In vitro pharmacokinetic and pharmacodynamic evaluation of S-013420 against Haemophilus influenzae and Streptococcus pneumoniae.

The pharmacokinetic (PK)/pharmacodynamic (PD) parameters and the antibacterial activity of S-013420, a novel bicyclolide, against Haemophilus influenzae and Streptococcus pneumoniae, including macrolide-resistant isolates, were investigated using an in vitro PD model. Various time-concentration curves were artificially constructed by modifying the PK data obtained in phase I studies. The activity against H. influenzae was evaluated using two parameters, that is, the area above the killing curve (AAC) and the viable cell reduction at 24 h. The relationships between the antibacterial activity of S-013420 and the three PK/PD parameters were investigated by fitting the data to the sigmoid maximum effective concentration model. The square of the correlation coefficient (R(2)) values for AAC versus the area under the concentration-time curve from 0 to 24 h (AUC(0-24))/MIC, the peak concentration (C(max))/MIC, and the cumulative percentage of a 24-h period that the drug concentration exceeded the MIC under steady-state PK conditions (%T(MIC)) were 0.92, 0.87, and 0.49, respectively. The R(2) values for viable cell reduction at 24 h versus AUC(0-24)/MIC, C(max)/MIC, and %T(MIC) were 0.93, 0.61, and 0.56, respectively. These results demonstrated that AUC(0-24)/MIC is the most significant parameter for evaluation of the antibacterial activity of S-013420. The values of AUC(0-24)/MIC required for maximum and static efficacy were 10.8 and 9.63, respectively, for H. influenzae and 16.3 to 22.3 and 4.66 to 9.01, respectively, for S. pneumoniae. This analysis is considered useful for determining the AUC value at the infection site, which would be required for efficacy in clinical use.

In vitro antibacterial activities of S-013420, a novel bicyclolide, against respiratory tract pathogens.

OBJECTIVES: The in vitro activity of S-013420, a novel bicyclolide, was investigated. METHODS: All test strains for this study were isolated from Japanese medical facilities. MICs were determined by the microbroth dilution method or agar dilution method according to the CLSI guidelines. In time-kill kinetics, viable cells were measured at 1, 2.5, 4 and 6 h after exposure to antimicrobials. The frequencies of single-step resistance acquisition at 4x MIC and 8x MIC were determined using 10(7) cfu of bacterial cells. RESULTS: S-013420 showed MIC(90) values of 0.125, 0.125, 8 and 0.5 mg/L for Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus influenzae and Moraxella catarrhalis, respectively. S-013420 showed the most potent activity against erythromycin-intermediate and -resistant S. pneumoniae with an MIC(90) of 0.25 mg/L and inhibited the growth of all strains of S. pyogenes with macrolide resistance genes at 1 mg/L. The MICs of S-013420 for atypical pathogens such as erythromycin-susceptible Mycoplasma pneumoniae and Chlamydophila pneumoniae were 0.00049-0.001 and 0.0039 mg/L, respectively, although the activity of S-013420, as well as other macrolide agents, against erythromycin-resistant M. pneumoniae was significantly weak. S-013420 caused a 3 log(10) reduction in viable cells against all test strains of S. pneumoniae and H. influenzae. Acquisition of resistance to S-013420 was not observed for three strains of S. pneumoniae. CONCLUSIONS: S-013420 shows potent in vitro activity against respiratory tract pathogens. Against streptococci, including erythromycin-resistant strains, S-013420 demonstrated the most potent in vitro activity among the antimicrobials tested.

Pharmacokinetics and disposition of CS-023 (RO4908463), a novel parenteral carbapenem, in animals.

