Antistaphylococcal activity of oritavancin and its synergistic effect in combination with other antimicrobial agents.

Oritavancin exhibited in vitro activity against 169 strains of vancomycin-susceptible, methicillin-resistant Staphylococcus aureus (MRSA) with MICs ranging from 0.03 to 1 µg/ml and against vancomycin-intermediate MRSA (VISA; n = 29), heterogeneous vancomycin-intermediate MRSA (hVISA; n = 5), and vancomycin-resistant MRSA (n = 5) strains, with MICs ranging from 0.12 to 4 µg/ml. For 10 MRSA isolates comprising 5 VISA and 5 hVISA strains, synergy between oritavancin and gentamicin, linezolid, or rifampin was observed against most of the strains tested using a time-kill method.

Activity of telavancin compared to other agents against coagulase-negative staphylococci with different resistotypes by time kill.

Among 10 coagulase-negative staphylococci, telavancin, quinupristin/dalfopristin, and tigecycline were the most potent antimicrobials. Telavancin exhibited bactericidal effect to 9 strains out of 10 tested at 4× MIC after 24 h of exposure similar to those of vancomycin and daptomycin. By contrast, linezolid was mainly bacteriostatic and teicoplanin was bactericidal to 7 strains tested at 4× MIC after 24 h.

Activity of ACHN-490 tested alone and in combination with other agents against Pseudomonas aeruginosa.

ACHN-490 was tested alone and in combination with cefepime, doripenem, imipenem, or piperacillin-tazobactam in a synergy time-kill analysis against 25 Pseudomonas aeruginosa strains with different resistance phenotypes. Each combination was synergistic against most isolates at 24 h, and antagonism was not observed. Combinations of ACHN-490 with cefepime, doripenem, imipenem, or piperacillin-tazobactam yielded synergies in ≥70% and ≥80% of strains at 6 and 12 h, respectively, and in ≥68% at 24 h.

Time-kill activity of the streptogramin NXL 103 against Gram-positive and -negative bacteria.

Against 33 Gram-positive and -negative bacteria, NXL 103 MICs were 0.03 to 1 µg/ml. NXL 103 was bactericidal by 12 h at 2 × MIC against all 5 pneumococci and at 2 × MIC after 24 h against all 5 group A and B ß-hemolytic streptococci. NXL 103 was bactericidal against all 8 Haemophilus influenzae strains at 2 × MIC and all 5 Moraxella catarrhalis strains at 4 × MIC after 24 h but was mainly bacteriostatic against 5 methicillin-resistant Staphylococcus aureus strains. After the exposure of one strain of each species to NXL 103 for 10 daily subcultures, the MICs remained within ± 1 dilution.

Antistaphylococcal activities of telavancin tested alone and in combination by time-kill assay.

Synergy time-kill studies against 40 methicillin-resistant Staphylococcus aureus (MRSA) strains of differing resistance phenotypes were conducted. Subinhibitory concentrations of telavancin were combined with sub-MIC concentrations of other antimicrobial agents that might be used in combination with telavancin to provide Gram-negative coverage. The highest incidence of synergy was found after 24 h with gentamicin (90% of strains), followed by ceftriaxone (88%), rifampin and meropenem (each 65%), cefepime (45%), and ciprofloxacin (38%) for combinations tested at or below the intermediate breakpoint for each agent.

Antistaphylococcal activity of ACHN-490 tested alone and in combination with other agents by time-kill assay.

Synergy time-kill studies of 47 methicillin-resistant Staphylococcus aureus strains with differing resistance phenotypes showed that combinations of subinhibitory concentrations of ACHN-490 and daptomycin yielded synergy against 43/47 strains at 24 h, while the combination was indifferent against the remaining 4 strains. ACHN-490 and ceftobiprole showed synergy in 17/47 strains tested at 24 h, while 6/47 strains showed synergy for subinhibitory combinations of ACHN-490 and linezolid.

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.

Activity of levofloxacin alone and in combination with a DnaK inhibitor against gram-negative rods, including levofloxacin-resistant strains.

Synergy time-kill testing of levofloxacin alone and in combination with CHP-105, a representative DnaK inhibitor, against 50 gram-negative rods demonstrated that 34 of the 50 strains tested showed significant synergy between levofloxacin and CHP-105 after 12 h and 24 h. Fourteen of these 34 organisms were quinolone resistant (levofloxacin MICs of > or =4 microg/ml).

