mupirocin and retapamulin

Impetigo, a highly contagious bacterial skin infection commonly occurring in young children, but adults may also be affected. The superficial skin infection is mainly caused by Staphylococcus aureus (S. aureus) and less frequently by Streptococcus pyogenes (S. pyogenes). Antimicrobial resistance has become a worldwide concern and needs to be addressed when selecting treatment for impetigo patients. An evidence-based impetigo treatment algorithm was developed to address the treatment of impetigo for pediatric and adult populations.. An international panel of pediatric dermatologists, dermatologists, pediatricians, and pediatric infectious disease specialists employed a modified Delphi technique to develop the impetigo treatment algorithm. Treatment recommendations were evidence-based, taking into account antimicrobial stewardship and the increasing resistance to oral and topical antibiotics.. The algorithm includes education and prevention of impetigo, diagnosis and classification, treatment measures, and follow-up and distinguishes between localized and widespread or epidemic outbreaks of impetigo. The panel adopted the definition of localized impetigo of fewer than ten lesions and smaller than 36 cm2 area affected in patients of two months and up with no compromised immune status. Resistance to oral and topical antibiotics prescribed for the treatment of impetigo such as mupirocin, retapamulin, fusidic acid, have been widely reported.. When prescribing antibiotics, it is essential to know the local trends in antibiotic resistance. Ozenoxacin cream 1% is highly effective against S. pyogenes and S. aureus, including methycyllin-susceptible and resistant strains (MRSA), and may be a suitable option for localized impetigo.J Drugs Dermatol. 2021;20(2):134-142. doi:10.36849/JDD.5475 \ \ THIS ARTICLE HAD BEEN MADE AVAILABLE FREE OF CHARGE. PLEASE SCROLL DOWN TO ACCESS THE FULL TEXT OF THIS ARTICLE WITHOUT LOGGING IN. NO PURCHASE NECESSARY. PLEASE CONTACT THE PUBLISHER WITH ANY QUESTIONS.

Topics: Aminopyridines; Anti-Bacterial Agents; Antimicrobial Stewardship; Bridged Bicyclo Compounds, Heterocyclic; Critical Pathways; Delphi Technique; Diterpenes; Drug Resistance, Bacterial; Evidence-Based Medicine; Fusidic Acid; Humans; Impetigo; Microbial Sensitivity Tests; Mupirocin; Practice Guidelines as Topic; Quinolones; Skin Cream; Staphylococcus aureus; Streptococcus pyogenes; Systematic Reviews as Topic

Topics: Administration, Topical; Amoxicillin-Potassium Clavulanate Combination; Anti-Bacterial Agents; Anti-Infective Agents, Local; Bacitracin; Bridged Bicyclo Compounds, Heterocyclic; Cephalexin; Clindamycin; Cloxacillin; Dicloxacillin; Diterpenes; Erythromycin; Fusidic Acid; Gentamicins; Humans; Impetigo; Meta-Analysis as Topic; Mupirocin; Randomized Controlled Trials as Topic

Retapamulin activity against 53 isolates obtained from a mupirocin-resistant community-acquired methicillin-resistant Staphylococcus aureus pediatric disease cluster was evaluated using broth microdilution. All strains were susceptible to retapamulin with minimum inhibitory concentrations ≤ 0.5 μg/mL. DNA sequence analysis of rplC and cfr identified one rplC strain variant that did not demonstrate reduced phenotypic susceptibility to retapamulin. These results demonstrate that retapamulin may be a useful alternative therapy for mupirocin-resistant community-acquired methicillin-resistant S. aureus, especially in disease clusters.

