Retapamulin is a semisynthetic derivative of the compound pleuromutilin, which is isolated through fermentation from Clitopilus passeckerianus (formerly Pleurotus passeckerianus). In vitro activity of retapamulin against isolates of Staphylococcus aureus as well as Streptococcus pyogenes has been demonstrated.
Antimicrobial Mechanism of Action
Retapamulin selectively inhibits bacterial protein synthesis by interacting at a site on the 50S subunit of the bacterial ribosome through an interaction that is different from that of other antibiotics. This binding site involves ribosomal protein L3 and is in the region of the ribosomal P site and peptidyl transferase center. By virtue of binding to this site, pleuromutilins inhibit peptidyl transfer, block P-site interactions, and prevent the normal formation of active 50S ribosomal subunits. Retapamulin is bacteriostatic against Staphylococcus aureus and Streptococcus pyogenes at the retapamulin in vitro minimum inhibitory concentration (MIC) for these organisms. At concentrations 1,000 times the in vitro MIC, retapamulin is bactericidal against these same organisms. Although cross-resistance between retapamulin and other antibacterial classes (such as clindamycin and oxazolidones) exist, isolates resistant to these classes may be susceptible to retapamulin.
Mechanisms of Decreased Susceptibility to Retapamulin
In vitro, 2 mechanisms that cause reduced susceptibility to retapamulin have been identified, specifically, mutations in ribosomal protein L3, the presence of Cfr rRNA methyltransferase or the presence of an efflux mechanism. Decreased susceptibility of S. aureus to retapamulin (highest retapamulin MIC was 2 mcg per mL) develops slowly in vitro via multistep mutations in L3 after serial passage in sub-inhibitory concentrations of retapamulin. There was no apparent treatment-associated reduction in susceptibility to retapamulin in the Phase 3 clinical program. The clinical significance of these findings is not known.
Based on in vitro broth microdilution susceptibility testing, no differences were observed in susceptibility of S. aureus to retapamulin whether the isolates were methicillin-resistant or methicillin-susceptible. Retapamulin susceptibility did not correlate with clinical success rates in patients with methicillin-resistant S. aureus. The reason for this is not known but may have been influenced by the presence of particular strains of S. aureus possessing certain virulence factors, such as Panton-Valentine Leukocidin (PVL). In the case of treatment failure associated with S. aureus (regardless of methicillin susceptibility), the presence of strains possessing additional virulence factors (such as PVL) should be considered.
Retapamulin has been shown to be active against the following microorganisms, both in vitro and in clinical trials [see Indications and Usage (1)].
Aerobic and Facultative Gram-Positive Bacteria: Staphylococcus aureus (methicillin-susceptible isolates only); Streptococcus pyogenes.
The clinical microbiology laboratory should provide cumulative results of the in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial.
Susceptibility Testing Techniques:
Dilution Techniques: Quantitative methods can be used to determine the MIC of retapamulin that will inhibit the growth of the bacteria being tested. The MIC provides an estimate of the susceptibility of bacteria to retapamulin. The MIC should be determined using a standardized procedure.1,2 Standardized procedures are based on a dilution method (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of retapamulin powder.
Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure requires the use of standardized inoculum concentrations.2,3 This procedure uses paper disks impregnated with 2 mcg of retapamulin to test the susceptibility of microorganisms to retapamulin.
Susceptibility Test Interpretive Criteria: In vitro susceptibility test interpretive criteria for retapamulin have not been determined for this topical antimicrobial. The relation of the in vitro MIC and/or disk diffusion susceptibility test results to clinical efficacy of retapamulin against the bacteria tested should be monitored.
