A 23-year-old man comes to the emergency department with fever, severe headache, and vomiting. He has not felt well for the past 2 weeks due to fatigue, intermittent low-grade fevers, and headaches. The patient is HIV positive and spent several months in prison 3 years ago. Temperature is 38.6 C (101.5 F). Neck stiffness is present on physical examination. A CT scan reveals no intracranial lesions. Cerebrospinal fluid analysis is notable for the following: Cerebrospinal fluid cultures grow Mycobacterium tuberculosis with significantly decreased activity of intracellular catalase peroxidase. The isolates would most likely exhibit resistance to which of the following agents?

Question

A 23-year-old man comes to the emergency department with fever, severe headache, and vomiting.  He has not felt well for the past 2 weeks due to fatigue, intermittent low-grade fevers, and headaches.  The patient is HIV positive and spent several months in prison 3 years ago.  Temperature is 38.6 C (101.5 F).  Neck stiffness is present on physical examination.  A CT scan reveals no intracranial lesions.  Cerebrospinal fluid analysis is notable for the following:  Cerebrospinal fluid cultures grow Mycobacterium tuberculosis with significantly decreased activity of intracellular catalase peroxidase.  The isolates would most likely exhibit resistance to which of the following agents?

Quizplus · Accepted Answer

This patient with HIV now has headaches, fevers, and cerebrospinal fluid cultures growing Mycobacterium tuberculosis; this presentation is consistent with tuberculous meningitis. The mechanism of action of isoniazid (INH) is the inhibition of mycolic acid synthesis by M tuberculosis. INH accomplishes this through an incompletely understood method. However, it is known that INH must be processed by mycobacterial catalase peroxidase for the drug to be activated within the bacteria, and that INH requires a specific protein sequence in its enzyme target (necessary for mycolic acid synthesis). For this reason, mycobacterial resistance to INH could be accomplished through non-expression of the catalase-peroxidase enzyme or through genetic modification of the INH binding site on the mycolic acid synthesis enzyme. (Choice A) Ethambutol appears to inhibit synthesis of the mycobacterial cell wall. Resistance to this drug develops when the mycobacteria increase production of arabinosyl transferase (an enzyme in the pathway to arabinogalactan, one of the key constituents of the mycobacterial cell wall). (Choice C) Because pyrazinamide must be converted to an active form by the mycobacterial enzyme pyrazinamidase, drug resistance can occur in those organisms that have modified their pyrazinamidase to be structurally ineffective. (Choice D) Resistance to rifampin in M tuberculosis is primarily due to a mutation in the gene that codes for a DNA-dependent RNA polymerase necessary for transcription and RNA prolongation. (Choice E) Streptomycin (used in some cases of tuberculosis) is an aminoglycoside that inhibits mycobacterial protein synthesis by disabling the bacterial ribosomal 30S subunit (which disrupts translation). Resistance to this drug is primarily achieved by a modification of the 30S ribosomal protein. Educational objective: Mycobacterial resistance to isoniazid (INH) can be accomplished through non-expression of the catalase-peroxidase enzyme or through genetic modification of the INH binding site on the mycolic acid synthesis enzyme.

A 23-Year-Old Man Comes to the Emergency Department with Fever