In vitro antistaphylococcal activities of two investigative fluoroquinolones, CI-960 and WIN 57273, compared with those of ciprofloxacin, mupirocin (pseudomonic acid), and peptide-class antimicrobial agents.

By using broth microdilution, 373 clinical isolates of staphylococci were studied to determine their susceptibilities to CI-960, WIN 57273, ciprofloxacin, mupirocin, vancomycin, teicoplanin, and ramoplanin. Test strains comprised 179 strains of Staphylococcus aureus and 194 strains of coagulase-negative species. Strains of S. aureus were susceptible to CI-960, which had a mode MIC of 0.032 micrograms/ml and an MIC for 90% of the strains of 2 micrograms/ml. CI-960 was equally active against methicillin-susceptible and -resistant S. aureus strains as well as ciprofloxacin-resistant strains. Similarly, WIN 57273 was highly active, with a mode MIC of 0.008 micrograms/ml and an MIC for 90% of the strains of 1 micrograms/ml. No cross-resistance to CI-960 and WIN 57273 among ciprofloxacin-resistant strains was detected. Mupirocin was four- to eightfold more active than ramoplanin, vancomycin, and teicoplanin. With regard to coagulase-negative staphylococci, CI-960 and WIN 57273 were the most active of the test compounds, inhibiting all strains at 0.5 and 1 micrograms/ml, respectively. Against the same strains, mupirocin was fourfold more active than ramoplanin and eightfold more active than vancomycin. Five strains of S. haemolyticus were found to be resistant to ciprofloxacin, while resistance to teicoplanin was found among strains of S. epidermidis, S. haemolyticus, S. hominis, S. saprophyticus, S. simulans, S. warneri, and S. xylosus.     

In vitro evaluation of WIN 57273, a new broad-spectrum fluoroquinolone

WIN 57273 is a new fluoroquinolone that has an expanded spectrum of activity against Staphylococcus spp. (MIC for 90% of isolates [MIC90], 0.008 microgram/ml), Enterococcus faecalis (MIC90, 0.06 microgram/ml), Bacillus spp. (MIC90, 0.03 micrograms/ml), Listeria monocytogenes (MIC90, 0.06 microgram/ml), Streptococcus spp. (MIC90, 0.03 microgram/ml), and Bacteroides fragilis group strains (MIC90, 0.5 microgram/ml). Like other fluoroquinolone compounds, WIN 57273 was active against members of the family Enterobacteriaceae (97% of strains inhibited by less than or equal to 2 micrograms/ml), Haemophilus, Branhamella, and Neisseria strains (100% susceptible), Acinetobacter spp. (100% susceptible), and Pseudomonas aeruginosa (68% susceptible). We observed that WIN 57273 was very active against cephalosporin- or aminoglycoside-resistant gram-negative strains but shared cross-resistance with other fluoroquinolones. Increasing inoculum concentrations had minimal effects on WIN 57273 MICs, and the drug was considered to be bactericidal based on reference MBC and kill curve analyses. Unlike most previously studied drugs in this class, WIN 57273 had increased activity (three- to fourfold) at low pH. Rates of mutation to WIN 57273 resistance at eight times its MIC were in the range of 5.6 x 10(-8) to greater than 1.4 x 10(-9). This new compound possesses a wide potential spectrum of use, and it should be evaluated further by in vitro and in vivo studies.     

In vitro activity of T-3761, a new fluoroquinolone.