Quality Control Parameters for Susceptibility Testing: In vitro susceptibility test quality control parameters were developed for retapamulin so that laboratories that test the susceptibility of bacterial isolates to retapamulin can determine if the susceptibility test is performing correctly. Standardized dilution techniques and diffusion methods require the use of laboratory control microorganisms to monitor the technical aspects of the laboratory procedures. Standard retapamulin powder should provide the following MIC and a 2-mcg retapamulin disk should produce the following zone diameters with the indicated quality control strains in Table 3.
|NA = Not applicable. a This quality control range is applicable using cation-adjusted Mueller-Hinton broth with 2% to 5% lysed horse blood. b This quality control limit is applicable using Mueller-Hinton agar with 5% sheep blood.|
|Microorganism||MIC Range (mcg/mL)||Disk Diffusion Zone Diameter (mm)|
|Staphylococcus aureus ATCC 29213||0.06-0.25||NA|
|Staphylococcus aureus ATCC 25923||NA||23-30|
|Streptococcus pneumoniae ATCC 49619||0.06-0.5a||13-19b|
Long-term studies in animals to evaluate carcinogenic potential have not been conducted with retapamulin.
Retapamulin showed no genotoxicity when evaluated in vitro for gene mutation and/or chromosomal effects in the mouse lymphoma cell assay, in cultured human peripheral blood lymphocytes, or when evaluated in vivo in a rat micronucleus test.
No evidence of impaired fertility was found in male or female rats given retapamulin 50, 150, or 450 mg per kg per day orally.
ALTABAX was evaluated in a placebo-controlled trial that enrolled adult and pediatric subjects aged 9 months and older for treatment of impetigo up to 100 cm2 in total area (up to 10 lesions) or a total body surface area not exceeding 2%. The majority of subjects enrolled (164/210, 78%) were under the age of 13. The trial was a double-blind, randomized, multi-center, parallel-group comparison of the safety of ALTABAX and placebo ointment, both applied twice daily for 5 days. Subjects were randomized to ALTABAX or placebo (2:1). Subjects with underlying skin disease (e.g., pre-existing eczematous dermatitis) or skin trauma, with clinical evidence of secondary infection, were excluded from these trials. In addition, subjects with any systemic signs and symptoms of infection (such as fever) were excluded from the trial. Clinical success was defined as the absence of treated lesions, or treated lesions had become dry without crusts with or without erythema compared with baseline, or had improved (defined as a decline in the size of the affected area, number of lesions or both) such that no further antimicrobial therapy was required. The intent-to-treat clinical (ITTC) population consisted of all randomized subjects who took at least 1 dose of trial medication. The clinical per protocol (PPC) population included all ITTC subjects who satisfied the inclusion/exclusion criteria and subsequently adhered to the protocol. The intent-to-treat bacteriological (ITTB) population consisted of all randomized subjects who took at least 1 dose of trial medication and had a pathogen identified at trial entry. The bacteriological per protocol (PPB) population included all ITTB subjects who satisfied the inclusion/exclusion criteria and subsequently adhered to the protocol.
Table 4 presents the results for clinical response at end of therapy (2 days after treatment) and follow-up (9 days after treatment), by analysis population.
|n = number with clinical success outcome, N = number in analysis population, PPC = Clinical Per Protocol Population, ITTC = Clinical Intent to Treat Population, PPB = Bacteriological Per Protocol Population, ITTB = Bacteriological Intent to Treat Population.|
|Analysis Population||ALTABAX||Placebo||Difference in Success Rates (%)||95% CI (%)|
|n/N||Success Rate (%)||n/N||Success Rate (%)|
|End of Therapy|
Table 5 presents the clinical success at end of therapy and follow-up by baseline pathogen.
|Table 5. Clinical Response at End of Therapy and Follow-Up for Subjects with Staphylococcus aureus and Streptococcus pyogenes at Baseline in the Per Protocol Bacteriological Population (PPB)|
|n/N = Number of clinical successes/number of pathogens isolated at baseline.|
|n/N||Success Rate (%)||n/N||Success Rate (%)|
|End of Therapy|
|Staphylococcus aureus (Methicillin-susceptible)||79/88||89.8||25/48||52.1|
|Staphylococcus aureus (Methicillin-susceptible)||71/84||84.5||19/44||43.2|
Examination of age and gender subgroups did not identify differences in response to ALTABAX among these groups. The majority of subjects entered into this trial were classified as white/Caucasian or of Asian heritage; when response rates by racial subgroups were viewed across trials, differences in response to ALTABAX were not identified.
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