Clinical Significance, Species Distribution, and Temporal Trends of Nontuberculous Mycobacteria, Denmark, 1991-2022.

Nontuberculous mycobacteria (NTM) are emerging as notable causative agents of opportunistic infections. To examine clinical significance, species distribution, and temporal trends of NTM in Denmark, we performed a nationwide register-based study of all unique persons with NTM isolated in the country during 1991-2022. We categorized patients as having definite disease, possible disease, or isolation by using a previously validated method. The incidence of pulmonary NTM increased throughout the study period, in contrast to earlier findings. Mycobacterium malmoense, M. kansasii, M. szulgai, and M. avium complex were the most clinically significant species based on microbiologic findings; M. avium dominated in incidence. This study shows the need for surveillance for an emerging infection that is not notifiable in most countries, provides evidence to support clinical decision-making, and highlights the importance of not considering NTM as a single entity.

Drug-Resistant Tuberculosis, Georgia, Kazakhstan, Kyrgyzstan, Moldova, and Ukraine, 2017-2022.

In 2021, the World Health Organization recommended new extensively drug-resistant (XDR) and pre-XDR tuberculosis (TB) definitions. In a recent cohort of TB patients in Eastern Europe, we show that XDR TB as currently defined is associated with exceptionally poor treatment outcomes, considerably worse than for the former definition (31% vs. 54% treatment success).

Lung abscess: an update on the current knowledge and call for future investigations.

PURPOSE OF REVIEW: Lung abscess is a severe and complex respiratory infection. The purpose of this review is to discuss recent publications on lung abscess, covering topics such as epidemiology, clinical presentation, diagnosis, and treatment and prevention. RECENT FINDINGS: Risk factors associated with lung abscess include structural lung disease, poor dental hygiene, and ventilator-associated pneumonia, while concerns are now raised regarding the potential of electronic cigarettes use as a risk factor. The complexity of lung abscess is reflected by the relative high number of case reports describing rare and complex cases. Early transthoracic drainage could improve in-hospital outcomes, while next-generation sequencing could become an important tool in diagnostics and future clinical studies. SUMMARY: High-quality evidence and guidelines to support treatment of lung abscess are lacking. Despite advancements, we call for prospective studies to evaluate the use of invasive procedures and antibiotic treatment regimens.

Efficacy and Tolerability of Concomitant Use of Bedaquiline and Delamanid for Multidrug- and Extensively Drug-Resistant Tuberculosis: A Systematic Review and Meta-Analysis.

The introduction of two novel drugs, bedaquiline and delamanid, has given hope for better and shorter treatments of drug-resistant tuberculosis. A systematic review was conducted to evaluate the efficacy and safety of concomitant bedaquiline and delamanid administration. Pooled estimates of World Health Organization-defined favorable treatment outcome and significant QTc-interval prolongation (QTc ≥500 ms or ≥60 ms increase from baseline) were calculated using a random-effects model. Thirteen studies including a total of 1031 individuals with multidrug-resistant/rifampicin-resistant tuberculosis who received bedaquiline and delamanid were included. The pooled estimate of favorable treatment outcome was 73.1% (95% confidence interval [CI]: 64.3-81.8%). Sputum culture conversion at 6 months ranged from 61% to 95%. Overall, the pooled proportion of QTc-prolongation was 7.8% (95% CI: 4.1-11.6%) and few cardiac events were reported (0.8%; n = 6/798). Rates of sputum culture conversion and favorable treatment outcome were high in patients treated concomitantly with bedaquiline and delamanid, and the treatment seemed tolerable with low rates of clinically significant cardiac toxicity.

Clinical spectrum and relevance of Mycobacterium malmoense: Systematic review and meta-analysis of 859 patients.

