MEDICAL MANAGEMENT OF TB - Home | Curry …nid... · Medical Management of TB – slide outline 1 ... * TBTC Study 22: San Francisco Department of Public Health Population Health

TB CASE MANAGEMENT AND CONTACT INVESTIGATION INTENSIVE March 27-30, 2017

Curry International Tuberculosis Center, UCSF 300 Frank H. Ogawa Plaza, Suite 520 Oakland, CA; Office (510) 238-5100

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 PAGES

1. Medical Management of TB – slide outline Presented by: Chris Keh, MD

1-25

SUPPLEMENTAL READING MATERIALS

None

TB CASE MANAGEMENT AND CONTACT INVESTIGATION INTENSIVE March 27-30, 2017

Curry International Tuberculosis Center, UCSF 300 Frank H. Ogawa Plaza, Suite 520 Oakland, CA; Office (510) 238-5100

ADDITIONAL RESOURCES

• Curry International Tuberculosis Center. Drug-resistant tuberculosis: a survival guide for

clinicians, third edition. 2016. URL: http://www.currytbcenter.ucsf.edu/sites/default/files/tb_sg3_book.pdf

• Curry International Tuberculosis Center. Drug-Induced Liver Injury, Archived webinar recorded October 16, 2013. URL: http://www.currytbcenter.ucsf.edu/trainings/tuberculosis-drug-induced-liver-injury

• Curry International Tuberculosis Center. Pediatric Tuberculosis: Online Presentation. 2010. URL: http://www.currytbcenter.ucsf.edu/products/view/pediatric-tuberculosis-online-presentation

• 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):1288-99.

• Curry International Tuberculosis Center. Medical Management of Tuberculosis: Online

Presentation. 2007. URL: http://www.currytbcenter.ucsf.edu/products/view/medical-management-tuberculosis-online-presentation

• 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. 2006 Oct 15;174(8):935-52. URL: http://www.atsjournals.org/doi/abs/10.1164/rccm.200510-1666ST?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed&#.UmlrbHzn_3s

• 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: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5211a1.htm

• Guidelines for the Treatment of Active Tuberculosis Disease, CDHS/CTCA Joint Guidelines. 2003.

URL: http://www.ctca.org/fileLibrary/file_65.pdf

• 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):13-17. URL: http://www.cdc.gov/mmwr/pdf/wk/mm4909.pdf (pages 13 to 17).

http://www.currytbcenter.ucsf.edu/sites/default/files/tb_sg3_book.pdf

http://www.currytbcenter.ucsf.edu/trainings/tuberculosis-drug-induced-liver-injury

http://www.currytbcenter.ucsf.edu/trainings/tuberculosis-drug-induced-liver-injury

http://www.currytbcenter.ucsf.edu/products/view/pediatric-tuberculosis-online-presentation

http://www.currytbcenter.ucsf.edu/products/view/medical-management-tuberculosis-online-presentation

http://www.currytbcenter.ucsf.edu/products/view/medical-management-tuberculosis-online-presentation

http://www.atsjournals.org/doi/abs/10.1164/rccm.200510-1666ST?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed&#.UmlrbHzn_3s

http://www.atsjournals.org/doi/abs/10.1164/rccm.200510-1666ST?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed&#.UmlrbHzn_3s

http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5211a1.htm

http://www.ctca.org/fileLibrary/file_65.pdf

http://www.cdc.gov/mmwr/pdf/wk/mm4909.pdf

TB Case Management and Contact Investigation IntensiveMarch 27-30, 2017Curry International Tuberculosis Center

Medical Management1

San Francisco Department of Public Health Population Health Division

Chris Keh, MD

TB Control, San Francisco Department of Public Health

Assistant Clinical Professor, Division of Infectious Diseases, UCSF

Curry International Tuberculosis Center, CMCI Intensive, March 27, 2017

Population Health Division

Medical Management of TB

Protecting and Promoting Health and Equity

San Francisco Department of Public Health


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


Medical Management2


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)


Medical Management3


What do these all have in common?

CITC/Firland TB Image Library; Masa Narita, MD, Thienkhai Vu, MD. http://www.currytbcenter.ucsf.edu/sites/default/files/product_tools/tbradlibrary/index.html





Medical Management4



• 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



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)


Medical Management5


The Drugs (first‐line)

• Rifampin (RIF), 10 mg/kg/d

• Isoniazid (INH), 5 mg/kg/d

• Pyrazinamide (PZA), 25 mg/kg/d

• Ethambutol (EMB), 15‐25 mg/kg/d


Rifamycins

• Includes: rifampin, rifabutin• Bactericidal; Inhibits protein synthesis• Cytochrome P450 Inducer = MANY drug‐drug interactions– Examples include: OCP, methadone, ART, anti‐seizure 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


Medical Management6


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)


Medical Management7


EMB

• Bacteriostatic at typical doses (bactericidal at high end of dosing range)

