MEDICAL MANAGEMENT OF TB

Transcription

1 TB CASE MANAGEMENT AND CONTACT INVESTIGATION INTENSIVE MEDICAL MANAGEMENT OF TB LEARNING OBJECTIVES Upon completion of this session, participants will be able to: 1. Describe the recommended treatment regimens and first-line medications for TB disease 2. Identify the common side effects of first-line tuberculosis medications and recommended monitoring 3. Describe evaluation and treatment of side effects of first-line tuberculosis medications 4. Define and describe appropriate completion of treatment for TB disease INDEX OF MATERIALS 1. of TB slide outline Presented by: Chris Keh, MD PAGES 1-25 SUPPLEMENTAL READING MATERIALS None, UCSF 300 Frank H. Ogawa Plaza, Suite 520 Oakland, CA; Office (510)

2 TB CASE MANAGEMENT AND CONTACT INVESTIGATION INTENSIVE ADDITIONAL RESOURCES. Drug-resistant tuberculosis: a survival guide for clinicians, third edition URL: Drug-Induced Liver Injury, Archived webinar recorded October 16, URL: Pediatric Tuberculosis: Online Presentation URL: Khan FA, Minion J, Pai M, et al. Treatment of active tuberculosis in HIV-coinfected patients: a systematic review and meta-analysis. Clin Infect Dis 2010 May 1;50(9): of Tuberculosis: Online Presentation URL: Saukkonen JJ, Cohn DL, Jasmer RM, Schenker S, Jereb JA, Nolan CM, et al. An official ATS statement: Hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med Oct 15;174(8): URL: American Thoracic Society/ Centers for Disease Control and Prevention/Infectious Diseases Society of America: Treatment of tuberculosis. MMWR.June 20, 2003; 52(RR11):1-77. URL: Guidelines for the Treatment of Active Tuberculosis Disease, CDHS/CTCA Joint Guidelines URL: Updated Guidelines for the Use of Rifabutin or Rifampin for the Treatment and Prevention of Tuberculosis Among HIV-Infected Patients Taking Protease Inhibitors or Nonnucleoside Reverse Transcriptase Inhibitors MMWR Morb Mortal Wkly Rep. 2000;49(9): URL: (pages 13 to 17)., UCSF 300 Frank H. Ogawa Plaza, Suite 520 Oakland, CA; Office (510)

3 of TB Protecting and Promoting Health and Equity Chris Keh, MD TB Control, Assistant Clinical Professor, Division of Infectious Diseases, UCSF, CMCI Intensive, March 27, 2017 Objectives Describe the recommended treatment regimens and first line medications for TB disease Identify the common side effects of first line tuberculosis medications and recommended monitoring Describe evaluation and treatment of side effects of first line tuberculosis medications Define and describe appropriate completion of treatment for TB disease 1

4 General Principles Never add a single drug to a failing regimen Completion of treatment is based on number of doses taken, not duration alone Duration of therapy (or number of doses needed) is dependent on: drugs used extent of disease response to treatment Co morbidities (e.g. HIV, immune compromise) Directly observed therapy (DOT) DOT should be considered for all patients with active TB. If resources do not allow for DOT, prioritize DOT for those with highest consequences for individual or public: Individual (pediatric, HIV, clinical worsening while on treatment) Public (sputum smear positive, correctional facility, drug resistance, dialysis, congregate living setting, marginally housed, prior TB treatment or relapsed disease, slow response to treatment) Potential for non adherence (psychiatric disease, pediatric, adverse reactions to meds, etoh/drug use, too ill to self manage / elderly / cognitive impairment) 2

5 What do these all have in common? CITC/Firland TB Image Library; Masa Narita, MD, Thienkhai Vu, MD. What do these all have in common? CITC/Firland TB Image Library; Masa Narita, MD, Thienkhai Vu, MD. 3

