In vivo efficacy of trovafloxacin (CP-99,219), a new quinolone with extended activities against gram-positive pathogens, Streptococcus pneumoniae, and Bacteroides fragilis.

The interesting in vitro antimicrobial activity and pharmacokinetics of the new quinolone trovafloxacin (CP-99,219) warranted further studies to determine its in vivo efficacy in models of infectious disease. The significance of the pharmacokinetic and in vitro antimicrobial profiles of trovafloxacin was shown through efficacy in a series of animal infection models by employing primarily oral therapy. Against acute infections, trovafloxacin was consistently more effective than temafloxacin, ciprofloxacin, and ofloxacin against Streptococcus pneumoniae and other gram-positive pathogens while maintaining activity comparable to that of ciprofloxacin against gram-negative organisms. In a model of murine pneumonia, trovafloxacin was more efficacious than temafloxacin, while ciprofloxacin failed against S. pneumoniae (50% protective doses, 2.1, 29.5, and >100 mg/kg, respectively). In addition to its inherent in vitro potency advantage against S. pneumoniae, these data were supported by a pharmacokinetic study that showed levels of trovafloxacin in pulmonary tissue of S. pneumoniae-infected CF1 mice to be considerably greater than those of temafloxacin and ciprofloxacin (twice the maximum drug concentration in serum; two to three times the half-life, and three to six times the area under the concentration-time curve). Against localized mixed anaerobic infections, trovafloxacin was the only agent to effectively reduce the numbers of recoverable CFU of Bacteroides fragilis ( >1,000-fold), Staphylococcus aureus (1,000-fold), and Escherichia coli ( >100-fold) compared with ciprofloxacin, vancomycin, metronidazole, clindamycin, cefoxitin, and ceftriaxone. The in vitro and in vivo antimicrobial activities of trovafloxacin and its pharmacokinetics in laboratory animals provide support for the ongoing and planned human phase II and III clinical trials.     

Pharmacokinetics and penetration into inflammatory fluid of trovafloxacin (CP-99,219).

A single 200-mg oral dose of trovafloxacin (CP-99,219) was given to each of eight healthy male volunteers, and the concentrations of the drug were measured in plasma, cantharides-induced inflammatory fluid, and urine over the subsequent 36 h. The mean maximum concentration observed in plasma was 2.9 micrograms/ml at a mean time of 0.75 h postdose. The mean maximum concentration observed in inflammatory fluid was 1.2 micrograms/ml at 4.0 h postdose. The mean elimination half-life in plasma was 7.8 h. The overall penetration into inflammatory fluid was 64%, as assessed by determining the ratio of the area under the concentration-time curves. Recovery of the dose in urine within the first 36 h postdose was 5.0% of the administered dose. Our results indicate that trovafloxacin, at a dosage of 200 mg once or twice daily, should be adequate for the treatment of systemic infections caused by most common bacterial pathogens.     

Susceptibilities of Mycoplasma pneumoniae, Mycoplasma hominis, and Ureaplasma urealyticum to a new quinolone, trovafloxacin (CP-99,219).

The susceptibilities of mycoplasmas to a new quinolone, trovafloxacin (CP-99,219), were compared with those to sparfloxacin and ofloxacin. Mycoplasma pneumoniae was as susceptible to trovafloxacin (MIC = 0.25 microgram/ml) as to sparfloxacin and fourfold less susceptible to ofloxacin. Mycoplasma hominis was highly susceptible to trovafloxacin (MIC = 0.06 microgram/ml) and sparfloxacin (MIC = 0.03 microgram/ml) and less susceptible to ofloxacin (MIC = 0.5 microgram/ml). Ureaplasma urealyticum was most susceptible to trovafloxacin, with susceptibilities ranging from 0.06 to 0.5 microgram/ml compared with 0.25 to 1.0 microgram of sparfloxacin per ml and 1 to 4 micrograms of ofloxacin per ml.     

Pharmacokinetics of a new quinolone, AM-833, in mice, rats, rabbits, dogs, and monkeys.

