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BACKGROUND AND OBJECTIVE: The identification of factors associated with long-term prognosis after community-onset pneumonia in elderly patients should be considered when initiating advance care planning (ACP). We aimed to identify these factors and develop a prediction score model. METHODS: Patients aged 65 years and older, who were hospitalized for pneumonia at nine collaborating institutions, were included. The prognosis of patients 180 days after the completion of antimicrobial treatment for pneumonia was prospectively collected. RESULTS: The total number of analysable cases was 399, excluding 7 outliers and 42 cases with missing data or unknown prognosis. These cases were randomly divided in an 8:2 ratio for score development and testing. The median age was 82 years, and there were 68 (17%) deaths. A multivariate analysis showed that significant factors were performance status (PS) ≥2 (Odds ratio [OR], 11.78), hypoalbuminemia ≤2.5 g/dL (OR, 5.28) and dementia (OR, 3.15), while age and detection of antimicrobial-resistant bacteria were not associated with prognosis. A scoring model was then developed with PS ≥2, Alb ≤2.5, and dementia providing scores of 2, 1 and 1 each, respectively, for a total of 4. The area under the curve was 0.8504, and the sensitivity and specificity were 94.6% and 61.7% at the cutoff of 2, respectively. In the test cases, the sensitivity and specificity were 91.7% and 63.1%, respectively, at a cutoff value of 2. CONCLUSION: Patients meeting this score should be considered near the end of life, and the initiation of ACP practices should be considered.
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Infecções Comunitárias Adquiridas , Pneumonia , Humanos , Feminino , Masculino , Infecções Comunitárias Adquiridas/microbiologia , Infecções Comunitárias Adquiridas/diagnóstico , Infecções Comunitárias Adquiridas/tratamento farmacológico , Prognóstico , Idoso , Idoso de 80 Anos ou mais , Pneumonia/diagnóstico , Pneumonia/microbiologia , Pneumonia/tratamento farmacológico , Pneumonia/mortalidade , Estudos Prospectivos , Fatores de Risco , Antibacterianos/uso terapêutico , Valor Preditivo dos Testes , Demência/diagnóstico , Demência/epidemiologiaRESUMO
BACKGROUND: Nursing- and healthcare-associated pneumonia (NHCAP) constitutes most of the pneumonia in elderly patients including aspiration pneumonia in Japan. Lascufloxacin (LSFX) possesses broad antibacterial activity against respiratory pathogens, such as Streptococcus spp. And anaerobes inside the oral cavity. However, the efficacy and safety of LSFX in NHCAP treatment remains unknown. We aimed to evaluate the efficacy and safety of LSFX tablets in the treatment of patients with NHCAP. METHODS: In this single-arm, open-label, uncontrolled study, LSFX was administered to patients with NHCAP at 24 facilities. The study participants were orally administered 75 mg LSFX once daily for 7 days. The primary endpoint was the clinical efficacy at the time of test of cure (TOC). The secondary endpoints included clinical efficacy at the time of end of treatment (EOT), early clinical efficacy, microbiological efficacy, and safety analysis. RESULT: During the study period, 75 patients provided written informed consent to participate and were included. Finally, 56 and 71 patients were eligible for clinical efficacy and safety analyses, respectively. The median age of the patients was significantly high at 86 years. All patients were classified as having moderate disease severity using the A-DROP scoring system. LSFX tablets demonstrated high efficacy rates of 78.6 % at TOC and 89.3 % at EOT. The risk factors for resistant bacteria or aspiration pneumonia did not affect clinical efficacy. No severe adverse events associated with the study drugs were observed. CONCLUSION: Oral LSFX is an acceptable treatment option for moderate NHCAP in elderly patients who can take oral medications.
