Tuberculosis Treatment: Drug Therapy, Case Management, & Special Considerations

Transcription

1 Tuberculosis Treatment: Drug Therapy, Case Management, & Special Considerations Take Home Information for Attendees of the 2014 Intergovernmental Panel Physicians Training Summit

2 Principles of Tuberculosis Treatment Standard Drug Regimen for PanscuceptibleTuberculosis: INH, RIF, PZA, EMB Intensive Phase 2 Months Continuation Phase 4 Months 4 Drugs Isoniazid Rifampin Ethambutol Pyrazinamide 2 Drugs Isoniazid Rifampin Intake of drugs observed 5-7 days a week Intake of drugs observed 3-5 days a week

3 General Principles of Therapy Always treat with a multiple-drug regimen Never add a single drug to a failing regimen Duration of treatment depends on the drugs used (the weaker the regimen, the longer the treatment) Isoniazid, rifampin, and pyrazinamide are the basis of modern short-course chemotherapy Schecter, 2012

4 Standard Drug Therapy for Tuberculosis Treatment Initial Phase Continuation Phase Isoniazid Rifampin Pyrazinamide Ethambutol 5 mg/kg up to 300 mg 10 mg/kg up to 600 mg mg/kg mg/kg Months Schecter, 2012

5 Pansusceptible Treatment Both are equally acceptible: 7 days a week Intensive phase: 56 doses Continuation phase: 126 doses 5 days a week Intensive phase: 40 doses Continuation phase: 90 doses 8 weeks 18 weeks 8 weeks 18 weeks ATS/CDC/IDSA guidelines Table 2

6 Challenges Associated with Standard Drug Therapy for Tuberculosis What are the side effects most commonly seen in patients/applicants undergoing tuberculosis treatment? INH RIF PZA EMB be What comorbidities or drug interactions should panel sites concerned about when an applicant is under treatment? Who is permitted to provide DOT? Under what circumstances should treatment regimens be adjusted? Extended?

7 Adverse Reactions Between 8-18% have drug regimens modified Most common side effects: Rash Gastrointestinal intolerance Liver toxicity Peripheral neuropathy (INH) Optic neuritis (ethambutol)- dose and duration dependent Gout, arthropathy (pyrazinamide)

8 Rash Any of the drugs can produce rash Hold all medications until rash subsides Serial re-challenge sequentially every 3-4 days to find cause Usual sequence is INH, rifampin, pyrazinamide, ethambutol

9 GI Intolerance Discern between transient vs. persistent Transient: pill burden, indigestion Persistent: anorexia, nausea, and fatigue may signify liver toxicity If hepatotoxicity suspected, hold meds and obtain liver function tests (LFTs) If LFTs are normal, restart meds and reassure

10 Liver Toxicity Most feared adverse reaction INH, rifampin, and pyrazinamide can all cause liver injury Warn patients to seek immediate attention if anorexia, nausea, emesis, abdominal discomfort, or jaundice develops 4-5 fold increased risk with hepatitis C Liver sparing regimen of ethambutol, quinolone, and injectable agent may be necessary if early in treatment and high-burden disease Prevention: avoidance of alcohol and monitoring LFTs if other drugs with potential liver toxicity are used

11 Liver Toxicity: Order of Re-challenge Depends on Circumstances Patterns of hepatitis Hepatocellular (increased transaminases): can be caused by all three 1 st line agents Cholestasis (high Alk phos and bilirubin) is usually due to rifampin INH hepatitis: often age-dependent Pyrazinamide hepatitis: often dose-dependent

12 Isoniazid (INH) Adverse Effects Asymptomatic transaminitis Up to 5X upper limit normal in 10-20% Clinical hepatitis With INH alone approximately 0.6%; 2.7% with RIF Peripheral neurotoxicity Less than 0.2% unless predisposing factors Central nervous system effects Not well quantified Lupus-like reaction Approximately 20% develop positive ANA; Lupus in less than 1%

13 Rifampin (RIF) Adverse Effects Cutaneous reactions Pruritus with or without rash in up to 6% Gastrointestinal reactions Variable incidence but usually mild Flu-like syndrome Occurs in % receiving 600 mg twice weekly Hepatoxicity Transient asymptomatic hyperbilirubinemia in 0.6% Clinical hepatitis uncommon, usually cholestatic Immunological reactions <0.1% develop platelets, anemia, renal failure

