2 ส งหาคม 2559 เวลา น. รศ.พญ. วน ทปร ยา พงษ สามารถ ภาคว ชาก มารเวชศาสตร คณะแพทยศาสตร ศ ร ราชพยาบาล

Transcription

1 Meet the Experts in TB, TB/HIV, DR TB: Childhood MDR-TB 2 ส งหาคม 2559 เวลา น. รศ.พญ. วน ทปร ยา พงษ สามารถ ภาคว ชาก มารเวชศาสตร คณะแพทยศาสตร ศ ร ราชพยาบาล

2 Case 1: A 12 Year- Old Boy with Admitted June 2015 Neck Mass for 2 Mo ม ก อนท คอด านขวาโตมา 2 เด อน ได ร บ การร กษา Amoxy/clavulanate 1 ส ปดาห ไม ด ข น No constitutional symptoms, no fever No history TB contact, ค ณพ อม เสมหะ ในคอมาประมาณ 3 เด อน Rt cervical LN 6x4 cm with central fluctuation 1x1 cm

3 Case 1: A 12 Year- Old Boy with Neck Mass for 2 Mo

4 Case 1: A 12 Year- Old Boy with Neck Mass for 2 Mo Airborne isolation Rt neck aspiration Gram stain : Numerous PMN, No bacteria seen, C/S for bact-ng AFB: Not found Direct PCR : Negative for MTB complex Gastric Wash x 3days AFB: Not found Direct PCR : Negative for MTB complex Anti HIV : Negative

5 Case 1: A 12 Year- Old Boy with Neck Mass for 2 Mo Contact investigation Commenced on IRZE F/U ID clinic 1mo (24 Jul 2015) CXR บ ดา 1 mo later: Pus and gastric aspirate C/S: MTB complex

6 Case 1: A 12 Year- Old Boy with Neck Mass for 2 Mo Aug 2015 (2 mo later) Rt neck aspiration AFB: Not found Direct PCR : Negative for TB complex Culture : Mycobacterium tuberculosis complex Gastric Wash x 3days AFB: Not found Direct PCR : Negative for TB complex Culture : Mycobacterium tuberculosis complex MDR-TB Resistant to INH, Rif, PZA Sensitive to Ethambutol

7 2 nd Line Drugs Susceptibilities Available 3 Mo after Diagnosis

8 2 nd Line Drugs Susceptibilities Available 3 Mo after Diagnosis

9 Outline: Childhood TB Burden of childhood TB Drug resistant TB in children Early diagnosis Treatment of drug-resistant and MDR-TB (2016 WHO Update) Treatment of MDR-TB meningitis

10 Burden of Childhood TB

11 Childhood TB The actual burden of TB in children is likely higher given the challenge in diagnosing childhood TB Burden 1 Million At least 1 million children become ill with TB each year. Children represent about 10-11% of all TB cases Mortality 136,000 This includes TB deaths among children who were HIVpositive Reporting disaggregated by age 5 Only 5 countries do not yet report to WHO the notification of cases among children

12 Thailand (Population in 2014: 68 million)

13 Drug Resistant TB in Children

14 Time to Start Treatment for Patients with Drug-Resistant TB Prolonging the time to the initiation of treatment in TB patients predisposes to unfavourable clinical and public health consequences Increased disease progression with higher bacillary load in sputum More lung damage Continued transmission Starting an adequate treatment regimen within 4 weeks of diagnosis or strong presumption of RR/MDR-TB was associated with positive outcome

15 Molecular Characterization of INH- Resistance among M. tuberculosis Resistance to INH is mediated by at least two genes 1 KatG InhA Loss /reduced catalase-peroxidase activity (required for activation INH to active form) Major mechanism, present in ~ 50 90% of all INH-resistant isolates [found 80.6% of INH-resistant TB in Thailand] 2 Associated with relatively high-level resistance to INH Also resistance to ethionamide (ETH) 86% of INH-resistant isolates with InhA were also ETH-resistant 3 Up to 25% of INH resistant isolates do not carry any of known mutations C/S and standard DST are necessary 4 1. Guo H, et al. J Med Microbiol 2006;55: Boonaiam S, et al. Clin Microbiol Infect (4): Schaaf HS, et al. Int J Tuberc Lung Dis 2009;13(11): Laurenzo D, et al. Acta Trop 2011 ;119(1):5-10.

