TREATMENT OF TB Dr. Seham Hafez Marwa Shaaban Rawy Pharm D Presented by: Marwa Shaaban Rawy Pharm D Supervised by: Dr. Seham Hafez

History of Selman Waksman, Nobel Laureate, 1952. Evidence of tubercular decay found in the skulls and spines of Egyptian mummies, tell us that TB has been plaguing humans for at least 4,000 years             Robert Koch, Nobel Laureate, 1905. discovered Mycobacterium tuberculosis Selman Waksman, Nobel Laureate, 1952. discovered streptomycin

GENERAL APPROACHES TO TREATMENT Monotherapy can be used only for infected patients who do not have active TB [latent TB infection (LTBI)] Once active disease is present, a minimum of two drugs and typically three or four drugs must be used simultaneously. For most patients, the shortest duration of treatment is 6 months, and 2 to 3 years may be necessary for advanced cases of multidrug resistant TB (MDR-TB).

NONPHARMACOLOGIC THERAPY Aim: (1) Prevent the spread of TB (respiratory isolation) (2) Return the patient to a state of normal weight and well-being Surgery may be needed to remove destroyed lung tissue, tuberculomas (space-occupying infected lesions) and certain extrapulmonary lesions. Directly Observed Therapy (DOT) The practice of a health care provider or other responsible person observing as the patient ingests and swallows the TB medications. preferred core management strategy for all patients with TB. Patient compliance is often low when multidrug schedules last for 6 mo. or longer Doses missed during an intermittent TB regimen decrease the efficacy of the regimen and increase the relapse rate Purpose: ensure adherence to TB therapy reduce the risk of developing drug resistance reduces the risk to the community. observe the patient for any apparent toxicities. DOT have been shown to decrease drug resistance as well as relapse and mortality rates and to improve cure rates.

Pharmacologic Therapy considered 1st-line because of their efficacy & acceptable degree of toxicity. considered 2nd-line drugs, either because they are no more effective than the first-line agents and their toxicities are often more serious or because they are particularly active against atypical strains of mycobacteria.

Pharmacologic Therapy Treating Active Disease Each case of active TB disease must be reported to the public health departments. Combination chemotherapy. It is critical to avoid monotherapy, and it is critical to avoid adding a single drug to a failing regimen. Isoniazid and rifampin should be used together whenever possible, as they are the best drugs for preventing drug resistance. Pyrazinamide has a special role in the first 2 months of treatment. 2nd-line drugs are used to suppress the emergence of drug resistance in conjunction with the first-line drugs or for preexisting drug-resistant TB. Recent research is placing emphasis on the potential role of quinolones such as levofloxacin and moxifloxacin in the treatment of TB. It is possible that future regimens may consider these agents part of the first-line drugs. Drug susceptibility testing should be done on the initial isolate for all patients with active TB. These data should guide the selection of drugs over the course of treatment

Pharmacologic Therapy Treating Active Disease The standard TB treatment regimen is: Initial phase Continuation phase For a total of 6 months of treatment A total of 9 months of isoniazid and rifampin treatment is recommended for patients at greater risk of failure and relapse, including: -Those with cavitation on initial chest radiograph -Those with positive cultures at the completion of the initial 2-month phase of treatment. - Patients treated initially without pyrazinamide. When INH and RIF cannot be used, treatment durations become 2 years or more. Isoniazid Rifampin Pyrazinamide, Ethambutol for 2 months Isoniazid Rifampin for 4 months

Drugs Used in the Treatment of T.B First-Line Agents Daily Dosing (Maxi-mal Dose) Primary Side Effects Comments  Isoniazid (INH) 5 mg/kg (300 mg) Children: 10–15 mg/kg Increased aminotransferases (transient and asymptomatic) Clinical hepatitis Peripheral neuropathy by interfering with pyridoxine (V B6) metabolism lupus-like syndrome Hypersensitivity most potent of the antitubercular drugs. potent inhibitor of several CYP450 isoenzymes but has minimal effects on CYP3A. INH inhibits hepatic metabolism of phenytoin ,carbamazepine, diazepam, increasing plasma concentrations & toxicity of these drugs which may need dose adjustment. Carbamazepine also may induce INH hepatitis by inducing its metabolism to toxic metabolites. Patients at risk of Peripheral neuropathy DM alcoholism HIV infection malnutrition renal failure Pregnancy Children Peripheral neuropathy preventable with supplemental pyridoxine 25 mg/day should be given with INH.

