eTable. List of Participating Sites
Customize your JAMA Network experience by selecting one or more topics from the list below.
Rosen T, Albareda N, Rosenberg N, et al. Efficacy and Safety of Ozenoxacin Cream for Treatment of Adult and Pediatric Patients With Impetigo: A Randomized Clinical Trial. JAMA Dermatol. 2018;154(7):806–813. doi:10.1001/jamadermatol.2018.1103
Is topical ozenoxacin safe and effective for patients with impetigo?
In this randomized, clinical trial of 412 patients, 112 of 206 (54.4%) achieved an effective clinical response and 115 of 125 (92.0%) achieved a microbiological response after 5 days of treatment with ozenoxacin cream, 1%, compared with placebo. Microbiological success was observed after 2 days of therapy.
In patients 2 months and older, ozenoxacin cream, 1%, appears to be effective and well tolerated for the treatment of impetigo, confirming the results of the first pivotal study.
Ozenoxacin, a novel topical antibacterial agent with potent bactericidal activity against gram-positive bacteria, has been developed as a cream with 1% active drug for the treatment of impetigo, a highly contagious bacterial skin infection.
To evaluate the efficacy, safety, and tolerability of ozenoxacin cream, 1%, after 5-day twice-daily topical treatment in patients with impetigo.
Design, Setting, and Participants
This randomized, double-blind, vehicle-controlled clinical trial included patients 2 months or older with impetigo who were enrolled at centers in 6 countries from June 2, 2014, through May 30, 2015. Data were analyzed based on intention to treat from July 9 through July 22, 2015.
Patients were randomized 1:1 to receive topical ozenoxacin or placebo control.
Main Outcomes and Measures
Efficacy was measured using the Skin Infection Rating Scale and microbiological culture. Safety and tolerability were also evaluated.
Among the 411 patients who received treatment (210 males [51.1%]; mean [SD] age, 18.6 [18.3] years), ozenoxacin demonstrated superior clinical success compared with placebo, which was evident after 5 days of therapy (112 of 206 [54.4%] vs 78 of 206 [37.9%]; P = .001). Ozenoxacin also demonstrated superior microbiological success compared with placebo after 2 days of therapy (109 of 125 [87.2%] vs 76 of 119 [63.9%]; P = .002). Ozenoxacin was well tolerated, with 8 of 206 patients experiencing adverse effects, with only 1 of these potentially related to the study treatment; none were serious.
Conclusions and Relevance
Topical ozenoxacin is effective and well tolerated in the treatment of impetigo in patients 2 months and older. This effect is demonstrated by rapid onset of response and superior clinical and microbiological response compared with placebo. Topical ozenoxacin represents a novel option for the treatment of impetigo.
ClinicalTrials.gov Identifier: NCT02090764
Impetigo is the most common bacterial skin infection in children, although the superficial crusting that characterizes this disorder may develop at any age.1-6 Lesions are typically located on the face, neck, and hands; pruritus and consequent scratching can transfer the infection to other parts of the body and to close contacts. Impetigo is a particular concern in day care centers and schools; to limit outbreaks, the American Academy of Pediatrics advises parents to keep children home from school until 24 hours after the initiation of appropriate antimicrobial therapy.7 In addition to limiting its spread, control of the disease is important to relieve symptoms, minimize scarring associated with excoriation, and prevent rare but serious systemic complications, such as glomerulonephritis3 or rheumatic heart disease.8
Topical treatments enable delivery of high local drug concentrations directly to the site of infection (ie, affected skin), thereby facilitating the antibiotic’s ability to overwhelm mutational resistance. In addition, topical therapies are formulated to be minimally absorbed, reducing the systemic adverse effects associated with oral therapies.9 Topical treatment is therefore preferred for localized, uncomplicated impetigo and is more effective than placebo.10 Topical treatment has also been shown to be equally or more effective than oral therapy, with oral therapies reserved for outbreaks affecting several individuals11 or when the use of topical therapy is impractical (ie, for more generalized or severe infections).12
Rates of resistance to commonly used topical antibiotics such as mupirocin are increasing; rates of mupirocin-resistant, methicillin-resistant Staphylococcus aureus (MRSA) are reported to range from 31% to as high as 81%, which has become a major concern in the United States and worldwide.13-15 Increasing antibiotic resistance is especially a concern for patients who present with empirically managed diseases such as impetigo,13 because these patients are often treated without the benefit of culture and sensitivity results to guide appropriate care.