16 Molecular Characterization of Rif- Resistance among M. tuberculosis Rif resistance: assumed to be a surrogate marker for MDR TB, > 90% of Rif resistant isolates are INH resistant 1 rpob gene: accounts for > 90% of rifampicin resistance GeneXpert MTB/RIF (1,500 Bht, turn-around time 2 hr) Children: sensitivity 68.8% for GLA vs 90.0% for sputum; specificity 99.3% for GLA and 98.5% for sputum for pulmonary TB diagnosis 2 Rif resistance : sensitivity 94 98% and specificity 98%, relative to phenotypic DST 3 Some false-positive results confirmatory drug sensitivity testing is needed WHO has recommended MDR treatment regimen in patients with Rif-resistant pending for culture-based investigation and DST 4 1. Drobniewski FA. Microbiol 1998;47: Bates M. Lancet Infect Dis 2013; 13: Niemz A, et al. Expert Rev Mol Diagn 2012;12(7): WHO. Rapid implementation of the Xpert MTB/RIF diagnostic test: technical and operational how to practical considerations, 2011.

17 Rapid Diagnostic Test to Identify 2 nd - Line Drug Resistance WHO reports that < 20% of 480,000 MDR-TB patients globally are currently being properly treated LPA for rapid detection of MDR-TB was endorsed by WHO in 2008 In 2009, a new LPA, the Genotype MTBDRsl test, DNA-based test that identifies genetic mutations in MDR- TB strains, resistant to fluoroquinolones and injectable 2nd-line TB drugs Yields results in hours, down from > 3 months currently required can quickly be placed on appropriate 2 nd -line regimens prevent development of XDR-TB 016/multidrug-resistant-tuberculosis/en/

18 Line-Probe Assay (LPA) MTBDRsl test, for the rapid determination of genetic mutations associated with resistance to Fluoroquinolones detection of the gyra gene Aminoglycosides (kanamycin, amikacin and streptomycin) & cyclic peptides (capreomycin) detection of the 16S rrna gene (rrs) Ethambutol embb gene (together with the genes emba and embc, codes for arabinosyl transferase) allows for testing and reporting results within 24 hours THE USE OF MOLECULAR LINE PROBE ASSAY FOR THE DETECTION OF RESISTANCE TO SECOND-LINE ANTI-TUBERCULOSIS DRUGS. WHO/HTM/TB/

19 Line-Probe Assay (LPA) THE USE OF MOLECULAR LINE PROBE ASSAY FOR THE DETECTION OF RESISTANCE TO SECOND-LINE ANTI-TUBERCULOSIS DRUGS. WHO/HTM/TB/

20 Accuracy of Line Probe Assay for the Detection of 2 nd -Line Drug Resistance and XDR-TB Drugs/XDR-TB Indirect testing Direct testing Pooled sensitivity (95%CI) Fluoroquinolones 88.8% (82.7, 92.9) Kanamycin 67.0% (50.4, 80.2) Amikacin 89.6% (84.0, 93.5) Capreomycin 80.3% (64.7, 90.1) XDR-TB detection 63.3% (36.8, 83.5) Pooled specificity (95%CI) 97.9% (94.8, 99.2) 99.4% (97.0, 99.9) 99.5% (96.1, 100) 97.1% (92.5, 98.9). 98.5% (96.0, 99.4). Pooled Sensitivity (95%CI) 83.5% (69.1, 91.9) 96.2% (67.5, 99.7) 93.2% (76.8, 98.3) 97.4% (70.4, 99.8) 90.2% (79.0, 95.8) Pooled specificity (95%CI) 97.4% (95.7, 98.4) 99.0% (78.4, 100.0) 99.4% (95.7, 100.0) 96.6% (88.9, 99.0). 96.6% (93.8, 99.9) Moderate sensitivity for the detection of fluoroquinolone and 2nd-line injectable resistance, with high test specificity. THE USE OF MOLECULAR LINE PROBE ASSAY FOR THE DETECTION OF RESISTANCE TO SECOND-LINE ANTI-TUBERCULOSIS DRUGS. WHO/HTM/TB/

21 Expert Group Meeting Report Geneva: February 2013 Line probe assay cannot be used as a replacement test for conventional phenotypic DST!!! (Strong recommendation - Very Low Quality of Evidence) Remarks: 1. May be used as a rule-in test for XDR-TB but cannot be used to define XDR-TB for surveillance purposes; 2. As cross-resistance between 2 nd -line injectables is incomplete, line probe assay cannot be used to identify individual drugs to be used for treatment; 3. May be used to guide infection control precautions while awaiting confirmatory results from conventional phenotypic testing THE USE OF MOLECULAR LINE PROBE ASSAY FOR THE DETECTION OF RESISTANCE TO SECOND-LINE ANTI-TUBERCULOSIS DRUGSWHO/HTM/TB/

22 Management of TB in Children

23 MDRTBguidelines2016.pdf

24 Shorter MDR-TB Regimen for Adults & Children Patients with rif-resistant or MDR- TB who Have not been previously treated with 2 nd -line drugs Resistance to fluoroquinolones and 2 nd -line injectable agents has been excluded or is highly unlikely a shorter MDR-TB regimen of 9-12 months may be used instead of a conventional regimen (conditional recommendation, very low certainty in the evidence).

