retapamulin and Staphylococcal-Skin-Infections

In atopic dermatitis (AD), the stratum corneum of patients appears to have alterations that predispose them to colonization and invasion by various bacteria, most notably Staphylococcus aureus (S. aureus). This bacterial co-existence is accepted to be an important factor in AD disease activity. Exactly when to initiate antimicrobial treatment is controversial, but such intervention, when warranted, has repeatedly been demonstrated to improve the course of AD. However, the increase in antibiotic resistance presents a therapeutic challenge in the management of AD patients, which highlights the need for novel mechanism topical antibacterial agents. Retapamulin is a relatively new pleuromutilin antibiotic designed for topical use. In vitro studies have demonstrated its low potential for the development of antibacterial resistance and high degree of potency against Gram-positive bacteria found in skin infections, including many S. aureus strains that are resistant to methicillin, fusidic acid, and mupirocin. Clinical studies exploring the treatment of secondarily infected dermatitis reveal that the efficacy of topical retapamulin is comparable to a 10-day course of oral cephalexin or to topical fusidic acid. Retapamulin appears to be a much needed antimicrobial option for treating the AD population due to their common carriage of bacterial pathogens and frequency of infectious complications.

Topics: Administration, Topical; Anti-Bacterial Agents; Bridged Bicyclo Compounds, Heterocyclic; Dermatitis, Atopic; Diterpenes; Drug Resistance, Bacterial; Gram-Positive Bacterial Infections; Humans; Skin Diseases, Infectious; Staphylococcal Skin Infections

Retapamulin is a new topical pleuromutilin antibiotic for the treatment of skin and skin-structure infections, including impetigo. In vitro studies indicate that retapamulin has a unique mode of action that minimizes the potential for target-specific cross-resistance with other antibacterials and a limited potential for resistance development. Its spectrum of activity includes the most likely causative pathogens Staphylococcus aureus and Streptococcus pyogenes. In the Global Surveillance Program, retapamulin was highly active in vitro, including against strains of S. aureus resistant to methicillin, mupirocin or fusidic acid. In clinical studies, retapamulin was noninferior to fusidic acid and oral cefalexin, achieving per-pathogen success rates of 86-99%. Topical retapamulin has a good safety profile and is associated with high patient compliance.

Topics: Administration, Cutaneous; Anti-Bacterial Agents; Bridged Bicyclo Compounds, Heterocyclic; Diterpenes; Drug Resistance, Bacterial; Global Health; Humans; Microbial Sensitivity Tests; Ointments; Population Surveillance; Skin Diseases, Bacterial; Staphylococcal Skin Infections; Staphylococcus aureus; Streptococcal Infections; Streptococcus pyogenes; Treatment Outcome

Topics: Administration, Topical; Animals; Anti-Bacterial Agents; Bridged Bicyclo Compounds, Heterocyclic; Diterpenes; Drug Resistance, Bacterial; Humans; Protein Synthesis Inhibitors; Skin Diseases, Bacterial; Staphylococcal Skin Infections; Streptococcal Infections; Treatment Outcome

