Lois M. Ednie

Antistaphylococcal Activity of Ceftobiprole, a New Broad-Spectrum Cephalosporin

ABSTRACT Ceftobiprole (formerly BAL9141), the active component of the prodrug BAL5788 (ceftobiprole medocaril), is a novel cephalosporin with expanded activity against gram-positive bacteria. Among 152 Staphylococcus aureus isolates, including 5 vancomycin-intermediate and 2 vancomycin-resistant strains, MIC50 and MIC90 values for ceftobiprole were each 0.5 μg/ml against methicillin-susceptible strains and 2 μg/ml against methicillin-resistant strains. Against 151 coagulase-negative staphylococci (including 4 vancomycin-intermediate strains), MIC50 and MIC90 values were, respectively, 0.125 μg/ml and 1 μg/ml against methicillin-susceptible and 1 μg/ml and 2 μg/ml against methicillin-resistant strains. Teicoplanin was less active than vancomycin against coagulase-negative strains. Linezolid, quinupristin-dalfopristin, and daptomycin were active against all strains, whereas increased MICs for amoxicillin-clavulanate, cefazolin, minocycline, gentamicin, trimethoprim-sulfamethoxazole, levofloxacin, rifampin, mupirocin, fusidic acid, and fosfomycin were sometimes observed. At 2× MIC, ceftobiprole was bactericidal against 11 of 12 test strains by 24 h. Prolonged serial passage in the presence of subinhibitory concentrations of ceftobiprole failed to select for clones with MICs >4 times those of the parents; the maximum MIC achieved for ceftobiprole after 50 passages (in 1 of 10 strains) was 8 μg/ml. Single-passage selections showed very low frequencies of resistance to ceftobiprole irrespective of genotype or phenotype; the maximal ceftobiprole MIC of recovered clones was 8 μg/ml.

Characterization of a Daptomycin-Nonsusceptible Vancomycin-Intermediate Staphylococcus aureus Strain in a Patient with Endocarditis

ABSTRACT We analyzed the emergence of daptomycin nonsusceptibility in a patient with persistent vancomycin-intermediate Staphylococcus aureus (VISA) bacteremia. The daptomycin-nonsusceptible VISAs cell wall demonstrated a reduction in muramic acid O-acetylation, a phenotypic parameter not previously reported for VISA; some isolates also contained a single point mutation in the mprF gene.

Antistaphylococcal Activity of Dalbavancin, an Experimental Glycopeptide

ABSTRACT 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 μg/ml and an MIC at which 90% of staphylococci were inhibited of 0.06 μg/ml by microdilution. For all strains, MICs of vancomycin, linezolid, ranbezolid, oritavancin, daptomycin, and quinupristin-dalfopristin were ≤4.0 μg/ml. Dalbavancin was bactericidal at four times the MIC against all six strains tested.

Antipneumococcal activity of ABT-773 compared to those of 10 other agents.

ABSTRACT MICs, time-kills, and postantibiotic effects (PAEs) of ABT-773 (a new ketolide) and 10 other agents were determined against 226 pneumococci. Against 78 ermB- and 44mefE-containing strains, ABT-773 MICs at which 50% of the isolates tested were inhibited (MIC50s) and MIC90s were 0.016 to 0.03 and 0.125 μg/ml, respectively. Clindamycin was active only against macrolide-resistant strains containing mefE (MIC50, 0.06 μg/ml; MIC90, 0.125 μg/ml). Activities of pristinamycin (MIC90, 0.5 μg/ml) and vancomycin (MIC90, 0.25 μg/ml) were unaffected by macrolide or penicillin resistance, while β-lactam MICs rose with those of penicillin G. Against 19 strains with L4 ribosomal protein mutations and two strains with mutations in domain V of 23S rRNA, ABT-773 MICs were 0.03 to 0.25 μg/ml, while macrolide and azalide MICs were all ≥16.0 μg/ml. ABT-773 was bactericidal at twice the MIC after 24 h for 8 of 12 strains (including three strains with erythromycin MICs greater than or equal to 64.0 μg/ml). Kill kinetics of erythromycin, azithromycin, clarithromycin, and roxithromycin against macrolide-susceptible strains were slower than those of ABT-773. ABT-773 had longer PAEs than macrolides, azithromycin, clindamycin, or β-lactams, including against ermB-containing strains. ABT-773, therefore, shows promising in vitro activity against macrolide-susceptible as well as -resistant pneumococci.

Comparative activities of clarithromycin, erythromycin, and azithromycin against penicillin-susceptible and penicillin-resistant pneumococci.

