Left ventricular assist device-associated driveline infections as a specific form of complicated skin and soft tissue infection/acute bacterial skin and skin structure infection - issues and therapeutic options.

PURPOSE OF REVIEW: This review comments on the current guidelines for the treatment of wound infections under definition of acute bacterial skin and skin structure infections (ABSSSI). However, wound infections around a catheter, such as driveline infections of a left ventricular assist device (LVAD) are not specifically listed under this definition in any of the existing guidelines. RECENT FINDINGS: Definitions and classification of LVAD infections may vary across countries, and the existing guidelines and recommendations may not be equally interpreted among physicians, making it unclear if these infections can be considered as ABSSSI. Consequently, the use of certain antibiotics that are approved for ABSSSI may be considered as 'off-label' for LVAD infections, leading to rejection of reimbursement applications in some countries, affecting treatment strategies, and hence, patients' outcomes. However, we believe driveline exit site infections related to LVAD can be included within the ABSSSI definition. SUMMARY: We argue that driveline infections meet the criteria for ABSSSI which would enlarge the 'on-label' antibiotic armamentarium for treating these severe infections, thereby improving the patients' quality of life.

Target attainment of intravenous lefamulin for treatment of acute bacterial skin and skin structure infections.

OBJECTIVES: Lefamulin is a pleuromutilin antibiotic approved for the treatment of community-acquired bacterial pneumonia (CABP). Its spectrum of activity, good penetration into soft tissues and low rates of cross-resistance also make lefamulin a potentially valuable option for treatment of acute bacterial skin and skin structure infections (ABSSSIs). A Phase 2 trial of lefamulin for ABSSSI indicated similar efficacy of 100 and 150 mg q12h IV dosing regimens. In the present study, the potential of lefamulin for this indication was further evaluated from a translational pharmacokinetic/pharmacodynamic perspective. METHODS: PTA was determined for various dosages using Monte Carlo simulations of a population pharmacokinetic model of lefamulin in ABSSSI patients and preclinical exposure targets associated with bacteriostasis and a 1-log reduction in bacterial count. Overall target attainment against MSSA and MRSA was calculated using lefamulin MIC distributions. RESULTS: Overall attainment of the bacteriostasis target was 94% against MSSA and 84% against MRSA for the IV dosage approved for CABP (150 mg q12h). Using the same target, for the 100 mg q12h regimen, overall target attainment dropped to 68% against MSSA and 50% against MRSA. Using the 1-log reduction target, overall target attainment for both regimens was <40%. CONCLUSIONS: Lefamulin at the currently approved IV dosage covers most Staphylococcus aureus isolates when targeting drug exposure associated with bacteriostasis, suggesting potential of lefamulin for the treatment of ABSSSIs. Lefamulin may not be appropriate in ABSSSI when rapid bactericidal activity is warranted.

Applications of nitric oxide-releasing nanomaterials in dermatology: Skin infections and wound healing.

Nitric oxide (NO) is produced in most cells in the skin and is an important regulator of essential cutaneous functions, including responses to UV irradiation, microbial defense, wound healing, melanogenesis and epidermal permeability barrier homeostasis. Harnessing the physiological activities of NO for therapeutic use is difficult because the molecule is highly reactive and unstable. A variety of exogenous NO delivery platforms have been developed and evaluated; however, they have limited clinical applications in dermatology due to instability and poor cutaneous penetration. NO-releasing nanomaterials overcome these limitations, providing targeted tissue delivery, and sustained and controlled NO release. This review provides a comprehensive and up-to-date evaluation of the use of NO-releasing nanomaterials in dermatology for the treatment of skin and soft tissue infections and wound healing.

Experience with dalbavancin use in various gram-positive infections within Aberdeen Royal Infirmary OPAT service.