INH hepatotoxicity Most patients with mild, subclinical hepatic damage do not progress to overt hepatitis and recover completely even while continuing INH. In contrast, continuation of INH in patients with symptoms of hepatitis increased the risk of mortality compared with immediate cessation. The risk of death from TB, however, is estimated to be 11 times higher than the risk of death from INH hepatotoxicity. Monitor: baseline and regular monitoring of LFTs High-risk patients : those who consume alcohol daily persons >35 years of age those taking other hepatotoxic drugs those with pre-existing liver disease black and Hispanic women all postpartum women. INH should be discontinued if the AST level exceeds 3 -5 times the ULN

Drugs Used in the Treatment of T.B First-Line Agents (Cont’d) Daily Dosing Primary Side Effects Comments  Rifampin (RIf) 10 mg/kg (600 mg) Children: 10–20 mg/kg (600 mg) Pruritis, rash Hepatotoxicity more likely to produce cholestasis, as manifested by  ALP & hyper-bilirubinemia without hepatocellular injury GI effects (nausea,anorexi, abdominal pain) flu-like Syndrome Thrombocytopenia Orange-red discoloration of body secretions (sweat, saliva, tears, urine). many drug interactions. potent inducer of CYP450 isoenzymes, especially CYP3A4. metabolism of warfarin, corticosteroids, antiretroviral agents, azole antifungals, quinidine, oral contraceptives (use an alternative method of birth control),cyclosporine, tacrolimus, theophylline, phenytoin, diazepam, propranolol, metoprolol, sulfonylureas, verapamil,nifedipine, diltiazem, enalapril, and simvastatin. (monitor conc &  dose If required) It is important to note that rifampin has the exact opposite effect on hepatic metabolism than INH. Rifampin is a stronger inducer than INH is an inhibitor as documented by the fact that INH-rifampin combination therapy induces the metabolism of diazepam, phenytoin, and other agents metabolized by CYP450 system.

Drugs Used in the Treatment of T.B First-Line Agents (Cont’d) Daily Dosing Primary Side Effects Comments  Rifabutin 5 mg/kg (300 mg) Neutropenia Uveitis GI symptoms polyarthralgia Hepatotoxicity rash derivative of rifampin the preferred drug for use in T.B patients infected with (HIV) who are concomitantly treated with protease inhibitors or nonnucleoside reverse transcriptase inhibitors, because it is a less potent inducer of CYP450 enzymes. Orange-red discoloration of body secretions. Pseudojaundice (skin discoloration with normal bilirubin) Drug interactions are less problematic than rifampin. The rifamycins differ in their ability to induce CYP450 isoenzymes,in which: Rifampin is the most potent, Rifapentine is intermediate, Rifabutin is the least potent enzyme inducer.

Drugs Used in the Treatment of T.B First-Line Agents (Cont’d) Daily Dosing Primary Side Effects Comments  Rifapentine 10 mg/kg (600 mg) Once weekly in continuation phase. Similar to rifampin Has activity comparable to that of rifampin but has a longer half-life than rifampin and rifabutin, which permits weekly dosing.  Pyrazinamide (PZA) Based on IBW: 40–55 kg: 1000 mg 56–75 kg: 1500 mg 76–90 kg: 2000 mg Hepatotoxicity nausea anorexia polyarthralgias rash hyperuricemia dermatitis Baseline LFTs and uric acid measurment; repeat if abnormal or patient at risk or symptomatic.

Drugs Used in the Treatment of T.B First-Line Agents (Cont’d) Daily Dosing Primary Side Effects Comments  Ethambutol (EMB) Adults Based on IBW 40–55 kg: 800 mg 56–75 kg: 1200 mg 76–90 kg: 1600 mg Optic neuritis with blurred vision, red green color blindness. (dose and duration related) skin rash drug fever Baseline visual acuity and color vision; test monthly 50% excreted unchanged in urine  Need dose adjustment in renal impairment.

