Epidemiology of interdigital infections of toe web spaces in Shanghai, China: Etiology, risk factors, and therapeutic approaches

We conducted a cross-sectional study at Hospital from January 2019 to December 2019, enrolling 57 patients with acute interdigital inammation. Patients received antibiotic therapy and underwent long-term follow-up. Clinical features and medical histories, including blood, bacterial, and mycologic examination results, cultures and drug susceptibility test results, and follow-up data were analyzed for pathogenic agents.


Background
Interdigital infections of the toe web space may present as relatively asymptomatic, mild, or scaling conditions or as acute forms with an exudative, macerated, painful in ammatory process that is frequently accompanied by a foul odor [1]. Clinically, these conditions had previously been diagnosed as tinea pedis and were considered to be purely dermatophyte induced. However, acute interdigital infections respond poorly to pure antifungal agents. Thus, the dermatophyte population cannot be solely responsible for the clinical spectrum seen in interdigital infections.
Dermatophyte fungi, however, are not the only pathogens found in toe-web intertrigo. Various species of Candida, gram-negative bacteria, and non-dermatophyte molds may be discovered in pathologic toe-webs and may play a contributing role in interdigital infections. Previous studies have demonstrated that Pseudomonas aeruginosa is the main causative agent of these clinical forms of infection, which are characterized by an acute ingravescent trend [2]. Likewise, gram-positive bacteria, such as Streptococci spp. and Staphylococcus aureus, have also been thought to cause interdigital infections, and their prevalence rates have gradually risen in recent years [1,3]. A relapse of symptoms has frequently been seen in patients with interdigital infections, despite active treatment [1,4]. Thus, an epidemiologic survey of interdigital infections has signi cant potential for improving outcomes for these patients.
To evaluate the incidence of acute ingravescent interdigital infections and their causative agents in Shanghai, China, we performed a cross-sectional study and epidemiologic survey of 57 patients with interdigital infections. The aim was to delineate the main clinical aspects, risk factors, causative organisms, age and seasonal distribution characteristics, and recommended therapeutic regimens.

Patients samples
Participants with acute in ammation of the interdigital spaces were enrolled in the study at Shanghai Dermatology Hospital from January to December 2019. Clinical characteristics of the patients included erythema, macerations, and marked erosions resulting from varying degrees of malodorous exudate in toe web spaces. Patient data, including age, sex, signs and symptoms of disease, medical history, and promoting factors were also recorded. At both the beginning and end of the treatment regimen, hematology and blood chemistry evaluations, direct uorescence microscopy of fungus, bacterioscopic smear examinations, mycologic and bacterial cultures, microbial identi cations, and antimicrobial susceptibility testing were performed on all patients. Exclusion criteria included topical or systemic use of antibiotics in the previous 4 weeks. Written informed consent was obtained from all participants. This study was approved by the Ethics Committee of Shanghai Dermatology Hospital, and the research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki.

Statistical analysis
Data were entered and managed in Microsoft Access. The database was then transferred into SPSS version 20.0 (Armonk, IBM Corp., NY) for statistical analysis. McNemar's tests were used for comparison of positive rates of direct microscopy and cultures. All statistical tests were two-sided, and results were considered signi cant at a P-value of < 0.05.

Results
Clinical features of patients with interdigital infections of toe web spaces During a year of observation, 57 patients with acute interdigital infections were recruited (Table 1). Men were affected more, with a men/women ratio of 3:1. The mean age of patients was 49.88 years (range: 7-97 years). Among all patients, 37 (64.91%) had both feet involved, and 20 (35.09%) had only one foot affected. The search for possible promoting factors showed that 23 (40.35%) patients had a history of scratching or rubbing because of pruritus and 12 (21.05%) patients had a history of performing a hotwater foot bath. Sixteen cases (28.07%) had a history of self-medication with locally available unreasonable treatments (such as keratolytic irritation medicines, antifungals, or corticosteroid creams) for a condition they suspected to be tinea pedis. Nine (15.79%) patients experienced pruritus and developed symptoms after rainfall; four (7.02%) reported that they had attended public swimming pools and baths. Primary dermatosis, such as allergic contact dermatitis and hyperhidrosis, were observed in ve (8.77%) patients. Clinical symptoms were similar in most patients and mainly manifested as erythema, vesicopustules, erosions, and marked maceration resulting from varying degrees of malodorous exudates. The color of the macerated lesions was yellowish-green (Figs. 1a-c) in 23 patients, and yellowish-white (Figs. 1g-i) in the other 34. The lesions affected the interdigital spaces of one or both feet, whereas the in ammatory process extended toward the digito-plantar sulcus, the sole, and even the back of the foot. The affected patients complained of itching, pain, burning, and restricted mobility.