The pharmacokinetics of AM-833 [6,8-difluoro-1-(2-fluoroethyl)-1, 4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid] were studied in mice, rats, rabbits, dogs, and monkeys by reversed-phase high-performance liquid chromatography. AM-833 was rapidly and completely absorbed from the digestive tracts of mice, rats, and dogs. About half of AM-833 bound to rat and dog serum proteins. Drug levels in lung, spleen, liver, and kidney tissues of rats and dogs were greater than the respective levels in serum but lower in brain tissue. Drug levels in tissues declined with the decrease in levels in serum. AM-833 penetrated rapidly and well into inflammatory exudate of rats. Elimination half-lives in serum were species dependent, ranging from 1.57 h in rabbits to 9.42 h in dogs. Profiles of drug levels in serum were dose related over a single dose range from 2 to 40 mg/kg and not modified significantly during multiple dosing in dogs. Unchanged AM-833 was excreted in urine and bile in both rats and dogs. The metabolism of AM-833 was suggested by evidence that 24-h total recovery of unchanged AM-833 in urine and bile accounted for about half of the intravenous dose in rats.     

Dose-ranging study of CP-99,219 (trovafloxacin) for treatment of uncomplicated gonorrhea.

Thirty-nine patients with uncomplicated gonorrhea were randomized to receive single, oral 50-, 100-, or 200-mg doses of trovafloxacin (CP-99,219), a new quinolone antibiotic. All 31 evaluable patients were cured of infection. Trovafloxacin was well tolerated. The trovafloxacin MICs at which 50 and 90% of 36 Neisseria gonorrhoeae isolates are inhibited were 0.002 and 0.004 mg/liter, respectively (MIC range, < 0.0005 to 0.008 mg/liter). These preliminary studies suggest that trovafloxacin is effective for the treatment of uncomplicated gonorrhea at single oral doses as low as 50 mg.     

In vivo efficacy of trovafloxacin (CP-99,217), a new quinolone, in experimental intra-abdominal abscesses caused by Bacteroides fragilis and Escherichia coli.

The efficacy of trovafloxacin in treating Bacteroides fragilis and Escherichia coli infections was investigated and compared to the efficacy of combined clindamycin and gentamicin therapy in an experimental model of intra-abdominal abscesses in rats. Rats were treated with different doses of CP-116,517-27, a parenteral prodrug of trovafloxacin. Response to treatment was evaluated by mortality rate and elimination of infection (cure rate). Mortality in the control group was 85.4%, whereas in rats treated with trovafloxacin, it was close to 0%. The highest cure rate (89.3%) resulted from the administration of 40 mg of CP-116,517-27 per kg of body weight three times a day (TID) for 10 days (equivalent to 18.15 mg of active drug trovafloxacin per rat per day). The therapeutic response with trovafloxacin was comparable to that of a combination therapy of clindamycin (75 mg/kg) plus gentamicin (20 mg/kg) TID (cure rate, 74%; mortality rate, 5%). The measured peak levels of trovafloxacin in serum and abscess pus were 2.6 +/- 0.3 and 5.2 micrograms/ml, respectively. The tumor necrosis factor alpha levels in the untreated animals were high compared to those for rats treated with trovafloxacin or clindamycin plus gentamicin. These results demonstrate that trovafloxacin as a single agent appears to be as successful as clindamycin plus gentamicin in the treatment of experimental intra-abdominal abscesses in rats.     

Pharmacokinetics of a fluoronaphthyridone, trovafloxacin (CP 99,219), in infants and children following administration of a single intravenous dose of alatrofloxacin

The pharmacokinetics of trovafloxacin following administration of a single intravenous dose of alatrofloxacin, equivalent to 4 mg of trovafloxacin per kg of body weight, were determined in 6 infants (ages 3 to 12 months) and 14 children (ages, 2 to 12 years). There was rapid conversion of alatrofloxacin to trovafloxacin, with an average +/- standard deviation (SD) peak trovafloxacin concentration determined at the end of the infusion of 4.3 +/- 1.4 microg/ml. The primary pharmacokinetic parameters (average +/- SD) analyzed were volume of distribution at steady state (1.6 +/- 0.6 liters/kg), clearance (151 +/- 82 ml/h/kg), and half-life (9.8 +/- 2.9 h). The drug was well tolerated by all children. There were no age-related differences in any of the pharmacokinetic parameters studied. Less than 5% of the administered dose was excreted in the urine over 24 h. On the basis of the mean area under the concentration-time curve of 30.5 +/- 10.1 microg. h/ml and the susceptibility (< or =0.5 microg/ml) of common pediatric bacterial pathogens to trovafloxacin, dosing of 4 mg/kg/day once or twice daily should be appropriate.     