25 WHO Recommendations On The Use of The Shorter MDR-TB Regimen In May 2016

26 Treatment Success: Shorter VS Conventional MDR-TB Regimens

27 Second-Line Drug Susceptibilities of MDR-TB in Thailand: strains of MDR-TB, including 58 XDR-TB strains, isolated from Siriraj Hospital, Bangkok, Thailand Chaiprasert A, et al. Int J Tuberc Lung Dis ;18(8):961-3.

28 Conventional MDR-TB Regimens for Adults & Children In patients with rif-resistant or MDR- TB, a regimen with at least 5 effective TB medicines during the intensive phase is recommended, including Pyrazinamide + 4 core 2 nd -line TB medicines 1 from group A (Fluoroquinolone) + 1 from group B (2 nd -line injectable agent)+ At least 2 from group C2 (conditional recommendation, very low certainty in the evidence). If the minimum of effective TB medicines cannot be composed as above may add an agent from group D2 and other agents from D3 to bring the total to five

29 Medicines for the Treatment of Rifampicin-Resistant and MDR-TB Not yet approved in children

30 Pyrazinamide Susceptibility among MDR-TB Isolates from Siriraj Hospital 150 M. tuberculosis isolates, consisting of 50 susceptible and 100 MDR-TB isolates tested for PZA susceptibility by BACTEC MGIT 960 PZA PZA resistance 6% among susceptible TB isolates 49% among MDR-TB isolates High rates PZA resistance among MDR-TB in Thailand Jonmalung J, et al. BMC Microbiol 2010;10:223.

31 Fluoroquinolones in MDR-TB Regimens The order of preference for the inclusion of the latergeneration is as follows: high-dose levofloxacin (750 mg/d), moxifloxacin and gatifloxacin Ofloxacin be phased out from MDR-TB regimens and that ciprofloxacin is never used

32 Dosing of Levofloxacin in Children Treated for Active or Latent MDR-TB For adults, levofloxacin doses of mg once daily yield the target maximal drug concentration (Cmax), 8 12 μg/ml the same target has been suggested for children Levofloxacin dosage should be 15 20mg/kg for Cmax 8 µg/ ml and a high target attainment across faucss,0 24/MIC values in children 2 years of age Mase SR, et al. Pediatr Infect Dis J 2016;35:

33 2 nd -Line Injectable Agents The choice of 3 standard agents to use amikacin, capreomycin or kanamycin Streptomycin Not included with the 2 nd -line drugs Can be used as if none of the 3 other agents can be used and the strain can be reliably shown not to be resistant In a study focused on hearing loss in children with TB, 24% of children treated for MDR-TB with an injectable agent had hearing loss and 64% of children had progression of hearing loss after finishing it (30% were HIV-infected) Seddon JA, et al. J Infect. 2013;66(4):320 9.

34 Other Core 2 nd -Line Agents When designing the core MDR-TB treatment regimen, > 2 of the following are to be included: Ethionamide (or prothionamide) Cycloserine (or terizidone) Linezolid Clofazimine * Usually in this order of preference, unless the balance of benefits-to-harms

35 High-Dose INH for MDR-TB Regimens for Adults & Children A meta-analysis of 9,153 patients with rif-resistant or MDR- TB showed a statistically-significant increased likelihood of treatment success in children with bacteriologically-confirmed MDR- TB if used high-dose INH in the regimen A randomised controlled trial of high-dose INH for MDR-TB in adults found no increased risk of hepatotoxicity High-dose isoniazid was very well tolerated in children with drug susceptible TB meningitis Ahuja SD, et al. PLoS Med 2012;9(8):e Epub 2012 Aug 28.