Activity of ceftobiprole compared with those of other agents against Staphylococcus aureus strains with different resistotypes by time-kill analysis.

Among 10 hospital- and community-acquired Staphylococcus aureus strains with differing methicillin and vancomycin resistotypes, all strains were susceptible to ceftobiprole at MICs

Activity of meropenem with and without ciprofloxacin and colistin against Pseudomonas aeruginosa and Acinetobacter baumannii.

Time-kill synergy studies showed that at 24 h, subinhibitory meropenem and ciprofloxacin concentrations of 0.06 to 128 and 0.03 to 32 microg/ml, respectively, showed synergy against 34/51 Pseudomonas aeruginosa strains; subinhibitory concentrations of meropenem (0.06 to 8 microg/ml) and colistin (0.12 to 1 microg/ml) showed synergy against 13 isolates. Subinhibitory meropenem and ciprofloxacin concentrations of 0.25 to 2 and 0.12 to 16 microg/ml, respectively, showed synergy against 18/52 Acinetobacter baumannii strains at 24 h. Subinhibitory meropenem and colistin concentrations of 0.03 to 64 and 0.06 to 8 microg/ml, respectively, showed synergy against 49 strains at 24 h.

Activity of daptomycin alone and in combination with rifampin and gentamicin against Staphylococcus aureus assessed by time-kill methodology.

The synergistic effects of daptomycin plus gentamicin or rifampin were tested against 50 Staphylococcus aureus strains, with daptomycin MICs ranging between 0.25 and 8 microg/ml. Daptomycin sub-MICs combined with gentamicin concentrations lower than the MIC yielded synergy in 34 (68%) of the 50 strains. Daptomycin combined with rifampin yielded synergy in one vancomycin-intermediate S. aureus strain only, and virtually all synergy occurred between daptomycin and gentamicin.

Activity of LBM415 compared to those of 11 other agents against Haemophilus species.

When tested against 254 Haemophilus influenzae strains, LBM415, a peptide deformylase inhibitor, gave MIC50 and MIC90 values of 2.0 microg/ml and 8.0 microg/ml, respectively. The MICs were independent of beta-lactam or quinolone susceptibility and the presence or absence of macrolide efflux or ribosomal protein mutations. The MICs of LBM415 against 23 H. parainfluenzae strains were similar to those against H. influenzae. In contrast, erythromycin, azithromycin, and clarithromycin gave unimodal MIC distributions, and apart from beta-lactamase-negative, ampicillin-resistant strains, all strains were susceptible to the beta-lactams tested. Apart from selected quinolone-resistant strains, all strains were susceptible to ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin, and gemifloxacin. Resistance to trimethoprim-sulfamethoxazole was common. The potencies of all drugs against 23 H. parainfluenzae strains were similar to those against H. influenzae. Time-kill studies with 10 Haemophilus strains showed LBM415 to be bactericidal at 2 x the MIC against 8 of 10 strains after 24 h. For comparison, the macrolides and beta-lactams were bactericidal against 8 to 10 strains each at 2 x the MIC after 24 h. Quinolones were bactericidal against all 10 strains tested at 2 x the MIC after 24 h. Against six H. influenzae strains, postantibiotic effects for LBM415 lasted between 0.8 and 2.2 h. In multistep resistance selection studies, LBM415 produced resistant clones in 7 of the 10 strains tested, with MICs ranging from 4 to 64 microg/ml. No mutations in deformylase (def) and formyltransferase (fmt) genes were detected in any of the LBM415-resistant mutants.

Activities of ceftobiprole, a novel broad-spectrum cephalosporin, against Haemophilus influenzae and Moraxella catarrhalis.

