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Efficacy and Safety of VB-1953 Topical Gel in Non-Responder Acne Patients with Clindamycin-Resistant Cutibacterium acnes.

ABSTRACT: 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?

SUBMITTER: Batra R

PROVIDER: S-EPMC7221013 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Efficacy and Safety of VB-1953 Topical Gel in Non-Responder Acne Patients with Clindamycin-Resistant Cutibacterium acnes.

Batra Rohit R Sadhasivam Suresh S Saini Swamini S Gupta Swati S Bisen Rahul Kumar Singh RKS Sinha Mau M Ghosh Shamik S Jain Shilpi S

Drugs in R&D 20200601 2

<h4>Background and objectives</h4>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.<h4>Methods</h4>An investigator-initiated, open label, single-arm clinic ...[more]

PMID: 32222937

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Project description:BackgroundTopical antibiotics are frequently used to treat acne vulgaris. Their prolonged use, often for longer durations than recommended, has led to antibiotic resistance in Cutibacterium acnes (C. acnes), a bacterium implicated in acne pathophysiology. Bacteriophage (phage), which specifically target C. acnes by a different mechanism of action and do not harm potentially beneficial bacteria, may offer an alternative approach for improvement of the appearance of acne prone skin.ObjectivesTo identify and characterize C. acnes targeting phage, carry out a comprehensive preclinical safety evaluation of phages selected for further development and examine their safety, tolerability and ability to target facial C. acnes when applied topically in a cosmetic clinical study including participants with mild-to-moderate acne.MethodsPhages were isolated by conventional microbiological methods also used to examine their breadth of host range on different C. acnes strains and specificity to this bacterial species. Safety assessment of three selected phages was carried out by complete genomic analysis to assure the absence of undesired sequences and by ex vivo models employed to evaluate the safety, irritability and potential systemic bioavailability of phage applied topically. A randomized, controlled clinical study assessed safety, tolerability and efficacy in targeting facial C. acnes.ResultsWide host range phages that also target antibiotic resistant C. acnes were identified. Their genomes were shown to be free of undesired genes. The three-phage cocktail, BX001, was not irritant to human skin or ocular tissues in ex vivo models and did not permeate through human epidermis. In a cosmetic clinical study, topically applied BX001 was safe and well tolerated and reduced the facial burden of C. acnes.ConclusionsCombined in silico and ex vivo approaches successfully predicted the observed safety and efficacy of C. acnes targeting phage when these were topically administered in a well-controlled cosmetic clinical study.

Project description:Cutibacterium acnes (former Propionibacterium acnes), is a bacterium characterized by high genomic variability, consisting of four subtypes and six major ribotypes. Skin is the largest neuroendocrine organ of the human body and many cutaneous hormones and neurohormones can modulate bacterial physiology. Here, we investigated the effect of catecholamines, i.e., epinephrine and norepinephrine, on two representative strains of C. acnes, of which the genome has been fully sequenced, identified as RT4 acneic and RT6 non-acneic strains. Epinephrine and norepinephrine (10-6 M) had no impact on the growth of C. acnes but epinephrine increased RT4 and RT6 biofilm formation, as measured by crystal violet staining, whereas norepinephrine was only active on the RT4 strain. We obtained the same results by confocal microscopy with the RT4 strain, whereas there was no effect of either catecholamine on the RT6 strain. However, this strain was also sensitive to catecholamines, as shown by MATs tests, as epinephrine and norepinephrine affected its surface polarity. Flow cytometry studies revealed that epinephrine and norepinephrine are unable to induce major changes of bacterial surface properties and membrane integrity. Exposure of sebocytes to control or catecholamine-treated bacteria showed epinephrine and norepinephrine to have no effect on the cytotoxic or inflammatory potential of either C. acnes strains but to stimulate their effect on sebocyte lipid synthesis. Uriage thermal spring water was previously shown to inhibit biofilm production by C. acnes. We thus tested its effect after exposure of the bacteria to epinephrine and norepinephrine. The effect of the thermal water on the response of C. acnes to catecholamines depended on the surface on which the biofilm was grown. Finally, an in-silico study revealed the presence of a protein in the genome of C. acnes that shows homology with the catecholamine receptor of Escherichia coli and eukaryotes. This study suggests that C. acnes may play a role as a relay between stress mediators (catecholamines) and acne.