6 What do these all have in common? Answer: These patients were all diagnosed with TB. Don t be tricked! TB can present: Cavitary Consolidation / infiltrate Effusion Nodule Fibrosis/scarring Miliary Adenopathy Bilateral, any lobe CITC/Firland TB Image Library; Masa Narita, MD, Thienkhai Vu, MD. General Principles, pan susceptible Initial Phase (initial 2 months of treatment) Prevents drug resistance until drug susceptibility testing (DST) is known Continuation Phase (subsequent 4 7 months of treatment Initial Phase (2 mo) Continuation Phase (4 7 mo) 4

7 The Drugs (first line) Rifampin (RIF), 10 mg/kg/d Isoniazid (INH), 5 mg/kg/d Pyrazinamide (PZA), 25 mg/kg/d Ethambutol (EMB), mg/kg/d Rifamycins Includes: rifampin, rifabutin Bactericidal; Inhibits protein synthesis Cytochrome P450 Inducer = MANY drugdrug interactions Examples include: OCP, methadone, ART, antiseizure medications, coumadin Complete medication review is needed and any new additions should be noted during treatment. Rifabutin: alternative for drug drug interaction (has lesser degree of induction) or intolerance to rifampin 5

8 INH Bactericidal, esp for rapidly dividing cells Inhibits mycolic acid (cell wall) synthesis Use Vitamin B6 in specific populations (uremia, HIV, diabetes, malnutrition) to prevent peripheral neuropathy Increases carbamazepine / phenytoin levels PZA Largest activity against dormant / semidormant bacteria within macrophages / acidic environment of caseous granulomas (bactericidal). One of the required drugs for shortening duration to 6 months Used in the first 2 months of treatment (initial phase) 6

9 EMB Bacteriostatic at typical doses (bactericidal at high end of dosing range) Inhibitor of cell wall synthesis First line medications Drug / dose Hepatotoxicity Specific adverse Additional Rifampin, 10mg/kg (max: 600 mg) INH, 5 mg/kg (max: 300 mg) + Rash, pruritus, hypersensitivity GI upset Thrombocytopenia Hemolytic anemia ++ Peripheral neuropathy Drug induced lupus CNS symptoms Optic neuritis PZA, 25 mg/kg ++ Gout Hyperuricemia Arthralgias Photosensitivity EMB, mg/kg Retrobulbar neuritis (doserelated, exacerbated by CKD) Co administer with B6 Dose adjustment to TIW in CrCl<30 Dose after HD Use higher dose only during initial months. Dose adjustment to TIW in CrCl<30 Dose after HD 7

10 Second line (commonly used) Drug / dose Hepatotoxicity Specific adverse Additional Rifabutin, 5 mg/kg (max: 300 mg) Moxifloxacin, 400mg qday Levaquin, 750mg qday (typically) Injectable (e.g. streptomycin, capreomycin, amikacin) mg/kg/day with max mg / day based on age + Anterior uveitis Leukopenia Thrombocytopenia Arthralgias Rare QTc prolongation Tendon rupture GI upset C diff risk QTc prolongation Tendon rupture GI upset C diff risk Nephrotoxicity Ototoxicity Electrolyte abnormalities <20% of rifampinresistant strains will have in vitro susceptibility to RFB Dose adjustment to TIW in CrCl<30 Adjust to BIW TIW depending on renal function and phase of treatment (i.e. continuation phase) New Treatment Guidelines,

