In vitro activity of fusidic acid (CEM-102, sodium fusidate) against Staphylococcus aureus isolates from cystic fibrosis patients and its effect on the activities of tobramycin and amikacin against Pseudomonas aeruginosa and Burkholderia cepacia.

We tested the MICs of fusidic acid (CEM-102) plus other agents against 40 methicillin-resistant Staphylococcus aureus (MRSA) isolates from cystic fibrosis patients and the activities of fusidic acid with or without tobramycin or amikacin against Pseudomonas aeruginosa, MRSA, and Burkholderia cepacia isolates from cystic fibrosis patients in a 24-h time-kill study. Fusidic acid was potent (MICs, 0.125 to 0.5 µg/ml; a single 500-mg dose of fusidic acid at 8 h averaged 8 to 12. 5 µg/ml with 91 to 97% protein binding) against all MRSA strains. No antagonism was observed; synergy occurred for one MRSA strain treated with fusidic acid plus tobramycin.

In vitro activity of CEM-101 against Streptococcus pneumoniae and Streptococcus pyogenes with defined macrolide resistance mechanisms.

CEM-101 had MIC ranges of 0.002 to 0.016 microg/ml against macrolide-susceptible pneumococci and 0.004 to 1 microg/ml against macrolide-resistant phenotypes. Only 3 strains with erm(B), with or without mef(A), had CEM-101 MICs of 1 microg/ml, and 218/221 strains had CEM-101 MICs of 64 microg/ml, while 17/19 strains had telithromycin MICs of 4 to 16 microg/ml; CEM-101 MICs were 0.015 to 1 microg/ml. By comparison, erm(A) and mef(A) strains had CEM-101 MICs of 0.015 to 0.5 microg/ml, clindamycin and telithromycin MICs of 64 microg/ml. Pneumococcal multistep resistance studies showed that although CEM-101 yielded clones with higher MICs for all eight strains tested, seven of eight strains had clones with CEM-101 MICs that rose from 0.004 to 0.03 microg/ml (parental strains) to 0.06 to 0.5 microg/ml (resistant clones); for only one erm(B) mef(A) strain with a parental MIC of 1 microg/ml was there a resistant clone with a MIC of 32 microg/ml, with no detectable mutations in the L4, L22, or 23S rRNA sequence. Among two of five S. pyogenes strains tested, CEM-101 MICs rose from 0.03 to 0.25 microg/ml, and only for the one strain with erm(B) did CEM-101 MICs rise from 1 to 8 microg/ml, with no changes occurring in any macrolide resistance determinant. CEM-101 had low MICs as well as low potential for the selection of resistant mutants, independent of bacterial species or resistance phenotypes in pneumococci and S. pyogenes.

Activity of telavancin against staphylococci and enterococci determined by MIC and resistance selection studies.

This study used CLSI broth microdilution to test the activity of telavancin and comparator antimicrobial agents against 67 methicillin (meticillin)-resistant Staphylococcus aureus (MRSA) isolates. Twenty-six vancomycin-intermediate S. aureus (VISA) strains were among the isolates tested; all strains were susceptible to telavancin at < or = 1 microg/ml, whereas 12/26 (46%) of these isolates were nonsusceptible to daptomycin at the same concentration. All strains were susceptible to quinupristin-dalfopristin, while resistance was found to all other drugs tested. Telavancin demonstrated potent activity against all vancomycin-susceptible isolates as well as against heterogeneously VISA and VISA resistance phenotypes. In multistep resistance selection studies, telavancin yielded one stable mutant after 43 days in one MRSA strain out of the 10 MRSA strains tested with the MIC rising eightfold from 0.25 microg/ml (parent) to 2 microg/ml. MICs for this clone did not increase further when passages were continued for the maximum 50 days. In contrast, daptomycin selected stable resistant clones (MIC increase of >4x) after 14 to 35 days in 4 of 10 MRSA strains with MICs increasing from 1 to 2 microg/ml (parents) to 4 to 8 microg/ml (resistant clones). Sequencing analysis of daptomycin resistance determinants revealed point mutations in the mprF genes of all four stable daptomycin-resistant clones. Teicoplanin gave rise to resistant clones after 14 to 21 days in 2 of 10 MRSA strains with MICs rising from 1 to 2 microg/ml (parents) to 4 to 16 microg/ml (stable resistant clones). Linezolid selected stable resistant clones after 22 to 48 days in 2 of 10 MRSA strains with MICs rising from 2 to 4 microg/ml (parents) to 32 microg/ml (resistant clones). Vancomycin yielded no resistant clones in 10 MRSA strains tested; however, MICs increased two- to fourfold from 1 to 8 microg/ml to 2 to 16 microg/ml after 50 days. No cross-resistance was found with any clone/antimicrobial combination. The two enterococci developed resistance to daptomycin, and one developed resistance to linezolid. Single-step mutation frequencies for telavancin (<4.0 x 10(-11) to <2.9 x 10(-10) at 2x MIC) were lower than the spontaneous mutation frequencies obtained with the comparators.

Resistance selection studies comparing the activity of razupenem (PTZ601) to vancomycin and linezolid against eight methicillin-resistant and two methicillin-susceptible Staphylococcus aureus strains.

Multistep and single-step resistance selection studies were performed with razupenem, linezolid, and vancomycin against 10 methicillin (meticillin)-resistant and -susceptible Staphylococcus aureus strains. After 20 daily subcultures, razupenem yielded only clones with MICs of >4 microg/ml in one strain (8 microg/ml) whose parent's MIC was already 4 microg/ml. After 18 to 49 passages in 6/10 strains, razupenem MICs rose from 0.016 to 2 microg/ml (parents) to 0.125 to 8 microg/ml (with clones stable after 10 drug-free subcultures). Single-step mutant selection frequencies were similarly low for razupenem and comparators.

Antistaphylococcal activity of dihydrophthalazine antifolates, a family of novel antibacterial drugs.

For a panel of 153 Staphylococcus aureus clinical isolates (including 13 vancomycin-intermediate or heterogeneous vancomycin-intermediate and 4 vancomycin-resistant strains), MIC(50)s and MIC(90)s of three novel dihydrophthalazine antifolates, BAL0030543, BAL0030544, and BAL0030545, were 0.03 and 0.25 microg/ml, respectively, for methicillin-susceptible strains and 0.03 and 128 microg/ml), although rates of endogenous resistance development were much lower for the dihydrophthalazines than for trimethoprim. Single-step platings of naïve staphylococci onto media containing dihydrophthalazine antifolates indicated considerable variability among strains with respect to preexistent subpopulations nonsusceptible to dihydrophthalazine antifolates.

In vitro capability of faropenem to select for resistant mutants of Streptococcus pneumoniae and Haemophilus influenzae.

When tested against nine strains of pneumococci and six of Haemophilus influenzae of various resistotypes, faropenem failed to select for resistant mutants after 50 days of consecutive subculture in subinhibitory concentrations. Faropenem also yielded low rates of spontaneous mutations against all organisms of both species. By comparison, resistant clones were obtained with macrolides, ketolides, and quinolones.