The in vitro activity of T-3761, a new fluoroquinolone antimicrobial agent which has an oxazine ring structure with a cyclopropyl moiety at C-10, was compared with those of other agents against 2,854 clinical isolates. T-3761 had a broad spectrum of activity and had potent activity against gram-positive and -negative bacteria. The MICs of T-3761 against 90% of the methicillin-susceptible Staphylococcus aureus, methicillin-susceptible and -resistant Staphylococcus epidermidis, and Clostridium spp. tested were 0.39 to 6.25 micrograms/ml. Its activity was comparable to those of ciprofloxacin and ofloxacin and four- to eightfold greater than those of norfloxacin and fleroxacin, but its activity was two- to eightfold less than that of tosufloxacin. Some isolates of ciprofloxacin-resistant S. aureus (MIC of ciprofloxacin, greater than or equal to 3.13 micrograms/ml) were still susceptible to T-3761 (MIC of T-3761, less than or equal to 0.78 micrograms/ml). The MICs of T-3761 against 90% of the streptococci and enterococci tested were 3.13 to 100 micrograms/ml. Its activity was equal to or 2- or 4-fold greater than those of norfloxacin and fleroxacin, equal to or 2- or 4-fold less than those of ofloxacin and ciprofloxacin, and 4- to 16-fold less than that of tosufloxacin. The activity of T-3761 against gram-negative bacteria was usually fourfold greater than those of norfloxacin, ofloxacin, and fleroxacin. Many isolates which were resistant to nonfluoroquinolone agents, such as minocycline- or imipenem-resistant S. aureus, ceftazidime-resistant members of the family Enterobacteriaceae, gentamicin- or imipenem-resistant Pseudomonas aeruginosa, and ampicillin-resistant Haemophilus influenzae and Neisseria gonorrhoeae, were susceptible to T-3761. The MBCs of T-3761 were either equal to or twofold greater than the MICs. The number of viable cells decreased rapidly during incubation with T-3761 at one to four times the MIC. At a concentration of four times the MIC, the frequencies of appearance of spontaneous mutants resistant to T-3761 against S. aureus, Escherichia coli, Serratia marcescens, and P. aeruginosa were 2.2 x 10(-8) to less than or equal to 1.2 x 10(-9). The 50% inhibitory concentrations of T-3761 for DNA gyrases isolated from E. coli and P. aeruginosa were 0.88 and 1.9 micrograms/ml, respectively.     

The activity of metal compounds against aerobic and anaerobic bacteria.

We evaluated the antimicrobial activity of two metal compounds, JM-1397 (OsO2[xylyl]2) and JM-2469 (AuCl[S2CPEt3]). Both inhibited methicillin-susceptible and methicillin-resistant Staphylococcus aureus at concentrations of 0.5-2 micrograms/ml, with a minimum inhibitory concentration (MIC90) of 1 microgram/ml for JM-1397 and 0.5 microgram/ml for JM-2469. Similar concentrations inhibited methicillin-susceptible and -resistant coagulase-negative staphylococci (S. epidermidis, S. haemolyticus, and S. saprophyticus). JM-2469 inhibited group A, B, C, F, and G beta-hemolytic streptococci and viridans group streptococci at 1-8 micrograms/ml (MIC90 4 micrograms/ml) but Enterococcus faecalis and E. faecium had MICs of 8-16 micrograms/ml. JM-1397 had MICs for these organisms of greater than 64 micrograms/ml. Bacteroides fragilis, other Bacteroides, and Clostridium species were inhibited by less than or equal to 0.12-4 micrograms/ml (MIC90, 0.5 microgram/ml). MICs of both compounds for Enterobacteriaceae and Pseudomonas spp. were greater than 64 micrograms/ml. These studies show that osmium and gold compounds have potential as topical agents against Gram-positive and anaerobic species.     

Bactericidal activity of the fluoroquinolone WIN 57273 against high-level gentamicin-resistant Enterococcus faecalis.

The fluoroquinolone WIN 57273 showed identical bactericidal activities (MBC for 90% of the strains = 0.25 micrograms/ml) for bacteremic strains of Enterococcus faecalis with and without high-level gentamicin resistance. WIN 57273 was bactericidal in time-kill measurements with highly gentamicin-resistant, ciprofloxacin-susceptible strains of E. faecalis. However, WIN 57273 was indifferent with penicillin for gentamicin-resistant E. faecalis and was not bactericidal for ciprofloxacin-resistant E. faecalis.     

In vitro activity of LY264826 compared to other glycopeptides and daptomycin.