Assuntos
Antibacterianos , Fluoroquinolonas , Pneumonia Associada a Assistência à Saúde , Humanos , Masculino , Feminino , Idoso de 80 Anos ou mais , Idoso , Antibacterianos/uso terapêutico , Antibacterianos/efeitos adversos , Antibacterianos/administração & dosagem , Fluoroquinolonas/uso terapêutico , Fluoroquinolonas/efeitos adversos , Fluoroquinolonas/administração & dosagem , Japão , Pneumonia Associada a Assistência à Saúde/tratamento farmacológico , Pneumonia Associada a Assistência à Saúde/microbiologia , Resultado do Tratamento , Administração Oral , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Cryptococcal meningitis (CM) is an invasive fungal infection with a poor prognosis that often occurs in both healthy individuals and compromised hosts, such as patients infected with human immunodeficiency virus (HIV). Unlike CM in HIV patients, evidence regarding CM in non-HIV patients is limited to small retrospective studies. OBJECTIVE: To identify the pretreatment prognostic factors for CM in non-HIV patients. METHODS: We conducted a large retrospective analysis of CM in non-HIV patients using data from a nationwide Japanese database. The study included hospitalized patients diagnosed with CM between 1 April 2010 and 31 March 2017. All-cause mortality was compared between patients with CM with and without HIV infection. Poor diagnostic factors were analysed in the non-HIV CM group. RESULTS: Overall, 533 (64 HIV and 469 non-HIV) patients met the criteria. The mortality rate at 90 days was significantly lower in the HIV group (6.3% vs. 25.4% p = .0002). In a logistic regression analysis of the non-HIV group, age ≥ 65 y (odds ratio [OR] 2.37, 95% CI 1.17-4.78), impaired consciousness (Japan Coma Scale ≥1) (OR 2.25, 95% CI 1.29-3.93), haemodialysis (OR 3.53, 95% CI 1.12-11.20) and previous corticosteroid usage (OR 2.40, 95% CI 1.37-4.19) were associated with poor prognosis at 30 days after diagnosis. CONCLUSION: More caution is suggested when treating non-HIV with CM in older patients with impaired consciousness, previous corticosteroid usage and haemodialysis.
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Infecções por HIV , Meningite Criptocócica , Humanos , Idoso , Meningite Criptocócica/tratamento farmacológico , Meningite Criptocócica/epidemiologia , Meningite Criptocócica/complicações , Infecções por HIV/complicações , HIV , Estudos Retrospectivos , Prognóstico , CorticosteroidesRESUMO
Candida auris is resistant to multiple antifungal agents. This study investigated its antifungal susceptibility and explored FKS1 mutations across the isolates from mice enterically colonized with wild-type C. auris and treated with echinocandin. Resistant C. auris with FKS1 mutations, including S639F, S639Y, D642Y, R1354H, or R1354Y, were isolated and found to be micafungin- and caspofungin-resistant in vivo; however, the MICs of isolates with mutation in R1354 remained below the micafungin breakpoint in vitro.
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Candida auris , Equinocandinas , Animais , Camundongos , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Farmacorresistência Fúngica/genética , Equinocandinas/farmacologia , Equinocandinas/genética , Trato Gastrointestinal , Micafungina/farmacologia , Testes de Sensibilidade Microbiana , Mutação/genéticaRESUMO
Data on antifungal susceptibility of Cryptococcus neoformans are limited in Japan. A total of 89 C. neoformans strains isolated from 83 non-human immunodeficiency virus-infected patients with cryptococcosis between 1997 and 2021 in Nagasaki, Japan, were investigated. Using the reference method M27-Ed4 by the Clinical and Laboratory Standards Institute, the minimum inhibitory concentration for 90% of isolates of fluconazole, itraconazole, voriconazole, amphotericin B, and flucytosine were 4, 0.125, 0.06, 0.5, and 4 µg/ml, respectively, which were below the reported epidemiological cutoff values, without any detectable non-wild-type strains. Our findings imply no increasing trend of antifungal-resistant C. neoformans in Nagasaki, Japan.
Cryptococcus neoformans strains obtained from non-human immunodeficiency virus-infected patients were observed to maintain good antifungal susceptibility to fluconazole, itraconazole, voriconazole, amphotericin B, and flucytosine over a 25-year-long period in Nagasaki, Japan.
