Tuberculousmeningitis: what is the best treatment regimen?

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1 Tuberculousmeningitis: what is the best treatment regimen? H S Schaaf Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University

2 Introduction TBM is the most serious complication of TB causing considerable morbidity and mortality even if treated with anti-tb drugs Outcome depends on the stage of TBM at the point of diagnosis, but even patients with early disease stage may deteriorate Rate of TBM is approximately 1:40 cases majority in young children <3 years of age Associated mainly with primary infection, but in some cases occur years after primary infection TBM is the most common bacterial meningitis in the Western Cape, and most likely, in South Africa

of TBM is approximately 1:40 cases majority in young children <3 years of age Associated mainly with primary infection, but in some

3 CT MRI Scans Courtesy Ronald van Toorn

4 Pathogenesis of TBM Haematogenous disseminationof bacilli from the primary complex establishes a cortical or meningeal focus. This focus soon (or later in some cases) proceeds to caseate and discharge its contents into the subarachnoid space. In some cases haematogenous dissemination may establish a caseatingfocus in the choroid plexus or in the walls of the ventricles from which TBM may develop. In a few cases a caseousprocess extends from adjacent structures (e.g. vertebrae or middle ear) to involve the CNS. Donald et al; Journal of Infection (2005) 50,

In some cases haematogenous dissemination may establish a caseatingfocus in the choroid plexus or in the walls of the ventricles from which

5 Axial T1 gadolinium T1 MRI demonstrating miliarynodules in the quadrigeminal cistern.

6 MRI T2 black = Tuberculoma Scans courtesy Ronald van Toorn

7 The Chemotherapy of Tuberculous Meningitis Before chemotherapy TBM was universally deadly The mean time from diagnosis to death in pretreatment era was 19 days (Lincoln EM. Tuberculousmeningitis i9n children. Am Rev Tuberc1947; 56: ) There is no place for a wait and see attitude to diagnosis a medical emergency.

was 19 days (Lincoln EM. Tuberculousmeningitis i9n children.

8 Components of TBM treatment Three major components: - Anti-TB chemotherapy -Management of raised intracranial therapy due to obstructive hydrocephalus (communicating vs. noncommunicating; medical vs. surgical) -Modulation of the destructive elements of the immune response, most important of which is the vasculitis Today only discuss anti-tb treatment Donald PR. The chemotherapy of TBM in children and adults. Tuerculosis 2010;90:375-92

surgical) -Modulation of the destructive elements of the immune response, most important of which is the

9 Main objectives in TB Rx To rapidly kill most bacilli in order to: - prevent disease progression - prevent transmission of infection - prevent development of drug-resistance To effect cure and prevent relapse (eliminate dormant bacilli) To do the above with minimal adverse events In CNS TB drugs need to cross the blood brain barrier

drug-resistance To effect cure and prevent relapse (eliminate dormant bacilli) To

10 1 st -line Anti-TB agents CSF penetration Anti-TB drug CSF Suggested dose Suggested dose penetration (children) (adults) Isoniazid Good 15 mg/kg Up to 500 mg Rifampicin Moderate to Poor 20 mg/kg Up to 1000 mg Pyrazinamide Good 40 mg/kg Up to 2000 mg Ethambutol Poor (±20% acute phase) Streptomycin Poor (±20% acute phase) If used 25 mg/kg Not recommended Up to 2500 mg Up to 1000 mg

Poor 20 mg/kg Up to 1000 mg Pyrazinamide Good 40 mg/kg Up to 2000 mg Ethambutol Poor (±20%

11 2 nd -line Anti-TB agents CSF penetration Anti-TB drug CNS Suggested dose penetration (children) Ethionamide Good (>80%) 20 mg/kg FQNs Moderate to - Levofloxacin Good 20 mg/kg - Moxifloxacin (50-60%) mg/kg (no evidence) Suggested dose (adults) mg 1000 mg 400 mg (800? QT problems?) Terizidone/Cs Good mg/kg mg 2 nd -line Inject Poor (<20%) 20 mg/kg Up to 1000 mg PAS Poor (20%) 200 mg/kg Up to 12 g daily Linezolid Good 10 mg/kg bd Up to 600 mg bd Clofazimine Poor 3-5 mg/kg 100 mg

750-1000 mg 1000 mg 400 mg (800? QT problems?

12 Best Drugs for treatment of TBM»INH»Fluoroquinolones»PZA»RMP»ETH»Cycloserine/terizidone»Newer drugs Linezolid

13 Woodfield J, Argent A. J Trop Pediatr 2008;54:220-4

14 It is of interest that this review found no evidence that the introduction of RMP has had a significant effect on the mortality of TBM in adults, whereas mortality in children has declined significantly. As a relatively high-dosage of RMP will often be used in childrenthis may have contributed to the much improved outcome in children.

