16007107 ade-of-anti tubercular-drugs-mdr-tb[1]

CATEGORIES OF TB CASES* AND TREATMENT REGIMENS UNDER RNTCP Category Characteristics Treatment regimen Intensive phase Continuation phase I New sputum +ve or Seriously ill sputum – ve, Seriously ill extra pulmonary 2 ( HRZE )3 4 ( HR )3 II Relapse, Failure Default 2 ( SHRZE )3 followed by 1 ( HRZE )3 5 ( HRE )3 III Not seriously ill-Sputum –ve , extra pulmonary 2 ( HRZ )3 4 ( HR ) 3

Reaction 1 Flushing and/or itching of the skin with or without a rash Involves the face and scalp; may cause redness/watering of the eyes, usually occurs 2-3 hours after drug ingestion Causative agents: Rifampin, Pyrazinamide Management Flushing is usually mild and resolves without therapy Antihistamine may be administered to treat or prevent the reaction

Reaction 2 Flushing and/or itching of the skin with or without a rash PLUS hot flashes, palpitations, headache and/or increased blood pressure Immediately after ingestion of certain foods usually resolves within 2 hours Causative agents Isoniazid + tyramine containing foods (cheese, red wine) or certain fish (tuna, Management Advise patient not to ingest foods listed above while receiving INH

Clinical Presentation-hives (raised, itchy rash) with or without fever Causative Agents INH < rifampin < PZA < ethionamide < cycloserine < ethambutol < PAS <SM Management Children Discontinue all drugs Rule out a viral infection If a viral infection is present, restart all of the TB medications (no rechallenge is required) If a viral infection is ruled out, follow rechallenge guidelines

Management Adults 1. Discontinue all drugs until the reaction resolves 2. Identify the causative drug by rechallenging (restarting) each drug every 4 days according to

Dr.U.P.Rathnakar.MD.DIH.PGDHM K.M.C. Mangalore

Causative Agents Ethionamide, (PAS), R, H Management- Children Qty, form of medication administered Is the child gagging when medicine is administered? Empty stomach? Other causes of vomiting?

Management- Adults Rule out Other causes of vomiting?

Ethionamide, (PAS), rifampin, rifabutin, ofloxacin, levofloxacin Rule out other causes With hold until diarrhoea resolves Restart drugs one at a time every 4 days Begin with drugs that are least likely to cause diarrhea Consider crushing pills/capsules If the patient was receiving a twice or thrice weekly regimen when the diarrhea began, consider switching to a 5x/week regimen

Clinical Presentation [Hepatotoxicity is very uncommon in children] Symptoms: nausea, vomiting, abdominal tenderness, discomfort near the ribs on the right upper abdomen, jaundice Signs: hepatic enlargement, increased LFTs Causative Agents INH + rifampin > INH alone >> pyrazinamide* alone > rifampin alone > ethionamide

Management in Adults Hold all drugs and obtain LFTs If LFTs are within the normal ranges, Manage Nausea/Vomiting If LFTs are elevated, hold drugs until symptoms resolve and the transaminases decreases to < 2x normal 1)E and Z should be started if drug therapy can not be held secondary to the patient’s clinical condition a) S if Z is suspected to be the cause of hepatotoxicity 2) Rechallenge the patient after resolution of signs and symptoms by adding drugs to the regimen every 4 days6: a) Rifampin for 3 days, if patients remains asymptomatic then add b) INH for 3 days, if patients remains asymptomatic then add c) Pyrazinamide (15-20mg/kg/d) for 3 days 3) If signs and symptoms recur with rechallenge, discontinue the responsible drug and modify the regimen and/or duration of therapy as required

Causative Agents Z>>E> H [Arthralgia only] Management do not require discontinuation Symptomatic treatment of joint pain and gouty arthralgia NSAIDs, Colchicine etc