Activity of the new fluoroquinolone trovafloxacin (CP-99,219) against DNA gyrase and topoisomerase IV mutants of Streptococcus pneumoniae selected in vitro.

The MICs of trovafloxacin, ciprofloxacin, ofloxacin, and sparfloxacin at which 90% of isolates are inhibited for 55 isolates of pneumococci were 0.125, 1, 4, and 0.5 microgram/ml, respectively. Resistant mutants of two susceptible isolates were selected in a stepwise fashion on agar containing ciprofloxacin at 2 to 10 times the MIC. While no mutants were obtained at the highest concentration tested, mutants were obtained at four times the MIC of ciprofloxacin (4 micrograms/ml) at a frequency of 1.0 x 10(-9). Ciprofloxacin MICs for these first-step mutants ranged from 4 to 8 micrograms/ml, whereas trovafloxacin MICs were 0.25 to 0.5 microgram/ml. Amplification of the quinolone resistance-determining region of the grlA (parC; topoisomerase IV) and gyrA (DNA gyrase) genes of the parents and mutants revealed that changes of the serine at position 80 (Ser80) to Phe or Tyr (Staphylococcus aureus coordinates) in GrlA were associated with resistance to ciprofloxacin. Second-step mutants of these isolates were selected by plating the isolates on medium containing ciprofloxacin at 32 micrograms/ml. Mutants for which ciprofloxacin MICs were 32 to 256 micrograms/ml and trovafloxacin MICs were 4 to 16 micrograms/ml were obtained at a frequency of 1.0 x 10(-9). Second-step mutants also had a change in GyrA corresponding to a substitution in Ser84 to Tyr or Phe or in Glu88 to Lys. Trovafloxacin protected from infection mice whose lungs were inoculated with lethal doses of either the parent strain or the first-step mutant. These results indicate that resistance to fluoroquinolones in S. pneumoniae occurs in vitro at a low frequency, involving sequential mutations in topoisomerase IV and DNA gyrase. Trovafloxacin MICs for wild-type and first-step mutants are within clinically achievable levels in the blood and lungs of humans.     

In vitro activity of the new fluoroquinolone CP-99,219.

The in vitro activity of the new fluoroquinolone CP-99,219 [7-(3-azabicyclo[3.1.0]hexyl)naphthyridone] was compared with those of four other quinolones against 541 gram-negative, 283 gram-positive, and 70 anaerobic bacterial isolates. CP-99,219 inhibited 90% of many isolates in the family Enterobacteriaceae at a concentration of < or = 0.25 micrograms/ml (range, < 0.008 to 1 microgram/ml), an activity comparable to those of tosufloxacin and sparfloxacin and two times greater than that of temafloxacin. Ninety percent of the Proteus vulgaris, Providencia rettgeri, Providencia stuartii, and Serratia marcescens isolates were inhibited by 0.5 to 2 micrograms of CP-99,219 per ml. CP-99,219 inhibited 90% of the Pseudomonas aeruginosa and Haemophilus influenzae isolates at 1 and 0.015 micrograms/ml, respectively. The compound inhibited methicillin-susceptible Staphylococcus aureus at 0.06 micrograms/ml, whereas a ciprofloxacin concentration of 1 microgram/ml was required to inhibit these organisms. CP-99,219 inhibited 90% of methicillin-resistant S. aureus isolates at a concentration of < or = 4 micrograms/ml, while ciprofloxacin and temafloxacin had MICs against these isolates of > 16 micrograms/ml. Streptococci were inhibited by < or = 0.25 micrograms/ml, an activity comparable to that of tosufloxacin. CP-99,219 was eight times more active than ciprofloxacin against Streptococcus pneumoniae. Bacteroides species were inhibited by CP-99,219 at a concentration of 2 micrograms/ml, whereas inhibition of these species required 4- and 16-microgram/ml concentrations of tosufloxacin and ciprofloxacin, respectively. The MBCs of CP-99,219 ranged from two to four times the MICs, and inoculum size had a minimal effect on MIC. CP-99,219 was active against P. aeruginosa at pH 5.5, with only a fourfold increase in MIC compared with values obtained at pH 7.5. The addition of up to 9 mM Mg(2+) increased the MIC range from 0.03 to 0.06 microgram/ml to 0.12 to 0.5 microgram/ml. In view of its excellent in vitro activity against both gram-positive and gram-negative bacteria, CP-99,219 merits further study to determine it's clinical pharmacologic properties and potential for therapeutic use.     

