Martin A. Shapiro

In vitro evaluation of cefdinir (FK482), a new oral cephalosporin with enhanced antistaphylococcal activity and β-lactamase stability

Cefdinir (FK482), a new oral cephalosporin with enhanced beta-lactamase stability, was tested by microbroth dilution against respiratory, urogenital, and skin and skin-structure bacterial pathogens. Included were beta-lactamase (beta LAC)-producing and -nonproducing isolates. Activity was compared with that of other orally administered beta-lactams. Cefdinir minimum inhibitory concentrations for 90% of isolates MIC90s (microgram/ml) were < or = 0.5 versus beta LAC+/oxacillin-susceptible Staphylococcus, aureus, S. epidermidis, and S. saprophyticus; < or = 0.06 versus Streptococcus groups A and B, and Neisseria gonorrhoeae beta LAC+; 0.125 versus S. pneumoniae penicillin-susceptible and Proteus mirabilis beta LAC+; 0.25 versus beta LAC+ versus strains of Moraxella catarrhalis, Escherichia coli, Klebsiella pneumoniae, and K. oxytoca; 0.5 versus Haemophilus influenzae beta LAC-; 1 versus H. influenzae beta LAC+; 4 versus Legionella pneumophila beta LAC+; and 8 versus Enterococcus faecalis beta LAC-strains. Cefdinir was equally effective against both standard and high inocula of S. aureus strains producing A, B, C, or D beta LAC types. MICs were also generated versus quality-control reference strains.

Pharmacokinetics of Clinafloxacin Enantiomers in Humans

The pharmacokinetics of R‐clinafloxacin and S‐clinafloxacin enantiomers of the broad‐spectrum fluoroquinolone antibiotic, clinafloxacin, were characterized in selected volunteer subjects and patients after the administration of oral and intravenous doses of racemic drug. The absorption of each enantiomer was rapid and nearly complete after a single, oral 400 mg racemic dose. The mean (± SD) bioavailability of R‐clinafloxacin was 87.5% ± 4.8% compared to 86.2% ± 5.8% for S‐clinafloxacin. The mean Cmax of each enantiomer was 1.19 μg/mL, with plasma concentrations of each enantiomer remaining above 0.1 μg/mL for at least 12 hours. No notable differences in the disposition of R‐clinafloxacin and S‐clinafloxacin were observed. After a single 400 mg intravenous dose of racemic drug, mean (± SD) t1/2 was 5.6 ± 0.3 hours and 5.7 ± 0.4 hours, plasma Cl was 329 ± 49 mL/min and 314 ± 45 mL/min, and Vdss was 138 ± 18 L and 134 ± 16 L for R‐ and S‐clinafloxacin, respectively. Two healthy volunteers each received a single 400 mg oral dose of racemic clinafloxacin (alone) and with oral administration of 1 gm probenecid separated by a 1‐week washout period between treatments. With probenecid coadministration, the increase in AUC0‐∞; was 75% and 83% for R‐clinafloxacin and was 71% and 75% for S‐clinafloxacin in each subject, respectively. Probenecid increased the total exposure (AUC) of both R‐clinafloxacin and S‐clinafloxacin, although it had no stereo‐selective effects on the disposition of either enantiomer. The antimicrobial potency of the isomers was also evaluated. In vitro susceptibility testing showed that the two compounds were comparable in their inhibitory activities, as all MICs were within twofold for each organism tested. These results demonstrate that in addition to their similar antimicrobial potency, R‐ and S‐clinafloxacin have nearly identical disposition characteristics and are eliminated by similar mechanisms that display no apparent enantioselectivity in man.

Bacterial Two-Component Signalling as a Therapeutic Target in Drug Design

Bacterial resistance to the currently available antibiotics is a worldwide problem with catastrophic potential (Kunin, 1993; Berkowitz, 1995; Domagala and Sanchez, 1997). In the US, overall mortality from infectious diseases has increased 58% with deaths from respiratory infections and septicemia up 20 and 83% respectively (Pinner et al., 1996). Increased resistance has been documented for every major group of pathogens with methicillin resistant Staphyloccus aureus (MRSA), vancomycin resistant enterococci (VRE) and β-lactam resistant streptococci causing the greatest alarm (Cormican and Jones, 1996; Howe et al., 1996). In fact, VRE has been described as the most feared nosocomial pathogen today (Hagman and Strausbaugh, 1996). The fear of vancomycin resistant MRS A has sparked calls for stringent preemptive controls (Edmund et al., 1996). Equally alarming is the dramatic increase in resistance among the gram negative organisms (Jones, 1996). Nosocomial pneumonias (often with resistant organisms) occur in 0.5–5% of all hospitalized patients with a mortality of 20–70%, and an added annual cost of

A novel rapid throughput phototolerance screen in mice

2.5 billion for increased care and treatment (Gaynes and Lynch, 1991; Swartz, 1994). So great and urgent is the problem that the prestigious journal Science has devoted two issues to bacterial resistance (Travis, 1994; Koshland, 1992), and the American Society for Microbiology formed a Task Force to define the problem and make recommendations. Their insightful report, issued in 1995 (Report 1995), called for an increased effort in the discovery of new drugs and new drug targets in bacteria.

Comparative in-vitro activity of enoxacin against penicillinase- and non-penicillinase−producing Neisseria gonorrhoeae

A relatively simple, rapid throughput phototolerance screen in small animals would be very useful in early drug development. It could prioritize or select potential lead compounds from among a number of analogs with similar biological activities. This study describes an in vivo mouse phototolerance screen established for that purpose. It also reports phototolerance data with standard reference drugs obtained using this screen.

The Synthesis, Structure-Activity, and Structure-Side Effect Relationships of a Series of 8-Alkoxy- and 5-Amino-8-alkoxyquinolone Antibacterial Agents

The in-vitro antigonococcal activity of enoxacin was measured by a broth microdilution method. Comparisons were made with five clinically relevant marketed drugs against 23 clinical isolates of Neisseria gonorrhoeae, including several penicillinase producers as well as multiply resistant strains. Results showed that enoxacin possessed potent activity against all organisms tested, with MIC values ranging from less than or equal to 0.013 to 0.05 micrograms/ml.