Primary cutaneous mucormycosis caused by Mucor irregularis

We describe a case of primary cutaneous mucormycosis in a 44‐year‐old man with an 18‐month history of infiltrative erythematous plaques and haemorrhagic crusting on the dorsum of his left hand. The isolate was identified as Mucor irregularis (formerly Rhizomucor variabilis) based on the fungus morphology and DNA sequencing results. Improvement was observed after a 6‐month treatment course of itraconazole. No recrudescence was seen during a follow‐up of 23 months after treatment.     

Staphylococcus aureus subverts cutaneous defense by d‐alanylation of teichoic acids

The Gram‐positive bacterium Staphylococcus aureus is a frequent skin colonizer that often causes severe skin infections. It has been reported that neutralizing the negatively charged bacterial surface through the incorporation of d ‐alanine in its teichoic acids confers reduced susceptibility of S. aureus towards cationic antimicrobial peptides (AMPs). Using a S. aureus strain deficient in d ‐alanylated teichoic acids (dltA mutant), we demonstrate that d ‐alanylation of its surface reduces the susceptibility of S. aureus to skin‐derived AMPs such as RNase 7 and human beta‐defensins. This is accompanied by a higher killing activity of skin extracts towards the S. aureus dltA mutant as well as towards clinical isolates expressing lower levels of dltA. We conclude that modulation of cell envelope d ‐alanylation may help S. aureus to persist on human skin through evasion of cutaneous innate defense provided by cationic skin‐derived AMPs.     

Staphylococcus aureus skin colonization is promoted by barrier disruption and leads to local inflammation

Experimental mouse models of bacterial skin infections that have been described show that pathogenic microorganisms can readily invade the epidermis and dermis to produce localized infections. We used an epicutaneous mouse skin infection model to determine how the level of barrier disruption by tape‐stripping correlates with persistence of Staphylococcus aureus skin colonization, concomitant induction of cutaneous inflammation and infection. Furthermore, we investigated how murine skin responds to S. aureus colonization in a physiologic setting by analysing proinflammatory cytokines and antimicrobial peptides in mouse skin. We show that previous cutaneous damage allows skin inflammation to develop and favours S. aureus persistence leading to cutaneous colonization, suggesting an interdependence of cutaneous bacteria and skin. Our study suggests that skin barrier defects favour S. aureus skin colonization, which is associated with profound cutaneous inflammation.     

Antifungal effect of TONS504‐photodynamic therapy on Malassezia furfur

Numerous reports indicate therapeutic efficacy of photodynamic therapy (PDT) against skin tumors, acne and for skin rejuvenation. However, few reports exist regarding its efficacy for fungal skin diseases. In order to determine the antifungal effect, PDT was applied on Malassezia furfur. M. furfur was cultured in the presence of a novel cationic photosensitizer, TONS504, and was irradiated with a 670‐nm diode laser. TONS504‐PDT showed a significant antifungal effect against M. furfur. The effect was irradiation dose‐ and TONS504 concentration‐dependent and the maximal effect was observed at 100 J/cm² and 1 μg/mL, respectively. In conclusion, TONS504‐PDT showed antifungal effect against M. furfur in vitro, and may be a new therapeutic modality for M. furfur‐related skin disorders.     

Successful treatment of a patient with cutaneous co-infection caused by Mucor irregularis and Klebsiella pneumoniae

The authors report a rare case of primary cutaneous mucormycosis caused by Mucor irregularis and cutaneous Klebsiella pneumoniae infections in a 67-year-old Chinese woman. After the administration of liposomal amphotericin B combined with cefoperazone/sulbactam sodium, the patient recovered. Invasive fungal infection combined with cutaneous bacterial infection should receive attention.     

