Pulmonary diseases due to mycobacteria cause significant morbidity and mortality to human health. In addition to tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), recent epidemiological studies have shown the emergence of non-tuberculous mycobacteria (NTM) species in causing lung diseases in humans. Although more than 170 NTM species are present in various environmental niches, only a handful, primarily Mycobacterium avium complex and M. abscessus, have been implicated in pulmonary disease. While TB is transmitted through inhalation of aerosol droplets containing Mtb, generated by patients with symptomatic disease, NTM disease is mostly disseminated through aerosols originated from the environment. However, following inhalation, both Mtb and NTM are phagocytosed by alveolar macrophages in the lungs. Subsequently, various immune cells are recruited from the circulation to the site of infection, which leads to granuloma formation. Although the pathophysiology of TB and NTM diseases share several fundamental cellular and molecular events, the host-susceptibility to Mtb and NTM infections are different. Striking differences also exist in the disease presentation between TB and NTM cases. While NTM disease is primarily associated with bronchiectasis, this condition is rarely a predisposing factor for TB. Similarly, in Human Immunodeficiency Virus (HIV)-infected individuals, NTM disease presents as disseminated, extrapulmonary form rather than as a miliary, pulmonary disease, which is seen in Mtb infection. The diagnostic modalities for TB, including molecular diagnosis and drug-susceptibility testing (DST), are more advanced and possess a higher rate of sensitivity and specificity, compared to the tools available for NTM infections. In general, drug-sensitive TB is effectively treated with a standard multi-drug regimen containing well-defined first- and second-line antibiotics. However, the treatment of drug-resistant TB requires the additional, newer class of antibiotics in combination with or without the first and second-line drugs. In contrast, the NTM species display significant heterogeneity in their susceptibility to standard anti-TB drugs. Thus, the treatment for NTM diseases usually involves the use of macrolides and injectable aminoglycosides. Although well-established international guidelines are available, treatment of NTM disease is mostly empirical and not entirely successful. In general, the treatment duration is much longer for NTM diseases, compared to TB, and resection surgery of affected organ(s) is part of treatment for patients with NTM diseases that do not respond to the antibiotics treatment. Here, we discuss the epidemiology, diagnosis, and treatment modalities available for TB and NTM diseases of humans.

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Of tuberculosis and non-tuberculous mycobacterial infections – a comparative analysis of epidemiology, diagnosis and treatment

Currently, there is a trend of increasing incidence in pulmonary non-tuberculous mycobacterial infections (PNTM) together with a decrease in tuberculosis (TB) incidence, particularly in developed countries. The prevalence of PNTM in underdeveloped and developing countries remains unclear as there is still a lack of detection methods that could clearly diagnose PNTM applicable in these low-resource settings. Since non-tuberculous mycobacteria (NTM) are environmental pathogens, the vicinity favouring host-pathogen interactions is known as important predisposing factor for PNTM. The ongoing changes in world population, as well as socio-political and economic factors, are linked to the rise in the incidence of PNTM. Development is an important factor for the improvement of population well-being, but it has also been linked, in general, to detrimental environmental consequences, including the rise of emergent (usually neglected) infectious diseases, such as PNTM. The rise of neglected PNTM infections requires the expansion of the current efforts on the development of diagnostics, therapies and vaccines for mycobacterial diseases, which at present, are mainly focused on TB. This review discuss the current situation of PNTM and its predisposing factors, as well as the efforts and challenges for their control.

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Pulmonary non-tuberculous mycobacterial infections: current state and future management.

Slaughterhouse wastewater is considered a reservoir for antibiotic-resistant bacteria and antibiotic residues, which are not sufficiently removed by conventional treatment processes. This study focuses on the occurrence of ESKAPE bacteria (Enterococcus spp., S. aureus, K. pneumoniae, A. baumannii, P. aeruginosa, Enterobacter spp.), ESBL (extended-spectrum β-lactamase)-producing E. coli, antibiotic resistance genes (ARGs) and antibiotic residues in wastewater from a poultry slaughterhouse. The efficacy of conventional and advanced treatments (i.e., ozonation) of the in-house wastewater treatment plant regarding their removal was also evaluated. Target culturable bacteria were detected only in the influent and effluent after conventional treatment. High abundances of genes (e.g., bla$_{TEM}$, bla$_{CTX-M-15}$, bla$_{CTX-M-32}$, bla$_{OXA-48}$, bla$_{CMY}$ and mcr-1) of up to 1.48 × 10$^{6}$ copies/100 mL were detected in raw influent. All of them were already significantly reduced by 1–4.2 log units after conventional treatment. Following ozonation, mcr-1 and bla$_{CTX-M-32}$ were further reduced below the limit of detection. Antibiotic residues were detected in 55.6% (n = 10/18) of the wastewater samples. Despite the significant reduction through conventional and advanced treatments, effluents still exhibited high concentrations of some ARGs (e.g., sul1, ermB and bla$_{OXA-48}$), ranging from 1.75 × 10$^{2}$ to 3.44 × 10$^{3}$ copies/100 mL. Thus, a combination of oxidative, adsorptive and membrane-based technologies should be considered.