Topics: Adolescent; Anti-Bacterial Agents; Bridged Bicyclo Compounds, Heterocyclic; Child; Child, Preschool; Community-Acquired Infections; Diterpenes; Humans; Infant; Infant, Newborn; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Mupirocin; Sequence Analysis, DNA; Staphylococcal Infections

Overall MRSA MUP, FA and RET resistance was low (5.1, 1.0 and 0.3%, respectively). MupA was the mechanism of high-level MUP resistance. All low-level MUP resistance isolates possessed an equivocal mutation N213D in IleS; of these, 2 reported an additional V588F mutation with an impact on the Rossman fold. FusA mutations, such as L461K, H457Q, H457Y and V90I were the primary FA mechanisms among high-level resistance isolates, most of which also contained fusC; however, all low-level resistance strains carried fusB. Except lsaE gene detected in one isolate, no other resistance mechanisms tested were found among RET-resistant isolates. Additionally, sixteen PFGE types (A-P) were observed, among which type B was the most common (49/76, 64.5%), followed by types E and G (4/76, 5.3% each) and types C and M (3/76, 3.9% each). All resistant strains were divided into 15 ST types by MLST. ST764 (24/76, 31.6%), ST630 (11/76, 14.5%), ST239 (9/76, 11.8%) and ST5 (7/76, 9.2%) were the major types. PFGE type B isolates with the aforementioned STs were mainly found in mupirocin resistant isolates.. MUP, FA and RET exhibited highly activity against the MRSA isolates. Acquired genes and chromosome-borne genes mutations were responsible for MUP and FA resistance; however, the mechanism for some RET-resistant isolates remains to be further elucidated. Also, the surveillance to MUP in MRSA should be strengthened to prevent elevated resistance due to the expansion of clones.

Topics: Anti-Bacterial Agents; Bacterial Typing Techniques; Bridged Bicyclo Compounds, Heterocyclic; China; Diterpenes; DNA, Bacterial; Drug Resistance, Multiple, Bacterial; Electrophoresis, Gel, Pulsed-Field; Fusidic Acid; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Multilocus Sequence Typing; Mupirocin; Mutation; Prevalence; Sequence Analysis, DNA; Staphylococcal Infections

To assess different concentrations and formulations of topical ozenoxacin using a mouse model of Staphylococcus aureus dermal infection for identification of the best formulation for treating patients with impetigo.. The efficacy of ozenoxacin formulations was compared with vehicle control, mupirocin and retapamulin ointments in a mouse model.. The most effective concentrations of ozenoxacin for reducing S. aureus counts after dermal application were 1 and 2%. Direct comparison of two batches of 1% ozenoxacin ointment and cream with 1% retapamulin and 2% mupirocin ointments in the mouse model showed superior efficacy of ozenoxacin.. 1% ozenoxacin ointment and cream were the most effective formulations in significantly reducing bacterial load in S. aureus dermally infected mice.

Topics: Administration, Topical; Aminopyridines; Animals; Animals, Outbred Strains; Anti-Bacterial Agents; Bridged Bicyclo Compounds, Heterocyclic; Disease Models, Animal; Diterpenes; Dose-Response Relationship, Drug; Humans; Impetigo; Mice; Mupirocin; Ointments; Quinolones; Skin Cream; Staphylococcus aureus; Treatment Outcome; Wound Infection

Impetigo, a bacterial skin infection that involves the superficial layers of the skin, is one of the most common skin infections in children ages 2 to 5 but can occur in individuals across the lifespan. This article discusses the diagnosis and management of impetigo in primary care.

Topics: Administration, Oral; Anti-Bacterial Agents; Bridged Bicyclo Compounds, Heterocyclic; Diterpenes; Erythromycin; Humans; Impetigo; Mupirocin; Nurse Practitioners; Ointments; Staphylococcus aureus

Mupirocin is a topical antimicrobial used to decolonize patients who carry methicillin-resistant Staphylococcus aureus (MRSA), and the topical agent retapamulin may be a potential alternative therapy. The goal of this study was to determine the in vitro activity of retapamulin as well as a panel of 15 antimicrobial agents, including mupirocin, for 403 MRSA isolates collected longitudinally from a naive population at the Veterans Affairs Puget Sound Health Care System. The MICs for retapamulin had a unimodal distribution, ranging from 0.008 to 0.5 μg/ml. One isolate had an MIC of >16 μg/ml, was also resistant to clindamycin and erythromycin, and was recovered from the nares of a patient undergoing hemodialysis. Twenty-four isolates (6%) and 11 isolates (3%) demonstrated low-level resistance (MICs of 8 to 64 μg/ml) and high-level resistance (MICs of ≥ 512 μg/ml), respectively, to mupirocin. Isolates were recovered from 10 patients both before and after mupirocin therapy. Of those, isolates from 2 patients demonstrated MIC changes postmupirocin therapy; in both cases, however, strain typing demonstrated that the pre- and postmupirocin strains were different. A total of 386 isolates (96%) had vancomycin MICs of ≤ 1.0 μg/ml; 340 isolates (84%) were resistant to levofloxacin, 18 isolates (4.5%) were resistant to trimethoprim-sulfamethoxazole, and 135 isolates (33%) had elevated MICs of 4 μg/ml for linezolid. The baseline levels of resistance were low for mupirocin (9%) and even lower for retapamulin (0.25%) Although the use of mupirocin is currently the standard therapy for decolonization practices, the activity of retapamulin warrants its consideration as an alternative therapy in MRSA decolonization regimens.