Causative Agents INH>>>ethambutol Management Peripheral neuropathy is uncommon if the patient is receiving pyridoxine( if peripheral neuropathy occurs, it can be treated with pyridoxine 100-200mg , while the patient is receiving INH Optic Neuritis Causative Agents Ethambutol>>INH Discontinue

Pregnancy[2HRZ+4HR] Breast feeding women- INH prophy., BCG Cortecosteroids-Serious, Hypersen.,etc. AIDS MAC

Prevent latent to active Contacts of positive case who show recent conversion Children with posive mantoux and a contact in family Neonates of tubercular mother Immunocompromized with Mantoux +ve Old case who received inadequate therapy H 300 mg x 6-12 mo H+ R x 6 months Other alternatives

MDR-TB is defined as resistance to isoniazid and rifampicin, with or without resistance to other anti-TB drugs. XDR-TB is defined as resistance to at least Isoniazid and Rifampicin (i.e. MDR-TB) plus resistance to any of the fluoroquinolones and any one of the second-line injectable drugs (amikacin, kanamycin, or capreomycin).

MDR-TB is a man made phenomenon Poor drugs Poor treatment Poor adherence ” Amplifier effect of Short Course Therapy” Use of DOTS in MDR-TB pts-More resistance to the drugs-

Treatment of MDR TB Addressed by DOTS PLUS guidelines MDR-TB management to be undertaken only at selected health institutions with experience, expertise and availability of required diagnostic and treatment facilities DOTS PLUS sites

Drug resistance suspected based on history of prior treatment (e.g. smear positive case after repeated treatment courses, Cat II failure etc.) and/or close Exposure to a possible source case confirmed to have drug-resistant TB Diagnosis of MDR-TB done through culture and drug susceptibility testing [DST]

Drug susceptibility test results of Pyrazinamide, streptomycin, and ethambutol are poorly reproducibile 2nd line anti-TB drugs should be interpreted with great caution due to limited capacity of laboratories, absence of quality-assurance, and lack of standardized methodology.

Preferably the standardized regimen as recommended in the national DOTS-Plus guidelines should be used [6 or(9) Km Ofx Eto Cs Z E / 18 Ofx Eto Cs E ] If results of 2nd line DST are available, an individualized regimen may be used in such patients after obtaining a detailed history of previous anti-TB treatment

At least 6 months of Intensive Phase (IP) should be given, Extended up to 9 months in patients who have a positive culture result taken at 4th month of treatment Minimum 18 months of Continuation Phase (CP) should be given following the Intensive Phase

Smear examination should be conducted monthly during IP Quarterly during CP Culture examination should be done at least at 4, 6, 12, 18 and 24 months

All patients and their family members intensively counselled prior to treatment initiation and during all follow-up visits Treatment under direct observation (DOT) over the entire course of treatment If DOT is not possible, attempts to ensure treatment adherence should be made by Checking empty blister packs; and Follow up visits at least every month

A systematic record of Treatment regimen, Doses, duration, Side-effects, Investigation Results Treatment outcome

Standardized treatment Representative DRS data in well-defined patient populations are used to design the regimen.

2. Standardized Treatment followed by individualized treatment Initially, all patients in receive the same regimen based on DST survey data from representative populations. The regimen is adjusted when DST results become available (often DST is only done to a limited number of drugs).

Empirical treatment followed by individualized treatment Each regimen is individually designed on the basis of patient history and then adjusted when DST results become available (often the DST is done of both first- and second-line drugs)

