Drug Treatment in Tuberculosis

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Chan Sook Yeen 15719547 / 01BP -200804-00015 Practice & Therapeutics D / PHA3THD Drug Treatment in Tuberculosis

Mycobacterium tuberculosis is a gram-positive bacteria having a genome sizes range to 4400kbp. Firstly discovered by Robert Koch while investigating on tuberculosis, acid-fast staining permitted the identification of the organism in tuberculous lesions. The presence on the surface of the mycobacterial cell of unique lipids called mycolic acids, found only in the genus Mycobacterium. Mycobacteriums are pleomorphic and may undergo branching or filamentous growth. M. tuberculosis is a slow grower, and visible colonies are produced from dilute inoculums only after days to weeks of incubation. A glycerol-whole egg medium (Lowerstein-Jensen medium) is often used in primary isolation of M. tuberculosis from pathological materials. M. tuberculosis is an obligated aerobic organism which grow in the highly oxygenated environment of the lungs. It uses its cell wall glycolipids to absorb hydroxyl radicals and superoxide anions, produced by phagocytes in which M. tuberculosis grow and persist. It develops resistance because of T cell-mediated immune response. Tuberculin test is used for diagnosis of M. tuberculosis. Tuberculosis (TB) is an infectious bacterial disease caused by Mycobacterium tuberculosis, which most commonly affects the lungs. It is transmitted from person to person via droplets from the throat and lungs of people with the active respiratory disease. In healthy people, infection with Mycobacterium tuberculosis often causes no symptoms, since the person¶s immune system acts to ³wall off´ the bacteria. They symptoms of active TB of the lung are coughing, sometimes with sputum or blood, chest pains, weakness, weight loss, fever and night sweats. Tuberculosis is treatable with a six-month course of antibiotics. It is clear that tuberculosis is once again a major public health issue. It remains the leading cause of death by infectious disease, second only to human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS). 3,4 WHO estimated one-third of the world¶s population is currently infected with the bacillus and that 1 billion people will be newly infected in the period of 2000-20, resulting in 35 million more deaths.5 Mortality rate of this disease is approximately 3million annually; at least 80% from the developing countries. About 15% of HIV-associated deaths in the Africa are caused by tuberculosis. In Malaysia, the number of cases detected annually has not declined substantially either. The WHO¶s Stop TB Department prepared a fourth edition of Treatment of tuberculosis¶ guidelines with several recommendations. Firstly, it recommends discontinuing the regimen based on just 2 months of rifampicin and change to the regimen based on a full 6 months of rifampicin will reduce the number of relapses and failures. Secondly, drug susceptibility testing (DST) at the start of therapy for all previously treated patients would reduce the risk of MTD-TB and help to improve the very poor outcomes and acess to lifesaving care in these previously treated patients. The retreatment regimen with first-line drugs is ineffective in MDR-TB should detection of MDR-TB would be an effective regimen started. Third recommendation is the detection of MDR-TB, expansion of DST capacity

within the context of country-specific, comprehensive plans for laboratory strengthening is required. Fourth, diagnosisng MDR-TB cases among previously treated patients and providing effective treatment will greatly help in halting the spread of MDR-TB. TB, most prevalent communicable infectious disease; remains a leading infectious killer globally caused by M. tuberculosis, which can produce either a silent, latent infection or a progressive, active disease.6 TB causes progressive tissue destruction and, eventually, death. Given increasing drug resistance, it is critical that a major effort is made to control TB before the most effective drugs are lost permanently. Monotherapy can be used only for infected patients who do not have active TB ± latent infection. Present of active disease, a minimum of two drugs, and generally three or four drugs, must be used simultaneously. The duration of treatment depends on the condition of the host, extent of disease, presence of drug resistance, and tolerance of medications. Duration of treatment takes at least 6 months to 2-3 years of treatment for cases of multidrugresistant TB (MDR-TB). Direct observed therapy by healthcare workers is a cost-effective way to ensure completion of treatment. Combination chemotherapy is required for treating active TB disease to decrease the probability of the emergence of resistant organisms. The patient should receive at least two drugs to which the isolate is susceptible, and generally four drugs are given at the onset of treatment. Rifampin and isoniazid are the best drugs for preventing drug resistance, followed by ethambutol, streptomycin, and pyrazinamide. First-line counter-attack drugs isoniazid, rifampicin, rifabutin, ethambutol, and pyrazinamide. Second-line drugs available are capreomycin, cycloserine, streptomycin (rarely in used now), clarithromycin and ciprofloxacin; used to treat infections likely to be resistant to first-line drugs or due to unwanted reactions occurrence. Compound therapy involves: an initial phase of treatment (about 2 months) with a combination of isoniazid, *rifampicin, and pyrazinamide (addition of ethambutol if the organism is suspected to be resistant) a second, continuation phase (about 4 months) of therapy with isoniazid and rifampicin; longer-term treatment is needed for patients with meningitis, bone/joint involvement or drug resistant infection.