PURPOSE: Dalbavancin, approved in 2014 for Gram-positive acute bacterial skin and skin structure infections (ABSSSI), has pharmacokinetics enabling treatment with one or two doses. Dalbavancin might be useful in outpatient parenteral antibiotic therapy (OPAT) of deep-seated infections, otherwise requiring inpatient admission. We documented our experience with pragmatic dalbavancin use to assess its effectiveness for varied indications, on- and off-label, as primary or sequential consolidation therapy. METHODS: Patients prescribed dalbavancin between 1 December 2021 and 1 October 2022 were screened for demographics of age, sex, Charlson comorbidity index (CCI), allergies, pathogens, doses of dalbavancin, other antibiotics administered and surgery. Where available, infection markers were recorded. The primary outcome was a cure at the end of treatment. Secondary outcomes included any adverse events and for those with treatment failures, response to salvage antibiotics. RESULTS: Sixty-seven per cent of patients were cured. Cure rates by indication were 93% for ABSSSI, 100% for bacteraemia, 90% for acute osteomyelitis, 0% for chronic osteomyelitis, 75% for native joint septic arthritis and 33% for prosthetic joint infection. Most bone and joint infections that were not cured did not have source control, and the goal of treatment was suppressive. Successful suppression rates were greater at 48% for chronic osteomyelitis and 66% for prosthetic joint infections. Adverse events occurred in 14 of 102 patients. CONCLUSION: This report adds to clinical experience with dalbavancin for off-label indications whilst further validating its role in ABSSSI. Dalbavancin as primary therapy in deep-seated infections merits investigation in formal clinical trials.

Current challenges in diagnosing and treating infectious skin diseases - a case series. / Choroby zakazne skóry jako wciaz aktualny problem diagnostyczny i terapeutyczny ­ przeglad nietypowych przypadków klinicznych.

Infectious skin diseases constitute a significant public health problem. Despite the systematic development of many modern diagnostic and therapeutic tools, they still pose a serious challenge for clinicians. Due to their prevalence and mild course in most cases, they are often marginalized, which can delay their diagnosis and treatment initiation. Such an approach in more clinically advanced cases can have serious consequences, sometimes leading to tragic outcomes. This work presents a series of four cases of common infectious skin diseases with an unusually atypical clinical picture: the history of a 49-year-old female patient with recurrent erysipelas of the right lower leg co-occurring with a SARS-CoV-2 infection, a 75-year-old male patient with a generalized form of herpes zoster, a 38-year-old female patient with a complicated severe course of head lice, and a 34-year-old male patient with a severe form of post-steroid mycosis. In each of these cases, difficulties in making the correct diagnosis were highlighted, even though they represent some of the most common bacterial, viral, parasitic, and fungal dermatoses. The paper discusses the risk factors for these diseases, the pathophysiology of their atypical course, the effects and challenges in the therapeutic approach conducted. Infectious skin dermatoses require aggressive treatment and should never be underestimated.

Drug Susceptibility Profiling of Prototheca Species Isolated from Cases of Human Protothecosis.

Prototheca are unicellular, achlorophyllous, yeast-like microalgae that occur in a wide range of natural habitats. At least five species have been implicated as the causative agents of opportunistic infections of men. Human protothecosis typically manifests as cutaneous, articular, or systemic disease. Treatment is largely empirical with poorly predictable and often unsuccessful outcomes. This is largely due to the frequently observed resistance of Prototheca species to conventional antimicrobial agents. This work is the first to perform drug susceptibility profiling exclusively on isolates from human cases of protothecosis. A total of 23 such isolates were tested against amphotericin B and 9 azoles, including efinaconazole and luliconazole, whose activities against Prototheca have never been studied before. Efinaconazole was the most active, with median minimum inhibitory concentration (MIC) and minimum algicidal concentration (MAC) values of 0.031 mg/L and 0.063 mg/L, respectively. Fluconazole and luliconazole had the lowest activity, with median MIC and MAC values of 128 mg/L. To conclude, amphotericin B and most of the azoles showed in vitro activity, with an algicidal rather than algistatic effect, against Prototheca. Still, the activity of individual drugs differed significantly between the species and even between strains of the same species. These differences can be attributed to a species-specific potential for acquiring drug resistance, which, in turn, might be linked to the treatment history of the patient from whom the strain was recovered. The results of this study underscore the potential clinical utility of efinaconazole as a promising therapeutic agent for the treatment of human protothecosis.

How to manage skin and soft-tissue infections in the emergency department.