• Inhibitor of cell wall synthesis


First‐line medicationsDrug / dose Hepatotoxicity Specific adverse Additional

Rifampin, 10mg/kg(max: 600 mg)

+ Rash, pruritus, hypersensitivityGI upsetThrombocytopeniaHemolytic anemia

INH, 5 mg/kg(max: 300 mg)

++ Peripheral neuropathyDrug‐induced lupusCNS symptomsOptic neuritis

Co‐administer with B6

PZA, 25 mg/kg ++ GoutHyperuricemiaArthralgiasPhotosensitivity

Dose adjustment to TIW in CrCl<30Dose after HD

EMB, 15‐25 mg/kg Retrobulbar neuritis (dose‐related, exacerbated by CKD)

Use higher dose only during initial months.Dose adjustment to TIW in CrCl<30Dose after HD


Medical Management8


Second‐line (commonly used)Drug / dose Hepatotoxicity Specific adverse Additional

Rifabutin, 5 mg/kg(max: 300 mg)

+ Anterior uveitisLeukopeniaThrombocytopeniaArthralgias

<20% of rifampin‐resistant strains will have in vitro susceptibility to RFB

Moxifloxacin, 400mg qday

Rare QTc prolongationTendon ruptureGI upsetC diff risk

Levaquin, 750mg qday(typically)

QTc prolongationTendon ruptureGI upsetC diff risk

Dose adjustment to TIW in CrCl<30

Injectable (e.g. streptomycin, capreomycin, amikacin)10‐15 mg/kg/day with max 750‐1000 mg / day based on age

NephrotoxicityOtotoxicityElectrolyte abnormalities

Adjust to BIW‐TIW depending on renalfunction and phase of treatment (i.e. continuation phase)


New Treatment Guidelines, 2016


Medical Management9


Treatment Regimens


Drug Regimens for Pan‐Susceptible Disease

CDC/MMWR, Treatment of Tuberculosis, 2016


Medical Management10


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, 2016




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 1st 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 +/‐ FQ

6‐9 months INH

RIF/EMB +/‐ FQ

9‐12 months (preferably with PZA during first 2 months)

INH

INH/EMB/FQ 12‐18 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)

RIF

INH/EMB/PZA 18 months (consider injectable in first 2‐3 months for extensive disease or to shorten duration to 12 mo)

RIF

INH/PZA/SM 9 months RIF

* CITC: Drug‐Resistant Tuberculosis: A Survival Guide for Clinicians, 3rd edition




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 TBLocation 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




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)




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: http://www.currytbcenter.ucsf.edu/products/view/tuberculosis‐drug‐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.




SteroidsMeningitis• 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

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

* Mayosi, et al, 2002; Strang, et al, 1988, 2004; Hakim, et al, 2000 * Thwaites, et al, 2004; Prasad, et al, 2008; Girgis, et al, 1991


Monitoring




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




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




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, 0.1‐2.7% depending on combo

• Fatal hepatitis <0.023%

– RIF • rare except in combination with other drugs

• Asymptomatic hyperbilirubinemia (0.6%)

• Cholestatic pattern of hepatitis




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)




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/ non‐hepatotoxic 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.




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 Effect of Food

RIF Best on empty stomachAvoid fatty meal

INH Best on empty stomachAvoid fatty meal (up to 50% reduction in peak)

PZA None

EMB None


Gastrointestinal (GI) Intolerance

• Symptoms: nausea, vomiting, diarrhea• Causes: any• Rule out hepatotoxicity first• Treatment:

– Anti‐emetics: Reglan, phenergan, zofran. Consider pre‐medication, 30‐60 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)




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 re‐challenge. May need hospitalization / urgent derm consult.

– If moderate symptoms and no anaphylaxis, HOLD meds, then re‐challenge 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




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 25‐50 mg daily in diabetes, pregnancy, HIV, kidney disease, alcoholism, breastfeeding women

• Treatment: consider either discontinuation of INH or increasing pyridoxine dosing (100‐200 mg/d)

• Ddx: consider other causes including thyroid disease, vitamin deficiency, other medications




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.




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),

http://www.cdc.gov/tb/education/rtmc/– Drug‐Resistant Tuberculosis: A Survival Guide for Clinicians, Curry

Center

• Med side effects:– Drug‐Induced Liver Injury,

http://www.currytbcenter.ucsf.edu/training/webarchive/tbdili/arch_tbdili.cfm

– Tuberculosis Drug Information Guide, Curry Center– ART‐TB DDI: Guidelines for the Use of Antiretroviral Agents in HIV‐1‐

Infected Adults and Adolescents, https://aidsinfo.nih.gov

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MEDICAL MANAGEMENT OF TB - Home | Curry …nid... · Medical Management of TB – slide outline 1 ... * TBTC Study 22: San Francisco Department of Public Health Population Health