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Antibiotic-resistant bacteria, antibiotic resistance genes, and antibiotic residues in wastewater from a poultry slaughterhouse after conventional and advanced treatments.

Diagnosing nontuberculous mycobacterial cervicofacial lymphadenitis in children: A systematic review.

To investigate the species distribution of non-tuberculous mycobacteria (NTM) among tuberculosis (TB) specimens collected from January 2013 to December 2018 at Peking Union Medical Hospital (Beijing), China. NTM species identification was carried out by DNA microarray chip. Mycobacterial species were detected in 1514 specimens from 1508 patients, among which NTM accounted for 37.3% (565/1514), increasing from a proportion of 15.6% in 2013 to 46.1% in 2018 (P < 0.001). Among the 565 NTM positive specimens, the majority (55.2%) were from female patients. Furthermore, patients aged 45–65 years accounted for 49.6% of the total patients tested. Among 223 NTM positive specimens characterized further, the majority (86.2%) were from respiratory tract, whilst 3.6 and 3.1% were from lymph nodes and pus, respectively. Mycobacterium intracellulare (31.8%) and Mycobacterium chelonae / Mycobacterium abscessus (21.5%) were the most frequently detected species, followed by M. avium (13.5%), M. gordonae (11.7%), M. kansasii (7.6%), and others. The proportion of NTM among mycobacterial species detected in a tertiary hospital in Beijing, China, increased rapidly from year 2013 to 2018. Middle-aged patients are more likely to be infected with NTM, especially females. Mycobacterium intracellulare and Mycobacterium chelonae/ Mycobacterium abscessus were the most frequently detected NTM pathogens. Accurate and timely identification of NTM is important for diagnosis and treatment.

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Prevalence of nontuberculous mycobacteria in a tertiary hospital in Beijing, China, January 2013 to December 2018

Antimicrobial resistance (AMR) is a global crisis for human public health which threatens the effective prevention and control of ever-increasing infectious diseases. The advent of pandrug-resistant bacteria makes most, if not all, available antibiotics invalid. Meanwhile, the pipeline of novel antibiotics development stagnates, which prompts scientists and pharmacists to develop unconventional antimicrobials. Bacteriophage-derived endolysins are cell wall hydrolases which could hydrolyze the peptidoglycan layer from within and outside of bacterial pathogens. With high specificity, rapid action, high efficiency, and low risk of resistance development, endolysins are believed to be among the best alternative therapeutic agents to treat multidrug resistant (MDR) bacteria. As of now, endolysins have been applied to diverse aspects. In this review, we comprehensively introduce the structures and activities of endolysins and summarize the latest application progress of recombinant endolysins in the fields of medical treatment, pathogen diagnosis, food safety, and agriculture.

Endolysin, a Promising Solution against Antimicrobial Resistance.

Environmental bacteria, nontuberculous mycobacteria (NTM), are recognized as one of the major human infection pathogens. NTM are prone to be mistaken as multidrug-resistant Mycobacterium tuberculosis and challenge our fight against TB. In addition, treatment of NTM per se is intractable. Remarkably, the distribution of NTM pathogenic species is geographically specific. Thus, it is very important to summarize the prevalent features and clinical symptoms of NTM pulmonary disease. However, In Nanjing district, southeast China, there is no such a report. Through investigating electronic medical records and analyzing data of clinical examination system (Lis), we retrospectively summarized the NTM species from 6012 clinical isolates from May 2017 to August 2018, and analyzed the association between NTM species and clinical symptoms. Of 6012 clinical specimens, 1461 (24.3%) could grow in the MGIT 960 broth. Among these positive isolates, 1213 (83%) were M. tuberculosis, 22 (1.5%) were M. bovis, and 226 (15.5%) were NTM. After deducting redundancy, those NTM specimens were confirmed from 154 patients, among which, 87 (56.5%) patients met the full ATS/IDSA NTM disease criteria. The most common etiologic agent was M. intracellulare (70.1%). NTM infection was associated with age, based on which 68.6% male patients and 77.8% female patients were over 50 years old. The older patients were more likely to have hemoptysis, but the younger patients were more likely to manifest chest congestion. Male patients were more likely to have shortness of breath and females were more likely to have hemoptysis. The most common radiographic presentation of NTM pulmonary disease was bronchiectasis, accounting for 39.1%. Remarkably, multiple and thin-walled cavities were outstanding. The most frequent comorbidity of NTM disease was previous tuberculosis (64%), followed by clinical bronchiectasis (19.5%), HIV (19.5%), and 6.9% chronic obstructive pulmonary disease (COPD). There was no association between NTM species and clinical symptoms. This study retrospectively investigated the prevalence of NTM pulmonary disease in Nanjing district, southeast China. Similar to Beijing area, north China, M. intracellulare was the major pathogenic NTM species. Clinical symptoms of the disease were not species-specific. Previous TB and HIV infection immensely enhanced risk of NTM disease.