PURPOSE OF REVIEW: Our purpose is to review the state-of-the-art on the management of skin and soft tissue infections (SSTI) in emergency departments (ED).Although the information is scarce, SSTI may account for 3-30% of all cases presenting to an ED, of which 25-40% require hospital admission.SSTI include very different entities in aetiology, location, pathogenesis, extension, and severity. Therefore, no single management can be applied to them all. A simple approach is to classify them as non-purulent, purulent, and necrotising, to which a severity scale based on their systemic repercussions (mild, moderate, and severe) must be added.The initial approach to many SSTIs often requires no other means than anamnesis and physical examination, but imaging tests are an indispensable complement in many other circumstances (ultrasound, computerized tomography, magnetic resonance imaging…). In our opinion, an attempt at etiological filiation should be made in severe cases or where there is suspicion of a causality other than the usual one, with tests based not only on cultures of the local lesion but also molecular tests and blood cultures. RECENT FINDINGS: Recent contributions of interest include the value of bedside ultrasound and the potential usefulness of biomarkers such as thrombomodulin to differentiate in early stages the presence of necrotising lesions not yet explicit.New antimicrobials will allow the treatment of many of these infections, including severe ones, with oral drugs with good bioavailability and for shorter periods. SUMMARY: The ED has an essential role in managing SSTIs, in their classification, in decisions on when and where to administer antimicrobial treatment, and in the rapid convening of multidisciplinary teams that can deal with the most complex situations.

Pharmacokinetics of intravenous daptomycin in Japanese pediatric patients: Pharmacokinetic comparisons supporting dosing recommendations in Japanese pediatric patients.

INTRODUCTION: The pharmacokinetics (PK) of daptomycin has not been previously characterized in Japanese pediatric patients with complicated skin and soft tissue infections (cSSTI) or bacteremia. An aim of the study includes evaluation of PK of daptomycin in Japanese pediatric patients and an appropriateness of the age-specific, weight-based dosing regimens in Japanese pediatric patients based on PK comparison with Japanese adult patients. METHODS: The phase 2 trial enrolled Japanese pediatric patients (age 1-17 years) with cSSTI (n = 14) or bacteremia (n = 4) caused by gram-positive cocci in order to evaluate safety, efficacy and PK. The Phase 3 trial in Japanese adult patients (SSTI n = 65, septicemia/right-sided infective endocarditis (RIE) n = 7) was referred to for PK comparison between adult and pediatric. Daptomycin concentrations in plasma were analyzed by reverse-phase high-performance liquid chromatography (HPLC). PK parameters were determined using non-compartmental analysis in Japanese pediatric and Japanese adult patients. The exposures in Japanese pediatric patients were graphically compared with those in Japanese adult patients. The relationship between daptomycin exposures and creatine phosphokinase (CPK) elevation was explored visually. RESULTS: Following administration of the age-specific, weight-based dosing regimens, daptomycin exposures were overlapping across age groups in pediatric patients with cSSTI with similar observations based on clearance. The distribution of individual exposure in Japanese pediatric patients was overlapping with that in Japanese adult patients. No apparent relationship between daptomycin exposures and CPK elevation in Japanese pediatric patients was observed. CONCLUSIONS: The results suggested that the age-specific, weight-based dosing regimens are considered to be appropriate in Japanese pediatric patients.

Reliable and rapid identification of terbinafine resistance in dermatophytic nail and skin infections.

BACKGROUND: Fungal infections are the most frequent dermatoses. The gold standard treatment for dermatophytosis is the squalene epoxidase (SQLE) inhibitor terbinafine. Pathogenic dermatophytes resistant to terbinafine are an emerging global threat. Here, we determine the proportion of resistant fungal skin infections, analyse the molecular mechanisms of terbinafine resistance, and validate a method for its reliable rapid identification. METHODS: Between 2013 and 2021, we screened 5634 consecutively isolated Trichophyton for antifungal resistance determined by hyphal growth on Sabouraud dextrose agar medium containing 0.2 µg/mL terbinafine. All Trichophyton isolates with preserved growth capacity in the presence of terbinafine underwent SQLE sequencing. Minimum inhibitory concentrations (MICs) were determined by the broth microdilution method. RESULTS: Over an 8-year period, the proportion of fungal skin infections resistant to terbinafine increased from 0.63% in 2013 to 1.3% in 2021. Our routine phenotypic in vitro screening analysis identified 0.83% (n = 47/5634) of Trichophyton strains with in vitro terbinafine resistance. Molecular screening detected a mutation in the SQLE in all cases. Mutations L393F, L393S, F397L, F397I, F397V, Q408K, F415I, F415S, F415V, H440Y, or A398 A399 G400 deletion were detected in Trichophyton rubrum. Mutations L393F and F397L were the most frequent. In contrast, all mutations detected in T. mentagrophytes/T. interdigitale complex strains were F397L, except for one strain with L393S. All 47 strains featured significantly higher MICs than terbinafine-sensitive controls. The mutation-related range of MICs varied between 0.004 and 16.0 µg/mL, with MIC as low as 0.015 µg/mL conferring clinical resistance to standard terbinafine dosing. CONCLUSIONS: Based on our data, we propose MIC of 0.015 µg/mL as a minimum breakpoint for predicting clinically relevant terbinafine treatment failure to standard oral dosing for dermatophyte infections. We further propose growth on Sabouraud dextrose agar medium containing 0.2 µg/mL terbinafine and SQLE sequencing as fungal sporulation-independent methods for rapid and reliable detection of terbinafine resistance.

Clinical efficacy of psychiatric nursing-based vancomycin in the treatment of Staphylococcus aureus infectious skin diseases.

To study the clinical effect of psychiatric nursing-based vancomycin in patients with staphylococcus aureus infectious skin disease. A retrospective analysis was performed on 100 patients with staphylococcus aureus infectious skin disease admitted to our hospital from March 2019 to July 2020. Al patients received psychiatric nursing and were divided into control group (mupiroxine) and experimental group (vancomycin) according to the treatment mode, with 50 patients in each group. The effective rate of treatment, adverse reactions, disappearance time of dermatological clinical symptoms and recurrence after one course of treatment were compared between the two groups. The effective rate of the experimental group was significantly higher than that of the control group (P<0.05).The incidence of adverse reactions and the disappearance time of clinical symptoms in the experimental group were significantly lower than those in the control group (P<0.05). After one course of treatment, the number of patients with recurrence in the experimental group was significantly lower than that in the control group (P<0.05). Vancomycin might be a boon for patients with staphylococcus aureus infectious skin diseases, with good effectiveness and safety profiles.

[Soft tissue infections]. / Weichgewebeinfektionen.

Acute skin and soft tissue infections are among the most frequent infections in medicine. There is a broad spectrum including simple local infections as well as severe and life-threatening diseases. Along with Staphylococcus aureus, group A Streptococci are mainly responsible for these illnesses. The therapeutic approach ranges from antiseptic local treatments to administering systemic antibiotics or emergency surgery. Treating physicians often face challenges when presented with soft tissue infections due to a great discrepancy between the first impression of the disease compared to a possibly quick progression as well as the wide range of sometimes confusing historic terms and definitions being used in the English and German language, for instance pyoderma, erysipelas or phlegmon. A recently more popular collective term emphasized by clinical trials is "acute bacterial skin and skin structure infections" (ABSSSI).

An exuberant case of protothecosis: an emergent disease in tropical dermatology.

Protothecosis is a rare condition caused by the aclorophylated algae of the genus Prototheca. We described an exuberant case treated as sporotrichosis with prolonged course which evolved to arm deformation. Itraconazole treatment for 8 months was inefective.

Effective Treatment of Cutaneous Mold Infections by Antimicrobial Blue Light That Is Potentiated by Quinine.

BACKGROUND: Cutaneous mold infections commonly result from an array of traumatic injuries that involve direct inoculation of contaminated soil into wounds. Here, we explored the use of antimicrobial blue light (aBL; 405 nm wavelength) and the combination of aBL with quinine hydrochloride (aBL + Q-HCL) for the treatment of cutaneous mold infections. METHODS: Efficacy of aBL and aBL + Q-HCL in killing clinically important pathogenic molds (Aspergillus fumigatus, Aspergillus flavus, and Fusarium oxyprorum) was investigated. Ultraperformance liquid chromatography identified and quantified endogenous porphyrins in the mold conidia. Finally, a mouse model of dermabrasion wound infected with a bioluminescent variant of A. fumigatus was developed to investigate the efficacy of aBL in treating cutaneous mold infections. RESULTS: We demonstrated that mold conidia are tolerant to aBL, but Q-HCL enhances efficacy. Transmission electron microscopy revealed intracellular damage by aBL. aBL + Q-HCL resulted in intracellular and cell wall damage. Porphyrins were observed in all mold strains, with A. fumigatus having the highest concentration. aBL and aBL + Q-HCL effectively reduced the burden of A. fumigatus within an established dermabrasion infection and limited recurrence posttreatment. CONCLUSIONS: aBL and aBL + Q-HCL may offer a novel approach for the treatment of mold infections.