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A 65-year-old Japanese woman repeatedly withdrew and resumed antibiotics against pulmonary non-tuberculous mycobacterial infection caused by Mycobacterium intracellulare for more than 10 years. Although she continued to take medications, her respiratory symptoms and chest computed tomography indicated an enlarged infiltrative shadow in the lingular segment of the left lung that gradually worsened over the course of a year or more. Bronchoscopy was performed and mycobacterial culture of the bronchial lavage fluid was negative, whereas Exophiala dermatitidis was detected. After administration of oral voriconazole was initiated, the productive cough and infiltrative shadow resolved. There are no characteristic physical or imaging findings of E. dermatitidis, and it often mimics other chronic respiratory infections. Thus, when confronting refractory non-tuberculous mycobacterial cases, it might be better to assume other pathogenic microorganisms, including E. dermatitidis, and actively perform bronchoscopy.
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Exophiala , Feoifomicose , Pneumonia , Humanos , Feminino , Idoso , Feoifomicose/diagnóstico , Feoifomicose/tratamento farmacológico , Feoifomicose/microbiologia , Micobactérias não Tuberculosas , Voriconazol/uso terapêutico , Pneumonia/tratamento farmacológico , Pulmão/diagnóstico por imagem , Pulmão/patologiaRESUMO
Inhaled liposomal antimicrobials are known to cause hypersensitivity pneumonitis. Amikacin liposome inhalation suspension (ALIS) is a promising novel antimicrobial agent against refractory Mycobacterium avium complex infections. The frequency of drug-induced lung injury caused by ALIS is relatively high. To date, no reports of ALIS-induced organizing pneumonia diagnosed by bronchoscopy are available. We report a case of a 74-year-old female patient presenting with non-tuberculous mycobacterial pulmonary disease (NTM-PD). She was treated with ALIS for refractory NTM-PD. Fifty-nine days after starting ALIS, the patient developed a cough, and her chest radiographs indicated deterioration. She was diagnosed with organizing pneumonia based on pathological findings of the lung tissues obtained by bronchoscopy. After switching from ALIS to amikacin infusion, her organizing pneumonia improved. It is difficult to distinguish between organizing pneumonia and an exacerbation of NTM-PD based on chest radiography alone. Therefore, it is essential to perform an active bronchoscopy for diagnosis.
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Pneumopatias , Infecções por Mycobacterium não Tuberculosas , Infecção por Mycobacterium avium-intracellulare , Pneumonia em Organização , Pneumonia , Humanos , Feminino , Idoso , Amicacina/efeitos adversos , Lipossomos/uso terapêutico , Antibacterianos/efeitos adversos , Infecção por Mycobacterium avium-intracellulare/tratamento farmacológico , Complexo Mycobacterium avium , Pneumonia/tratamento farmacológico , Pneumopatias/microbiologia , Micobactérias não Tuberculosas , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológicoRESUMO
The diagnosis of pulmonary lymphoma using small tissue samples is difficult and often requires surgical procedures; thus, a less invasive sampling method is desirable. Moreover, pulmonary involvement in adult T-cell lymphoma (ATL) is often difficult to diagnose, especially in cases without characteristic flower cells. Here, we present the case of a 78-year-old man, in whom pathological examination of the transbronchial lung biopsy (TBLB) specimen did not reveal malignant findings; therefore, transbronchial lung cryobiopsy (TBLC) in combination with endobronchial ultrasonography (EBUS) was used to diagnose ATL based on the pathological findings. A literature review identified 18 cases of pulmonary lymphomas diagnosed using TBLC. Among the 19 cases, including our own, 16 cases were of B-cell lymphoma (84.2%), and the present case is the first case of ATL diagnosed using TBLC. Eighty percent of the cases underwent a biopsy (more than two samples) of the middle or lower lobe and were diagnosed without major complications. EBUS was used with TBLC in three cases to identify the location of the pulmonary lesions. In the present case, EBUS was also useful for avoiding vascular biopsy. Although large-scale prospective studies are required to establish precise guidelines for diagnosing pulmonary lymphomas using TBLC, our case report and review contributes to a deeper understanding of the diagnosis of rare diseases.