To evaluate the clinical and bacteriological efficacy of topical retapamulin ointment 1% versus oral linezolid in the treatment of patients with secondarily infected traumatic lesions (SITLs; excluding abscesses) or impetigo due to methicillin-resistant Staphylococcus aureus (MRSA).. A randomized, double-blind, double-dummy, multicenter, comparative study (NCT00852540).. Patients recruited from 36 study centers in the United States.. Patients 2 months or older with SITL (including secondarily infected lacerations or sutured wounds) or impetigo (bullous and nonbullous) suitable for treatment with a topical antibiotic, with a total Skin Infection Rating Scale score of 8 or greater, including a pus/exudate score of 3 or greater.. Patients received retapamulin ointment 1% (plus oral placebo), twice daily for 5 days or oral linezolid (plus placebo ointment) 2 or 3 times daily for 10 days.. Primary end point: clinical response (success/failure) at follow-up in patients with MRSA at baseline (per-protocol population). Secondary efficacy end points: clinical and microbiologic response and outcome at follow-up and end of therapy; therapeutic response at follow-up.. The majority of patients had SITL (70.4% [188/267] and 66.4% [91/137] in the retapamulin and linezolid groups, respectively; intent-to-treat clinical population). Clinical success rate at follow-up was significantly lower in the retapamulin versus the linezolid group (63.9% [39/61] vs 90.6% [29/32], respectively; difference in success rate -26.7%; 95% CI, -45.7 to -7.7).. Clinical success rate at follow-up in the per-protocol MRSA population was significantly lower in the retapamulin versus the linezolid group. It could not be determined whether this was related to study design, bacterial virulence, or retapamulin activity.

Topics: Administration, Oral; Administration, Topical; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bridged Bicyclo Compounds, Heterocyclic; Child; Child, Preschool; Diterpenes; Double-Blind Method; Female; Humans; Impetigo; Infant; Infant, Newborn; Linezolid; Male; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Ointments; Staphylococcal Skin Infections; Treatment Outcome; Wounds and Injuries; Young Adult

To evaluate whether retapamulin 1% is clinically superior to a placebo in the treatment of patients with secondarily infected traumatic lesions.. The study was a double-blind, placebo-controlled, parallel-group, phase 3 study.. Patients were recruited from 5 countries.. The aforementioned patients were all 2 months or older and diagnosed with secondarily infected traumatic lesions.. Study medication was applied twice daily for 5 days.. Primary end point: clinical response (success/failure) at follow-up. Secondary efficacy end points included clinical and microbiological outcomes at end of therapy (on days 7-9); microbiological and therapeutic responses at follow-up.. A total of 508 patients were recruited for the study; 359 patients were included in the primary efficacy analysis population (246 received retapamulin; 113 received the placebo). Secondarily infected abrasions were the most common secondarily infected traumatic lesions present (56.3%), Staphylococcus aureus being the most frequently isolated pathogen at baseline (60.1%); 15.1% infections were methicillin-resistant. At follow-up, patients receiving retapamulin had higher clinical success rates than those receiving the placebo (74.8% vs 66.4%, respectively) in the primary efficacy analysis population; however, the treatment difference was not statistically significant (8.4%; 95% confidence interval, -1.6 to 18.4). The proportion of patients experiencing adverse events, which were typically mild or moderate in severity, was similar between the retapamulin (5.6%, 19/342) and placebo groups (4.8%, 8/165).. Clinical success rates were higher with retapamulin versus placebo in the treatment of patients with secondarily infected traumatic lesions, but the difference between treatment groups was not significant. Retapamulin was well tolerated.

Topics: Administration, Topical; Adolescent; Anti-Bacterial Agents; Bridged Bicyclo Compounds, Heterocyclic; Child; Child, Preschool; Diterpenes; Double-Blind Method; Drug Resistance, Bacterial; Female; Humans; Infant; Male; Ointments; Placebo Effect; Staphylococcal Skin Infections; Streptococcal Infections; Treatment Outcome

Patients with atopic dermatitis (AD) are known to have a predisposition to colonization or infection by microbial organisms, including both Staphylococcus aureus and herpes simplex virus (HSV). S aureus infection leads to exacerbation of eczema and may induce flares in atopic skin by mediating inflammation. Retapamulin 1% ointment is a unique topical antibiotic formulation that may be a suitable option for the treatment of clinically infected AD.. A single-center, open-label pilot study was conducted to investigate the efficacy and safety of retapamulin 1% (Altabax, Stiefel/ GlaxoSmithKline) ointment for the treatment of secondarily infected atopic dermatitis in subjects aged 9 months to 98 years old (n=29).. Twice-daily application of retapamulin 1% produced a mean 8.1-point reduction from baseline in the mean Skin Infection Rating Scale score. The majority of subjects achieved clinical cure with topical retapamulin therapy. Retapamulin 1% ointment was effective against S aureus isolates, including methicillin-resistant Staphylococcus aureus (MRSA). Treatment was well tolerated.. Retapamulin 1% is effective for the treatment of atopic dermatitis infected with S aureus, and demonstrates efficacy against both methicillin-susceptible and methicillin-resistant strains. Given its efficacy and good tolerability in this pilot study, retapamulin 1% ointment should be further evaluated as a treatment for infected atopic dermatitis. It may provide convenience and efficacy with a low risk for development of bacterial resistance.

