Tuberculosis was one of the major causes of death until the beginning of the 20^th century. Half of the patients with active pulmonary tuberculosis died within two years, a quarter recovered and a quarter became chronic positive cases. In 1943 the Swedish researcher Lehmann discovered the anti-tuberculous action of para-aminosalicylic acid (PAS). In 1946 the development of streptomycin led to a true revolution in treatment (Sellman Waksman, Nobel Prize 1952). In 1952 isoniazid (INH) was discovered as a tuberculostatic. Rifampicin then followed in 1970.

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Tuberculosis bacteria have a fixed, spontaneous and predictable frequency of DNA mutations, resulting in resistance to a drug. These mutations are independent of each other. This means that resistance to one product is generally not associated with resistance to another drug. The presence of resistant bacteria is a consequence of selection of these prior mutations, not a consequence of the administration of medication (the resistance is not triggered by medication). If only one drug were used, these resistant bacteria would be selected for. If a person were initially infected with bacteria resistant for example to INH, and that person is treated with INH and rifampicin, bacteria with rifampicin resistance will be selected. There will then be a relapse of the illness, but this time with bacteria resistant to both INH and rifampicin. These bacteria can then in turn be transmitted to other people. Treatment regimens must always consist of more than one drug. The period of treatment is long, since mycobacteria only divide slowly and are often not metabolically active for long periods (only bacteria with an active metabolism can be killed by products which act by disorganising the metabolism). Resistant bacteria will also be more easily selected if the drugs are taken irregularly or for too short a period. Poor compliance is the main reason for failure of therapy (and not primary microbial resistance). This has consequences not only for the patient, but also for people in contact. There is only a small risk of multidrug-resistant bacteria emerging spontaneously and yet in recent years these forms have become a real problem. Multiresistance means that there is resistance to at least isoniazid and rifampicin, and possibly there may be simultaneous resistance to other drugs. After instituting the correct medicinal therapy, the infectiveness of a tuberculosis patient falls very quickly to nil (in approximately 2 weeks).

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Steroids are often included in the treatment of tuberculous meningitis and tuberculous pericarditis (less inflammation and postinfectious fibrosis). Clinical arguments for the use of steroids in other cases are less clear, unless there is Addison’s syndrome.

Empyema drainage is carried out using a thorax drain. This is often inserted at the 5^th – 6^th intercostal space, just posterior to the anterior axillary line, or otherwise at the centre of the collected fluid. Bronchopleural fistulas often have to be corrected surgically.

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Sometimes various drugs are processed into one tablet at a fixed ratio: e.g. INH-RMP (Rifamate®) and INH-RMP-PZA (Rifater®).

Asymptomatic immunocompetent people who develop a positive Mantoux test (conversion from negative to positive) have a 2-23% chance (depending on their age) of developing reactivation tuberculosis during their lifetime (on average 5% the first year, 10% during their whole life). The risk of reactivation tuberculosis for HIV infected subjects is 5-10% per year. Administration of isoniazid 300 mg daily (adults) for 6 months, reduces the risk of reactivation of tuberculosis by approximately 90 % in immunocompetent people. The risk is also reduced in this way in HIV-infected, PPD-positive patients, but the optimum period for taking this medication has not yet been determined.

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Rifamycins are a group of structurally related complex macrocyclic antibiotics which are produced by Streptomyces mediterranei. Rifampicin is a semisynthetic derivative of one of these molecules (rifamycin B). Rifampin (rifampicin) is a zwitterion and is soluble in water at an acidic pH. Intestinal absorption is reduced by food. Oral administration of rifampicin produces peak concentrations in plasma in 2 to 4 hours. After ingestion of 600 mg this value is about 7 microgram/ml, but there is considerable variability. Following absorption from the gastrointestinal tract, rifampicin is rapidly eliminated in the bile and an enterohepatic circulation ensues. During this time there is progressive deacetylation of the drug, such that nearly all of the antibiotic in the bile is in the deacetylated form after 6 hours. This metabolite retains full bacterial activity. The half-life of rifampicin varies from 1.5 to 5 hours and is increased in the presence of hepatic dysfunction. There is progressive shortening of the half-life by about 40% during the first 14 days of treatment, due to induction of hepatic microsomal enzymes. Adjustment of the dosage is not necessary in patients with impaired renal function. Rifampicin is distributed throughout the body and is present in effective concentrations in many organs and body fluids, including the CSF. This is exemplified by the fact that the drug may impart an orange-red colour to the urine, faeces, saliva, sputum, tears and sweat. Patients should be so warned.

Microbial resistance may occur as a one-step process and is due to an alteration of the target of this drug, the mycobacterial DNA-dependent RNA polymerase.

Spontaneous resistance to this product occurs in one in 10⁷ to 10⁸ mycobacteria, which means that monotherapy must not be used. Rifampicin (RMP) is given on an empty stomach. It has a powerful bactericidal action on both intracellular and extracellular bacteria. It stains the urine and tears orange/pink. There may be pruritus and nausea. Hepatitis is an important side effect. If the hepatitis is severe (which is rare) and the combination of INH and RMP has been used, then both drugs must be discontinued. Upon normalisation of the liver tests, treatment with INH alone can be started again. Rifampicin increases the breakdown of a number of other drugs including oral contraceptives. No side effects upon the foetus are known, and rifampicin is probably safe. It is expensive. The dose is 10 mg/kg/day, for adults to a maximum of 600 mg/day.

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Rifabutin (Ansamycin®) is a related product and is used in the treatment of tuberculosis if the patient is taking HIV-protease inhibitors. Rifapentin (Priftin®) is a new product which appears promising in treatment and prevention. Experience with this drug is still limited.