Ozenoxacin is a novel topical antibiotic that has demonstrated potent bactericidal activity against pathologically relevant gram-positive strains, particularly Staphylococcus and Streptococcus species. Topical ozenoxacin has negligible systemic absorption16 and an expanded spectrum against methicillin-, mupirocin-, and ciprofloxacin-resistant strains of S aureus17-19 and may therefore represent an important localized therapy for impetigo.
This randomized clinical trial was a multicenter, double-blind, vehicle-controlled, parallel group, phase 3 study comparing ozenoxacin cream, 1%, with placebo in patients with a clinical diagnosis of impetigo. Central randomization via an interactive web response system was used to allocate patients to treatment groups, stratified by age subset, to ensure a 1:1 distribution and avoid selection bias. The study was conducted from June 2, 2014, through May 30, 2015, in 34 centers in 6 countries (United States [n = 16], Russia [n = 6], South Africa [n = 3], Germany [n = 4], Romania [n = 4], and Spain [n = 1]). A list of participating centers is found in the eTable in Supplement 1. This study was conducted in compliance with ICH Good Clinical Practice guidelines for conducting, recording, and reporting clinical trials and for archiving essential documents.20 Consistent with ethical principles for the protection of human research participants,21 no trial procedures were performed on trial candidates until written informed consent or assent had been obtained. The informed consent form, protocol, and amendments for the study were submitted to and approved by the institutional review board or independent ethics committee for each respective trial site or country. The trial protocol is available in Supplement 2.
Patients were deemed to be eligible if they were 2 months or older, had a clinical diagnosis of impetigo, and had a total Skin Infection Rating Scale (SIRS) score of at least 3 (including exudate and/or pus score of at least 1 of a possible 3). The total affected area at baseline measured from 2 to 100 cm2, and for patients younger than 12 years, the total area could not exceed 2% of the body surface area. Patients with concomitant underlying skin disease, such as preexisting eczematous dermatitis with clinical evidence of secondary infection or the presence of a bacterial infection that could not be appropriately treated by a topical antibiotic, were also excluded.
Patients were randomized to receive ozenoxacin cream, 1%, or placebo. During the 5-day treatment period, patients or their caregivers were instructed to apply a thin layer of study cream (a fingertip unit, approximately 0.5 g, would cover the maximum extension of 100 cm2) to the baseline affected area(s) twice daily. Assessments were conducted during visits before therapy (baseline; visit 1), during therapy (day 3; visit 2), at the end of therapy (day 6; visit 3), and after therapy (days 10-13; visit 4).
At each visit, patients were assessed by the investigator with regard to the number and location of affected areas, as well as the total area of impetigo. The affected area was then graded using a SIRS evaluation rating for each of the following 5 signs and symptoms: blistering, exudate and/or pus, crusting, erythema and/or inflammation, and itching and/or pain, on a scale of 0 (absent) to 3 (severe) (possible range of scores, 0-15). The classification of clinical success, based on this SIRS score, was defined as a score of 0 (absent) for blistering, exudate and/or pus, crusting, and itching and/or pain, and no greater than 1 (mild) for erythema and/or inflammation, such that no additional antimicrobial therapy of the baseline affected area(s) was necessary. Microbiological samples were taken at all study visits from the affected area identified at baseline, provided that culturable material was present and, at the discretion of the investigator, could be collected.
The primary efficacy end point of the study was the clinical response (clinical success or clinical failure) at end of therapy (visit 3) in the intention-to-treat clinical population. For the primary end point, clinical success was defined as total absence of the treated lesions (SIRS scores of 0 for blistering, exudate and/or pus, crusting, and itching and/or pain and ≤1 for erythema and/or inflammation, such that no additional antimicrobial therapy of the baseline affected area[s] was necessary). Improvement (defined as >10% decrease in total SIRS score compared with baseline, not fulfilling the criteria of individual SIRS scores for cure) and failure were both considered clinical failure.