Topics: Anti-Bacterial Agents; ATP-Binding Cassette Transporters; Bacterial Proteins; Bridged Bicyclo Compounds, Heterocyclic; Diterpenes; Humans; Linezolid; Longitudinal Studies; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Mupirocin; Staphylococcal Infections; United States; Veterans

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

Twenty-five serial passages of Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus and 50 passages of methicillin-resistant Staphylococcus aureus resulted in no significant increase in NVC-422 MICs, while ciprofloxacin MICs increased 256-fold for E. coli and 32-fold for P. aeruginosa and S. aureus. Mupirocin, fusidic acid, and retapamulin MICs for MRSA increased 64-, 256-, and 16-fold, respectively. No cross-resistance to NVC-422 was observed with mupirocin-, fusidic acid-, and retapamulin-resistant strains.

Topics: Anti-Bacterial Agents; Bridged Bicyclo Compounds, Heterocyclic; Ciprofloxacin; Diterpenes; Drug Resistance, Multiple, Bacterial; Escherichia coli; Fusidic Acid; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Mupirocin; Pseudomonas aeruginosa; Staphylococcus aureus; Taurine

XF-73 is a dicationic porphyrin drug with rapid Gram-positive antibacterial activity currently undergoing clinical trials for the nasal decolonization of Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus (MRSA). In multistep (55-passage) resistance selection studies in the presence of subinhibitory concentrations of XF-73, retapamulin, mupirocin, fusidic acid, and vancomycin against four Network on Antimicrobial Resistance in Staphylococcus aureus MRSA strains, there was no >4-fold increase in the MIC for XF-73 after 55 passages. In contrast, there was an increase in the MICs for retapamulin (from 0.25 μg/ml to 4 to 8 μg/ml), for mupirocin (from 0.12 μg/ml to 16 to 512 μg/ml), for fusidic acid (from 0.12 μg/ml to 256 μg/ml), and for vancomycin (from 1 μg/ml to 8 μg/ml in two of the four strains tested). Further investigations using S. aureus NRS384 (USA300) and daptomycin demonstrated a 64-fold increase in the MIC after 55 passages (from 0.5 μg/ml to 32 μg/ml) with a >4-fold increase in the MIC obtained after only five passages. Sequencing analysis of selected isolates confirmed previously reported point mutations associated with daptomycin resistance. No cross-resistance to XF-73 was observed with the daptomycin-resistant strains, suggesting that whereas the two drugs act on the bacterial cell membrane, their specific site of action differs. XF-73 thus represents the first in a new class of antibacterial drugs, which (unlike the comparator antibiotics) after 55 passages exhibited a ≤4-fold increase in MIC against the strains tested. Antibacterial drugs with a low propensity for inducing bacterial resistance are much needed for the prevention and treatment of multidrug-resistant bacteria both within and outside the hospital setting.