LY264826 a new naturally occurring glycopeptide inhibited 90% of methicillin-susceptible and -resistant Staphylococcus aureus at 1 micrograms/ml. LY264826 had similar activity against methicillin-susceptible and -resistant coagulase-negative staphylococci. The LY264826 MIC90 for Streptococcus pyogenes was 0.25 microgram/ml, twofold more active than vancomycin and twofold less active than teicoplanin. LY264826 was eightfold more active than vancomycin and twofold more active than teicoplanin against enterococci. LY264826 inhibited Streptococcus pneumoniae at 0.25 microgram/ml and Listeria monocytogenes at 0.5 microgram/ml. Clostridium were inhibited by less than or equal to 0.25 microgram/ml of LY264826 and peptococci, peptostreptococci, and Fusobacterium were inhibited by less than 0.5 microgram/ml. Bacteroides species were LY284826 -resistant as were all Enterobacteriaceae, Flavobacterium, and Neisseria spp. Minimum bactericidal and inhibitory concentrations (MBCs and MICs) were within a dilution for S. aureus, S. pyogenes, and S. pneumoniae, but greater than or equal to 32-fold greater for enterococci.     

In vitro activity and beta-lactamase stability of a new penem, CGP 31608.

The in vitro activity of CGP 31608, a new penem, against aerobic and anaerobic organisms was evaluated and compared with those of other beta-lactams. CGP 31608 inhibited Escherichia coli, Klebsiella pneumoniae, K. oxytoca, Proteus mirabilis, Citrobacter diversus, and Salmonella, Shigella, Aeromonas, and Yersinia spp. with MICs for 50% of the strains (MIC50s) of 2 to 4 micrograms/ml and MIC90s of 4 micrograms/ml, compared with cefotaxime, ceftazidime, aztreonam, and imipenem MICs of less than 0.25 microgram/ml. MIC90s were 8 micrograms/ml for Enterobacter species and C. freundii, for which other agents had MICs of 32 micrograms/ml, except imipenem, which had equal activity. The MIC90 for Proteus vulgaris, Morganella morganii, Providencia stuartii, and Providencia rettgeri was 8 micrograms/ml, compared with less than 2 micrograms/ml shown by the other agents. Acinetobacter species resistant to other agents except imipenem were inhibited by 4 micrograms/ml, as were Pseudomonas aeruginosa, including piperacillin-, ceftazidime-, and gentamicin-resistant isolates. The MIC for P. cepacia, P. fluorescens, and P. acidovorans was less than or equal to 8 micrograms/ml, but that for P. maltophilia was greater than or equal to 128 micrograms/ml. Hemolytic streptococci A, B, C, G, and F were inhibited by less than 1 micrograms/ml, but the MIC for Streptococcus faecalis was greater than or equal to 32 micrograms/ml. MICs for Staphylococcus aureus methicillin-susceptible and -resistant strains were less than or equal to 1 microgram/ml, as were those for methicillin-susceptible and -resistant S. epidermidis. Bacteroides fragilis and Clostridium species and Fusobacterium spp. were inhibited by less than or equal to 4 micrograms/ml. CGP 31608 was not hydrolyzed by plasmid beta-lactamases TEM-1, TEM-2, SHV-1, PSE-1, OXA-2, PSE-4, or by S. aureus. Chromosomal beta-lactamases of type Ia in Enterobacter cloacae P99 and Morganella morganii, Ic in P. vulgaris, K-1 in K. oxytoca, and Id in P. aeruginosa also did not hydrolyze CGP 31608. It inhibited TEM-1, but the 50% inhibitory concentration was 14.2 micrograms/ml compared with 0.15 micrograms/ml for the P99 enzyme. CGP 31608 induced beta-lactamases in P. aeruginosa, E. cloacae, C. freundii and Providencia rettgeri, but there was no increase in MICs for the isolates and it did not select strains derepressed for beta-lactamase production. Synergy of CGP 31608 and gentamicin was found against 90% P. aeruginosa, 60% Enterobacter cloacae, and 50% Serratia marcescens strains. No synergy was found with rifampin. A postantibiotic effect was found against E. coli.     

In vitro activity of LY264826, a new glycopeptide antibiotic, against gram-positive bacteria isolated from patients with cancer.