Topics: Administration, Cutaneous; Adolescent; Adult; Aged; Anti-Bacterial Agents; Bridged Bicyclo Compounds, Heterocyclic; Child; Child, Preschool; Dermatitis, Atopic; Diterpenes; Female; Follow-Up Studies; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Ointments; Pilot Projects; Staphylococcal Skin Infections; Staphylococcus aureus; Treatment Outcome; Young Adult

Retapamulin is a semisynthetic pleuromutilin compound with in vitroactivity against Gram-positive bacteria, no cross-resistance to other classes of antimicrobial agents in current use and a low potential for development of resistance. A 1% ointment formulation has been developed for clinical use, and a placebo-controlled trial of impetigo in 210 patients produced significantly higher rates of clinical and microbiological success compared with placebo - 85.6 versus 52.1% and 91.2 versus 50.9%, respectively. Additional comparative studies in over 1900 patients showed noninferiority to topical fusidic acid and oral cephalexin and a low frequency of adverse events. In 2007, retapamulin was approved in the USA for topical treatment of impetigo caused by Streptococcus pyogenes and methicillin-susceptible Staphylococcus aureus, and in the EU for topical treatment of impetigo and infected wounds caused by S. pyogenes and S. aureus, with approvals including adults and children over 9 months of age.

Topics: Administration, Topical; Adult; Anti-Bacterial Agents; Bridged Bicyclo Compounds, Heterocyclic; Child; Child, Preschool; Diterpenes; Humans; Impetigo; Infant; Pleuromutilins; Polycyclic Compounds; Skin Diseases, Infectious; Staphylococcal Skin Infections; Treatment Outcome

New antibacterial agents with activity against pathogenic strains resistant to established antibiotics are needed to treat patients with secondarily infected dermatitis (SID).. We sought to determine the clinical safety and efficacy of topical retapamulin ointment 1% versus oral cephalexin for the treatment of SID.. Patients with SID were randomly assigned to retapamulin ointment 1% (twice daily [bid]) for 5 days, or oral cephalexin (500 mg bid) for 10 days. The primary efficacy end point was clinical response at follow-up. Secondary outcomes included microbiologic response at follow-up, safety, and compliance.. Retapamulin was as effective as cephalexin (clinical success rates at follow-up: 85.9% and 89.7%, respectively). Microbiologic success rates at follow-up were 87.2% for retapamulin and 91.8% for cephalexin. Retapamulin was well tolerated and the topical formulation was preferred over the oral drug.. An imbalance existed in the number of patients with the clinical outcome "unable to determine" (15 retapamulin, 2 cephalexin), mainly because of their failure to attend the study visit. If those who failed to attend visits (who did not withdraw as a result of drug-related events) are removed from the analysis, the clinical success rates are 89.9% for retapamulin and 89.7% for cephalexin.. Retapamulin ointment 1% (bid) for 5 days was as effective as oral cephalexin (bid) for 10 days in treatment of patients with SID, and was well tolerated.

