Nontuberculous Mycobacterial Pulmonary Disease in the Immunocompromised Host

Varley, Cara D.; Streifel, Amber C.; Bair, Amanda M.; Winthrop, Kevin L.

doi:10.1016/j.ccm.2023.06.007

Cited by 4 publications

(1 citation statement)

References 106 publications

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“…Abdominal organs, including lymph nodes, liver, spleen and gastrointestinal tracts are the main targets for M. genavense infection [ 5 ]. Despite the improvements in survival by antiretroviral therapies (ART) in the recent years, the prognosis of this infection remains poor [ 5 ] due to the long treatment periods and high prevalence of side effects, plus non-specific diagnostic and treatment tools [ 6 – 8 ].…”

Section: Introductionmentioning

confidence: 99%

Disseminated mycobacterium genavense infection with central nervous system involvement in an HIV patient: a case report and literature review

Hassanzadeh,

Hasannezhad,

Abbasian

et al. 2024

BMC Infect Dis

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Background Immunodeficient patients, particularly HIV patients, are at risk of opportunistic infections. Nontuberculous mycobacteria can cause severe complications in immunodeficient patients. Case Presentation We describe a 57-year-old HIV patient, primarily presented with coughs and constitutional symptoms, with a unique Mycobacterium genavense abdominal, pulmonary, and central nervous system infection, accompanied by intracranial masses. Conclusion The diagnosis of NTM, including M. genavense, must always be considered by clinicians in immunodeficient patients, especially those with HIV, who have a compromised immune system.

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Section: Introductionmentioning

confidence: 99%

Disseminated mycobacterium genavense infection with central nervous system involvement in an HIV patient: a case report and literature review

Hassanzadeh,

Hasannezhad,

Abbasian

et al. 2024

BMC Infect Dis

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Durlobactam to boost the clinical utility of standard of care β-lactams against Mycobacterium abscessus lung disease

Negatu,

Aragaw,

Gebresilase

et al. 2024

Antimicrob Agents Chemother

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β-Lactams present several desirable pharmacodynamic features leading to the rapid eradication of many bacterial pathogens. Imipenem (IPM) and cefoxitin (FOX) are injectable β-lactams recommended during the intensive treatment phase of pulmonary infections caused by Mycobacterium abscessus (Mab). However, their potency against Mab is many-fold lower than against Gram-positive and Gram-negative pathogens for which they were optimized, putting into question their clinical utility. Here, we show that adding the recently approved durlobactam-sulbactam (DUR-SUL) pair to either IPM or FOX achieves growth inhibition, bactericidal, and cytolytic activity at concentrations that are within those achieved in patients and below the clinical breakpoints established for each agent. Synergies between DUR-SUL and IPM or FOX were confirmed across a large panel of clinical isolates. Through in vitro resistant mutant selection, we also show that adding DUR-SUL abrogates acquired resistance to IPM and FOX. Since the use of β-lactam injectables is firmly grounded in clinical practice during the intensive treatment phase of Mab pulmonary disease, their potentiation by FDA-approved DUR-SUL to bring minimum inhibitory concentration distributions within achievable concentration ranges could offer significant short-term benefits to patients, while novel β-lactam combinations are optimized specifically against Mab pulmonary infections, for which no reliable cure exists.

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Toward better cures for Mycobacterium abscessus lung disease

Dartois,

Dick

2024

Clin Microbiol Rev

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SUMMARY The opportunistic pathogen Mycobacterium abscessus (Mab) causes fatal lung infections that bear similarities—and notable differences—with tuberculosis (TB) pulmonary disease. In contrast to TB, no antibiotic is formally approved to treat Mab disease, there is no reliable cure, and the discovery and development pipeline is incredibly thin. Here, we discuss the factors behind the unsatisfactory cure rates of Mab disease, namely intrinsic resistance and persistence of the pathogen, and the use of underperforming, often parenteral and toxic, repurposed drugs. We propose preclinical strategies to build injectable-free sterilizing and safe regimens: (i) prioritize oral bactericidal antibiotic classes, with an initial focus on approved agents or advanced clinical candidates to provide immediate options for desperate patients, (ii) test drug combinations early, (iii) optimize novel leads specifically for M. abscessus , and (iv) consider pharmacokinetic-pharmacodynamic targets at the site of disease, the lung lesions in which drug tolerant bacterial populations reside. Knowledge and tool gaps in the preclinical drug discovery process are identified, including validated mouse models and computational platforms to enable in vitro mouse-human translation. We briefly discuss recent advances in clinical development, the need for readouts and biomarkers that correlate with cure, and clinical trial concepts adapted to the uniqueness of Mab patient populations for new regimen development. In an era when most pharmaceutical firms have withdrawn from antimicrobial drug discovery, the breakthroughs needed to fill the regimen development pipeline will likely come from partnerships between academia, biotech, pharma, non-profit organizations, and governments, with incentives that reward cooperation.

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Nontuberculous Mycobacterial Pulmonary Disease in the Immunocompromised Host

Cited by 4 publications

References 106 publications

Disseminated mycobacterium genavense infection with central nervous system involvement in an HIV patient: a case report and literature review

Disseminated mycobacterium genavense infection with central nervous system involvement in an HIV patient: a case report and literature review

Durlobactam to boost the clinical utility of standard of care β-lactams against Mycobacterium abscessus lung disease

Toward better cures for Mycobacterium abscessus lung disease

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