10.5826/dpc.1401a59
Gram-negative bacterial toe web infection (GNTWI) is a common dermatologic condition affecting the interdigital spaces. The clinical presentation ranges from mild erythema to exudative maceration of the web spaces that may extend to in other areas of the foot and lead to cellulitis in severe cases. Pseudomonas aeruginosa is the most commonly identified etiologic agent. Occlusive and humid environments, pre-existing dermatologic conditions, and fungal infections increase the risk of developing GNTWI. GNTWI has a broad differential diagnosis including erythrasma, tinea pedis, pitted keratolysis, eczematous dermatitis, and malignancies. Diagnosis is performed using bacterial and fungal cultures. There is a lack of a standardized treatment regimen for GNTWI. While GNTWI is fairly common, it may still be under-recognized by dermatologists due to the limited medical literature. This article presents a review of GNTWI, its clinical features, epidemiologic factors, etiologic agents, predisposing factors, diagnostic methods, and therapeutic options.
text/xml
2160-9381
3500
en
Shari Lipner
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
Pseudomonas aeruginosa
Gram-Negative Toe Web Infections
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Review
2024-01-31
2023-05-04
2024-01-31
2024-02-21
e2024059
Dermatol Pract Concept
Gram-negative bacterial toe web infection (GNTWI) is a common dermatologic condition affecting the interdigital spaces. The clinical presentation ranges from mild erythema to exudative maceration of the web spaces that may extend to in other areas of the foot and lead to cellulitis in severe cases. Pseudomonas aeruginosa is the most commonly identified etiologic agent. Occlusive and humid environments, pre-existing dermatologic conditions, and fungal infections increase the risk of developing GNTWI. GNTWI has a broad differential diagnosis including erythrasma, tinea pedis, pitted keratolysis, eczematous dermatitis, and malignancies. Diagnosis is performed using bacterial and fungal cultures. There is a lack of a standardized treatment regimen for GNTWI. While GNTWI is fairly common, it may still be under-recognized by dermatologists due to the limited medical literature. This article presents a review of GNTWI, its clinical features, epidemiologic factors, etiologic agents, predisposing factors, diagnostic methods, and therapeutic options.
Shari Lipner
2024/01/31
10.5826/dpc.1401a59
e2024059
Department of Dermatology, Weill Cornell Medicine, New York, NY, USA
2160-9381
Pseudomonas aeruginosa
en
e2024059
Rozenblat M, Last O, Fisher S, Ziv M. Acetic acid treatment for toe web infection caused by Pseudomonas Aeruginosa combined with fungal infection: A case series of ten patients. Dermatol Ther. 2019;32(3):e12883. DOI:10.1111/dth.12883. PMID: 30920153.
Gram-Negative Toe Web Infections
https://dpcj.org/index.php/dpc/article/download/3500/2442
                       Gram-Negative Toe Web Infections
                                          Kelita A. Waterton1, Shari R. Lipner2


1 SUNY Downstate Health Sciences University College of Medicine, Brooklyn, NY, USA
2 Department of Dermatology, Weill Cornell Medicine, New York, NY, USA



Key words: Gram-negative bacteria, toe web infection, toe web intertrigo, Pseudomonas
Citation: Waterton KA, Lipner SR. Gram-Negative Toe Web Infections. Dermatol Pract Concept. 2024;14(1):e2024059. DOI: https://doi.
org/10.5826/dpc.1401a59
Accepted: July 9, 2023; Published: January 2024
Copyright: ©2024 Waterton et al. This is an open-access article distributed under the terms of the Creative Commons Attribution-
NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use,
distribution, and reproduction in any medium, provided the original authors and source are credited.
Funding: None.
Competing Interests: None.
Authorship: Both the authors have contributed significantly to this publication.
Corresponding Author: Dr. Shari R. Lipner, Department of Dermatology, Weill Cornell Medicine 1305 York Ave, 9th floor, New York, N.Y.
10021, USA. Email: SHL9032@med.cornell.edu