Topics: Administration, Cutaneous; Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bridged Bicyclo Compounds, Heterocyclic; Cephalexin; Child; Child, Preschool; Dermatitis; Dermatitis, Atopic; Diterpenes; Double-Blind Method; Female; Follow-Up Studies; Humans; Infant; Infant, Newborn; Male; Methicillin Resistance; Middle Aged; Ointments; Skin Diseases, Infectious; Staphylococcal Skin Infections; Staphylococcus aureus; Streptococcal Infections; Streptococcus pyogenes; Treatment Outcome

Topical antimicrobial and antiseptic agents are commonly used in the management of minor skin and soft tissue infections (SSTIs). Resistance to mupirocin has been documented in Staphylococcus aureus isolates causing SSTIs. Data are limited, however, on the prevalence of retapamulin resistance or tolerance to antiseptics. We sought to determine the prevalence of decreased susceptibility to retapamulin and mupirocin as well as the potential for decreased chlorhexidine susceptibility of S. aureus isolates from SSTIs in children. Two hundred isolates from patients with a single SSTI and 200 isolates from patients with ≥3 previous episodes from the years 2010 to 2012 were selected from an S. aureus surveillance study. Screening for retapamulin resistance was performed by the broth macrodilution method; mupirocin MICs were determined by Etest. PCR was performed for the presence of the smr gene associated with elevated MICs/minimum bactericidal concentrations (MBCs) to chlorhexidine. Among the isolates screened, 38 isolates (9.5%) exhibited retapamulin resistance, of which 22 (57.9%) were methicillin-resistant S. aureus (MRSA). Two isolates (0.5%) displayed cross-resistance to retapamulin and linezolid. Thirty-nine isolates (9.8%) were found to have mupirocin resistance. smr-positive S. aureus accounted for 14% of isolates. The proportion of smr-positive organisms increased during the study (P = 0.005). The prevalence of in vitro resistance to topical antimicrobials among S. aureus isolates causing SSTI in healthy children in our community is almost 10%. Retapamulin resistance was associated with cross-resistance to linezolid in 0.5% of isolates. In addition, there was an increase in the proportion of smr-positive isolates. Further research including clinical correlations with these findings is warranted.

Topics: Adult; Aged; Anti-Bacterial Agents; Bridged Bicyclo Compounds, Heterocyclic; Chlorhexidine; Diterpenes; Drug Resistance, Multiple, Bacterial; Female; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Mupirocin; Soft Tissue Infections; Staphylococcal Skin Infections; Staphylococcus aureus

Mupirocin has been used topically for treating skin and skin structure infections and for nasal decolonization before surgical interventions. Pleuromutilin compounds, including retapamulin, provide similar treatment/interventional options. Rates of resistance of Staphylococcus aureus to mupirocin and other agents used to treat skin and skin structure infections vary between countries and medical centers, including those in the United States. These resistance rates may be associated with higher usage and/or improper epidemiologic practices.. This study aimed to determine rates of resistance to topical and other class agents against S aureus isolates collected from SSSIs.. Isolates were obtained from outpatients at 6 US dermatology centers in 5 states. Demographic data were collected from medical records, and each patient completed a study questionnaire on recent history of skin infections, antibiotic use, and hospitalization. Each isolate was tested against cephalothin, clindamycin, erythromycin, gentamicin, mupirocin, tetracycline, retapamulin, and trimethoprim/sulfamethoxazole.. Although methicillin-resistance rates varied between centers (range, 15.8%-35.5%), macrolide resistance was ~50% at all of the sites in this study. Mupirocin-resistant isolates were observed much more frequently from 1 center (33.9%), and nearly all demonstrated high-level resistance. Only 1 retapamulin-resistant isolate (0.5%) was observed, with a minimum inhibitory concentration of 16 µg/mL. The other agents had relatively low resistance rates, which varied between centers and were dependent on susceptibility to methicillin.. Although the rate of mupirocin-resistant S aureus isolates collected in this investigation was >10%, retapamulin resistance was infrequent. Surveillance of topical agents to determine resistance rates against targeted bacteria is necessary.

