RESUMEN
Skin infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and the spread of antimicrobial resistance are a major problem in Japan. Here, we investigated the susceptibility of S. aureus clinical isolates to ozenoxacin (OZNX), a topical antimicrobial approved for superficial skin infection treatment in Japan. Susceptibility to OZNX was measured in 110 skin-derived methicillin-susceptible S. aureus (MSSA) and 130 MRSA strains isolated in 2019 and 2020 in Japan. The broth microdilution method was performed, and results were analyzed according to the Clinical and Laboratory Standard Institute (M07 and M100) guidelines. The results were compared with those of other antimicrobials used against S. aureus. The minimum inhibitory concentrations (MIC)90 of OZNX for MSSA and MRSA were 0.12 and 0.25 µg/mL, respectively, indicating that OZNX exhibited the same or stronger antibacterial activity than that of the other antimicrobials tested, such as nadifloxacin, fucidic acid, and gentamicin. No strains exhibited reduced OZNX susceptibility. Notably, a low MIC of OZNX was observed even for strains with reduced susceptibility to nadifloxacin, a similar quinolone-based topical antimicrobial. OZNX is a highly potent antimicrobial used in Japan for superficial skin infections caused by S. aureus, such as impetigo contagiosa and related diseases.
Asunto(s)
Antiinfecciosos , Staphylococcus aureus Resistente a Meticilina , Quinolonas , Infecciones Estafilocócicas , Aminopiridinas , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Antiinfecciosos/uso terapéutico , Gentamicinas/uso terapéutico , Humanos , Japón , Meticilina/uso terapéutico , Pruebas de Sensibilidad Microbiana , Quinolonas/farmacología , Quinolonas/uso terapéutico , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus aureusRESUMEN
The in vitro microbicidal activity of benzoyl peroxide against Cutibacterium acnes, Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Pseudomonas aeruginosa, Candida albicans, Malassezia furfur, Malassezia restricta, and Malassezia globosa was investigated. These strains were incubated for 1 h in the presence of 0.25, 0.5, 1, or 2 mmol/L benzoyl peroxide in phosphate buffered saline supplemented with 0.1% glycerol and 2% Tween 80. After exposure to benzoyl peroxide, counts of viable Gram-positive bacteria and fungi were markedly decreased, whereas counts of Gram-negative bacteria were unchanged. Transmission electron microscopy images showed a decrease in electron density and the destruction of C. acnes and M. restricta cell walls after exposure to 2 mmol/L benzoyl peroxide. In conclusion, this study showed that benzoyl peroxide has a potent and rapid microbicidal activity against Gram-positive bacteria and fungi that are associated with various cutaneous diseases. This suggests that the direct destruction of bacterial cell walls by benzoyl peroxide is an essential mechanism of its rapid and potent microbicidal activity against microorganisms.
Asunto(s)
Peróxido de Benzoílo , Propionibacterium acnes , Malassezia , Pruebas de Sensibilidad MicrobianaRESUMEN
BACKGROUND: Amenamevir (AMNV) is a helicase-primase inhibitor with antiviral activity against herpesviruses [herpes simplex viruses (HSV)-1 and -2, and varicella-zoster virus], which are associated with the development of acute herpetic pain (AHP) and postherpetic neuralgia. However, the inhibitory effects of helicase-primase inhibitors on AHP and postherpetic neuralgia remain incompletely understood. OBJECTIVE: In this study, we investigated the effects of AMNV on AHP and postherpetic pain (PHP) in HSV-1-infected mice accompanied by zosteriform-like skin lesions. METHODS: HSV-1 was percutaneously infected on the femoral region of mice. AMNV was orally administered twice a day for 5 days. Pain-related response in the hind paw was evaluated using a paintbrush. The infiltration of inflammatory cells in dorsal root ganglion (DRG) and spinal cord (SC) was evaluated by hematoxylin and eosin staining. The viral load in DRG and the expression of pain-related genes in SC were measured by real-time PCR. RESULTS: Pain response was begun to be observed from day 3 post-infection (pi) in HSV-1-infected mice. AMNV administered repeatedly from day 3 pi or day 4 pi, but not day 5 pi, showed an inhibitory effect on the development of AHP and the transition to PHP. Repeated AMNV administration inhibited inflammatory cell infiltration and increases in the viral load and the expression of pain-related genes (ATF-3, TNF-α, COX-2). CONCLUSION: These results demonstrate that AMNV potently suppresses the development of AHP and the transition to PHP as a consequence of decreased viral load in DRG and reduced expression of pain-related genes in SC.