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Doenças Pulmonares Intersticiais , Neoplasias Pulmonares , Linfoma de Células T , Linfoma , Masculino , Humanos , Adulto , Idoso , Doenças Pulmonares Intersticiais/diagnóstico , Broncoscopia/métodos , Pulmão/diagnóstico por imagem , Pulmão/patologia , Biópsia/métodos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Linfoma/patologia , Linfoma de Células T/patologiaRESUMO
BACKGROUND: Cryptococcal meningitis (CM) is an opportunistic infectious disease that occurs in immunocompromised hosts, not only in patients living with HIV, but also in patients without HIV. The evidence regarding the treatment for CM in patients without HIV is mainly found in small retrospective studies and is extremely limited. OBJECTIVES: In the present study, we compared the efficacy of liposomal amphotericin B (L-AMB) alone and in combination with flucytosine (5-FC) for the induction treatment of CM in patients without HIV. PATIENTS/METHODS: Data were gathered from the Japanese Diagnosis Procedure Combination database obtained from hospitals throughout Japan. The study included 517 patients without HIV but having CM who fulfilled the inclusion and exclusion criteria. We analysed the average effect of adding 5-FC to L-AMB treatment using the survival time within 14 days of the diagnosis after adjustment of the baseline clinical characteristics with associations with both selections of the treatment and the prognosis. RESULTS: A total of 146 and 217 CM patients received L-AMB and L-AMB with 5-FC, respectively, within 7 days of diagnosis. L-AMB with 5-FC showed better prognosis than L-AMB on day 14 (mortality 6% vs. 11%, hazard ratio, 0.5775; 95% confidence interval, 0.2748-1.213; p = 0.1, Wald test). CONCLUSIONS: From the results of this real-world database study, we revealed that the combination therapy of 5-FC on L-AMB for induction therapy might have an advantage on the survival time of NHNT patients with CM as well as PLHIV patients with CM.
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Meningite Criptocócica , Anfotericina B , Antifúngicos , Quimioterapia Combinada , Flucitosina/uso terapêutico , Humanos , Meningite Criptocócica/tratamento farmacológico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
OP0595 (RG6080) is a novel diazabicyclooctane that inhibits class A and C serine beta-lactamases. Although the combination of OP0595 and cefepime (FEP) showed good in vitro activity against extended-spectrum-beta-lactamase (ESBL)-producing pathogens, the effect of the combination therapy against severe infections, such as pneumonia or bacteremia, remains unknown in vivo In this study, we investigated the efficacy and pharmacokinetics of the combination therapy of OP0595 and FEP in a mouse model of pneumonia caused by Klebsiella pneumoniae harboring SHV- and CTX-M-9-type ESBLs. The infected BALB/c mice were intraperitoneally administered saline (control), 100 mg/kg of body weight of FEP, 20 mg/kg of OP0595, or both FEP and OP0595, twice a day. The MIC of FEP against the bacteria was 8 mg/liter and markedly improved to 0.06 mg/liter with the addition of 0.5 mg/ml of OP0595. In the survival study, the combination of FEP and OP0595 significantly improved the survival rate compared with that reported with either OP0595 or FEP alone (P < 0.001). The number of bacteria in the lungs and blood significantly decreased in the combination therapy group compared to that reported for the monotherapy groups (P < 0.001). In addition, the in vivo effect depended on the dose of FEP. However, pharmacokinetic analysis revealed that the percentage of time above MIC remained constant when increasing the dose of FEP in combination with 20 mg/kg of OP0595. The results of our study demonstrated the in vivo effectiveness of the combination of OP0595 and FEP.
