retapamulin and Staphylococcal-Infections

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

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

A series of novel thioether pleuromutilin derivatives incorporating various heteroaromatic substituents into the C14 side chain have been reported. Structure-activity relationship (SAR) studies resulted in compounds 52 and 55 with the most potent in vitro antibacterial activity among the series (MIC = 0.031-0.063 μg/mL). Further optimization to overcome the poor water solubility of compound 55 resulted in compounds 87, 91, 109, and 110 possessing good in vitro antibacterial activity with increased hydrophilicity. Compound 114, the water-soluble phosphate prodrug of compound 52, was also prepared and evaluated. Among the derivatives, compound 110 showed moderate pharmacokinetic profiles and good in vivo efficacy in both MSSA and MRSA systemic infection models. Compound 110 was further evaluated in CYP450 inhibition assay and displayed intermediate in vitro inhibition of CYP3A4.

Topics: Aminopyridines; Animals; Anti-Bacterial Agents; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Diterpenes; Drug Design; Drug Resistance, Bacterial; Drug Stability; Female; Humans; Hydrophobic and Hydrophilic Interactions; In Vitro Techniques; Male; Methicillin-Resistant Staphylococcus aureus; Mice; Microbial Sensitivity Tests; Pleuromutilins; Polycyclic Compounds; Rats; Rats, Sprague-Dawley; Solubility; Staphylococcal Infections; Staphylococcus; Streptococcus; Structure-Activity Relationship; Sulfides

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

A phosphate prodrug strategy was investigated to address the problem of poor aqueous solubility of pleuromutilin analogues. Water-soluble phosphate prodrugs 6a, 6b and 6c of pleuromutilin analogues were designed and synthesized. Three compounds all exhibited excellent aqueous solubility (>50mg/mL) at near-neutral pH and sufficient stability in buffer solution. In particular, the phenol pleuromutilin prodrug 6c displayed favourable pharmacokinetic profiles and comparable potency with vancomycin against MSSA and MRSA strains in vivo.

Topics: Animals; Anti-Bacterial Agents; Diterpenes; Gram-Positive Bacteria; Mice; Microbial Sensitivity Tests; Phosphates; Pleuromutilins; Polycyclic Compounds; Prodrugs; Rats; Rats, Sprague-Dawley; Solubility; Staphylococcal Infections; Structure-Activity Relationship; Water

Linezolid resistance has dominantly been mediated by mutations in 23S rRNA or ribosomal protein L4 genes. Recently, cfr has demonstrated the ability to produce a phenotype of resistance to not only oxazolidinones, but also other antimicrobial classes (phenicols, lincosamides, pleuromutilins, and streptogramin A). We describe the first detection of cfr-mediated linezolid resistance in Staphylococcus aureus and Staphylococcus epidermidis recovered from human infection cases monitored during the 2007 LEADER Program.

Topics: Acetamides; Anti-Bacterial Agents; Anti-Infective Agents; Bacterial Proteins; Drug Resistance, Bacterial; Humans; Linezolid; Methyltransferases; Microbial Sensitivity Tests; Molecular Sequence Data; Oxazolidinones; Sequence Analysis, DNA; Staphylococcal Infections; Staphylococcus aureus; Staphylococcus epidermidis

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

Topics: Amino Acid Substitution; Animals; Bacterial Toxins; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials as Topic; Community-Acquired Infections; Diterpenes; Electrophoresis, Gel, Pulsed-Field; Exotoxins; Genetic Variation; Humans; Leukocidins; Methicillin Resistance; Mice; Staphylococcal Infections; 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