Intractable Nocardial mycetoma with possible colonisation by Candida species.

A Japanese male in his 30s with no underlying medical condition presented with painless nodules after being bitten by a dog during a stay in Bali, Indonesia, 7 years earlier. He was referred to our department with multiple ulcers, nodules, and masses on the right leg. The final diagnosis was mycetoma caused by Nocardia vulneris, which may have been exacerbated by colonization of Candida parapsilosis and C. tropicalis as these yeasts were isolated by culture from the tissue. Treatment with minocycline hydrochloride and sulfamethoxazole trimethoprim showed partial efficacy, but the addition of posaconazole achieved significant efficacy. This suggests that the surmised coexistence of pathogenic yeasts of lower virulency may have made mycetoma in this case intractable.

Therapeutic efficacy of rifalazil (KRM-1648) in a M. ulcerans-induced Buruli ulcer mouse model.

Buruli ulcer (BU) is a skin disease caused by Mycobacterium ulcerans infection that requires long-term antibiotic treatment and/or surgical excision. In this study, we investigated the therapeutic efficacy of the rifamycin derivative, rifalazil (RLZ) (also known as KRM-1648), in an advanced M. ulcerans infection model. Six-week-old female BALB/c mice were infected with 3.25 x 104 colony-forming units (CFU) of M. ulcerans subcutaneously into the bilateral hind footpads. At 33 days post-infection, when the footpads exhibited significant redness and swelling, mice were treated orally with 5 or 10 mg/kg of RLZ for up to 15 weeks. Mice were followed for an additional 15 weeks following treatment cessation. Untreated mice exhibited a progressive increase in footpad redness, swelling, and erosion over time, and all untreated mice reached to endpoint within 5-8 weeks post-bacterial injection. In the RLZ-treated mice, footpad redness and swelling and general condition improved or completely healed, and no recurrence occurred following treatment cessation. After 3 weeks of treatment, the CFU counts from the footpads of recovered RLZ-treated mice showed a 104 decrease compared with those of untreated mice. We observed a further reduction in CFU counts to the detection limit following 6 to 15 weeks of treatment, which did not increase 15 weeks after discontinuing the treatment. Histopathologically, bacteria in the treated mice became fragmented one week after RLZ-treatment. At the final point of the experiment, all the treated mice (5mg/kg/day; n = 6, 10mg/kg/day; n = 7) survived and had no signs of M. ulcerans infection. These results indicate that the rifamycin analogue, RLZ, is efficacious in the treatment of an advanced M. ulcerans infection mouse model.

Hansen's disease (leprosy) in Japan, 1947-2020: an epidemiologic study during the declining phase to elimination.

OBJECTIVES: Leprosy, or Hansen's disease was a major public health problem in Japan in the early 20th century. Today, the number of new cases has decreased significantly. We aimed to investigate the trends of leprosy in Japan over the past 73 years and the challenges faced in recent years. METHODS: We assessed the data on newly registered cases of leprosy from 1947 to 2020. RESULTS: A total of 10,796 newly registered cases of leprosy were reported during the study period, of which 7573 were registered in mainland Japan, 2962 in Okinawa, and 250 were of foreign origin. Most autochthonous cases were born before 1950 in mainland Japan and before 1975 in Okinawa. The number of nonautochthonous cases surpassed that of autochthonous cases in 1992. Nonautochthonous cases originated from 26 countries, particularly Brazil and the Philippines. Three cases of antimicrobial resistance have been detected among nonautochthonous cases since 2004. CONCLUSION: Our data suggest that ongoing transmission of leprosy likely ceased in the 1940s in mainland Japan and in the 1970s in Okinawa. With the recent rise of nonautochthonous cases with globalization, continuous surveillance and efforts to maintain leprosy services within the country are necessary even after reaching the state of elimination.

Cutaneous nontuberculous mycobacterial infections in Japan: Review of the Japanese literature.

