tigecycline and Streptococcal-Infections

Exposure-response analyses were performed for the microbiological and clinical efficacy of tigecycline in the treatment of complicated skin and skin-structure infections, where Staphylococcus aureus and streptococci are the predominant pathogens. A prospective method was developed to create homogeneous patient populations for PK-PD analyses. Evaluable patients from three clinical trials were pooled for analysis. Patients received a tigecycline 100-mg loading dose/50 mg every 12 h or a 50-mg loading dose/25 mg every 12 h. At the test-of-cure visit, microbiologic and clinical responses were evaluated. Patients were prospectively evaluated and classified into cohorts based on baseline pathogens: S. aureus only (cohort 1), monomicrobial S. aureus or streptococci (cohort 2), two gram-positive pathogens (cohort 3), polymicrobial (cohort 4), or other monomicrobial infections (cohort 5). A prospective procedure for combining cohorts was used to increase the sample size. Logistic regression evaluated steady-state 24-h area under the concentration-time curve (AUC(24))/MIC ratio as a predictor of response, and classification and regression tree (CART) analyses were utilized to determine AUC/MIC breakpoints. Analysis began with pooled cohorts 2 and 3, the focus of these analyses, and included 35 patients with 40 S. aureus and/or streptococcal pathogens. CART analyses identified a significant AUC/MIC breakpoint of 17.9 (P = 0.0001 for microbiological response and P = 0.0376 for clinical response). The continuous AUC/MIC ratio was predictive of microbiological response based on sample size (P = 0.0563). Analysis of all pathogens combined decreased the ability to detect exposure-response relationships. The prospective approach of creating homogeneous populations based on S. aureus and streptococci pathogens was critical for identifying exposure-response relationships.

Topics: Adult; Aged; Anti-Bacterial Agents; Area Under Curve; Double-Blind Method; Female; Humans; Logistic Models; Male; Microbial Sensitivity Tests; Middle Aged; Minocycline; Skin Diseases, Bacterial; Staphylococcal Skin Infections; Staphylococcus aureus; Streptococcal Infections; Streptococcus; Tigecycline; Treatment Outcome

A novel series of fully synthetic 8-azatetracyclines was prepared and evaluated for antibacterial activity. Compounds were identified that overcome both efflux (tet(K)) and ribosomal protection (tet(M)) tetracycline resistance mechanisms and are active against Gram-positive and Gram-negative organisms. Two compounds were identified that exhibit comparable efficacy to marketed tetracyclines in in vivo models of bacterial infection.

Topics: Administration, Oral; Animals; Anti-Bacterial Agents; Aza Compounds; Biological Availability; Escherichia coli Infections; Gram-Negative Bacteria; Gram-Positive Bacteria; Injections, Intravenous; Mice; Microbial Sensitivity Tests; Rats; Rats, Sprague-Dawley; Sepsis; Streptococcal Infections; Structure-Activity Relationship; Tetracycline Resistance; Tetracyclines

We describe 66 ciprofloxacin-nonsusceptible Streptococcus pyogenes isolates recovered from colonized and infected children. The ParC S79A substitution was frequent and associated with the emm6/sequence type 382 (emm6/ST382) lineage. The ParC D83G substitution was detected in two isolates (emm5/ST99 and emm28/ST52 lineages). One isolate (emm89/ST101) had no quinolone resistance-determining region codon substitutions or other resistance mechanisms. Five of 66 isolates were levofloxacin resistant. Although fluoroquinolones are not used in children, they may be putative disseminators of fluoroquinolone-nonsusceptible strains in the community.

Topics: Amino Acid Substitution; Anti-Bacterial Agents; Antigens, Bacterial; Bacterial Outer Membrane Proteins; Bacterial Typing Techniques; Carrier Proteins; Child; Ciprofloxacin; Drug Resistance, Bacterial; Humans; Molecular Epidemiology; Norfloxacin; Point Mutation; Portugal; Streptococcal Infections; Streptococcus pyogenes