Assuntos
Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Compostos Azabicíclicos/farmacologia , Compostos Azabicíclicos/uso terapêutico , Cefalosporinas/farmacologia , Cefalosporinas/uso terapêutico , Lactamas/farmacologia , Lactamas/uso terapêutico , Pneumonia/tratamento farmacológico , Animais , Bacteriemia/tratamento farmacológico , Bacteriemia/microbiologia , Cefepima , Infecções por Klebsiella/tratamento farmacológico , Infecções por Klebsiella/microbiologia , Klebsiella pneumoniae/efeitos dos fármacos , Klebsiella pneumoniae/patogenicidade , Camundongos , Testes de Sensibilidade Microbiana , beta-Lactamases/genética , beta-Lactamases/metabolismoRESUMO
Background: Arbekacin is an aminoglycoside that shows strong antimicrobial activity against Gram-positive bacteria, including MRSA, as well as Pseudomonas aeruginosa . The therapeutic effectiveness of arbekacin is directly related to C max at the infection site. To maximize drug delivery to the respiratory tract and minimize the systemic toxicity, arbekacin optimized for inhalation, ME1100, is under development. In this study, we investigated the efficacy and pharmacokinetics of ME1100 in a murine model of ventilator-associated pneumonia caused by P. aeruginosa by using a customized investigational nebulizer system. Methods: The mice were treated for 5â min, once daily, with placebo, 3, 10 or 30â mg/mL ME1100 or 30â mg/mL amikacin. Results: In the survival study, the survival rate was significantly improved in the 10 and 30â mg/mL ME1100 treatment groups compared with that in the placebo group. The number of bacteria in the lungs was significantly lower in the 30â mg/mL ME1100 treatment group at 6â h after the initial treatment, compared with all other groups. In the pharmacokinetic study, the C max in the 30â mg/mL ME1100 treatment group in the epithelial lining fluid (ELF) and plasma was 31.1 and 1.2â mg/L, respectively. Furthermore, we compared the efficacy of ME1100 with that of amikacin. Although there were no significant differences in ELF and plasma concentrations between 30 mg/mL of ME1100 and 30 mg/mL of amikacin, ME1100 significantly improved the survival rate compared with amikacin. Conclusions: The results of our study demonstrated the in vivo effectiveness of ME1100 and its superiority to amikacin.
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Amicacina/uso terapêutico , Antibacterianos/uso terapêutico , Dibecacina/análogos & derivados , Pneumonia Associada à Ventilação Mecânica/tratamento farmacológico , Infecções por Pseudomonas/tratamento farmacológico , Administração por Inalação , Amicacina/administração & dosagem , Amicacina/farmacocinética , Animais , Antibacterianos/farmacocinética , Dibecacina/administração & dosagem , Dibecacina/química , Dibecacina/farmacocinética , Dibecacina/uso terapêutico , Modelos Animais de Doenças , Composição de Medicamentos , Pulmão/microbiologia , Camundongos , Testes de Sensibilidade Microbiana , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/efeitos dos fármacosRESUMO
The innate immune system plays an important role in early immunity against respiratory tract infection. Although airway epithelial cells produce mucus to eliminate pathogens and irritants, hypersecretion of mucus is harmful for the host as it may cause airway obstruction and inhibit influx of antimicrobial agents. It has been reported that several antimicrobial agents have an immunomodulatory effect in vitro and in vivo, but little is known about whether tedizolid, a novel oxazolidinone, can modulate immune responses. In this study, we evaluated whether tedizolid can suppress MUC5AC production in human airway epithelial cells stimulated by methicillin-resistant Staphylococcus aureus (MRSA). Compared with the control, tedizolid significantly inhibited MUC5AC protein production and mRNA overexpression at concentrations of both 2 and 10 µg/mL (representative of trough and peak concentrations in human epithelial lining fluid). Among the mitogen-activated protein kinase inhibitors tested, only extracellular signal-regulated protein kinase 1/2 (ERK1/2) phosphorylation was inhibited by tedizolid as indicated by western blot analysis. These results indicate that tedizolid inhibits the overproduction of MUC5AC protein by inhibiting phosphorylation of ERK1/2. This study revealed that tedizolid suppresses excessive mucin production in human airway epithelial cells. The immunomodulatory effect of tedizolid may improve outcomes in patients with severe respiratory infectious diseases caused by MRSA.
