tuberculous meningitis: update and perspectivestuberculous meningitis: update and perspectives juan...

Tuberculous meningitis:

Update and Perspectives

Juan Ambrosioni MD, PhD

Infectious Diseases Service, Hospital Clinic-IDIBAPS, Barcelona, Spain

Tuberculous meningitis:

Update and Disappointments

Juan Ambrosioni MD, PhD

Infectious Diseases Service, Hospital Clinic-IDIBAPS, Barcelona, Spain

Content

• 1-Background and overview of TM

• 2-Current recommendations

• 3-Recent trials

• 4-Perspectives

• 5-Take-home messages

• 6-Questions and open discussion

Background and overview of TM

• Approximately 1% of all TB cases

• The clinical presentation of TB with the highest mortality (Higher than 30% in most series)

• Even with appropriate therapy, high prevalence of neurological sequels (death or permanent disability approx. 50%)

• More frequent in young children and in HIV positive individuals


• Bad prognosis related to a series of reasons:-Delayed diagnosis

-Suboptimal antimicrobial regimens

Non-specific clinical presentation

Thwaites GE, et al. Lancet Neurol. 2013




-Poor sensitivity of direct CSF examination

-Time to get culture results

-Insufficient validation and S and S of

molecular tests




Thwaites GE, et al. Lancet Neurol. 2013

Content



• 3-Recent trials

• 4-Perspectives



Current recommendations

• 4 drugs (H-R-Z-E or S) for at least 2 months +

2 drugs (H-R) for 7-10 months

+ steroids

• Almost unchanged for 40 years

H, Z, S 1940s-1950s

E, R 1960s

Treatment of tuberculosis guidelines. 4th ed. Geneva: World Health Organization, 2010

Thwaites G, et al. J Infect 2009. Thwaites G, et al. New Eng J Med 2004.

• If resistant strain, regimen and duration must be

adapted

•If MDR suspected, add two drugs empirically

Content



• 3-Recent trials

• 4-Perspectives



Recent trials

Recent trials

Ruslami R et al. Lancet Infect Dis 2013

Heemskerk et al. N Engl J Med 2016

•Double blind trial in two hospitals in Vietnam

•Adult patients with suspected tuberculous meningitis

•Primary Endpoint: mortality at 9 months


R 15mg/kg

Levof 20mg/Kg

Content



• 3-Recent trials

• 4-Perspectives



The three drugs are highly protein-bound, unlikely to

reach high CSF concentrations…

Linezolid?

Both retrospective studies in China (one in children,

one in adults), small and with several limitations…

Good CSF penetration, experience with other CNS infections

<15% of confirmed cases (36 cases

and 50 controls)

Li H et al. Ped Infect Dis J 2016

Sun F et al. AAC 2014

Only 16 cases y 17 controls (BR

group), <% of confirmed

The TM-MADA Project

•Consortium:

-Hospital Clinic-IDIBAPS, Barcelona, Spain

-Hôpitaux Universitaires de Genève, Switzerland

-Centre Hospitalier Universitaire de Bordeaux, France

-Institut Pasteur de Madagascar

-4 University Centres in Madagascar (Tananarivo,

Fianarantsoa, Tamatave, Tulear)

-MSF and WHO consultancy

Created on the basis of a previous study Mada-Xpert

(Manuscript on preparation)

The TM-MADA Project

Not funded by EDCTP (NEJM paper published at that time)

Now redesigning the trial (probably Linezolid in the intervention arm)

Content



• 3-Recent trials

• 4-Perspectives



Take-home messages

•TM remains a disease with extremely high mobidity

and mortality

•Treatment has remained unchanged for decades

•Large trials have failed to prove the benefit of new

approaches (quinolones, increased dose R)

•Other strategies needed!!!

•High clinical index of suspicion and early treatment

remain the most important elements to improve

prognosis

Questions and discussion

• Open to questions…

• Thank you very much for your attention

tuberculous meningitis: update and perspectivestuberculous meningitis: update and perspectives juan...

Documents