Ceftobiprole, a broad-spectrum pyrrolidinone-3-ylidenemethyl cephem currently in phase III clinical trials, had MICs between 0.008 microg/ml and 8.0 microg/ml for 321 clinical isolates of Haemophilus influenzae and between < or =0.004 microg/ml and 1.0 microg/ml for 49 clinical isolates of Moraxella catarrhalis. Ceftobiprole MIC(50) and MIC(90) values for H. influenzae were 0.06 microg/ml and 0.25 microg/ml for beta-lactamase-positive strains (n = 262), 0.03 microg/ml and 0.25 microg/ml for beta-lactamase-negative strains (n = 40), and 0.5 microg/ml and 2.0 microg/ml for beta-lactamase-negative ampicillin-resistant strains (n = 19), respectively. Ceftobiprole MIC(50) and MIC(90) values for beta-lactamase-positive M. catarrhalis strains (n = 40) were 0.12 microg/ml and 0.5 microg/ml, respectively, whereas the ceftobiprole MIC range for beta-lactamase-negative M. catarrhalis strains (n = 9) was < or =0.004 to 0.03 microg/ml. Ceftriaxone MICs usually were generally at least twofold lower than those of ceftobiprole, whereas amoxicillin-clavulanate MICs usually were higher than those of ceftobiprole. Azithromycin and telithromycin had unimodal MIC distributions against H. influenzae, with MIC(90) values of azithromycin and telithromycin of 2 microg/ml and 4 microg/ml, respectively. Except for selected quinolone-nonsusceptible H. influenzae strains, moxifloxacin proved highly active, with MIC(90) values of 0.12 microg/ml. Time-kill analyses showed that ceftobiprole, ceftriaxone, cefpodoxime, amoxicillin-clavulanate, azithromycin, telithromycin, and moxifloxacin were bactericidal at 2x MIC by 24 h against all 10 H. influenzae strains surveyed. Only modest increases in MICs were found for H. influenzae or M. catarrhalis clones after 50 serial passages in the presence of subinhibitory concentrations of ceftobiprole, and single-passage selection showed that the selection frequency of H. influenzae or M. catarrhalis clones with elevated ceftobiprole MICs is quite low.

Antipneumococcal activity of DW-224a, a new quinolone, compared to those of eight other agents.

DW-224a is a new broad-spectrum quinolone with excellent antipneumococcal activity. Agar dilution MIC was used to test the activity of DW-224a compared to those of penicillin, ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin, gemifloxacin, amoxicillin-clavulanate, cefuroxime, and azithromycin against 353 quinolone-susceptible pneumococci. The MICs of 29 quinolone-resistant pneumococci with defined quinolone resistance mechanisms against seven quinolones and an efflux mechanism were also tested. DW-224a was the most potent quinolone against quinolone-susceptible pneumococci (MIC(50), 0.016 microg/ml; MIC(90), 0.03 microg/ml), followed by gemifloxacin, moxifloxacin, gatifloxacin, levofloxacin, and ciprofloxacin. beta-Lactam MICs rose with those of penicillin G, and azithromycin resistance was seen mainly in strains with raised penicillin G MICs. Against the 29 quinolone-resistant strains, DW-224a had the lowest MICs (0.06 to 1 microg/ml) compared to those of gemifloxacin, clinafloxacin, moxifloxacin, gatifloxacin, levofloxacin, and ciprofloxacin. DW-224a at 2x MIC was bactericidal after 24 h against eight of nine strains tested. Other quinolones gave similar kill kinetics relative to higher MICs. Serial passages of nine strains in the presence of sub-MIC concentrations of DW-224a, moxifloxacin, levofloxacin, ciprofloxacin, gatifloxacin, gemifloxacin, amoxicillin-clavulanate, cefuroxime, and azithromycin were performed. DW-224a yielded resistant clones similar to moxifloxacin and gemifloxacin but also yielded lower MICs. Azithromycin selected resistant clones in three of the five parents tested. Amoxicillin-clavulanate and cefuroxime did not yield resistant clones after 50 days.

Activity of retapamulin against Streptococcus pyogenes and Staphylococcus aureus evaluated by agar dilution, microdilution, E-test, and disk diffusion methodologies.