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Primary Antituberculosis Drugs: Isoniazid is highly specific for mycobacteria, inhibiting the growth of resting organisms ± the synthesis of mycolic acids, important cell wall constituents (e.g. is bacteriostatic) but can kill dividing bacteria. It is readily absorbed from the gastrointestinal tract and from intramuscular injection sites, thus effective against intracellular organisms and is widely distributed throughout the tissues and body fluids, including CSF. This enable penetrations into µcaseous¶ tuberculosis lesions (i.e. necrotic lesions with a cheese-like consistency). It is also reported to combine with an enzyme, uniquely found in isoniazidsensitive strain of mycobacteria, disrupting cellular metabolism. Isoniazid should be given on an empty stomach whenever possible.58 Resistance to the drug, caused by reduced

penetration into the bacterium, perhaps, but cross-resistance with other tuberculostatic drugs does not occur. N-acetyltransferase-2 (acetylation metabolism) forms the principal metabolite acetylisnoiazid, which lacks antimycobacterial activity. Half-life of isoniazid in rapid inactivators is 1 hour. Slow acetylators have isoniazid half-lives of 3-4 hours and may be at an increased risk of neurotoxicity. The association of acetylator status and risk of hepatotoxicity, however, appears to be weak.7 Poor absorption and rapid clearance of isoniazid results in poor clinical outcomes.8,9 Isoniazid is excreted in the urine. Risk factors for hepatotoxicity include patient age, pre-existing liver disease, excessive alcohol intake, pregnancy, and postpartum state. Resultant in neurotoxicity, it mostly present as peripheral neuropathy or, in overdose, as seizures and coma. An allergic skin eruption is the commonest unwanted effect. Isoniazid may inhibit the metabolism of phenytoin, carbamazepine, primidone, and warfarin10 may result in toxicity of these drugs. Patients should be closely monitored when treating with these agents, and appropriate dose adjustments should be made when necessary. Rifampicin (rifampin) routinely used during the 1970s allowed for true short-course treatment of TB (6-9 months).11,12 It acts by binding to, and inhibiting, DNA-dependent RNA polymerase in prokaryotic but not in eukaryotic cells. Rifampicin also is active against a broad array of other bacteria. RNA polymerase alteration, primarily rpoB gene, leads to most forms of rifampicin resistance.13,14 Rifampicin shows concentration-dependent killing. Larger doses produce effective killing of bacteria and mycobacteria. High-dose rifampicin fell out of favour, caused flu-like symptoms. Rifampicin is given orally and is widely distributed in the tissues and body fluids, giving an orange tinge to saliva, sputum, tears and sweat. In CSF, it reaches 10-40% of its serum concentration. It is excreted partly in urine, partly in bile, some undergo enterohepatic cycling. The metabolite (25-desacetylrifampicin) retains antibacterial activity but is less well absorbed from the gastrointestinal tract. It is given at 600mg daily or intermittently. The half-life is 1-5 hours, becoming shorter during treatment because of induction of hepatic microsomal enzymes. Common adverse effects include rash, fever, and gastrointestinal distress. Liver damage with jaundice has been reported and has proved fatal in a few patients, and liver function should be assessed before treatment is started. Rifampicin induce hepatic enzymes, especially cytochrome P450 3A4, may enhance elimination of other drugs, notably the protease inhibitors used to treat HIV. Rifabutin may be of benefit in HIV-patients instead of rifampicin.15 Rifampicin causes induction of hepatic metabolising enzymes, resulting in an increase in the degradation of warfarin, glucocorticoids, narcotic analgesics, oral antidiabetic drugs, dapsone and oestrogen, the last effect leading to failure of oral contraceptives due to increased clearance of hormones, leading to unexpected pregnancies. Addition of pyrazinamide to the first 2 months of treatment with isoniazid and rifampicin shorten the durations to 6 months. Pyrazinamide is inactive at neutral pH but tucerculostatic at acid pH. It is effective against the intracellular organisms in macrophages because, after phagocytosis, the organisms are contained in phagolysosomes where the pH is