Nontuberculous mycobacteria cause a wide range of infections, including cutaneous infections, in both immunocompromised and immunocompetent patients. Although pulmonary nontuberculous mycobacterial infections have increased significantly in Japan in recent years, there is less evidence on clinical and microbiological characteristics of cutaneous nontuberculous mycobacterial infections in Japan. We reviewed 86 Japanese cases reported between July 2016 and November 2021 and analyzed them in conjunction with the eight patients from our institution who were diagnosed with cutaneous nontuberculous mycobacterial infections by culture between 2015 and 2021. In the aggregate series, the average patient age was 60 years, and the ratio of immunocompromised hosts was 53%, both of which were higher than those in previous reports from other countries. No female predominance was observed, unlike in pulmonary nontuberculous mycobacteria infections. Rapidly growing mycobacteria accounted for 58% of the cases (n = 54), whereas slowly growing mycobacteria for 43% (n = 40). Mycobacterium marinum (also known as Mycobacteroides marinum) (n = 20, 21%) was the most common cause, followed by Mycobacterium chelonae (n = 18, 19%), Mycobacterium abscessus (also known as Mycobacteroides abscessus) (n = 15, 16%), and Mycobacterium ulcerans (n = 11, 12%). While clinical appearance was variable, M ulcerans infections usually presented with ulcers, while nodules were common among infections caused by M chelonae and M marinum. Disseminated infections involving multiple organs were observed in 23 patients (24%). Thirty-two cases (30%) were preceded by exposure, including raising or handling fish, trauma, and invasive medical procedures. Most patients were treated with more than two antibiotics and responded to therapy.

Host-Related Laboratory Parameters for Leprosy Reactions.

Leprosy reactions are acute inflammatory episodes that complicate the course of a Mycobacterium leprae infection and are the major cause of leprosy-associated pathology. Two types of leprosy reactions with relatively distinct pathogenesis and clinical features can occur: type 1 reaction, also known as reversal reaction, and type 2 reaction, also known as erythema nodosum leprosum. These acute nerve-destructive immune exacerbations often cause irreversible disabilities and deformities, especially when diagnosis is delayed. However, there is no diagnostic test to detect or predict leprosy reactions before the onset of clinical symptoms. Identification of biomarkers for leprosy reactions, which impede the development of symptoms or correlate with early-onset, will allow precise diagnosis and timely interventions to greatly improve the patients' quality of life. Here, we review the progress of research aimed at identifying biomarkers for leprosy reactions, including its correlation with not only immunity but also genetics, transcripts, and metabolites, providing an understanding of the immune dysfunction and inflammation that underly the pathogenesis of leprosy reactions. Nevertheless, no biomarkers that can reliably predict the subsequent occurrence of leprosy reactions from non-reactional patients and distinguish type I reaction from type II have yet been found.

Human pathogenic Mycobacterium kansasii (former subtype I) with zoonotic potential isolated from a diseased indoor pet cat, Japan.

Nontuberculous mycobacterial (NTM) infections in humans have increased in prevalence in recent decades. Mycobacterium kansasii is one of the most prevalent human pathogenic NTM species worldwide. Herein, we report the first isolation of M. kansasii from an indoor domestic cat in Japan. Comparative genome sequence analysis of the feline isolate showed this pathogen is genetically identical to human pathogenic M. kansasii. This finding suggests that M. kansasii has a potential risk of zoonoses and requires the "One Health" approach to control NTM infection.

Relationship between Plantar Pressure and Sensory Disturbance in Patients with Hansen's Disease-Preliminary Research and Review of the Literature.

Orthoses and insoles are among the primary treatments and prevention methods of refractory plantar ulcers in patients with Hansen's disease. While dynamic plantar pressure and tactile sensory disturbance are the critical pathological factors, few studies have investigated whether a relationship exists between these two factors. In this study, dynamic pressure measured using F-scan system and tactile sensory threshold evaluated with monofilament testing were determined for 12 areas of 20 feet in patients with chronic Hansen's disease. The correlation between these two factors was calculated for each foot, for each clinical category of the foot (0-IV) and across all feet. A significant correlation was found between dynamic pressure and tactile sensation in Category II feet (n = 8, p = 0.016, r2 = 0.246, Spearman's rank test). In contrast, no significant correlation was detected for the entire foot or within the subgroups for the remainder of the clinical categories. However, the clinical manifestation of lesion areas showed high variability: (1) pressure concentrated, sensation lost; (2) margin of pressure concentration, sensation lost; (3) pressure concentrated, sensation severely disturbed but not lost; and (4) tip of the toe. These results may indicate that, even though there was a weak relationship between dynamic pressure and tactile sensation, it is important to assess both, in addition to the basics of orthotic treatment in patients with Hansen's disease presenting with refractory plantar ulceration.