11 Treatment Regimens Drug Regimens for Pan Susceptible Disease CDC/MMWR, Treatment of Tuberculosis,

12 Who should receive extended therapy (i.e. at least 9 mo)? Identify those at risk of treatment failure / relapse Cavitary disease on CXR, delayed culture conversion*: Cavitary disease on CXR: 5 6% relapse Delayed culture conversion (culture positive after 2 months of treatment): 5 6% relapse Cavitary disease on CXR + delayed culture conversion: 21% relapse PZA < 2 months during intensive phase Consideration: HIV not on ART, cancer/chemotherapy, extensive disease, delayed clinical/radiographic response, silicosis, poorly controlled diabetes * TBTC Study 22 HIV infection Daily regimen recommended High rates of relapse seen in once weekly, BIW, TIW regimens Emergence of rifamycin resistance in intermittent therapy Duration of treatment (for pan susceptible, pulmonary disease, unless other risk for relapse) On ART 6 mo (2HRZE, 4HR) Off ART 9 mo (2HRZE, 7HR) Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV 1 infected adults and adolescents. Department of Health and Human Services. CDC/MMWR, Treatment of Tuberculosis,

13 HIV infection Drug drug interactions must be carefully reviewed, in particular with antiretroviral therapy and rifamycins (see DHHS HIV guidelines). Work closely with HIV provider as newer agents have DDI (TAF, dolutegravir) ART start CD4<50: within 2 weeks of TB tx start CD4 50: by 8 12 weeks of TB tx start TB meningitis: should not be initiated in 1 st 8 weeks Paradoxic reactions (IRIS) can occur during treatment Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV 1 infected adults and adolescents. Department of Health and Human Services. CDC/MMWR, Treatment of Tuberculosis, 2016 Alternate regimens (in order of preference) Regimen Duration Pattern of resistance RIF/PZA/EMB 6 9 months INH +/ FQ RIF/EMB +/ FQ INH/EMB/FQ INH/EMB/PZA 9 12 months (preferably with PZA during first 2 months) months (preferably with PZA during first 2 months; consider injectable in first 2 3 months for extensive disease or to shorten duration to 12 mo) 18 months (consider injectable in first 2 3 months for extensive disease or to shorten duration to 12 mo) INH/PZA/SM 9 months RIF * CITC: Drug Resistant Tuberculosis: A Survival Guide for Clinicians, 3rd edition INH RIF RIF 11

14 Treatment Completion Determined by the total number of doses ingested over a period of time, not by the duration of treatment E.g. 6 month daily regimen: patient should complete 182 doses (6 months worth of doses) within 9 months Extra pulmonary TB Location Duration Special Considerations Pleural 6 mo Drainage if possible recommended. Empyema: surgery, optimal duration unknown Lymphadenitis 6 mo LN s may enlarge or develop new LN s during and after Rx Pericarditis 6 mo Consider steroids Genitourinary 6 mo May need stent / nephrostomy w/ urology Peritoneal 6 mo Disseminated 6 9 mo Longer course for immune compromised / children Bone / Joint 6 12 mo Longer course typically recommended with hardware CNS / meningitis 9 12 mo Recommend steroids during first 6 8 weeks 12

15 Scenario A patient with pan susceptible pulmonary TB is started on standard therapy, but has a worsening CXR 2 months into treatment. What do you do? Treatment failure Red flags Delayed culture conversion (i.e. > 60 days); may need to use smears as surrogate while awaiting cultures Worsening imaging at 2 months Worsening or persistent symptoms at 2 months At risk large burden of disease, cavitary, diabetic Recommendations Determine if development of resistance has occurred (repeat DST, molecular testing) and if regimen needs to be expanded Assess if malabsorption present Assess adherence Check drug levels (TDM) 13

16 Therapeutic Drug Monitoring (TDM) Typically performed when concerned about treatment failure, malabsorption Routine TDM is controversial due to lack of clinical significance. Typically a send out (e.g. National Jewish, University of Florida) Monitor peak concentrations (e.g. 2 and 6 hour post dose), reference the CITC drug guide for timing: information guide 2nd edition 0 Scenario An intern pages you about a patient with recent diagnosis of TB pericarditis and wonders about the role of steroids. 14