low. Resistance develops readily, but cross-resistance with isoniazid does not occur. The drug is well absorbed after oral administration and is widely distributed, penetration well into the meninges. Excretion takes place in the kidney, mainly by glomerular filtration. The most common toxicities oh pyrazinamide are gastrointestinal distress, arthralgias, and elevation in the serum uric acid concentration.13,16 Most patients do not experience true gout, associated with high concentration of plasma urates. Hepatotoxicity is the major adverse effect and is dose-related; this is now less likely with lower dose/shorter course regimens, however, liver function should be assessed before treatment. Ethambutol has no effect onorganism other than mycobacteria, generally bacteriostatic. If the organism is susceptible to isoniazid, rifampicin, and pyrazinamide, ethambutol can be stopped. Resistance emerges rapidly if the drug is used alone. Ethambutol is given orally and is well absorbed, reaching therapeutic concentrations in the CSF in tuberculous meningitis. In the blood, it is taken up by erythrocytes and slowly released. Ethambutol is partly metabolised and is excreted in the urine. The half-life is 3-4 hours. Ethambutol should not be given with antacids.17 In renal failure patients, the dose should be reduced to three times per week.18,19 Retrobulbar (optic) neuritis is the major adverse effect, which is dose-related and is more likely to occur if renal function is decreased. It results in visual disturbances manifesting initially as red-green colour blindness progressing to a decreased visual acuity. Monthly monitoring is necessary during prolonged treatment, using Snellen wall charts for visual acuity and Ischihara red-green colour discrimination cards.13,20 Second-line Antituberculosis Drugs: Streptomycin is one of three aminoglycoside antibiotics (along with amikacin and kanamycin) which are active against mycobacteria. Although labelled only for intramuscular dosing, streptomycin can be given safely as intravenous infusions )100mL of dextroxe 5% water or normal saline) over 30 minutes, similar to the other aminoglycosides.21 Streptomycin is renal cleared by glomerular filtration and must be given less often in renal dysfunction patients.13,16,20 It occasionally causes mild, reversible nephrotoxicity and ototoxicity, which may become permanent with continued use.13 Older patients and those of long duration therapy are most likely suffer hearing loss, whereas vestibular toxicity is highly unpredictable. Resistance to streptomycin is known by performing a susceptibility test as a guide to the selection of this injectable drug. Cycloserine is a broad-spectrum antibiotic which inhibits the growth of many bacteria, including coliforms and mycobacteria. It is only used to treat Multidrug resistantTuberculosis (MDR-TB). It acts by competitively inhibiting bacterial cell wall synthesis, preventing the formation of D-alanine (major building block), thus preventing the synthesis of peptidoglycan cell wall. Cycloserine is water soluble and destroyed at acidic pH; well absorbed orally and is best taken on an empty stomach76 attaining peak concentration within 4 hours. It is distributed throughout the tissues and body fluids, and reaches concentration in the CSF equivalent to those in the blood. It is cleared in urine by means of kidneys¶ glomerular filtration and requires dosage reduction in renal failure. Cycloserine can produce dose-related CNS toxicity, including lethargy, confusion, or unusual behaviour. Its use is

limited to tuberculosis that is resistant to other drugs. The addition of pyridoxine 50mg daily may improve patient tolerance of cycloserine. Capremycin is a peptide antibiotic given by intramuscular injection. There is some cross-reaction with the aminoglycoside kanamycin. Unwanted effects include kidney damage and injury to the eighth nerve, with consequent deafness and ataxia. The drug should not be given at the same time as streptomycin or other drugs which cause damage to the eighth nerve.