14 Ethambutol (EMB) Adverse Effects Retrobulbar neuritis Less than 1% with dose of 15 mg/kg 18% with more than 30 mg/kg/day Peripheral neuritis Rare Cutaneous reactions Approximately % require discontinuation of drug

15 Pyrazinamide (PZA) Adverse Effects Hepatotoxicity About 1% develop clinical hepatitis, can be severe Gastrointestinal symptoms Mild anorexia and nausea are common Non-gouty polyarthralgia Up to 40% receiving daily PZA, not serious Hyperuricemia Asymptomatic - expected effect Acute gouty arthritis - rare except if pre-existing gout Cutaneous reactions Transient morbilliform rash, self-limited Photosensitive dermatitis

16 Isoniazid Drug Interactions Isoniazid - Relatively potent inhibitor of several cytochrome P450 isozymes, but not CYP3A Inhibitory activity of INH increases the serum concentrations of phenytoin, carbamazepine, and diazepam Rifampin has opposite effect and outweighs inhibitory effect of INH INH may increase toxicity to acetaminophen, valproate, serotonergic antidepressants, disulfiram, warfarin, and theophylline

17 Rifamycins Drug Interactions Rifamycins - Induce various isozymes of the cytochrome P450 system resulting in a decrease in serum concentration of many drugs Enzyme induction: Rifampin>rifapentine>rifabutin Corticosteroids, steroid contraceptives, oral hypoglycemic agents, oral anticoagulants, phenytoin, cimetidine, digitalis, antiretroviral agents

18 Summary: Common Drug Side Effects Side Effects Drug G.I. Effects Ethionamide PAS Quinolones Clofazimine Aminoglycosides Rifabutin Headache Quinolones INH Cycloserine Ethambutol Ethionamide Skin Problems Clofazimine Cycloserine INH Rifabutin PAS Ethionamide Ethambutol Photosensitivity Clofazimine Quinolones Hepatotoxicity INH Pyrazinamide Rifabutin Ethionamide PAS Quinolones Behavioral Changes Cycloserine INH Quinolones Ethionamide

19 Summary: Common Drug Side Effects (Cont.) Side Effects Drug Musculoskeletal/joint Pyrazinamide Quinolones Rifabutin Rifampin INH Visual changes, eye pain Ethambutol Rifabutin Clofazimine INH (high-dose) Linezolid Hearing loss, tinnitus, loss of balance Aminoglycosides Capreomycin Dizziness Aminoglycosides/capreomycin Cycloserine Quinolones Peripheral Neuropathy INH Ethionamide Cycloserine Ethambutol Hypothyroidism Ethionamide PAS Hypokalemia/hypomagn Aminoglycoside/capreomycin Lima, Aug 2011

20 Drug Therapy for Tuberculosis Treatment: Extending Therapy Initial Continuation Phase* Isoniazid Rifampin Pyrazinamide Ethambutol 0 1 2* months *If cavitary disease and culture positive at 2 months, extend continuation phase from 4 to 7 months. Schecter, 2012

21 Alternative Regimens Drug Resistance Mono INH resistance 6 month regimen of Rif, PZA, and EMB (+/-fluoroquinolone(fqn)) 12 months Rif, EMB (+/- FQN) Mono Rifampin resistance 12 month regimen of INH, PZA, and EMB (+/-FQN) 18 month regimen of INH, EMB MDR TB 4-6 drugs, always including a FQN and injectable drug if susceptible, for months post culture conversion (the injectable drug for a minimum of 6 months) Schecter, 2012

22 Special Situations Treatment Interruptions Initial phase < 14 days Continue treatment If total not completed in 3 months re-start from the beginning 14 days Re-start from the beginning Continuation phase < 80% completed AND interruption < 3 months Continue treatment If not completed in 6 months restart from the beginning < 80% completed AND interruption 3 months Re-start from the beginning 80% completed Continue treatment Miriti, 2011

23 Treatment of Drug Resistant Cases What are the categories of drugs used for the treatment of drug-resistant cases? Once drug resistance is identified, how should a treatment regiment be determined? Describe some of the treatment concerns associated with drug-resistant cases? How can risks be minimized?