INTRODUCTION: The clinical relevance of Mycobacterium malmoense isolation from pulmonary specimens has been considered high compared with other non-tuberculous mycobacteria. In this study, we aimed to analyse all published clinical data of patients with M. malmoense isolation to investigate the clinical spectrum, relevance, and outcomes of infections with this uncommon mycobacterium. METHODS: A systematic review of PubMed, Web of Science, Embase, and Scopus was performed to identify all clinical data about M. malmoense. Random effects meta-analyses of proportions were calculated for clinical relevance, treatment success, and mortality, as well as for other clinical characteristics. A logistic regression analysis, investigating predictors of mortality, as well as Kaplan-Meier survival analyses, were performed. RESULTS: One hundred and eighty eight patients with individual data from 112 articles and 671 patients with pooled data from 12 articles were included in the meta-analyses. Of patients with individual data, pulmonary infection was the most common manifestation (n = 106/188, 56.4%). One third (n = 61/188, 32.4%) suffered from isolated extra-pulmonary and 21/188 (11.2%) from disseminated disease. In 288 patients with pooled data and pulmonary affection, clinical relevance was high with 68% (95% CI 44-85%) of patients fulfilling criteria for clinical disease. Macrolide and rifamycin-containing regimens were associated with improved survival (adjusted OR 0.12, 95% CI 0.03-0.42, p = 0.002, and 0.23, 95% CI 0.04-0.86, p = 0.03, for lethal events, respectively). CONCLUSION: In this study, we provide a detailed clinical description of M. malmoense infections. The pathogen is of high clinical relevance for the individual patient with more than 2 out of 3 patients having relevant disease and >40% of manifestations being extra-pulmonary or disseminated. Macrolide and rifamycin-containing regimens are associated with improved survival.

Pulmonary infections with nontuberculous mycobacteria.

This review focuses on the treatment of nontuberculous pulmonary disease caused by Mycobacterium avium complex and M. abscessus. It covers treatment indications, antibiotic choice, resistance and side effects. Treatment of nontuberculous pulmonary disease is complex, lengthy, and fraught with side effects. Increased attention on this disease is needed in order to alleviate the severe consequences of this growing disease. Cooperation between pulmonologists and infectious disease specialists is needed to ensure uniform treatment, and to account for the heterogeneity seen in patients and mycobacteria alike.

The role of whole genome sequencing in identifying occupational tuberculosis among healthcare workers: two case reports.

In this case report, we present case reports for two nurses, both working in departments of respiratory medicine, who developed tuberculosis (TB). For each individual case, whole genome sequencing (WGS) revealed only one specific match within a genomic distance of <6 single-nucleotide polymorphisms. The subsequent epidemiological investigations confirmed that both nurses had relevant exposures to their corresponding match 1139 and 1704 days before presenting with TB symptoms, respectively. Twenty-two studies were identified that reported using genotyping to identify occupational transmission of Mycobacterium tuberculosis to healthcare workers. Only two studies applied WGS, both conducted in resource-rich countries, comparable to the present Danish investigation. When comparing the two WGS studies to the other studies that used older genotyping techniques, WGS provided a higher resolution and much more detailed information. Consequently, the epidemiological investigations were more straightforward. In conclusion, WGS is a powerful tool for determining whether M. tuberculosis transmission is occupational as demonstrated for the two cases in this study.

Incidence and clinical significance of non-tuberculous mycobacteria among migrants in Denmark: A nationwide register-based cohort study from 1991 through 2021.

BACKGROUND: There is limited knowledge about non-tuberculous mycobacteria (NTM) infections in migrants. We aimed to assess the incidence and clinical significance of NTM among migrants in Denmark. METHOD: Nationwide register-based cohort study of migrants with a positive NTM culture in Denmark from 1991 through 2021, stratified by patient demographics, disease localisation, species, and clinical significance. RESULTS: 433 migrants had a positive NTM culture, resulting in an overall incidence rate (IR) of 3.7 (95%CI 3.3-4.0) per 100,000 migrants. Overall NTM IRs for definite disease were 1.0 (95%CI 0.9-1.2), possible disease 1.0 (95%CI 0.8-1.2), and isolation 1.7 (95%CI 1.4-1.9) per 100,000 migrants. Migrants had considerably higher age- and sex-adjusted NTM IRs of positive cultures (incidence rate ratio [IRR] = 2.1, 95%CI 1.9-2.3, p < 0.001), possible disease (IRR = 2.4, 95%CI 2.0-3.0, p < 0.001), and isolation (IRR = 4.6, 95%CI 3.9-5.4, p < 0.001) compared to Danish-born, but not of definite disease (IRR = 1.1, 95%CI 0.9-1.3, p = 0.562). IRs of migrants with positive NTM cultures did not increase over time (-0.8 %/year, p = 0.133). CONCLUSIONS: Migrants have a higher, but stable, burden of NTM compared with Danish-born. The higher rates likely reflect that more specimens are examined for Mycobacterium tuberculosis. Microbiologically classified definite NTM disease is not substantially more common among migrants.

