Transcript Case presentation

Principles of designing a TB and
MDR-TB drug regimen
Christoph Lange & Giovanni Sotgiu
Case presentation
41 y.o. Ethopian male
Air plane engineer
14 d fever, night sweats
TST 18 mm
CXR: lymphadenopathy
TCT: lymphadenopathy
endosonography/cardia:
-epithelioid-cell granuloma
Started HREZ therapy
Case presentation
2.5 months later: Hospital admission with ongoing fever and
persistent mediastinal lymphadenopathy
sputum and BAL:
mediastinal Bx:
Bone marrow Bx:
- AFB-negative
- no pathology seen in LN
- „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
MDR- and XDR- tuberculosis
Donald et al. NEJM 2009
Definition of MTB drug resistance
Mono-drug-resistence
Resistance against one (firstline) drug, INH, RMP, EMB,
PZA
Uncomplicated treatment.
Duration of treatment may be
prolonged
Poly-drug-resistance
Resistance against > 1 (firstline) 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
Moxifloxacin for the treatment against
tuberculosis
n = 74
n = 72
Conde et al. Lancet 2009
Moxifloxacin for the treatment against
tuberculosis
Dormann et al. AJRCCM 2009
FLQ-drug resistance of
M. tuberculosis is associated to treatment
failure and death in MDR-TB
Migliori et al. ERJ 2008
FLQ-drug resistance of
M. tuberculosis in Mumbai, India
Agrawal et al. IJTLD 2009
Diarylquinoline TMC207 for the treatment
against MDR-tuberculosis
Diacon et al. NEJM 2009
Linezolid for the treatment against MDRtuberculosis: adverse events
Migliori et al. ERJ 2009
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 highrgrade 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