Topics: Anti-Bacterial Agents; Bridged Bicyclo Compounds, Heterocyclic; Daptomycin; Diterpenes; Fusidic Acid; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Molecular Structure; Mupirocin; Polymerase Chain Reaction; Porphyrins; Sequence Analysis, DNA; Vancomycin

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

To determine the in vitro activity of retapamulin and other topical antibiotics (mupirocin, bacitracin, and fusidic acid) usually employed for nasal decolonization, against methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA), and linezolid and methicillin-resistant S. aureus.. The minimum inhibitory concentrations (MICs) were determined on Mueller-Hinton agar according to the guidelines of the Clinical and Laboratory Standards Institute and of the European Committee for Antimicrobial Susceptibility Testing. Presence of the cfr gene in linezolid and methicillin-resistant S. aureus isolates was detected using polymerase chain reaction.. Retapamulin inhibited all the isolates of MSSA and MRSA at 0.125 mg/L, but the 18 linezolid-resistant-MRSA strains proved resistant, with MICs over 32 mg/L. Most MSSA isolates (9/10) were susceptible to mupirocin with MICs under 0.19 mg/L, although this value decreased to half against MRSA, and almost all linezolid-resistant MRSA (17/18) strains were resistant to mupirocin with an MIC range of between 8 mg/L and 28 mg/L. The MIC of fusidic acid increased substantially against linezolid-resistant MRSA, whereas that of bacitracin showed no differences.. Retapamulin demonstrated excellent in vitro activity against MSSA and MRSA strains, but not against MRSA isolates harbouring the cfr gene. The results of this in vitro study support cut-off values for retapamulin of ≤ 0.5, 1, and ≥ 2 mg/L for susceptible, intermediate, and resistant strains, respectively.

Topics: Acetamides; Anti-Bacterial Agents; Bacitracin; Bacterial Proteins; Bridged Bicyclo Compounds, Heterocyclic; Diterpenes; Linezolid; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Mupirocin; Oxazolidinones; Polymerase Chain Reaction; Staphylococcus aureus

Staphylococcus aureus (S. aureus) is the leading cause of nosocomial infections and responsible for more than 11 million skin and soft tissue infections annually. Impetigo is a common skin infection and the most common bacterial skin infection in children aged two to five years. The emergence of S. aureus isolates resistant to commonly utilized antibacterials for skin infections (beta-lactams, erythromycin, fluoroquinolones and mupirocin) makes successful treatment an ongoing challenge. To treat skin infections such as impetigo, antibacterials with a short dosing schedule and low propensity to develop resistance should be used. In 2007, retapamulin was the first agent for human use approved in the pleuromutilin class of antibacterials in the United States (U.S.), and is the first topical antibacterial indicated to treat impetigo in over 20 years. In vitro, retapamulin is highly potent against S. aureus and has a lower propensity to develop resistance than mupirocin. In clinical studies, the convenient five-day b.i.d. (twice-daily) dosing of retapamulin is highly effective against impetigo due to methicillin- susceptible S. aureus and Streptococcus pyogenes and may play an important role in limiting the development of resistance against systemic agents.

Topics: Anti-Bacterial Agents; Bridged Bicyclo Compounds, Heterocyclic; Diterpenes; Drug Resistance, Bacterial; Fluoroquinolones; Mupirocin; Staphylococcus aureus; Vancomycin Resistance

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

Retapamulin MICs of > or =2 microg/ml were noted for 6 of 5,676 S. aureus recent clinical isolates evaluated. The ABC proteins VgaAv and VgaA were found to be responsible for the reduced susceptibility to pleuromutilins exhibited by these six isolates.

Topics: Anti-Bacterial Agents; ATP-Binding Cassette Transporters; Bacterial Proteins; Bridged Bicyclo Compounds, Heterocyclic; Diterpenes; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Molecular Sequence Data; Pleuromutilins; Polycyclic Compounds; Sequence Analysis, DNA; Staphylococcus aureus