The distribution, metabolism, and excretion of CS-023 (RO4908463), a new carbapenem, were investigated in rats and monkeys after a single intravenous administration of [(14)C]CS-023. In addition, the drug's pharmacokinetics were examined in rats, dogs, and monkeys. Whole-body autoradioluminograms of rats indicated that the radioactivity is distributed throughout the body immediately after administration except for the central nervous system and testes. The highest radioactivity was found in the kidneys, which are responsible for the excretion of CS-023. R-131624 with an open beta-lactam ring, the pharmacologically inactive form, was detected in the plasma and urine as the major metabolite. In rat plasma, the R-131624 levels became higher than CS-023 levels at 30 min postdose and thereafter, while in monkey plasma, CS-023 accounted for most of the radioactivity, with low levels of R-131624. More than 80% of the radioactivity administered was recovered in the urine, and CS-023 and R-131624 accounted for 29.6% and 31.4%, respectively, of the dose in rats and 51.2% and 18.5%, respectively, of the dose in monkeys. The faster metabolism to R-131624 in rats than in monkeys was likely due to the metabolism by dehydropeptidase I in rat lungs. The plasma elimination half-life of CS-023 was 0.16 h in rats, 0.75 h in dogs, and 1.4 h in monkeys. There were no appreciable interspecies differences among the animals tested in either volume of distribution (172 to 259 ml/kg) or serum protein binding (5.0 to 15.6%). The total clearance in monkeys (1.62 ml/min/kg) was lower than that in rats (15.1 ml/min/kg) or dogs (4.19 ml/min/kg).

Pharmacokinetics of CS-023 (RO4908463), a novel parenteral carbapenem, in healthy male Caucasian volunteers.

The CS-023 concentration in plasma after administration by infusion to healthy volunteers at a dose of 700 mg was decreased, with a half-life of 1.7 h, and the cumulative urinary excretion was 59.4% of the dose. The total clearance, renal clearance, and volume of distribution were 8.12 liters/h, 4.14 liters/h, and 17.2 liters, respectively.

Antifungal activities of R-135853, a sordarin derivative, in experimental candidiasis in mice.

The activities of R-135853, a novel sordarin derivative that possesses a 1,4-oxazepane ring moiety, were evaluated in vitro and in vivo. R-135853 exhibited potent in vitro activities against Candida albicans (fluconazole-susceptible strains), Candida glabrata, Candida tropicalis, and Cryptococcus neoformans, with MICs at which 90% of isolates were inhibited of 0.03, 1, 0.5, and 0.5 microg/ml, respectively. R-135853 also exhibited potent activities against fluconazole-susceptible dose-dependent and fluconazole-resistant strains of C. albicans, with MICs ranging from 0.03 to 0.06 mug/ml. However, R-135853 exhibited weak or no activity against Candida parapsilosis, Candida krusei, and Aspergillus spp. R-135853 exhibited dose-dependent efficacy against experimental murine hematogenous candidiasis induced by C. albicans when it was administered by both the subcutaneous and the oral routes and reduced viable cell counts in the kidneys significantly when it was administered at 50 mg/kg of body weight/dose (administration three times a day). In this model, R-135853 also exhibited dose-dependent efficacy by single oral administration. Subcutaneous administration of R-135853 exhibited dose-dependent efficacy against experimental murine esophageal candidiasis induced by fluconazole-resistant C. albicans, against which fluconazole at 50 mg/kg/dose was ineffective, and reduced viable cell counts in the esophagus significantly when it was administered at 10 and 50 mg/kg/dose. R-135853 eradicated C. albicans from the esophagi of one and four of five mice when it was administered at 10 and 50 mg/kg/dose, respectively. These results suggest that R-135853 is promising for the treatment of disseminated or mucosal candidiasis, including fluconazole-refractory infections.

In vivo antibacterial activity of S-3578, a new broad-spectrum cephalosporin: methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa experimental infection models.

The in vivo antibacterial activity of S-3578, a new parental cephalosporin, was compared with those of cefepime, ceftriaxone, ceftazidime, imipenem-cilastatin, and vancomycin. The efficacy of S-3578 against systemic infections caused by methicillin-resistant Staphylococcus aureus (MRSA) SR3637 (50% effective dose [ED(50)], 7.21 mg/kg of body weight) was almost the same as that of vancomycin. In contrast, cefepime and imipenem-cilastatin were less active against this pathogen (ED(50)s, >100 and >100 mg/kg, respectively). S-3578 was the most effective compound against penicillin-resistant Streptococcus pneumoniae SR20946 (ED(50), 1.98 mg/kg). S-3578 (10 mg/kg) induced a significant reduction in the numbers of viable MRSA SR17764 and Pseudomonas aeruginosa SR10396 organisms in polymicrobial pulmonary infections. The therapeutic efficacy of S-3578 was more potent than that of the combination of vancomycin and ceftazidime. High levels of S-3578 were detected in plasma in vivo, and its efficacy against experimentally induced infections in mice caused by MRSA and P. aeruginosa reflected its potent in vitro activity. We conclude that S-3578 is a promising new cephalosporin for the treatment of infections caused by gram-positive and -negative bacteria, including MRSA and P. aeruginosa.