Different strains of Propionibacterium acnes modulate differently the cutaneous innate immunity

Acne is a chronic inflammatory illness of the pilosebaceous follicle where innate immunity plays a central role. In acne, the density of Propionibacterium acnes is increased in the pilosebaceous unit. We hypothesized that the severity of acne is not only dependent on the proliferation of P. acnes but also dependent on the pro‐inflammatory potential of P. acnes strains and consequently constitutes potential triggering factor for acne scarring. We investigated pro‐inflammatory potential of five different strains of P. acnes and P. avidum in skin explants and the preventive effect of zinc gluconate. The expression of immune markers was studied by immunohistochemistry, RT‐qPCR and ELISA. P. acnes strains modulate differently the expression of immune markers both at gene and at protein levels. P. acnes type III had the highest pro‐inflammatory potential by up‐regulating the expression of PAR‐2, TNF‐alpha, MMP‐13 and TIMP‐2, whereas P. avidum had the weakest by up‐regulating only MMP‐13 and TIMP‐2. Preincubation of zinc gluconate, which is a modulator of innate immunity, down‐regulates the expression of most immune markers induced by P. acnes, PAR‐2, TIMP‐2, up‐regulates MMP‐1, TIMP‐1. Our results demonstrate that different P. acnes strains have different inflammatory potential targeting markers of cutaneous innate immunity, and that inflammatory potential can be down‐regulated by zinc gluconate. As such, the inflammatory potential of P. acnes strains on acne skin may influence the severity of inflammatory acne lesions and scars.     

Molecular characterization of the skin fungal microbiome in patients with psoriasis

The skin surface is colonized by a wide variety of fungi and bacteria. While many of these organisms, including Malassezia, Candida, Streptococcus and Staphylococcus species, are associated with provocation and/or exacerbation of psoriasis, a detailed analysis of the cutaneous fungal microbiome in psoriatic patients has yet to be performed. To identify the disease‐specific fungal microbiota on psoriatic scale samples, fungal rRNA gene sequences from 12 psoriatic patients and 12 healthy controls were analyzed by pyrosequencing. A total of 317 806 high‐quality sequences were obtained, representing 142 genera. Malassezia species were the most abundant sequences in both populations (46.9 ± 14.0% in psoriasis vs 76.0 ± 14.6% for healthy controls). Principal coordinate analysis revealed that the fungal microbiomes were independent. Although an association between the cutaneous fungal microbiome and psoriasis has yet to be established, our data indicate that the microbiome in patients with psoriasis is independent of that in healthy controls.     

UVB induces epidermal 11β‐hydroxysteroid dehydrogenase type 1 activity in vivo

Detrimental consequences of ultraviolet radiation (UVR) in skin include photoageing, immunosuppression and photocarcinogenesis, processes also significantly regulated by local glucocorticoid (GC) availability. In man, the enzyme 11β‐hydroxysteroid dehydrogenase type 1 (11β‐HSD1) generates the active GC cortisol from cortisone (or corticosterone from 11‐dehydrocorticosterone in rodents). 11β‐HSD1 oxo‐reductase activity requires the cofactor NADPH, generated by hexose‐6‐phosphate dehydrogenase. We previously demonstrated increased 11β‐HSD1 levels in skin obtained from photoexposed versus photoprotected anatomical regions. However, the direct effect of UVR on 11β‐HSD1 expression remains to be elucidated. To investigate the cutaneous regulation of 11β‐HSD1 following UVR in vivo, the dorsal skin of female SKH1 mice was irradiated with 50, 100, 200 and 400 mJ/cm² UVB. Measurement of transepidermal water loss, 11β‐HSD1 activity, mRNA/protein expression and histological studies was taken at 1, 3 and 7 days postexposure. 11β‐HSD1 and hexose‐6‐phosphate dehydrogenase mRNA expression peaked 1 day postexposure to 400 mJ/cm² UVB before subsequently declining (days 3 and 7). Corresponding increases in 11β‐HSD1 protein and enzyme activity were observed 3 days postexposure coinciding with reduced GC receptor mRNA expression. Immunofluorescence studies revealed 11β‐HSD1 localization to hyperproliferative epidermal keratinocytes in UVB‐exposed skin. 11β‐HSD1 expression and activity were also induced by 200 and 100 (but not 50) mJ/cm² UVB and correlated with increased transepidermal water loss (indicative of barrier disruption). UVB‐induced 11β‐HSD1 activation represents a novel mechanism that may contribute to the regulation of cutaneous responses to UVR exposure.     