Topics: Administration, Topical; Anti-Bacterial Agents; Bridged Bicyclo Compounds, Heterocyclic; Clindamycin; Diterpenes; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Mupirocin; Staphylococcal Skin Infections; Staphylococcus aureus; Surgical Wound Infection; United States

Meticillin-resistant Staphylococcus aureus (MRSA) is a rapidly spreading pathogen associated predominantly with skin infections. The lack of clinical evidence indicating the best treatment strategy to combat MRSA skin infections prompted us to investigate the efficacy of available treatment options in an experimental skin wound infection model in mice. Mice were treated either topically with retapamulin (1%), fusidic acid (2%) or mupirocin (2%) or systemically with linezolid (50-100 mg/kg/day) or vancomycin (50-200 mg/kg/day) twice daily for 3 days or 6 days and the total bacterial loads in the skin lesions were determined. Retapamulin, fusidic acid and mupirocin treatment for 3 days reduced the bacterial loads by 2.5, 2.9 and 2.0 log(10) CFU, respectively, and treatment for 6 days by 5.0, 4.2 and 5.1 log(10) CFU, respectively, compared with non-treated controls (P < 0.001). Systemic treatment with linezolid for 6 days reduced the bacterial loads by 1.6 log(10) CFU compared with non-treated mice (P < 0.001), whereas vancomycin treatment showed no effect on reducing the bacterial loads in infected skin lesions. These findings suggest that topical treatment with retapamulin and mupirocin is significantly more effective than systemic treatment with linezolid and vancomycin in eradicating MRSA in skin wounds. Retapamulin and mupirocin may provide an alternative to fusidic acid treatment of MRSA in skin wounds when resistance to fusidic acid is suspected.

Topics: Acetamides; Animals; Anti-Bacterial Agents; Anti-Infective Agents, Local; Bacterial Load; Bridged Bicyclo Compounds, Heterocyclic; Diterpenes; Female; Fusidic Acid; Linezolid; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Mupirocin; Oxazolidinones; Staphylococcal Skin Infections; Vancomycin; Wound Infection

Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) frequently causes skin and soft tissue infections, including impetigo, cellulitis, folliculitis, and infected wounds and ulcers. Uncomplicated CA-MRSA skin infections are typically managed in an outpatient setting with oral and topical antibiotics and/or incision and drainage, whereas complicated skin infections often require hospitalization, intravenous antibiotics, and sometimes surgery. The aim of this study was to develop a mouse model of CA-MRSA wound infection to compare the efficacy of commonly used systemic and topical antibiotics. A bioluminescent USA300 CA-MRSA strain was inoculated into full-thickness scalpel wounds on the backs of mice and digital photography/image analysis and in vivo bioluminescence imaging were used to measure wound healing and the bacterial burden. Subcutaneous vancomycin, daptomycin, and linezolid similarly reduced the lesion sizes and bacterial burden. Oral linezolid, clindamycin, and doxycycline all decreased the lesion sizes and bacterial burden. Oral trimethoprim-sulfamethoxazole decreased the bacterial burden but did not decrease the lesion size. Topical mupirocin and retapamulin ointments both reduced the bacterial burden. However, the petrolatum vehicle ointment for retapamulin, but not the polyethylene glycol vehicle ointment for mupirocin, promoted wound healing and initially increased the bacterial burden. Finally, in type 2 diabetic mice, subcutaneous linezolid and daptomycin had the most rapid therapeutic effect compared with vancomycin. Taken together, this mouse model of CA-MRSA wound infection, which utilizes in vivo bioluminescence imaging to monitor the bacterial burden, represents an alternative method to evaluate the preclinical in vivo efficacy of systemic and topical antimicrobial agents.