24 Potential Regimens for the Management of Patients with Drug- Resistant Tuberculosis Pattern of Drug Resistance Suggested Regimen Duration of Treatment (months) Comments INH (± SM) RIF, PZA, EMB (an FQN may strengthen the regimen for patients with extensive disease) 6 In BMRC trials, 6-month regimens have yielded 95% success rates if four drugs were used in the initial phase and RIF plus EMB or SM was used throughout.* Additional studies suggest results were best if PZA was also used throughout the 6 months. INH and RIF (± SM) FQN, PZA, EMB, IA, ± alternative agent Extended treatment is needed to lessen the risk of relapse. INH and RIF (± SM) and EMB or PZA FQN (EMB or PZA if active), IA, and two alternative agents 24 Use of first line agents to which there is susceptibility. Add two or more alternative agents in case of extensive disease. RIF INH, EMB, FQN, supplemented with PZA for the first 2 months (an IA may be included for the first 2-3 months for patients with extensive disease) Daily and thee times weekly regimens of INH, PZA and SM given for 9 months were effective in a BMRC trial. * Source: Mitchison DA, Nunn AJ. Influence of initial drug resistance on the response to short-course chemotherapy of pulmonary tuberculosis. Am Rev Respir Dis 1986; 133: Source: Hong Kong Chest Service, British Medical Resource Council. Five year follow-up of a control trial of five 6 month regimens of chemotherapy for tuberculosis. Am Rev Respir Dis 1987; 136: Source: Hong Kong Chest Service, British Medical Resource Council. Controlled trail of 6-month and 9-month regimens of daily and intermediate streptomycin plus isoniazid plus pyrazinamide for pulmonary tuberculosis in Hong Kong. Am Rev Respir Dis 1977;115: Lauzardo, 2012

25 Guiding Principles for Treating MDR-TB Consult with experts in coordination with country you are screening for. Use guidelines in Drug-Resistant Tuberculosis A Survival Guide for Clinicians, 2 nd edition (Curry National TB Center). Medication regimen must be based on drug susceptibility results. A single new drug should never be added to a failing regimen. Employ at least three previously unused drugs to which there is in vitro susceptibility. One of these should be an injectable agent. Do not limit the regimen to three agents if other previously unused drugs that are likely to be active are available. Simultaneous use of two injectable agents is not recommended. Resistance to PZA is uncommon in the absence of resistance to other first-line drugs. Lauzardo, 2012

26 Guiding Principles for Treating MDR-TB Intermittent therapy should not be used for tuberculosis caused by drug-resistant organisms, except perhaps for injectable agents after an initial period of daily therapy. The use of drugs to which there is demonstrated in vitro resistance is not encouraged. The use of INH is associated with better survival rates in patients with the strain- W variety of MDR M. tuberculosis that are susceptible to higher concentrations of INH. Resistance to RIF is associated with cross-resistance to rifabutin and rifapentine. There is no cross-resistance between streptomycin and the other injectable agents, however cross-resistance between amikacin and kanamycin is universal. Lauzardo, 2012

27 DOT: The Basics What is true DOT? Why Directly Observed Therapy (DOT)? Who is permitted to provide DOT? Please discuss the importance of documentation in DOT

28 Directly Observed Therapy (DOT) Patients are observed to ingest each dose of antituberculosis medications, to maximize the likelihood of completion of therapy Enablers: assist the patient in completing therapy. e.g. follow-up missed appointments Incentives: Interventions to motivate the patient. e.g. US immigrant visa Tan, SLEC

29 Why DOT? Adherence to treatment is the single most important factor predicting cure of tuberculosis and prevention of acquired drug resistance DOT: Effect on Resistance and Relapse Self-treatment N=407 (pre 1987) DOT N=581 (1987 +) Primary Resistance 13% 6.7% Secondary Resistance 10.3% 1.4% Relapse 20.9% 5.5% MDR relapse 6.1% 0.9% schecter Schecter, 2012