Asunto(s)
Dolor Agudo/tratamiento farmacológico , Antivirales/administración & dosificación , Herpes Simple/tratamiento farmacológico , Neuralgia Posherpética/tratamiento farmacológico , Oxadiazoles/administración & dosificación , Dolor Agudo/inmunología , Dolor Agudo/virología , Administración Oral , Animales , Modelos Animales de Enfermedad , Femenino , Herpes Simple/complicaciones , Herpes Simple/inmunología , Herpes Simple/virología , Herpesvirus Humano 1/inmunología , Herpesvirus Humano 1/aislamiento & purificación , Humanos , Ratones , Neuralgia Posherpética/inmunología , Neuralgia Posherpética/virología , Carga Viral/efectos de los fármacos , Carga Viral/inmunologíaRESUMEN
Ozenoxacin is a topical quinolone showing potent antimicrobial activities against Gram-negative and Gram-positive bacteria and is widely used for the treatment of inflammatory acne. However, the anti-inflammatory activities of ozenoxacin have not been examined so far. In the present study, we investigated the in vitro and in vivo anti-inflammatory effects of ozenoxacin. The production of interleukin (IL)-6 and IL-8 by human epidermal keratinocytes stimulated by heat-killed Cutibacterium acnes was significantly inhibited by ozenoxacin at concentrations from 1 to 30 µg ml-1. Likewise, the production of IL-6, IL-8, and tumor necrosis factor alpha by stimulated THP-1 cells, a human monocyte cell line, was inhibited by ozenoxacin at concentrations from 1 to 30 µg ml-1. The production of IL-1ß by THP-1 was also inhibited by ozenoxacin at the concentration of 30 µg ml-1. Phosphorylation of the mitogen-activated protein kinases and degradation of IκB-α, an inhibitory factor of NF-κB in keratinocytes and THP-1 cells, was increased by stimulation with heat-killed C. acnes. Of these activated intracellular pathways, the p38 phosphorylation pathway was remarkably reduced by ozenoxacin in both keratinocytes and THP-1 cells. In addition, the application of 2% ozenoxacin suppressed the increase in the ear thickness of rats induced by an intracutaneous injection of heat-killed C. acnes. These findings suggest that ozenoxacin possesses an anti-inflammatory activity, which may contribute to its therapeutic effects on inflammatory acne.
Asunto(s)
Aminopiridinas/farmacología , Antiinflamatorios/farmacología , Inflamación/tratamiento farmacológico , Quinolonas/farmacología , Acné Vulgar/tratamiento farmacológico , Acné Vulgar/patología , Aminopiridinas/administración & dosificación , Animales , Antiinflamatorios/administración & dosificación , Línea Celular , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Humanos , Inflamación/microbiología , Inflamación/patología , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Masculino , Propionibacterium acnes/patogenicidad , Quinolonas/administración & dosificación , Ratas , Ratas Sprague-Dawley , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Atopic dermatitis (AD)-like dermatitis can be induced by repeated topical application of an ointment containing Dermatophagoides farinae body (Dfb) extract in NC/Nga mice. This AD-like murine model also exhibits a biphasic increase in the number of scratching behaviour after topical application of Dfb ointment. In this study, we investigated the possible mechanisms underlying the scratching behaviour in each phase. An increase in the content of mast cell-derived mediators such as histamine and 5-hydroxytryptamine in the lesional skin and increased vascular permeability were observed in the early phase after the Dfb ointment application. Chlorpheniramine (H1 receptor antagonist) and cromoglycate (mast cell stabilizer) reduced the scratching behaviour in the early phase but not that in the later phase. Furthermore, the content of various endogenous pruritogens such as interleukin-31 and thymic stromal lymphopoietin in the lesional skin was increased 1 or 24 hours after the Dfb ointment application. Elevated expression of proteinase-activated receptor-2 (PAR-2) was also observed in the epidermis. Finally, gabexate (serine protease inhibitor) reduced the scratching behaviour in both phases, and anti-PAR2 antibody also showed a tendency to reduce both scratching behaviours. These findings suggest that immediate-type allergic reactions caused by mast cell degranulation and PAR-2 activation by proteases are involved in the scratching behaviour in this AD-like model.