Clofazimine is a potent drug for Mycobacterium leprae but weak activity against M. Tuberculosis and M. Avium. It is used in doses of 100 to 200 mg daily in advanced cases of MDR-TB or Mycobacterium Avium complex (MAC) especially when therapeutic options are limited.13,10 It has a terminal elimination half-life of weeks long. Gastrointestinal distress and skin discoloration are the most important adverse reaction. Uncommon side effect, severe gastrointestinal pain may occur because of deposition of clofazimine crystals within the intestines; this may require surgical correction. Thiacetazone, a weak agent used rarely due to its low cost; skin reactions including rash and Stevens-Johnson¶s syndrome may occur. Thiacetazone must discontinued permanently as soon as rash appears. Similar to trimethoprim-sulfamethoxazole, the incidence of skin reactions is much higher in AIDS patients.22 Quinolones; Levofloxacin, ciprofloxacin, and moxifloxacin are sometimes used to treat MDR-TB. Quinolones are useful because most are available in oral and intravenous dosage forms; an advantage for the critically ill patients. -lactam and -lactamase inhibitor combination have been used in salvage regimens of TB patients with no other options, but are not used routinely to treat TB. Being replaced by Ethambutol as a first-line therapy in the 1960s for better tolerance is paminosalicylic acid. Gastrointestinal disturbances are its most common adverse effects. diarrhea is usually self-limited, with symptoms improving after the first 1 to 2 weeks of therapy. Hypersensitivity may occur and, rarely, severe hepatitis. New drugs and delivery system by nitroimidazopyran PA 824, which is chemically related to metronidaxole and tinidazole, has activity against M. tuberculosis in vitro.23,24 This class, along with oxazolidinones, may produce useful agents for TB. Linezolid has been used in a few TB patients.2 Prolong usage of linezolid requires careful monitoring of hematologic indices for potential anaemia and thrombocytopenia. Chemical modification of existing compounds, such as pyrazinamide, may produce new TB drugs. Finally, continuing research on the construction of the mycobacterial cell wall and intracellular pathways may lead to agents with unique activity against this genus. Corticosteroids as adjunctive therapy may be of benefit in some patients with tuberculous meningitis or pericarditis to relieve inflammation and pressure. Corticosteroids should be avoided in most other circumstances because they detract from the immune response to TB. There is a current clinical study suggesting that moxifloxacin-containing regiments may be effective for as short as four months than that of six months conventional

 

ther antituberculosis drugs are:

therapy for TB management ± (Phase II clinical trial by Bayer in collaboration with the TB Alliance to evaluate shorter treatment regimens for TB). 25 In conclusion, WHO progress report 2011 states, progress is being made, but the response rate is far from sufficient given the MDR-TB threat facing the world. Evidence suggests that failure to involve all care providers used by TB suspects and patients hampers case detection, delays diagnosis, leads to inappropriate and incomplete treatment, contributes to increasing drug resistance and places an unnecessary financial burden on patients.

Appendix Clinical presentation of Tuberculosis Signs and symptoms Patients typically present with weight lost, fatigue, a productive cough, fever, and night sweats Frank hemoptysis

Physical examination Dullness to chest percussion, rales, and increased vocal fremitus are observed frequently on auscultation

Laboratory tests Moderate elevations in the white blood cell (WBC) count with a lymphocyte predominance

Chest radiograph Patchy or nodular infiltrates in the apical areas of the upper lobes or the superior segment of the lower lobes Cavitation that may show air-fluid levels as the infection progresses

Treatment of tuberculosis: Guidelines First-line (adults) : Isoniazid, Rifampicin, Pyrazinamide, Ethambutol,*Streptomycin Second-line drugs: Capreomycin, Cycloserine, Streptomycin

*(patients >60 years of age and patients weigh less than 50kg may not be able to tolerate more than 500-750mg daily. A recommendation of dose reduction to 10mg/kg/day in this age group)

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