High efficacy of the F-ATP synthase inhibitor TBAJ-5307 against nontuberculous mycobacteria in vitro and in vivo.

The F1FO-ATP synthase engine is essential for viability and growth of nontuberculous mycobacteria (NTM) by providing the biological energy ATP and keeping ATP homeostasis under hypoxic stress conditions. Here, we report the discovery of the diarylquinoline TBAJ-5307 as a broad spectrum anti-NTM inhibitor, targeting the FO domain of the engine and preventing rotation and proton translocation. TBAJ-5307 is active at low nanomolar concentrations against fast- and slow-growing NTM as well as clinical isolates by depleting intrabacterial ATP. As demonstrated for the fast grower Mycobacterium abscessus, the compound is potent in vitro and in vivo, without inducing toxicity. Combining TBAJ-5307 with anti-NTM antibiotics or the oral tebipenem-avibactam pair showed attractive potentiation. Furthermore, the TBAJ-5307-tebipenem-avibactam cocktail kills the pathogen, suggesting a novel oral combination for the treatment of NTM lung infections.

Characteristics and Outcomes of Anti-interferon Gamma Antibody-Associated Adult Onset Immunodeficiency.

PURPOSE: Anti-interferon gamma antibody (AIGA) is a rare cause of adult onset immunodeficiency, leading to severe disseminated opportunistic infections with varying outcomes. We aimed to summarize the disease characteristics and to explore factors associated with disease outcome. METHODS: A systematic literature review of AIGA associated disease was conducted. Serum-positive cases with detailed clinical presentations, treatment protocols, and outcomes were included. The patients were categorized into controlled and uncontrolled groups based on their documented clinical outcome. Factors associated with disease outcome were analyzed with logistic regression models. RESULTS: A total of 195 AIGA patients were retrospectively analyzed, with 119(61.0%) having controlled disease and 76 (39.0%) having uncontrolled disease. The median time to diagnosis and disease course were 12 months and 28 months, respectively. A total of 358 pathogens have been reported with nontubercular mycobacterium (NTM) and Talaromyces marneffei as the most common pathogens. The recurrence rate was as high as 56.0%. The effective rates of antibiotics alone, antibiotics with rituximab, and antibiotics with cyclophosphamide were 40.5%, 73.5%, and 75%, respectively. In the multivariate logistic analysis, skin involvement, NTM infection, and recurrent infections remained significantly associated with disease control, with ORs of 3.25 (95% CI 1.187 ~ 8.909, P value = 0.022), 4.74 (95% CI 1.300 ~ 17.30, P value = 0.018), and 0.22 (95% CI 0.086 ~ 0.551, P value = 0.001), respectively. The patients with disease control had significant AIGA titer reduction. CONCLUSIONS: AIGA could cause severe opportunistic infections with unsatisfactory control, particularly in patients with recurrent infections. Efforts should be made to closely monitor the disease and regulate the immune system.

Attenuated heme oxygenase-1 responses predispose the elderly to pulmonary nontuberculous mycobacterial infections.

Pulmonary infections with nontuberculous mycobacteria (P-NTM), such as by Mycobacterium avium complex (M. avium), are increasingly found in the elderly, but the underlying mechanisms are unclear. Recent studies suggest that adaptive immunity is necessary, but not sufficient, for host defense against mycobacteria. Heme oxygenase-1 (HO-1) has been recognized as a critical modulator of granuloma formation and programmed cell death in mycobacterial infections. Old mice (18-21 mo) infected with M. avium had attenuated HO-1 response with diffuse inflammation, high burden of mycobacteria, poor granuloma formation, and decreased survival (45%), while young mice (4-6 mo) showed tight, well-defined granuloma, increased HO-1 expression, and increased survival (95%). To further test the role of HO-1 in increased susceptibility to P-NTM infections in the elderly, we used old and young HO-1+/+ and HO-1-/- mice. The transcriptional modulation of the JAK/STAT signaling pathway in HO-1-/- mice due to M. avium infection demonstrated similarities to infected wild-type old mice with upregulation of SOCS3 and inhibition of Bcl2. Higher expression of SOCS3 with downregulation of Bcl2 resulted in higher macrophage death via cellular necrosis. Finally, peripheral blood monocytes (PBMCs) from elderly patients with P-NTM also demonstrated attenuated HO-1 responses after M. avium stimulation and increased cell death due to cellular necrosis (9.69% ± 2.02) compared with apoptosis (4.75% ± 0.98). The augmented risk for P-NTM in the elderly is due, in part, to attenuated HO-1 responses, subsequent upregulation of SOCS3, and inhibition of Bcl2, leading to programmed cell death of macrophages, and sustained infection.

