Christoph Lange & Giovanni Sotgiu Principles of designing a TB and MDR-TB drug regimen.
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Transcript of Christoph Lange & Giovanni Sotgiu Principles of designing a TB and MDR-TB drug regimen.
Christoph Lange & Giovanni Sotgiu
Principles of designing a TB and MDR-TB drug regimen
41 y.o. Ethopian maleAir plane engineer14 d fever, night sweats
TST 18 mmCXR: lymphadenopathyTCT: lymphadenopathyendosonography/cardia: -epithelioid-cell granuloma
Started HREZ therapy
Case presentation
Case presentation
2.5 months later: Hospital admission with ongoing fever and persistent mediastinal lymphadenopathy
sputum and BAL: - AFB-negative mediastinal Bx: - no pathology seen in LNBone marrow Bx: - „inflammation“, no granulomas, no lymphomas
Case presentation
Day 4 in hospital:Continuation of Tx with HR
Day 14 in hospital:GI-bleeding from cardia erosion
Day 14 in hospital:MTB-culture from sputum +again HRZE therapy
Day 15 in hospital:TCT: miliary pattern
Case presentation
D 70 D 90
Case presentation
Day 16 in hospital:Transfer to a department of surgery because of repeated GI bleeding
Day 16-24 in hospital:Repeated attempts for arterial embolization
Day 22 in hospital:Preliminary result of drug resistance testing
Case presentation
Day 22 in hospital:Change of the therapy to moxifloxacin, capreomycin, linezolid, terizidone und protionamide
Day 16 in hospital:The patient dies due to GI bleeding despite mass transfusions
Greinert et al. Med Klin 2007
Donald et al. NEJM 2009
MDR- and XDR- tuberculosis
Definition of MTB drug resistance
Mono-drug-resistence Resistance against one (first-line) drug, INH, RMP, EMB, PZA
Uncomplicated treatment. Duration of treatment may be prolonged
Poly-drug-resistance Resistance against > 1 (first-line) drugs, but sensitivity to INH and/or RMP
Usually uncomplicated treatment. Duration of treatment is is prolonged
Multi-drug-resistance
MDR
Resistance against at least INH and RMP
Complicated treatment. Duration of treatment is prolonged to > 18 months
Outcome depends on level of drug resistance
Extensively-drug-resistance
XDR
MDR plus resistance to
- any fluoroquinolone- amikacin, capreomycin
or kanamycin
Complicated treatment. Duration of treatment is prolonged to > 24 months
Outcome depends on level of drug resistance
Drugs for the treatment against tuberculosis
WHO 2009
Standard TB drug regimen for new cases
Re-treatment regimen for previous treated cases
Drug resistance in strains of MDR and XDR- TB in Germany 2004-2006
Eker et al. Emerg Infec Dis 2008
www.tballiance.org
Conde et al. Lancet 2009
n = 74
n = 72
Moxifloxacin for the treatment against tuberculosis
Moxifloxacin for the treatment against tuberculosis
Dormann et al. AJRCCM 2009
Migliori et al. ERJ 2008
FLQ-drug resistance ofM. tuberculosis is associated to treatment
failure and death in MDR-TB
FLQ-drug resistance ofM. tuberculosis in Mumbai, India
Agrawal et al. IJTLD 2009
Diarylquinoline TMC207 for the treatment against MDR-tuberculosis
Diacon et al. NEJM 2009
Migliori et al. ERJ 2009
Linezolid for the treatment against MDR-tuberculosis: adverse events
7 steps of drug treatment in MDR/XDR-tuberculosis
1. Use drugs shown to be sensitive in in vitro drug sensitivity testing.
2. Drugs are added until n > 5
3. Use any first line oral agent to which the organism is sensitive: Isoniazid, rifampin, ethambutol, pyrazinamide
4. Use an injectable drug (aminoglycoside or capreomycin) to which the organism is sensitive. Continue the injectable drug at least 6 months after culture conversion since it is frequently one of only two bactericidal components in the therapy
5. Use a fluoroquinolone. Consider use of moxifloxacin in cases of drug resistance to ciprofloxacin or levofloxacin
6. Add as many second line drugs as are needed to reach a number of > 5. Cycloserin and ethionamid are considerd first choice. PAS and linezolid are used in cases with highr-grade drug resistance
7. If the regimen does not contain > 5 adequate drugs consider the additional use of amoxicilin/clavulanic acid or clofazimine
Conclusions
• Drug resistant strains of MTB are increasing worldwide• Causes for the emergence of MTB drug resistance are variable (healthcare
mismanagment, unavailability of drugs, direct transmission of MTB resistant strains in vulnerable populations)
• The treatment prognosis is dependant upon the level of drug resistance and the availability of second line drugs
• Therapy of MDR/XDR TB is longlasting (> 18 months) and frequently requires modifications due to adverse effects of the drugs
• There is a need for biomarkers to predict the duration of therapy in individual patients
• There is a need for the development of new drugs against MTB but not much is changing for now