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.

Pharmacokinetics and tissue penetration of a new carbapenem, doripenem, intravenously administered to laboratory animals.

The pharmacokinetic properties of doripenem following 20 mg/kg i.v. infusion were studied in various laboratory animals. The concentrations of doripenem in plasma, urine and tissue samples were determined by bioassay. Mean AUC0(0-infinityS) (microg x h/ml) and urinary recoveries (UR, %, 0-24 h) were 14.1 and 36.3 in mice, 9.3 and 42.1 in rats, 47.9 and 47.6 in rabbits, 78.6 and 83.1 in dogs and 44.1 and 51.0 in monkeys, respectively. In monkeys, with co-administration of probenecid, the mean AUC(0-infinity) of doripenem increased about 2.2 times and urinary excretion was delayed slightly. In mice, the doripenem level was highest in the blood plasma, followed by the kidney, liver, lung, heart and spleen. These doripenem levels in various tissues rapidly decreased and no accumulation was observed. Serum protein binding rates (%) of doripenem were 25.2 in mice, 35.2 in rats, 11.8 in rabbits, 10.2 in dogs, 6.1 in monkeys and 8.1 in humans, respectively.

Novel broad-spectrum and long-acting parenteral cephalosporins having an acyl cyanamide moiety at the C-3 terminal: Synthesis and structure-activity relationships.

A series of novel 7ß-[2-(2-aminothiazole-4-yl)-2-(Z)-(alkoxyimino)acetamido]-cephalosporins having pyridinium-linked acyl cyanamide at the C-3 position were prepared and their antibacterial activities and pharmacokinetics profiles were evaluated. Most of the compounds exhibited potent antibacterial activities against penicillin-resistant Streptococcus pneumoniae (PRSP) and ß-lactamase non-producing penicillin-resistant Haemophilus influenzae (BLNAR). Introduction of a propenyl group between the cephalospoin core and the side chains at the C-3 position improved the pharmacokinetics profile. Among these compounds, 7ß-[2-(2-aminothiazole-4-yl)-2-(Z)- (alkoxyimino)acetamido]-3-(pyridin-1-ium-1-yl)prop-1-en-1-yl)cephalosporins (32j) showed well-balanced antibacterial activity against S. pneumoniae and H. influenzae which included resistant strains and also other Gram-positive or Gram-negative pathogens. Furthermore, 32j showed a long half-life comparable to that of Ceftriaxone in mice and monkeys.

Pharmacodynamic assessment based on mutant prevention concentrations of fluoroquinolones to prevent the emergence of resistant mutants of Streptococcus pneumoniae.

The objective of this study was to investigate the relationship between pharmacokinetic and pharmacodynamic parameters, on the basis of the mutant prevention concentration (MPC) concept, and the emergence of resistant mutants of Streptococcus pneumoniae to fluoroquinolone antibacterials. Some clinical isolates with various MIC and MPC values of moxifloxacin and levofloxacin were exposed under conditions simulating the time-concentration curves observed when moxifloxacin (400 or 80 mg, once a day) or levofloxacin (200 mg, twice a day) was orally administered by using an in vitro pharmacodynamic model. The decrease in susceptibility was evaluated by altering the population analysis profiles after moxifloxacin or levofloxacin treatment for 72 h. When the area under the concentration-time curve from 0 to 24 h (AUC(0-24))/MPC and peak concentration (C(max))/MPC were above 13.41 and 1.20, respectively, complete eradication occurred and no decrease in susceptibility was observed. On the other hand, when AUC(0-24)/MPC and C(max)/MPC were below 0.84 and 0.08, respectively, the susceptibility decreased. However, the time inside the mutant selective window and the time above the MPC did not show any correlation with the decrease in susceptibility. These results suggest that AUC(0-24)/MPC and C(max)/MPC are important parameters for predicting the emergence of resistant mutants and that higher values indicate greater effectiveness.

Determination of erythromycin A in rat plasma and urine by high-performance liquid chromatography with chemiluminescence detection using Tris(2,2'-bipyridine)ruthenium(II).