In vitro activity of S-3578, a new broad-spectrum cephalosporin active against methicillin-resistant staphylococci.

The in vitro antibacterial activity of S-3578, a new parenteral cephalosporin, against clinical isolates was evaluated. The MICs of the drug at which 90% of the isolates were inhibited were 4 micro g/ml for methicillin-resistant Staphylococcus aureus (MRSA) and 2 micro g/ml for methicillin-resistant Staphylococcus epidermidis, which were fourfold higher than and equal to those of vancomycin, respectively. The anti-MRSA activity of S-3578 was considered to be due to its high affinity for penicillin-binding protein 2a (50% inhibitory concentration, 4.5 micro g/ml). In time-kill studies with 10 strains each of MRSA and methicillin-susceptible S. aureus, S-3578 caused more than a 4-log(10) decrease of viable cells on the average at twice the MIC after 24 h of exposure, indicating that it had potent bactericidal activity. Furthermore, in population analysis of MRSA strains with heterogeneous or homogeneous resistance to imipenem, no colonies emerged from about 10(9) cells on agar plates containing twice the MIC of S-3578, suggesting the low frequency of emergence of S-3578-resistant strains from MRSA. S-3578 was also highly active against penicillin-resistant Streptococcus pneumoniae (PRSP), with a MIC(90) of 1 micro g/ml, which was comparable to that of ceftriaxone. S-3578 also had antibacterial activity against a variety of gram-negative bacteria including Pseudomonas aeruginosa, though its activity was not superior to that of cefepime. In conclusion, S-3578 exhibited a broad antibacterial spectrum and, particularly, had excellent activity against gram-positive bacteria including methicillin-resistant staphylococci and PRSP. Thus, S-3578 was considered to be worthy of further evaluation.

Efficacy of CS-758, a novel triazole, against experimental fluconazole-resistant oropharyngeal candidiasis in mice.

The therapeutic efficacy of CS-758, a novel triazole, was evaluated against experimental murine oropharyngeal candidiasis induced by Candida albicans with various susceptibilities to fluconazole. Against infections induced by strains with various susceptibilities to fluconazole, the efficacy of fluconazole was strongly correlated with the MIC of fluconazole, as measured by the NCCLS method, and agreed with the NCCLS interpretive breakpoints, suggesting that the efficacies of new drugs could be predicted by using this model. The results of the fungal burden study corresponded with the results of the histopathological study. CS-758 exhibited potent in vitro activity (MICs, 0.004 to 0.06 micro g/ml) against the strains used in this murine model including fluconazole-susceptible dose-dependent and fluconazole-resistant strains (fluconazole MICs, 16 to 64 micro g/ml). CS-758 exhibited excellent efficacy against the infections induced by all the strains including a fluconazole-resistant strain, and the reductions in viable cell counts were significant at 10 and 50 mg/kg of body weight/dose. Fluconazole was not effective even at 50 mg/kg/dose against infections induced by a fluconazole-resistant strain (fluconazole MIC, 64 micro g/ml). These results suggest that CS-758 is a promising compound for the treatment of oropharyngeal candidiasis including fluconazole-refractory infections.

In vitro and in vivo activities of CS-758 (R-120758), a new triazole antifungal agent.

The activity of CS-758 (R-120758), a new triazole antifungal agent, was evaluated and compared with those of fluconazole, itraconazole, and amphotericin B in vitro and with those of fluconazole and itraconazole in vivo. CS-758 exhibited potent in vitro activity against clinically important fungi. The activity of CS-758 against Candida spp. was superior to that of fluconazole and comparable or superior to those of itraconazole and amphotericin B. CS-758 retained potent activity against Candida albicans strains with low levels of susceptibility to fluconazole (fluconazole MIC, 4 to 32 microg/ml). Against Aspergillus spp. and Cryptococcus neoformans, the activity of CS-758 was at least fourfold superior to those of the other drugs tested. CS-758 also exhibited potent in vivo activity against murine systemic infections caused by C. albicans, C. neoformans, Aspergillus fumigatus, and Aspergillus flavus. The 50% effective doses against these infections were 0.41 to 5.0 mg/kg of body weight. These results suggest that CS-758 may be useful in the treatment of candidiasis, cryptococcosis, and aspergillosis.