The in vitro activity of LY264826, a novel glycopeptide antibiotic produced by Amycolatopsis orientalis, was compared with those of vancomycin, teicoplanin, and oxacillin against 311 gram-positive clinical isolates from patients with cancer, LY264826 had lower MICs for 90% of isolates (MIC90) than vancomycin for all species tested. It was active against oxacillin-resistant isolates including Staphylococcus aureus (MIC90, 0.5 micrograms/ml), Staphylococcus haemolyticus (MIC90, 2.0 micrograms/ml), Enterococcus spp. (MIC90, 0.5 micrograms/ml), Bacillus cereus (MIC90, 0.25 micrograms/ml), and Corynebacterium jeikeium (MIC90, 0.12 micrograms/ml). For S. aureus, including oxacillin-resistant isolates, the MICs of LY264826 were similar to those of teicoplanin. For coagulase-negative staphylococci, however, LY264826 had MICs that were 4- to 32-fold lower than those of teicoplanin. Against most streptococcal species the activities of LY264826 and teicoplanin were similar. Bactericidal activity against Staphylococcus spp. and most Streptococcus pyogenes isolates was less than or equal to 1 dilution of the MIC. One isolate of S. pyogenes and all Enterococcus faecalis strains tested were tolerant of LY264826, with MBCs greater than or equal to 32-fold greater than the MICs. The addition of 50% human serum resulted in a significant increase in activity only against Staphylococcus epidermidis. Variations in pH from 6.4 to 8.4 and in inoculum from 10(3) to 10(7) CFU/ml did not significantly affect the activity of LY264826.     

Activity of new quinolones against ciprofloxacin-resistant staphylococci.

Because of the development of newer fluoroquinolones with improved activity against gram-positive organisms, we elected to compare the inhibitory properties of ofloxacin, temafloxacin, sparfloxacin, PD131628, PD127391, and WIN57273 against 105 ciprofloxacin-resistant staphylococci. Based on comparison of MICs for 90% of the organisms (MIC90s), WIN57273 was the most active agent against oxacillin-resistant Staphylococcus aureus; the MIC90 was 0.5 microgram/ml. Against oxacillin-resistant, coagulase-negative staphylococci, PD127391 and WIN57273 were the most active agents; the MIC90 was 0.5 microgram/ml. Against isolates of staphylococci for which ciprofloxacin MICs were greater than or equal to 32 micrograms/ml, WIN57273 and PD127391 still exhibited high activity, inhibiting 100 and 95% of the isolates, respectively, at 2 micrograms/ml. The spontaneous mutation rates for ciprofloxacin-susceptible staphylococci were lowest for ofloxacin. The frequency of spontaneous mutations of ciprofloxacin-resistant staphylococci was low; however, the MICs of PD127391 and WIN57273 for these mutant isolates were greater than 2 micrograms/ml. WIN57273 and PD127391 are two potent new quinolones with high levels of activity against highly ciprofloxacin-resistant staphylococci. There is, however, a major concern of selection of spontaneous mutants resistant to these newer agents.     

In-vitro activity of WIN 57273 compared to the activity of other fluoroquinolones and two beta-lactam antibiotics.

WIN 57273, a new fluoroquinolone, was four to 128-fold more active than ciprofloxacin and ofloxacin against Gram-positive bacteria. The MIC90 for Staphylococcus aureus was 0.015 mg/l and for S. epidermidis, 0.03 mg/l. All Lancefield group A, B, C, & G streptococci, Streptococcus bovis and S. pneumoniae were inhibited by less than or equal to 0.06 mg/l compared to 0.5 mg/l for tosufloxacin and 2 mg/l for ciprofloxacin. For anaerobic bacteria WIN 57273 had an MIC90 for bacteroides of 1 mg/l, and for Clostridium spp. 0.015.mg/l. WIN 57273 was less active than ciprofloxacin against Enterobacteriaceae, with an MIC90 of 1 mg/l, including aminoglycoside and cephalosporin-resistant isolates. The MIC90 of WIN 57273 for Pseudomonas aeruginosa was 2 mg/l, compared to 0.5 mg/l for ciprofloxacin. Haemophilus influenzae, Moraxella catarrhalis, Neisseria gonorrhoeae, and Legionella spp. were inhibited by 0.06 mg/l. WIN 57273 was more active against Gram-negative bacteria at acid pH, but activity was decreased by magnesium ions and an increase in inoculum. Resistant strains were selected after passage on antibiotic-containing agar.     

