Mechanism Of Action
ALTABAX is an antibacterial agent [see Microbiology].
In post-hoc analyses of manually over-read 12-lead ECGs from healthy subjects (N = 103), no significant effects on QT/QTc intervals were observed after topical application of retapamulin ointment on intact and abraded skin. Due to the low systemic exposure to retapamulin with topical application, QT prolongation in patients is unlikely [see Pharmacokinetics].
In a trial of healthy adult subjects, retapamulin ointment, 1% was applied once daily to intact skin (800 cm² surface area) and to abraded skin (200 cm² surface area) under occlusion for up to 7 days. Systemic exposure following topical application of retapamulin through intact and abraded skin was low. Three percent of blood samples obtained on Day 1 after topical application to intact skin had measurable retapamulin concentrations (lower limit of quantitation 0.5 ng per mL); thus Cmax values on Day 1 could not be determined. Eighty-two percent of blood samples obtained on Day 7 after topical application to intact skin and 97% and 100% of blood samples obtained after topical application to abraded skin on Days 1 and 7, respectively, had measurable retapamulin concentrations. The median Cmax value in plasma after application to 800 cm² of intact skin was 3.5 ng per mL on Day 7 (range: 1.2 to 7.8 ng per mL). The median Cmax value in plasma after application to 200 cm² of abraded skin was 11.7 ng per mL on Day 1 (range: 5.6 to 22.1 ng per mL) and 9.0 ng per mL on Day 7 (range: 6.7 to 12.8 ng per mL).
Plasma samples were obtained from 380 adult subjects and 136 pediatric subjects (aged 2 to 17 years) who were receiving topical treatment with ALTABAX topically twice daily. Eleven percent had measurable retapamulin concentrations (lower limit of quantitation 0.5 ng per mL), of which the median concentration was 0.8 ng per mL. The maximum measured retapamulin concentration in adults was 10.7 ng per mL and in pediatric subjects (aged 2 to 17 years) was 18.5 ng per mL.
A single plasma sample was obtained from 79 pediatric subjects (aged 2 to 24 months) who were receiving topical treatment with ALTABAX twice daily. Forty-six percent had measurable retapamulin concentrations greater than 0.5 ng per mL) compared with 7% in pediatric subjects aged 2 to 17 years. A higher proportion (69%) of pediatric subjects aged 2 to 9 months had measurable concentrations of retapamulin compared with subjects aged 9 to 24 months (32%). Among pediatric subjects aged 2 to 9 months (n = 29), 4 subjects had retapamulin concentrations that were higher (greater than or equal to 26.9 ng per mL) than the maximum concentration observed in pediatric subjects aged 2 to 17 years (18.5 ng per mL). Among pediatric subjects aged 9 to 24 months (n = 50), 1 subject had a retapamulin concentration that was higher (95.1 ng per mL) than the maximum level observed in pediatric subjects aged 2 to 17 years.
Retapamulin is approximately 94% bound to human plasma proteins, and the protein binding is independent of concentration. The apparent volume of distribution of retapamulin has not been determined in humans.
In vitro studies with human hepatocytes showed that the main routes of metabolism were monooxygenation and di-oxygenation. In vitro studies with human liver microsomes demonstrated that retapamulin is extensively metabolized to numerous metabolites, of which the predominant routes of metabolism were mono-oxygenation and N-demethylation. The major enzyme responsible for metabolism of retapamulin in human liver microsomes was cytochrome P450 3A4 (CYP3A4).
Retapamulin elimination in humans has not been investigated due to low systemic exposure after topical application.
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 methicillinsusceptible. 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].
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 inoculums 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.
Table 3: Acceptable Quality Control Ranges for
|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|
|NA = Not applicable.
aThis quality control range is applicable using cation-adjusted Mueller-Hinton broth with 2% to 5% lysed horse blood.
bThis quality control limit is applicable using Mueller-Hinton agar with 5% sheep blood.
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.
Table 4: Clinical Response at End of Therapy and at
Follow-Up by Analysis Population
|Analys is Population||ALTABAX Success||Placebo Success||Difference in Success Rates (%)||95% CI(%)|
|n/N||Rate (%)||n/N||Rate (%)|
|End of Therapy|
|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.|
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||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|
|n/N = Number of clinical successes/number of pathogens isolated at baseline.|
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.
1. Clinical and Laboratory Standards Institute (CLSI) Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically: Approved Standard-Eighth Edition. CLSI Document M07-A9, Vol. 32, No. 2. CLSI, Wayne, PA, Jan. 2012.
2. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing: Nineteenth Informational Supplement. CLSI Document M100-S22. Vol. 32, No. 3. CLSI, Wayne, PA, Jan. 2012.
3. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Susceptibility Tests. Approved Standard-Tenth Edition. CLSI Document M02-A11, Vol. 32, No. 1. CLSI, Wayne, PA, Jan. 2012.
Last reviewed on RxList: 12/5/2016
This monograph has been modified to include the generic and brand name in many instances.
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