Mycobacterium chelonae-abscessus Complex Infection After Flatfoot Reconstruction.

Mycobacterium infections involving tuberculosis in the foot are rare but cases are readily available in published studies. Atypical or nontuberculosis mycobacterium foot infections are rare, especially those involving the soft tissue and bone, and have been infrequently reported. To date, no case reports involving atypical mycobacterium infection after elective foot surgery have been reported. We present the case of a 49-year-old female who underwent flatfoot reconstruction, with a resultant Mycobacterium chelonae-abscessus infection and osteomyelitis postoperatively. The patient ultimately underwent hardware removal with multiple debridements. The patient was treated ultimately with a 6-week course of intravenous antibiotics and 5 months of oral antibiotics for the mycobacterium infection and osteomyelitis. At the last follow-up examination, the patient remained healed with a satisfactory outcome. We also provide a literature review of mycobacterium infections in the foot.

Gastroesophageal Reflux Disease Increases Susceptibility to Nontuberculous Mycobacterial Pulmonary Disease.

BACKGROUND: Gastroesophageal reflux disease (GERD) is a common comorbidity of nontuberculous mycobacteria (NTM) pulmonary disease (PD). Although GERD is associated with more symptoms and severe disease in patients with NTM PD, whether GERD is associated with an increased risk of NTM PD developing is unknown. RESEARCH QUESTION: Does GERD influence the development of NTM PD? Are there any factors associated with an increased risk of NTM PD among patients with GERD? What is the impact of NTM PD on the health-care use of patients with GERD? STUDY DESIGN AND METHODS: Data from the Korean National Health Insurance Service National Sample Cohort between 2002 and 2015 were used. The incidence and risk of NTM PD were compared between patients with GERD (GERD cohort; n = 17,424) and patients matched for age, sex, type of insurance, and Charlson Comorbidity Index (matched cohort; n = 69,696). Using the GERD cohort, the factors associated with incident NTM PD also were evaluated. RESULTS: During a median follow-up duration of 5.1 years, the age- and sex-adjusted incidence of NTM PD was significantly higher in the GERD cohort (34.8 per 100,000 person-years [PY]) than in the matched cohort (10.5 per 100,000 PY; P < .001), with a subdistribution hazard ratio (HR) of 3.36 (95% CI, 2.10-5.37). Regarding risk factors associated with NTM PD, age of 60 years or older (adjusted HR, 3.57; 95% CI, 1.58-8.07) and bronchiectasis (adjusted HR, 18.69; 95% CI, 6.68-52.28) were associated with an increased risk of incident NTM PD in the GERD cohort. Compared with patients with GERD who did not demonstrate NTM PD, those with NTM PD showed higher all-cause (13,321 PY vs 5,932 PY; P = .049) and respiratory disease-related (5,403 vs 801; P = .011) ED visits or hospitalizations. INTERPRETATION: GERD is associated with an increased incidence of NTM PD. Older age and bronchiectasis are risk factors for NTM PD in patients with GERD. NTM PD in patients with GERD is associated with increased health-care use.

A Two-Step Real-Time PCR Method To Identify Mycobacterium tuberculosis Infections and Six Dominant Nontuberculous Mycobacterial Infections from Clinical Specimens.