Pharmacokinetic studies of CP-74,667, a new quinolone, in laboratory animals.

The pharmacokinetics of CP-74,667 (7-(8'-methyl-3',8'-diazabicyclo[3.2.1]oct-3'-yl)-1-cyclopropyl-6- fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid) were studied following oral or parenteral administration in mice, rats, rabbits, dogs, and cynomolgus monkeys. The mean peak levels of CP-74,667 in serum following a single oral dose of 20 mg/kg of body weight were similar in all species, with a range of 3.7 micrograms/ml in mice to 5.6 micrograms/ml in dogs. In contrast, elimination half-lives were species dependent, with mean values of 2.1, 1.8, 4.5, 7.8, and 13.1 h in mice, rats, rabbits, dogs, and monkeys, respectively. The oral bioavailability of CP-74,667 was 100% in dogs and monkeys, as determined by intravenous-oral crossover experiments. The maximum concentration of drug in serum and area under the concentration-time curve (AUC) of CP-74,667 in dogs were proportional to dose over the range of 5 to 40 mg/kg. Accumulation of drug in serum was observed following the administration of four once-a-day doses of 7.1 mg/kg in monkeys (mimicking a 500-mg human dose), with significant increases in half-life, maximum and minimum concentrations of drug in serum, and AUC. The good tissue penetration of CP-74,667 suggested by a volume of distribution in excess of 2 liters/kg in dogs and monkeys was confirmed by tissue distribution studies with the same species, which demonstrated tissue concentrations (except for those in brain tissue) greater than 1.45 times higher than corresponding levels in serum. The mean urinary recoveries of unchanged drug were 17.7% in rats, 7.8% in monkeys, and 4.9% in dogs. Metabolism studies in dogs, following intravenous dosing, indicated that renal excretion of CP-74,667-related materials accounted for 41.6% of the administered dose, while biliary recoveries accounted for 6.8%. The CP-74,667 N-oxide metabolite was the primary drug-related material eliminated via renal excretion (37.2% of dose). The pharmacokinetics of CP-74,667 describe a quinolone with complete oral absorption, linear pharmacokinetics, a long elimination half-life, and wide distribution into tissues.     

In vitro antimicrobial activity of CP-99,219, a novel azabicyclo-naphthyridone.

CP-99,219 is a trifluoronaphthyridone with significant antibacterial activity that includes the family Enterobacteriaceae (MICs for 90% of the strains tested [MIC90s], < or = 0.015 to 0.5 micrograms/ml), Moraxella catarrhalis, Haemophilus influenzae, and gonococci (MICs, < or = 0.015 micrograms/ml). Legionella spp. were also CP-99,219 susceptible, with MICs of 0.008 to 0.12 micrograms/ml. CP-99,219 demonstrated activity greater than that of ciprofloxacin, ofloxacin, or enoxacin against Pseudomonas aeruginosa (MIC90, 1 microgram/ml), Xanthomonas maltophilia (MIC90, 2 micrograms/ml), Staphylococcus haemolyticus (MIC90, 0.5 micrograms/ml), Enterococcus faecalis (MIC90, 1 microgram/ml), and pneumococci (MIC90, 0.12 micrograms/ml). Numerous ciprofloxacin-resistant isolates were susceptible to CP-99,219, a new compound showing potential value for further in vivo trials.     

