Retapamulin (DB01256): A Comprehensive Pharmacological and Clinical Monograph

1.0 Executive Summary

Retapamulin is a semi-synthetic, small-molecule antibiotic and the first representative of the pleuromutilin class approved for human topical use.[1] Developed by GlaxoSmithKline, it is marketed under the brand names Altabax and Altargo for the treatment of uncomplicated bacterial skin infections.[1] Its primary clinical indication is for impetigo caused by susceptible strains of

Staphylococcus aureus (methicillin-susceptible only) and Streptococcus pyogenes.[1]

The therapeutic value of retapamulin stems from its novel mechanism of action. It selectively inhibits bacterial protein synthesis by binding to a unique site on the 50S ribosomal subunit, an interaction distinct from all other classes of ribosomal inhibitors.[4] This unique binding confers a low intrinsic potential for target-specific cross-resistance with other established antibiotic classes, a significant advantage in an era of increasing antimicrobial resistance.[4]

Clinical trials have established its efficacy. A 5-day, twice-daily regimen of 1% retapamulin ointment was demonstrated to be significantly superior to placebo in treating impetigo and non-inferior to both topical sodium fusidate and a 10-day course of oral cephalexin for certain skin infections.[7] Its safety profile is favorable, characterized predominantly by mild and infrequent local application site reactions, with minimal systemic absorption in adults and older children.[10]

Despite these strengths, retapamulin's clinical utility and market success have been constrained by several critical factors. A notable paradox exists between its excellent in vitro activity against methicillin-resistant S. aureus (MRSA) and its inadequate clinical efficacy against MRSA infections, leading to a contraindication for such use.[12] Furthermore, its clinical development program lacked a large-scale, head-to-head comparative trial against mupirocin, the widely accepted standard of care, creating an evidence gap that has positioned it as a more expensive alternative rather than a proven replacement.[3] These limitations, coupled with commercial considerations, ultimately led to the withdrawal of its marketing authorization in the European Union.[13] Retapamulin's lifecycle thus serves as an important case study on the complex interplay between scientific innovation, clinical evidence, and commercial viability in the modern antibiotic market.

2.0 Chemical Identity and Pharmaceutical Properties

2.1 Nomenclature and Identifiers

Retapamulin is a small-molecule drug substance belonging to the pleuromutilin class of antibiotics.[14] It is systematically identified by a range of chemical and regulatory codes to ensure unambiguous reference in scientific literature, clinical practice, and regulatory documentation.

• Generic Name: Retapamulin [15]
• DrugBank ID: DB01256 [14]
• CAS Number: 224452-66-8 (A deprecated CAS number, 345632-67-9, has also been noted) [1]
• IUPAC Name: (3aS,4R,5S,6S,8R,9R,9aR,10R)-6-ethenyl-5-hydroxy-4,6,9,10-tetramethyl-1-oxodecahydro-3a,9-propano-3aH-cyclopentaannulen-8-yl${oct-3-yl]sulfanyl$}$acetate [1]
• Other Key Identifiers:
• Anatomical Therapeutic Chemical (ATC) Code: D06AX13 [15]
• Unique Ingredient Identifier (UNII): 4MG6O8991R [14]
• PubChem CID: 6918462 [1]
• Synonyms: The compound has been referred to by its developmental code, SB-275833, and by a misspelling, Aitabax.[14]

2.2 Physicochemical Characteristics

The physical and chemical properties of retapamulin dictate its formulation as a topical agent and influence its pharmacokinetic behavior.

• Molecular Formula: C30​H47​NO4​S [15]
• Molecular Weight: Approximately 517.76 g/mol [16]
• Physical Description: Retapamulin is a white to pale-yellow solid.[7]
• Solubility Profile: It is practically insoluble in water but demonstrates solubility in organic solvents such as dimethyl sulfoxide (DMSO) and ethanol.[16] Its lipophilic nature is quantified by a partition coefficient (log D) of +1.89 in an octanol/water system.[7]
• Formulation: For clinical use, retapamulin is formulated as an off-white, smooth ointment at a concentration of 1% w/w (10 mg of retapamulin per gram of ointment). The ointment base is primarily soft white paraffin. The formulation may also contain butylated hydroxytoluene (BHT) as an antioxidant.[7]

2.3 Development and Brand Information

Retapamulin was developed and originally marketed by the pharmaceutical company GlaxoSmithKline (GSK).[1] It is a semi-synthetic derivative of pleuromutilin, a natural diterpene antibiotic produced via fermentation of the basidiomycete fungus

Clitopilus passeckerianus.[5] While other pleuromutilin derivatives like tiamulin and valnemulin have been used in veterinary medicine, retapamulin was the first to be approved for human use.[21] It is known commercially by two primary brand names:

Altabax, used predominantly in the United States, and Altargo, used in the European Union and other international markets.[1]

The origin of retapamulin as a semi-synthetic compound derived from a fungal metabolite is a foundational element of its pharmacological profile. This distinct chemical lineage, separate from purely synthetic antibiotics or other natural product classes, results in a novel molecular structure. This structural novelty is the direct antecedent to its unique mechanism of action, which in turn provides the key therapeutic rationale for its development: a low probability of encountering pre-existing, target-specific cross-resistance with other antibiotic classes that have been in widespread clinical use for decades.[2] This attribute is particularly valuable in the context of globally rising antimicrobial resistance.