Alternative method of grouping anti tuberculosis drugs GROUPING DRUGS (ABBREVIATION) Group 1 – First-line oral antituberculosis agents Isoniazid (H); Rifampicin (R); Ethambutol (E); Pyrazinamide (Z) Group 2 – Injectable antituberculosis agents Streptomycin (S); Kanamycin (Km); Amikacin (Am); Capreomycin (Cm); Viomycin (Vi) Group 3 Fluoroquinolones Ciprofloxacin (Cfx); Ofloxacin (Ofx); Levofloxacin, (Lfx); Moxifloxacin (Mfx); Gatifloxacin (Gfx) Group 4 – Oral bacteriostatic agents Ethionamide (Eto); Protionamide (Pto); Cycloserine (Cs); Terizidone (Trd)a; P-aminosalicylic acid (PAS); Thioacetazone (Th) Group 5 – Antituberculosis agents with unclear efficacy (not recommended by WHO for routine use in MDR-TB patients) Clofazimine (Cfz); Amoxicillin/Clavulanate (Amx/ Clv); - Clarithromycin (Clr); Linezolid (Lzd)

Example of standard drug code used to describe a regimen [6 or(9) Km Ofx Eto Cs Z E / 18 Ofx Eto Cs E ] The initial phase 6drugs and lasts 6 months or 9 months Phase without the injectable continues all the oral agents for 18 months Total treatment of 24 months. The injectable agent is kanamycin (Km), but there is an option for capreomycin (Cm).

Basic Principles-1 Use at least 4 drugs certain or highly likely to be effective depending on following factors DST results show susceptibility. No previous history of treatment failure with the drug. No known close contacts with resistance to the drug. Drug resistance survey indicates resistance is rare in similar patients. The drug is not commonly used in the area. If at least 4 drugs are not certain to be effective, use 5–7 drugs depending on the specific drugs and level of uncertainty.

Basic Principles-2 Do not use drugs for which resistance crosses over All rifamycins (rifampicin, rifabutin, rifapentene, rifalazil) have high levels of cross-resistance. Fluoroquinolones :In vitro data showing that some higher-generation fluoroquinolones remain susceptible when lower-generation fluoroquinolones are resistant. In these cases, it is unknown whether the higher-generation fluoroquinolones remain clinically effective. Not all aminoglycosides and polypeptides cross-resist; in general, only kanamycin and amikacin fully cross-resist.

Basic Principles-3 Eliminate drugs that are not safe in the patient Known severe allergy or unmanageable intolerance. High risk of severe adverse effects including renal failure, deafness, hepatitis, depression and/or psychosis. Quality of the drug is unknown or questionable.

Basic Principles-4 Include drugs from Groups 1–5 in a hierarchical order Use any Group 1 (oral first-line) drugs that are likely to be effective Use an effective aminoglycoside or polypeptide by injection based on potency (Group 2 drugs). Use a fluoroquinolone (Group 3). Use the remaining Group 4 drugs to make a regimen of at least 4 effective drugs. For regimens with ≤4 effective drugs, add second-line drugs most likely to be effective, to give up to 5–7 drugs in total, on the basis that at least 4 are highly likely to be effective. The number of drugs will depend on the degree of uncertainty. Use Group 5 drugs as needed so that at least 4 drugs are likely to be effective.

Basic Principles-5 Be prepared to prevent, monitor and manage adverse effects for each of the drugs selected. Ensure laboratory services for haematology, biochemistry, serology and audiometry are available. Establish a clinical and laboratory baseline before starting the regimen. Initiate treatment gradually for a difficult-to-tolerate drug, split daily doses of Eto/Pto, Cs and PAS. Ensure ancillary drugs are available to manage adverse effects. Implement DOT for all doses.

Mono- and Poly-drug resistance PATTERN RESISTANCE SUGGESTED REGIMEN MINIMUM OF DRUG DURATION OF Treatment COMMENTS H (± S) R, Z and E 6–9 A fluoroquinolone may strengthen the regimen for patients with extensive disease. H and Z R, E and fluoroquinolones 9–12 A longer duration of treatment should be used for patients with extensive disease. H and E R, Z and fluoro- 9–12 A longer duration of treatment should be used for patients with extensive disease.