Pathogens isolated in interdigital infections
Bacteriological studies were performed for all patients (Fig. 2). The most common pathogens isolated from the interdigital infections were P. aeruginosa (23/57, 40.35%) and S. aureus (

Seasonal and age distribution curves of patients with interdigital infections
The onset of interdigital infections revealed a seasonal distribution, but they mainly occurred between March and November (Fig. 3a), and the incidence peak occurred in July. With gram-negative bacterial infections, represented by P. aeruginosa, the main incidence peak occurred in spring, and the subincidence peak occurred in autumn. As the most common gram-positive bacteria, the main morbidity season of S. aureus infection was summer.

Treatment
All patients received mycological and bacteriological tests simultaneously. The patients received corresponding antifungal and/or antibiotic therapy according to the results of the direct examination for fungus and bacteria. Systemic levo oxacin treatment was used in 57 episodes; among them, two cases were changed to erythromycin based on drug sensitivity tests. In cases in which yeasts or dermatophytes were observed, therapy was supplemented with systemic antifungal drugs. In addition to the systemic antimicrobial therapy, symptomatic treatment included oral antihistamines and topical therapy, such as compound philodendron liquid and boric acid lotion, oil, or paste. The patients who had a negative mycological test at the initial visit underwent repeat mycological testing after antibiotic therapy. When applicable, antifungal therapy was started. Finally, all patients were given health education instruction, including information on frequent footgear changing, keeping the feet dry, avoiding scratching and scalding, and active treatment of local primary skin diseases.

After 2 weeks of systemic and local treatments, all patients experienced a signi cant reduction in pruritus and pain. Infections in all patients improved markedly, with rapid resolution of maceration (Figs. 1d-f, j-l).
Even with strict monitoring of the microbial ora, four patients (7.02%) experienced relapse by the 6month follow-up.