Table 1: Key Identifiers and Physicochemical Properties of Retapamulin

Property	Value
Generic Name	Retapamulin
DrugBank ID	DB01256
CAS Number	224452-66-8
IUPAC Name	(3aS,4R,5S,6S,8R,9R,9aR,10R)-6-ethenyl-5-hydroxy-4,6,9,10-tetramethyl-1-oxodecahydro-3a,9-propano-3aH-cyclopentaannulen-8-yl${oct-3-yl]sulfanyl$}$acetate
Molecular Formula	C30​H47​NO4​S
Molecular Weight	517.76 g/mol
Physical Appearance	White to pale-yellow solid
Solubility	Insoluble in water; soluble in DMSO and ethanol
Brand Names	Altabax, Altargo

3.0 Pharmacology

3.1 Pharmacodynamics: The Pleuromutilin Mechanism of Action

Retapamulin exerts its antibacterial effect through the selective inhibition of bacterial protein synthesis, a mechanism common to many antibiotic classes. However, its specific mode of interaction with the bacterial ribosome is unique and defines its pharmacological class.[1]

3.1.1 Unique Interaction with the 50S Ribosomal Subunit

Retapamulin binds with high potency (dissociation constant, Kd​, of 3 nM) to a novel site on the 50S subunit of the bacterial ribosome.[16] This binding site is located within domain V of the 23S ribosomal RNA (rRNA) at the peptidyl transferase center (PTC), in proximity to ribosomal protein L3.[14] This location is distinct from the binding sites of other major classes of 50S inhibitors, such as macrolides, lincosamides, and streptogramins, which minimizes the potential for target-specific cross-resistance.[4] In contrast to its high affinity for prokaryotic ribosomes, retapamulin is ineffective at inhibiting eukaryotic protein synthesis, demonstrating its selective toxicity for bacteria.[16]

3.1.2 Multi-Pronged Inhibition of Protein Synthesis

By occupying this unique ribosomal site, retapamulin disrupts protein synthesis through several concerted mechanisms, effectively halting bacterial proliferation [4]:

1. Inhibition of Peptidyl Transfer: It sterically hinders the PTC, preventing the crucial step of transferring the growing polypeptide chain from the transfer RNA (tRNA) in the P-site to the aminoacyl-tRNA in the A-site.[5]
2. Blocking P-site Interactions: It partially blocks the P-site, interfering with the correct binding of initiator tRNA and thereby disrupting the initiation phase of translation.[7]
3. Prevention of 50S Subunit Formation: It prevents the normal assembly and formation of active 50S ribosomal subunits, further reducing the cell's capacity for protein synthesis.[4]

3.1.3 Bacteriostatic and Bactericidal Activity

At clinically relevant concentrations, retapamulin's action is predominantly bacteriostatic, meaning it inhibits the growth and reproduction of bacteria without directly killing them.[3] This is sufficient for treating localized skin infections, where the host immune system can then clear the inhibited pathogens. However, at concentrations approximately 1,000 times higher than its Minimum Inhibitory Concentration (MIC), retapamulin can exhibit bactericidal (cell-killing) activity.[14] Such high concentrations are achievable at the site of topical application but not systemically.

3.2 Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

The pharmacokinetic profile of retapamulin is characterized by low systemic absorption, which is central to its use as a topical agent and its overall safety profile.

3.2.1 Topical Absorption and Systemic Exposure

Systemic absorption following topical application of the 1% ointment is minimal in most patient populations.[21]

• Influence of Skin Integrity: Absorption is very low through intact skin but increases when the epidermal barrier is compromised, such as on abraded skin. In studies with healthy adults, the median maximum plasma concentration (Cmax​) was 3.5 ng/mL after application to intact skin, compared to 9.8 ng/mL after application to abraded skin.[7]
• Age-Dependent Absorption: A critical pharmacokinetic finding is the significantly higher systemic exposure observed in very young pediatric patients. In clinical studies, measurable plasma concentrations were detected in 69% of infants aged 2 to 9 months, compared to 32% of children aged 9 to 24 months, and only 7-11% of patients aged 2 years and older.[10] This age-dependent variability is a primary driver of specific safety recommendations in the infant population.

3.2.2 Distribution

Data regarding the tissue distribution of retapamulin in humans is not available.[7] For the small fraction of the drug that is systemically absorbed, it is highly bound (approximately 94%) to human plasma proteins.[21]

3.2.3 Metabolism

Systemically absorbed retapamulin is extensively metabolized in the liver. The primary metabolic pathway involves the Cytochrome P450 3A4 (CYP3A4) enzyme system, which catalyzes mono-oxygenation and di-oxygenation reactions to produce multiple inactive metabolites.[7]

3.2.4 Excretion

The precise routes and extent of excretion of retapamulin and its metabolites in humans have not been determined.[1]

The drug's pharmacokinetic profile directly shapes its clinical utility and safety considerations. The minimal systemic absorption in adults and older children is the basis for its favorable systemic safety profile and its limitation to topical use for superficial infections only.[4] Concurrently, the finding of significantly higher systemic exposure in infants under 24 months, combined with its known metabolism by CYP3A4, creates a clinically relevant risk. This elevated exposure could lead to significant drug-drug interactions if co-administered with strong CYP3A4 inhibitors (e.g., ketoconazole), which could dangerously increase retapamulin plasma levels. This causal link between age-dependent pharmacokinetics and metabolic pathways is the direct scientific foundation for the explicit clinical warning against such co-administration in patients younger than 24 months.[10]

4.0 Microbiology

4.1 Spectrum of Activity

Retapamulin's antibacterial spectrum is focused on Gram-positive organisms, which are the most common causative pathogens in uncomplicated skin and skin structure infections.[4]

• Primary Target Pathogens: It is highly active against Staphylococcus aureus (methicillin-susceptible isolates, MSSA) and Streptococcus pyogenes (Group A Streptococcus), the two principal etiologic agents of impetigo.[1]
• Other Susceptible Organisms: In vitro studies have demonstrated its activity against a range of other bacteria, including coagulase-negative staphylococci (Staphylococcus epidermidis), Streptococcus agalactiae (Group B Streptococcus), and viridans group streptococci. It also exhibits activity against several anaerobic species relevant to skin flora and infections, such as Propionibacterium acnes, Peptostreptococcus species, Prevotella species, Fusobacterium species, and Porphyromonas species.[7]
• Inherently Resistant Organisms: Gram-negative enteric bacteria (Enterobacteriaceae), Pseudomonas aeruginosa, and Enterococcus faecalis are inherently resistant to retapamulin.[27]

4.2 In Vitro Potency and Susceptibility

Retapamulin demonstrates high potency against its target pathogens in laboratory settings, as measured by MIC values. Global surveillance studies have shown that the concentration required to inhibit 90% of isolates (MIC90) for S. aureus and S. pyogenes is typically in the range of ≤0.03 to 0.12 μg/mL.[4]

A key microbiological feature of retapamulin is its retained activity against strains that have developed resistance to other antibiotic classes. In vitro, it remains potent against isolates of S. aureus that are resistant to methicillin (MRSA), mupirocin, and fusidic acid.[6] This resistance-breaking profile was a cornerstone of its developmental promise.

4.3 Mechanisms of Bacterial Resistance

While the potential for resistance development to retapamulin is considered low, several mechanisms have been identified.[6]

1. Target Site Mutation: The most common mechanism involves point mutations in the gene encoding ribosomal protein L3 (rplC). These mutations alter the drug's binding site on the ribosome, reducing its affinity. The development of such mutations is a slow, multi-step process, which is thought to make the emergence of resistance during a short course of therapy unlikely.[7]
2. Efflux Pumps: The presence of an ATP-binding cassette (ABC) transporter, encoded by the vgaAv gene, can confer low-level resistance by actively pumping retapamulin out of the bacterial cell.[7]
3. Target Site Modification: The plasmid-mediated cfr (chloramphenicol-florfenicol resistance) gene encodes an rRNA methyltransferase. This enzyme modifies an adenine residue at position 2503 in the 23S rRNA, which is part of the drug's binding site. This modification confers broad cross-resistance to several classes of antibiotics that bind in this region, including phenicols, lincosamides, oxazolidinones, streptogramin A, and pleuromutilins (a phenotype known as PhLOPS).[27]

Despite these potential mechanisms, no development of resistance was observed during the clinical trial program for retapamulin.[21] This supports the premise that its unique mechanism of action makes it less susceptible to rapid resistance selection compared to some other topical agents.[2] However, a notable disconnect exists between this promising microbiological profile and its ultimate clinical application. While the development of new antibiotics is often driven by the need to overcome resistance to existing therapies, and retapamulin's

in vitro activity against mupirocin- and fusidic acid-resistant strains would seem to position it perfectly for this role, its approved indication is for general uncomplicated impetigo.[22] It was not specifically studied or approved for treating infections known to be caused by resistant pathogens. This failure to fully leverage its most significant microbiological strength in its clinical development strategy may have contributed to its perception as a niche alternative rather than an essential tool for combating resistance.

5.0 Clinical Efficacy and Performance

The clinical efficacy of retapamulin 1% ointment has been evaluated in a series of phase III trials for primary impetigo and secondarily infected skin lesions.

5.1 Evidence in Primary Impetigo

5.1.1 Pivotal Placebo-Controlled Trials

The superiority of retapamulin over placebo for the treatment of impetigo was firmly established in a randomized, double-blind, multicenter trial (Study 103469). In this study, patients aged 9 months and older received either retapamulin ointment twice daily for 5 days or a placebo ointment. The primary endpoint was clinical success at the end of therapy (day 7). In the intent-to-treat (ITT) population, the clinical success rate was 85.6% for the retapamulin group compared to 52.1% for the placebo group, a statistically significant difference (p<0.0001).[2] Microbiological success rates were similarly superior for retapamulin (91.2% vs. 50.9%).[2]

5.1.2 Comparative Trials vs. Sodium Fusidate

To establish its efficacy relative to an existing active treatment, retapamulin was compared to sodium fusidate 2% ointment in a randomized, observer-blinded, non-inferiority study. Patients received either retapamulin twice daily for 5 days or sodium fusidate three times daily for 7 days. The results demonstrated that retapamulin was non-inferior to sodium fusidate. In the per-protocol population, clinical efficacy was 99.1% for retapamulin versus 94.0% for sodium fusidate.[8] Another smaller study reported similar clinical success rates between retapamulin (84%) and fusidic acid (80%) in children with primary impetigo.[32]

5.2 Evidence in Secondarily Infected Lesions

The utility of retapamulin was extended to secondarily infected traumatic lesions (SITLs), such as small lacerations, sutured wounds, and abrasions. In two large, identical, randomized, double-blind trials, a 5-day course of topical retapamulin was compared to a 10-day course of oral cephalexin. The studies demonstrated that topical retapamulin was non-inferior to systemic cephalexin, with comparable clinical success rates at follow-up (e.g., 88.7% for retapamulin vs. 91.9% for cephalexin in one study).[3] These findings support the use of localized topical therapy as an effective alternative to systemic antibiotics for uncomplicated infections, thereby reducing the potential for systemic side effects and broader antibiotic pressure.[4]

5.3 The MRSA Paradox: In Vitro Activity vs. Clinical Outcomes

A critical and defining limitation of retapamulin is the discrepancy between its laboratory performance and its clinical efficacy against methicillin-resistant Staphylococcus aureus (MRSA). As established, retapamulin demonstrates excellent in vitro potency against MRSA isolates, including those resistant to other topical agents like mupirocin.[6] This profile suggested it could be a valuable new weapon against this challenging pathogen.

However, clinical trial data did not support this potential. In studies of secondarily infected wounds, clinical success rates for infections caused by MRSA were found to be inadequate and significantly lower than for those caused by MSSA (68.6% vs. 92.2%, respectively).[12] In another unpublished study, retapamulin was significantly less effective than oral linezolid for treating MRSA skin infections (63.9% vs. 90.6% success).[12] This failure to translate promising

in vitro data into clinical success for one of the most significant resistant skin pathogens severely curtailed the drug's therapeutic niche. Consequently, prescribing information explicitly warns that retapamulin should not be used to treat infections known or suspected to be caused by MRSA.[12] This paradox effectively relegated the drug from a potential solution for difficult-to-treat infections to an alternative for more common, susceptible ones, placing it in direct competition with cheaper, established generic therapies.

5.4 Comparative Analysis with Mupirocin

Mupirocin is widely considered a first-line standard of care for the topical treatment of impetigo in many clinical guidelines.[3] A significant gap in retapamulin's clinical development program is the absence of a large, pivotal, head-to-head trial comparing it directly with mupirocin.[3] Such a trial would have been essential to definitively establish its place in therapy relative to the market leader.

The limited comparative data comes from a small, double-blind, community-based study in 57 children, which found retapamulin to be as effective as mupirocin based on wound size reduction and culture results. Notably, patients treated with retapamulin had a significantly lower (better) post-treatment score on the Skin Infection Rate Scale (SIRS) (p=0.015).[38]

Without more robust comparative data, retapamulin is generally positioned as an effective alternative to mupirocin, not a proven superior agent.[3] Its potential advantages lie in a more convenient dosing schedule (twice daily for 5 days vs. mupirocin's three times daily for up to 10-12 days) and a theoretically lower potential for resistance development.[3] However, these benefits are weighed against its significantly higher cost compared to generic mupirocin.[3] This lack of direct, compelling evidence of at least non-inferiority in a large trial made it difficult for clinicians and formulary committees to justify its routine use over the established, less expensive standard of care.

Table 2: Summary of Pivotal Phase III Clinical Trials for Retapamulin

Study Reference	Indication	Patient Population (N)	Treatment Arms	Primary Endpoint	Key Efficacy Results (% Success)
Study 103469 7	Impetigo	210	Retapamulin 1% BID for 5 days vs. Placebo BID for 5 days	Clinical success at end of therapy (Day 7)	85.6% vs. 52.1% (p<0.0001)
Oranje et al. 2007 8	Impetigo	519	Retapamulin 1% BID for 5 days vs. Sodium Fusidate 2% TID for 7 days	Clinical success (non-inferiority)	99.1% vs. 94.0% (Per-protocol; non-inferiority met)
Study 030A/030B 7	Secondarily Infected Traumatic Lesions	1,904 (total)	Retapamulin 1% BID for 5 days vs. Oral Cephalexin 500 mg BID for 10 days	Clinical success at follow-up (non-inferiority)	88.7% vs. 91.9% (Study 030A; non-inferiority met)