  ABSTRACT             Gram-negative bacterial toe web infection (GNTWI) is a common dermatologic condition affecting
                       the interdigital spaces. The clinical presentation ranges from mild erythema to exudative maceration
                       of the web spaces that may extend to in other areas of the foot and lead to cellulitis in severe cases.
                       Pseudomonas aeruginosa is the most commonly identified etiologic agent. Occlusive and humid envi-
                       ronments, pre-existing dermatologic conditions, and fungal infections increase the risk of developing
                       GNTWI. GNTWI has a broad differential diagnosis including erythrasma, tinea pedis, pitted kera-
                       tolysis, eczematous dermatitis, and malignancies. Diagnosis is performed using bacterial and fungal
                       cultures. There is a lack of a standardized treatment regimen for GNTWI. While GNTWI is fairly
                       common, it may still be under-recognized by dermatologists due to the limited medical literature. This
                       article presents a review of GNTWI, its clinical features, epidemiologic factors, etiologic agents, pre-
                       disposing factors, diagnostic methods, and therapeutic options.




Introduction                                                            Fusarium, and Neoscytalidium, gram-positive bacteria such
                                                                        as Streptococci spp, Staphylococcus aureus, and Coryneform
Gram-negative toe web infection (GNTWI) was first de-                   bacteria as well as gram-negative bacteria, most notably
scribed as a distinct dermatological entity by Amonette                 Pseudomonas aeruginosa [2,4].
and Rosenburg in 1973 and is a relatively common disor-
der characterized by purulent, erythematous macerations in
                                                                        Objectives
toe web spaces and surrounding areas of the foot such as
the plantar region and underneath the toes [1-3]. Patients              Despite its prevalence and potential for progression to severe
                                             2
typically present with pruritis and pain. Toe web infections            infection and disability, GNTWI has been infrequently dis-
may be due to yeast and fungal infections such as Candida,              cussed in the medical literature. This review aims to provide


Review | Dermatol Pract Concept. 2024;14(1):e2024059                                                                                 1
a summary of current evidence-based data regarding clinical      200 cases of toe web infections reported similar age distri-
characteristics, diagnosis, etiologic agents, promoting fac-     bution with a median age of 51 years and an age range of
tors, and treatment of GNTWI.                                    11-93 years [1].

                                                                 Clinical Manifestation
Methods                                                          GNTWI presents as an exudative, erythematous maceration
A literature search was conducted using the PubMed data-         with malodorous discharge in the toe web spaces (Figure 2) [7].
base with the search term “toe web infection”. Our search        There may be accompanying vesicles, pustules, papulove-
was limited to articles published prior to August 31, 2022. A    sicles, cracking and fissuring [5,7,8]. The skin may have
total of 129 articles were retrieved from the original search    greenish discoloration in culture-positive pseudomonas toe
and an additional 21 articles were included after a review       web infections [6]. With progressive disease, patients may
of reference lists of review articles. Of the 150 articles, 53   develop a well-demarcated punched-out edge with a hy-
were excluded if they were non-English, non-full text, and/or    perkeratotic rim [9]. One case report described a patient
duplicates. We further screened the remaining 97 articles for    who presented with erythematous patches in their toe web
relevance, determined by title and abstract, which excluded      spaces, before developing the characteristic maceration [10].
an additional 81 articles. We included the remaining 16 arti-    Patients often exhibit symptoms of pain, burning, pruritus,
cles from this search based on their relevance to the research   and edema which can become severe and limit mobility [11].
topic (Figure 1).                                                The infection can extend beyond the interdigital spaces and
                                                                 involve both plantar and dorsal regions of the toes and feet
                                                                 [5,9]. GNTWI may also progress to other more severe skin
Results                                                          conditions such as erysipelas and cellulitis. One case-control
Epidemiology                                                     study comparing 114 cases of erysipelas to 208 matched
                                                                 controls, demonstrated a significant independent association
There are few reports on the incidence of GNTWI. A pro-
                                                                 between toe web infections and erysipelas of the leg, likely
spective clinical and epidemiologic survey demonstrated an
                                                                 due to disruption of the cutaneous barrier [12]. Another
average incidence of 13.6 cases per year with a male/female
                                                                 case-control study, with 61 cases of cellulitis and 122 con-
ratio of 4:1 across 123 patients [5]. Another study showed a
                                                                 trols, calculated the population-attributable risk (PAR) of
similar sex pattern, with 72.5% of 200 GNTWI cases being
                                                                 independent risk factors, including obesity, skin disruption,
men [1]. GNTWI typically presents in middle-aged adults
                                                                 history of surgery to the lower limb, and toe-web intertrigo.
but can also present in children and older adults. One retro-
                                                                 The authors ­reported that in comparison to the other risk
spective review of 62 cases reported an age range of 10-94
                                                                 factors, ­patients with clinical evidence of toe web infection
years and a median age of 52.5 years [6]. A cohort study of
                                                                 (mild scaling to an exudative, macerated, or erosive process
                                                                 of the toe web space) had the highest (48.9%) PAR for cel-
                                                                 lulitis [13].