30 Principles of DOT Every dose throughout the course of treatment must be observed by a health-care worker Worker watches applicant swallow each dose of medication and checks mouth for retained pills Not acceptable to dispense on a weekly or monthly basis DOT required during intensive and continuation phases. Total number of doses most important Applicant may take one-two weekend doses unobserved, but those are not counted toward total # of doses. Will not extend treatment if patient adherent to DOT. Staff must understand principles of DOT Miriti, 2011

31 Who Can and Cannot Deliver DOT for Immigration Purposes CAN Physician Nurse Other trained health worker CANNOT Family member Non trained health worker Non health care worker Miriti, 2011

32 Observing and Documenting the Dose Prepares the medications Watches the applicant swallow the medications Tan, 2011

33 Checking mouth for swallowed dose Miriti, 2011

34 Observing and Documenting the Dose Checks the mouth for retained medications Documents the doses Tan, 2011

35 Case Management What should be included in the intake process be when an applicant/patient begins treatment? Establishing a regimen Setting a treatment schedule/culture Patient education TB treatment file What are your recommendations for optimal applicant/patient management? What situations should indicate that greater patient/applicant Who is permitted to provide DOT? management is required when someone is under treatment? How does case management change when treating a drug-resistant case?

36 Creating a TB DOT File TB treatment file should include Referral letter and DS forms indicating basis for TB diagnosis TB Patient record card Contains current photo of patient Lists home address, telephone number, alternate number for the patient supporter, disease category, patient classification, drugs used TB treatment compliance card Side effect monitoring card Patient appointment card Miriti, 2011

37 Anti-TB Drug Patient Packs Miriti, 2011

38 Patient Education Objectives To provide correct information To prevent defaulters and ensure completion of treatment To get family support To improve success of contact investigation To improve infection control Tan, SLEC

39 Patient Education Comprehensive TB disease, transmission, control Medications and possible side effects Duration of treatment and required DOT compliance Lifestyle changes Good nutrition and hygiene Contact evaluation Treatment monitoring: sputum analysis and CXR schedule (psychological preparation and financial implications for self payers.) Miriti, 2011

40 Patient Education Explain immigration process Repeat TB testing and repeat medical examination required at the end of TB treatment TB treatment must be completed successfully to be medically cleared for travel TB patient education is a continuous process from initial visit through the end of treatment. Miriti, 2011

41 Patient Monitoring Baseline laboratories and follow up laboratory results Daily signs and symptoms check (DON T assume there are no side effects if the patient doesn t initiate conversation) Weight (weekly) Vital Signs (daily/weekly) Observe every patient swallow every pill Document the dose Pulmonary evaluation (monthly) Schedule and follow-up on results of sputum smears, cultures and DST Schedule for Chest X-ray Track patients lost to follow-up Oladele, 2013

42 Routine Monitoring and Frequency Signs and symptoms monthly Sputum conversion Weight LFTs Side effects: MD evaluations End of treatment 2 specimens monthly until cultures negative for 2 consecutive months monthly Baseline, 1 month and prn Monthly: includes visual acuity and red/green discrimination, GI complaints, check for jaundice Minimum at baseline, 3 months and end of therapy 2 sputa for smear and culture Schecter, 2012

43 Sputum Smear and Culture Monitoring During Treatment Schedule Pansusceptible, Mono or Poly-drug resistance (not MDR) No DST 1st month Two specimens* One specimen 2nd month Two specimens* One specimen 3rd month 4th month 5th month 6th month Treatment completion Two specimens* (if culture pending from 1st month) No specimens needed if cultures obtained after treatment months #1 and #2 are negative Two specimens One specimen One specimen One specimen One specimen Two specimens *Obtain at end of month Tan, SLEC

44 Management of Treatment Failure, Relapse 90-95% of patients treated for pulmonary TB will have negative sputum cultures by 3 months If still culture positive after 3 months of therapy: Recheck drug susceptibility tests Assess adherence Consider malabsorption of drugs Schecter, 2012

45 Management of Treatment Failure, Relapse Treatment failure Culture positive after 4 months of therapy: If the patient is seriously ill or sputum AFB smear +, an empirical regimen should be started with at least two new drugs If the patient is not seriously ill consider waiting for the results of drug susceptibility testing If malabsorption suspected, consider IV therapy (INH, rifampin, moxifloxacin) Schecter, 2012