A 43-year-old immigrant from Southern Asia suffers from a cough that has lasted for several months duration. He comes to the clinic today because of recent onset hemoptysis. On further evaluation, he reports a 15-lb weight loss over the past four months. Sputum cultures grow acid-fast bacilli that are susceptible to most antimycobacterial drugs in vitro. Isoniazid monotherapy in this patient would most likely result in:

Question

A 43-year-old immigrant from Southern Asia suffers from a cough that has lasted for several months duration.  He comes to the clinic today because of recent onset hemoptysis.  On further evaluation, he reports a 15-lb weight loss over the past four months.  Sputum cultures grow acid-fast bacilli that are susceptible to most antimycobacterial drugs in vitro.  Isoniazid monotherapy in this patient would most likely result in:

Quizplus · Accepted Answer

This patient most likely has active tuberculosis, which should never be treated with drug monotherapy due to the rapid emergence of antibiotic resistance in M. tuberculosis. Isoniazid resistance specifically occurs by two selective gene mutations. The first is a decrease in bacterial expression of the catalase-peroxidase enzyme that is required for isoniazid activation once the drug enters the bacterial cell. The second mechanism of resistance occurs through modification of the protein target binding site for isoniazid. Treatment of active tuberculosis is accomplished by combining multiple antibiotics to avoid selecting for resistant strains. Commonly used drug regimens include isoniazid and rifampin in addition to streptomycin, ethambutol, and/or pyrazinamide. Isoniazid monotherapy may be used for patients who have a positive PPD and a negative chest x-ray (i.e., no evidence of clinical disease). (Choice A) For isoniazid monotherapy to result in the selective survival of intracellular bacilli would suggest that isoniazid is unable to penetrate into (or is otherwise degraded by) macrophages that house M. tuberculosis. However, this is not the case. Isoniazid can reach therapeutic levels within macrophages, areas of caseous necrosis, and cerebrospinal fluid. (Choice B) Decreased transport protein expression at the cell surface would interfere with the effectiveness of drugs that require protein-mediated transport into the bacterial cell to reach the intended target (eg, fluoroquinolones, macrolides, aminoglycosides). (Choice C) β-lactamase induction within bacterial cells would not result from isoniazid exposure because isoniazid is not a beta-lactam antibiotic. (Choice D) Rapid mycobacterial elimination from the body occurs when a small inoculum is recognized and quickly destroyed by the cell-mediated immune system. This happens in the majority of exposures. By the time tuberculosis has progressed to active, symptomatic disease, large caseous and liquefactive necrotic granulomas have usually formed and a lengthy treatment period with appropriate multidrug therapy is required to eradicate the organism. Antibiotic therapy for tuberculosis lasts a minimum of six months. Educational Objective: Active tuberculosis is never treated with drug monotherapy due to the fast emergence of mycobacterial antibiotic resistance from rapid, selective gene mutations. Isoniazid monotherapy may be used for patients who have a positive PPD and a negative chest x-ray (ie, no evidence of clinical disease). __________ References: The catalase-peroxidase gene and isoniazid resistance of Mycobacterium tuberculosis. (http://www.ncbi.nlm.nih.gov/pubmed/1501713) Modification of the NADH of the isoniazid target (InhA) from Mycobacterium tuberculosis. (http://www.ncbi.nlm.nih.gov/pubmed/9417034)

A 43-Year-Old Immigrant from Southern Asia Suffers from a Cough