Drug-resistant tuberculosis is a global cause of concern.

The number of patients with drug-resistant tuberculosis (DR-TB) is increasing worldwide. This review summarises the global epidemiology of DR-TB and current treatment challenges. Luckily, novel regimens comprising bedaquiline, pretomanid, linezolid, and moxifloxacin have seemingly mitigated the global threat posed by DR-TB. However, emerging resistance against bedaquiline and pretomanid, among other factors, persists as ongoing concerns in the global fight against DR-TB. While the new regimens are groundbreaking, the sustained development of novel drugs targeting the most resistant forms of tuberculosis is of utmost importance for future efforts against DR-TB.

Treatment outcomes and risk factors for an unsuccessful outcome among patients with highly drug-resistant tuberculosis in Ukraine.

OBJECTIVES: To describe demographics, clinical features, and treatment outcomes of patients with highly drug-resistant tuberculosis (TB) in Ukraine, and to evaluate risk factors for an unsuccessful outcome. METHODS: Data from patients with multi-, pre-extensively, or extensively drug-resistant TB were collected prospectively from TB dispensaries in 15 out of 24 Ukrainian oblasts (regions) from 2020 to 2021. Treatment outcomes were evaluated using WHO definitions. Risk factors for an unsuccessful outcome were identified using a multivariable logistic regression model. RESULTS: Among 1748 patients, the overall proportion of successful outcomes was 58% (95% confidence interval [95% CI] 56-60) (n = 1015/1748), ranging from 65% (95% CI: 62-69) (n = 531/814) for multidrug-resistant TB to 54% (95% CI: 49-58) (n = 301/563) for pre-extensively drug-resistant TB and 49% (95% CI: 44-55) (n = 183/371) for extensively drug-resistant TB. Results were similar across oblasts, with few exceptions. The strongest risk factors for an unsuccessful outcome were extensively drug-resistant TB (adjusted OR [aOR] 3.23; 95% CI: 1.88-5.53), total serum protein below 62 g/L in adults and below 57 g/L for children and adolescents (aOR 2.79; 95% CI: 1.93-4.04), psychiatric illness (aOR 2.79; 95% CI: 1.46-5.33), age at TB diagnosis >65 years (aOR 2.50; 95% CI: 1.42-4.42), and alcohol misuse (aOR 2.48; 95% CI: 1.89-3.26). DISCUSSION: The overall proportion of successful outcomes among Ukrainians treated for highly drug-resistant TB was 58%, notably better compared with previous years, but still low for extensively drug-resistant TB. Risk factors for unsuccessful outcomes highlight that addressing socioeconomic factors in TB management is crucial. Efforts in maintaining TB dispensaries during and following the ongoing war are highly warranted.

Nontuberculous mycobacterial infections in a Danish region between 2011 and 2021: evaluation of trends in diagnostic codes.

INTRODUCTION: Nontuberculous mycobacteria (NTM) are emerging as human pathogens at increasing rates. In Denmark, few studies of NTM exist, but these have not been able to confirm an increasing trend. Existing studies have not utilised clinical data or investigated geographical variations. METHODS: A retrospective cohort study of patients with an ICD-10 diagnostic code of NTM infection in a Danish region, Central Denmark Region, between 2011 and 2021. Incidence rates per 100,000 citizens were calculated using data from Statistics Denmark. A Spearman's rank correlation coefficient was computed to assess the linear relationship between years and annual incidence rates. RESULTS: We identified 265 patients, 53.2% (n = 141) females, with a median age of 65.0 years (IQR 47-74). The age distribution was bimodal with peaks in extreme age groups between 0-14 years of age (n = 35, 13.2%) and above 74 years (n = 63, 23.8%). Most patients were coded with a pulmonary infection (51.3%, n = 136), 35.1% (n = 93) with other/unspecified infection and 13.6% (n = 36) with a skin infection. Incidence rates ranged from 1.3 (2013) to 2.5 (2021) per 100,000 citizens. There was a highly positive linear correlation of NTM incidence rates over the years (r = 0.75, p = 0.010) suggesting an increasing trend. CONCLUSION: More than one-third with an NTM infection based on ICD-10 codes were found in extreme age groups. At least half of the patients had a pulmonary infection. Contradicting previous data from Denmark, we found an increasing trend of NTM, potentially suggesting an increase in clinically relevant disease, a higher awareness and test rate, or improved coding.