In vitro activities of two ketolides, HMR 3647 and HMR 3004, against gram-positive bacteria

The in vitro activities of two new ketolides, HMR 3647 and HMR 3004, were tested by the agar dilution method against 280 strains of gram-positive bacteria with different antibiotic susceptibility profiles, including Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium, Streptococcus spp. (group A streptococci, group B streptococci, Streptococcus pneumoniae, and alpha-hemolytic streptococci). Seventeen erythromycin-susceptible (EMs), methicillin-susceptible S. aureus strains were found to have HMR 3647 and HMR 3004 MICs 4- to 16-fold lower than those of erythromycin (MIC at which 50% of isolates were inhibited [MIC50] [HMR 3647 and HMR 3004], 0.03 microgram/ml; range, 0.03 to 0.06 microgram/ml; MIC50 [erythromycin], 0.25 microgram/ml; range, 0.25 to 0.5 microgram/ml). All methicillin-resistant S. aureus strains tested were resistant to erythromycin and had HMR 3647 and HMR 3004 MICs of > 64 micrograms/ml. The ketolides were slightly more active against E. faecalis than against E. faecium, and MICs for individual strains varied with erythromycin susceptibility. The MIC50s of HMR 3647 and HMR 3004 against Ems enterococci (MIC < or = 0.5 microgram/ml) and those enterococcal isolates with erythromycin MICs of 1 to 16 micrograms/ml were 0.015 microgram/ml. E. faecalis strains that had erythromycin MICs of 128 to > 512 micrograms/ml showed HMR 3647 MICs in the range of 0.03 to 16 micrograms/ml and HMR 3004 MICs in the range of 0.03 to 64 micrograms/ml. In the group of E. faecium strains for which MICs of erythromycin were > or = 512 micrograms/ml, MICs of both ketolides were in the range of 1 to 64 micrograms/ml, with almost all isolates showing ketolide MICs of < or = 16 micrograms/ml. The ketolides were also more active than erythromycin against group A streptococci, group B streptococci, S. pneumoniae, rhodococci, leuconostocs, pediococci, lactobacilli, and diphtheroids. Time-kill studies showed bactericidal activity against one strain of S. aureus among the four strains tested. The increased activity of ketolides against gram-positive bacteria suggests that further study of these agents for possible efficacy against infections caused by these bacteria is warranted.     

Comparative in vitro activity of WIN 57273, a new fluoroquinolone antimicrobial agent.

The in vitro activity of WIN 57273, a new fluoroquinolone antimicrobial agent, was evaluated against approximately 600 bacterial isolates. The new drug was 4- to 128-fold more active than ciprofloxacin against a broad range of gram-positive organisms, with the new drug inhibiting 90% of strains of each species except Enterococcus faecium at concentrations of less than or equal to 0.25 microgram/ml. WIN 57273 was four- to eightfold less active than ciprofloxacin against many members of the family Enterobacteriaceae, but the MICs of the new drug for 90% of strains tested (MIC90s) were less than or equal to 8 micrograms/ml (range, 0.25 to 8 micrograms/ml) for all species. Branhamella catarrhalis, Haemophilus influenzae, Neisseria gonorrhoeae, and Legionella spp. were highly susceptible (MIC90s, less than or equal to 0.06 microgram/ml). WIN 57273 demonstrated excellent activity against anaerobes (MIC90s, less than or equal to 0.25 microgram/ml), and the drug was also more active than ciprofloxacin against 30 strains of Mycobacterium avium-M. intracellulare (MIC, 0.1 to 1.0 microgram/ml). The activity of WIN 57273 against gram-positive organisms was minimally affected by pH and increased at low pH (5.4) against gram-negative organisms. The bactericidal activity of WIN 57273 was demonstrated by time-kill techniques against selected organisms. The frequencies of spontaneous resistance to the new agent were low, but resistant colonies could be selected after serial passage of initially susceptible organisms through incremental concentrations of the drug.     