Activities of clarithromycin, erythromycin, and azithromycin against 120 pneumococci from the United States were tested by agar dilution MIC. All three compounds yielded MICs at which 90% of the isolates were inhibited (MIC90S) of < or = 0.125 micrograms/ml against penicillin-susceptible and -intermediate strains, but MIC90S against resistant strains were > 128.0 micrograms/ml. All erythromycin-resistant strains were also resistant to clarithromycin and azithromycin. Clarithromycin yielded MICs which were generally one or two dilutions lower than those of the other two compounds for all strains. The respective bacteriostatic and bactericidal values (micrograms per milliliter) for two susceptible, two intermediate, and two resistant strains were 0.004 to 0.03 and 0.016 to 0.03 (0.004 to 0.03/0.016 to 0.03) (clarithromycin), 0.008 to 0.06/0.016/0.016 to 0.125 (erythromycin), and 0.016 to 0.06/0.03 to 0.125 (azithromycin); clarithromycin yielded the lowest values. All compounds were uniformly bactericidal after 24 h only; erythromycin was bactericidal at eight times the MIC, and azithromycin and clarithromycin were both bactericidal at two time the MIC. The relevance of these in vitro differences requires clarification by clinical trials.

Derivatives of a Vancomycin-Resistant Staphylococcus aureus Strain Isolated at Hershey Medical Center

ABSTRACT Antimicrobial susceptibilities and genetic relatedness of the vancomycin-resistant Staphylococcus aureus strain (VRSA) isolated at Hershey, Pa. (VRSA Hershey), and its vancomycin-susceptible and high-level-resistant derivatives were studied and compared to 32 methicillin-resistant S. aureus strains (MRSA) isolated from patients and medical staff in contact with the VRSA patient. Derivatives of VRSA were obtained by subculturing six VRSA colonies from the original culture with or without vancomycin. Ten days of drug-free subculture caused the loss of vanA in two vancomycin-susceptible derivatives for which vancomycin MICs were 1 to 4 μg/ml. Multistep selection of three VRSA clones with vancomycin for 10 days increased vancomycin MICs from 32 to 1,024 to 2,048 μg/ml. MICs of teicoplanin, dalbavancin, and oritavancin were also increased from 4, 0.5, and 0.12 to 64, 1, and 32 μg/ml, respectively. Pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing analysis indicated that VRSA Hershey was the vanA-acquired variety of a common MRSA clone in our hospital with sequence type 5 (ST5). Three of five vancomycin-intermediate S. aureus strains tested from geographically different areas were also ST5, and the Michigan VRSA was ST371, a one-allele variant of ST5. Derivatives of VRSA Hershey had differences in PFGE profiles and the size of SmaI fragment that carries the vanA gene cluster, indicating instability of this cluster in VRSA Hershey. However induction with vancomycin increased glycopeptide MICs and stabilized the resistance.

Activities and Postantibiotic Effects of Gemifloxacin Compared to Those of 11 Other Agents against Haemophilus influenzae and Moraxella catarrhalis

ABSTRACT The activity of gemifloxacin against Haemophilus influenzae and Moraxella catarrhalis was compared to those of 11 other agents. All quinolones were very active (MICs, ≤0.125 μg/ml) against 248 quinolone-susceptible H. influenzae isolates (40.7% of which were β-lactamase positive); cefixime (MICs, ≤0.125 μg/ml) and amoxicillin-clavulanate (MICs ≤4.0 μg/ml) were active, followed by cefuroxime (MICs, ≤16.0 μg/ml); azithromycin MICs were ≤4.0 μg/ml. For nine H. influenzae isolates with reduced quinolone susceptibilities, the MICs at which 50% of isolates are inhibited (MIC50s) were 0.25 μg/ml for gemifloxacin and 1.0 μg/ml for the other quinolones tested. All strains had mutations in GyrA (Ser84, Asp88); most also had mutations in ParC (Asp83, Ser84, Glu88) and ParE (Asp420, Ser458), and only one had a mutation in GyrB (Gln468). All quinolones tested were equally active (MICs, ≤0.06 μg/ml) against 50 M. catarrhalis strains; amoxicillin-clavulanate, cefixime, cefuroxime, and azithromycin were very active. Against 10 H. influenzae strains gemifloxacin, levofloxacin, sparfloxacin, and trovafloxacin at 2× the MIC and ciprofloxacin at 4× the MIC were uniformly bactericidal after 24 h, and against 9 of 10 strains grepafloxacin at 2× the MIC was bactericidal after 24 h. After 24 h bactericidal activity was seen with amoxicillin-clavulanate at 2× the MIC for all strains, cefixime at 2× the MIC for 9 of 10 strains, cefuroxime at 4× the MIC for all strains, and azithromycin at 2× the MIC for all strains. All quinolones except grepafloxacin (which was bactericidal against four of five strains) and all ß-lactams at 2× to 4× the MIC were bactericidal against five M. catarrhalis strains after 24 h; azithromycin at the MIC was bactericidal against all strains after 24 h. The postantibiotic effects (PAEs) against four quinolone-susceptible H. influenzae strains were as follows: gemifloxacin, 0.3 to 2.3 h; ciprofloxacin, 1.3 to 4.2 h; levofloxacin, 2.8 to 6.2 h; sparfloxacin, 0.6 to 3.0 h; grepafloxacin, 0 to 2.1 h; trovafloxacin, 0.8 to 2.8 h. At 10× the MIC, no quinolone PAEs were found against the strain for which quinolone MICs were increased. Azithromycin PAEs were 3.7 to 7.3 h.