The function of peroxisome proliferator-activated receptors PPAR-γ and PPAR-δ in Mycobacterium leprae-induced foam cell formation in host macrophages.

Leprosy is a chronic infectious disease caused by Mycobacterium leprae (M. leprae). In lepromatous leprosy (LL), skin macrophages, harboring extensive bacterial multiplication, gain a distinctive foamy appearance due to increased intracellular lipid load. To determine the mechanism by which M. leprae modifies the lipid homeostasis in host cells, an in vitro M. leprae infection system, using human macrophage precursor THP-1 cells and M. leprae prepared from the footpads of nude mice, was employed. RNA extracted from skin smear samples of patients was used to investigate host gene expressions before and after multidrug therapy (MDT). We found that a cluster of peroxisome proliferator-activated receptor (PPAR) target genes associated with adipocyte differentiation were strongly induced in M. leprae-infected THP-1 cells, with increased intracellular lipid accumulation. PPAR-δ and PPAR-γ expressions were induced by M. leprae infection in a bacterial load-dependent manner, and their proteins underwent nuclear translocalization after infection, indicating activation of PPAR signaling in host cells. Either PPAR-δ or PPAR-γ antagonist abolished the effect of M. leprae to modify host gene expressions and inhibited intracellular lipid accumulation in host cells. M. leprae-specific gene expressions were detected in the skin smear samples both before and after MDT, whereas PPAR target gene expressions were dramatically diminished after MDT. These results suggest that M. leprae infection activates host PPAR signaling to induce an array of adipocyte differentiation-associated genes, leading to accumulation of intracellular lipids to accommodate M. leprae parasitization. Certain PPAR target genes in skin lesions may serve as biomarkers for monitoring treatment efficacy.

Efficacy and safety of a combination regimen of phenothrin and ivermectin lotion in patients with head lice in Okinawa, Japan.

In Japan, pyrethroid-resistant head lice have been increasing; however, only 0.4% phenothrin, a pyrethroid drug, is available as an over the counter formulation. In recent years, Sumithrin® Lotion containing 5% phenothrin (PHT) was approved for scabies. In the USA, Sklice® Lotion containing 0.5% ivermectin (IVM) is used for the treatment of pyrethroid-resistant head lice. Therefore, to enhance the treatment of head lice in Japan, we conducted a clinical study to confirm the efficacy and safety of a combination regimen of PHT and IVM (PI regimen). Twelve cases were enrolled and PHT was applied to all patients on day 1. On day 8, five patients (41.7%) were lice free, and PHT was applied again. Notably, seven patients were not lice free and were switched to IVM. The rate of patients who were lice free on the PI regimen, which was the primary end-point, was 75.0% on day 15 and 91.7% on day 22. No adverse events were reported. A genetic analysis of the head lice collected at each visit revealed a kdr mutation in all patients. These results suggest that the PI regimen is safe and effective for the treatment of pyrethroid-resistant head lice in Japan.

Targeting the Mycobacterium ulcerans cytochrome bc1:aa3 for the treatment of Buruli ulcer.

Mycobacterium ulcerans is the causative agent of Buruli ulcer, a neglected tropical skin disease that is most commonly found in children from West and Central Africa. Despite the severity of the infection, therapeutic options are limited to antibiotics with severe side effects. Here, we show that M. ulcerans is susceptible to the anti-tubercular drug Q203 and related compounds targeting the respiratory cytochrome bc1:aa3. While the cytochrome bc1:aa3 is the primary terminal oxidase in Mycobacterium tuberculosis, the presence of an alternate bd-type terminal oxidase limits the bactericidal and sterilizing potency of Q203 against this bacterium. M. ulcerans strains found in Buruli ulcer patients from Africa and Australia lost all alternate terminal electron acceptors and rely exclusively on the cytochrome bc1:aa3 to respire. As a result, Q203 is bactericidal at low dose against M. ulcerans replicating in vitro and in mice, making the drug a promising candidate for Buruli ulcer treatment.