The comparative activity of fleroxacin, three other quinolones and eight unrelated antimicrobial agents.

The in vitro activity of fleroxacin, a new trifluorinated quinolone was evaluated against 432 bacterial isolates. Fleroxacin was 1- to 2-fold less active than ciprofloxacin and at least as active as ofloxacin and lomefloxacin against most members of the family Enterobacteriaceae. The MICs of fleroxacin for 90% of strains tested (MIC90) were < or = 0.25 micrograms/ml against all isolates of Enterobacteriaceae except Citrobacter freundii (MIC90, 4 micrograms/ml) and Serratia marcescens (MIC90, 2 micrograms/ml). Fleroxacin was as active as ciprofloxacin, ofloxacin and lomefloxacin against Pseudomonas spp, (MIC90 for all quinolones tested were > 8 micrograms/ml). Acinetobacter and Haemophilus influenzae were very susceptible to fleroxacin; however fleroxacin was 1-fold less active than lomefloxacin against Acinetobacter and at least 1-fold less active than ciprofloxacin or ofloxacin against H. influenzae. Methicillin-susceptible and -resistant strains of Staphylococcus epidermidis and methicillin-susceptible strains of S. aureus were very susceptible to fleroxacin, with an MIC90 < or = 1 microgram/ml (range 0.5-1 microgram/ml). Methicillin-resistant S. aureus and Staphylococcus spp. other than aureus and epidermidis were not susceptible to fleroxacin (MIC90 > 8 micrograms/ml). In addition, fleroxacin as well as ciprofloxacin, ofloxacin and lomefloxacin were inactive against Enterococcus spp. (MIC90 > 8 micrograms/ml). Streptococcus pneumoniae and S. pyogenes were resistant to both fleroxacin and lomefloxacin but were very susceptible to ciprofloxacin and ofloxacin. These results suggest that fleroxacin represents a valid therapeutic option in the treatment of infections caused by most Enterobacteriaceae and some species of staphylococcus.     

Antistaphylococcal activities of sparfloxacin (CI-978; AT-4140), ofloxacin, and ciprofloxacin.

The activity of sparfloxacin (CI-978; AT-4140) was compared with those of ofloxacin and ciprofloxacin against clinical isolates of Staphylococcus aureus and Staphylococcus epidermidis. All 10 ciprofloxacin-resistant staphylococci had reduced susceptibility to sparfloxacin and ofloxacin. Against 105 ciprofloxacin-susceptible strains of S. aureus, the sparfloxacin MIC for 90% of strains tested was at least fourfold lower than those of ciprofloxacin and ofloxacin, while against 104 ciprofloxacin-susceptible strains of S. epidermidis, the MIC of sparfloxacin for 90% of strains tested was twofold lower than that of ciprofloxacin and fourfold lower than that of ofloxacin. MBCs of sparfloxacin were less than or equal to 4 x MICs. The effects of inoculum size and pH variations, as well as the presence of serum, on the MICs of sparfloxacin were minimal. Subinhibitory concentrations of sparfloxacin did reduce adherence of S. epidermidis.     

WIN 57273 is bactericidal for Legionella pneumophila grown in alveolar macrophages.

The in vitro antimicrobial activity of WIN 57273, a new quinolone antimicrobial agent, was determined for 21 Legionella strains, using broth macrodilution and agar dilution testing methods; ciprofloxacin and erythromycin were tested as well. Three different buffered yeast extract media were used for the agar dilution studies, two of which were made with starch rather than charcoal. Broth macrodilution susceptibility testing was performed with buffered yeast extract broth and two Legionella pneumophila strains. Antimicrobial inhibition of L. pneumophila growth in guinea pig alveolar macrophages was also studied, using a method able to detect bacterial killing. The MICs for 90% of the 21 strains of Legionella spp. grown on buffered charcoal yeast extract medium were 0.125 microgram/ml for WIN 57273, 0.25 microgram/ml for ciprofloxacin, and 1.0 micrograms/ml for erythromycin. These MICs were falsely high, because of inhibition of drug activity by the medium used. Use of less drug-antagonistic, starch-containing media did not support good growth of the test strains. The broth macrodilution MICs for two strains of L. pneumophila serogroup 1 were less than or equal to 0.03 microgram/ml for WIN 57273 and ciprofloxacin and 0.125 microgram/ml for erythromycin. WIN 57273, ciprofloxacin, and erythromycin all inhibited growth of L. pneumophila in guinea pig alveolar macrophages at concentrations of 1 microgram/ml, but only WIN 57273 prevented regrowth or killed L. pneumophila after removal of extracellular antimicrobial agent.     