Key secondary efficacy end points included the following:
Clinical response at visit 3 incorporating combined criteria of clinical success (defined as a total absence of the treated lesions [lesion extension score, 0] or the treated lesions became dry without crusts compared with baseline [SIRS score of 0 for exudate and crusting]), or improvement (defined as decrease in the size of the affected area, number of lesions, or both), such that no further antimicrobial therapy was necessary. This broader measure, which includes improvement in the definition of clinical success, reflects previously accepted methods for other topical antibiotics approved for impetigo.
Bacteriologic response at visits 2 and 3.
Therapeutic response (combined clinical and microbiological response) at visit 3.
Evaluation of safety was based on adverse events, vital signs, and physical examination. In addition, the microbiological susceptibility of the pathogens to ozenoxacin, methicillin (oxacillin sodium), ciprofloxacin hydrochloride, retapamulin, mupirocin, and fusidic acid identified at visit 1 and the presence of genes for Panton-Valentine leukocidin (PVL) and phenol-soluble modulin (PSM) were analyzed.
Data were analyzed from July 9 through July 22, 2015. A 2-group χ2 test with a 5% 2-sided significance level had 90% power to detect a difference of 15% in proportions at visit 3 with the assumption that the clinical success rate in the ozenoxacin group was 35% when the sample size was 185 for each group. The P value of the χ2 test (without continuity correction) and corresponding 95% asymptotic (Wald) CI for the difference in success rates for ozenoxacin vs placebo were provided, with P < .05 indicating statistical significance.
Exploratory logistic regression analysis was also performed for the primary efficacy end point, which included the number of affected areas, baseline total affected area, baseline total SIRS, age, race, country, and treatment compliance. Summary tabulations of treatment-emergent adverse events and vital signs and physical examination results were presented. All data analyses were performed using SAS, version 9.2 (SAS Institute Inc). The primary and secondary efficacy analysis was based on the intention-to-treat clinical population (n = 412). For microbiological response the main analysis was based on the intention-to-treat bacteriologic population (n = 244). All safety analyses were based on the safety population.
A total of 412 patients were randomly assigned to receive ozenoxacin cream, 1%, or placebo (Figure). One patient who was randomized to the placebo group was not treated and was excluded from the safety evaluation. Of the 411 patients who received treatment (210 males [51.1%] and 201 females [48.9%]; mean [SD] age, 18.6 [18.3] years), 386 (93.9%) completed the study. Overall, 13 patients in the placebo group discontinued the study owing to worsening of condition. Four patients withdrew owing to adverse events (1 in the ozenoxacin group and 3 in the placebo group), 4 were lost to follow-up (2 in each group), 3 withdrew consent (2 in the ozenoxacin group and 1 in the placebo group), and 2 discontinued for other reasons (1 in each group).
Baseline characteristics for treated patients were generally well balanced across study treatment groups. Patients ranged in age from 2 months to 80 years. Slightly more than half of the patients (226 [55.0%]) were older than 2 months and younger than 12 years, and 139 (33.8%) were 18 years or older. Regardless of age, lesions were most commonly located on the face (217 [52.8%]). One hundred sixty-seven patients (40.6%) had 1 affected area, and 189 (46.0%) had 2 to 4 affected areas. The most commonly found pathogen was S aureus in 223 patients (54.3%). Demographic and baseline characteristics are described in Table 1.
Of the patients randomized to the ozenoxacin group, 112 of 206 completing the study (54.4%) achieved clinical success vs 78 of 206 (37.9%) in the placebo group at the end of 5 days of therapy, and the difference was statistically significant (P = .001), confirming the superiority of ozenoxacin over placebo in patients with impetigo (Table 2). After application of previously accepted methods for the clinical evaluation of other topical antibiotics approved for impetigo (secondary end point),22-26 183 of 206 patients (88.8%) in the ozenoxacin group achieved clinical success at visit 3 (Table 2), compared with 161 of 206 (78.2%) for the placebo group (P = .003). After 2 days of therapy (at visit 2), 156 patients in the ozenoxacin group (75.7%) achieved a positive clinical response (early cure or improvement) compared with 122 patients in the placebo group (59.2%).
