloxacin, and 0.5 micrograms/ml for both ciprofloxacin and fleroxacin. With four species of gram-negative bacilli, mutants resistant to two to four times the sparfloxacin MIC occurred spontaneously at frequencies of 10(-7) to 10(-9): single-step high-level resistance was not observed. In vitro-selected sparfloxacin-resistant mutants displayed cross-resistance to other quinolones, as did clinical isolates of ciprofloxacin-resistant S. aureus. Tosufloxacin MICs with broth microdilution methods were four- to eightfold greater than those obtained with agar dilution methods. The two procedures gave comparable results when sparfloxacin or ciprofloxacin was being tested.     

Steady-state pharmacokinetics of fleroxacin in patients with skin and skin structure infections.

Steady-state pharmacokinetics of oral fleroxacin were studied in six males who had skin or skin structure infections and who were receiving 400 mg of fleroxacin once a day. Blood samples (n = 10) and total urine output were collected during a 24-h dosing interval. Fleroxacin concentrations in serum and urine were determined by high-performance liquid chromatography. The maximum concentration in serum and the time to achieve that maximum were 6.2 +/- 2.2 micrograms/ml and 0.94 +/- 0.62 h, respectively. The absorption half-life, alpha half-life, beta half-life, apparent steady-state volume of distribution, apparent total body clearance, and renal clearance were 0.56 +/- 0.37 h, 0.78 +/- 0.51 h, 10.56 +/- 1.40 h, 0.85 +/- 0.31 liters/kg, 129.2 +/- 19.6 ml/min, and 53.3 +/- 16.7 ml/min, respectively. Fleroxacin disposition in this patient population was similar to that in noninfected volunteers with normal renal function.     

Antimicrobial activity of Ro 24-6778, a covalent bonding of desmethylfleroxacin and desacetylcefotaxime

A new "dual action" cephalosporin (Ro 24-6778), representing an ester-linked desacetylcefotaxime and desmethylfleroxacin was tested against 287 aerobic bacteria. Ro 24-6778 was found to be very active (minimal inhibitory concentrations [MIC90], less than or equal to 0.5 micrograms/ml) against Enterobacteriaceae, Streptococcus spp., and Aeromonas hydrophila. Moderate Ro 24-6778 activity (MIC90, 1-8 micrograms/ml) was demonstrated against Bacillus spp., Staphylococcus spp. (including oxacillin-resistant strains), Flavobacterium spp., Enterococcus durans, and Acinetobacter anitratus. More Ro 24-6778-resistant strains (MIC90, 16- greater than 32 micrograms/ml) were usually found among the enterococci, Xanthomonas hydrophila, Pseudomonas spp., and Achromobacter xyloxidans isolates. These preliminary Ro 24-6778 MIC test results show a spectrum superior (93.4% of strains susceptible at less than or equal to 8 micrograms/ml) to the comparison drugs (cefotaxime or fleroxacin) and possible clinical utility for therapy of many fluoroquinolone- or cephalosporin-resistant strains.     

Characterization of peripheral-compartment kinetics of antibiotics by in vivo microdialysis in humans.