The in vitro activity of retapamulin against 106 Staphylococcus aureus isolates and 109 Streptococcus pyogenes isolates was evaluated by the agar dilution, broth microdilution, E-test, and disk diffusion methodologies. Where possible, the tests were performed by using the CLSI methodology. The results of agar dilution, broth microdilution, and E-test (all with incubation in ambient air) for S. aureus yielded similar MICs, in the range of 0.03 to 0.25 microg/ml. These values corresponded to zone diameters between 25 and 33 mm by the use of a 2-microg retapamulin disk. Overall, 99% of the agar dilution results and 95% of E-test results for S. aureus were within +/-1 dilution of the microdilution results. For S. pyogenes, the MICs obtained by the agar and broth microdilution methods (both after incubation in ambient air) were in the range of 0.008 to 0.03 microg/ml, and E-test MICs (with incubation in ambient air) were 0.016 to 0.06 microg/ml. For S. pyogenes, 100% of the agar dilution MIC results were within +/-1 dilution of the broth microdilution results. E-test MICs (after incubation in ambient air) were within +/-1 and +/-2 dilutions of the broth microdilution results for 76% and 99% of the isolates, respectively. E-test MICs for S. pyogenes strains in CO(2) were up to 4 dilutions higher than those in ambient air. Therefore, it is recommended that when retapamulin MICs are determined by E-test, incubation be done in ambient air and not in CO(2), due to the adverse effect of CO(2) on the activity of this compound. Diffusion zones (with incubation in CO(2)) for S. pyogenes were 18 to 24 mm. Retapamulin MICs for all strains by all methods (with incubation in ambient air) were < or =0.25 microg/ml. These results demonstrate that S. pyogenes (including macrolide-resistant strains) and S. aureus (including methicillin-resistant and vancomycin-nonsusceptible strains) are inhibited by very low concentrations of retapamulin and that all four testing methods are satisfactory for use for susceptibility testing.

Antipneumococcal activity of dalbavancin compared to other agents.

Against 307 pneumococci of various resistotypes, dalbavancin MICs were 0.008 to 0.125 microg/ml. All strains were susceptible to vancomycin, teicoplanin, linezolid, and quinupristin-dalfopristin. Dalbavancin at 2x MIC was bactericidal against all 10 pneumococci tested after 24 h. Vancomycin and teicoplanin killed 10 and 8 strains, respectively, at 2x MIC after 24 h.

Antistaphylococcal activity of DX-619, a new des-F(6)-quinolone, compared to those of other agents.

The in vitro activity of DX-619, a new des-F(6)-quinolone, was tested against staphylococci and compared to those of other antimicrobials. DX-619 had the lowest MIC ranges/MIC(50)s/MIC(90)s (microg/ml) against 131 Staphylococcus aureus strains (32), and ciprofloxacin (>32/>32). Raised quinolone MICs were associated with mutations in GyrA (S84L) and single or double mutations in GrlA (S80F or Y; E84K, G, or V) in all S. aureus strains tested. A recent vancomycin-resistant S. aureus (VRSA) strain (Hershey) was resistant to available quinolones and was inhibited by DX-619 at 0.25 microg/ml and sitafloxacin at 1.0 microg/ml. Vancomycin (except VRSA), linezolid, ranbezolid, tigecycline, and quinupristin-dalfopristin were active against all strains, and teicoplanin was active against S. aureus but less active against coagulase-negative staphylococci. DX-619 produced resistant mutants with MICs of 1 to >32 microg/ml after <50 days of selection compared to 16 to >32 microg/ml for ciprofloxacin, sitafloxacin, moxifloxacin, and gatifloxacin. DX-619 and sitafloxacin were also more active than other tested drugs against selected mutants and had the lowest mutation frequencies in single-step resistance selection. DX-619 and sitafloxacin were bactericidal against six quinolone-resistant (including the VRSA) and seven quinolone-susceptible strains tested, whereas gatifloxacin, moxifloxacin, levofloxacin, and ciprofloxacin were bactericidal against 11, 10, 7, and 5 strains at 4x MIC after 24 h, respectively. DX-619 was also bactericidal against one other VRSA strain, five vancomycin-intermediate S. aureus strains, and four vancomycin-intermediate coagulase-negative staphylococci. Linezolid, ranbezolid, and tigecycline were bacteriostatic and quinupristin-dalfopristin, teicoplanin, and vancomycin were bactericidal against two, eight, and nine strains, and daptomycin and oritavancin were rapidly bactericidal against all strains, including the VRSA. DX-619 has potent in vitro activity against staphylococci, including methicillin-, ciprofloxacin-, and vancomycin-resistant strains.

Antipneumococcal activity of ceftobiprole, a novel broad-spectrum cephalosporin.