In vitro activity of a new fluoroquinolone, CP-99,219, against strains of Neisseria gonorrhoeae.

The susceptibilities of 216 strains of Neisseria gonorrhoeae to a new fluoroquinolone, CP-99,219 were determined. For strains for which the MICs of ciprofloxacin were < or = 0.06 microgram/ml, the MICs at which 90% of the isolates are inhibited (MIC90s) of CP-99,219, ciprofloxacin, and ofloxacin were 0.008, 0.015, and 0.03 microgram/ml, respectively. For strains for which the MICs of ciprofloxacin were 0.125 to 0.5 microgram/ml, the MIC90s of CP-99,219, ciprofloxacin, and ofloxacin were 0.06, 0.25, and 0.5 microgram/ml, respectively. For strains for which the MICs of ciprofloxacin and ofloxacin were 2.0 micrograms/ml, the MIC of CP-99,219 was 0.25 microgram/ml.     

In vitro activity of CP-99,219, a new fluoroquinolone, against clinical isolates of gram-positive bacteria.

The in vitro activity of the fluoroquinolone CP-99,219 against gram-positive bacteria was compared with those of five other antimicrobial agents. Against ciprofloxacin-susceptible staphylococci and against streptococci, MICs were < or = 0.12 and < or = 0.5 microgram/ml, respectively. CP-99,219 was also more active than ciprofloxacin against ciprofloxacin-resistant staphylococci, most enterococci, Leuconostoc spp., and lactobacilli.     

Evaluation of CP-99,219, a new fluoroquinolone, for treatment of experimental penicillin- and cephalosporin-resistant pneumococcal meningitis.

CP-99,219 is a new fluoroquinolone that has excellent activity against gram-positive organisms including penicillin- and cephalosporin-resistant Streptococcus pneumoniae strains. In our well-established rabbit model of meningitis, we conducted experiments to determine the concentrations of CP-99,219 in cerebrospinal fluid (CSF) after intravenous administration and its ability to eradicate two penicillin-resistant pneumococcal isolates. The peak and trough concentrations of CP-99,219 in the CSF were from 19 to 25% of the concentrations simultaneously obtained in serum and were unaffected by concomitant dexamethasone administration. Compared with untreated (control) animals, three doses of CP-99,219 given 5 h apart significantly reduced the bacterial count in CSF by 5 to 6 log10 CFU at 10 h. Although 47% of the dexamethasone-treated animals and 18% of those not given the steroid had positive cultures at 24 h (14 h after administration of the last antibiotic dose), the mean bacterial counts did not change from those observed at 10 h. Additionally, only results for animals infected with one of the two pneumococcal strains appeared to be affected by concomitant dexamethasone therapy.     

Pharmacokinetics of KRM-1648, a new benzoxazinorifamycin, in rats and dogs.

The pharmacokinetics of 3'-hydroxy-5'-(4-isobutyl-1-piperazinyl) benzoxazinorifamycin (KRM-1648) in rats and dogs given a single oral dose of 3, 30, or 100 mg/kg of body weight were studied. In the rats, the concentrations of KRM-1648 in plasma, whole blood, and tissues peaked between 2.0 and 24.0 h, with elimination half-lives ranging from 6.2 to 19.5 h. The peak concentrations and the areas under the concentration-versus-time curves (AUC) for whole blood and tissues were 2 to 277 times higher than those for plasma. The high levels of KRM-1648 in tissues were consistent with its large volume of distribution (in excess of 10 liters/kg). A nonlinear increase in peak concentrations and AUCs for plasma, whole blood, and tissues occurred as the dose was increased and was consistent with the dose-dependent decrease in bioavailability. In the dogs, KRM-1648 levels in plasma and whole blood also exhibited a late time to the peak concentration (ranging from 4.0 to 11.2 h), a long elimination half-life (ranging from 15.2 to 24.0 h), and nonlinear kinetics. KRM-1648 exhibited high levels of plasma protein binding (more than 99%) and a high degree of affinity for lipoproteins in the plasma of both animals. After administration of KRM-1648, measurable levels of its metabolites, 25-deacetyl KRM-1648 in rats and 25-deacetyl KRM-1648 and 30-hydroxy KRM-1648 in dogs, were found in the biological samples tested. Thus, KRM-1648 is characterized by a high tissue affinity, a long elimination half-life, and nonlinear pharmacokinetics.     