Mono- and Poly-drug resistance PATTERN RESISTANCE SUGGESTED REGIMEN MINIMUM OF DRUG DURATION OF Tratment COMMENTS R H, E, fluoroquinolones, plus at least 2 months Z 12–18 An injectable agent may strengthen the regimen for of patients with extensive R and E (± S) H, Z, fluoroquinolones, plus an injectable agent for at least the first 2–3 months 18 A longer course (6 months) of the injectable agent may strengthen the regimen for patients with extensive disease

PATTERN RESISTANCE SUGGESTED REGIMEN MINIMUM OF DRUG DURATION OF Treatment COMMENTS R and Z (± S) H, E, fluoroquinolones, plus an injectable agent for at least the first 2-3 months 18 A longer course (6 months) of the injectable agent may strengthen the regimen for patients with extensive disease. H, E, Z (± S) R, fluoroquinolones, plus an oral second-line agent, plus an injectable for 2-3 months 18 A longer course of the injectable agent

Mono- and Poly-drug resistance These guidelines are based On evidence from the pre-Rifampicin era, Observational studies, General principles of microbiology Therapeutics in TB, Extrapolations from established Evidence and expert opinion. Effective drugs should not be withheld for later use.

Pregnancy Not much experience with MDR TB & pregnancy All women on MDR TB-Birth control measures Risk/Benifits discussed with pt. Tt started ii/iii trimester unless life threatening Avoid AG-May be added after delivery Aim-Achieve sputum conversion before delivery Pregnancy is not a contraindication for treatment of active drug-resistant TB Avoid injectable agents- Capreomycin used if unavoidable Avoid ethionamide.-Nausea, TERATOGENIC

Breastfeeding Encourage breast feeding if negative Chemotherapy is the best way to prevent transmission of tubercle bacilli to baby. Most antituberculosis drugs will be found in the breast milk It is recommended to provide infant formula options When infant formula is provided, fuel for boiling water and apparatus (stove, heating pans and bottles) must also be provided, AND training on how to prepare and use the infant formula.

Contraception A woman receiving rifampicin treatment may choose between Oral contraceptive pill containing a higher dose of estrogen (50 μg); Or use of another form of contraception.

Surgery Local/unilateral resection Adjunct to chemotherapy

HIV & MDR TB Not much difference Diagnosis is difficult and delayed ADE are more common Failure of Anti-TB/Anti Retroviral therapy can occur HAART should be started within 2 weeks of initiation of MDRTBtreatment

Children Children with TB are often culture-negative. Guided by the results of DST and the history of the contact 's exposure to antituberculosis drugs MDR-TB is life threatening, and no antituberculosis drugs are absolutely contraindicated in children. Benefit of Fluoroquinolones in treating MDR-TB in children outweighs any risk. Dosed according to body weight All drugs, dosed at the higher end of the recommended ranges except ethambuto l.

Diabetes mellitus With MDR-TB are at risk for poor outcomes. Diabetes mellitus may potentiate the adverse effects of drugs,-renal dysfunction and peripheral neuropathy Use of ethionamide or protionamide may make it more difficult to control insulin levels.

Renal insufficiency Adjustment of antituberculosis medication in renal insufficiency Dose and/or the interval between dosing should be adjusted

Liver disorders The first-line drugs isoniazid, rifampicin and pyrazinamide associated with hepatotoxicity. Rifampicin is least likely to cause hepatocellular damage, although it is associated with cholestatic jaundice. Pyrazinamide is the most hepatotoxic of the three first-line drugs. Among the second-line drugs, ethionamide, protionamide and PAS can also be hepatotoxic, But less than any of the first-line drugs. Patients with chronic liver disease should not receive pyrazinamide.

Seizure disorders The first step is to determine whether the seizure disorder is under control Whether the patient is taking anti-seizure medication. If the seizures are not under control, control of seizures will be needed before the start of drug-resistant TB therapy. Cycloserine should be avoided Drug interactions-Mono and poly-resistant cases, the use of isoniazid and rifampicin Seizures that present for the first time during antituberculosis therapy Likely to be the result of an adverse effect of one of the anti tuberculosis drugs.