                                                                 Promoting Factors
                                                                 Occlusive and Humid Environments
                                                                 Humid and occlusive environments are risk factors for de-
                                                                 veloping GNTWI. In a review of 123 cases of GNTWIs, Aste
                                                                 and colleagues reported that 14% of patients had either pri-
                                                                 mary or secondary hyperhidrosis. About 10% of cases in the
                                                                 same study reported exposure to wet environments, such as
                                                                 swimming pools, public baths, or public showers [5]. In a
                                                                 survey study by Hope et al. examining 514 coal miners, 61%
                                                                 of those who reported frequent wet feet had gram-negative
                                                                 bacilli cultured, compared with 48% of miners whose feet
                                                                 remained appreciably dry [8]. It is theorized that in wet envi-
                                                                 ronments, moisture washes away the protective surface lip-
                                                                 ids, which then encourages the overgrowth of opportunistic
                                                                 bacteria [14].
                                                                     Frequent wearing of closed-toe or tight-fighting shoes is
Figure 1. Article selection method.                              common among patients diagnosed with GNTWI. In a case



2                                                                                Review | Dermatol Pract Concept. 2024;14(1):e2024059
Figure 2. Clinical manifestations of Gram-negative toe web infection GNTWI. (A,B) The dorsal feet showing erythema and erosions;
(C) Plantar feet showing scale and maceration; (D​​​​​​​) Third toe web space of the right foot showing maceration and erosions.



report of two individuals with GNTWI, both patients fre-          Mycosis
quently wore steel work boots for occupational purposes [15].     Skin maceration secondary to fungal infections has been pos-
Tight interdigital spaces may cause occlusive environments,       tulated to promote growth and invasion of gram-negative
which can lead to toe web erosion [4]. In a retrospective         bacteria, particularly in areas such as the toe web spaces.
multicenter study of 62 patients with GNTWI, Goiset and           Leyden and Kligman conducted a study involving several
colleagues reported that 42% of patients were frequently ex-      experimental manipulations of the interspace microflora to
posed to humidity, occlusion, or both [6].                        analyze the interaction of dermatophytes and resident bac-
                                                                  teria. In one of their experiments, while all ten subjects had
Pre-existing Dermatologic Conditions                              presence of gram-negative bacteria in their toe web spaces,
Patients with GNTWI often have histories of other der-            those with dermatophytosis developed considerable hyper-
matologic conditions and infections. Hassab-El-Naby and           keratosis, erythema, and maceration for an extended period
colleagues conducted a review of 100 cases of toe web             (7-10 days), while those without dermatophytosis had only
space infections to study common etiological causes. Of           minor signs and symptoms of infection, such as mild macer-
the 38 GNTWI patients specifically, 53% had concurrent            ation, which normalized within 1-2 days.17 Thus, they postu-
biopsy-confirmed interdigital eczema [16]. Similarly, a retro-    lated that while gram-negative bacteria alone have a limited
spective review of 62 cases of GNTWI identified concomitant       capacity to cause disease, in the setting of dermatophytosis,
or prior interdigital eczema in 66% and psoriasis in 11% of       disruption of the integrity of the protective stratum corneum
patients. Among the 19 patients with recurrent GNTWI in           layer may favor invasion of opportunistic bacteria [18].
this same study, 42% were associated with an eczema flare            In addition, dermatophytes produce penicillin and
and 16% were associated with a psoriasis flare [6]. Aste et       streptomycin-like substances, which disrupt the bacterial
al also reported allergic contact dermatitis in 20% of their      flora and create an environment that preferentially selects
patients with GNTWI [5].                                          for antibiotic-resistant bacteria [6,19]. Antibiotic-resistant