17 Meningitis Decreases mortality and disability (limited data) 6 8 week tapered course (examples): Prednisone 60mg with taper by 10 mg each week Dexamethasone: 0.3 to 0.4 mg/kg/day x 2wk, 0.2 mg/kg/day x 1wk, 0.1 mg/kg/day x 1wk, 4 mg per day and taper 1 mg off the daily dose each week Steroids Pericarditis May lower mortality, decrease need for pericardiectomy, prevent constriction (limited data) More recent studies suggest steroids prevent constrictive pericarditis and to use only in patients at risk for this No longer routinely recommended. Consider in: large effusion, high inflammatory cells or markers in fluid, or early signs of constriction * Thwaites, et al, 2004; Prasad, et al, 2008; Girgis, et al, 1991 * Mayosi, et al, 2002; Strang, et al, 1988, 2004; Hakim, et al, 2000 Monitoring 15

18 Baseline evaluation CBC Renal profile Liver function testing, uric acid HIV screening Hepatitis B/C screening (for IVDU, foreign born Asia/Africa, HIV) Weight Visual acuity, red green color discrimination History and Physical Imaging (CXR for pulmonary, may be other imaging for extra pulm) Monitoring Monthly: Face to face symptom review Adherence Visual acuity, color discrimination (if on EMB) Weight: re dose medications as needed CXR (for pulmonary TB) or other imaging: every 3 6 months, end of treatment Sputum: Smear positive: at least q2 weeks until smear conversion then monthly until culture conversion Smear negative: monthly until culture conversion 16

19 Lab Monitoring Routine lab monitoring is not typically recommended except for those at high risk or symptomatic. Regardless, clinical monitoring is a MUST! LFT: Underlying hepatic disease Pregnancy or post partum HIV IVDU or ETOH abuse Consider: Age >50 yo, concomitant hepatotoxic medications Creatinine Underlying renal disease PZA, EMB require renal dosing if creatinine clearance <30 CBC Underlying hematologic abnormalitiy Rifabutin (can cause leukopenia, thrombocytopenia) Management of Adverse Reactions 17

20 Scenario A patient with Pott s disease develops fatigue and anorexia while on TB treatment. You check LFT s and AST 200, ALT 150. What do you do? Drug induced Liver Injury (DILI) Causative: PZA (1%) INH Asymptomatic elevation <5x ULN in 10 20% Clinical hepatitis, % depending on combo Fatal hepatitis <0.023% RIF rare except in combination with other drugs Asymptomatic hyperbilirubinemia (0.6%) Cholestatic pattern of hepatitis 18

21 DILI (management) HOLD medications for the following or any GI complaint: abdominal pain, diarrhea, fatigue, nausea/vomiting, anorexia, malaise, jaundice, dark urine. Check LFT s If LFT <5x upper limit of normal (ULN) and asymptomatic, okay to restart but may need closer monitoring. If LFT <3x ULN and symptomatic, okay to restart with supportive measures, e.g. treatment of gastritis or nausea. May need closer monitoring. DILI (management) STOP medications for the following: Asymptomatic + LFT >5x upper limit of normal (ULN) Symptomatic + LFT >3x ULN Screen for hepatitis (A, B, C) or other underlying causes of liver disease (alcohol use, other hepatotoxic medications). Check INR. Determine if urgent evaluation or admission is needed (e.g. >10x ULN or any evidence of liver failure asterixis, confusion, dehydration, coagulopathy) 19

22 DILI (re challenge) Monitor LFTs weekly until 2x ULN (some programs completely normal), before re challenging with medications. If severe TB disease, may need to start liver sparing regimen. Seek consultation in re introduction of medications Choice in med re challenge depends on co morbidities (cirrhosis), degree of hepatitis (mild vs severe), susceptibilities (pan susceptible or pending), phase (initial or continuation), and most likely suspect (PZA>INH>RIF). Typically, start least suspect agent first (along w/ nonhepatotoxic meds), monitor LFTs in 3 7 days, and if remain normal then re challenge with next agent. Scenario A patient complains to you about nausea and wonders if he can split doses or take them with food. 20