Ceftobiprole (previously known as BAL9141), an anti-methicillin-resistant Staphylococcus aureus cephalosporin, was very highly active against a panel of 299 drug-susceptible and -resistant pneumococci, with MIC(50) and MIC(90) values (microg/ml) of 0.016 and 0.016 (penicillin susceptible), 0.06 and 0.5 (penicillin intermediate), and 0.5 and 1.0 (penicillin resistant). Ceftobiprole, imipenem, and ertapenem had lower MICs against all pneumococcal strains than amoxicillin, cefepime, ceftriaxone, cefotaxime, cefuroxime, or cefdinir. Macrolide and penicillin G MICs generally varied in parallel, whereas fluoroquinolone MICs did not correlate with penicillin or macrolide susceptibility or resistance. All strains were susceptible to linezolid, quinupristin-dalfopristin, daptomycin, vancomycin, and teicoplanin. Time-kill analyses showed that at 1x and 2x the MIC, ceftobiprole was bactericidal against 10/12 and 11/12 strains, respectively. Levofloxacin, moxifloxacin, vancomycin, and teicoplanin were each bactericidal against 10 to 12 strains at 2x the MIC. Azithromycin and clarithromycin were slowly bactericidal, and telithromycin was bactericidal against only 5/12 strains at 2x the MIC. Linezolid was mainly bacteriostatic, whereas quinupristin-dalfopristin and daptomycin showed marked killing at early time periods. Prolonged serial passage in the presence of subinhibitory concentrations of ceftobiprole failed to yield mutants with high MICs towards this cephalosporin, and single-passage selection showed very low frequencies of spontaneous mutants with breakthrough MICs towards ceftobiprole.

Antistaphylococcal activity of dalbavancin, an experimental glycopeptide.

Dalbavancin, tested against 146 staphylococci, was more potent than other drugs tested, with an MIC at which 50% of staphylococci were inhibited of 0.03 microg/ml and an MIC at which 90% of staphylococci were inhibited of 0.06 microg/ml by microdilution. For all strains, MICs of vancomycin, linezolid, ranbezolid, oritavancin, daptomycin, and quinupristin-dalfopristin were

Antipneumococcal activities of two novel macrolides, GW 773546 and GW 708408, compared with those of erythromycin, azithromycin, clarithromycin, clindamycin, and telithromycin.

The MICs of GW 773546, GW 708408, and telithromycin for 164 macrolide-susceptible and 161 macrolide-resistant pneumococci were low. The MICs of GW 773546, GW 708408, and telithromycin for macrolide-resistant strains were similar, irrespective of the resistance genotypes of the strains. Clindamycin was active against all macrolide-resistant strains except those with erm(B) and one strain with a 23S rRNA mutation. GW 773546, GW 708408, and telithromycin at two times their MICs were bactericidal after 24 h for 7 to 8 of 12 strains. Serial passages of 12 strains in the presence of sub-MICs yielded 54 mutants, 29 of which had changes in the L4 or L22 protein or the 23S rRNA sequence. Among the macrolide-susceptible strains, resistant mutants developed most rapidly after passage in the presence of clindamycin, GW 773546, erythromycin, azithromycin, and clarithromycin and slowest after passage in the presence of GW 708408 and telithromycin. Selection of strains for which MICs were >/=0.5 microg/ml from susceptible parents occurred only with erythromycin, azithromycin, clarithromycin, and clindamycin; 36 resistant clones from susceptible parent strains had changes in the sequences of the L4 or L22 protein or 23S rRNA. No mef(E) strains yielded resistant clones after passage in the presence of erythromycin and azithromycin. Selection with GW 773546, GW 708408, telithromycin, and clindamycin in two mef(E) strains did not raise the erythromycin, azithromycin, and clarithromycin MICs more than twofold. There were no change in the ribosomal protein (L4 or L22) or 23S rRNA sequences for 15 of 18 mutants selected for macrolide resistance; 3 mutants had changes in the L22-protein sequence. GW 773546, GW 708408, and telithromycin selected clones for which MICs were 0.03 to >2.0 microg/ml. Single-step studies showed mutation frequencies <5.0 x 10(-10) to 3.5 x 10(-7) for GW 773546, GW 708408, and telithromycin for macrolide-susceptible strains and 1.1 x 10(-7) to >4.3 x 10(-3) for resistant strains. The postantibiotic effects of GW 773546, GW 708408, and telithromycin were 2.4 to 9.8 h.