Microbiological success was achieved by 109 of 125 patients (87.2%) in the ozenoxacin group and 76 of 119 (63.9%) in the placebo group at visit 2 (P = .002) and by 115 of 125 (92.0%) and 87 of 119 (73.1%), respectively, at visit 3 (P = .005); the results were statistically significant at both time points (Table 3). Thus, more patients in the ozenoxacin group achieved a positive clinical response and first microbiological eradication earlier during treatment compared with patients in the placebo group. In addition, the overall therapeutic success rate (combined clinical and microbiological response) was higher in the ozenoxacin group than the placebo group (72 of 125 [57.6%] vs 41 of 119 [34.5%]; difference in success rates [95% CI], 0.226 [0.102-0.350]; P < .001) The treatment comparison used only the outcomes of success and failure. Therapeutic failure occurred in 51 of 125 patients (40.8%) in the ozenoxacin group and 73 of 119 (61.3%) in the placebo group.
Staphylococcus aureus was the most predominant organism (223 of 411 [54.3%]), and the next most common species identified was Streptococcus pyogenes (39 of 411 [9.5%]), both of which are known pathogens in this disease state based on clinical and epidemiologic literature. Other microorganisms identified by culture included Staphylococcus epidermidis, Staphylococcus capitis, and Staphylococcus hominis, which may be commensal in nature. Additional analyses using different analysis populations (per protocol clinical, intention-to-treat bacteriologic, and per protocol bacteriologic) confirmed the robustness of the efficacy results.
Thirty-two patients in the ozenoxacin group had resistant S aureus strains identified at baseline that were resistant to at least one of the tested antibacterials (methicillin [oxacillin], ciprofloxacin, retapamulin, mupirocin, and fusidic acid), and 1 patient had S pyogenes strains resistant to at least 1 of the above-mentioned antibacterial drugs. All patients with drug-resistant infections achieved clinical cure or improvement at visit 3, including 10 of 10 patients with mupirocin-resistant S aureus and 8 of 8 patients with MRSA. Staphylococcus aureus isolates in this study were also tested for the presence of PVL and PSM genes, which are virulence and resistance factors that can contribute to more severe disease. Ozenoxacin demonstrated similar clinical and bacteriologic success rates whether or not these genes were present.
Regardless of the number of affected areas, total area, baseline total SIRS score, age, race, country, and treatment compliance, a greater percentage of patients in the ozenoxacin group achieved clinical success compared with the percentage of patients in the placebo group. The treatment effect consistently demonstrated statistical significance.
Rates of adverse event were low in both groups, and 15 of 411 patients experienced adverse events, including 8 of 206 (3.9%) in the ozenoxacin group and 7 of 205 (3.4%) in the placebo group. Of these, 3 adult patients experienced adverse events considered by the investigator to be at least potentially related to the study treatment, including 1 patient in the ozenoxacin group who experienced rosacea and seborrheic dermatitis and 2 in the placebo group who experienced dermatitis and skin tightness (1 each). No serious adverse events occurred, and none of the events that were assessed as related to the study drug occurred in more than 1 patient. Ozenoxacin was well tolerated, and no patterns or safety signals were observed. The lack of systemic adverse effects is consistent with previous studies16,27,28 that demonstrated that topically applied ozenoxacin has negligible systemic absorption.
Impetigo is a bacterial skin infection caused mainly by S aureus and S pyogenes, with lesions that are highly contagious and can spread rapidly by direct contact.4 Rapid, effective treatment is important to reduce the spread of pathogens and decrease transmission of infection to minimize outbreaks and potentially avoid complications. Of growing concern, rates of resistance to commonly used topical antibiotics such as mupirocin29,30 are increasing, and antibiotic resistance is becoming a major concern in the United States and worldwide.31,32 These factors have driven the need for new agents with different modes of action that possess activity against drug-resistant strains.