Comparative in vitro activities of trovafloxacin (CP-99,219) against 221 aerobic and 217 anaerobic bacteria isolated from patients with intra-abdominal infections.

Four hundred thirty-eight bacteria cultured from specimens of patients with serious intra-abdominal infections were tested by agar dilution against trovafloxacin and other quinolones and antimicrobial agents. Trovafloxacin inhibited 435 strains (99.3%) at < or =2 microg/ml. All the quinolones had similar activities against Enterobacteriaceae and Pseudomonas sp., but trovafloxacin showed superior activities against streptococci, enterococci, and anaerobic organisms. Because of its excellent in vitro activities against diverse bacteria, trovafloxacin has potential use as a single agent for polymicrobial infections.     

Comparative in vitro activities of trovafloxacin (CP-99,219) against 445 gram-positive isolates from patients with endocarditis and those with other bloodstream infections.

The in vitro activity of trovafloxacin (CP-99,219), a new fluoroquinolone, was compared with the in vitro activities of other commonly used quinolones and other antimicrobial agents against 445 gram-positive microorganisms isolated between 1986 and 1995 from patients with endocarditis and those with other bloodstream infections. The MICs at which 90% of the isolates are inhibited (MIC90) of trovafloxacin for methicillin-susceptible staphylococci, viridans group streptococci, and enterococci were 0.06, 0.25, and 0.5 mg/liter, respectively. The MIC90 of trovafloxacin for vancomycin-resistant enterococci as well as for methicillin-resistant Staphylococcus aureus and methicillin-susceptible and ciprofloxacin-resistant S. aureus, isolated from sources other than blood, was 1 mg/liter. For the quinolones the rank order of activity was trovafloxacin > sparfloxacin > ciprofloxacin = ofloxacin > pefloxacin. Depending on the species tested, trovafloxacin was 4- to 64-fold more active than ciprofloxacin. Further experimental and in vivo studies are warranted to evaluate the efficacy of trovafloxacin in the treatment of bacterial endocarditis and other infections caused by gram-positive organisms.     

Pharmacokinetics of SCH 56592, a new azole broad-spectrum antifungal agent, in mice, rats, rabbits, dogs, and cynomolgus monkeys

SCH 56592 is a new broad-spectrum azole antifungal agent that is in phase 3 clinical trials for the treatment of serious systemic fungal infections. The pharmacokinetics of this drug candidate were evaluated following its intravenous (i.v.) or oral (p.o.) administration as a solution in hydroxypropyl-beta-cyclodextrin (HPbetaCD) or oral administration as a suspension in 0.4% methylcellulose (MC) in studies involving mice, rats, rabbits, dogs, and cynomolgus monkeys. SCH 56592 was orally bioavailable in all species. The oral bioavailability was higher with the HPbetaCD solution (range, 52 to approximately 100%) than from the MC suspension (range, 14 to 48%) and was higher in mice ( approximately 100% [HPbetaCD] and 47% [MC]), rats ( approximately 66% [HPbetaCD] and 48% [MC]), and dogs (72% [HPbetaCD] and 37% [MC]) than in monkeys (52% [HPbetaCD] and 14% [MC]). In rabbits, high concentrations in serum suggested good oral bioavailability with the MC suspension. The i.v. terminal-phase half-lives were 7 h in mice and rats, 15 h in dogs, and 23 h in monkeys. In rabbits, the oral half-life was 9 h. In species given increasing oral doses (mice, rats, and dogs), serum drug concentrations were dose related. Food produced a fourfold increase in serum drug concentrations in dogs. Multiple daily doses of 40 mg of SCH 56592/kg of body weight for eight consecutive days to fed dogs resulted in higher concentrations in serum, indicating accumulation upon multiple dosing, with an accumulation index of approximately 2.6. Concentrations above the MICs and minimum fungicidal concentrations for most organisms were observed at 24 h following a single oral dose in MC suspension in all five species studied (20 mg/kg for mice, rats, and rabbits and 10 mg/kg for dogs and monkeys), suggesting that once-daily administration of SCH 56592 in human subjects would be a therapeutically effective dosage regimen.     