Discussion
Interdigital infection is a spectrum of relatively common, troubling, and neglected disorders [3], especially in the humid and rainy climates of southern China. It was rst described as a speci c dermatologic entity by Amonette and Rosenberg in 1973 [5]. A variety of terms have been used to describe this disorder, including gram-negative bacterial toe web infection, which is characterized as an acute bacterial infection of the toe web spaces due to Pseudomonas spp. alone, or with other gram-negative bacteria. However, gram-positive bacteria, such as E. faecalis and S. aureus, have also been isolated as pathogenic germs from interdigital infections [4,6]. Meanwhile, the prevalence of this disease caused by gram-positive bacteria has been rising in recent years [2,7]. In the present study, we examined 57 cases of pathological toe webs and found P. aeruginosa to be the causative agent in 40.35% of cases and S. aureus in 36.84% of cases. We suggest that gram-positive bacteria are present in a considerable number of cases of interdigital infection; thus, as a possible pathogen, they are worthy of attention. Consequently, the original term "gram-negative bacterial toe web infection" might not cover all causative infectious agents; perhaps interdigital infection is the most suitable term for this disease.
The interdigital space is typically colonized by polymicrobial ora [8,9]. We found 40 patients with positive microscopic fungi before and after antibiotic treatment. Previous studies have suggested that a strong correlation exists between dermatophytes and bacteria [8]. The former organism seems to act as a triggering factor, while the latter organism may play a role in the symptoms associated with interdigital infections. Dermatophytes initiate damage to the stratum corneum, thus, facilitating bacterial invasion; consequently, penicillin-and streptomycin-like antibacterial substances are produced, favoring speci c colonization and overgrowth of the physiological skin ora by gram-negative bacteria and antibioticresistant gram-positive bacteria [10,11]. Moreover, we observed that the positive rate of fungal cultures was signi cantly lower in acute interdigital infections that were not treated with antibiotics. Fifteen patients were found to be positive for microscopic fungi even with effective antibiotic therapy. It is postulated that the cases of unsuccessful fungal tests may be due to factors caused by bacterial overgrowth and the in ammatory response [11][12][13]. As fungal infections might be a triggering factor for interdigital infections and may cause false-negative results during the acute phase, it is recommended to repeat testing for fungi at the end of the antibiotic treatment.
Interestingly, we noted that the incidence of interdigital infections caused by different types of bacteria had obvious seasonal and age distribution characteristics. We speculated that the seasonal peaks of interdigital infections may be mainly related to air temperature, humidity, proliferation of fungi, and personal habits required for bacterial production. P. aeruginosa interdigital infections were frequently seen to increase during spring and autumn. The rate of fungal infections accompanying P. aeruginosa interdigital infections was found to be up to 96.65%. We speculated that the morbidity of interdigital infections caused by P. aeruginosa might be related to the proliferation of fungi. The optimal culture temperature of dermatophytes ranges from 22℃ to 28℃, and these temperatures usually appear in spring and autumn in Shanghai; furthermore, gram-negative bacteria, particularly P. aeruginosa, thrive in a warm, moist, and occluded environment [14][15][16]. As people prefer to wear porous sandals in the summer, leading to the feet being in less moist occlusive conditions, P. aeruginosa interdigital infections become uncommon. In addition, the most common age group affected by P. aeruginosa interdigital infections was the 60-69 years group. This corresponds with the age of onset of tinea pedis [17]. Furthermore, other predisposing factors, such as scratching or rubbing, unreasonable treatment, and hot-water scalding are more common in this age group (data not shown). Interdigital infection caused by S. aureus was more liable to occur in summer and might be associated with more frequent attendance at swimming pools and public baths and prolonged exposure to rain. These conditions increase the risk of foot exposure to S. aureus. Moreover, the prevalence of occupations by interdigital infections caused by S. aureus may be explained by professional and non-professional reasons or the practice of strenuous exercise, all of which are prone to skin damage and increase the risk of S. aureus infection.
With high recurrence rates and possible complications, such as immobility, cellulitis, wound healing disorders, and autosensitization dermatitis, interdigital infections present a frequent therapeutic challenge in clinical practice [4,5,18]. However, data supporting a standardized regimen remain insu cient [19]. Therefore, we theorized a therapeutic algorithm for interdigital infections through a yearlong cross-sectional study (Fig. 4). In order to prevent relapse and reduce complications, we suggest the following: rst, levo oxacin may be a preferred rst-line therapy administered before drug sensitivity testing because it was much more effective and provided excellent results against both gram-negative and gram-positive bacterial interdigital infections [1]. Subsequently, the therapeutic regimen could be adjusted based on drug sensitivity tests. Second, effective monitoring of local primary skin diseases, such as tinea pedis, onychomycosis, and allergic dermatitis, might be a critical factor in reducing relapse of interdigital infections. Third, health education for patients, such as lifestyle changes, has generally been ignored and may prove to be a simple method for prevention. Finally, recent literature has con rmed that immersing feet in 1% acetic acid is a relatively effective adjuvant treatment to signi cantly reduce relapse of interdigital infections caused by P. aeruginosa [20][21][22].
The present study has some limitations. First, only acute symptomatic cases were included in this study.
It was di cult to research asymptomatic, mild cases since these cases usually fail to attract attention from patients. However, we believe that the prognosis of interdigital infections is favorable if there is an early, accurate diagnosis and appropriate treatment. Topical antibiotics alone or in combination with topical antifungal agents, produce good curative effects for mild cases. Second, because of the small sample size and limited study period, future research should include larger sample sizes with longer study periods to better elucidate the epidemiological characteristics of interdigital infections.

Conclusions
This epidemiologic study of the characteristics of interdigital infections in Shanghai, China, may provide a basis for diagnosing causative pathogens and suggest an effective management which, subsequently, may help reduce recurrence and improve outcomes. Availability of data and materials

Abbreviations
The datasets used and/or analyzed during the current study are available from the corresponding author in reasonable request.
The rst draft of the manuscript was written by QY and WL. Material preparation and data collection were implemented by SK and XL. Laboratory testing and data analysis was performed by HY, ZG, and JC. LY contributed to the study design, revised, and nalized the manuscript. All authors read and approved the nal version of the manuscript.