Psychiatric disorders High baseline incidence of depression and anxiety in patients with MDR-TB,-socioeconomic stress factors related to the disease. Cycloserine is not absolutely contraindicated for the psychiatric patient.

Substance dependence Complete abstinence from alcohol or other substances encouraged If the treatment is repeatedly interrupted because of the patient’s dependence, therapy should be suspended until successful treatment Cycloserine has higher incidence of adverse effects in patients dependent on alcohol or other substances, including a higher incidence of seizures.

HIV/MDR TB/Drug interactions Nonenteric-coated didanosine contains an aluminium/magnesium-based antacid Given jointly with fluoroquinolones, results in decreased fluoroquinolone absorption It should therefore be given six hours before or two hours after fluoroquinolone administration.

Drug interactions in the treatment of drug-resistant TB and HIV Rifamycins (rifampicin, rifabutin), while not used in MDR-TB treatment,are needed in the treatment of many poly- and mono-resistant cases. Rifamycins may lower the levels of protease inhibitors and non-nucleoside reverse transcriptase inhibitors,. Rifabutin has the least effect

Drug toxicity in the treatment of drug-resistant TB and HIV HIV patients have a higher rate of adverse drug reactions to both TB and non-TB medications Peripheral neuropathy (stavudine, a minoglycosides, cycloserine, pyrazinamide), Cutaneous and hypersensitivity reactions (thioacetazone) Gastrointestinal adverse effects renal toxicity (injectables) Neuropsychiatric effects (cycloserine, efavirenz).

Antituberculosis drug abbreviations Am Amikacin Lfx Levofloxacin Amx/Clv Amoxicillin/Clavulanate Lzd Linezolid Cfx Ciprofloxacin Mfx Moxifloxacin Cfz Clofazimine Ofx Ofloxacin Clr Clarithromycin PAS P-aminosalicylic acid Cm Capreomycin Pto Protionamide Cs Cycloserine R Rifampicin E Ethambutol S Streptomycin Eto Ethionamide Th Thioacetazone Gfx Gatifloxacin Trd Terizidone H Isoniazid Vi Viomycin Km Kanamycin Z Pyrazinamide

Adverse effects, management Seizures------------- Cs , H, Fluoro Suspend suspected agent pending resolution of seizures. Initiate anticonvulsant therapy (e.g. phenytoin, valproic acid). Increase pyridoxine to maximum daily dose (200 mg/Day) Restart suspected agent or reinitiate suspected agent at lower dose, if essential to the regimen. Discontinue suspected agent if this can be done without compromising regimen.

Peripheral Cs, H Neuropathy S, Km, Am, Cm, Vi, Fluoro Increase pyridoxine to maximum daily dose (200 mg per day). Change injectable to capreomycin Initiate therapy with tricyclic antidepressants such as amitriptyline. Non-steroidal anti-inflammatory drugs or acetaminophen may help alleviate symptoms. Lower dose of suspected agent, if this can be done without compromising regimen. Discontinue suspected agent if this can be done without compromising regimen

Hearing loss S, KM, Am, Cir, Cm Compare with baseline audiometry Change CapreomycinLowe dose/ frequency Discontinue if possible [Weigh risk]

Psychotic Eto/Pto symptoms Cs, H, fluoro quinolones, Stop suspected agent for a short period of time. Some patients will need to continue antipsychotic while psychotic symptoms are brought under control. Lower doses of suspecting agent if regimen is not compromized Discontinue suspected agent if possible

Hypothyroidism PAS/Eto/Pto Initiate thyroxine therapy

Gastritis PAS/Eto/Pto H2-blockers, proton-pump inhibitors, or antacids. Stop suspected agent(s) for short periods of time (e.g, one to seven days). Lower dose of suspected agent, if this can be done without compromising regimen. Discontinue suspected agent if this can be done without compromising regimen.

