MEDICAL MANAGEMENT OF TBnid]/3._medical...TUBERCULOSIS CASE MANAGEMENT AND CONTACT INVESTIGATION...

TUBERCULOSIS CASE MANAGEMENT AND CONTACT INVESTIGATION INTENSIVE

MARCH 19-22, 2019

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: Michelle Haas, MD

26

SUPPLEMENTAL MATERIAL

None

ADDITIONAL REFERENCES

• Nahid P, Dorman SE, Alipanah N, Barry PM, Brozek JL, Cattamanchi A, et al. Official American

Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of

America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis. Clin Infect Dis.

2016 Oct 1;63(7):e147-e195. doi: 10.1093/cid/ciw376. Epub 2016 Aug 10. URL:

https://www.cdc.gov/tb/publications/guidelines/pdf/clin-infect-dis.-2016-nahid-cid_ciw376.pdf

• 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

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

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

• 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

https://www.cdc.gov/tb/publications/guidelines/pdf/clin-infect-dis.-2016-nahid-cid_ciw376.pdf

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.ctca.org/fileLibrary/file_65.pdf

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



TUBERCULOSIS CASE MANAGEMENT AND CONTACT INVESTIGATION INTENSIVE

MARCH 19-22, 2019

• 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.cdc.gov/mmwr/pdf/wk/mm4909.pdf

Medical Management of TuberculosisMichelle Haas, MDDenver Metro TB Control Program, Denver Public Health

TB Case Management and Contact Investigation IntensiveMarch 19-22, 2019 1

© 2017 Denver Public Health

Medical Management of Tuberculosis

Michelle Haas, MD

Associate Director, Denver Metro TB Control Program Denver Public Health

Assistant Professor of Medicine, Division of Infectious Diseases, UC Denver

Curry International Tuberculosis Center, CMCI Intensive March 19—22nd, 2019

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



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)



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






• 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)



The Drugs (first-line)

• Rifampin (RIF, “R”), 10 mg/kg/d

• Isoniazid (INH, “H”), 5 mg/kg/d

• Pyrazinamide (PZA, “Z”), 25 mg/kg/d

• Ethambutol (EMB, “E”), 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



INH

• Bactericidal, especially 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

• Greatest 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)



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)

+ 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



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 renal function and phase of treatment (i.e. continuation phase)

Treatment Guidelines, 2016



Treatment Regimens

Drug Regimens for Pan-Susceptible Disease

CDC/MMWR, Treatment of Tuberculosis, 2016



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• None of the above: 2% 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 Interruptions

• Very common due to side effects

• General principle: the earlier the break in therapy and the longer in duration, the more serious the effect

• Decision to continue or restart the treatment- no set guidelines

Treatment Interruptions

Treatment Guidelines, 2016 (Table 6), NYC example



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



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: https://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.

http://www.currytbcenter.ucsf.edu/products/view/tuberculosis-drug-information-guide-2nd-edition-0



Steroids

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

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!

• LFTs:• 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

http://www.cdc.gov/tb/education/rtmc/

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

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