Drugs Used in the Treatment of T.B Second-Line Agents Daily Dosing Primary Side Effects Comments  Cycloserine 10–15 mg/kg per day, usually 500–750 mg/day in two doses CNS toxicity Monthly assessments of neuropsychiatric status May exacerbate seizure disorders or mental illness. Monitor serum conc. (peak 20–35 mg/L desirable) Need dose adjustment in renal impairment. although this is the dose recommended generally, most clinicians with experience using cycloserine indicate that it is unusual for patients to be able to tolerate this amount. Serum concentration measurements are often useful in determining the optimal dose for a given patient.

Drugs Used in the Treatment of T.B Second-Line Agents (Cont’d) Daily Dosing Primary Side Effects Comments  Ethionamide 15–20 mg/kg per day, usually 500–750 mg/day in a single daily dose or two divided doses GI effects hepatotoxicity neurotoxicity endocrine effects (alopecia, impotence, gynecomastia, hypothyroidism) Difficulty in diabetes management Must be given with meals and antacids. Monitoring: -Aminotransferases -TSH at baseline and monthly Intervals.

Drugs Used in the Treatment of T.B Second-Line Agents (Cont’d) Daily Dosing Primary Side Effects Comments  Streptomycin  Amikacin/ Kanamycin  Capreomycin -15 mg/kg/d (1 g) -10 mg/kg in persons older than 50 years of age (750 mg). Usual dose: 750–1000 mg administered I.M or I.V, given as a single dose 5–7 days/week, and reduced to 2-3 times per week after the first 2–4 months or after culture Conversion. Ototoxicity neurotoxicity Nephrotoxicity Ototoxicity, (< Streptomycin) Monitoring: -Baseline audiogram, vestibular testing, and SCr. -Monthly assessments of renal function and auditory Symptoms.

Drugs Used in the Treatment of T.B Second-Line Agents (Cont’d) Daily Dosing Primary Side Effects Comments  Para – aminosalicylic acid (PAS) 8–12 g/day in two or three doses GI intolerance Hepatotoxicity Malabsorption Syndrome Hypothyroidism Monitoring: LFTs and TSH Levofloxacin  Moxifloxacin  Gatifloxacin 500–1000 mg/d 400 mg daily Nausea Diarrhea Headache Dizziness Do not give with divalent and/or trivalent cations (e.g., aluminum, magnesium, iron)

Pharmacologic Therapy Special Populations Treating Active Disease: TB in children: May be treated with regimens similar to those used in adults , although some physicians extend treatment to 9 months. Pediatric doses of isoniazid and rifampin on a milligram per kilogram basis are higher than those used in adults. TB in pregnant women: untreated TB represents a far greater risk to a pregnant woman and her fetus than does the treatment administration of antituberculosis drugs is not an indication for termination of pregnancy. Receive the usual treatment of isoniazid,rifampin, and ethambutol for 9 months. (not teratogenic) Pyrazinamide is not recommended for use during pregnancy because of insufficient safety data. Pyridoxine should be provided.(25 mg/day) Other drugs should be avoided

Pharmacologic Therapy Special Populations (Cont’d) Human Immunodeficiency Virus: Patients with AIDS may be managed with chemotherapeutic regimens similar to those used in immunocompetent individuals, although treatment is often extended to 9 month. The precise duration remains a matter of debate. Highly intermittent regimens (twice or once weekly) are not recommended for HIV-positive TB patients. Prognosis has been particularly poor for HIV-infected patients infected with MDR-TB. Some patients with AIDS malabsorb their oral medications, and drug interactions are common.

Pharmacologic Therapy Special Populations (Cont’d) Renal Failure: Isoniazid and rifampin (hepatically cleared) do not require dose modification in renal failure. Renally cleared TB drugs include: EBM, cycloserine, ethionamide, aminoglycosides (e.g., amikacin, kanamycin, andstreptomycin), capreomycin, levofloxacin. Dosing intervals need to be extended for these drugs. Serum concentration monitoring must be performed for cycloserine to avoid dose-related toxicities in renal failure patients.

Pharmacologic Therapy Special Populations (Cont’d) Hepatic Failure: Elevations of serum transaminase concentrations generally are not correlated with the residual capacity of the liver to metabolize drugs, so these markers cannot be used directly as guides for residual metabolic capacity. Hepatically cleared TB drugs include isoniazid, rifampin, pyrazinamide, ethionamide, and p-aminosalicylic acid and these drugs may cause hepatotoxicity esp. in patients with liver impairment. These patients require close monitoring, and TDM may be the most accurate way to dose them.