Influence of Bile Acids on Clindamycin Hydrochloride Skin Permeability: In Vitro and In Silico Preliminary Study.

BACKGROUND AND OBJECTIVE: Topical clindamycin formulations are widely used in clinical practice, but poor bioavailability and restricted skin penetration considerably limit their therapeutic efficacy. Penetration enhancement represents a promising and rational strategy to overcome the drawbacks of conventional topical pharmaceutical formulations. We aim to assess the influence of cholic acid (CA) and deoxycholic acid (DCA) on the permeability of clindamycin hydrochloride by performing the in vitro skin parallel artificial membrane permeability assay (skin-PAMPA) at two relevant pH values (5.5 and 6.5) and the interactions of tested substances with skin ATP-binding cassette (ABC) transporters in silico. METHODS: After the incubation period, the clindamycin hydrochloride concentrations in both compartments were determined spectrophotometrically, and the apparent permeability coefficients (Papp) were calculated. Vienna LiverTox web service was used to predict the interactions of clindamycin and bile acids with potential drug transporters located in human skin. RESULTS: Both CA and DCA at the highest studied concentration of 100 µM in the tested solutions increased the skin-PAMPA membrane permeability of clindamycin hydrochloride. This effect was more pronounced for CA and at a higher studied pH value of 6.5, which is characteristic of most dermatological indications treated with topical clindamycin preparations. Clindamycin transport may also be mediated by ABC transporters located in skin and facilitated in the presence of bile acids. CONCLUSIONS: The results of this study provide a solid foundation for further research directed at the improvement of topical formulations using bile acids as penetration-enhancing excipients, as well as the therapeutic efficacy of clindamycin hydrochloride.

Detección de resistencia inducible a clindamicina en aislados cutáneos de Staphylococcus spp. por métodos fenotípicos y genotípicos / Detection of inducible resistance to clindamycin in cutaneous isolates of Staphylococcus spp. by phenotypic and genotypic methods

Introducción. La resistencia de estafilococos a macrólidos, lincosamidas y estreptograminas del tipo B (antibióticos MLSB) puede ser debida a varios mecanismos de resistencia y entre ellos los dos más importantes son la expulsión activa (fenotipo MSB) y la modificación de la diana en el ribosoma (fenotipo MLSB). Este último mecanismo confiere resistencia cruzada a los 3 grupos de antimicrobianos (resistencia MLSB). La expresión fenotípica de la resistencia MLSB puede ser de carácter constitutivo (cMLSB) o inducible (iMLSB). Métodos. Se estudiaron 117 estafilococos resistentes a eritromicina procedentes de muestras cutáneas que fueron seleccionados a partir de 536 aislados clínicos de estafilococos. El estudio fenotípico se realizó mediante la técnica de difusión por doble disco. La presencia de los genes ermA, ermC, ermB y msrA implicados en la resistencia se estudiaron por reacción en cadena de la polimerasa (PCR) en tiempo real. Resultados. El fenotipo MSB fue el más frecuente, encontrándose en el 11,2% de las cepas (7,2% Staphylococcus aureus y 23% ECN) y la tasa de resistencia inducible iMLSB, fue estadísticamente significativa más alta 7,4% (5,2% en S. aureus y 14% en ECN) que la tasa de resistencia constitutiva cMLSB, 3,2% (1,7% en S. aureus y 7,4% en ECN). Todos los aislados con el fenotipo MSB presentaron el gen msrA y el gen ermC fue el más frecuentemente detectado en las cepas resistentes a clindamicina con fenotipo MLSB (constitutivo o inducible). Conclusión. La buena correlación entre los métodos fenotípicos (doble difusión con discos) y genotípicos permiten inferir el mecanismo de resistencia a eritromicina y clindamicina, seleccionar el tratamiento antimicrobiano más adecuado, así como apreciar las diferencias epidemiológicas en su distribución (AU)

Introduction. Resistance to macrolides, lincosamides and type B streptogramins (MLSB) in Staphylococcus isolates can be due to several mechanisms. The most important are an active efflux mechanism (MSB phenotype) and ribosomal target modification (MLSB phenotype); this latter mechanism confers resistance to all three groups of antimicrobials (MLSB resistance). Expression of MLSB resistance can be constitutive (cMLSB) or inducible (iMLSB). Methods. A group of 117 erythromycin-resistant Staphylococcus spp. clinical isolates from cutaneous samples were selected from 536 recent clinical isolates of this microorganism. Resistance phenotypes were determined by the double disk diffusion test. Presence of the ermA, ermC, ermB and msrA genes was detected by real time PCR. Results. The MSB phenotype was the most common, comprising 11.2% (7.2% in S. aureus and 23% in CoNS) of the erythromycin-resistant strains. The rate of iMLSB resistance was significantly higher, 7.4% (5.2% in S. aureus and 14% in CoNS), than the rate of cMLSB resistance, 3.2% (1.7% in S. aureus and 7.4% in CoNS). The msrA gene was present in all isolates with the MSB phenotype, and the ermC gene was the most common among clindamycin-resistant strains with the MLSB phenotype (constitutive or inducible). Conclusion. The good correlation between the phenotypic (disk-diffusion) and genotypic (real time PCR) methods used allows prediction of the mechanisms of erythromycin and clindamycin resistance, provides insight into the epidemiological differences in their distribution, and is an aid to selecting the most appropriate antimicrobial therapy (AU)