Topics: Acetamides; Administration, Oral; Administration, Topical; Animals; Anti-Bacterial Agents; Bacterial Load; Bridged Bicyclo Compounds, Heterocyclic; Clindamycin; Community-Acquired Infections; Daptomycin; Diabetes Mellitus, Type 2; Disease Models, Animal; Diterpenes; Doxycycline; Linezolid; Luminescent Measurements; Male; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Inbred C57BL; Mupirocin; Oxazolidinones; Skin; Soft Tissue Infections; Staphylococcal Infections; Staphylococcal Skin Infections; Trimethoprim, Sulfamethoxazole Drug Combination; Vancomycin; Wound Healing

Staphylococcus aureus skin infections represent a significant public health threat because of the emergence of antibiotic-resistant strains such as methicillin-resistant S. aureus (MRSA). As greater understanding of protective immune responses and more effective antimicrobial therapies are needed, a S. aureus skin wound infection model was developed in which full-thickness scalpel cuts on the backs of mice were infected with a bioluminescent S. aureus (methicillin sensitive) or USA300 community-acquired MRSA strain and in vivo imaging was used to noninvasively monitor the bacterial burden. In addition, the infection-induced inflammatory response was quantified using in vivo fluorescence imaging of LysEGFP mice. Using this model, we found that both IL-1α and IL-1β contributed to host defense during a wound infection, whereas IL-1β was more critical during an intradermal S. aureus infection. Furthermore, treatment of a USA300 MRSA skin infection with retapamulin ointment resulted in up to 85-fold reduction in bacterial burden and a 53% decrease in infection-induced inflammation. In contrast, mupirocin ointment had minimal clinical activity against this USA300 strain, resulting in only a 2-fold reduction in bacterial burden. Taken together, this S. aureus wound infection model provides a valuable preclinical screening method to investigate cutaneous immune responses and the efficacy of topical antimicrobial therapies.

Topics: Administration, Topical; Animals; Anti-Bacterial Agents; Bridged Bicyclo Compounds, Heterocyclic; Community-Acquired Infections; Dermatitis; Dermoscopy; Disease Models, Animal; Diterpenes; Drug Monitoring; Green Fluorescent Proteins; Interleukin-1alpha; Interleukin-1beta; Male; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Fluorescence; Mupirocin; Staphylococcal Skin Infections

Retapamulin, the first pleuromutilin antimicrobial agent approved for the topical treatment of skin infections in humans, was tested against 987 clinical isolates representing 30 species and/or resistance groups. MICs were determined along with disk diffusion zone diameters using a 2-microg disk. Population distribution and MIC versus disk zone diameter scattergrams were analyzed to determine microbiological MIC cutoff values and inhibition zone correlates. Minimum bactericidal concentrations were performed on a smaller subset of key species. The retapamulin MIC(90) against 234 Staphylococcus aureus isolates and 110 coagulase-negative staphylococci was 0.12 microg/ml. Retapamulin MIC(90)s ranged from 0.03 to 0.06 microg/ml against beta-hemolytic streptococci including 102 Streptococcus pyogenes, 103 Streptococcus agalactiae, 59 group C Streptococcus, and 71 group G Streptococcus isolates. The MIC(90) against 55 viridans group streptococci was 0.25 microg/ml. Retapamulin had very little activity against 151 gram-negative bacilli and most of the Enterococcus species tested. Based on the data from this study, for staphylococci, MICs of or=2 microg/ml with corresponding disk diffusion values of >or=20 mm, 17 to 19 mm, and or=15 mm can be proposed for susceptible-only microbiological cutoffs.

Topics: Anti-Bacterial Agents; Anti-Infective Agents, Local; Bridged Bicyclo Compounds, Heterocyclic; Disk Diffusion Antimicrobial Tests; Diterpenes; Drug Resistance, Bacterial; Enterococcus; Gram-Negative Bacteria; Humans; In Vitro Techniques; Microbial Sensitivity Tests; Mupirocin; Skin Diseases, Bacterial; Staphylococcal Skin Infections; Staphylococcus aureus; Streptococcus