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Antibacterianos/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Mucina-5AC/biossíntese , Organofosfatos/farmacologia , Oxazóis/farmacologia , Mucosa Respiratória/microbiologia , Animais , Células Cultivadas , Meios de Cultivo Condicionados , Células Epiteliais/microbiologia , Expressão Gênica/efeitos dos fármacos , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/imunologia , Staphylococcus aureus Resistente à Meticilina/fisiologia , Camundongos , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Mucina-5AC/genética , NF-kappa B/antagonistas & inibidores , Fosforilação/efeitos dos fármacosRESUMO
Tedizolid (TZD) is a second-generation oxazolidinone and demonstrates potent in-vitro activity against multidrug-resistant Gram-positive bacteria. Phase III studies in patients with acute bacterial skin and skin structure infections (ABSSSI) have demonstrated the non-inferiority of TZD to linezolid (LZD). However, there are only a few studies that show the effect of TZD in pulmonary infections. In this study, we investigated the effect of TZD in a murine model of hematogenous pulmonary infection caused by methicillin-resistant Staphylococcus aureus (MRSA). The mice were treated either twice daily with saline (control), 25mg/kg of vancomycin (low-VAN), 110mg/kg of vancomycin (high-VAN), 120mg/kg of LZD or once daily with 20mg/kg of TZD. As compared to the control, the low- and high-VAN treatment groups, LZD and TZD significantly improved the survival rate, reduced the bacterial count in the lungs. Furthermore, TZD decreased the area of central bacterial colony zone (CBCZ) at 36h post-inoculation, compared with the control. In addition, we investigated the immunomodulatory effect of TZD by evaluating the plasma concentrations of the inflammatory cytokines. Although there were no significant differences in the bacterial count in the lungs amongst the drugs at 26h post-inoculation, TZD and LZD significantly improved the plasma concentrations of TNF-alpha, IL-6 and MIP-2, in comparison with the control. In this study, both TZD and LZD demonstrated antimicrobial and immunomodulatory efficacy in a murine model of hematogenous pulmonary infection caused by MRSA.
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Antibacterianos/administração & dosagem , Fatores Imunológicos/administração & dosagem , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Organofosfatos/administração & dosagem , Oxazóis/administração & dosagem , Pneumonia Estafilocócica/tratamento farmacológico , Animais , Antibacterianos/farmacologia , Carga Bacteriana , Citocinas/sangue , Modelos Animais de Doenças , Fatores Imunológicos/farmacologia , Pulmão/microbiologia , Masculino , Camundongos , Organofosfatos/farmacologia , Oxazóis/farmacologia , Plasma/química , Pneumonia Estafilocócica/microbiologia , Análise de Sobrevida , Resultado do TratamentoRESUMO
Patients with chronic pulmonary aspergillosis (CPA) have a poor prognosis and CPA occurs in patients with various underlying diseases. Recently, the number of patients with CPA complicated by nontuberculous mycobacteria (NTM) has increased. Additionally, complications of both diseases have several problems like drug interactions. Since the impact of NTM on the outcome of CPA is not well understood, we investigated the risk factors for developing CPA and the clinical characteristics of CPA patients with or without NTM. We retrospectively investigated the medical records of NTM and CPA patients who were admitted to Nagasaki University Hospital between April 2008 and September 2013. Comorbid diseases, causative microorganisms, radiological findings, and outcomes were evaluated. During the study period, 82 and 41 patients were diagnosed as having NTM and CPA, respectively. Nine patients were coinfected with NTM and CPA, and cavitary type NTM and steroid usage were independent risk factors of development of CPA. Mortality rates in the coinfection group were significantly higher than those of the NTM without CPA group (P = .003, log-rank test). The rate of treatment initiation in the co-infection group (33.3%) was significantly lower than in the CPA without NTM group (84.4%) (P = .006). However, there were no significant differences in cumulative survival rate between both groups (P = .760, log-rank test). Cavity formation and steroid usage were the independent risk factors for NTM patients to develop CPA within long observation period, and development of CPA made outcomes poor. It is important to diagnose the development of CPA early and initiate treatment for CPA.