We determined the in vitro activity of retapamulin, a novel pleuromutilin antibiotic, against 664 Staphylococcus aureus isolates from the UK, including many resistant to fusidic acid and/or highly resistant to mupirocin.. MICs were determined on Mueller-Hinton agar in accordance with the CLSI guidelines. Susceptibility was categorized using CLSI criteria, where available; otherwise the European Committee for Antimicrobial Susceptibility Testing (EUCAST)/BSAC criteria were used (for mupirocin and fusidic acid). Mutations in the rplC gene, which encodes ribosomal protein L3, were sought by PCR and DNA sequencing.. The S. aureus included 488 (73%) methicillin-resistant isolates (oxacillin MICs >2 mg/L), 336 isolates (51%) resistant to fusidic acid (MICs >1 mg/L) and 254 (38%) with high-level mupirocin resistance (MICs >256 mg/L); 103 (16%) isolates were resistant both to fusidic acid and to high levels of mupirocin. Retapamulin inhibited 663 (99.9%) isolates at < or =0.25 mg/L. A single methicillin-resistant S. aureus isolate, also with high-level mupirocin resistance, required a retapamulin MIC of 2 mg/L, but its reduced susceptibility to retapamulin was not associated with any mutation in ribosomal protein L3.. Retapamulin demonstrated excellent activity in vitro against S. aureus isolates, irrespective of their level of resistance to other antibacterials. These results support the EUCAST epidemiological cut-off value for retapamulin of < or =0.5 mg/L against S. aureus.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Bridged Bicyclo Compounds, Heterocyclic; Diterpenes; DNA Mutational Analysis; Drug Resistance, Bacterial; Fusidic Acid; Humans; Microbial Sensitivity Tests; Mupirocin; Ribosomal Protein L3; Ribosomal Proteins; Staphylococcal Infections; Staphylococcus aureus; United Kingdom

To assess their effects on susceptibility to retapamulin in Staphylococcus aureus, first-, second-, and third-step mutants with elevated MICs to tiamulin and other investigational pleuromutilin compounds were isolated and characterized through exposure to high drug concentrations. All first- and second-step mutations were in rplC, encoding ribosomal protein L3. Most third-step mutants acquired a third mutation in rplC. While first- and second-step mutations did cause an elevation in tiamulin and retapamulin MICs, a significant decrease in activity was not seen until a third mutation was acquired. All third-step mutants exhibited severe growth defects, and faster-growing variants arose at a high frequency from most isolates. These faster-growing variants were found to be more susceptible to pleuromutilins. In the case of a mutant with three alterations in rplC, the fast-growing variants acquired an additional mutation in rplC. In the case of fast-growing variants of isolates with two mutations in rplC and at least one mutation at an unmapped locus, one of the two rplC mutations reverted to wild type. These data indicate that mutations in rplC that lead to pleuromutilin resistance have a direct, negative effect on fitness. While reduction in activity of retapamulin against S. aureus can be seen through mutations in rplC, it is likely that target-specific resistance to retapamulin will be slow to emerge due to the need for three mutations for a significant effect on activity and the fitness cost of each mutational step.

Topics: Anti-Bacterial Agents; Bridged Bicyclo Compounds, Heterocyclic; Diterpenes; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Mutation; Pleuromutilins; Polycyclic Compounds; Ribosomal Protein L3; Ribosomal Proteins; Staphylococcus aureus

The effect of topically applied retapamulin ointment was evaluated using various dosing regimens in the Staphylococcus aureus and Streptococcus pyogenes wound infection model. Retapamulin (1%, wt/wt) was efficacious using twice-daily (b.i.d.) applications for 4 or 5 days. These data underpinned the decision to evaluate 1% retapamulin b.i.d. in clinical trials.

Topics: Administration, Topical; Animals; Anti-Bacterial Agents; Anti-Infective Agents, Local; Bridged Bicyclo Compounds, Heterocyclic; Colony Count, Microbial; Diterpenes; Drug Resistance, Bacterial; Methicillin Resistance; Mice; Mupirocin; Ointments; Staphylococcal Infections; Staphylococcus aureus; Surgical Wound Infection

The in vitro activity of retapamulin was determined and compared to that of topical and community antibiotics. The MIC(90)s of retapamulin against Staphylococcus aureus and Streptococcus pyogenes were 0.12 microg/ml and 0.016 microg/ml, respectively. Retapamulin has a low propensity to select resistance and produces an in vitro postantibiotic effect.

Topics: Anti-Infective Agents, Local; Bacteria; Bridged Bicyclo Compounds, Heterocyclic; Diterpenes; Drug Resistance, Bacterial; Haemophilus influenzae; Humans; Microbial Sensitivity Tests; Moraxella catarrhalis; Mupirocin; Pleuromutilins; Polycyclic Compounds; Skin Diseases, Bacterial; Staphylococcus; Streptococcus