15 Intensified treatment did not result in increased toxicity. 6 month mortality was substantially lower in (adult) patients given high-dose rifampicin intravenously (ten [35%] vs20 [65%]), which could not be explained by HIV status or severity of disease at the time of presentation (adjusted HR 0 42; 95% CI ; p=0 03). Published online October 25,

[35%] vs20 [65%]), which could not be explained by HIV status or severity of disease at the time of

16 Ellardet al. Am Rev RespirDis 1993; 148: INH in CSF: at the dosages generally used (about 8-10 mg/kg, (as in this study) the drug exposures achieved in the CSF are similar to those attained in the serum (and by implication in the lungs) with the doses normally employed (5 to 6 mg/kg) for treatment of pulmonary tuberculosis.

8-10 mg/kg, (as in this study) the drug exposures achieved in the CSF are similar

17 Recent experience DS-TBM in children Study in Western Cape: 6HRZEth (HIV-uninfected) and 9HRZEth (HIV-infected) with strict home-based care in selected cases or hospitalised care for full duration of Rx 184 children TBM stage I 12%, St II 53%, St III 35% In 23 (12.5%) cases Rx was prolonged to 7-15 months. Reasons were: Hepatic toxicity (raised ALT only) 8; Rx interruption 3; TB brain abscesses 6; INH-monoresistance 2; and TB-IRIS -4 Outcome at end of Rx: -Normal 43%; Mild sequelae 37%; Severe sequelae 16% and Death in 4%. Van ToornR, Schaaf HS, et al. PIDJ in press

5%) cases Rx was prolonged to 7-15 months.

18 What should we consider when deciding on a TBM treatment regimen? No RCT (some by Thwaites) on TBM treatment, very little information on relapse of TBM and few options as far as drugs are concerned Stage of TBM: early diagnosis (stage 1 or early stage 2) much better prognosis than late stage 2 or stage 3 irrespective of available anti-tb drugs. Is DOT available or not? Missing doses increase risk for relapse consider longer Rx duration What is the risk of INH resistance in the population? History of contact with drug-resistant TB case, e.g. MDR- TB, or history of failure of 1st-line treatment? Risk of drug adverse effects?

diagnosis (stage 1 or early stage 2) much better prognosis than late stage 2 or stage 3 irrespective of available anti-tb drugs. Is DOT available or not?

19 One explanation for the good outcomes in our study for children with HMR-TB might be that until the diagnosis was made and appropriate treatment started, they received a number of effective drugs with good CSF penetration. Using either the old or the new WHO guidelines, this would not have been the case. inha mutation = low-level INH resistant, ETH resistant katg mutation = high-level INH resistant, ETH susceptible Combination HRZEth could therefore be sufficient even if INHresistance present if given for 9 months Seddon JA, Schaaf HS, et al. PIDJ 2012;31:711

Using either the old or the new WHO guidelines, this would not have been the case.

20 ETH and INH resistance in relation mutations of inha and katg genes SchaafHS, et al. EurJ MicrobiolInfect Dis 2006; 26:

21 Previously recommended TBM regimens WHO 2009: 2HRZS/4HR (or 7-10HR) adults WHO 2010: 2HRZE/10HR children AAP/ATS/IDSA 2012: 2HRZE(or Eth or S)/7-10HR) Indian Academy of Paeds 2009: 2HRZS(orE)/6-7HR SA NTP 2009: 2HRZE/4HR (but maybe for longer) SA NTP 2004: 3HRZEth/6HREth Other regimens (individual) - Ellard et al 1993: 2-3HRZS/6-9HRZ -Thwaiteset al 2004: 3HRZS/6HRZ (E for S if HIV+) -Thwaiteset al 2009: 2HRZE(S)/10HR - Donald et al 1998: 6HRZEth (children)

22 Suggested TBM regimens (Children) Drug-susceptible TBM: Strict DOT: 6HRZEth (HIV-uninfected) and 9HRZEth (HIV-infected) No DOT: 9HRZEth (most of SA) H 15mg/kg; R 20 mg/kg; Z 40 mg/kg; Eth 20 mg/kg Benefits: Covers missed doses, slow response and even INH monoresistant TB in many cases Risks: Hepatotoxicity low risk. Monitor for new-onset vomiting, abdominal pain, jaundice (late) GIT disturbance Hypothyroidism (temporary)

23 Suggested TBM regimens (Children) INH-resistant TBM Depending on mutation conferring resistance either low-level INH resistant or ethionamide resistant, therefore combination/choice RIF, PZA, Hd-INH, Eth, LFX, Tzdx 9 months Most likely overkill, but this is adding two drugs with good CSF penetration

24 Suggested TBM regimens (Children) MDR TBM Which mutation conferring INH resistance? >50% resistant to PZA and/or EMB Choice of drugs limited, outcome often poor, therefore use whatever available Hd-INH, PZA, Eth limited by possible resistance LFX (or MFX), TZD, AM, PAS, +/-LZD

25 Conclusions Most important in TBM is EARLY DIAGNOSIS TB drugs important, but also management of raised intracranial pressure and vasculitis Use effective anti-tb regimens especially look at CSF penetration of drugs Directly observed therapy and/or longer treatment duration Watch for complications of TBM and drugs

Screening and preventive therapy for MDR/XDR-TB exposed/infected children (and adults)

Screening and preventive therapy for MDR/XDR-TB exposed/infected children (and adults) H S Schaaf Department of Paediatrics and Child Health, and Desmond Tutu TB Centre Stellenbosch University, and Tygerberg