Review | Dermatol Pract Concept. 2024;14(1):e2024059                                                                          3
gram-negative bacteria then proliferate, promoting pro-             also be used to provide further information regarding the eti-
gression to GNTWI [18]. Though tinea pedis is frequently            ologic agents, as well as guide appropriate treatment [14,16].
suspected in patients with GNTWI, dermatophytes are of-             A KOH preparation will show the presence of hyphae indic-
ten not identified on fungal culture [6]. The paradoxical de-       ative of a fungal infection [16]. A Wood lamp examination
crease in dermatophyte presence with clinical progression of        may help identify Pseudomonas infections, showing charac-
macerated toe web spaces may be due to prior application of         teristic green fluorescence [24].
antifungal agents or production of an inhibitory substance
by some gram-negative bacteria [5,6,20,21].                         Differential Diagnoses
                                                                    GNTWI may present similarly to various infectious and
Etiology
                                                                    noninfectious conditions that involve the toe web spaces.
The surface of the human foot, especially the toe web space
                                                                    Therefore, several diagnoses should be considered before
has a diverse microbiome and a substantially greater ­fungal
                                                                    treatment [7].
biodiversity when compared to other skin areas [22]. In a
study examining the toe web spaces of 77 patients, the mi-          Erythrasma
crobial ecology of normal toe webs was compared to toe              Interdigital erythrasma is a superficial, localized, mild infec-
webs with erythema and/or inflammation, maceration, se-             tion due to Corynebacterium minutissimum. This bacterium
vere fissures, malodor, and erosions. Among the normal              typically affects the stratum corneum in warm and wet ar-
interspaces, a polymicrobial flora primarily composed of            eas of the skin such as interdigital regions [26]. Erythrasma
coagulase-negative staphylococci, micrococci, and cory-             may present with maceration with fissuring or scaling [27].
neform organisms, as well as smaller numbers of gram-­              Wood lamp examination shows characteristic coral-pink flu-
negative rods, yeasts, and dermatophytes were identified            orescence. Confirmation of the diagnosis is performed with
[18,23]. While gram-positive bacteria have been identified as       gram stains or cultures [26].
the predominant colonizers of healthy toe web spaces, Hope
et al isolated over 30 distinct gram-negative species from          Fungal Infections
men with affected toe webs [8,25]. Pseudomonas aeruginosa           Tinea pedis is a common dermatophyte infection of the feet
is the most common etiologic agent identified in GNTWI              that may also be suspected in patients who present with scal-
though it is often found in the presence of other gram-­            ing, maceration, erosion, and erythema of the interdigital
negative bacteria [6].                                              skin [28]. Candidal intertrigo of the toe web spaces can
    Aste et al. isolated Pseudomonas aeruginosa (46.4%)             similarly present with erythema, desquamation, erosion,
among other pathogens (Escherichia coli (13.8%), ­Proteus           malodor, and maceration [24]. Tinea pedis and candidal
mirabilis (7.8%), Morganella morganii (7.1%), Entero-               intertrigo may be confirmed by KOH with microscopy or
bacter cloacae (7.1%), Klebsiella pneumoniae (6.2%),                culture of skin scrapings [24,28]. However, macerated toe
Acinetobacter spp (5.5%), Serratia marcescens (3.1%), and           webs that persist despite appropriate antifungal therapies
Alcaligenes faecalis (3.1%)) at lesser frequencies, among 123       should be further investigated for other etiologies such as
cases of GNTWI. Furthermore, fungal species were present            gram-­negative bacterial infections.
in 6% of cases and gram-positive bacteria were present in
17% of cases where gram-negative bacteria were isolated [5].        Pitted Keratolysis
    In a case series of 17 patients with 32 TWI episodes, includ-   Pitted keratolysis (PK) is a superficial, skin infection due
ing recurrences, Lin et al reported growth of gram-negative         to gram-positive bacteria, including Corynebacterium spp,
bacteria in 86% of their cultures. Pseudomonas aeruginosa           ­Actinomyces spp, Dermatophilus sp., and Kytococcus sed-
(55%), Enterococcus facealis (41%), Staphylococcus aureus           entarius [29]. PK primarily affects the stratum corneum and
(41%), and coagulase-negative staphylococci were the most           may present as pits that coalesce into erosions on the plantar
frequently isolated species. The rate of multi-organism in-         feet [30]. Though it is primarily diagnosed clinically, dermos-
fection was 93%, with Pseudomonas aeruginosa being the              copy and histopathological examination may aid in diagno-
most common concomitant pathogen. A similar Pseudomo-               sis. The dermatoscopic findings are pits with interrupted
nas aeruginosa predominance was reported in several other           dermatoglyphic lines and scattered arrangements while his-
studies, with frequency as high as 84.5% [1,4,6].                   topathologic features include the presence of pits, bacteria,
                                                                    and color alteration of keratin [29].
Diagnosis
Toe web infections are diagnosed by performing bacterial            Eczematous Dermatitis
and fungal cultures of the affected area. Potassium hydrox-         Eczematous dermatitis may present on plantar feet and in-
ide preparations (KOH), or Wood lamp examination may                terdigital spaces such as toe webs [16,18]. While eczematous