Tuberculosis (TB) is an ongoing threat to public health, and furthermore, the incidence of infections by nontuberculous mycobacteria (NTM), whose symptoms are not distinguishable from TB, is increasing globally, thus indicating a need for accurate diagnostics for patients with suspected mycobacterial infections. Such diagnostic strategies need to include two steps, (i) detecting the mycobacterial infections and, if the case is an NTM infection, (ii) identifying the causative NTM pathogen. To eliminate a false-positive TB diagnosis for a host vaccinated by the bacillus Calmette-Guérin (BCG) strain of Mycobacterium bovis, a new target specific for M. tuberculosis species was selected, together with the species-specific targets for the six dominant NTM species of clinical importance, i.e., M. intracellulare, M. avium, M. kansasii, M. massiliense, M. abscessus, and M. fortuitum. Using sets of primers and probes, a two-step real-time multiplex PCR method was designed. The diagnostic performance was assessed by using a total of 1,772 clinical specimens from patients with suspected TB or NTM infection. A total of 69.4% of M. tuberculosis and 28.8% of NTM infections were positive for the primary step of the real-time PCR corresponding to the culture within 10 weeks, and mycobacterial species of 75.5% of the NTM-positive cases were identified by the secondary step. The two-step method described herein presented promising results and similar diagnostic sensitivity and specificity to commercially available real-time PCR kits for detecting TB and NTM infections. The method also enabled the identification of mycobacterial species in three-quarters of NTM infection cases, thus providing a better treatment strategy. IMPORTANCE Tuberculosis (TB) is an ongoing threat to public health. In addition, infection by nontuberculous mycobacteria (NTM) is a nonnegligible issue for global public health, with increasing incidences. Since the antimicrobial treatment strategy needs to be differed by the causative pathogen, a rapid and accurate diagnostic method is necessary. In this study, we developed a two-step molecular diagnostic method using clinical specimens of TB and NTM infection-suspected patients. The diagnostic power of the new method using the novel target was similar to the widely used TB detection kit, and, among the NTM-positive specimens, three-quarters of the NTM species were able to be identified. This simple and powerful method will be useful as it is, and it could be applied easily to a point-of-care diagnostic apparatus for better application to patients, especially those living in developing countries.

Non-Tuberculosis Mycobacterium Periprosthetic Joint Infections Following Total Hip and Knee Arthroplasty: Case Series and Review of the Literature.

OBJECTIVE: Periprosthetic joint infection (PJI) caused by non-tubercular mycobacteria (NTM) is uncommon but catastrophic. However, conclusive clinical data on PJI caused by NTM are lacking. In this case series and systematic review, the clinical manifestations, diagnosis, and management of NTM PJI are summarized and analyzed. METHODS: From 2012 to 2020, we retrospectively analyzed consecutive PJI cases caused by NTM in our institution. A literature review was also conducted from January 2000 to December 2021, utilizing the PubMed, MEDLINE, Cochrane Library, and EMBASE databases to identify all reported NTM-induced PJI cases. The clinical characteristics, demographics, pathogen identification, treatment protocols, and prognosis of NTM PJI were summarized and analyzed. RESULTS: In this retrospective analysis, seven patients infected with NTM following total joint arthroplasty at our institution were included, including six cases of PJI caused by NTM and one case of septic arthritis (SA) caused by NTM. There were six men and one woman, and their average age was 62.3 years. The average interval between TJA and PJI onset was 4 months. The preoperative serological markers, including the mean ESR (51 mm/h), CRP (4.0 mg/dL), fibrinogen (5.7 g/L), and D-dimer (1.1 g/L), were increased. Six patients underwent staged revision surgery, and one patient with SA received antibiotic-loaded bone cement beads to treat the infection. After an average of 33 months of observation following surgical intervention, none of the patients showed any symptoms of infection recurrence. From 2000 to 2021, 68 patients with NTM PJI were found in 39 studies in the published literature. Reinfections occurred within 1 year after arthroplasty in more than half (53.2%) of the patients. M. fortuitum and M. abscesses were the most prevalent rapidly growing mycobacteria (RGM) in all PJI patients, whereas Mycobacterium avium intracellulare (MAC) was the most prevalent slowly growing mycobacterium (SGM). The corresponding antibiotics were amikacin and ethambutol. The rate of culture-negative without specific clinical symptoms was as high as 36.4% (12/33), while 45% (18/40) utilized additional diagnostic techniques such as NGS. A final clinical follow-up record was available for 59 patients (86.7%; mean follow-up period, 29 months), and 10.1% of patients failed to respond to treatment. CONCLUSION: Orthopaedic surgeons should consider NTM in patients with negative routine cultures who are at risk for Mycobacterium infection. Treatment options rely on the accurate result of microbiologic identification and drug sensitivity testing, and to achieve this, it may be necessary to send multiple culture specimens, extend the culture time, and change the culture medium. Every effort should be made to identify NTM and its various subtypes through modern diagnostic tools if necessary.