Mycobacterium marinum: A Challenging Cause of Protracted Tenosynovitis.

Mycobacterium marinum infections are rare, and they can be difficult to diagnose and treat. This may lead to further spread of the infection and complications, such as tenosynovitis, pyomyositis, and osteomyelitis. A 40-year-old previously healthy man presented with tenosynovitis of the extensor tendons on the second phalanx of his right hand. He was initially treated with steroid injections without any effect. Followingly, ulceration and an abscess developed on the dorsal site of the hand. At this point, it came to the physician's knowledge that the patient had been cleaning an aquarium before onset of symptoms. After progression to massive tenosynovitis, the patient was admitted and underwent multiple surgical debridements. Briefly, after the first surgery, an interferon-γ release assay was positive, and treatment for M. marinum with rifampicin and azithromycin was initiated after eight months of symptoms. Later, a surgical biopsy showed acid-fast bacilli, and a polymerase chain reaction confirmed the diagnosis of M. marinum. In this case story, we highlight the difficulties of diagnosing and managing this complicated infection, describe the considerable morbidity associated with it, and suggest that local tissue concentrations could be useful to improve clinical outcomes, as these concentrations are potentially suboptimal.

Disseminated Mycobacterium genavense infection in a patient with a history of sarcoidosis.

We present a case of Mycobacterium genavense infection in a man in his 60s with a history of sarcoidosis, treated for 24 years with systemic corticosteroids and later methotrexate as monotherapy. He presented with low grade fever, dyspnoea and right-sided thoracic pain and was admitted due to a treatment-refractory infection. After a prolonged period of symptoms and diagnostics, acid-fast bacilli were demonstrated in pleural fluid and PCR revealed M. genavense The patient was treated with intravenous amikacin, peroral azithromycin, rifampicin and ethambutol for a total of 18 months, with a good clinical and radiological treatment response. Infection with M. genavense is rare in HIV-negative immunocompromised hosts. Diagnosing and treating mycobacterial infections, especially for more rare species, remains a challenge as clinical evidence is sparse. Nonetheless, the disease-causing infection must be considered in symptomatic and immunocompromised patients.

The In vitro activity of carbapenems alone and in combination with ß-lactamase inhibitors against difficult-to-treat mycobacteria; Mycobacterium tuberculosis, Mycobacterium abscessus, and Mycobacterium avium complex: A systematic review.

Difficult-to-treat mycobacterial infections are increasing globally. There is an urgent need of new treatment alternatives for multidrug-resistant Mycobacterium tuberculosis (MTB), as well as nontuberculous mycobacteria such as the Mycobacterium abscessus complex (MABC) and Mycobacterium avium complex (MAC). Recently, new carbapenems and combinations of carbapenems with ß-lactamase inhibitors have become available, but activity data in vitro against mycobacteria are so far scarce. Therefore, we performed a systematic review collating the minimum inhibitory concentrations (MICs) of carbapenems, with or without a ß-lactamase inhibitors for MTB, MABC, and MAC. The databases PubMed and Web of Science were searched for the relevant articles in English up until September 21, 2022. Screening of studies was performed by two independent reviewers. MIC data by recommended methods with at least five individual MICs were included. Data were reported as MIC range, MIC50, modal MIC, and/or histograms when individual MICs were available. The study protocol was registered at PROSPERO (CRD42021258537). After screening, a total of 75 studies with MIC data for carbapenems with or without ß-lactamase inhibitors were included in the review. For MTB, the oral carbapenem tebipenem combined with the ß-lactamase inhibitor clavulanic acid resulted in the most significant reduction of MICs. For MABC, the addition of avibactam to tebipenem resulted in a 64-fold reduction of modal MIC. Data were insufficient for the analysis of MAC. Carbapenems, and in particular the novel oral compound tebipenem, in combination with clavulanic acid for MTB and avibactam for MABC may be an untapped potential for difficult-to-treat mycobacterial infections.