Antianaerobe Activity of RBX 7644 (Ranbezolid), a New Oxazolidinone, Compared with Those of Eight Other Agents

ABSTRACT The activity of ranbezolid (RBX 7644), a new oxazolidinone, against 306 anaerobes was compared with those of 11 other agents. The MICs at which 50% of the isolates tested are inhibited and those at which 90% of the isolates tested are inhibited (in micrograms per milliliter) were as follows: ranbezolid, 0.03 and 0.5; linezolid, 2 and 4; vancomycin, >16 and >16; teicoplanin, 1 and >16; quinupristin-dalfopristin, 1 and >8; amoxicillin-clavulanate, 0.5 and 2; imipenem, 0.125 and 1; clindamycin, 0.25 and 8; metronidazole, 1 and 4; gatifloxacin, 0.5 and 4; and moxifloxacin, 0.5 and 2, respectively. Ranbezolid had very good in vitro activity against both gram-negative and -positive anaerobes.

Antistreptococcal Activity of Telithromycin Compared with Seven Other Drugs in Relation to Macrolide Resistance Mechanisms in Russia

ABSTRACT The susceptibilities of 468 recent Russian clinical Streptococcus pneumoniae isolates and 600 Streptococcus pyogenes isolates, from 14 centers in Russia, to telithromycin, erythromycin, azithromycin, clarithromycin, clindamycin, levofloxacin, quinupristin-dalfopristin, and penicillin G were tested. Penicillin-nonsusceptible S. pneumoniae strains were rare except in Siberia, where their prevalence rate was 13.5%: most were penicillin intermediate, but for three strains (two from Smolensk and one from Novosibirsk) the MICs of penicillin G were 4 or 8 μg/ml. Overall, 2.5% of S. pneumoniae isolates were resistant to erythromycin. Efflux was the prevalent resistance mechanism (five strains; 41.7%), followed by ribosomal methylation encoded by constitutive erm(B), which was found in four isolates. Ribosomal mutation was the mechanism of macrolide resistance in three isolates; one erythromycin-resistant S. pneumoniae isolate had an A2059G mutation in 23S rRNA, and two isolates had substitution of GTG by TPS at positions 69 to 71 in ribosomal protein L4. All S. pyogenes isolates were susceptible to penicillin, and 11% were erythromycin resistant. Ribosomal methylation was the most common resistance mechanism for S. pyogenes (89.4%). These methylases were encoded by erm(A) [subclass erm(TR)] genes, and their expression was inducible in 96.6% of isolates. The rest of the erythromycin-resistant Russian S. pyogenes isolates (7.6%) had an efflux resistance mechanism. Telithromycin was active against 100% of pneumococci and 99.2% of S. pyogenes, and levofloxacin and quinupristin-dalfopristin were active against all isolates of both species.

In Vitro Antianaerobic Activity of Ertapenem (MK-0826) Compared to Seven Other Compounds

ABSTRACT Ertapenem, imipenem, meropenem, ceftriaxone, piperacillin, piperacillin-tazobactam, clindamycin, and metronidazole were agar dilution MIC tested against 431 anaerobes. Imipenem, meropenem, and ertapenem were the most active β-lactams (MICs at which 50% of the strains are inhibited [MIC50s], 0.125 to 0.25 μg/ml; MIC90s, 1.0 to 2.0 μg/ml). Time-kill studies revealed that ertapenem at two times the MIC was bactericidal for 9 of 10 strains after 48 h. The kinetics for other β-lactams were similar to those of ertapenem.