The Treatment of Tuberculosis

The Treatment of Tuberculosis

Treating TB Old concepts Nutritional support Fresh Air, elevation, caves Sanatoriums Weimar Exercise Surgical Death rate in 1900 was 194/100K

British Sanatorium 1880s

a Denver sanatorium in the 1920s

Before 1940s: open air (sanatorium) 1946: streptomycin 1952: isoniazid 1970: rifampin Treatment

The aims of treatment of TB are: to cure the patient to prevent death from active TB or its late effects to prevent relapse of TB to decrease transmission of TB to others to prevent the development of acquired drug resistance It is vital to achieve these aims while preventing the selection of resistant bacilli in infectious patients.

First Line Anti-Tuberculosis Drugs Isoniazid (INH, H) Rifampicin (RIF, R) Pyrazinamide (PZA, Z) Ethambutol (EMB, E) Streptomycin (SM, S)

Modern TB Chemotherapy INH kills rapidly growing organisms and dormant organisms PZA kills TB bacilli inside the macrophage and cavities RIF and PZA kill slowly growing organisms sterilizing activity INH, RIF and EMB protect each other from development of resistance

Activities of Antituberculosis Drugs Drug Early bactericidal activity Preventing drug resistance Sterilizing activity Isoniazid ++++ +++ ++ Rifampicin ++ +++ ++++ Pyrazinamide + + +++ Streptomycin ++ ++ ++ Ethambutol ++ - +++ ++ + Highest ++++ High +++ Intermediate ++ Low +

Group 1. First-line oral antituberculosis drugs Isoniazid - H Rifampicin - R Ethambutol - E Pyrazinamide - Z Rifabutin - Rfb Rifapentine - Rpt Group 1 anti-tb drugs, the most potent and best tolerated, should be used if there is good laboratory evidence and clinical history that suggests that a drug from this group is effective. For patients with strains resistant to low concentrations of isoniazid but susceptible to higher concentrations, the use of high-dose isoniazid may have some benefit Rifabutin and Rifapentine have similar microbiological activity as rifampicin

Group 2. Injectable anti-tb drugs (injectable agents or parental agents) Streptomycin - S Kanamycin - Km Amikacin - Am Capreomycin Cm All patients should receive a second-line Group 2 injectable agent in the intensive phase of MDR-TB treatment unless resistance is documented or highly suspected. Either kanamycin, amikacin or capreomycin can be used as a first choice if all meet the criteria of likely to be effective There are high rates of streptomycin resistance in strains of MDR-TB; therefore, streptomycin is not considered a second-line anti-tb injectable agent

Group 3. Fluoroquinolones Levofloxacin - Lfx Moxifloxacin - Mfx Gatifloxacin - Gfx Fluoroquinolones are often the most effective anti- TB drugs in an MDR-TB regimen All MDR-TB patients should be treated using latergeneration fluoroquinolones levofloxacin or moxifloxacin

Group 4. Oral bacteriostatic second-line antituberculosis drugs Ethionamide - Eto Prothionamide - Pto Cycloserine - Cs Terizidone - Trd Para-aminosalicylic acid - PAS Para-aminosalicylate sodium - PAS-Na Group 4 drugs are added on the basis of estimated susceptibility, drug history, efficacy, adverse effects profile and cost

Group 5. Group 5 drugs are not recommended by WHO for routine use in MDR-TB treatment Bedaquiline - Bdq Delamanid - Dlm Linezolid - Lzd Clofazimine - Cfz Amoxicillin/clavulanate - Amx/Clv Imipenem/cilastatin - Ipm/Cln Meropenem - Mpm High-dose isoniazid - High dose H Thioacetazone - T Clarithromycin - Clr

Group 5 Group 5 drugs are not recommended by WHO for routine use in MDR-TB treatment Although all of them have demonstrated some activity at least in vitro or in animal models, the quality of the evidence of their efficacy and safety in humans for the treatment of drug-resistant TB varies Most of these drugs are, with the exception of bedaquiline and delamanid, not registered for treatment of MDR-TB making their use off-label However, they remain as options in cases where adequate regimens are impossible to design with medications from Groups 1 4 If a situation requires the use of Group 5 drugs, often experts will recommend using two to three drugs from the group given the limited knowledge of efficacy