Table 3: Comparative Profile: Retapamulin vs. Mupirocin and Fusidic Acid

Feature	Retapamulin	Mupirocin	Fusidic Acid
Antibiotic Class	Pleuromutilin	Monoxycarbolic acid	Fusidane (steroid-like)
Mechanism of Action	Inhibits protein synthesis (unique site on 50S ribosome)	Inhibits isoleucyl-tRNA synthetase	Inhibits elongation factor G (EF-G)
Standard Dosing	Twice daily for 5 days	Three times daily for up to 10-12 days	Three to four times daily for 7 days
Spectrum (Clinical)	MSSA, S. pyogenes	MSSA, MRSA, S. pyogenes	MSSA, S. pyogenes
MRSA Activity	Ineffective in clinical trials	Clinically effective (resistance is a concern)	Resistance rates are high in many regions
Potential for Resistance	Considered low	Emerging resistance is a known concern	Widespread resistance reported globally
Cost Profile	Higher (Brand name)	Lower (Generic available)	Varies (Not available in US)

6.0 Safety and Tolerability Profile

6.1 Analysis of Adverse Events from Clinical Trials

Across a pooled analysis of clinical trials involving over 2,100 patients, retapamulin was found to be generally well-tolerated.[8]

• Common Adverse Events: The safety profile is dominated by local, application-site reactions. The most common drug-related adverse event was application site irritation, reported in approximately 1.4% to 2% of patients.[2] Other local events occurring in ≤2% of patients include pruritus (itching), pain, and erythema (redness).[3]
• Systemic Adverse Events: Due to minimal systemic absorption, systemic side effects are infrequent. Those reported in 1-2% of patients include headache, diarrhea, nausea, and nasopharyngitis.[3] In trials comparing topical retapamulin to oral cephalexin, gastrointestinal side effects like diarrhea were reported less frequently in the retapamulin group.[10]
• Serious Adverse Events: Serious adverse reactions are rare. Hypersensitivity reactions, including angioedema, have been reported post-marketing.[25] The development of severe local irritation, blistering, or sensitization is grounds for immediate discontinuation of the medication.[10]

Table 4: Summary of Reported Adverse Events (≥1% Incidence) from Pooled Clinical Trials

Adverse Event	Retapamulin 1% Ointment (N=2,115)	Oral Cephalexin (N=819)	Placebo (N=71)
Application Site Irritation	1.4%	N/A	0%
Diarrhea	<2%	1.7%	N/A
Application Site Pruritus	<2%	N/A	1.4%
Headache	1-2%	N/A	N/A
Nausea	1% (adults)	N/A	N/A
Nasopharyngitis	1-2%	N/A	N/A
	3

6.2 Warnings, Precautions, and Contraindications

• Contraindications: There are no absolute contraindications listed in the manufacturer's labeling.[19] However, its use is contraindicated in patients with a known hypersensitivity to retapamulin or any component of the ointment.[35]
• Warnings and Precautions:
• Local Irritation: Treatment should be discontinued if sensitization or severe local irritation occurs.[10]
• Mucosal Use: Retapamulin ointment is for external dermatological use only and should not be applied to eyes or mucosal surfaces (oral, intranasal, intravaginal). Epistaxis (nosebleed) has been reported following inadvertent application to the nasal mucosa.[10]
• Microbial Overgrowth: As with any antibiotic, prolonged use carries a risk of promoting the overgrowth of non-susceptible organisms, including fungi.[10]
• Carcinogenesis and Mutagenesis: Long-term animal studies to evaluate carcinogenic potential have not been conducted. Retapamulin was not genotoxic in a standard battery of in vitro and in vivo assays.[11]

6.3 Use in Specific Populations

• Pediatric Use: The safety and effectiveness of retapamulin have been established in pediatric patients aged 9 months to 17 years.[10] It is not approved for use in infants younger than 9 months of age, as safety and efficacy have not been established in this group.[26] The higher systemic absorption in children under 24 months requires special consideration regarding drug interactions.[10]
• Pregnancy: Retapamulin is classified as FDA Pregnancy Category B.[3] There are no adequate and well-controlled studies in pregnant women. However, given the negligible systemic absorption following topical administration, maternal use is not expected to result in significant fetal exposure.[10] Animal studies showed no teratogenicity, with developmental toxicity observed only at systemic exposures far exceeding those achievable in humans.[10]
• Lactation: It is not known whether retapamulin is excreted in human milk. Because systemic absorption is very low, it is considered unlikely to reach the bloodstream of a breastfed infant or cause adverse effects. It is advised to apply the ointment away from the breast area to avoid direct infant ingestion.[10]

7.0 Significant Drug Interactions

Drug interactions with topical retapamulin are limited due to its low systemic absorption. However, one clinically significant interaction has been identified and requires specific management, particularly in the pediatric population.

7.1 Interactions with CYP3A4 Inhibitors

The small fraction of retapamulin that is systemically absorbed is primarily metabolized by the hepatic enzyme CYP3A4.[7] Consequently, co-administration with drugs that strongly inhibit this enzyme can lead to increased plasma concentrations of retapamulin. A clinical study in healthy adult males demonstrated that co-administration of oral ketoconazole (a strong CYP3A4 inhibitor) increased the systemic exposure (both

AUC and Cmax​) of topically applied retapamulin by 81%.[10] Other strong CYP3A4 inhibitors include itraconazole, clarithromycin, ritonavir, and grapefruit juice.[25]

7.2 Clinical Management and Recommendations

The clinical management of this interaction is nuanced and based directly on the age-dependent pharmacokinetic profile of retapamulin.