Ozenoxacin belongs to a new generation of topical antibiotics with potent selective inhibition of DNA replication and is structurally characterized as a nonfluorinated quinolone. Ozenoxacin has demonstrated bactericidal activity against the most common gram-positive pathogens associated with skin and soft tissue infection, including MRSA and mupirocin- and fusidic acid–resistant strains.31-35 Ozenoxacin has also exhibited greater inhibitory activity than other quinolones for bacterial DNA gyrase and topoisomerase IV, enzymes critical for the transcription and replication processes of bacterial DNA,20,21 which may account for its activity against quinolone-resistant strains.
In this study, ozenoxacin demonstrated a superior clinical and microbiological response compared with placebo after 5 days of therapy and early bacteriologic eradication after 2 days of treatment. These results were statistically significant and consistent with the results of a previously conducted phase 3 clinical trial.36 When analyzing these data using previously accepted methods for the clinical evaluation of other topical anti-infectives for impetigo,23-26,29,30 ozenoxacin demonstrated a 90.1% clinical success rate vs placebo (P = .003). These differences in methods (respective definitions of clinical success shown in Table 2) should be considered when comparing efficacy rates across compounds.
Data from this and a previous pivotal phase 3 study36 demonstrate that ozenoxacin is a rapid, effective new treatment for impetigo. With concerns over widespread antibiotic resistance, ozenoxacin is an important potential treatment option with an expanded spectrum against bacterial pathogens, including those resistant to mupirocin, ciprofloxacin, and methicillin (including MRSA). Ozenoxacin, a topical antibiotic with negligible skin absorption, has the potential to substantially improve the management of impetigo, as well as reduce the spread of pathogens and decrease transmission of infection. The ability of ozenoxacin to eradicate drug-susceptible and drug-resistant organisms is important in clinical medicine, because the organism strain and potential for resistance is generally not known at the initiation of therapy.
One limitation of this study is the small number of children with bullous impetigo included. Data in children younger than 6 months are also limited.
The capacity to eradicate drug-susceptible and drug-resistant organisms in this study has important relevance in clinical medicine, because the organism strain and potential for resistance is generally not known at the initiation of therapy. Thus, the consistent clinical and bacteriologic effects demonstrated by ozenoxacin cream, 1%, in this second phase 3 pivotal study in children as young as 2 months further support its use as an important empirical therapeutic option for patients with impetigo.
Accepted for Publication: March 23, 2018.
Corresponding Author: Nuria Albareda, BS, Ferrer Internacional, SA, Diagonal 549, 08029 Barcelona, Spain (email@example.com).
Published Online: June 13, 2018. doi:10.1001/jamadermatol.2018.1103
Author Contributions: Ms Albareda and Dr Rosenberg had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Albareda, Rosenberg, Alonso.
Acquisition, analysis, or interpretation of data: Rosen, Albareda, Rosenberg, Roth, Zsolt, Hebert.
Drafting of the manuscript: Rosen, Albareda, Rosenberg, Roth.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Albareda.
Obtained funding: Albareda.
Administrative, technical, or material support: Albareda, Rosenberg, Roth, Hebert.
Study supervision: Rosen, Albareda, Rosenberg, Alonso, Zsolt, Hebert.
Conflict of Interest Disclosures: Dr Rosen reported serving as a consultant for Medimetriks Pharmaceuticals, Inc. Ms Albareda and Drs Alonso and Zsolt reported being employees of Ferrer Internacional, SA. Drs Rosenberg and Roth reported being employees of Medimetriks Pharmaceuticals, Inc. No other disclosures were reported.
Funding/Support: This study was supported in part by Ferrer Internacional, SA.
Role of the Funder/Sponsor: The sponsor was involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; decision to submit the manuscript for publication.
Additional Contributions: Igor Martin, Degree, Chiltern International Spain, SA, Tres Cantos, Spain, provided statistical support as an employee. Content Ed Net, Madrid, Spain, provided editorial assistance, which was not compensated.
Create a personal account or sign in to: