Lori Brennan

Multicity Outbreak of Linezolid-Resistant Staphylococcus epidermidis Associated with Clonal Spread of a cfr-Containing Strain

We report a multicity outbreak of cfr-containing linezolid-resistant Staphylococcus epidermidis in Ohio. Thirty-nine isolates were obtained from 2 hospitals. Two clones with different mechanisms of linezolid resistance were circulating in hospital A. One of these contained the cfr gene, and the other a ribosomal mutation. The clone containing cfr was identical in both hospitals.

Novel quinoline derivatives as inhibitors of bacterial DNA gyrase and topoisomerase IV.

A structurally novel set of inhibitors of bacterial type II topoisomerases with potent in vitro and in vivo antibacterial activity was developed. Dual-targeting ability, hERG inhibition, and pharmacokinetic properties were also assessed.

Effects of environmental factors on the in vitro potency of azithromycin

The effects of media, pH, cations, serum, CO2 or anaerobic atmosphere, inoculum size and time of incubation on the in vitro potency of azithromycin were determined. The potency of azithromycin against all genera was particularly sensitive to changes in pH. The MIC forStaphylococcus aureus strains ranged from 50 µg/ml at pH 6 to ≤ 0.025 µg/ml at pH 8; for erythromycin the MIC change was less (1.6 to 0.05 µg/ml). Incubation for 18 h in 5 % CO2 or an anaerobic atmosphere (10 % CO2, 10 % H2, 80 % N2) lowered the pH by approximately 0.8 units with gram-negative organisms and 0.4 units with gram-positive organisms. This resulted in an MIC eight times greater than the aerobic MIC. In addition, the MIC100 for azithromycin and erythromycin againstBacteroides strains growing in Wilkins-Chalgren broth fell from 3.1 µg/ml in the anaerobic atmosphere to 0.2 and 0.4 µg/ml, respectively, when using the Oxyrase enzyme system to remove oxygen. With the Oxyrase system, the pH of the medium at the MIC remained at 7.2, while it fell to 6.7 in the anaerobic gas mixture. An increase in potency for both agents was also observed with other anaerobic species when using the Oxyrase system. The addition of serum produced an increase in potency of azithromycin and erythromycin that correlated with an increase in pH during incubation, despite the use of buffered media. Adding cations to Mueller-Hinton broth resulted in increased MICs for gram-negative organisms; the highest increases observed were four-fold forEscherichia coli. The activity of control antibiotics was not affected to the same degree as that of azithromycin. Increasing the incubation period from 24 to 48 h did not change the MIC values of azithromycin forStaphylococcus aureus orEscherichia coli; however, the MBC values were lower at 48 h and equalled the MIC values. Inoculum size or manner of preparation had no significant effect on the potency of azithromycin.

Lack of emergence of significant resistance in vitro and in vivo to the new azalide antibiotic azithromycin

In vitro experiments were performed in which 6 to 12 strains ofStaphylococcus aureus, Streptococcus pyogenes, Haemophilus influenzae andEnterobacteriaceae were passaged nine times in sub-lethal concentrations of azithromycin or control antibiotics.Streptococcus pyogenes andStaphylococcus aureus quickly became resistant to rifampin as the MIC90 increased from 0.1 to > 50 µg/ml for both species. The MIC90 of azithromycin, erythromycin, amoxicillin and cefaclor increased by three dilutions forStaphylococcus aureus. The MIC values of azithromycin forStreptococcus pyogenes, Haemophilus influenzae andEnterobacteriaceae strains did not change significantly. However, forHaemophilus influenzae and theEnterobacteriaceae strains, the MIC values of erythromycin and oral cephalosporins increased four-fold. In the in vivo experiments, mice infected withStaphylococcus aureus orEscherichia coli contaminated sutures were administered azithromycin for three days, and on day 6 viable bacterial cells were recovered from the infection site. The sustained tissue concentrations of azithromycin indicated that the organisms would have been continuously exposed to azithromycin at the site of infection. Colonies isolated from azithromycin-treated and non-treated mice were cultured and their susceptibility to azithromycin compared. The azithromycin MIC values forStaphylococcus aureus cultures from treated and non-treated animals were identical. The azithromycin MICs forEscherichia coli recovered from treated animals were on average, less than one dilution higher than for control cultures. Emergence of significant resistance to azithromycin in the laboratory was not observed with the pathogens tested.

Novel 3-fluoro-6-methoxyquinoline derivatives as inhibitors of bacterial DNA gyrase and topoisomerase IV ☆

Novel (non-fluoroquinolone) inhibitors of bacterial type II topoisomerases (NBTIs) are an emerging class of antibacterial agents. We report an optimized series of cyclobutylaryl-substituted NBTIs. Compound 14 demonstrated excellent activity both in vitro (S. aureus MIC90=0.125μg/mL) and in vivo (systemic and tissue infections). Enhanced inhibition of Topoisomerase IV correlated with improved activity in S. aureus strains with mutations conferring resistance to NBTIs. Compound 14 also displayed an improved hERG IC50 of 85.9μM and a favorable profile in the anesthetized guinea pig model.