• Adults and Children (24 months and older): In this population, the baseline systemic exposure to retapamulin is very low. Therefore, even with an 81% increase, the resulting plasma concentrations are not considered clinically significant. No dosage adjustments are necessary when retapamulin is co-administered with strong CYP3A4 inhibitors in this age group.[10]
• Infants and Children (younger than 24 months): This patient group represents a critical exception. As established, these younger children exhibit significantly higher baseline systemic absorption of retapamulin. The potential for a further 81% increase in exposure from a co-administered CYP3A4 inhibitor raises safety concerns. Therefore, the concomitant use of retapamulin with strong CYP3A4 inhibitors is not recommended in patients younger than 24 months.[10] This recommendation is a clear example of how pharmacokinetic variability in a specific sub-population directly translates into a critical patient safety guideline.

The concurrent use of retapamulin with other topical products on the same area of skin has not been studied and is therefore not recommended.[10]

8.0 Clinical Application: Dosage and Administration

8.1 Approved Indications and Usage Guidelines

• Indications: Retapamulin 1% ointment is indicated for the topical treatment of primary impetigo caused by methicillin-susceptible Staphylococcus aureus or Streptococcus pyogenes in adults and pediatric patients aged 9 months and older.[1] In some jurisdictions, including the EU and Canada, the indication is broader, also including the short-term treatment of infected small lacerations, abrasions, or sutured wounds.[8]
• Dosage Regimen: A thin layer of the ointment should be applied to the affected area twice daily for a duration of 5 days.[39]
• Application Area Limitation: To minimize potential systemic exposure, the total area of application is limited. In adults, the total treatment area should not exceed 100 cm2. In pediatric patients, it should not exceed 2% of the total body surface area.[3]

8.2 Patient Counseling Information

Patients or caregivers should be instructed on the proper use of retapamulin ointment to ensure efficacy and safety.

• Method of Application: The ointment is for external (dermatological) use only. It must not be applied in the eyes or on mucous membranes such as the inside of the mouth, nose, or vagina.[10] Hands should be washed before and after application. After applying a thin layer, the treated area may be covered with a sterile bandage or gauze dressing if desired.[19]
• Completing Therapy: It is important to complete the full 5-day course of treatment, even if the infection appears to have improved, to ensure complete eradication of the bacteria and reduce the risk of recurrence.[40]
• When to Seek Re-evaluation: If the skin infection does not show signs of improvement within 3 to 4 days, or if it worsens, the patient should discontinue use and consult their healthcare provider for re-evaluation.[26]

9.0 Regulatory History and Market Status

9.1 FDA Approval Pathway and Timeline (US)

Retapamulin was developed by GlaxoSmithKline and submitted to the U.S. Food and Drug Administration (FDA) for review.[2] The New Drug Application (NDA) was accepted for review on February 14, 2006.[46] On

April 12, 2007, the FDA approved retapamulin 1% ointment under the brand name Altabax for the topical treatment of impetigo.[1] At the time, its approval was notable as it represented the first new class of prescription topical antibacterial to be approved in the United States in nearly 20 years.[2] More recent reports indicate that the Altabax brand has since been discontinued in the U.S. market, suggesting a commercial withdrawal.[25]

9.2 EMA Approval and Subsequent Withdrawal (EU)

Following its approval in the U.S., retapamulin was granted marketing authorisation in the European Union by the European Medicines Agency (EMA) on May 24, 2007, under the brand name Altargo.[1] The indication in the EU was for the short-term treatment of impetigo as well as infected small lacerations, abrasions, or sutured wounds.[44]

However, on February 25, 2019, the European Commission officially withdrew the marketing authorisation for Altargo in the EU.[13] This action was taken at the request of the marketing authorisation holder, Glaxo Group Ltd. The company cited purely

"commercial reasons" for its decision to permanently discontinue the product, and the withdrawal was not related to any new safety or efficacy concerns.[13]

9.3 Current Market Position and Therapeutic Niche

The regulatory lifecycle of retapamulin, particularly its voluntary withdrawal from the major European market, serves as a compelling case study on the distinction between regulatory success and commercial success. Despite achieving regulatory approval based on sufficient evidence of safety and efficacy, retapamulin struggled to gain a significant foothold in the market. It was positioned as a niche alternative to well-established, inexpensive generic topical antibiotics like mupirocin and fusidic acid.[3] Several factors likely contributed to this outcome: its higher cost as a branded product [3]; the critical clinical limitation of being ineffective against MRSA infections [12]; and the strategic failure to generate head-to-head clinical trial data against the primary standard of care, mupirocin.[3] For a new antibiotic in a market with entrenched, low-cost options, demonstrating non-inferiority is often insufficient to drive adoption. Without a clear advantage in a difficult-to-treat population or proven superiority over the standard of care, its novel mechanism alone was not enough to ensure commercial viability.

