South-east Asia is well known for its tropical weather, with high humidity being its most striking feature. Several cutaneous infections seen in this region involve organisms that mainly originate from soil and natural water sources. Here, we review the pathogenesis, clinical features, investigations and treatment of skin and subcutaneous infections of melioidosis, penicilliosis, sporotrichosis and Mycobacterium marinum that are endemic in south-east Asia.
Melioidosis is a disease caused by Burkholderia pseudomallei, a Gram-negative bacillus which is a natural inhabitant of soil and environmental water. It is endemic to south-east Asia and northern Australia  and imported cases occur in travellers to these areas.
In Thailand, B. pseudomallei accounts for up to approximately 20% of community-acquired bacteraemias . The disease has a male preponderance, especially in those who have occupational or recreational contact with soil and water. Diabetes mellitus, alcoholism, renal disease, chronic lung disease, thalassaemia and steroid therapy increase the risk of acquiring the infection [3,4] but it is also known to occur in otherwise healthy patients. For cutaneous melioidosis, however, these traditional risk factors appear to be less important.
Infection occurs by percutaneous inoculation, aerosol inhalation or ingestion of contaminated food or water . The incubation period is highly variable and it ranges between 1 and 21 days  to the longest duration reported being 62 years . Mortality is much higher in septicaemic (30–70%) than in nonsepticaemic patients (5–20%) . Clinical features are protean and vary from indolent, chronic infection to an acute fulminant septicaemia. The skin is the third commonest organ to be involved after the lungs and genitourinary tract in Malaysia and Thailand . Skin and soft tissue involvement accounts for 13–24% of clinical presentation of melioidosis in a case series from Australia .
Cutaneous melioidosis may present as primary or secondary lesions. Primary lesions present as chronic ulcers, abscesses, cellulitis and necrotizing fasciitis [11,12]. Patients with primary cutaneous disease tend to be younger, and have less predisposing factors for melioidosis, milder disease and better outcome compared to melioidosis of other organs . Studies have also shown that children with melioidosis in south-east Asia are more likely to have localized disease [13,14]. Secondary cutaneous lesions may present as pustules from haematogenous spread or as extensions from an underlying infection such as osteomyelitis or lymphangitis . Other rarer presentations include scrotal abscess, Fournier's gangrene, parotitis and prostatitis [16–19].
Positive culture of B. pseudomallei remains the gold standard for the diagnosis of melioidosis. Isolation of the organism from a patient with suspected melioidosis should be viewed as highly likely to represent infection  but the special selective media may require up to 5 days of incubation for a positive result .
Patients with cutaneous melioidosis warrant thorough investigation to look for disseminated disease. Blood and other cultures, chest radiograph and abdominopelvic imaging should be performed. Direct PCR assay provides a more rapid and specific test result and is a promising tool for clinical use. This assay, however, is less sensitive to culture especially when performed on blood [22,23]. The usefulness of a serological test to detect B. pseudomallei – specific antibodies such as the indirect haemagglutination assay and enzyme-linked immunosorbent assays are limited in endemic areas because the background positivity may reach up to 50% .
The recommended treatment regimen is prolonged and consists of an intensive phase followed by a maintenance or oral eradication phase. During the intensive phase, intravenous ceftazidime or carbapenem is administered for 10–14 days. The oral eradication therapy is given for 3–6 months. Recently a study showed noninferiority and better tolerability of trimethoprim–sulphamethoxazole (TMP-SMX) alone compared to TMP-SMX along with doxycycline for 20 weeks [25▪▪]. Optimal duration of treatment, however, remains undetermined and it varies in different localities. There have been reports of cutaneous melioidosis treated with solely oral antibiotics with or without surgical drainage with good outcomes [7,14] but there are no clinical trials comparing the outcome of the two treatment approaches in localized cutaneous disease.
The search for an ideal vaccine is still ongoing and vaccine candidates include live attenuated, whole cell killed, subunit, plasmid DNA and dendritic cell vaccines. A cost-effectiveness analysis in Thailand has shown that a vaccine may be cost-effective especially when applied to high-risk groups . A live attenuated vaccine was found to be the most effective immunogen in mice but its potential to cause life-threatening disease that is difficult to treat and the possibility that it may become a latent infection render it unsuitable for use in humans .
Penicilliosis is caused by a dimorphic fungus Penicillium marneffei, which is now renamed Talaromyces marneffei. It is the third most common opportunistic infection in HIV patients in south-east Asia  and may occur in HIV patients travelling to endemic areas . Its exact incidence remains unknown but it mirrors the changes in the trend of HIV pandemicity in this region.