Revised interpretation of oxacillin MICs for Staphylococcus epidermidis based on mecA detection.

In 1992 and 1993, at The Ohio State University Medical Center, a larger proportion of Staphylococcus epidermidis strains required oxacillin MICs of 1 to 2 micrograms/ml than did Staphylococcus aureus strains. mecA genotype was correlated with antimicrobial susceptibility for selected clinical S. epidermidis strains. All 14 strains that required oxacillin MICs of < or = 0.25 microgram/ml and 2 of 5 strains that required oxacillin MICs of 0.5 microgram/ml were susceptible by 1-microgram oxacillin disk test and were mecA negative. Three of 5 strains that required oxacillin MICs of 0.5 microgram/ml and all 18 strains that required oxacillin MICs of > or = 1.0 microgram/ml were resistant by oxacillin disk test and were mecA positive. Current National Committee for Clinical Laboratory Standards MIC interpretive criteria may underestimate methicillin resistance among S. epidermidis strains.     

In vitro activity of HRE 664, a penem antibiotic

HRE 664, a new penem antibiotic, inhibited 90% of Escherichia coli, Klebsiella, Citrobacter diversus, Proteus mirabilis, Proteus vulgaris, Salmonella, Shigella, Providencia, Aeromonas, and Morganella at less than or equal to 2 micrograms/ml but was considerably less active than cefotaxime, ceftazidime, and imipenem. It did not inhibit Pseudomonas aeruginosa (MIC greater than 128 micrograms/ml). HRE 664 inhibited Enterobacter spp., Citrobacter freundii, and Serratia marcescens at 1-8 micrograms/ml, two- to fourfold higher MICs than imipenem. HRE 664 inhibited methicillin-susceptible Staphylococcus aureus and Staphylococcus epidermidis at less than or equal to 0.12 micrograms/ml, but methicillin-resistant S. aureus and S. epidermidis were resistant. Group A, C, and G streptococci and Streptococcus pneumoniae were inhibited by 0.06 micrograms/ml. Bacteroides and Clostridium species were inhibited by 0.25 micrograms/ml comparable to imipenem. HRE 664 was not hydrolyzed by beta-lactamases TEM-1, TEM-2, TEM-3, TEM-5, SHV-1, PSE-1, PSE-4, OXA-2, OXA-3, K-1, P99, Morganella, P. vulgaris, and S. aureus PC-1 but was hydrolyzed by the beta-lactamase of Xanthomonas maltophilia.     

In vitro activity of Ro 23-9424, a dual-action cephalosporin, compared with activities of other antibiotics.

The in vitro activity of Ro 23-9424, which is desacetyl-cefotaxime linked to fleroxacin, was compared with the activities of cefotaxime, desacetyl-cefotaxime, fleroxacin, ofloxacin, and ciprofloxacin. It inhibited the majority of members of the family Enterobacteriaceae, except for some Serratia marcescens, Citrobacter freundii, and Enterobacter cloacae strains, at less than or equal to 0.25 microgram/ml and had an MIC for 90% of strains tested (MIC90) of 8 micrograms/ml against Pseudomonas aeruginosa. Most group A, B, C, and G streptococci and Streptococcus pneumoniae were inhibited at less than or equal to 0.25 microgram/ml. Ninety percent of the staphylococci were inhibited at less than or equal to 4 micrograms/ml, except for some methicillin-resistant Staphylococcus aureus isolates. The MIC90S of Ro 23-9424 for Enterococcus faecalis and Listeria monocytogenes were greater than or equal to 16 micrograms/ml. Ninety percent of Clostridium perfringens isolates were inhibited by less than or equal to 2 micrograms/ml, whereas Bacteroides fragilis had an MIC90 of 32 micrograms/ml. There was a minimal inoculum size effect. The MICs and MBCs were either identical or within a twofold dilution. The MICs of Ro 23-9424 for Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, Enterobacter cloacae, Citrobacter freundii, Pseudomonas aeruginosa, and Staphylococcus aureus increased 16- to 128-fold after 2 weeks of transfer in the presence of Ro 23-9424, showing that the presence of two agents does not prevent resistance.     