4                                                                              Review | Dermatol Pract Concept. 2024;14(1):e2024059
dermatitis is typically diagnosed clinically, a skin biopsy may       In their review of 123 cases of GNTWI, Aste et al utilized
be performed in equivocal cases, and patch testing may be          a combination of topical antiseptics and antibiotics. Toe webs
used to rule out allergic contact dermatitis [31]. In a study of   were cleaned and debrided and treated with a combination of
etiological causes of toe web intertrigo among 100 patients,       amikacin 5% gel and application of hot compresses with 2%
Hassab-El-Naby et al identified biopsy-proven interdigital         to 5% solutions of acetic acid daily for 15 days [5]. Similarly,
eczema in 52% of patients. However, patients with macer-           Lin et al treated their 17 GNTWI patients with antiseptic
ated toe web spaces who do not respond to treatment for            solutions, including aluminum chloride, potassium perman-
allergic dermatitis, irritant contact dermatitis, or dyshidrotic   ganate, povidone-iodine, and gentamicin in addition to sys-
atopic eczema should undergo a workup for GNTWI [16].              temic antibiotics twice daily. After one to two weeks of this
                                                                   combination therapy, all patients experienced a significant
Malignancy                                                         reduction in pruritus and pain, as well as maceration [18].
Malignancy should be considered in the differential di-               Foot soaking has been reported for treatment for
agnosis of GNTWI. Pempinello et al reported a case of a            ­GNTWI. In their case series, Rozenblat et al treated ten pa-
74-year-old man with plantar verrucous carcinoma that was          tients with evidence of Pseudomonal GNTWI and concomi-
initially diagnosed as a skin infection. He had an ulcer for       tant fungal infection patients with acetic acid 1% immersion
6-years that was unsuccessfully treated with multiple exci-        for 20 minutes between 10 days and 3 weeks. In addition
sions and targeted parenteral antibiotic therapy before re-        to the acetic acid 1% immersion, six (60%) patients were
ceiving the correct diagnosis [32]. In another case report, a      treated with bifonazole gel, two (20%) were treated with
77-year-old man with a 6-month history of hyperkeratosis           local clotrimazole, one (10%) was treated with oral terbina-
in the third and fourth web spaces of his left foot, initially     fine, and one (10%) with oral itraconazole. All were treated
diagnosed as intractable toe web intertrigo and treated with       for 10-14 days but the daily regimen was not mentioned.
oral and topical therapies, was later diagnosis as verrucous       They reported that 80% of their patients had full resolution,
carcinoma [33]. Therefore, malignancy may be amongst sev-          while the remaining 20% achieved a partial response [34].
eral diagnoses considered for GNTWI that are refractory to         In a case report, Tan et al also treated a 53-year-old man,
treatment.                                                         with a twice-daily foot soak containing an herbal decoction
                                                                   (Rhei radix et rhizome; Scutellariae radix; Coptidis rhizome;
Management                                                         Phellodendrichinensis cortex) along with ciprofloxacin in-
To date, there are no treatment guidelines for GNTWI. When         travenously daily for seven days and reported resolution of
Amonette and Rosenberg first described GNTWI in 1972,              maceration and infection within two weeks [10].
they concluded that there was no single or simple therapeutic
                                                                   Systemic
agent that was regularly effective. They used combinations
of 0.5% silver nitrate solution, Castellani paint, and gen-        The most commonly reported systemic treatment for­
tamicin sulfate to treat 12 patients with GNTWI and none           GNTWI is oral ciprofloxacin [5,7,18]. In a case report of
produced consistent results across patients. Only 9 of 12 pa-      a 47-year-old male with GNTWI caused by Pseudomonas
tients had complete resolution of their toe web infection with     aeruginosa with autosensitization dermatitis, there was
combination therapy. They reported that the remaining three        gradual improvement following two weeks of 250 mg oral
patients initially had no response to therapy, but achieved        ciprofloxacin twice daily with gauze dressings and topical
adequate improvement after persistent use, however they did        application of tobramycin [7]. Aste et al also demonstrated
not define length of treatment [3].                                complete eradication after 10 days of 500 mg oral cipro-
                                                                   floxacin twice daily for patients presenting with severe cases
Topical                                                            of GNTWI (number of patients treated not specified) [5].
As polymicrobial toe web infections are common with                Other systemic therapies used to treat GNTWI included
­GNTWI, treatment often requires topical antibacterial, anti-      fluconazole, terbinafine, prednisone, amoxicillin/clavulanic
septic, antifungal, and/or steroidal therapies in combination      acid, cephalosporin, clindamycin, penicillin, oxacillin, am-
with systemic treatment. In Goiset et al retrospective study of    picillin trimethoprim-sulfamethoxazole, tigecycline, and
62 patients with GNTWI, 54.8% were treated with topicals           other fluoroquinolones. The dosage, length of treatment,
and 45.2% were treated with both systemic antibiotics and          and number of patients treated were not reported in these
topical treatment. The length of treatment was not described       studies [1,18]. Patients with multi-drug-resistant Pseudomo-
in this study. The topical regimens varied by the patient and      nas aeruginosa present additional management challenges.
included hydrogen peroxide, boric acid, silver sulfadiazine,       A 39-year-old male with GNTWI caused by Acinetobacter
gentamicin, or topical steroids. Dosing and length of treat-       baumannii, was successfully treated with oral trimethoprim–­
ment were not specified [6].                                       sulfamethoxazole (160-800 mg/q12h) for 14 days.