Orbital and conjunctival nontuberculous mycobacteria infection.

A 64-year-old female developed refractory red-eye with itching and watery discharge 2 weeks after being injured by a comb in the left eye. It presented as diffuse pinkish thickening of the bulbar conjunctiva. Biopsy and histological examinations revealed granulomatous inflammation with microgranuloma. Acid-fast-positive bacilli were found within the tissue, which was identified by culture 5 weeks later as Mycobacterium Abscessus. The orbital computed tomography with contrast medium showed irregular enhancement with an ill-defined margin along the inferior sclera. Due to symptomatic and recurrent bulbar conjunctival thickening and abscess-like lesion formations, wide excision of the conjunctival and orbital granuloma with amniotic membrane transplantation was performed twice. Conjunctiva inflammation subsided after the surgical treatment was combined with 4 months of topical and parenteral antimycobacterial treatment. The presentation, diagnosis, and treatment of ocular nontuberculous mycobacterial (NTM) infection will be discussed in this article. NTM can cause infections of all adnexal and ocular tissues in patients with ocular trauma or surgical history. The pathological findings were granulomatous inflammation without true caseating. Periocular cutaneous, adnexal, and orbital NTM infections remain rare and require surgical debridement and long-term parenteral antibiotic therapy.

Follow-up of 1887 patients receiving tumor necrosis-alpha antagonists: Tuberculin skin test conversion and tuberculosis risk.

OBJECTIVES: To evaluate the characteristics of patients who developed tuberculosis while receiving tumor necrosis factor-alpha (TNF-α) antagonists and the related factors with tuberculosis. METHODS: Patient's demographics, tuberculin skin test (TST), isoniazid prophylaxis and type of TNF-α antagonist were recorded. TST conversion (≥5 mm increase) was evaluated for patients who had baseline and 1-year TST. RESULTS: Files of 1887 patients who were receiving TNF-α antagonists between August 2005 and June 2015 were evaluated. TST significantly increased at the end of 1 year (n = 748 baseline:7.36 ± 7.2 mm vs. 1 year:9.52 ± 7.5 mm, P < 0.001). One-third of patients (31.2%) who had negative TST at baseline had positive TST at 1 year. Tuberculosis developed in 22 patients (1.16%). The annual incidence of tuberculosis was 423/100 000 patient-year. TNF-α antagonist indications were ankylosing spondylitis (n = 8), inflammatory bovel diseases (n = 7) and rheumatoid arthritis (n = 4). Ten (45.5%) patients received infliximab, six (27.3%) patients received etanercept and six (27.3%) patients received adalimumab. Nineteen (86.4%) patients were under isoniazid prophylaxis. Twelve patients had extrapulmonary tuberculosis (54.5%; four lymph node, three pleura, two periton, one pericarditis, one intestinal, one joint). Atypical mycobacterium was detected in one patient. Adalimumab treatment (9.5× increase), male sex (15.6× increase) and previous tuberculosis disease history (11.5× increase) were risk factors for active tuberculosis. Conversion of TST was not found related with tuberculosis. CONCLUSIONS: Despite the high proportion of isoniazid prophylaxis, the incidence of tuberculosis in our patients receiving TNF-α antagonist was higher than the literature. Adalimumab treatment, male sex and previous tuberculosis disease history were found as risk factors for tuberculosis.