Characterization of Prototheca CYP51/ERG11 as a possible target for therapeutic drugs.

Prototheca spp. are achlorophyllous algae, ubiquitous in nature. An increasing number of human and animal cases of Prototheca infection (protothecosis) are reported, and antifungal azoles, which inhibit sterol 14α-demethylase (CYP51/ERG11) involved in ergosterol biosynthesis, have empirically been used for the treatment of protothecosis. Although Prototheca, like fungi, has ergosterol in the cell membrane, efficacy of the antifungal azoles in the treatment of protothecosis is controversial. For investigating the interaction of azole drugs with Prototheca CYP51/ERG11, the CYP51/ERG11 genomic genes of four strains of P. wickerhamii and one strain each of P. cutis and P. miyajii were isolated and characterized in this study. Compared with the CYP51/ERG11 gene of chlorophyllous Auxenochlorella Protothecoides, it is possible that ProtothecaCYP51/ERG11 gene, whose exon-intron structure appeared to be species-specific, lost introns associated with the loss of photosynthetic activity. Analysis of the deduced amino acid sequences revealed that Prototheca CYP51/ERG11 and fungal CYP51/ERG11 are phylogenetically distant from each other although their overall structures are similar. Our basic in silico studies predicted that antifungal azoles could bind to the catalytic pocket of Prototheca CYP51/ERG11. It was also suggested that amino acid residues away from the catalytic pocket might affect the drug susceptibility. The results of this study may provide useful insights into the phylogenetic taxonomy of Prototheca spp. in relationship to the CYP51/ERG11 structure and development of novel therapeutic drugs for the treatment of protothecosis. LAY SUMMARY: Cases of infection by microalgae of Prototheca species are increasing. However, effective treatment has not been established yet. In this study, gene and structure of Prototheca's CYP51/ERG11, an enzyme which might serve as a target for therapeutic drugs, were characterized for the first time.

A Critical Reappraisal of Off-Label Use of Photodynamic Therapy for the Treatment of Non-Neoplastic Skin Conditions.

BACKGROUND: In the past 30 years, topical photodynamic therapy (PDT) has been investigated for the treatment of a broad spectrum of cosmetic, inflammatory, and infectious skin conditions with variable, and often contrasting, results. However, the non-expert clinician may be in difficulty evaluating these results because different sensitizers, concentrations, formulations, light sources, and irradiation protocols have been used. In addition, many of these studies have poor quality design being case reports and uncontrolled studies of few cases. SUMMARY: With the aim to clarify the potential usefulness of PDT for the treatment of infectious and inflammatory skin diseases as well as selected cosmetic indications, we searched for randomized controlled clinical trials, non-randomized comparative studies, retrospective studies, and case series studies with a number of at least 10 patients, published since 1990. Later, we reappraised the results in order to give a simple critical overview. Key Messages: Evidence from the literature seems to strongly support the use of ALA- and MAL-PDT for the treatment of common skin diseases such as acne, warts, condylomata, and Leishmania skin infection and for photorejuvenation, i.e., the correction of selected cosmetic changes of aging and photoaging. For other disorders, the level of evidence and strength of recommendation are lower, and controlled randomized studies with prolonged follow-ups are necessary in order to assess the clinical usefulness and other potential advantages over current treatment options.

A multifaceted intervention improves antibiotic stewardship for skin and soft tissues infections.