Asunto(s)
Conducta Animal , Dermatitis Atópica/metabolismo , Hipersensibilidad/metabolismo , Prurito/metabolismo , Animales , Anticuerpos/uso terapéutico , Antipruriginosos/uso terapéutico , Conducta Animal/efectos de los fármacos , Permeabilidad Capilar/efectos de los fármacos , Clorfeniramina/uso terapéutico , Mezclas Complejas , Cromolin Sódico/uso terapéutico , Citocinas/metabolismo , Dermatitis Atópica/inducido químicamente , Dermatitis Atópica/inmunología , Dermatophagoides farinae , Modelos Animales de Enfermedad , Epidermis/metabolismo , Femenino , Gabexato/uso terapéutico , Histamina/metabolismo , Hipersensibilidad/inmunología , Factores Inmunológicos/uso terapéutico , Interleucinas/metabolismo , Mastocitos/metabolismo , Ratones , Pomadas , Prurito/inducido químicamente , Prurito/tratamiento farmacológico , Prurito/inmunología , Receptor PAR-2/inmunología , Receptor PAR-2/metabolismo , Inhibidores de Serina Proteinasa/uso terapéutico , Serotonina/metabolismo , Linfopoyetina del Estroma TímicoRESUMEN
Ozenoxacin, a novel non-fluorinated topical quinolone, is used for the treatment of acne vulgaris in Japan. We investigated bactericidal activity and post-antibiotic effect (PAE) of ozenoxacin against Propionibacterium acnes, a major causative bacterium of acne vulgaris. The minimum inhibitory concentrations (MICs) of ozenoxacin against 3 levofloxacin-susceptible strains (MIC of levofloxacin; ≤4 µg/mL) and 3 levofloxacin-resistant strains (MIC of levofloxacin; ≥8 µg/mL) ranged from 0.03 to 0.06 µg/mL and from 0.25 to 0.5 µg/mL, respectively. These MICs of ozenoxacin were almost the same or lower than nadifloxacin and clindamycin. The minimum bactericidal concentrations (MBCs) of ozenoxacin against the levofloxacin-susceptible and -resistant strains were from 0.06 to 8 µg/mL and from 0.5 to 4 µg/mL, respectively. These MBCs were lower than those of nadifloxacin and clindamycin. In time-kill assay, ozenoxacin at 1/4, 1 and 4 times the respective MIC against both levofloxacin-susceptible and -resistant strains showed a concentration-dependent bactericidal activity. Ozenoxacin at 4 times the MICs against the levofloxacin-susceptible strains showed more potent and more rapid onset of bactericidal activity compared to nadifloxacin and clindamycin at 4 times the respective MICs. The PAEs of ozenoxacin at 4 times the MICs against the levofloxacin-susceptible strains were from 3.3 to 17.1 h, which were almost the same or longer than nadifloxacin and clindamycin. In contrast, the PAEs were hardly induced by any antimicrobial agents against the levofloxacin-resistant strains. The present findings suggest that ozenoxacin has a potent bactericidal activity against both levofloxacin-susceptible and -resistant P. acnes, and a long-lasting PAE against levofloxacin-susceptible P. acnes.