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Coinfecção/patologia , Infecções por Mycobacterium não Tuberculosas/complicações , Infecções por Mycobacterium não Tuberculosas/patologia , Aspergilose Pulmonar/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Coinfecção/epidemiologia , Coinfecção/mortalidade , Feminino , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Infecções por Mycobacterium não Tuberculosas/epidemiologia , Infecções por Mycobacterium não Tuberculosas/mortalidade , Aspergilose Pulmonar/epidemiologia , Aspergilose Pulmonar/mortalidade , Estudos Retrospectivos , Fatores de Risco , Análise de SobrevidaRESUMO
Invasive aspergillosis (IA) and mucormycosis are life-threatening diseases, especially among immunocompromised patients. Drug-resistant Aspergillus fumigatus strains have been isolated worldwide, which can pose a serious clinical problem. As IA mainly occurs in patients with compromised immune systems, the ideal therapeutic approach should aim to bolster the immune system. In this study, we focused on Vγ9Vδ2 T cells that exhibit immune effector functions and examined the possibility of harnessing this unconventional T cell subset as a novel therapeutic modality for IA. A potent antifungal effect was observed when A. fumigatus (Af293) hyphae were challenged by Vγ9Vδ2 T cells derived from peripheral blood. In addition, Vγ9Vδ2 T cells exhibited antifungal activity against hyphae of all Aspergillus spp., Cunninghamella bertholletiae, and Rhizopus microsporus but not against their conidia. Furthermore, Vγ9Vδ2 T cells also exhibited antifungal activity against azole-resistant A. fumigatus, indicating that Vγ9Vδ2 T cells could be used for treating drug-resistant A. fumigatus. The antifungal activity of Vγ9Vδ2 T cells depended on cell-to-cell contact with A. fumigatus hyphae, and degranulation characterized by CD107a mobilization seems essential for this activity against A. fumigatus. Vγ9Vδ2 T cells could be developed as a novel modality for treating IA or mucormycosis. IMPORTANCE: Invasive aspergillosis (IA) and mucormycosis are often resistant to treatment with conventional antifungal agents and have a high mortality rate. Additionally, effective antifungal treatment is hindered by drug toxicity, given that both fungal and human cells are eukaryotic, and antifungal agents are also likely to act on human cells, resulting in adverse effects. Therefore, the development of novel therapeutic agents specifically targeting fungi is challenging. This study demonstrated the antifungal activity of Vγ9Vδ2 T cells against various Aspergillus spp. and several Mucorales in vitro and discussed the mechanism underlying their antifungal activity. We indicate that adoptive immunotherapy using Vγ9Vδ2 T cells may offer a new therapeutic approach to IA.
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Aspergilose , Mucormicose , Humanos , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Aspergillus fumigatus , Mucormicose/tratamento farmacológico , Aspergilose/tratamento farmacológico , Aspergilose/microbiologia , Fungos , AspergillusRESUMO
Candida vulturna is a recently discovered and not widely documented ascomycetous yeast phylogenetically related to the outbreak-causing and multidrug-resistant Candida auris. A middle-aged Japanese man with no discernible immunodeficiency was admitted to hospital with ileal diverticulitis. Following laparoscopic right hemicolectomy against abscess formation on postoperative day (POD) 7, continuous fungemia occurred due to Candida haemulonii, identified using a conventional method by confirming the biochemical phenotype. Micafungin was initiated; however, the fungus was persistently isolated from blood cultures. Eventually, the antifungal agent was changed to a combination of liposomal amphotericin B (L-AMB) and caspofungin (CPFG), which cleared the infection, and no pathogens were detected in the blood cultures on POD 31. Contrast-enhanced computed tomography showed septic emboli in the lungs and spleen; however, no evidence of vasculitis was observed. Moreover, sequential echocardiography did not reveal any signs of infectious endocarditis. Finally, CPFG and L-AMB were administered to the patient for 7 and 9 weeks, respectively, during which the patient's symptoms did not relapse. The strain was later genetically identified as C. vulturna. This case report illustrates a clinical presentation of C. vulturna and provides the diagnostic approach and treatment methods for this pathogen.
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Tuberculous meningitis is an infectious disease with high mortality. Literature describing intrathecal therapy for tuberculous meningitis is scarce. We herein report a case of refractory tuberculous meningitis in a 52-year-old woman with underlying neuropsychiatric systemic lupus erythematosus. Despite systemic treatment with anti-tuberculosis drugs and dexamethasone, her meningeal irritation deteriorated. Intrathecal isoniazid and prednisolone administration was therefore initiated, and the symptoms of severe meningeal irritation improved along with head magnetic resonance imaging and cerebrospinal fluid findings. This case report highlights the efficacy of intrathecal isoniazid and steroid injections for refractory tuberculous meningitis, particularly in patients with severe meningeal irritation.