OBJECTIVE: Assess the effectiveness of a multifaceted stewardship intervention to reduce frequency and duration of inappropriate antibiotic use for emergency department (ED) patients with skin and soft tissue infections (SSTI). We hypothesized the antibiotic stewardship program would reduce antibiotic duration and improve guideline adherence in discharged SSTI patients. DESIGN: Nonrandomized controlled trial. SETTING: Academic EDs (intervention site and control site). PATIENTS OR PARTICIPANTS: Attending physicians and nurse practitioners at participating EDs. INTERVENTION(S): Education regarding guideline-based treatment of SSTI, tests of antimicrobial treatment of SSTI, implementation of a clinical treatment algorithm and order set in the electronic health record, and ED clinicians' audit and feedback. RESULTS: We examined 583 SSTIs. At the intervention site, clinician adherence to guidelines improved from 41% to 51% (aOR = 2.13 [95% CI: 1.20-3.79]). At the control site, there were no changes in adherence during the "intervention" period (aOR = 1.17 [0.65-2.12]). The between-site comparison of these during vs. pre-intervention odds ratios was not different (aOR = 1.82 [0.79-4.21]). Antibiotic duration decreased by 26% at the intervention site during the intervention compared to pre-intervention (Adjusted Geometric Mean Ratio [95% CI] = 0.74 [0.66-0.84]). Adherence was inversely associated with SSTI severity (severe vs mild; adjusted OR 0.42 [0.20-0.89]) and purulence (0.32 [0.21-0.47]). Mean antibiotic prescription duration was 1.95 days shorter (95% CI: 1.54-2.33) in the time period following the intervention than pre-intervention period. CONCLUSIONS: A multifaceted intervention resulted in modest improvement in adherence to guidelines compared to a control site, driven by treatment duration reductions.

5-Fluorouracil in Dermatology: The Diverse Uses Beyond Malignant and Premalignant Skin Disease.

BACKGROUND: 5-fluorouracil (5-FU) is widely used for treatment of malignant and premalignant skin cancers; however, its use in other common cutaneous conditions has been less widely reported. OBJECTIVE: We investigated the off-label uses of 5-FU beyond malignant and premalignant skin disease. METHODS: We conducted a literature review searching multiple databases to evaluate the evidence for the off-label uses of 5-FU. The level of evidence was evaluated and selected accordingly listing the studies with the highest level of evidence first using the Oxford Centre of Evidence-Based Medicine 2011 guidance. RESULTS: We found underlying evidence to support the use of 5-FU for a wide range of noncancerous cutaneous indications including scarring (keloid, hypertrophic), pigmentary disorders (vitiligo, idiopathic guttate hypomelanosis), cutaneous infections (viral warts, molluscum contagiosum), inflammatory dermatoses (Darier's disease, Hailey-Hailey disease and sarcoidosis), and cosmetic indications (photoaging, treatment of filler nodules and granulomas). CONCLUSION: In selected patients, 5-FU can be as effective as more established treatments, with fewer side-effects.

Infectious Dermatoses in Sport: A Review of Diagnosis, Management, and Return-to-Play Recommendations.

ABSTRACT: Infectious dermatoses represent a significant source of morbidity and missed athletic participation among athletes. Close quarters and skin trauma from contact sports can lead to outbreaks among teams and athletic staff. The National Collegiate Athletic Association and National Federation of State High School Associations have published guidance with recommended management and return-to-play criteria for common fungal, bacterial, viral, and parasitic rashes. In addition to rapidly diagnosing and treating infectious dermatoses, team physicians should counsel athletes and athletic staff on proper equipment care and personal hygiene to reduce infection transmission. Clinicians should always consult sport and athlete governing bodies for sport-specific recommendations.

National Trends in Incidence of Purulent Skin and Soft Tissue Infections in Patients Presenting to Ambulatory and Emergency Department Settings, 2000-2015.

Nationally representative data from 2000-2015 demonstrated a rise in the incidence of outpatient visits for skin infections, peaking in 2010-2013, followed by a plateau. While cephalexin was the most frequently prescribed antibiotic at the beginning, trimethoprim-sulfamethoxazole was most frequently prescribed by the end of the study period.

Nocardia takedensis: a newly recognized pathogen responsible for skin and soft tissue infections.

Nocardia takedensis was first isolated in 2005, from soil in Japan. We report here two cases of lymphangitis in France (2012-2017) caused by N. takedensis both occurring after skin injury while gardening, which enabled its inoculation. The two patients were immunocompromised and successfully treated by an antimicrobial agent active on the isolated strain, trimethoprim-sulfamethoxazole and amoxicillin-clavulanic acid for patient one and patient two, respectively. Our study along with previous ones supports the idea of a newly recognized cutaneous opportunistic pathogen and reinforces the recommendation of using gloves during soil exposure for immunocompromised patients. Lastly, according to data found in the literature, we would recommend trimethoprim-sulfamethoxazole as an efficient empirical antibiotic therapy in case of cutaneous infection caused by N. takedensis.