Penicilliosis is endemic in countries such as Malaysia, Thailand, Vietnam, Cambodia, southern China and India  most likely due to the humidity, which is an important factor in P. marneffei infection [31▪]. Occupational and other exposures to soil, particularly in the rainy seasons, have been identified as a significant risk factor for disseminated penicilliosis  and this suggests the soil as the main reservoir for the organism. Isolation of P. marneffei in organs of bamboo rats which rarely come in contact with humans also supported that both humans and rats may have acquired the infection from a common environmental source such as the soil [33,34].
Penicilliosis transmission is via an airborne route. Inhaled P. marneffei conidia are engulfed by the macrophages and processed in the reticulo-endothelial system . The organisms then remain dormant and proliferate upon deterioration of the immune system of the host. It is considered as one of the AIDS-defining illnesses in south-east Asia as it affects patients with CD4 (cluster of differentiation 4) count lower than 200 cell/μl. Infection in HIV negative patient is rare but has been reported .
The spectrum of infection ranges from isolated cutaneous to disseminated infection. Cutaneous penicilliosis presents as multiple dome-shaped skin-coloured, umbilicated papules and nodules with or without central necrosis on the face and trunk. Other associated symptoms and signs such as fever, malaise, weight loss, anaemia, lymphadenopathy and hepatosplenomegaly are present in disseminated penicilliosis . In more than 70% of HIV patients, the presence of cutaneous penicilliosis suggests disseminated infection [38,39] and this warrants further investigation to determine the involvement of other organs. HIV-negative children with penicilliosis need to be screened for primary immunodeficiency diseases, which may predispose them to the infection .
Isolation of P. marneffei from tissue culture is the gold standard for diagnosis . Preliminary diagnosis can be made in the presence of classic cutaneous lesions and visualization of the organism in the skin biopsy using Gomori-methenamine silver or Wright's stain. Histologically, P. marneffei is an oval-shaped yeast-like organism measuring 3–8 μm with central septation . In cases of disseminated penicilliosis, fungal cultures from bone marrow aspiration provide 100% yield, followed by skin biopsy (90%) and blood cultures (76%) . PCR-based detection is the investigation of choice as it provides highly sensitive and rapid diagnosis .
Intravenous amphotericin B at 0.6 mg/kg/day for 2 weeks followed by 10 weeks of oral itraconazole 400 mg daily is the recommended treatment in severe or disseminated infection. Success in treating severe infections using itraconazole or fluconazole alone has been reported [44▪] but fluconazole is the least effective azole against P. marnaffei in vitro. Voriconazole has been shown to be effective in several studies and is now a recommended alternative treatment for both severe and mild disease forms in the United States. In HIV patients, secondary prophylaxis with itraconazole 200 mg daily is recommended to prevent relapse or reinfection after a successful treatment . This can be safely discontinued once the patient has sustained CD4 count of more than 100 cells/μl . Primary prevention for penicilliosis is recommended in immunocompromised patients. It was demonstrated that fluconazole 400 mg weekly is as efficacious as itraconazole 200 mg daily in preventing infection . If left untreated, penicilliosis will be fatal. Early diagnosis and treatment improves a patient's outcome.
Sporotrichosis is a subacute or chronic granulomatous subcutaneous mycosis caused by traumatic inoculation of Sporothrix schenckii, a saprophytic dimorphic fungus which is commonly found in soil and plant matter. Zoonotic transmission from cats and other animals has also been described . The clinical presentation is divided into four types: lymphocutaneous, fixed cutaneous, disseminated and extracutaneous. The lymphocutaneous type is the commonest variant followed by fixed cutaneous in this region .
Lesions most commonly affect the extremities in adolescents and adults, but in infants and children, the face is the most common site [51,52]. Most cases are limited to skin and soft tissues but disseminated disease and extracutaneous involvement are rare and occur in immunocompromised individuals .
Disseminated sporotrichosis has also been reported to occur and worsen after initiation of HAART in two patients with AIDS as part of immune reconstitution inflammatory syndrome . Sporotrichosis outbreaks have been reported from various countries such as Western Australia (from contaminated hay)  and Brazil (from infected cats) .
Diagnosis is often made based on history, physical signs, histopathological examination and positive cultures. Identification using PCR can also be performed on tissue biopsy for rapid diagnosis .
Management of cutaneous sporotrichosis depends on its variant. For fixed and lymphocutaneous types, oral itraconazole for 3–6 months, or terbinafine or a saturated solution of potassium iodide (SSKI) is recommended. For disseminated or extracutaneous disease (pulmonary, meningeal, osteoarticular), intravenous amphotericin B is advocated with itraconazole as the ‘step-down’ treatment to complete the duration of at least 12 months .