Review | Dermatol Pract Concept. 2024;14(1):e2024059                                                                             5
A 53-year-old male with a complicated hospital course                data on GNTWI precludes an accurate estimation of in-
secondary to multi-drug resistant Pseudomonas aeruginosa             cidence and prevalence. The therapeutic management of
showed improvement after 7 days of IV tigecycline (50mg/q12h)        ­GNTWI can be quite challenging due to the risk of antibiotic
and a 6-month course of oral terbinafine (250 mg/d) [15].            resistance and the lack of standardization of treatment meth-
While some studies have demonstrated success with the use of         ods. Treatment involves general measures such as mitigat-
topical therapies for GNTWI, most of the literature supports         ing risk factors, treating underlying dermatologic diseases,
utilizing systemic therapies or a combination of systemics and       and keeping the feet and web spaces dry. Topical gentamicin
topicals [5]. Therefore, topical therapies may be attempted first,   may be appropriate for management of mild GNTWI, while
followed by systemic therapy alone or as an adjunct topical          oral ciprofloxacin is preferred for moderate to severe cases.
therapy for severe and persistent cases [5,10,18].                   Further research is needed to provide evidence-based data
                                                                     to support treatment guidelines, reduction of predisposing
Recurrence of GNTWI                                                  factors and recurrences, and ultimately, improved outcomes
Recurrence of GNTWI has been reported in several studies.            for patients.
In a prospective clinical trial of 123 cases of GNTWI collected
over a 10-year period, 7% of patients had recurrences [5].           References
In a case series of 17 GNTWI outpatient cases collected over
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