Primary Cutaneous Mucormycosis in an Extremely Preterm Infant Successfully Treated with Liposomal Amphotericin B

Cutaneous mucormycosis is a rare but often fatal invasive fungal infection that occurs most commonly in patients with diabetes, malignancy, and other immunocompromising conditions. We report an extremely preterm (<28 weeks) baby boy who developed polymicrobial sepsis and primary cutaneous mucormycosis within his first 10 days of life. He was successfully treated with medical management alone since he was not a candidate for surgery. Successful treatment of cutaneous mucormycosis without surgical debridement has been reported on only two other occasions. This case highlights the importance of rapid and thorough evaluation of skin lesions when evaluating preterm infants and other immunocompromised patients, even when other sources of infection have been identified.     

Relationship between quinolone use and resistance of Staphylococcus epidermidis in patients with acne vulgaris

Staphylococcus epidermidis is a bacterium known to inhabit the skin. In treatment of acne vulgaris, the cutaneous milieu is exposed to oral or topical antimicrobials. We previously reported that the antimicrobial resistance of Cutibacterium acnes isolated from acne patients is affected by antimicrobial use. The aim of this study was to investigate the relationship between quinolone use and resistance in skin bacteria, particularly S. epidermidis, from acne patients. A total of 92 and 87 S. epidermidis strains isolated from clinic patients and hospital outpatients with acne vulgaris, respectively, were tested. No significant difference was found between the prevalence of methicillin‐resistant S. epidermidis (MRSE) strains from clinic patients (37.0%) and hospital outpatients (39.1%). The MRSE strains (20.6%, 14/68 strains) showed a significantly higher ratio of high‐level levofloxacin resistance (minimum inhibitory concentrations were 64 to ≥256 μg/mL) compared with methicillin‐susceptible S. epidermidis strains (2.7%, 3/111 strains) (P < 0.01). The rate of levofloxacin resistance in C. acnes strains, which were isolated from the same samples of acne patients, showed a strong positive correlation with that in S. epidermidis strains (r = 0.93, P < 0.01). The high‐level levofloxacin‐resistant strains were frequently found in patients with history of quinolone use compared with those without (P < 0.01). Our data showed for the first time that antimicrobial administration for acne treatment affects the antimicrobial resistance in not only C. acnes but also S. epidermidis. Thus, caution should be exercised in antimicrobial use for acne treatment to prevent increasing antimicrobial resistance in these species.     

Case of disseminated cutaneous Mycobacterium chelonae infection mimicking cutaneous vasculitis

Mycobacterium chelonae is a non‐tuberculous, rapidly growing mycobacteria and is widely distributed in the natural environment. In the immunocompetent status, localized cutaneous infections such as cellulitis and subcutaneous abscesses commonly occur after traumatic injury. However, disseminated cutaneous infections occur on a background of immunosuppression. Cutaneous M. chelonae infection presents with a variety of skin eruptions. We report a case of disseminated M. chelonae infection mimicking cutaneous vasculitis. The patient was treated with long‐term oral corticosteroids and injected etanercept for the treatment of rheumatoid arthritis and asthma. Because the skin eruptions were preceded by asthma and rheumatoid arthritis and the pathological findings showed fibrinoid necrosis around the vascular of dermis, cutaneous vasculitis was first suspected. The culture from the pus revealed the bacterium which grew within 5 days on Ogawa's culture medium suggesting a rapidly growing mycobacteria. This bacterium was identified as M. chelonae by the DNA–DNA hybridization method. We chose 800 mg/day clarithromycin and 500 mg/day levofloxacin as a result of the drug‐sensitivity test. After 6 months of the treatment, infection symptoms disappeared. Rapidly growing mycobacteria should be considered in the differential diagnosis of infections in patients under immunosuppression caused by diseases or drugs such as corticosteroids and biologic agents. Repeated bacterial examinations are important and required for the diagnosis of rapidly growing mycobacteria.     