The calculation of pharmacokinetic/pharmacodynamic surrogates from concentrations in serum has been shown to yield important information for the evaluation of antibiotic regimens. Calculations based on concentrations in serum, however, may not necessarily be appropriate for peripheral-compartment infections. The aim of the present study was to apply the microdialysis technique for the study of the peripheral-compartment pharmacokinetics of select antibiotics in humans. Microdialysis probes were inserted into the skeletal muscle and adipose tissue of healthy volunteers and into inflamed and noninflamed dermis of patients with cellulitis. Thereafter, volunteers received either cefodizime (2,000 mg as an intravenous bolus; n = 6), cefpirome (2,000 mg as an intravenous bolus; n = 6), fleroxacin (400 mg orally n = 6), or dirithromycin (250 mg orally; n = 4); the patients received phenoxymethylpenicillin (4.5 x 10(6) U orally; n = 3). Complete concentration-versus-time profiles for serum and tissues could be obtained for all compounds. Major pharmacokinetic parameters (elimination half-life, peak concentration in serum, time to peak concentration, area under the concentration-time curve [AUC], and AUC/MIC ratio) were calculated for tissues. For cefodizime and cefpirome, the AUCtissue/AUCserum ratios were 0.12 to 0.35 and 1.20 to 1.79, respectively. The AUCtissue/AUCserum ratios were 0.34 to 0.38 for fleroxacin and 0.42 to 0.49 for dirithromycin. There was no visible difference in the time course of phenoxymethylpenicillin in inflamed and noninflamed dermis. We demonstrated, by means of microdialysis, that the concept of pharmacokinetic/pharmacodynamic surrogate markers for evaluation of antibiotic regimens originally developed for serum pharmacokinetics can be extended to peripheral-tissue pharmacokinetics. This novel information may be useful for the rational development of dosage schedules and may improve predictions regarding therapeutic outcome.     

In vitro activity of Ro 23-9424, a dual-action antibacterial agent, against bacterial isolates from cancer patients compared with those of other agents.

The in vitro activity of Ro 23-9424 against bacterial isolates from patients with cancer was compared with those of fleroxacin, ciprofloxacin, cefoperazone, and ceftazidime. Ro 23-9424 inhibited the majority of the members of the family Enterobacteriaceae and all Aeromonas isolates at a concentration of less than or equal to 1.0 micrograms/ml. It was also active against Acinetobacter spp. and Haemophilus influenzae, including beta-lactamase-producing strains. The MIC for 90% of isolates (MIC90) of Pseudomonas aeruginosa was 16.0 micrograms/ml. All group A and B streptococci were inhibited by less than or equal to 0.25 micrograms/ml, and 90% of group G streptococci and Streptococcus pneumoniae were inhibited by 1.0 micrograms/ml. All methicillin-susceptible strains of Staphylococcus aureus and 60% of methicillin-resistant strains were susceptible to 2.0 micrograms of Ro 23-9424 per ml, whereas the MIC90 for Staphylococcus epidermidis and Staphylococcus hominis isolates was 4.0 micrograms/ml. Staphylococcus haemolyticus and Enterococcus spp. were less susceptible; MIC90s for them were 16.0 and 32.0 micrograms/ml. Ro 23-9424 has a broad antibacterial spectrum and potential utility for therapy of infections in cancer patients.     

The pharmacokinetics and therapeutic efficacy of fleroxacin and pefloxacin in a rat abscess model

The penetration, pharmacokinetics and therapeutic efficacy of fleroxacin and pefloxacin were investigated in a rat abscess model. Abscesses were induced by implanting a dialysis tube unit contaminated with Serratia marcescens in the subcutaneous tissue. Simultaneous serum, interstitial fluid (IF) and abscess fluid concentrations of the investigated antibiotics were measured 24 and 96 h after implantation. The concentrations were determined at various time intervals after the last intramuscular administration of each drug (20 mg/kg). Peak fleroxacin and pefloxacin concentrations in the serum of the infected animals were 14.6 +/- 4.7 mg/l and 13 +/- 2.9 mg/l respectively, peak fleroxacin and pefloxacin abscess fluid concentrations after 24 h were 12.3 +/- 2.5 mg/l and 8.9 +/- 2.2 mg/l, respectively (85% and 68% of peak serum concentrations). Abscess fluid concentrations at 96 h were: fleroxacin 4.7 +/- 2.6 mg/l and pefloxacin 4.5 +/- 1.7 mg/l. Both antimicrobials persisted significantly longer in the abscess fluid than in serum. Both drugs failed to sterilize the abscesses following a single administration; however after four consecutive administrations all abscesses became sterile. We conclude that fleroxacin and pefloxacin may be suitable for the therapy of closed space infections caused by susceptible micro-organisms.