Asunto(s)
Aminopiridinas/farmacología , Antibacterianos/farmacología , Propionibacterium acnes/efectos de los fármacos , Quinolonas/farmacología , Infecciones por Bacterias Grampositivas/microbiología , Humanos , Levofloxacino/farmacología , Pruebas de Sensibilidad MicrobianaRESUMEN
Ozenoxacin, a novel non-fluorinated topical quinolone, was assessed for in vitro antimicrobial activity against clinical isolates of propionibacteria and staphylococci according to the broth microdilution method recommended by the Clinical and Laboratory Standards Institute. The isolates used in this study were collected from Japanese patients with acne vulgaris during a period from 2012 to 2013. The MIC90s of ozenoxacin against Propionibacterium acnes (n=266), Propionibacterium granulosum (n=10), Staphylococcus aureus (n=23), Staphylococcus epidermidis (n=229) and other coagulase-negative staphylococci (n=82) were ≤0.06, ≤0.06, ≤0.06, 0.125 and ≤0.06 µg ml-1, respectively. The antimicrobial activity of ozenoxacin against the clinical isolates of propionibacteria and staphylococci was greater than that of five reference antimicrobial agents which have been used for the treatment of acne vulgaris. The MICs of ozenoxacin were correlated with those of nadifloxacin in P. acnes and S. epidermidis isolates. However, the MICs of ozenoxacin were 0.25-0.5 µg ml-1 and 0.5-8 µg ml-1 against nadifloxacin-resistant P. acnes (MIC: ≥8 µg ml-1; n=8) and S. epidermidis (MIC: ≥64 µg ml-1; n=10), respectively. These results indicated the potent antimicrobial activity against P. acnes and S. epidermidis isolates resistant to nadifloxacin. Topical ozenoxacin could represent an alternative therapeutic drug for acne vulgaris based on its potent antimicrobial activity against the isolates of propionibacteria and staphylococci from acne patients.
Asunto(s)
Acné Vulgar/microbiología , Aminopiridinas/farmacología , Antiinfecciosos/farmacología , Propionibacterium/efectos de los fármacos , Quinolonas/farmacología , Staphylococcus/efectos de los fármacos , Pueblo Asiatico , Fluoroquinolonas/farmacología , Humanos , Pruebas de Sensibilidad Microbiana , Propionibacterium/aislamiento & purificación , Quinolizinas/farmacología , Staphylococcus/aislamiento & purificaciónRESUMEN
Ozenoxacin, a novel non-fluorinated topical quinolone, was assessed for in vitro antimicrobial activity against each 50 isolates of methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA), and Streptococcus pyogenes according to the broth microdilution method recommended by the Clinical and Laboratory Standards Institute. The isolates used in this study were recovered from cutaneous specimens of Japanese adult and pediatric patients who visited hospitals in 2014. The MIC90s of ozenoxacin against MSSA, MRSA and S. pyogenes isolates from adult patients were ≤0.06, 4 and ≤0.06 µg/mL, respectively. The MIC90s of ozenoxacin against MSSA and S. pyogenes isolates from pediatric patients were equal to those against the adult isolates. On the other hand, the MIC90s of ozenoxacin against the pediatric MRSA isolates was 0.12 µg/mL, and was 32 times lower than that against the adult isolates. The antimicrobial activity of ozenoxacin against MSSA, MRSA and S. pyogenes was equal to or greater than those of 7 reference antimicrobial agents had been used for the treatment of skin infections. The MICs of ozenoxacin was highly correlated with those of nadifloxacin and levofloxacin in the 50 MRSA isolates (r(2) = 0.906 and 0.833, respectively). However, ozenoxacin kept the potent antimicrobial activity with the MIC ranging from 1 to 4 µg/mL even against MRSA low susceptible (MIC: >64 µg/mL) to nadifloxacin or levofloxacin. Ozenoxacin could represent the first-in-class non-fluorinated quinolone for the topical treatment of various superficial skin infections caused by MSSA, MRSA and S. pyogenes.