In vitro activity of quinupristin/dalfopristin against clinical isolates of common gram-positive bacteria in Taiwan

The MICs of quinupristin/dalfopristin against common Gram-positive bacteria isolated from various clinical specimens at a university hospital in Taiwan were determined by the agar dilution method. The tested bacteria included methicillin-resistant Staphylococcus aureus (MRSA), methicillin-susceptible S. aureus (MSSA), methicillin-resistant Staphylococcus epidermidis (MRSE), methicillin-susceptible S. epidermidis (MSSE), Streptococcus pyogenes, Streptococcus pneumoniae, and Enterococcus faecalis. With the exception of E. faecalis all bacteria were susceptible to quinupristin/dalfopristin. The MIC50 and MIC90 were, respectively, 0.25 microgram/mL and 0.5 microgram/mL for both MRSA and MSSA; 0.25 microgram/mL and 0.5 microgram/mL for MRSE; 0.25 microgram/mL and 0.25 microgram/mL for MSSE; 0.125 microgram/mL and 0.125 microgram/mL for S. pyogenes; and < or = 0.03 microgram/mL and 0.25 microgram/mL for S. pneumoniae. Eighty-two percent of the tested E. faecalis isolates were intermediately resistant or resistant to quinupristin/dalfopristin, with an MIC50 of 2 micrograms/mL and an MIC90 of 4 micrograms/mL. Quinupristin/dalfopristin seems to be a promising antimicrobial agent against common Gram-positive bacteria other than E. faecalis in Taiwan.     

In vitro activity of RP 59500, a semisynthetic injectable pristinamycin, against staphylococci, streptococci, and enterococci.

The in vitro activity of RP 59500, a semisynthetic pristinamycin, was compared with the activities of vancomycin, oxacillin, ampicillin, gentamicin, ciprofloxacin, and rifampin against five Staphylococcus species, five Streptococcus species, and four Enterococcus species. For staphylococci, MICs were 0.13 to 1 microgram/ml and the MICs for 90% of the strains tested (MIC90s) were 0.13 to 0.5 microgram/ml; there were no differences between oxacillin-susceptible and -resistant strains. For streptococci, MICs were 0.03 to 4 micrograms/ml and MIC90s were 0.25 to 2 micrograms/ml; viridans group streptococci were the least susceptible streptococci. For enterococci, MICs were 0.25 to 32 micrograms/ml and MIC90s were 2 to 4 micrograms/ml; Enterococcus faecalis was the least susceptible. Vancomycin was the only comparative drug with consistent activity against all species of gram-positive cocci. With RP 59500, raising the inoculum 100-fold, lowering the pH of cation-adjusted Mueller-Hinton broth to 5.5, or omitting cation supplementation had little effect on MICs, but 50% serum increased MICs 2 to 4 dilution steps. The differences between MBCs and MICs were greater for staphylococci and enterococci than for streptococci. Time-kill studies with 24 strains indicated that RP 59500 concentrations 2-, 4-, and 16-fold greater than the MICs usually killed bacteria of each species at similar rates; reductions in CFU per milliliter were less than those observed with oxacillin or vancomycin against staphylococci and less than those observed with ampicillin against enterococci. RP 59500 antagonized the bactericidal activities of oxacillin and gentamicin against Staphylococcus aureus ATCC 29213 and that of ampicillin against E. faecalis ATCC 29212. Against the latter, combination with gentamicin was indifferent. RP 59500 has a broad spectrum of in vitro activity against gram-positive cocci; combining it with other drugs is not advantageous.