Multi Drug Resistant (MDR) Tuberculosis

Antituberculous Therapy

• First-line agents : Isoniazid , Rifampin , Ethambutol 

, Pyrazinamide.

• Second-line agents: Fluoroquinolones & injectable Aminoglycosides:

( Kanamycin , Amikacin ,Streptomycin) & Capreomycin.

Antituberculous Therapy

• less effective second line agents : Ethionamide , Cycloserine, Aminosalicylic Acid Alternative agents : Clofazimine, Amoxicillin –Clavulanate , Linezolid , Carbapenems, Thioacetazone, & Clarithromycin

OUTLINE

1. Drug resistant TB (one drug).

2. Multi drug resistant TB ( tow drugs) .

3. Extensive drug resistant TB ( four drugs or more ).

Definitions

1. Drug resistant TB:

M.Tuberculosis that is resistant to one of the first-line anti TB :

  Isoniazid ,  Rifampin, Pyrazinamide ,  Ethambutol, Streptomycin.

Definitions

2. Multi drug resistant TB (MDR TB) :M.Tuberculosis that is resistant to two

most potent first-line agents Isoniazid & Rifampin.

Definitions

3. Extensively drug-resistant TB (XDR TB) : M.Tuberculosis that is resistant to at least:  Isoniazid , Rifampcin, Fluoroquinolones.

plus one injectable agent : ( Amikacin , Kanamycin or Capreomycin  ). 

TB History  

•  Drug resistance first noted in the 1940s to streptomycin.

• Multi-drug regimens to decrease the risk of drug resistance.

TB History

• Outbreak of MDR TB in mid 1990s (HIV).

• China ,USA , Spain ,Italy.

Tugela Ferry   • Tugela Ferry  

•  International alarm first surfaced in 2006 with the detection of a large cluster of cases of XDR TB.

• 1539 individual patients with suspected TB

• 542 patients positive TB.

• 221 patients ( 41%) MDR and 53 XDR.

Tugela Ferry   • Important observation :

• All 44 of the 53 patients with XDR TB were HIV seropositive and with median CD4 count was 63 cells/microL. Viral loads were not available.

• 52 out of 53 of the patients died.

• 70 % of patient died within 30 days from the time of sputum collection.

Tugela Ferry  

• Two healthcare workers were among the XDR cases.

• Resistance to all of the six drugs tested at the time ( isoniazid , rifampin , ethambutol , streptomycin ,ciprofloxacin and kanamycin ).

MDR VS XDR

• Descriptive analysis of US TB cases reported from 1993 to 2007, a total of 83 XDR TB cases:

1. XDR TB cases more disseminated TB disease. 

2. 26 XDR TB cases (35 %) died during treatment, of whom 21 (81 %) were known to be HIV-infected.

3. Mortality was higher among XDR TB.

DIAGNOSIS

• The clinical manifestations and radiographic features of drug resistant TB are comparable to those of drug susceptible disease !!

A careful history must be obtained !!!

HISTORY

•  Demographic and historical features that should raise the suspicion of drug resistant TB include :

1-Previous treatment for active TB, self administered ,or treatment failure.

HISTORY

2-HIV infected patients ( malabsorption, drug interactions ART ).

3- TB in a region with known high rates of drug resistance.

4- Failure to respond to empiric therapy, particularly if adherence has been documented.

LAB TEST

• Culture and Sensitivity testing of sputum.

Rapid testing (Nucleic acid tests):• -GeneXpert MTB/RIF accuracy for rifampin

resistance 98 % ( in 2 hours ).•  MTBDRplus

detecting rifampin and isoniazid resistance mutations 99 % sensitive and specific (4days).

• Direct DNA sequencing analysis of sputum. 

LAB TEST

• These assays hold promise for the early and rapid detection.

• Limitations: cost effective & identification only Rifampin & Isoniazid.

TREATMENT OF MONORESISTANT TB

1- INH monoresistant :• Rifamycin , Pyrazinamide & Ethambutol (6-9 months) or 4 months after culture conversion.

which is based on trials conducted by the Hong Kong Chest Service/British Medical Research Council; these demonstrated success rates of 95 to 98 percent among 107 patients with INH-resistant disease

TREATMENT OF MONORESISTANT TB

2.Rifampin monoresistance:• Less common than Isoniazid resistance.

• More in HIV patients (CD4 cell counts <100/microL).

TREATMENT OF MONORESISTANT TB

• Isoniazid , Pyrazinamide plus Streptomycin for 9 months. This regimen has shortest

duration, & good efficacy. OR

• Isoniazid , pyrazinamide plus  ethambutol for at least 12 months.

• Adding streptomycin  or quinolone in first 3 months ?? 

TREATMENT OF MONORESISTANT TB

3-Pyrazinamide monoresistance:•  9 months regimen of Isoniazid & Rifampin . • Success rate >96 % .

TREATMENT OF MDR

GOAL!• Include first-line agents plus whatever additional

drugs are necessary to ensure that at least four drugs active against the most prevalent drug resistant strains are included in the regimen 

• Injectable agent is a must.

Treatment XDR

GOAL !at least four drugs active

• Use of third-line agents: Linezolid , Clofazimine, Amoxicillin-Clavulanate , Meropenem-clavulanate or or Clarithromycin .

• Surgery:

Is effective for patients with localized pulmonary disease which can be completely resected.

PREVENTION MDR TB

•  Appropriate therapy.

• Guarantee adherence to therapy.

• HIV control and prevention .

TAKE HOME MESSAGE 1. HX of HIV should rise suspicion of MDR .2. MDR & XDR RX 4 active drug.3. Multi drug regimen with adherence decrease

further genetic mutation and resistant.

THANK YOU

Done by: AMER ALBOUSHMEDICAL INTERN

Umm Al-Qura University

Questions ?