ABSTRACT
RWJ-416457, an investigational pyrrolopyrazolyl-substituted oxazolidinone, inhibited the growth of linezolid-susceptible staphylococci, enterococci, and streptococci at concentrations of < or =4 microg/ml, generally exhibiting two- to fourfold-greater potency than that of linezolid. Time-kill studies demonstrated bacteriostatic effects for both RWJ-416457 and linezolid.
Subject(s)
Anti-Bacterial Agents/pharmacology , Oxazolidinones/pharmacology , Acetamides/chemistry , Anti-Bacterial Agents/chemistry , Drug Resistance, Bacterial , Enterococcus/drug effects , Linezolid , Microbial Sensitivity Tests , Molecular Structure , Oxazolidinones/chemistry , Staphylococcus/drug effects , Streptococcus/drug effectsABSTRACT
In vitro activities of erythromycin A, telithromycin, and two investigational ketolides, JNJ-17155437 and JNJ-17155528, were evaluated against clinical bacterial strains, including selected common respiratory tract pathogens. Against 46 macrolide-susceptible and -resistant Streptococcus pneumoniae strains, the MIC(90) (MIC at which 90% of the isolates tested were inhibited) of the investigational ketolides was 0.25 microg/ml, twofold lower than that of telithromycin and at least 64-fold lower than that of erythromycin A. Against erm(B)-containing pneumococci, the MIC(90) of all the ketolides was 0.06 microg/ml. The MIC(90) of the investigational ketolides against mef(A)-containing pneumococci or pneumococci with both mef(A) and erm(B) was 0.25 microg/ml, two-and fourfold lower, respectively, than that of telithromycin. In contrast, the MICs of the investigational ketolides against macrolide-resistant S. pneumoniae strains with ribosomal mutations were similar to or, in some cases, as much as eightfold higher than those of telithromycin. Against Haemophilus influenzae, MICs of all the ketolides were < or =2 microg/ml. Against three Moraxella catarrhalis isolates, the MIC of the ketolides was 0.25 microg/ml. The ketolides inhibited in vitro protein synthesis, with 50% inhibitory concentrations ranging from 0.23 to 0.27 microM. In time-kill studies against macrolide-susceptible and erm- or mef-containing pneumococci, the ketolides were bacteriostatic to slowly bactericidal, with 24-h log(10) decreases ranging from 2.0 to 4.1 CFU. Intervals of postantibiotic effects for the ketolides against macrolide-susceptible and -resistant S. pneumoniae were 3.0 to 8.1 h.
Subject(s)
Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Ketolides/pharmacology , Naphthyridines/pharmacology , Respiratory Tract Infections/microbiology , Colony Count, Microbial , Drug Resistance, Bacterial , Erythromycin/pharmacology , Haemophilus influenzae/drug effects , Humans , Ketolides/chemistry , Microbial Sensitivity Tests , Moraxella catarrhalis/drug effects , Naphthyridines/chemistry , Staphylococcus/drug effects , Streptococcus pneumoniae/drug effectsABSTRACT
A series of oxazolidinone antibacterial agents containing a 5-substituted isoxazol-3-yl moiety were synthesized via a nitrile oxide [3+2] dipolar cycloaddition reaction. These compounds were screened against a panel of susceptible and resistant Gram-positive organisms. Several analogs from this series were comparable to or more potent than linezolid in vitro.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Isoxazoles/chemical synthesis , Oxazolidinones/chemical synthesis , Animals , Anti-Bacterial Agents/pharmacology , Drug Evaluation, Preclinical/methods , Female , Isoxazoles/pharmacology , Mice , Microbial Sensitivity Tests/methods , Oxazolidinones/pharmacologyABSTRACT
Escherichia coli and Klebsiella pneumoniae isolates with extended-spectrum beta-lactamases (ESBLs) or AmpC cephalosporinases generally respond as predicted to NCCLS tests for ESBL production. However, inoculum size may affect MICs. The effect of inoculum level in clinical isolates expressing beta-lactamases were studied at inocula within 0.5 log unit of the standard inoculum, using broth microdilution methodology with ceftazidime, cefotaxime, cefepime, cefpodoxime, and aztreonam. Strains with TEM-1 or no beta-lactamases gave consistent MIC results with inocula of 10(5) and 10(6) CFU/ml. When the bacteria were screened for ESBL production and the lower inoculum was used, several strains with ESBLs, including CTX-M-10, TEM-3, TEM-10, TEM-12, TEM-6, SHV-18, and K1, gave false-negative results for one or more antimicrobial agents (MICs below the NCCLS screening concentration for detecting suspected ESBLs). When the higher inoculum was used, MICs of at least one antimicrobial agent increased at least fourfold in strains producing TEM-3, TEM-10, TEM-28, TEM-43, SHV-5, SHV-18, and K1. All antimicrobial agents showed an inoculum effect with at least one ESBL producer. Confirmatory clavulanate effects were seen for both inocula for all ESBL-producing strains with all antimicrobial agents tested, except for the CTX-M-10-producing E. coli with ceftazidime and the SHV-18-producing K. pneumoniae with cefotaxime. In kinetic studies, cefpodoxime and cefepime were hydrolyzed by ESBLs in a manner similar to that of cefotaxime. When total beta-lactamase activity and hydrolysis parameters were evaluated, however, no single factor was predictive of inoculum effects. These results indicate that the NCCLS screening and confirmation tests are generally predictive of ESBL production, but false-negative results can arise when a lower inoculum is used in testing.
Subject(s)
Bacterial Proteins , Escherichia coli/enzymology , Klebsiella pneumoniae/enzymology , beta-Lactamases/biosynthesis , Cephalosporins/metabolism , Drug Resistance, Bacterial , Escherichia coli/drug effects , Humans , Hydrolysis , Klebsiella pneumoniae/drug effects , Microbial Sensitivity Tests , Penicillin G/metabolismABSTRACT
A novel series of oxazolidinones containing a pyrroloaryl substituent was synthesized and screened against a representative panel of susceptible and resistant Gram-positive bacteria. Several members of this series were found to have antibacterial activity comparable to or better than linezolid.