Project description:BACKGROUND:Antibiotics have been used for decades against Cutibacterium acnes (previously known as Propionibacterium acnes; C. acnes). Alarmingly, antibiotic resistance to this bacterium has become a worldwide problem in recent years. No studies are available on the antibiotic susceptibility patterns of C. acnes among Jordanian acne patients and how that is influenced by antibiotic use. This study aims to assess antibiotic resistance patterns of C. acnes clinical isolates and neighboring Gram-positive normal flora of the skin obtained from acne patients attending dermatology clinics in Amman -Jordan appraising the role of antibiotic consumption. METHODS:This is a cross-sectional study of acne patients presenting to selected dermatology outpatient clinics over a 6-month study period. Swabs obtained from inflamed lesions were cultured aerobically and anaerobically. Isolates were identified and screened for antibiotic susceptibility. In addition, all patients were asked to fill in a questionnaire that included questions about the history of antibiotic treatment. RESULTS:C. acnes was isolated from lesions of 100 patients out of 115 participants included in this study. 73% of the isolates were resistant to erythromycin and 59% to clindamycin 37% to doxycycline, 36% to tetracycline, 31% to trimethoprim / sulfamethoxazole, 15% to levofloxacin, and 3% to minocycline. Multi drug resistance (MDR) in C. acnes isolates as well as Staphylococcus aureus (S. aureus) and Staphylococcus epidermidis (S. epidermidis) with a similar pattern of resistance were detected from the same patient in most cases. A pattern of higher resistance towards variable antibiotic was observed in patients previously treated with antibiotics for acne management. CONCLUSIONS:The findings of this study demonstrate the distribution of antibiotic resistance of C. acnes towards used antibiotics and emphasizes the influence of antibiotic consumption on development of antibiotic resistance. The similar pattern of resistance between skin bacteria tested in this study highlights the genetic transfer of resistance between skin commensals including S. aureus and S. epidermidis hence promoting its circulation in the community.

Project description:The Gram-positive bacterium Cutibacterium acnes (previously Propionibacterium acnes), plays an important role in the pathogenesis and progression of the dermatological skin disorder acne vulgaris. The methanolic extract of Helichrysum odoratissimum (L.) Sweet (HO-MeOH) was investigated for its ability to target bacterial growth and pathogenic virulence factors associated with acne progression. The gas chromatography-mass spectrometry (GC-MS) analysis of HO-MeOH identified ?-humulene (3.94%), ?-curcumene (3.74%), and caryophyllene (8.12%) as major constituents, which correlated with previous reports of other Helichrysum species. The HO-MeOH extract exhibited potent antimicrobial activity against C. acnes (ATCC 6919) with a minimum inhibitory concentration (MIC) of 7.81 µg/ml. It enhanced the antimicrobial activity of benzoyl peroxide (BPO). The extract showed high specificity against C. acnes cell aggregation at sub-inhibitory concentrations, preventing biofilm formation. Mature C. acnes biofilms were disrupted at a sub-inhibitory concentration of 3.91 µg/ml. At 100 µg/ml, HO-MeOH reduced interleukin-1? (IL-1?) cytokine levels in C. acnes-induced human keratinocytes (HaCaT) by 11.08%, highlighting its potential as a comedolytic agent for the treatment of comedonal acne. The extract exhibited a 50% inhibitory concentration (IC50) of 157.50 µg/ml against lipase enzyme activity, an enzyme responsible for sebum degradation, ultimately causing inflammation. The extract's anti-inflammatory activity was tested against various targets associated with inflammatory activation by the bacterium. The extract inhibited pro-inflammatory cytokine levels of IL-8 by 48.31% when compared to C. acnes-induced HaCaT cells at 7.81 µg/ml. It exhibited cyclooxygenase-II (COX-II) enzyme inhibition with an IC50 of 22.87 µg/ml. Intracellular nitric oxide (NO) was inhibited by 40.39% at 7.81 µg/ml when compared with NO production in lipopolysaccharide (LPS)-induced RAW264.7 cells. The intracellular NO inhibition was potentially due to the 2.14 fold reduction of inducible nitric oxide synthase (iNOS) gene expression. The HO-MeOH extract exhibited an IC50 of 145.45 µg/ml against virulent hyaluronidase enzyme activity, which is responsible for hyaluronan degradation and scar formation. This study provides scientific validation for the traditional use of H. odoratissimum as an ointment for pimples, not only due to its ability to control C. acnes proliferation but also due to its inhibitory activity on various targets associated with bacterial virulence leading to acne progression.

Dataset Information

Efficacy and Safety of VB-1953 Topical Gel in Non-Responder Acne Patients with Clindamycin-Resistant Cutibacterium acnes.

Publications

Efficacy and Safety of VB-1953 Topical Gel in Non-Responder Acne Patients with Clindamycin-Resistant Cutibacterium acnes.

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