36 High-Dose INH for MDR-TB Regimens for Adults & Children MDR-TB treatment regimens: be further strengthened with high-dose INH (15 20 mg/kg/day) and/or ethambutol Strains bearing inha gene may have a low minimum inhibitory concentration (MIC) to INH can be overcome by high-dose INH In settings with elevated prevalence of high-level INH resistance associated with katg mutations, highdose isoniazid may be less effective and should not be used

37 Case 1: A 12 Year- Old Boy with Neck Mass for 2 Mo Jan 2016 ( 5 mo after MDR- TB regimen: Kanamycin, levofloxacin, ethionamide, ethambutol) อาการด ข น ก อนย บ นน ต วข นด hearing test (Nov 2015: normal, TFT: normal) ส งเกตก อนท คอโตข นมา 2-3 ว น (2.5 cm) ร บประทานยาสม าเสมอ ยายพา ไปฉ ดยาท อนาม ยใกล บ านท กคร ง ท มาตรวจท รพ.ศ ร ราช ฉ ด จ นทร -ศ กร (5 ว น/เด อน)

38 Case 2: A 2-Mo-Old M with Fever and Vomiting for 9 d เด กชายไทย อาย 2 เด อน ภ ม ลาเนา กร งเทพมหานคร 9 ว นก อนมา รพ.ศ ร ราช ม ไข ส ง อาเจ ยน 3-4 คร ง/ว น ถ ายเหลว 2 คร ง ไม ซ ม ไป admit ท รพ. เอกชน CBC: Hb 10 g/dl, Hct 31%, PLt 472,000 /ul, WBC 11,400/ ul(n26% L61% Mo10% E2%) UA: WBC 0-1, Stool exam: WBC 1-2 Stool rotavirus antigen : negative Rapid influenza A: negative Dengue IgM: negative CXR : RLL infiltration

39 History Rx: Cefotaxime 150 MKDay และ Amikacin 15 Mkday หล งได ยา 2 ว นย งม ไข o c จ งปร บขนาดยา Cefotaxime เป น 200 MKDay ไม ได ท า Lumbar puncture Ultrasound Brain : Communicating hydrocephalus, Refer มารพ. ศ ร ราช Past history : G4P3 GA 36 wk, ANC รพ.เอกชน ผล serology negative all, C/S due to maternal severe preeclampsia, BW 1,800 gm, HC 30.5 cm, Lt 43 cm, symmetrical SGA, APGAR 9,10, หล งคลอดม ป ญหา thrombocytopenia Plt 63,000 CMV PCR : negative CMV IgM, Toxo IgM, Rubella IgM, HSV IgM : negative U/S brain : IVH gr I, no calcification ปฏ เสธประว ต contact TB Vaccination : BCG 1 HBV 2 DTP 1 OPV1

40 Physical Examination T 37.7 c, HR 144/min, RR 36/min, BP 83/60 mmhg, O2sat 100%, capillary refill 2 sec BW 4,220 gm (P50), Lt 58 cm (P75), HC 40.5cm (P90- P97), AF 4x4 cm minimal bulging Lungs: clear, equal breath sound Skin: presence of BCG scar at Lt. shoulder CNS: downward gaze both eyes, pupils 2 mm BRTL, Kernig s sign : positive, Brudzinski s : positive, equal movement all extremities, normal tone, reflex all 2+, Babinski s : plantar flexion, Moro reflex +

41 Investigations Lumbar Puncture OP 33 cmh2o, CP 15 cmh2o RBC 755 cells/cumm WBC 12 cells/cumm ( N1% L76% M23%), Protein 82 mg/dl, sugar/bs 29/126 mg/dl

42 Investigations CSF and gastric wash : Positive for MDR TB (KatG amd rpob gene)

43 Treatment of TB Meningitis Related to Rifampicin- Resistant or MDR-TB Strains

44 Treatment of TB Meningitis Related to MDR-TB Strains Best guided by drug susceptibility and the properties to penetrate CNS Patients with RR-/MDR-TB meningitis Fluoroquinolones: good CNS penetration Ethionamide (or prothionamide), Cycloserine (or terizidone) Linezolid PZA has good CNS penetration large percentage of MDR-TB strains may be resistant. INH penetrates the CNS very well high-dose INH is recommended as part of the treatment regimen unless high-level resistance is known PAS and ethambutol do not penetrate the CNS well and should not be counted as effective drugs for MDR-TB meningitis. Kanamycin, amikacin and streptomycin only penetrate the CSF in the presence of meningeal inflammation Little data on the CNS penetration of capreomycin, clofazimine, bedaquiline or delamanid.

45 Conclusions MDR-TB is an increasing global problem including among pediatric population Rapid diagnosis and promptly appropriate treatment are crucial and associated with better outcomes

46 THANK YOU FOR YOUR KIND ATTENTION

47 Conventional MDR-TB Regimens for Adults & Children There is no change in the recommended use of the new TB drugs from those defined by the WHO interim guidance on bedaquiline (2013) and delamanid (2014) (no recommendation for use in children). The two drugs now occupy a unique subgroup within the Add-on agents used to treat MDR- TB.