Lung abscess: Clinical characteristics of 222 Danish patients diagnosed from 2016 to 2021.

INTRODUCTION: Lung abscess (LA) is a serious respiratory infection often followed by several weeks of antibiotic treatment. This study described the clinical presentation of LA, treatment duration and mortality in a contemporary Danish population. METHODS: In a retrospective multicenter cohort study at four Danish hospitals, patients diagnosed with LA were identified using the International Classification of Diseases and Related Health Problems 10th revision (ICD-10) between 2016 and 2021. A predefined data collection tool was used to extract data on demographics, symptoms, clinical findings and treatment. RESULTS: Of 302 patients, 222 with LA were included after review of patient records (76%). Mean age was 65 years (54-74), 62.9% was male and 74.9% were ever-smokers. Chronic obstructive pulmonary disease (COPD) (35.1%), use of sedatives (29.3%) and alcohol abuse (21.8%) were common risk factors. Dental status was reported in 51.4%, whereof 41.6% had poor dental status. Patients presented with cough (78.8%), malaise (61.3%) and fever (56.8%) Patients were hospitalized for a median of 14 days (interquartile ranges, IQR 7-21) and median duration of antibiotic treatment was 38 days (IQR 30-51). All-cause mortality after 1, 3 and 12 months was 2.7%, 7.7% and 15.8%, respectively. CONCLUSION: Risk factors for LA include COPD and use of sedatives, alcohol abuse, and poor dental status. Despite long-term antibiotic treatment, long-term mortality is markedly high.

Global treatment outcomes of extensively drug-resistant tuberculosis in adults: A systematic review and meta-analysis.

INTRODUCTION: Historically, extensively drug-resistant tuberculosis has been notoriously difficult to treat with devasting outcomes. As we are coming to the end of an era where the 2006 extensively drug-resistant tuberculosis definitions and old treatment regimens are being replaced, we aimed to estimate the proportion of extensively drug-resistant tuberculosis patients globally who achieved successful treatment outcomes. METHODS: We conducted a systematic review of PubMed/MEDLINE, Scopus, Web of Science, and Embase from January 1, 2005, through April 3, 2023. Included studies reported WHO treatment outcomes, or adaptions hereof, for pre-extensively and/or extensively drug-resistant tuberculosis patients according to the 2006 WHO definition. Eligible studies included cohorts of at least 10 adults (aged>18 years) that were not pregnant. Using a random-effects model, we calculated pooled proportions of treatment outcomes and performed sensitivity and subgroup analyses. PROSPERO registration number: CRD42022340961. RESULTS: Among 5056 studies reviewed, we identified 94 studies from 26 countries, involving 10,223 extensively drug-resistant tuberculosis patients. The pooled proportion of successful treatment outcomes was 44.2% (95%CI: 38.3-50.3). Sensitivity analyses consistently produced similar estimates. A slight improvement in treatment outcomes was observed after 2013. Furthermore, 25 studies reported outcomes for 3564 individuals with pre-extensively drug-resistant tuberculosis, of which 63.3% achieved successful treatment (95%CI: 43.1-72.5). CONCLUSION: Globally, the success rate of extensively drug-resistant tuberculosis treatment is 44.2%, far below the WHO's target rate of 75%. These results may serve as a reference for future studies assessing extensively drug-resistant tuberculosis treatment outcomes under the 2021 definition treated with better treatment regimens available. Comprehensive surveillance data of extensively drug-resistant tuberculosis outcomes from the whole world are desirable to monitor treatment progress.

[Cocaine-induced asthma exacerbation].