23 Dosing Administration First line meds should be administered together as a single dose Single dose leads to a higher, more effective peak concentration Facilitates DOT implementation Prefer administration with food rather than splitting doses Drug RIF INH PZA EMB Effect of Food Best on empty stomach Avoid fatty meal Best on empty stomach Avoid fatty meal (up to 50% reduction in peak) None None Gastrointestinal (GI) Intolerance Symptoms: nausea, vomiting, diarrhea Causes: any Rule out hepatotoxicity first Treatment: Anti emetics: Reglan, phenergan, zofran. Consider premedication, minutes prior to TB meds. Probiotics / loperamide for diarrhea Light snack prior to medications Consider bedtime dosing (if on video DOT or on SAT) Treat gastritis with H2 blocker or proton pump inhibitor Evaluate for other causes: ulcer, pancreatitis, C diff, kidney injury, biliary causes (gallstones) 21

24 Rash (mild) Causative: any drugs, esp RIF, PZA Symptoms: maculopapular rash, flushing, pruritus Treatment: Antihistamines (e.g. claritin, hydroxyzine, benadryl) Triamcinolone cream / steroid cream Low dose steroids (10 20mg/day) if above unsuccessful For flushing: Avoid tyramine containing foods with INH (wine, salami, cheese) and certain fish (tuna) Avoid sun / use sunblock (PZA/FQ) Rash (mod severe) Drugs should NOT be continued if: systemic symptoms, fever, urticaria, angioedema, blisters, SOB, anaphylaxis DRESS: most commonly RIF, INH, EMB Treatment: If serious (e.g. Stevens Johnson, anaphylaxis, TEN) do NOT rechallenge. May need hospitalization / urgent derm consult. If moderate symptoms and no anaphylaxis, HOLD meds, then rechallenge once rash improves. Antihistamines / steroids as needed. Consider derm referral. Rechallenge start with the most important drug first, unless thought to be the inciting agent May need desensitization for those meds deemed to be necessary 22

25 Arthralgias / Gout Arthralgias (up to 40%): Causative: PZA>>EMB, INH, RIF Treatment: NSAIDs or ASA Gout (rare): Causative: PZA>>EMB Elevated uric acid Prevention: consider allopurinol or optimization of gout at time of TB med start Treatment: NSAIDs, allopurinol, colchicine Peripheral neuropathy Causative: INH>>EMB Occurs <0.2% with INH at conventional dosing (10mg/kg/d) Prevention: pyridoxine mg daily in diabetes, pregnancy, HIV, kidney disease, alcoholism, breastfeeding women Treatment: consider either discontinuation of INH or increasing pyridoxine dosing ( mg/d) Ddx: consider other causes including thyroid disease, vitamin deficiency, other medications 23

26 Optic neuritis Causative: EMB>>INH Screening: monthly visual acuity, red green color discrimination (Ishihara plates) Symptoms: blurry vision, vision loss, spots, red green color issues, eye pain Treatment: hold medications, urgent ophthalmology evaluation to determine etiology Additional pearls Consider risk / benefit of EMB in children whose visual acuity cannot be monitored. Situations where you might avoid PZA: Pregnancy, severe liver disease, gout, advanced age Use fixed dose combinations when possible. Avoid splitting doses if possible. 24

27 Helpful resources Treatment Guidelines: ATS/CDC/IDSA, Treatment of Drug Susceptible Tuberculosis, 2016 Local/State specific guidelines (e.g. CDHS/CTCA Joint Guidelines for the Treatment of Active Tuberculosis Disease) Regional Training and Medical Consultation Centers (RTMCC), Drug Resistant Tuberculosis: A Survival Guide for Clinicians, Curry Center Med side effects: Drug Induced Liver Injury, bdili.cfm Tuberculosis Drug Information Guide, Curry Center ART TB DDI: Guidelines for the Use of Antiretroviral Agents in HIV 1 Infected Adults and Adolescents, 25