Disseminated cutaneous Mycobacterium kansasii infection presenting with Rosai–Dorfman disease‐like histological features in a patient carrying anti‐interferon‐γ autoantibodies

Typical cutaneous non‐tuberculous mycobacteria (NTM) infections show a histopathology pattern of granulomas with admixed Langhans giant cells, and abscesses may be observed in acute lesions. Herein, we describe a patient carrying a high titer of autoantibodies to interferon (IFN)‐γ with disseminated Mycobacterium kansasii infection presenting with emperipolesis and Rosai–Dorfman disease (RDD)‐like histopathological features characterized by remarkable, large, pale‐staining “RD cells”, which were CD68 and S100 positive and CD1a negative. The patient was misdiagnosed with RDD initially, but exhibited a poor response to all interventions. A re‐biopsy revealed Langhans‐type multinucleated giant cells; multiple definite acid‐fast bacilli were also found. M. kansasii was isolated from cultured tissues. Anti‐NTM treatment was initiated. After treatment, all lesions resolved almost completely within the following month. High‐titer anti‐IFN‐γ autoantibodies were detected during follow up, leading to the diagnosis of adult‐onset immunodeficiency syndrome. In conclusion, patients carrying high‐titer autoantibodies to IFN‐γ who also have a disseminated cutaneous M. kansasii infection may present with RDD‐like histopathological features, which may be a pitfall in the diagnosis of disseminated cutaneous NTM infections.     

Mycobacterium abscessus Hand‐and‐Foot Disease in Children: Rare or Emerging Disease?

Mycobacterium abscessus is emerging as an important cause of cutaneous infections in sporadic cases and outbreak settings. Although immunosuppressed or elderly patients are most commonly affected, in 2006 an outbreak of clinically distinct cutaneous lesions on the hands and feet caused by M. abscessus in a population of healthy children using a public swimming pool was reported. This article describes an outbreak of skin infection in a population of healthy Italian children attending the same school and using the same swimming pool. In January 2010 we identified three children with multiple, painful nodules on the palms and soles. M. abscessus was isolated from one child's lesions. A public health investigation was conducted and a team of dermatologists and public health officers visited all of the children; 514 children were screened and 29 cases were identified overall. All of the affected children had used the school's swimming pool. These children were treated with oral clarithromycin for 4 to 8 weeks. Because of the long period of time between the presentation and diagnosis of the first cases, the possibility that the number of cases may have been underestimated cannot be excluded. To our knowledge, this is the second largest reported cluster of M. abscessus skin infection suspected to be related to swimming pool exposure in a population of otherwise healthy children. It is unclear whether this disease is rare or should be considered as an emerging clinical entity.     

Interaction of Mycobacterium leprae with the HaCaT human keratinocyte cell line: new frontiers in the cellular immunology of leprosy

Leprosy is a chronic granulomatous disease caused by Mycobacterium leprae affecting the skin and peripheral nerves. Despite M. leprae invasion of the skin and keratinocytes importance in innate immunity, the interaction of these cells in vitro during M. leprae infection is poorly understood. Conventional and fluorescence optical microscopy, transmission electronic microscopy, flow cytometry and ELISA were used to study the in vitro interaction of M. leprae with the HaCaT human keratinocyte cell line. Keratinocytes uptake of M. leprae is described, and modulation of the surface expression of CD80 and CD209, cathelicidin expression and TNF‐α and IL‐1β production of human keratinocytes are compared with dendritic cells and macrophages during M. leprae interaction. This study demonstrated that M. leprae interaction with human keratinocytes enhanced expression of cathelicidin and greatly increased TNF‐α production. The highest spontaneous expression of cathelicidin was by dendritic cells which are less susceptible to M. leprae infection. In contrast, keratinocytes displayed low spontaneous cathelicidin expression and were more susceptible to M. leprae infection than dendritic cells. The results show, for the first time, an active role for keratinocytes during infection by irradiated whole cells of M. leprae and the effect of vitamin D on this process. They also suggest that therapies which target cathelicidin modulation may provide novel approaches for treatment of leprosy.     