Asthma is one of the most common chronic diseases in children and adults. Cocaine is associated with asthma exacerbations. In Denmark, the prevalence of cocaine use has been increasing in recent years. This is a case report of a 47-year-old male with acute asthma exacerbation after cocaine use. Cocaine use is probably an underestimated reason for acute asthma exacerbations.

Treatment outcomes for multidrug- and rifampicin-resistant tuberculosis in Central and West Africa: a systematic review and meta-analysis.

OBJECTIVES: We aimed to investigate published data on treatment outcomes of multidrug-resistant (MDR)/rifampicin-resistant tuberculosis (TB) in Central and West Africa because these, to the best of our knowledge, are sparsely available. METHODS: Systematic review and meta-analysis. RESULTS: A total of 14 studies were included, representing 4268 individuals in 14 of the 26 countries. Using a random-effects model meta-analysis, we observed a pooled success rate of 80.8% (95% confidence interval [CI] 56.0-93.3) for the Central African subgroup and 69.2% (95% CI 56.3-79.7) for the West African subgroup (P = 0.0522). The overall treatment success for all studies was 74.6% (95% CI 65.0-82.2). We found high heterogeneity among included studies (I2 = 96.1%). The estimated proportion of successfully treated individuals with MDR/rifampicin-resistant TB was considerably higher than the global estimate provided by the World Health Organization (59%), reaching the 2015 World Health Organization target of at least 75% treatment success for MDR-TB. CONCLUSION: The use of shorter treatment regimens and the standardized treatment conditions, including directly observed therapy in these studies, could have contributed to a high treatment success. Yet, the available literature was not fully representative of the regions, possibly highlighting the sparse resources in many of these countries. The review was registered at PROSPERO (https://www.crd.york.ac.uk/prospero/) (CRD42022353163).

Global trends of pulmonary infections with nontuberculous mycobacteria: a systematic review.

OBJECTIVES: To describe the global trends of pulmonary nontuberculous mycobacteria (NTM) infection and disease. METHODS: A systematic review of studies including culture-based NTM data over time. Studies reporting on pulmonary NTM infection and/or disease were included. Information on the use of guideline-based criteria for disease were collected, in which, infection is defined as the absence of symptoms and radiological findings compatible with NTM pulmonary disease. The trends of change for incidence/prevalence were evaluated using linear regressions, and the corresponding pooled estimates were calculated. RESULTS: Most studies reported increasing pulmonary NTM infection (82.1%) and disease (66.7%) trends. The overall annual rate of change for NTM infection and disease per 100,000 persons/year was 4.0% (95% confidence interval [CI]: 3.2-4.8) and 4.1% (95% CI: 3.2-5.0), respectively. For absolute numbers of NTM infection and disease, the overall annual change was 2.0 (95% CI: 1.6-2.3) and 0.5 (95% CI: 0.3-0.7), respectively. An increasing trend was also seen for Mycobacterium avium complex infection (n = 15/19, 78.9%) and disease (n = 10/12, 83.9%) and for Mycobacterium abscessus complex (n = 15/23, 65.2%) infection (n = 11/17, 64.7%) but less so for disease (n = 2/8, 25.0%). CONCLUSION: Our data indicate an overall increase in NTM worldwide for both infection and disease. The explanation to this phenomenon warrants further investigation.

Disseminated Mycobacterium avium complex infection in a woman with anti-interferon-γ autoantibodies.

Defects in the interleukin-12/interferon-gamma (IFN-γ) pathway and anti-IFN-γ antibodies have been associated with severe nontuberculous mycobacteria (NTM) infections. Consequently, disseminated NTM infections should prompt investigations for immunodeficiency. Herein, we report a case of a treatment refractory and ultimately disseminated and fatal Mycobacterium avium complex infection in a 71-year-old woman of Thai origin. Simultaneously, she had recurrent Salmonella kentucky cultured from stool samples and chronic perianal HSV-2 lesions. Late in the course of disease, anti-IFN-γ autoantibodies were demonstrated. Clinical studies investigating immunomodulating therapy and treatment among patients with anti-IFN-γ autoantibodies are lacking and, in this case, treatment seemed of a more palliative nature.