Pitted keratolysis. A systematic review of published cases and a proposed therapeutic algorithm

INTRODUCTION

Pitted keratolysis (PK) is a chronic superficial bacterial infection caused by various Gram-positive species within the genera Corynebacterium, Actinomyces, Dermatophilus, and Micrococcus sedentarius.^1,2 This condition primarily affects the stratum corneum and is characterized by the presence of hyperhidrosis, crateriform pits measuring between 1 and 7 mm, and superficial erosions. The clinical presentation of this condition includes sliminess of skin, malodor, pain or pruritus, and burning sensation. It is most commonly observed on the soles of the feet but may also affect the palms of the hands, particularly among individuals who wear unventilated, occlusive footwear, which can lead to heat and humidity within the microenvironment.³

This condition is more prevalent among men than women. Among the risk factors, occupations such as farming, manual labor, athletic activities, military training, housework, and adolescent activities have been associated with an increased prevalence.^4,5 These occupations often involve the use of footwear that lacks ventilation and allows heat and moisture to accumulate. Consequently, the growth of these microorganisms is encouraged.^4,5 All these microorganisms have the ability to produce keratolytic enzymes that dissolve the stratum corneum, developing the characteristic lesions. Associated risk factors include poor hygiene and hyperhidrosis.⁶ Prolonged immersion of the hands and feet in water and detergents, in addition to the wearing of occlusive footwear, has been identified as a series of factors leading to PK. Prolonged immersion of the hands and feet in water has been demonstrated to cause increased hydration, in addition to the onset of hyperhidrosis. Similarly, the application of detergents has been shown to elevate skin pH, thereby stimulating bacterial proliferation. Furthermore, the presence of footwear has been demonstrated to create conditions conducive to bacterial proliferation. The proliferation of these bacteria results in the production of keratolytic enzymes, such as keratinase (produced by Dermatophilus congolensis) and proteinase (produced by Kytococcus sedentarius). These enzymes contribute to the degradation of the stratum corneum, leading to the formation of pits on the skin.³

Few studies describe the different characteristics of clinical presentation, diagnosis, and treatment for PK.^3–6 Although PK is considered a chronic, non-inflammatory, indolent, and probably underdiagnosed bacterial infection of the skin, there is no consensus or clinical guidelines for its management. For this reason, the objective of this study is to perform a systematic review of the literature to determine the most effective therapeutic options and to establish a management algorithm.

MATERIAL AND METHODS

This systematic review adheres to the guidelines outlined in the preferred reporting items for systematic reviews and meta-analyses (PRISMA). The screening and study selection process is demonstrated with a PRISMA flow diagram [Figure 1]. The search was conducted using the terms “pitted keratolysis” OR “pitted keratolysis AND management” OR “pitted keratolysis AND treatment.” We conducted a systematic search across three databases (PubMed, EmBase, and Web of Science databases) up to December 2024. Abstracts without full-text articles were excluded. Studies were included without language restrictions. Non-English studies were translated into English using DeepL Translate.

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Figure 1:

Flow of study review and selection process.

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This study includes both clinical trials and observational studies, including case-control, cohort, and case series or case reports of patients with PK at any sex, race, and age. The inclusion criteria comprised (1) published studies of patients with PK and (2) the availability of viable data on therapeutic outcomes. The exclusion criteria were (1) in vitro-based studies without clinical outcomes, (2) unavailability of full text or abstract, (3) conference abstracts, and (4) articles that were not derived from primary data comprising meta-analysis, systematic review, review articles, guidelines, and commentary.

Two authors (AB and AT) examined the titles and abstracts independently. These two authors also performed data extraction and independently evaluated the bias risks, and disagreements were resolved through consensus and consultation with a third author (AG).

Risk-of-Bias 2 (RoB2) assessment tools by the Cochrane Collaboration were used to assess the quality of randomized controlled trials (RCTs) across five domains: bias arising from the randomization process, bias due to deviations from intended interventions, bias due to missing outcome data, bias in the measurement of the outcome, and bias in the selection of the reported result. Quality of RCT was defined as “low risk of bias,” “high risk of bias,” or “some concerns.”⁷ Moreover, methodological quality and synthesis for case series and case reports were employed for the evaluation of quality assessment for case series and case reports comprising eight items across four domains: selection, ascertainment, causality, and reporting.⁸

RESULTS

Treatment

At present, there is no consensus regarding the clinical management of this condition. Our study aimed to perform a comprehensive review of the literature to identify and analyze the current evidence on disease treatment. The literature on the management of PK is characterized by a substantial variability, particularly in terms of scope and methodological rigor. Some recommendations appear consistent, but it must be acknowledged that the supporting evidence is limited, as the majority of studies are case reports with a small sample size. Nevertheless, the evidence indicates that the various treatment modalities under consideration offer very high efficacy in the short term. The range of treatment options is extensive and includes monotherapy, combined topical therapy, or topical therapy with systemic treatment [Figure 2].