A simple and sensitive method was developed for the determination of erythromycin A (EA), decladinosyl erythromycin A (dClEA) and erythromycin B (EB) in rat plasma and urine by high-performance liquid chromatography with electrogenerated chemiluminescence detection using Tris(2,2'-bipyridine)ruthenium(II). The recovery rates of EA, dClEA and EB were 97, 94 and 85% from rat plasma and 89, 83 and 93% from rat urine, respectively. The calibration curves were linear over the concentration ranges 0.05-5 microg/mL for plasma and 0.5-50 microg/mL for urine. The precision and accuracy for all analytes in rat plasma were < or =9.0 and -6.3-7.2%, and those in urine were < or =9.4% and -6.1-7.6%, respectively. This method proved to be a powerful tool for determination of EA, dClEA and EB concentrations in samples from rats.

A new type of ketolide bearing an N-aryl-alkyl acetamide moiety at the C-9 iminoether: synthesis and structure-activity relationships.

A new type of ketolide bearing an N-aryl-alkyl acetamide moiety at the C-9 iminoether and its analogues were prepared, and their antibacterial activities and pharmacokinetic properties were evaluated. We found that the introduction of an (R)-alkyl group between the amide and iminoether groups could improve the pharmacokinetic properties while maintaining the activity against erythromycin-resistant Streptococcus pneumoniae. Among the ketolides prepared with the (R)-alkyl group, compound 5p with an N-(3-quinoxalin-6-yl-propyl)-propionamide moiety was found to have in vivo efficacy comparable to CAM with potent in vitro antibacterial activities against the key respiratory pathogens including Haemophilus influenzae and erythromycin-resistant S. pneumoniae.

A new type of ketolides bearing an N-aryl-alkyl acetamide moiety at the C-9 iminoether synthesis and structure-activity relationships.

A new type of ketolides, bearing an N-aryl-alkyl acetamide moiety at the C-9 iminoether and a cyclic carbonate at the C-11,12 position was prepared and the antibacterial activities of the compounds were evaluated. Some of the derivatives showed potent antibacterial activity against both Haemophilus influenzae and Streptococcus pneumoniae, which are clinically important respiratory tract pathogens. Among the derivatives prepared, compound 5s with a quinolin-4-yl moiety was found to have potent and well-balanced activity against S. pneumoniae and H. influenzae including erythromycin-resistant strains.

Determination of absolute configurations of light-atom molecules by means of direct detection of Bijvoet differences.

The absolute configurations of two light-atom molecules were determined sufficiently well by direct detection of Bijvoet differences. The compounds examined were (I) beta-cytidine C9H13N3O5 and (II) (S)-3-[(R)-4,4,4-Trifluoro-3-[4-methoxyphenyl]butanoyl]-4-(phenylmethyl)oxazolidin-2-one, C21H20NO4F3. Both compounds crystallize in orthorhombic system with the space group P2(1)2(1)2(1) and Z = 4. The crystal structures were carefully refined by the technique of conventional structure analysis. All possible reflections were measured on a laboratory diffractometer with Cu Kalpha radiation. The multiple-diffraction effect was often observed especially as remarkable intensity enhancement in weak reflections. After such unreliable reflections were eliminated by comparisons among the equivalent mates, data were averaged to a set of Bijvoet pairs. Afterwards, additional measurements by the psi-scan technique were tested. Since psi-scan data showed a slight systematic error probably owing to some shape-effect, an artificial absorption correction DIFABS was adopted to remove the error. Small but significant intensity differences could be detected for many Bijvoet pairs, and the absolute configurations were correctly determined without ambiguity in all cases. The R and wR values for separate refinements of enantiomorphs supported the results with slight differences. Flack parameters indicated no contradictions as well.

Slow-releasing potential of vancomycin-loaded porous hydroxyapatite blocks implanted into MRSA osteomyelitis.

Although antibiotic-loaded hydroxyapatite blocks have been used for the treatment of chronic osteomyelitis, their long-term potential for releasing antibiotic into human bones is not well known. Five patients with chronic osteomyelitis due to methicillin-resistant Staphylococcus aureus (MRSA) infection were effectively treated with local implantation of vancomycin-loaded hydroxyapatite blocks. Blocks were removed during the following reconstructive surgeries when the releasing capability of the blocks, and the bacteriocidal activity of the remaining vancomycin in these blocks could be evaluated. Vancomycin was rapidly released within 1 month after implantation, and by 3 months 90% of vancomycin had leaked from the blocks. At 18 months vancomycin still remained in a bacteriocidal form in the hydroxyapatite blocks, though the blocks had no releasing potential or the eluted vancomycin had been changed to a different form. Vancomycin-loaded porous hydroxyapatite blocks would be useful for the treatment of chronic osteomyelitis or implant-associated osteomyelitis due to MRSA.