Synergistic activity of the novel des-fluoro(6) quinolone, garenoxacin (BMS-284756), in combination with other antimicrobial agents against Pseudomonas aeruginosa and related species.

Non-fermentative Gram-negative bacteria (Pseudomonas aeruginosa, Burkholderia cepacia, Stenotrophomonas maltophilia and Acinetobacter spp.) are intrinsically less susceptible to many antimicrobial agents. Two-drug combinations have been used to treat infections caused by less susceptible pathogens.

In vitro and in vivo activities of a novel cephalosporin, BMS-247243, against organisms other than staphylococci.

BMS-247243, a novel cephalosporin inhibitory for methicillin-resistant staphylococci, primarily has activity against gram-positive bacteria. The activities of BMS-247243, cefotaxime, and ceftriaxone against streptococci and Streptococcus pneumoniae were similar. BMS-247243 inhibits Enterococcus faecalis but not Enterococcus faecium.

In vitro and in vivo activities of a novel cephalosporin, BMS-247243, against methicillin-resistant and -susceptible staphylococci.

The recent emergence of methicillin-resistant Staphylococcus aureus (MRSA) with decreased susceptibility to vancomycin has intensified the search for alternative therapies for the treatment of infections caused by this organism. One approach has been to identify a beta-lactam with improved affinity for PBP 2a, the target enzyme responsible for methicillin resistance in staphylococci. BMS-247243 is such a candidate, with MICs that inhibit 90% of isolates tested (MIC(90)s) of 4, 2, and 8 microg/ml for methicillin-resistant strains of S.

Bactericidal mechanism of gatifloxacin compared with other quinolones.

The quinolones differ in their mechanisms of bacterial killing. The rate of bacterial killing by quinolones can be influenced by the addition of bacterial protein or RNA synthesis inhibitors, and the growth phase of the bacterium. In this study, we compared the killing activities of gatifloxacin, trovafloxacin, ciprofloxacin and norfloxacin against staphylococci, pneumococci and Escherichia coli.

Synergistic activities of gatifloxacin in combination with other antimicrobial agents against Pseudomonas aeruginosa and related species.

Drug combinations have been used to treat serious infections caused by Pseudomonas, Burkholderia, Stenotrophomonas, and Acinetobacter. In this study, the combined drug effects of gatifloxacin (GAT) and nonquinolones were determined by time-kill analysis at clinically achievable drug concentrations. Synergy (>or=2 log(10)-enhanced killing at 24 h) was observed with GAT plus amikacin or a beta-lactam against 50 to 75% of strains, including strains nonsusceptible to one or both drugs.

Correlation between genotype and phenotypic categorization of staphylococci based on methicillin susceptibility and resistance.

Positive correlation between methicillin and oxacillin susceptibility test results and the detection of the mecA gene was observed for Staphylococcus aureus, S. epidermidis, and S. haemolyticus as well as among mecA(+) strains of other species of coagulase-negative staphylococci (CNS).

Activity of gatifloxacin against strains resistant to ofloxacin and ciprofloxacin and its ability to select for less susceptible bacterial variants.

Gatifloxacin is an 8-methoxy fluoroquinolone. On quinolones, this side chain imparts increased activity against Gram-positive bacteria and enhanced killing. Gatifloxacin was tested against ofloxacin non-susceptible (ofloxacin MIC>2 mg/l) strains of Streptococcus pneumoniae (gatifloxacin MIC(90), 1 mg/l) and methicillin-resistant Staphylococcus aureus (MRSA, gatifloxacin MIC(90), 4 mg/l), and to ciprofloxacin non-susceptible (ciprofloxacin MIC>1 mg/l) strains of Escherichia coli (gatifloxacin MIC(90),>16 mg/l) and ciprofloxacin non-susceptible (ciprofloxacin MIC>0.

Comparative killing kinetics of the novel des-fluoro(6) quinolone BMS-284756, fluoroquinolones, vancomycin and beta-lactams.

The primary bactericidal classes used therapeutically as single agents, are the quinolones and the cell-wall active agents. In this study, their rates of killing were compared. The des-fluoro(6) quinolone BMS-284756 (T-3811ME), fluoroquinolones (trovafloxacin, levofloxacin) and cell wall-active agents (beta-lactams, vancomycin) were evaluated against Enterobacteriaceae, Staphylococcus aureus, streptococci, and Enterococcus faecalis.

Activity of gatifloxacin and ciprofloxacin in combination with other antimicrobial agents.

The influence of non-quinolone antimicrobial agents on the antibacterial activities of gatifloxacin and ciprofloxacin was determined using chequerboard, fractional inhibitory concentration, (FIC) and time-kill analysis methods. In the chequerboard method, the quinolones were tested in combination with ten antimicrobial agents (macrolides, aminoglycosides, beta-lactams, vancomycin, rifampicin and chloramphenicol) against five bacterial strains (one strain each of Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Enterococcus faecalis and Streptococcus pneumoniae). In no incidence was antagonism (FIC > or = 4) or synergy (FIC < or = 0.

Antibacterial spectrum of a novel des-fluoro(6) quinolone, BMS-284756.