Asunto(s)
Aminopiridinas/farmacología , Antibacterianos/farmacología , Resistencia a la Meticilina , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Quinolonas/farmacología , Enfermedades Cutáneas Bacterianas/tratamiento farmacológico , Streptococcus pyogenes/efectos de los fármacos , Administración Cutánea , Adolescente , Adulto , Aminopiridinas/administración & dosificación , Aminopiridinas/uso terapéutico , Antibacterianos/administración & dosificación , Antibacterianos/uso terapéutico , Niño , Femenino , Fluoroquinolonas/administración & dosificación , Fluoroquinolonas/farmacología , Fluoroquinolonas/uso terapéutico , Humanos , Japón , Levofloxacino/uso terapéutico , Masculino , Staphylococcus aureus Resistente a Meticilina/aislamiento & purificación , Pruebas de Sensibilidad Microbiana , Quinolizinas/administración & dosificación , Quinolizinas/farmacología , Quinolizinas/uso terapéutico , Quinolonas/administración & dosificación , Quinolonas/uso terapéutico , Crema para la Piel/administración & dosificación , Crema para la Piel/uso terapéutico , Enfermedades Cutáneas Bacterianas/microbiología , Infecciones Cutáneas Estafilocócicas/tratamiento farmacológico , Infecciones Cutáneas Estafilocócicas/microbiología , Streptococcus pyogenes/aislamiento & purificaciónRESUMEN
Atopic dermatitis (AD) is a chronic inflammatory skin disease accompanied by severe itching and eczematous lesion. In this study, we applied an ointment containing Dermatophagoides farinae body (Dfb) extract repeatedly on the dorsal skin of NC/Nga mice with barrier disruption to investigate the characteristics of this murine model of human AD. Following repeated topical application of Dfb ointment twice weekly for 2 weeks, the dermatitis score increased gradually, accompanied by an elevation of total immunoglobulin E level in plasma. Topical application of Dfb ointment also caused epidermal hyperplasia and accumulation of inflammatory cells in the lesional skin and increased expression of T-helper (Th) 1/Th2/Th17 cytokines in axillary lymph node cells. Furthermore, increased sprouting of intraepidermal nerve fibres was observed with an increase in the content of nerve growth factor and decrease in that of semaphorin 3A in the lesional skin. These findings suggest that the characteristics in this model were similar to those observed in patients with AD. Interestingly, it was observed for the first time that scratching behaviour increased in a biphasic fashion by topical application of Dfb ointment in addition to an increase in spontaneous scratching behaviour in this model. It is also suggested that further clarifying the underlying mechanisms of scratching behaviour in this model leads not only to elucidating the pathogenesis of AD but also to discovering novel therapeutic drugs for AD.
Asunto(s)
Antígenos Dermatofagoides , Dermatitis Atópica/etiología , Animales , Citocinas/metabolismo , Dermatitis Atópica/sangre , Modelos Animales de Enfermedad , Femenino , Inmunoglobulina E/sangre , Ganglios Linfáticos/citología , Ganglios Linfáticos/metabolismo , Ratones , Factor de Crecimiento Nervioso/metabolismo , Prurito/inmunología , Semaforina-3A/metabolismo , Piel/metabolismoRESUMEN
Benzoyl peroxide (BPO), a therapeutic agent for acne vulgaris, was assessed for in vitro antimicrobial activity against Propionibacterium acnes using a novel broth microdilution testing that improved BPO solubility. We searched for a suitable culture medium to measure the minimum inhibitory concentration (MIC) of BPO against P. acnes and finally found the Gifu anaerobic medium (GAM) broth supplemented with 0.1(v/v)% glycerol and 2(v/v)% Tween 80, in which BPO dissolved up to 1250 µg/mL and P. acnes grew well. The MICs and minimum bactericidal concentrations (MBCs) of BPO against 44 clinical isolates of P. acnes collected from Japanese patients with acne vulgaris were determined by our testing method using the supplemented GAM broth. The MICs of BPO were 128 or 256 µg/mL against all isolates of P. acnes regardless of susceptibility to nadifloxacin or clindamycin. The MBCs of BPO were also 128 or 256 µg/mL against the same isolates. Moreover, BPO at the MIC showed a rapid bactericidal activity against P. acnes ATCC11827 in time-kill assay. In conclusion, we could develop a novel assay for the MIC and MBC determinations of BPO against P. acnes, which is reliable and reproducible as a broth microdilution testing and the present results suggest that BPO has a potent bactericidal activity against P. acnes.