Co‐infection of Scedosporium apiospermum and Mycobacterium chelonae in an immunocompetent host

A 75‐year‐old man presented with multiple, scaly, erythematous, grouped papules, nodules and plaques with tenderness ranging from the right forearm to hand dorsum and the right lower leg for 2–3 months. Five months prior to presentation, the patient had received an antibiotic skin test on his right forearm. Lesions appeared approximately 2–3 months after the antibiotic skin test, slowly progressing without clinical improvement. Culture for fungus on the right forearm revealed growth of Scedosporium apiospermum. The tissue acid‐fast bacilli (AFB) culture for the right forearm and right leg revealed growth of non‐tuberculous mycobacteria which was Mycobacterium chelonae, and subsequent tissue polymerase chain reaction of both sites reported positive signs of M. chelonae. On diastase periodic acid‐Schiff stain of the biopsy specimen of the right forearm, fungal hyphae were found while rod‐shaped bacilli could be seen in AFB stain for the biopsy specimen of the right leg. The patient was treated with oral clarithromycin and ciprofloxacin along with an oral antifungal agent for 13 weeks. After the treatment, the lesions subsided and left a scar. We report a rare case of co‐infection of S. apiospermum and M. chelonae in an immunocompetent host.     

Mitochondrial dysfunction in affected skin and increased mitochondrial DNA in serum from patients with psoriasis

Psoriasis is characterized by keratinocyte proliferation and chronic inflammation, but the pathogenesis is still unclear. Dysregulated mitochondria (mt) could lead to reduced apoptosis and extracellular secretion of mtDNA, acting as “innate pathogen” triggering inflammation. Serum was obtained from healthy volunteers and psoriatic patients. Mitochondrial DNA was extracted from the serum and amplified with quantitative PCR (qPCR). Punch biopsies were obtained from lesional and non‐lesional psoriatic skin (10 cm apart) and from healthy volunteers, were placed in RNA later and were stored at ?80°C until RNA was extracted and cDNA was synthesized; gene expression of uncoupling protein 2 (UCP2), Dynamin‐related protein 1 (Drp1) and calcineurin, involved in the regulation of mitochondria function, was detected with qPCR. Mitochondrial DNA was significantly increased (7s, P = 0.0496 and Cytochrome B, CytB, P = 0.0403) in the serum of psoriatic patients (n = 63) as compared to controls (n = 27). Gene expression was significantly reduced for UCP2 (P = 0.0218), Drp1 (P = 0.0001) and calcineurin (P = 0.0001) in lesional psoriatic skin, as compared to non‐lesional or control skin. Increased serum extracellular mtDNA in psoriatic patients and decreased expression of mitochondrial regulatory proteins in psoriatic skin suggest increased inflammation and reduced keratinocyte apoptosis, respectively. Inhibitors of mtDNA secretion and/or UCP2 stimulants may be potential treatment options.     

Impairment of Th cell response in Card9 knockout mice with cutaneous mucormycosis caused by Rhizopus arrhizus

Card9 is a signalling adaptor protein in the downstream of many innate pattern recognition receptors (PRRs) and exerts a significant role in antifungal immunity. To date, Card9 deficiency has been reported to be related to increased susceptibility to many fungal infections. In this study, we established mucormycosis murine model of Rhizopus arrhizus (R. arrhizus) using wild‐type (WT) mice and Card9 knockout (Card9^?/?) mice to investigate the antifungal effect of Card9 against R. arrhizus infection. Card9^?/? mice were more susceptible to R. arrhizus infection than WT mice, which could be related to the impaired NF‐κB pathway activation, local cytokine production and Th cell responses in Card9^?/? mice.     

