Myah L. McCrary

Background: Nontuberculous mycobacteria (NTM) are ubiquitous. NTM can affect different organs and may cause disseminated diseases, but the pulmonary form is the most common form. Pulmonary NTM is commonly seen in patients with underlying diseases. Pulmonary Mycobacterium avium complex (MAC) is the most common NTM disease and M. abscessus (MAB) is the most challenging to treat. This review is prepared with the following objectives: (a) to evaluate new methods available for the diagnosis of pulmonary MAC or MAB, (b) to assess advances in developing new therapeutics and their impact on treatment of pulmonary MAC or MAB, and (c) to evaluate the prospects of preventive strategies including vaccines against pulmonary MAC or MAB. Methods: A literature search was conducted using PubMed/MEDLINE and multiple search terms. The search was restricted to the English language and human studies. The database query resulted in a total of 197 publications. After the title and abstract review, 64 articles were included in this analysis. Results: The guidelines by the American Thoracic Society (ATS), European Respiratory Society (ERS), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), and Infectious Diseases Society of America (IDSA) are widely applicable. The guidelines are based on expert opinion and there may be a need to broaden criteria to include those with underlying lung diseases who may not fulfill some of the criteria as ‘probable cases’ for better follow up and management. Some cases with only one culture-positive sputum sample or suggestive histology without a positive culture may benefit from new methods of confirming NTM infection. Amikacin liposomal inhalation suspension (ALIS), gallium containing compounds and immunotherapies will have potential in the management of pulmonary MAC and MAB. Conclusions: the prevalence of pulmonary NTM is increasing. The efforts to optimize diagnosis and treatment of pulmonary NTM are encouraging. There is still a need to develop new diagnostics and therapeutics.

Acute ischemic stroke (AIS) is caused by clotting in the cerebral arteries, leading to brain oxygen deprivation and cerebral infarction. Recombinant human tissue plasminogen activator (tPA) is currently the only FDA-approved drug for ischemic stroke. However, tPA has to be administered within 4.5 h from the disease onset and delayed treatment of tPA can increase the risk of neurovascular impairment, including neuronal cell death, blood-brain barrier (BBB) disruption, and hemorrhagic transformation. A key contributing factor for tPA-induced neurovascular impairment is activation of matrix metalloproteinase-9 (MMP-9). We used a clinically-relevant mouse embolic model of focal-cerebral ischemia by insertion of a single embolus of blood clot to block the right middle cerebral artery. We showed that administration of the potent and highly selective gelatinase inhibitor SB-3CT extends the time window for administration of tPA, attenuating infarct volume, mitigating BBB disruption, and antagonizing the increase in cerebral hemorrhage induced by tPA treatment. We demonstrated that SB-3CT attenuates tPA-induced expression of vascular MMP-9, prevents gelatinase-mediated cleavage of extracellular laminin, rescues endothelial cells, and reduces caveolae-mediated transcytosis of endothelial cells. These results suggest that abrogation of MMP-9 activity mitigates the detrimental effects of tPA treatment, thus the combination treatment holds great promise for extending the therapeutic window for tPA thrombolysis, which opens the opportunity for clinical recourse to a greater number of patients. Significance Statement Endovascular thrombectomy benefited patients with disproportionately severe clinical deficit relative to infarct volume and provides a surgical option for treatment of ischemic stroke. Tissue-plasminogen activator (tPA) is the only FDA-approved clot-dissolving drug for treatment of ischemic stroke. However, its beneficial effect is seen only within 4.5 hours from the onset of stroke, with better outcomes observed the sooner treatment is given. Major risk is MMP-9−mediated neurovascular impairment. We document that early administration of the pharmacological agent SB₃CT reduces MMP-9 levels and mitigates the side effects associated with tPA. Furthermore, it extends the time window for treatment with tPA after stroke holding great potential for both disease intervention and benefiting patients who might not otherwise be candidates for treatment with tPA.