Azoles are currently the preferred choice of treatment but due to the high cost, several studies were carried out to determine the efficacy and safety of alternative regimens. Bonifaz et al. showed that pulse itraconazole was effective in treating cutaneous sporotrichosis. In a comparative study, Song et al. demonstrated similar efficacy and safety of itraconazole pulse regimen (200 mg bd for 1 week with a 3 week break) to the continuous (100 mg bd) regimen. Terbinafine 250 mg daily is equally efficacious as itraconazole 100 mg daily for cutaneous sporotrichosis  and has also been shown to be a well tolerated alternative in cases when itraconazole is contraindicated or resulted in significant drug interactions . Ketoconazole is not recommended because of its inferior efficacy and significant adverse effects . SSKI is the oldest drug used for sporotrichosis and remains the mainstay of treatment in certain endemic areas. It is cheap and effective and therefore ideal for resource-limited settings . It is initiated at a dosage of five drops three times daily, increasing to 40–50 drops three times daily as tolerated .
M. marinum infection is rare but it is the most common nontuberculous mycobacterial infection in humans. The incidence in south-east Asia is not known due to the difficulty in obtaining positive cultures. This ubiquitous waterborne organism occupies both salt and fresh water. Its infection should be suspected in patients with a history of domestic, occupational and recreational exposure to unchlorinated water. Direct cutaneous inoculation of the organism through abrasions would result in granulomatous skin lesions within weeks or months .
The organism grows optimally at 25–32 °C, which explains its predilection for cooler parts of the body, that is the extremities. A nodule or pustule develops after an incubation period of 2–3 weeks, which ruptures to form an ulcer or suppurative abscess. Untreated, the lesions may heal spontaneously with scarring or progress to form multiple sporotrichoid lesions . Its clinical features have been classified into four categories: single/limited (<3 lesions), numerous lesions in sporotrichoid distribution (>3 lesions), deep infection with or without skin involvement (such as arthritis, tenosynovitis and/or osteomyelitis) and disseminated infection (lungs and other organs) . Disseminated disease is rare and has only been documented in immunocompromised patients  including those on tumour necrosis factor (TNF) inhibitors . Diagnosis is often delayed due to its rarity, prior treatment with corticosteroids and lack of history of exposure to aquatic environment.
Skin biopsies should be sent for histopathological examination and culture, although poor yield (<15%) of positive isolates has been reported . To improve the yield, clinicians should alert the microbiology laboratory regarding the possibility of this infection so that appropriate incubation and culture measures can be taken . Antibiogram results, if available, will be invaluable to guide management. Species identification of mycobacterium can be performed using PCR analysis  but this investigation may not be available in many centres.
There are no randomized-controlled trials to establish the treatment of choice for cutaneous infection. Choice of antibiotics and duration of treatment are often based on personal preference of the managing physician, local or international society guidelines. Empirical treatment has to be given in cases wherein the culture is negative. Monotherapies using minocycline, doxycycline or TMP-SMX are well tolerated and effective . Optimal duration of treatment varies, ranging from 1 to 25 months (median 3.5 months) .
A review by Rallis et al. concluded that monotherapy is recommended for limited superficial infection using tetracyclines (minocycline 100 mg bd or doxycycline 100 mg bd), TMP-SMX 800 mg bd or clarithromycin 500 mg bd. Other effective alternatives include ciprofloxacin 500 mg bd and azithromycin 500 mg od. A combination of two drugs may be required in the presence of drug resistance. In immunocompromised patients or a patient who presents with nodules, abscess and/or sporotrichoid lesions, a combination of rifampicin 600 mg od and ethambutol 15–25 mg/kg/day is the most recommended regimen . Clinicians should be aware that most M. marinum are intrinsically resistant to isoniazid, streptomycin and pyrazinamide [73,74].
Surgical excision of a localized disease is an option in certain cases. Other effective adjunctive treatment includes local heat therapy, cryotherapy, photodynamic therapy and electrodessication . Surgical debridement may be indicated in cases wherein deeper structures are involved. In disseminated disease, combination therapy of three drugs may be required .
Preventive measures to reduce M. marinum infections include advising ‘fish fanciers’ to wear gloves when handling fish tank or tropical fish and for immunosuppressed individuals to avoid direct contact with aquarium or aquatic animals. Free chlorine concentrations in swimming pool and tub water should be maintained within the ranges recommended by the Centers for Disease Control and Prevention . Common disinfectants such as ethyl alcohol, benzyl-4-chlorophenol and sodium chlorite have been shown to be the most effective to reduce or eliminate the organism from an aquarium or aquaculture facility . There are no vaccines available but research on the use of M. marinum as potential immunotherapy for tuberculosis is under way .
Melioidosis, penicilliosis, sporotrichosis and M. marinum are endemic in south-east Asia. A high index of suspicion is required in diagnosing these infections in individuals who have visited the endemic area when they present with typical cutaneous lesions. Tissue biopsy for histology and culture is vital and PCR may facilitate instant and accurate diagnosis. Treatment for melioidosis and M. marinum requires prolonged duration of combination therapy. Appropriate antifungal treatment improves outcome in penicilliosis and sporotrichosis.
The authors thank Universiti Kebangsaan Malaysia for the support in preparation of this manuscript.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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