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Figure 2:

Proposed algorithm for pitted keratolysis.

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DISCUSSION

There is a paucity of standardization regarding the criteria for full or partial resolution or treatment failure. The need to compare these treatments in a face-to-face setting would permit an objective assessment of the relative merits of different treatments. It would also provide a more robust basis for developing recommendations and quality measures for the implementation of such treatments, thereby enhancing the reliability and utility of the resulting treatment guidelines.

To summarize data on the epidemiologic, clinical, and treatment outcomes of PK, we performed a systematic review of the literature on PK up to December 2021. Our results suggest that PK occurs predominantly in male patients between the second and sixth decades of life. Hyperhidrosis, the use of occlusive footwear for occupational activities, or environments with higher humidity and maceration were risk factors for the development of the disease.

The etiological agents were Corynebacterium sp. species occurring in warm and humid conditions. Clinical manifestations included lesions primarily on the soles of the feet, particularly in areas of pressure such as the metatarsal region, heel, or lateral edge of the foot on Wallace’s line. Hyperhidrosis (excessive sweating) and maceration (skin irritation) are often associated with the disease. The clinical presentation describes 1–3 mm pitting or crater-like lesions in appearance. The most common accompanying symptom was pruritus.

Topical erythromycin 2%–4% followed by topical clindamycin alone or in combination with benzoyl peroxide 2.5%–5% was the most commonly used topical treatment. The most effective systemic antibiotic includes erythromycin 250 mg twice daily alone or in combination with topical erythromycin. Additional treatments provide some benefit. However, these have been less studied. The employment of azoles is strongly suggested in circumstances of superficial fungal infections, such as tinea pedis. In the context of PK, however, the efficacy of azoles is constrained by their association with bacterial processes.

It is evident from the articles reviewed that the recommendations pertaining to diagnosis, monitoring, prevention,³³ and PK treatment vary considerably, reflecting the lack of consensus on the optimal approach to managing these conditions in the absence of clear-cut guidelines. It is possible that these discrepancies may be due to the diverse populations included, with discrepancies existing elsewhere in regard to the quality of evidence. Here, expert opinion appears to be the primary means of determining the evidence quality.

This review enables the formulation of specific recommendations and the development of a proposed treatment algorithm. Following diagnosis, the first-line treatment is typically a topical antibiotic or benzoyl peroxide 5% for a period of 4 weeks. In the event of continued unresponsiveness, a topical antibiotic combined with benzoyl peroxide is advised for 3 weeks. If the response to the first two lines of treatment is unfavorable, the third line of treatment includes oral antibiotics. These may include erythromycin, which should be taken at a dose of 250– 500 mg three or four times per day for a duration of 2–4 weeks, or azithromycin, which should be taken at a dose of 500 mg every eight hours for a duration of 2–3 weeks. If the response remains inadequate, additional treatment may be considered, such as BTX-A or keratolytic or paint treatments [Figure 2].

This study represents the inaugural systematic review of the therapeutic interventions for PK. However, it must be acknowledged that this study has a number of limitations that require further consideration. The majority of the literature is composed of case reports, which adds to the considerable variability in the management of the disease and high risk of bias. This includes differences in treatment doses and the duration of the therapy.

The development of KP is associated with a number of risk factors, including poor hygiene and hyperhidrosis.³

Therefore, it is recommended that³³:

1. The procedure entails the meticulous practice of daily foot washing, accompanied by the subsequent maintenance of optimal dryness.

2. It is recommended that socks be changed daily and that shoes be allowed to dry for 1–2 days prior to reuse.

3. The utilization of cotton or linen socks is advised.

4. A 20% aluminum chloride solution can be used in order to decrease the severity of hyperhidrosis. This solution can be administered up to three times per day. The application of drying talcum powder should be performed once or twice daily on the feet and shoes.

CONCLUSION

The present review compiles an array of studies, primarily comprising case reports and case series that advocate various treatments for PK. However, these studies lack substantial evidence and a robust, multidisciplinary consensus. A rigorous assessment of these therapeutic approaches is imperative to establish their efficacy and safety profile in the treatment of patients.