10.0 Expert Synthesis and Concluding Remarks

Retapamulin represents a significant scientific achievement in antibacterial drug development, marking the successful introduction of the pleuromutilin class into human medicine. Its unique mechanism of action, targeting a novel site on the bacterial ribosome, provided a sound scientific basis for its development, offering a low potential for cross-resistance with other antibiotic classes and potent in vitro activity against key skin pathogens.

Clinically, its strengths are well-documented. It demonstrated clear superiority over placebo and non-inferiority to active comparators like sodium fusidate and oral cephalexin in treating uncomplicated superficial skin infections. Furthermore, its favorable safety profile, characterized by minimal systemic absorption and predominantly local side effects, combined with a convenient twice-daily, 5-day dosing regimen, offered tangible advantages for patient compliance.

However, the trajectory of retapamulin also highlights critical challenges that can impede the success of a new antimicrobial agent. The most significant of these was the "MRSA paradox"—the stark failure to translate excellent in vitro activity against this formidable pathogen into meaningful clinical efficacy. This single limitation profoundly constrained its therapeutic potential, preventing it from filling a crucial unmet need in treating resistant infections. Compounding this was the absence of robust, direct comparative data against mupirocin, the established and less expensive standard of care. This evidence gap left clinicians and healthcare systems with little compelling reason to adopt a more costly alternative for routine infections.

In conclusion, retapamulin is a clinically effective and safe topical antibiotic whose scientific novelty did not fully translate into sustained market success. Its story underscores a crucial reality in modern pharmaceutical development: regulatory approval is only the first hurdle. To thrive in a competitive therapeutic area with established, low-cost generics, a new agent must demonstrate a clear and compelling value proposition—be it through superior efficacy, an improved safety margin, or, most critically for an antibiotic, reliable effectiveness in a resistant patient population where other options fail. The commercial withdrawal of retapamulin from major markets suggests that, despite its scientific merits, it was ultimately unable to clear this high bar.

