RESUMEN
AIMS: This study aimed to assess the pharmacokinetic/pharmacodynamic (PK/PD) targets of danofloxacin to minimize the risk of selecting resistant Pasteurella multocida mutants and to identify the mechanisms underlying their resistance in an in vitro dynamic model, attaining the optimum dosing regimen of danofloxacin to improve its clinical efficacy based on the mutant selection window (MSW) hypothesis. METHODS AND RESULTS: Danofloxacin at seven dosing regimens and 5 days of treatment were simulated to quantify the bactericidal kinetics and enrichment of resistant mutants upon continuous antibiotic exposure. The magnitudes of PK/PD targets associated with different efficacies were determined in the model. The 24 h area under the concentration-time curve (AUC) to minimum inhibitory concentration (MIC) ratios (AUC24h/MIC) of danofloxacin associated with bacteriostatic, bactericidal and eradication effects against P. multocida were 34, 52, and 64 h. This translates to average danofloxacin concentrations (Cav) over 24 h being 1.42, 2.17, and 2.67 times the MIC, respectively. An AUC/MIC-dependent antibacterial efficacy and AUC/mutant prevention concentration (MPC)-dependent enrichment of P. multocida mutants in which maximum losses in danofloxacin susceptibility occurred at a simulated AUC24h/MIC ratio of 72 h (i.e. Cav of three times the MIC). The overexpression of efflux pumps (acrAB-tolC) and their regulatory genes (marA, soxS, and ramA) was associated with reduced susceptibility in danofloxacin-exposed P. multocida. The AUC24h/MPC ratio of 19 h (i.e. Cav of 0.8 times the MPC) was determined to be the minimum mutant prevention target value for the selection of resistant P. multocida mutants. CONCLUSIONS: The emergence of P. multocida resistance to danofloxacin exhibited a concentration-dependent pattern and was consistent with the MSW hypothesis. The current clinical dosing regimen of danofloxacin (2.5 mg kg-1) may have a risk of treatment failure due to inducible fluoroquinolone resistance.
Asunto(s)
Antibacterianos , Farmacorresistencia Bacteriana , Fluoroquinolonas , Pruebas de Sensibilidad Microbiana , Pasteurella multocida , Pasteurella multocida/efectos de los fármacos , Pasteurella multocida/genética , Fluoroquinolonas/farmacología , Antibacterianos/farmacología , Farmacorresistencia Bacteriana/genética , MutaciónRESUMEN
ß-Lactam antibiotics are the mainstay for the treatment of staphylococcal infections, but their utility is greatly limited by the emergence and rapid dissemination of methicillin-resistant Staphylococcus aureus (MRSA). Herein, we evaluated the ability of the plant-derived monoterpene carvacrol to act as an antibiotic adjuvant, revitalizing the anti-MRSA activity of ß-lactam antibiotics. Increased susceptibility of MRSA to ß-lactam antibiotics and significant synergistic activities were observed with carvacrol-based combinations. Carvacrol significantly inhibited MRSA biofilms and reduced the production of exopolysaccharide, polysaccharide intercellular adhesin, and extracellular DNA and showed synergistic biofilm inhibition in combination with ß-lactams. Transcriptome analysis revealed profound downregulation in the expression of genes involved in two-component systems and S. aureus infection. Mechanistic studies indicate that carvacrol inhibits the expression of staphylococcal accessory regulator sarA and interferes with SarA-mecA promoter binding that decreases mecA-mediated ß-lactam resistance. Consistently, the in vivo experiment also supported that carvacrol restored MRSA sensitivity to ß-lactam antibiotic treatments in both murine models of bacteremia and biofilm-associated infection. Our results indicated that carvacrol has a potential role as a combinatorial partner with ß-lactam antibiotics to address MRSA infections.
Asunto(s)
Bacteriemia , Staphylococcus aureus Resistente a Meticilina , Animales , Ratones , Staphylococcus aureus Resistente a Meticilina/genética , Staphylococcus aureus Resistente a Meticilina/metabolismo , Antibióticos Betalactámicos , Staphylococcus aureus , Monobactamas , Biopelículas , CatéteresRESUMEN
This study aimed to determine the prevalence of double eyelid among two main Mongoloid ethnicities, the Malays and Chinese who reside in Malaysia. We also measured their periorbital tissue parameters for application in anthropology, optometry, ophthalmology, oculoplastic surgery and maxillofacial trauma surgery. The images of the 103 Malay and 97 Chinese volunteers were captured using indirect 3D photogrammetry, and quantitative measurement was obtained using the software provided by the manufacturer. All Malays and 70.1% of Chinese in this cross section population had double eyelid on both eyes. The mean pretarsal skin height was 3.99 mm for the Malays and 2.29 mm for the Chinese. The Malays appeared to have shorter eyebrow height (11.10 mm) compared to the Chinese (11.79 mm). An opposite pattern could be seen in the measurement of upper eyelid crease height between the Malays (8.33 mm) and the Chinese (4.91 mm). Of note, the intercanthal distance of the Chinese (IDC = 35.85 mm) was wider and their interpupillary distance was narrower (IPD = 62.85 mm) compared to the Malays' (ICD = 34.21 mm; IPD = 64.04 mm). In conclusion, there were significant differences in the prevalence of double eyelid and periorbital tissue measurements between the Malays and Chinese.