Pharmacokinetics of the cephalosporin SM-1652 in mice, rats, rabbits, dogs, and rhesus monkeys.

The pharmacokinetics of SM-1652 were studied in mice, rats, rabbits, dogs, and rhesus monkeys. The plasma half-lives of SM-1652, administered intravenously at a dose of 20 mg/kg, were 11.0 min in mice, 26.0 min in rats, 65.8 min in rabbits, 72.6 min in dogs, and 150.9 min in monkeys. The 24-h urinary excretion of SM-1652 was 30 to 35% of the dose in mice and rats, 70 to 75% in rabbits and dogs, and 45% in monkeys. Biliary excretion of the antibiotic over a 24-h period was 60 and 19% in rats and rabbits, respectively; it was 19% in dogs over a 9-h period after SM-1652 administration. Approximately 95% of the intravenous dose of SM-1652 was recovered as the unchanged form in the urine and bile of rats and rabbits. The binding of SM-1652 to serum protein was 44.0% in mice, 46.0% in rats, 90.4% in rabbits, 93.2% in monkeys, 30.0% in dogs, and 96.3% in humans.     

Activity of trovafloxacin (CP-99,219) against Legionella isolates: in vitro activity, intracellular accumulation and killing in macrophages, and pharmacokinetics and treatment of guinea pigs with L. pneumophila pneumonia.

The activity of trovafloxacin against 22 clinical Legionella isolates was determined by broth microdilution susceptibility testing. The trovafloxacin concentration required to inhibit 90% of strains tested was < or = 0.004 micrograms/ml, in contrast to 0.032 micrograms/ml for ofloxacin. In guinea pig alveolar macrophages, trovafloxacin achieved intracellular levels up to 28-fold over the extracellular concentration, which was similar to the levels obtained with erythromycin. Trovafloxacin (0.25 micrograms/ml) reduced bacterial counts of two L. pneumophila strains grown in guinea pig alveolar macrophages by > 2 log10 CFU/ml, without regrowth, under drug-free conditions over a 3-day period; trovafloxacin was significantly more active than ofloxacin or erythromycin (0.25 to 1 microgram/ml) in this assay. Single-dose (10 mg of prodrug CP-116,517-27 per kg of body weight given intraperitoneally [i.p.], equivalent to 7.5 mg of trovafloxacin per kg) pharmacokinetic studies performed in guinea pigs with L. pneumophila pneumonia revealed peak serum and lung trovafloxacin levels to be 3.8 micrograms/ml and 5.0 micrograms/g, respectively, at 0.5 h and 4.2 micrograms/ml and 2.9 micrograms/g, respectively, at 1 h. Administration of a lower prodrug dose (1.4 mg of trovafloxacin equivalent per kg i.p.) gave levels in lung and serum of 0.4 microgram/g and 0.4 microgram/ml, respectively, 1 h after drug administration. The terminal half-lives of elimination from serum and lung were 0.8 and 1.1 h, respectively. All 15 infected guinea pigs treated for 5 days with CP-116,517-27 once daily (10 mg/kg/day i.p., equivalent to 7.5 mg of trovafloxacin per kg/day) survived for 10 days after antimicrobial therapy, as did all 15 guinea pigs treated with ofloxacin once daily (10 mg/kg/day i.p.) for 5 days. None of 13 animals treated with saline survived. In a second experiment with animals, trovafloxacin (1.4 mg/kg/day i.p. for 5 days) protected all 16 guinea pigs from death, whereas all 15 animals treated with saline died. Trovafloxacin is an effective antimicrobial agent against Legionella in vitro and in vivo, with the ability to concentrate in macrophages and kill intracellular organisms.