Works cited

1. Retapamulin - Wikipedia, accessed September 27, 2025, https://en.wikipedia.org/wiki/Retapamulin
2. GlaxoSmithKline Announces FDA Approval of Altabax(TM) (Retapamulin Ointment), 1%, accessed September 27, 2025, https://www.biospace.com/glaxosmithkline-announces-fda-approval-of-altabax-tm-retapamulin-ointment-1-percent
3. Retapamulin (Altabax) 1% Topical Ointment for the Treatment of Impetigo - AAFP, accessed September 27, 2025, https://www.aafp.org/pubs/afp/issues/2007/1115/p1537.html
4. Topical retapamulin in the management of infected traumatic skin ..., accessed September 27, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC2697516/
5. Retapamulin - PMC, accessed September 27, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC2830591/
6. Microbiological profile of a new topical antibacterial: retapamulin ointment 1% - PubMed, accessed September 27, 2025, https://pubmed.ncbi.nlm.nih.gov/19344241/
7. www.tga.gov.au, accessed September 27, 2025, https://www.tga.gov.au/sites/default/files/auspar-retapamulin-131111-pi.docx
8. Retapamulin: a review of its use in the management of impetigo and other uncomplicated superficial skin infections - PubMed, accessed September 27, 2025, https://pubmed.ncbi.nlm.nih.gov/18416589/
9. Topical Retapamulin Ointment, 1%, Versus Sodium Fusidate ..., accessed September 27, 2025, https://pubmed.ncbi.nlm.nih.gov/17911992/
10. ALTABAX (retapamulin ointment), for topical use - accessdata.fda.gov, accessed September 27, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022055s007lbl.pdf
11. Altabax (Retapamulin): Side Effects, Uses, Dosage, Interactions ..., accessed September 27, 2025, https://www.rxlist.com/altabax-drug.htm
12. Retapamulin - PMC, accessed September 27, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4654036/
13. Altargo - Public statement - European Medicines Agency, accessed September 27, 2025, https://www.ema.europa.eu/en/documents/public-statement/public-statement-altargo-withdrawal-marketing-authorisation-european-union_en.pdf
14. Retapamulin - PubChem, accessed September 27, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Retapamulin
15. Retapamulin - brand name list from Drugs.com, accessed September 27, 2025, https://www.drugs.com/ingredient/retapamulin.html
16. Retapamulin | Antibiotics chemical | Mechanism | Concentration, accessed September 27, 2025, https://www.selleckchem.com/products/retapamulin.html
17. retapamulin - Drug Central, accessed September 27, 2025, https://drugcentral.org/drugcard/2371
18. Retapamulin ( 98 ) 224452-66-8 Sigma-Aldrich, accessed September 27, 2025, https://www.sigmaaldrich.com/US/en/product/sigma/sbr00057
19. ALTABAX (retapamulin) Ointment, 1%. - accessdata.fda.gov, accessed September 27, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022055s002lbl.pdf
20. Australian public assessment report for Retapamulin - Therapeutic Goods Administration (TGA), accessed September 27, 2025, https://www.tga.gov.au/sites/default/files/auspar-retapamulin-131111.pdf
21. 9 Retapamulin: A New Option for Impetigo - PEDIATRIC PHARMACOTHERAPY - The University of Virginia, accessed September 27, 2025, https://med.virginia.edu/pediatrics/wp-content/uploads/sites/237/2015/12/200709.pdf
22. The Efficacy, Safety and Tolerability of Retapamulin as a Treatment Option for Impetigo and Other Uncomplicated Superfici, accessed September 27, 2025, https://inabj.org/index.php/ibj/article/download/22/263
23. Retapamulin: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed September 27, 2025, https://go.drugbank.com/drugs/DB01256
24. Retapamulin | Davis's Drug Guide for Rehabilitation Professionals, accessed September 27, 2025, https://fadavispt.mhmedical.com/content.aspx?bookid=1873§ionid=139024406
25. Retapamulin | Drug Lookup | Pediatric Care Online, accessed September 27, 2025, https://publications.aap.org/pediatriccare/drug-monograph/18/6075/Retapamulin
26. Retapamulin Topical Dosage Guide + Max Dose, Adjustments - Drugs.com, accessed September 27, 2025, https://www.drugs.com/dosage/retapamulin-topical.html
27. Altargo, INN-retapamulin - European Medicines Agency, accessed September 27, 2025, https://www.ema.europa.eu/en/documents/product-information/altargo-epar-product-information_en.pdf
28. Retapamulin activity against mupirocin-resistant strains of methicillin-resistant Staphylococcus aureus - PMC, accessed September 27, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8713557/
29. Retapamulin: Current Status and Future Perspectives - Brieflands, accessed September 27, 2025, https://brieflands.com/articles/archcid-114970
30. (PDF) Retapamulin 1% Ointment - ResearchGate, accessed September 27, 2025, https://www.researchgate.net/publication/246763312_Retapamulin_1_Ointment
31. Efficacy and safety of retapamulin ointment as treatment of impetigo ..., accessed September 27, 2025, https://pubmed.ncbi.nlm.nih.gov/18341664/
32. A randomized open label parallel group study comparing the safety, effectiveness and adherence between 2% fusidic acid cream versus 1% retapamulin ointment in children with impetigo | International Journal of Basic & Clinical Pharmacology, accessed September 27, 2025, https://www.ijbcp.com/index.php/ijbcp/article/view/3222
33. Attachment 1: Product information for AusPAR Retapamulin; Altargo; GlaxoSmithKline Australia - Therapeutic Goods Administration (TGA), accessed September 27, 2025, https://www.tga.gov.au/sites/default/files/auspar-retapamulin-131111-pi.pdf
34. ALTARGO™, accessed September 27, 2025, https://registrasiobat.pom.go.id/files/assesment-reports/obat_baru/ALTARGO.pdf
35. product monograph, accessed September 27, 2025, https://pdf.hres.ca/dpd_pm/00011986.PDF
36. What is the best treatment for impetigo?, accessed September 27, 2025, https://cdn-uat.mdedge.com/files/s3fs-public/Document/September-2017/6306_JFP_ClinInquiry1.pdf
37. Impetigo Agents, Topical Review - Medicaid.nv.gov, accessed September 27, 2025, https://www.medicaid.nv.gov/Downloads/provider/NVRx_DCR_20090326_Impetigo_Agents_Topical.pdf
38. Untitled, accessed September 27, 2025, https://pps.org.ph/wp-content/uploads/2018/10/SS7-2.pdf
39. Retapamulin (topical application route) - Side effects & dosage - Mayo Clinic, accessed September 27, 2025, https://www.mayoclinic.org/drugs-supplements/retapamulin-topical-application-route/description/drg-20070924
40. Retapamulin: MedlinePlus Drug Information, accessed September 27, 2025, https://medlineplus.gov/druginfo/meds/a607049.html
41. Retapamulin - Drugs and Lactation Database (LactMed®) - NCBI Bookshelf, accessed September 27, 2025, https://www.ncbi.nlm.nih.gov/books/NBK501907/
42. Altabax Food, Alcohol, Supplements and Drug Interactions - ScriptSave WellRx, accessed September 27, 2025, https://www.wellrx.com/altabax/lifestyle-interactions/
43. Retapamulin topical Uses, Side Effects & Warnings - Drugs.com, accessed September 27, 2025, https://www.drugs.com/mtm/retapamulin-topical.html
44. Union Register of medicinal products - Public health - European ..., accessed September 27, 2025, https://ec.europa.eu/health/documents/community-register/html/h390.htm
45. Retapamulin - Mechanism, Indication, Contraindications, Dosing, Adverse Effect, Interaction, Hepatic Dose | Drug Index | Pediatric Oncall, accessed September 27, 2025, https://www.pediatriconcall.com/drugs/retapamulin/73
46. Altabax (retapamulin) FDA Approval History - Drugs.com, accessed September 27, 2025, https://www.drugs.com/history/altabax.html
47. Drug Approval Package: Altabax (Retapamulin) NDA #022055, accessed September 27, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022055s000TOC.cfm
48. Altabax: Retapamulin ointment, 1% recently approved by FDA as new molecular entity, accessed September 27, 2025, https://www.managedhealthcareexecutive.com/view/altabax-retapamulin-ointment-1-recently-approved-fda-new-molecular-entity