General Principles inThe Treatment of TB Dr NahId Ali Sherbini
Introduction Tuberculosis (TB) is the most common cause of infection-related death worldwide. In 1993, the World Health Organization (WHO) declared TB to be a global public health emergency. Mycobacterium tuberculosis is the most common cause of TB.
Current therapy of TB follows several basic principles1. successful treatment requires more than one drug to which the organisms are susceptible .2. drugs must be taken in appropriate dose .3. drugs must be taken regularly.4. drugs must continue for a sufficient period of time.
Basic Principles of Combination Drug RegimensIthas to be chosen based on knowledge of the likely drug susceptibility .Most include at least two effective drugs.Fixed drug combinations contains INH,RIF or INH,RIF,PZA.
DOT Itis the best way to reassure completion of appropriate therapy. One report from Texas compare 407 episodes of TB between 1980-1986 treated with standard therapy.&581 episodes of TB between 1986-1992 treated with DOT. Results: despite higher rate of TB among IV drug abuse &homelessness.
Results Lower rate of 1ry drug resistance 6.7 Vs 13% Lower rate of acquired drug resistance 2.1 Vs 14% Lower relapse rate 5.5 Vs 20.9%
Recommended Regimens by ATS/CDC/IDSAInitial phase Continuation phaseReg drugs duration Reg drugs duration1 INH 7d/w 1a INH 7d/w for18w RIF or 5d/w /RIF or 5d/w 18w PZA 1b INH 2x/w for 18w EMB /RIF PUPLISHED IN 2004
Initial phase Continuation phaseReg drugs duration Reg drugs duration2 INH 7d/w 2a INH 2x/w RIF for 2w /RIF for 18w PZA 2x/w 2b INH once/w EMB for 6w /RPF for 18w
Major Anti-TB drugs1st line therapy INH daily dose of 5mg/kg RIF daily dose of 10 mg /kg RIFABUTIN daily dose of 5mg/kg RIFAPANTINE weekly dose of 10mg/kg PZA daily dose of 15- 30 mg/kg EMB daily dose of 15-20 mg/kg
2nd line therapy Reserved for: Drug intolerance (include hypersensitivity) Resistance to 1st line drugs FDA approved :Cycloserine , Ethionamide ,Streptomycin & Capreomycin Not approved but used to treat MDR-TB:Levofloxacin , Moxifloxacin, Gatifloxacin, P-aminosalicylic acid & Amikacin /Kanamycin.
Classified as 2nd for many reasons1. Lack of clinical experience with the drug relative to 1st line .2. More toxicity.3. Unfavourable pharmacokinitic4. Increase incidence & severity of adverse events
MonitoringAdverse effects Clinical response to therapy
Monitoring of adverse effects Baseline :AST ,BIL, ALPPLTCREATININEVISUAL ACUITYRED- GREEN COLOR DISCRIMINATION
Repeated Measurement should be:obtained in the following conditions1. The baseline results are abnormal2. A drug reaction is suspected3. HIV infection4. Liver disease5. Pregnancy or 1st 3 months of post partum period6. Patients on combination therapy with PZA
INH Drug Interactions & Monitoring Drug Interaction Phenytoin Monitoring Routine monitoring is not necessary For patients with pre-existing liver disease or who develop abnormal liver function test should be measured monthly and when symptoms occur Prevention VitaminB6 may prevent peripheral neuropathy and CNS effects
)Rifampin (RIF Adverse effects: Cutaneous reactions Gastrointestinal reactions Flu-like syndrome Hepatotoxicity Severe immunologic reactions Orange discoloration of bodily fluids Patientsshould be informed in advance of urine and contact lens discoloration
RIF Monitoring Monitoring No routine monitoring required Whengiven with drugs that interact, may necessitate regular measurements of the serum concentrations of the drugs in question
)Rifabutin (RFB Adverse effects: Hematologic toxicity Uveitis GI symptoms Polyarthralgia Hepatitis Rash Orange discoloration of bodily fluids Drug interactions and monitoring – see RIF
)Rifapentine (RPT Adverse effects: Similarto those associated with RIF May increase metabolism of co-administered drugs that are metabolized by hepatic enzymes Drug Interactions: Are likely to be similar to those of RIF Monitoring: Similar to that for RIF
(Ethambutol (EMB Adverse effect: Opticneuritis (impaired perception of the red and green colors( Cutaneous reactions Monitoring Baseline and monthly tests of visual acuity and color vision Educate patient about self monitoring their vision and reporting any visual changes to their physician immediately
(Pyrazinamide (PZA Adverse effects: Hepatotoxicity GIsymptoms Non-gouty polyarthralgia Hyperuricemia Acute gouty arthritis Rash Monitoring Serum uric acid measurements are not routinely recommended Liver function tests should be performed when the drug is used in patients with underlying liver disease
Second-Line Anti-TB Medications Cycloserine Psychosis, seizures Ethionamide and PAS GI upset Fluoroquinolones Tendon rupture Aminoglycosides Deafness Renal failure
Importance of Monitoring Closemonitoring of patients throughout treatment can: Prevent serious complications Promote continuity of care Improve patient-health care provider relationship Encourage adherence Ensure successful completion of treatment
Response to Therapy Patients of pulmonary TB should have monthly sputum smear until two consecutive negative smears. For extrapulmonary depends on site.