Clinical and bacteriological evaluation of adapalene 0.1% gel plus nadifloxacin 1% cream versus adapalene 0.1% gel in patients with acne vulgaris

This multicenter, randomized parallel group study investigated the efficacy and tolerability of adapalene 0.1% gel plus nadifloxacin 1% cream (combination therapy) compared with adapalene gel (monotherapy) during 12‐week treatment of acne vulgaris. A total of 184 Japanese patients aged above 12 years with moderate to severe acne as indicated by the Japanese severity grading criteria were randomized to combination therapy (n = 84) and monotherapy (n = 100) groups, both having comparable demographic and baseline characteristics. Adapalene was applied only to inflammatory acne lesions in order to minimize skin irritation and ensure the treatment results. Efficacy and safety evaluations, treatment compliance and satisfaction with drug application were periodically monitored. The combination therapy provided a significantly greater efficacy than adapalene in decrement of inflammatory papulopustular lesions at 4 weeks and thereafter (P = 0.0056). The overall judgment of the therapeutic efficacy by the physician at the end of study revealed a significant difference (P = 0.02496) between the groups in favor of combination therapy. Dryness was reported in a greater proportion of patients undergoing monotherapy than combination therapy at weeks 2 and 4 (P = 0.04652). The patient self‐assessment in satisfaction with the drug application at the end of study revealed a significant difference (P = 0.00268) between the groups in favor of combination therapy. Among 76 strains of Propionibacterium acnes isolated from 87 patients, no strain was resistant to nadifloxacin. Thus, the simultaneous use of adapalene and nadifloxacin may provide an additive and complementary effect, resulting in clinical superiority and greater patient adherence compared to adapalene monotherapy.     

Exploration of a standard treatment for Buruli ulcer through a comprehensive analysis of all cases diagnosed in Japan

Buruli ulcer (BU) is a refractory skin ulcer caused by Mycobacterium ulcerans or M. ulcerans ssp. shinshuense, a subspecies thought to have originated in Japan or elsewhere in Asia. Although BU occurs most frequently in tropical and subtropical areas such as Africa and Australia, the occurrence in Japan has gradually increased in recent years. The World Health Organization recommends multidrug therapy consisting of a combination of oral rifampicin (RFP) and i.m. streptomycin (SM) for the treatment of BU. However, surgical interventions are often required when chemotherapy alone is ineffective. As a first step in developing a standardized regimen for BU treatment in Japan, we analyzed detailed records of treatments and prognoses in 40 of the 44 BU cases that have been diagnosed in Japan. We found that a combination of RFP (450 mg/day), levofloxacin (LVFX; 500 mg/day) and clarithromycin (CAM; at a dose of 800 mg/day instead of 400 mg/day) was superior to other chemotherapies performed in Japan. This simple treatment with oral medication increases the probability of patient adherence, and may often eliminate the need for surgery.     

Cutaneous manifestations and dermoscopic findings are important clues to the diagnosis of Talaromyces marneffei in HIV patients with immune reconstitution inflammatory syndrome: A case report and literature review

Talaromyces (formerly Penicillium) marneffei is a dimorphic fungus that causes talaromycosis (formerly penicilliosis). The condition is predominantly found in patients with HIV. Important diagnostic clues are a history of living or travelling in endemic areas, and central umbilicated skin lesions. Dermoscopy is particularly useful for providing rapid bedside information, with a round, whitish, amorphous structure being the most common finding. Immune reconstitution inflammatory syndrome (IRIS) may occur. Driven by the initiation of antiretroviral therapy, IRIS is an exaggerated response of T cells to pathogens. Although mycobacterial and cryptococcal opportunistic infections are common with IRIS, a linkage between T. marneffei and IRIS has rarely been reported. Here, we report on a literature review of patients with HIV who developed IRIS associated with talaromycosis. Dermatologists should be aware of the cutaneous and dermoscopic findings of talaromycosis as they provide important clues that enable its early diagnosis and treatment.