New Drugs in TB Treatment Bedaquiline, formerly TMC207, is a new diarylquinoline antibiotic with specific activity against Mycobacterium tuberculosis and several nontuberculous mycobacteria It acts by inhibiting ATP synthase, interfering with the energy generation needed by the bacterial cell Based on clinical evaluations for safety, tolerability and efficacy, bedaquiline has recently received accelerated approval for the treatment of pulmonary multidrug-resistant TB in adults

New Drugs in TB Treatment Delamanid (OPC-67683), a nitro-dihydroimidazooxazole derivative, is a new antituberculosis medication that inhibits mycolic acid synthesis and has shown potent in vitro and in vivo activity against drug-resistant strains of Mycobacterium tuberculosis Delamanid was associated with an increase in sputum-culture conversion at 2 months among patients with multidrug-resistant tuberculosis

Second-line Drugs Increased treatment difficulties Expensive,unavailable More side effects Difficult Ab penetration Longer treatment Controversy Standard treatments Everything it takes

Determining the Case Definition Bacteriology History of TB Site of Disease Smear-negative Pulmonary NO New Smear-positive Extra-pulmonary Severity of Disease TB CASES YES Return after default Relapse Failure

New case new, smear-positive tuberculosis cases new smear-negative cases with extensive parenchymal lesions new cases with severe extrapulmonary tuberculosis (disseminated, meningeal, pericardial, peritoneal, bilateral pleural, spinal, intestinal and genitourinary)! A new case is defined as a patient who has never previously been treated for tuberculosis or who has received treatment for less than one month.

Retreatment smear-positive cases who have already received treatment for at least one month in the past who need to receive re-treatment. Among these patients three groups can be distinguished: Relapses patients who have been treated and declared cured, but whose smear examinations are once again positive Failures patients whose smear examinations have remained positive or have once again become positive 5 or more months after starting treatment Return after interruption patients who return to the health centre smear-positive after interrupting treatment for more than two consecutive months

Chronic cases chronic cases defined as smearpositive cases of pulmonary tuberculosis who have already received a supervised re-treatment regimen Resistant form of TB

Treatment regimens initial intensive phase, which rapidly reduces the bacterial population the initial intensive phase consists of at least four drugs continuation phase, which destroys those bacteria that remain the continuation phase is given for 4 months if the two most bactericidal drugs, isoniazid and rifampicin, are used, and for 6 months if isoniazid and a bacteriostatic drug are used

Treatment schedules recommended by tuberculosis case Tuberculosis case Recommended treatment schedule Initial phase Continuation phase - New case of smearpositive PTB - Severe forms of smearnegative PTB - Severe extrapulmonary tuberculosis 2 EHRZ (SHRZ) 2 EHRZ (SHRZ) 2 EHRZ (SHRZ) 6 HE or 6 TH 4 HR 4 HR

Treatment of Active TB Four drug regimen for first 2 months: INH 300 mg Rifampin 600 mg PZA 15-30 mg/kg Ethambutol 15-25 mg/kg or streptomycin 15 mg/kg Two drug regimen for next 4 months: INH and rifampin

Treatment schedules recommended by tuberculosis case Tuberculosis case Recommended treatment schedule Initial phase Continuation phase Smear-positive pulmonary tuberculosis: Relapse Failure Return after interruption 2 SHRZE/1 HRZE 5 HRE

Ongoing Diagnostic Monitoring Monthly sputum collection (until two negative smears) Look for smear positive cases after initial two months of therapy Liver function tests if abnormalities on screening or risk factors for hepatitis

Monitoring the efficacy of treatment with bacteriological examinations At the end of the initial phase sputum conversion is observed in most cases. If the patient is still smear-positive the initial phase should be prolonged by 1 month At the end of the 4th month for 6-month regimens, and at the end of the 5th month for 8-month regimens During the last month (at the 6th or 8th month, depending on the regimen). These smear examinations confirm the success or failure of the treatment In the case of extrapulmonary tuberculosis, followup is essentially clinical

Treatment outcome Cured: at least two negative examinations (one after the end of the initial intensive phase of treatment and another during the last month of treatment). Treatment completed: the patient has received a full course of treatment but has not undergone the necessary bacteriological examinations. Failure: still positive or positive once again after the 5th month of treatment.