Hepatitis Z,H,R, Eto,Pto,PAS, E,Fluoro Stop all therapy pending resolution of hepatitis. Eliminate other potential causes of hepatitis. Consider suspending most likely agent permanently. Reintroduce remaining drugs, one at a time with the most hepatotoxic agents first, while monitoring liver function.

Renal S, Km, Am, toxicity Cm, Vi Discontinue suspected agent. Consider using capreomycin if an aminoglycoside had been the prior injectable in regimen. Consider dosing 2 to 3 times a week if drug is essential to the regimen and patient can tolerate Adjust all TB medications according to the creatinine clearance.

Renal impairment and dose/interval adjustment Drug Modification GFRml/mt >50 10-50 <10 Km, D,I 7.5-15mg/kg/24h 4-7.5mg 3/kg/48 E I 20mg/kg/24h 20mg/kg/24-36h 20/kg/48 Z D 30mg/kg/24h 30mg/kg/24h 15-30/kg/24 Ofx D 100% 50-75% 50% Eto D 100% 100% 50% Cs D 100% 50-100% 50% PAS D 100% 50-75% 50%

Optic neuritis E Stop E. Refer patient to an ophthalmologist. Usually reverses with cessation of E Rare case reports of optic neuritis have been attributed to SM

Elec. diturb [HypoMagn Cm, Hypo kalemia] Km,Am, S Check potassium. If potassium is low also check magnesium (and calcium if hypocalcaemia is suspected). Replace electrolytes as needed.

Arthralgias Z, Fluoro. Initiate therapy with non-steroidal anti-inflammatory drugs. Lower dose of suspected agent, if this can be done without compromising regimen. Discontinue suspected agent if this can be done without compromising regimen. Symptoms of arthralgia generally diminish over time, even without intervention. Uric acid levels may be elevated in patients on pyrazinamide. Allopurinol appears not to correct the uric acid levels in such cases.

Indications for suspending treatment Signs indicating treatment failure include: • Persistent positive smears or cultures past months 8–10 of treatment; • Progressive extensive and bilateral lung disease on chest X-ray with no option for surgery; • High-grade resistance with no option to add two additional agents; • Overall deteriorating clinical condition that usually includes weight loss and respiratory insufficiency.

End-of-life supportive measures Pain control and symptom relief. Relief of respiratory insufficiency.—Oxygen Nutritional support. Small and frequent meals Nausea and vomiting Regular medical visits. Hospitalization, or nursing home care. Oral care, prevention of bedsores, bathing and prevention of muscle contractures Infection control measures.

Can XDR-TB be cured or treated? Yes, in some cases. Several countries with good TB control programmes have shown that cure is possible for up to 30% of affected people. But successful outcomes depend on the extent of the drug resistance, Severity of the disease Patient’s immune system Access to laboratories that can provide early and accurate diagnosis so that effective treatment is provided as soon as possible. All six classes of second-line drugs are available to clinicians who have special expertise in treating such cases.

Chemoprophylaxis of Tuberculosis Exposed to tuberculosis but no evidence of infection Infected(positive tuberculin test: induration >5 mm [HIV infected or other immunosuppressed patients and recent contacts of TB patients]) Infected, positive tuberculin test (induration >10 mm [not immunocompromised but with risk factors for TB]) and no apparent disease H/O tuberculosis but in whom the disease is currently "inactive"

Chemoprophylaxis H 300mg/day[10mg/kg] x 12 months Or R+Z x 2 mo Or H+R x 6 months

Chemoprophylaxis-Primary Tuberculin negative, below 3 years Close contact with infectious pt Reduces serious clinical TB in 60-90% INH 5mg/kg x 3 months BCG after 3 mo. If negative INH resistance BCG? Can be given along with INH

Chemoprophylaxis-Secondary Treating latent infection to prevent progression to active disease. High risk patients, TT positive[Infection occurred] INH For 1 year Recent tuberculin converts ? Ex TB pts-Glucocorticoid therapy, Immunosuppresants,

16007107 ade-of-anti tubercular-drugs-mdr-tb[1]

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