Introduction: Recalcitrant dermatophytic infections of the glabrous skin (tinea corporis/cruris/faciei) pose a huge challenge to healthcare systems. Combinations of oral and topical drugs may potentially improve cure rates but the same has never been objectively assessed for this condition in laboratory or clinical studies.The presentstudy was undertaken with an aim of identifying synergistic combinations of oral and topical antifungals by testing clinical isolates obtained from patients with recalcitrant tinea corporis/cruris. Materials and Methods: Forty two patients with tinea corporis/cruris who had failed oral antifungals or had relapsed within 4 weeks of apparent clinical cure were recruited. Twenty one isolates were identified on sequencing (all T.mentagrophytes/interdigitale species complex ) andwere subjected to antifungal susceptibility testing (AFST) andsqualene epoxidase (SQLE) gene mutation analysis. Finally, five isolates – four with underlying SQLE gene mutations, and one wild type strain, were chosen for checkerboard studies using various combinations of antifungal agents. Results: Most isolates (n=16) showed high MICs to TRB (0.5->16μg/ml), with SQLE gene mutations present in all isolates with MICs ≥0.5μg/ml. Synergistic interactions were seen with combinations of itraconazole with luliconazole, TRB and ketoconazole, PGMC with luliconazole and with the triple combination of Propylene glycol Monocaprylate (PGMC) with luliconazole and ketoconazole. Conclusions: In vitro synergistic interactions provide a sound scientific basis for possible clinical use of antifungal combinations. Hence, these synergistic combinations may be tested for clinical utility in the wake of rising resistance among dermatophytic infections of the glabrous skin.

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Acne vulgaris is a multifactorial skin disease associated with the colonization of Propionibacterium acnes. Antibiotics are a mainstay of treatment for acne, yet the emergence of resistance against the currently approved antibiotics is a serious concern. In this case report, a slow responder had multiple Propionibacterium acnes isolates with varied levels of sensitivity to the conventional antibiotics. The bacterial isolates obtained from acne samples collected from the patient were analyzed for phylogeny, and was found to be largely restricted to two different lineage patterns. Propionibacterium acnes phylotype IA1, which is considered to be pathogenic, displayed clindamycin sensitivity, but phylotype IB, which is associated with commensals, exhibited high clindamycin resistance. Sensitivity analysis revealed uniform resistance to macrolides, but susceptibility to tetracycline and nadifloxacin. These results implicate Propionibacterium acnes in the pathophysiology of acne vulgaris, although the lines between commensal and pathological phylotypes may be blurred. Switching the patient to a combination of minocycline and nadifloxacin resulted in a significant improvement in the clinical lesions. Such a science-driven judicious selection of antibiotics can minimize the probability of development of resistance, and might be the way forward in the treatment of acne.

Acne is a multifactorial skin disease, underpinned by colonization of Propionibacterium acnes and inflammation. The emergence of resistant P. acnes strains has affected the current acne treatment algorithm. This setback served as an impetus for rationally designing a library of next-generation antibiotics that exhibit a bactericidal effect on resistant P. acnes and exert an immunomodulatory function to reduce inflammation. In silico screening showed that one of the molecules, VCD-004, exhibits improved mode of binding to bacterial DNA gyrase. VCD-004 shows high potency against clinical isolates of resistant P. acnes and excellent efficacy in vivo. Furthermore, VCD-004 exhibits a superior mutant prevention index, suggesting that it impedes the development of resistance better than clindamycin. Additionally, it shows optimal skin penetration and has a potent anti-inflammatory effect via reduction of proinflammatory cytokines (IL-6) independent of its antibacterial action. VCD-004 affects P. acnes-induced nuclear accumulation of NF-κB in THP-1 cells. The in vitro viability of human keratinocytes in the presence of VCD-004 indicates a desirable therapeutic window for topical use. Such rationally designed bactericidal and immunomodulatory dual pharmacophore-based lipophilic molecule(s) can emerge as the next-generation topical therapy for acne with underlying resistant P. acnes etiology.

Background and Objectives The emergence of resistant strains of Cutibacterium acnes can limit the efficacy of currently approved antibiotics for acne. VB-1953 is a next-generation antibiotic that exerts a bactericidal effect on resistant C. acnes. In this study, we investigated the safety, tolerability, and efficacy of VB-1953 topical gel in patients with moderate to severe acne having clindamycin-resistant C. acnes. Methods An investigator-initiated, open label, single-arm clinical study was conducted in patients with moderate to severe facial acne vulgaris showing poor or no response to previous clindamycin treatment. Nineteen subjects were enrolled in the study based on laboratory screening for the presence of clindamycin-resistant C. acnes in acne swab samples collected from patients. VB-1953 2% gel was applied on the entire face twice daily over 12 weeks. The primary efficacy endpoints were absolute changes in inflammatory and noninflammatory lesion counts from baseline at week 12, while the secondary efficacy endpoint was the proportion of subjects achieving Investigator Global Assessment success (score of 0 or 1) or a grade 2 or higher improvement from baseline at week 12. The presence and severity of local skin reactions (erythema, edema, scaling/ dryness, burning/stinging, pruritus) were evaluated for safety. Additionally, the detection and quantification of drug-resistant C. acnes strains were performed in the laboratory using acne swab samples collected from patients. Results The occurrence of treatment-emergent adverse events or changes in vital signs, physical examinations, and urinalysis for any of the patients during the course of the entire study were clinically insignificant. Topical application of 2% VB-1953 topical gel resulted in a significant reduction of mean absolute inflammatory and noninflammatory lesion counts by 53.1% and 52.2%, respectively (p < 0.0001 for both), with an Investigator Global Assessment success of 26.3% at week 12 compared with baseline. Resistant bacteria were reduced by (94.3 ± 1%; p < 0.05) within 12 weeks of treatment with VB-1953. Conclusion These results indicate that VB-1953 topical gel can be a safe and effective therapy for moderate to severe acne with underlying resistant C. acnes in subjects who had not responded to previous antibiotic treatments. Key PointsThe efficacy and safety of the bactericidal antibiotic VB-1953 (2%) topical gel was evaluated for acne treatment in an investigator-initiated, open-label, single-arm study in acne patients who did not respond to or showed poor response to previous clindamycin treatment and had clindamycin-resistant Cutibacterium acnes.In the era of emerging antimicrobial resistance, the selection of VB-1953 for acne treatment can play a key role in improving clinical outcomes in acne patients and in public health.