Treatment outcome Died: whatever the cause of death. Transferred out: the patient has been transferred to another health centre while on treatment but the final outcome of the treatment is not known at the centre where the patient was registered. Where the final outcome is known, this should be recorded, rather than transferred out. Defaulted: the patient has not turned up to collect drugs for more than 2 months since the last visit.

Problems of TB therapy Toxicity e.g. liver Multiple therapy Prolonged treatment Drug interactions e.g. anti HIV drugs

Directly observed treatment means that an observer watches the patient swallowing their tablets, in a way that is sensitive and supportive to the patient's needs. This ensures that a TB patient takes the right antituberculosis drugs, in the right doses, at the right intervals

Directly Observed Therapy (DOT) Health care worker watches patient swallow each -Dose of medication -Every pill, every day -Self-administered is NOT DOT REMEMBER DOT for all patients on all regimens NO exceptions

Directly Observed Therapy (DOT) DOT can lead to reductions in relapse and acquired drug resistance Use DOT with other measures to promote adherence DOT is the key to CURE

Directly Observed Therapy (DOT)

What is DOTS? D.O.T.S stands for Directly-Observed Treatment Short Course It is a comprehensive strategy endorsed by the World Health Organization (WHO) and International Union Against Tuberculosis and Lung Diseases (IUATLD) to detect and cure TB patients

DOTS PLUS A case management strategy under development, designed to manage MDR- TB using second line drugs within the DOTS strategy in low and middle income countries. To prevent further development and spread of MDR-TB.

Drug Resistance

Definition of Drug Resistant TB Confirmed mono-resistance: tuberculosis in patients whose infecting isolates of M. tuberculosis are confirmed to be resistant in vitro to one first-line antituberculosis drug

Definition of Drug Resistant TB Confirmed poly-resistance: tuberculosis in patients whose infecting isolates are resistant in vitro to more than one first-line antituberculosis drug, other than both isoniazid and rifampicin

Definition of Drug Resistant TB Multi-Drug Resistance (MDR): resistance to at least both isoniazid and rifampicin extensive-drug Resistance (XDR): resistance to any fluoroquinolone, and at least one of three second-line injectable drugs (capreomycin, kanamycin and amikacin), in addition to multidrug resistance Treatment based on susceptibilities Higher risk of mortality

Drug Resistance Definitions Primary drug resistance Applies to previously untreated patients who are found to have drug- resistant organisms, presumably because they have been infected from an outside source of resistant Mycobacterium tuberculosis. Acquired drug resistance Applies to patients who initially have drugsusceptible bacteria that become drugresistant due to inadequate, inappropriate, or irregular treatment or, more importantly, because of non-adherence in drug taking.

Causes of Resistance Irregular Self Administration with Failure to closely supervise Care of patients by non specialists Increased immigration

Persons at Increased Risk for Drug Resistance History of treatment with TB drugs Contacts of persons with drug resistant TB Smears or cultures remain positive despite 2 months of TB treatment Received inadequate treatment regimens for >2 weeks

Inadequate Treatment Multi-factorial Lack of adherence/intermittent or interrupted therapy Malabsorption Inappropriate regimens; to properly treat TB one must always add at least two drugs to a failing regimen Sub-therapeutic dosing Expired or substandard drugs

Standardized treatment Regimens are designed on the basis of representative DRS data of specific treatment categories However, suspected MDR-TB should always be confirmed by DST results whenever possible. All patients in a defined group or category receive the same treatment regimen

Empirical treatment Each regimen is individually designed on the basis of the previous history of antituberculosis treatment and with the help of representative DRS survey data Commonly, an empirical treatment is adjusted in each patient when his or her DST results become available