Drug-Resistant Tuberculosis DEFINITIONS D rug-resistant tuberculosis" refers to cases of tuberculosis caused by an isolate of Mycobacterium tuberculosis, which is resistant to one of the first-line antituberculosis drugs: isoniazid, rifampin, pyrazinamide, or ethambutol. Multidrug-resistant tuberculosis (MDR-TB( is caused by an isolate of M. tuberculosis, which is resistant to at least isoniazid and rifampin. Primary drug-resistance : occur in a patient who has never received antituberculosis therapy. Secondary resistance refers to the development of resistance during or following chemotherapy, for what had previously been drug-susceptible TB.
DIAGNOSIS The diagnosis of drug-resistant tuberculosis depends upon the collection and processing of adequate specimens for culture and sensitivity testing prior to the institution of therapy . Sputum cultures are positive in 85 to 90 percent of cases of pulmonary tuberculosis, and every attempt should be made to collect adequate material before treatment is initiated.
The following are important risk . factors for drug resistance Previous treatment for tuberculosis especially if prolonged. Contact with another patient known to have drug resistant disease. Immigration from an area with a high incidence of drug resistance. HIV seropositivity. Substance abuse. Homelessness.
Management of treatment failure Retreatment of patients with MDR-TB should be made after careful review of previous medications. This includes patients whose : -disease is progressing despite compliance with the drug regimen, -patients presenting for treatment who have been noncompliant with previous regimens.
The following general principles apply in these settings• Any agent taken previously for more than 30 days is likely to have decreased efficacy.• An empiric retreatment regimen should include at least four drugs likely to be effective, one of them a parenteral agent. This will usually entail the use of second- line drugs that have increased toxicity compared with first line drugs.
Patients considered to be at high risk for relapse who have localized disease may benefit from surgical resection. Patients should receive either hospital- based or domiciliary DOT. The implications of treatment failure and further acquired resistance are such that these cases should receive highest priority for DOT.
Glucocorticoid Controversial Predinsone 1mg /kg po od initialy has been used in combination with anti-TB drugs for life threatening complication such as meningitis &pericarditis.
Surgical Care Pulmonary resection in patients with TB may be required in drug-resistant cases because of the high likelihood of failure of the medication regimen. Surgical resection also may be required in patients with advanced disease with extensive caseation necrosis. Tubercular abscesses and bronchopleural fistulae also should be removed surgically.
Immunotherapy for Tuberculosis Protectiveimmunity against Mycobacterium tuberculosis is believed to be mediated by T-lymphocytes that produce the type 1 (Th1) helper T cell cytokines IFN- and interleukin (IL)-2
Administration of low-dose recombinant human interleukin 2 (rhuIL-2) in combination with multidrug chemotherapy to patients with multidrug-resistant tuberculosis (MDR TB) induces measurable changes in in vitro immune response parameters which are associated with changes in the clinical and bacteriologic status of the patients
interleukin-2 (IL-2) has received increasing attention as an immunomodulatory drug in human infectious diseases. This cytokine is a pivotal regulator of cell- mediated immunity and has been shown to induce the proliferation and differentiation of lymphoid cells .
reported that patients with MDR TB treated with low-dose recombinant human IL-2 (rhuIL-2), in combination with optimized antituberculosis chemotherapy, show evidence of an enhanced antimicrobial response.
Changes included decreased sputum bacterial load and viability, improved chest X-ray results, and decreased symptoms in approximately 60% of patients .
IL-2stimulates expansion and enhanced functional capacity of natural killer cells, which can eliminate intracellular M. tuberculosis . Small studies also suggested that IL-2 has favorable clinical effects on patients with multidrug-resistant tuberculosis.
Potential Effects of IL-2 1st:in patients with multidrug-resistant tuberculosis, current therapy is suboptimal, and adjunctive immunomodulation may facilitate initial bacillary clearance and increase cure rates.
2nd: potential use for immunotherapy is to shorten the duration of treatment for drug- susceptible tuberculosis, reducing cost and increasing treatment completion rate 3rd: down regulate the host inflammatory responses. All are still in vitro experiments .