The association of psychiatric medication use with adherence in patients with HIV.

Over two million new cases of HIV infection will occur annually, worldwide. Triple drug anti-retroviral therapy (ART) decreases the viral load in patients with HIV, helping to stop progression of HIV infection to AIDs. Our study assessed how pharmacologic treatment for mental health issues affects medication adherence and viral load in patients with HIV. We conducted a retrospective chart review of 163 patients with HIV who had at least 2 visits at the HIV-clinic at Ascension St. John Hospital. Data were collected on demographics, medications, CD4 counts and viral loads. Data were analyzed using Student's t-test, the χ2 test, the Mann-Whitney U test and logistic regression. "Poor Compliance" was defined as at least 2 consecutive visits with a CD4 count <200 µL and/or with viral load ≥100 IU/ml. Patients taking antidepressants were less likely to have poor compliance than those not on anti-depressants (6.3% vs. 22.3%, p = 0.04). A similar association was found for patients taking any psychiatric drug (7.0% vs. 23.5%, p = 0.02). On multivariable analysis, the odds of poor compliance were 6.3 times higher in patients who stopped HIV therapy for greater than one week between visits (p = 0.004) and 3.6 times lower in patients taking any psychiatric medication (p = 0.05).

TXA709, an FtsZ-Targeting Benzamide Prodrug with Improved Pharmacokinetics and Enhanced In Vivo Efficacy against Methicillin-Resistant Staphylococcus aureus.

The clinical development of FtsZ-targeting benzamide compounds like PC190723 has been limited by poor drug-like and pharmacokinetic properties. Development of prodrugs of PC190723 (e.g., TXY541) resulted in enhanced pharmaceutical properties, which, in turn, led to improved intravenous efficacy as well as the first demonstration of oral efficacy in vivo against both methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA). Despite being efficacious in vivo, TXY541 still suffered from suboptimal pharmacokinetics and the requirement of high efficacious doses. We describe here the design of a new prodrug (TXA709) in which the Cl group on the pyridyl ring has been replaced with a CF3 functionality that is resistant to metabolic attack. As a result of this enhanced metabolic stability, the product of the TXA709 prodrug (TXA707) is associated with improved pharmacokinetic properties (a 6.5-fold-longer half-life and a 3-fold-greater oral bioavailability) and superior in vivo antistaphylococcal efficacy relative to PC190723. We validate FtsZ as the antibacterial target of TXA707 and demonstrate that the compound retains potent bactericidal activity against S. aureus strains resistant to the current standard-of-care drugs vancomycin, daptomycin, and linezolid. These collective properties, coupled with minimal observed toxicity to mammalian cells, establish the prodrug TXA709 as an antistaphylococcal agent worthy of clinical development.

Ceftaroline-heteroresistant Staphylococcus aureus.

Heteroresistance refers to the presence, within a large population of antimicrobial-susceptible microorganisms, of subpopulations with lesser susceptibilities. Ceftaroline is a novel cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA). The aim of this study was to detect the prevalence of ceftaroline heteroresistance in vitro in a select group of S. aureus strains. There were 57 isolates selected for evaluation, 20 MRSA, 20 vancomycin-intermediate S. aureus (VISA), 7 daptomycin-nonsusceptible S. aureus (DNSSA), 6 linezolid-nonsusceptible S. aureus (LNSSA), and 4 heteroresistant VISA (hVISA) isolates. MICs and minimal bactericidal concentrations were determined using the broth microdilution method according to CLSI guidelines. All of the isolates were analyzed by pulsed-field gel electrophoresis. The staphylococcal cassette chromosome mec element (SCCmec) types were determined by a multiplex PCR. Population analysis profiles (PAPs) were performed to determine heteroresistance for all of the isolates using plates made by adding various amounts of ceftaroline to brain heart infusion agar. The frequencies of resistant subpopulations were 1 in 10(4) to 10(5) organisms. We determined that 12 of the 57 (21%) isolates tested were ceftaroline-heteroresistant S. aureus (CHSA). CHSA occurred among strains with reduced susceptibilities to vancomycin, daptomycin, and linezolid but occurred in none of the USA-300 isolates tested. Evaluation of the heteroresistant strains demonstrated that the phenotype was unstable. Further studies are needed to determine whether CHSA has a role in clinical failures and to determine the implications of our study findings.

In Vitro Activity of Retapamulin against Staphylococcus aureus Resistant to Various Antimicrobial Agents.

Retapamulin and six other antimicrobial agents were evaluated against 155 methicillin-resistant Staphylococcus aureus (MRSA) isolates, including strains resistant to vancomycin, linezolid, daptomycin, and mupirocin by microdilution tests. Time-kill assays were performed against representative MRSA, vancomycin-intermediate S. aureus (VISA), and vancomycin-resistant S. aureus (VRSA) isolates. Retapamulin and mupirocin demonstrated MIC90s of 0.12 µg/ml and 8 µg/ml, respectively, with resistance seen in 2.6% and 10% of isolates, respectively. Retapamulin maintained good activity against 94% (15/16) of mupirocin-resistant isolates.