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Characterization of non-tuberculous mycobacterial pulmonary disease in Nanjing district of China

An Enterobacter hormaechei isolate (ECL-90) simultaneously harboring blaNDM-1, blaIMP-4 and mcr-9.1 was recovered from the secretion specimen of a 24-year-old male patient in a tertiary hospital in China. The whole genome sequencing of this isolate was complete, and 4 circular plasmids with variable sizes were detected. MLST analysis assigned the isolate to ST418, known as a carbapenemase-producing epidemic clone in China. blaIMP-4 and mcr-9.1 genes were co-carried on an IncHI2/2A plasmid (pECL-90-2) and blaNDM-1 was harbored by an IncX3 plasmid (pECL-90-3). The genetic context of mcr-9.1 was identified as a prevalent structure, “rcnR-rcnA-pcoE-pcoS-IS903-mcr-9-wbuC”, which is a relatively unitary model involved in the mobilization of mcr-9. Meanwhile, blaNDM-1 gene was detected within a globally widespread structure known as NDM-GE-U.S (“ISAba125– blaNDM-1–blaMBL”). Our study warrants that the convergence of genes mediating resistance to last-resort antibiotics in epidemic clones would largely facilitate their widespread in clinical settings, thus representing a potential challenge to clinical treatment and public health. Importance Carbapenemase-producing Enterobacteriaceae (CPE) spread at a high rate and colistin is the last-resort therapeutic for the infection caused by CPE. However, the emergence of plasmid-borne mcr genes highly facilitates the wide dissemination of colistin resistance, thus largely threatens the clinical use of colistin. Here, we for the first time characterized a clinical Enterobacter hormaechei strain co-producing blaNDM-1, blaIMP-4 and mcr-9.1 belonging to an epidemic clone (ST418). The accumulation of genes mediating resistance to last-resort antibiotics in epidemic clones would largely facilitate their widespread in clinical settings, which may cause disastrous consequence with respect to antimicrobial resistance. Understanding how resistance genes were accumulated in a single strain could help us to track the evolutionary trajectory of drug resistance. Our finding highlights the importance of surveillance on the epidemic potential of colistin-resistant CPE, and effective infection control measures to prevent the resistance dissemination.

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Characterization of a Clinical Enterobacter hormaechei Strain Belonging to Epidemic Clone ST418 Co-carrying blaNDM-1, blaIMP-4 and mcr-9.1


 Background: Since December 2019, the outbreak of COVID-19 has spread quickly and thumped many countries and regions. The epidemic of central China was under the spotlight and attracted much more attentions. However, there are few reports describing COVID-19 patients in the regions outside of Wuhan, which are undergoing the change from sporadic imported cases to community-acquired transmission.Methods: The electronic medical records of 74 laboratory-confirmed patients of COVID-19 were retrospectively reviewed and analyzed. Their epidemiological, demographic, clinical and radiological characteristics were systematically summarized. The difference between severe patients and non-severe patients were also analyzed statistically.Results: The 74 COVID-19 patients were composed of 4 (5.4%) mild patients, 56 (75.7%) common patients, 13 (17.6%) severe patients and 1 (1.4%) critical patient. 43 were male, and 31 were female, with the average age 48.1±17.5. No significant difference of susceptibility was observed between genders, and almost people with all age were susceptible to SARS-CoV-2 infection. Before Jan 26, only imported sporadic cases were observed. However, from that day onward, family cluster infection cases increased dramatically, up to 70.3% (52/74), which were mainly from 15 family. The incubation period spanned from 0 to 19 days, with the median 5, and 81.4% had symptom onset within 7 days. At admission, 31.1% of patients had underlying diseases and the most common underlying diseases were hypertension (13.5%) and diabetes (5.4%). The most common symptoms were fever (90.5%), cough (75.7%), fatigue (36.5%) and chest distress (32.4%). 36.5% and 16.2% of patients had leukopenia and lymphocytopenia. 43.2% of patients had increased C reactive protein (CRP), and 40.5% had higher erythrocyte sedimentation rate (ESR) and 21.6% had higher calcitonin. 74.3% of patients had obvious lesions in both lung lobes and 56.8% of lesions manifested as ground glass opacity. Compared with non-severe group, the severe/critical group were significantly older and had more underlying diseases. After treatment, all patients improved and were discharged. No medical professional infection and death case were reported.Conclusion: The epidemic of COVID-19 in Nanjing were mainly caused by family cluster infection. The entire prevalence and illness were much milder than those of Wuhan. The disease of COVID-19 could be controlled and cured.

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Weixiao Wang

Papers

Endolysin, a Promising Solution against Antimicrobial Resistance.

Characterization of non-tuberculous mycobacterial pulmonary disease in Nanjing district of China

Characterization of a Clinical Enterobacter hormaechei Strain Belonging to Epidemic Clone ST418 Co-carrying blaNDM-1, blaIMP-4 and mcr-9.1

Epidemiological and clinical characteristics of COVID-19 patients in Nanjing