Examkin

Soru

Zorluk: ZorInfectious Disease Mechanisms

A 45-year-old man with a history of advanced human immunodeficiency virus infection is admitted to the hospital for evaluation of a 4-week history of low-grade fever, drenching night sweats, diffuse abdominal pain, and a 6-kg (13.2-lb) weight loss. He has not been compliant with his antiretroviral therapy. His most recent CD4 T-lymphocyte count is 35 cells/mm³. Laboratory studies show a hemoglobin of 8.2 g/dL and an elevated serum alkaline phosphatase level. Blood cultures obtained using a lysis-centrifugation system grow non-tuberculous acid-fast bacilli. The patient is initiated on a multidrug antimicrobial regimen. Three months later, he returns with recurrent fever, and repeat blood cultures isolate the same pathogen. Susceptibility testing reveals newly acquired high-level resistance to the macrolide component of his regimen. This resistance is most likely mediated by a structural alteration in which of the following cellular targets?

  1. A
    16S ribosomal RNA
  2. B
    Arabinosyltransferase
  3. 23S ribosomal RNACevap
  4. D
    DNA-dependent RNA polymerase
  5. E
    DNA gyrase

Cevap

The resistance is mediated by a structural alteration in the 23S ribosomal RNA.
The patient's presentation of advanced HIV with severe immunosuppression (CD4 < 50 cells/mm³), systemic symptoms, severe anemia, and lysis-centrifugation blood cultures growing non-tuberculous acid-fast bacilli is classic for disseminated Mycobacterium avium complex (MAC). The standard treatment for MAC includes a macrolide (such as clarithromycin or azithromycin) combined with ethambutol, with or without rifabutin. The question specifically asks for the mechanism of resistance to the macrolide component. Macrolides inhibit bacterial protein synthesis by binding reversibly to the 23S ribosomal RNA (rRNA) of the 50S ribosomal subunit, preventing translocation of the growing peptide chain. High-level macrolide resistance in MAC (and many other bacterial pathogens) is most commonly acquired through a spontaneous point mutation in the rrl gene, which encodes this 23S rRNA. This mutation causes a structural alteration in the binding pocket that prevents the macrolide from attaching to its target, rendering the drug ineffective.

Adım Adım Çözüm

1
Analyze the patient's clinical presentation and laboratory findings.
The patient has advanced HIV (CD4 < 50), fever, night sweats, weight loss, anemia, and positive blood cultures for non-tuberculous acid-fast bacilli, establishing a diagnosis of disseminated Mycobacterium avium complex (MAC).
Establishing the correct infectious etiology is required to determine the standard treatment regimen.
2
Identify the standard pharmacological therapy for the diagnosed infection.
Standard treatment for MAC involves a macrolide (clarithromycin or azithromycin) and ethambutol, often supplemented with a rifamycin (like rifabutin).
The question specifically asks about resistance to the 'macrolide component' of the multidrug regimen.
3
Determine the cellular target of macrolide antibiotics.
Macrolides exert their bacteriostatic effect by binding to the 50S ribosomal subunit to inhibit bacterial protein synthesis.
Identifying the normal mechanism of action is necessary to deduce the mechanism of resistance.
4
Identify the specific structural target and resistance mechanism for macrolides.
Macrolides specifically bind to the 23S rRNA of the 50S subunit; resistance in MAC typically occurs via a point mutation in the rrl gene encoding this 23S rRNA.
This structural alteration directly answers the question regarding the cellular target of resistance.

Anahtar Kavram

The primary mechanism of acquired macrolide resistance in Mycobacterium avium complex (MAC) is a structural alteration of the drug's target site due to a point mutation in the rrl gene, which encodes the 23S ribosomal RNA of the 50S ribosomal subunit.
Tahmini Süre:1m 30s
Bu soruyu puanla

Konular

Infectious Disease Mechanisms

Bu konudan daha fazla soru