The in vitro spectrum of a novel des-fluoro(6) quinolone, BMS-284756, was compared with those of five fluoroquinolones (trovafloxacin, moxifloxacin, levofloxacin, ofloxacin, and ciprofloxacin). BMS-284756 was among the most active and often was the most active quinolone against staphylococci (including methicillin-resistant strains), streptococci, pneumococci (including ciprofloxacin-nonsusceptible and penicillin-resistant strains), and Enterococcus faecalis. BMS-284756 inhibited approximately 60 to approximately 70% of the Enterococcus faecium (including vancomycin-resistant) strains and 90 to 100% of the Enterobacteriaceae strains and gastroenteric bacillary pathogens at the anticipated MIC susceptible breakpoint ( View Article and Find Full Text PDF

Comparative killing rates of fluoroquinolones and cell wall-active agents.

Killing rates of fluoroquinolones, beta-lactams, and vancomycin were compared against Enterobacteriaceae, Staphylococcus aureus, pneumococci, streptococci, and Enterococcus faecalis. The times required for fluoroquinolones to decrease viability by 3 log(10) were 1.5 h for Enterobacteriaceae, 4 to 6 h for staphylococci, and >/=6 h for streptococci and enterococci.

Antibacterial activity of BMS-180680, a new catechol-containing monobactam.

The in vitro activities of a new catechol-containing monobactam, BMS-180680 (SQ 84,100), were compared to those of aztreonam, ceftazidime, imipenem, piperacillin-tazobactam, ciprofloxacin, amikacin, and trimethoprim-sulfamethoxazole. BMS-180680 was often the most active compound against many species of the family Enterobacteriaceae, with MICs at which 90% of the isolates were inhibited (MIC90s) of < or = 0.5 microg/ml for Escherichia coli, Klebsiella spp.

Differences in the resistant variants of Enterobacter cloacae selected by extended-spectrum cephalosporins.

The rates of development of resistance to ceftriaxone, ceftazidime, cefepime, and cefpirome in 10 strains of Enterobacter cloacae were determined by daily transfer for 7 days to fresh medium containing twofold serial dilutions of the antibiotics. Development of resistance to ceftriaxone was the most rapid; this was followed by ceftazidime, cefpirome, and cefepime. Resistant variants selected by ceftriaxone and ceftazidime were cross-resistant and produced very high levels of beta-lactamase.

Structure-activity relationships of carbapenems that determine their dependence on porin protein D2 for activity against Pseudomonas aeruginosa.

A number of carbapenem derivatives were examined to determine the structure-activity relationships required for dependence on porin protein D2 for activity against Pseudomonas aeruginosa. As suggested by J. Trias and H.

Activity of carbapenem BMS-181139 against Pseudomonas aeruginosa is not dependent on porin protein D2.

The broad antipseudomonal spectrum of the carbapenem BMS-181139 includes clinical strains and laboratory mutants of Pseudomonas aeruginosa that are resistant to imipenem. Unlike other known carbapenems (meropenem, panipenem, biapenem, and BO-2727), which have reduced activity against imipenem-resistant strains of P. aeruginosa, BMS-181139 was equally active against imipenem-susceptible (D2-sufficient) and imipenem-resistant (D2-deficient) strains.

In vitro activity of BMS-181139, a new carbapenem with potent antipseudomonal activity.

The in vitro activities of the carbapenem BMS-181139 were determined in comparison with those of imipenem, meropenem, ciprofloxacin, ceftriaxone, and vancomycin. BMS-181139 was the most active against species of Pseudomonas and related genera Alteromonas and Burkholderia, with MICs for 147 of 149 isolates of < 4 micrograms/ml. Of 22 imipenem-resistant (MIC > 8 micrograms/ml) P.

Development of resistance in Pseudomonas aeruginosa to broad-spectrum cephalosporins via step-wise mutations.

Step-wise resistance to cefepime, ceftazidime, cefotaxime, and cefpirome were determined for 16 Pseudomonas aeruginosa strains by daily transfer for 7 days to fresh media containing two-fold serial dilution of antibiotic. By the third transfer 4 of 16 strains (25%) were resistant (MIC > or = 32 mg/L) to ceftazidime compared with none, five (31%) and ten (60%) strains becoming resistant to cefepime, cefpirome and cefotaxime (MIC > or = 64 mg/L), respectively. At the end of the 7 day serial transfer, only four (25%) of the 16 strains were resistant to cefepime, in contrast to nine (56%) cefpirome resistant, 12 (75%) ceftazidime resistant and 13 (81%) cefotaxime resistant.

The synthesis, antibacterial, and beta-lactamase inhibitory activity of a novel asparenomycin analog.

An analog, 6-(2'-hydroxyethylidene)-4 beta-methyl-1-azabicyclo[3.2.0]hept-2-ene-2- carboxylate (11), of the carbapenem beta-lactamase inhibitor, asparenomycin A, was synthesized.

Emergence of homogeneously methicillin-resistant Staphylococcus aureus.

Forty-seven clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA), collected between 1986 and 1990 from 29 institutions, were analyzed for susceptibility to various antibiotics. Twenty-six strains were homogeneously methicillin resistant (i.e.