Individualized treatment Each regimen is designed based on the patient s past history of TB treatment and individual DST results

The basic principles Regimens should be based on the history of drugs taken by the patient Regimens should consist of at least four drugs with either certain, or almost certain, effectiveness Drugs are administered at least six days a week An injectable agent (an aminoglycoside or capreomycin) is used for a minimum of 6 months Treatment is for a minimum duration of 18 months beyond conversion Each dose is given as DOT throughout the treatment

Step 1 Begin with any First line agents to Which the isolate is Susceptible Use any available First-line drugs PLUS One of these Fluoroquinolones PLUS One of these Injectable agents Add a Fluoroquinolone And an injectable Drug based on susceptibilities Pyrazinamide Ethambutol Levofloxacin Moxifloxacin Amikacin Capreomycin Streptomycin Kanamycin BS

Step 1 Begin with any First line agents to Which the isolate is Susceptible Use any available First-line drugs PLUS One of these Fluoroquinolones PLUS One of these Injectable agents Add a Fluoroquinolone And an injectable Drug based on susceptibilities Pyrazinamide Ethambutol Levofloxacin Moxifloxacin Amikacin Capreomycin Streptomycin Kanamycin Step 2 Add 2 nd line drugs until you have 4-6 drugs to which isolate is susceptible (which have not been used previously) Pick one or more of these Oral second line drugs Cycloserine Ethionamide PAS

Step 1 Begin with any First line agents to Which the isolate is Susceptible Use any available First-line drugs PLUS One of these Fluoroquinolones PLUS One of these Injectable agents Add a Fluoroquinolone And an injectable Drug based on susceptibilities Pyrazinamide Ethambutol Levofloxacin Moxifloxacin Amikacin Capreomycin Streptomycin Kanamycin Step 2 Add 2 nd line drugs until you have 4-6 drugs to which isolate is susceptible (which have not been used previously) Step 3 Pick one or more of these Oral second line drugs Cycloserine Ethionamide PAS Consider use of these If there are not 4-6 drugs available consider 3 rd line in consult with MDRTB experts Third line drugs Imipenem Linezolid Macrolides Amoxicillin/Clavulanate BS

Treatment of Active TB INH resistant TB: Rifampin, PZA, and ethambutol for 6 months Rifampin resistant TB: INH, PZA, and streptomycin for 9 months or INH and ethambutol for 18 months MDR/XDR TB: Based on susceptibility patterns

Treatment of MDR TB in RM Standardized treatment (WHO): Initial phase - 6 months: Cm, Eth, Z, Lfx, Cs,(PAS) Continuation phase 18 months: Eth, Z, Lfx, Cs,(PAS) DOT

Consequences of MDR Delay in diagnosis Treatment duration extended 18 to 24 mo. Second line drugs Effectiveness decreases Toxicity increases Expensive to treat Community transmission

How we can prevent MDR TB Initial treatment with standardized regimens (HRZE) Directly observed therapy (DOT) Drug susceptibility testing for all retreatment cases Infection control precautions Monitor drug resistance through surveys Effective contact management

Interventions to prevent drug-resistant TB 1. Early detection and high quality treatment of drug-susceptible TB 2. Early detection and high quality treatment of drug-resistant TB 3. Effective implementation of infection control measures 4. Strengthening and regulation of health systems 5. Addressing underlying risk factors and social determinants

XDR= HR + 1 FQ + 1 Injectable (KM or AMK or CM) 1 st -line oral INH RIF PZA EMB (Rfb) Injectables SM KM AMK CM Fluoroquinolones Cipro Oflox Levo Moxi (Gati) Oral bacteriostatic 2nd line ETA/PTA PASA CYS Unclear efficacy Not routinely recommended, efficacy unknown, e.g., amoxacillin/clavulanic acid, clarithromycin, clofazamine, linezolid, inmipenem/cilastatin, high dose isonizid 59

Drug treatment of sensitive TB

Drug treatment of MDR TB

Drug treatment of XDRTB

Treatment options for XDR?

www.cdc.gov/tb/xdrtb/

Tuberculosis anywhere is Tuberculosis everywhere

???????????