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Vasculite Associada ao Lúpus do Sistema Nervoso Central , Tuberculose Meníngea , Feminino , Humanos , Pessoa de Meia-Idade , Isoniazida/uso terapêutico , Tuberculose Meníngea/tratamento farmacológico , Tuberculose Meníngea/diagnóstico , Antituberculosos/uso terapêutico , Prednisolona/uso terapêuticoRESUMO
BACKGROUND: Evidence regarding the association of the usage of biologic agents (Etanercept, Tocilizumab, adalimumab and so on), such as anti-tumor necrosis factor α, with the incidence and risk factors of non-tuberculous Mycobacteria (NTM) infection is limited. Therefore, this study aimed to investigate the incidence and risk factors of NTM and their associations with biologic agents' usage, and also investigated the potential of Mycobacterium avium complex (MAC) antibodies as a predictor of NTM infection development. METHODS: This retrospective study included 672 patients with autoimmune diseases from four hospitals in Nagasaki, Japan, from January 1, 2011, to June 30, 2019, who fulfilled the inclusion criteria. RESULTS: Of the 672 patients, 9 (1.3%) developed complicated NTM infection, including two with disseminated infection, after the introduction of biologic agents. Of the nine patients, two died due to NTM infection but none tested positive for MAC antibodies prior to initiation of biologic agents. The mortality rate was higher in patients complicated with NTM than without NTM (22.2% vs 2.6%, P = 0.024). The corticosteroids dosage at the time of initiating the biologic agents was significantly higher in the NTM group than in the non-NTM group (median, 17 mg vs 3 mg, P = 0.0038). CONCLUSION: In the patients undergoing therapy with biologic agents, although NTM complication was rare, it could be fatal. In particular, for patients on a relatively high dose corticosteroids, careful observation is essential for identifying NTM complication, even if the MAC antibody test is negative.
Assuntos
Artrite Reumatoide , Produtos Biológicos , Infecções por Mycobacterium não Tuberculosas , Infecção por Mycobacterium avium-intracellulare , Humanos , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Infecções por Mycobacterium não Tuberculosas/epidemiologia , Infecções por Mycobacterium não Tuberculosas/complicações , Estudos Retrospectivos , Complexo Mycobacterium avium , Micobactérias não Tuberculosas , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Infecção por Mycobacterium avium-intracellulare/epidemiologia , Fatores Biológicos/uso terapêutico , Fatores de Risco , Corticosteroides/uso terapêutico , Produtos Biológicos/efeitos adversosRESUMO
Allergic bronchopulmonary aspergillosis (ABPA) and chronic pulmonary aspergillosis (CPA) are diseases caused by Aspergillus infection, and CPA can develop from ABPA in some cases. We herein report a patient with CPA overlapping with ABPA. Serum cytokine levels were evaluated at 4 time points: the ABPA diagnosis, CPA diagnosis, 6 months after the start of voriconazole (VRCZ), and 12 months after re-administration of VRCZ. Interleukin (IL)-13 levels decreased upon glucocorticoid treatment, whereas IL-25 and IL-33 levels decreased rapidly with the initiation of antifungals. Early antifungal therapy may be important to control disease progression and prevent CPA overlap.
RESUMO
Outbreaks of invasive infections, with high mortality rates, caused by multidrug-resistant Candida auris have been reported worldwide. Although hotspot mutations in FKS1 are an established cause of echinocandin resistance, the actual contribution of these mutations to echinocandin resistance remains unknown. Here, we sequenced the FKS1 gene of a caspofungin-resistant clinical isolate (clade I) and identified a novel resistance mutation (G4061A inducing R1354H). We applied the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system to generate a recovered strain (H1354R) in which only this single nucleotide mutation was reverted to its wild-type sequence. We also generated mutant strains with only the R1354H mutation introduced into C. auris wild-type strains (clade I and II) and analyzed their antifungal susceptibility. Compared to their parental strains, the R1354H mutants exhibited a 4- to 16-fold increase in caspofungin minimum inhibitory concentration (MIC) while the H1354R reverted strain exhibited a 4-fold decrease in caspofungin MIC. In a mouse model of disseminated candidiasis, the in vivo therapeutic effect of caspofungin was more closely related to the FKS1 R1354H mutation and the virulence of the strain than its in vitro MIC. The CRISPR-Cas9 system could thus aid in elucidating the mechanism underlying drug resistance in C. auris.