Pyrazinamide is a powerful bactericide and acts only on intracellular bacteria. In vitro it is only active in an acid environment. M. tuberculosis does not grow under these conditions in vitro, however, so PZA is not included in a traditional antibiogram. Resistance to pyrazinamide can only be traced via molecular biological techniques. It was previously assumed that the low pH in a phagolysosome of a macrophage, explained the in-vivo action of the product, but doubts about this are now emerging. Pyrazinamide is a pro-drug. It is hydrolysed to pyrazinoic acid, the active metabolite, by the mycobacterial enzyme pyrazinamidase. The details of the metabolism and the anti-tuberculous action are as yet unclear. Liver toxicity and hyperuricaemia with gout are side effects. The dose is 35 mg/kg/day, with a maximum for adults of 2 to 2.5 g/day. There are insufficient data on pregnancy, but the drug is probably safe.

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This is a weak to moderately active bacteriostatic product. Optical neuritis is a potential side-effect with long term use. An early symptom of this is loss of colour vision. The patient has difficulty in distinguishing between red and green. This is ascertained by using a book which contains specific coloured patterns (Ishihara test). Regular eye controls are indicated. Ethambutol may be given to pregnant women. The dose is 15 to 25 mg/kg/day. Lower doses are necessary in renal insufficiency.

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Powerful antibiotic active only against extracellular bacteria (neutral pH). It is not absorbed from the intestine and is administered IM. There are, however, important side effects on the kidneys and the 8^th cranial nerve (equilibrium and hearing). Damage to the kidneys, unlike hearing, is reversible when the drug is stopped soon enough. The ototoxicity is attributable to an effect on the sensory cochlear and vestibular epithelium. Carriers of a certain mitochondrial DNA mutation are said to be at higher risk of toxic effects (matrilineal transmission). Pregnancy and renal insufficiency are contra-indications for the use of aminoglycosides. The dose of streptomycin is 15 to 20 mg/kg/day (lower for older people). Other aminoglycosides such as kanamycin or amikacin have an inferior antimycobacterial action.

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Thioacetazone (= thiosemicarbazone) has low activity and is inexpensive. Other commonly used names for thiacetazone are thioacetazone and amithiozone. Among its important side effects are cutaneous reactions, which are worse in AIDS patients. Dose 4 mg/kg/day, adults 150 mg/day.

Para-aminosalicylic acid (12-15 gr/day) : virtually abandoned.

Cycloserine (750 mg/day) are second choice drugs which are less effective, have more side effects, but can sometimes be used where there is resistance. Cycloserine is well absorbed after oral administration. Cycloserine is an orally effective tuberculostatic agent that distributes well throughout body fluids, including the CSF. It is metabolized, and both parent and metabolite are excreted in urine. Accumulation occurs with renal insufficiency. Adverse effects involve CNS disturbances, epileptic seizure activity may be exacerbated. Peripheral neuropathies are also a problem.

Ethionamide (750-1000 mg/day) is a structural analog of isoniazid (it is a thioamide), but it is believed not to act by the same mechanism. Its oral administration is effective, and the drug is widely distributed throughout the body, including the cerebrospinal fluid. Metabolism is extensive. Ethionamide can inhibit acetylation of isoniazid. The urine is the main route of excretion. Adverse effects include gastric irritation, hepatotoxicity, peripheral neuropathies, and optic neuritis.

Capreomycin (1 gr/day) is a polypeptide antimicrobial substance consisting of a mixture of capreomycine IA, IB, IIA and IIB. It is administered via deep IM injection. The side effects on the kidneys and the eight cranial nerve is similar to that of aminoglycoside antibiotics such as streptomycin. Hypokalemia has been reported. Eosinophilia commonly occurs with capreomycin.

Others : the quinolones ofloxacin or ciproxin may also be used. The S(-) enantiomer of ofloxacin is levofloxacin and it is not active against mycobacteria. Some of the new macrolides such as clarithromycin [Biclar®, Heliclar®] are promising. Research is being carried out as to whether the new class of oxazolidinones, the class of linezolid (Zyvox®), are agents which have an antituberculous action. The use of gamma-interferon via aerosol is being studied as adjuvant therapy for multidrug-resistant tuberculosis. This substance activates macrophages. The treatment of multidrug-resistant tuberculosis is approximately 100 times as expensive as the traditional treatment of non-resistant tuberculosis. Sometimes surgery (partial lung resection) is needed.

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Mycobacteria replicate in the vacuoles of macrophages and their environment changes when macrophages are activated and form granulomas. The bacteria respond by switching their metabolism away from carbohydrates and towards using fatty acids. In chronic persistent M. tuberculosis the enzyme isocitrate lyase is very important in this respect. This enzyme plays a key role in the glyoxylate shunt (in the Krebs-Kornberg cycle). Two molecules of acetylCoA are converted to succinate in this biochemical cycle. Fats form an important source of acetylCoA. Succinate is a precursor for glucose synthesis. The glyoxylate cycle permits the bacterium to synthesise carbohydrates from fatty acids. If the gene for isocitrate lyase is destroyed, the intracellular survival of the bacterium is jeopardised. The enzyme does not occur in humans. Research is now being carried out as to whether inhibiting this enzyme could be beneficial in the treatment of tuberculosis.

Mycobacterium tuberculosis multiplies slowly and can remain inactive for a long time. Metabolically inactive bacteria are insensitive to antibiotics. Therapy of pulmonary tuberculosis has to be long-term (not less than 6 months) and even longer (one year) for other forms such as tuberculosis of the bone or meningeal tuberculosis. There are various regimens. Local guidelines should be observed, if they exist. At present DOTS is popular (directly observed treatment, short course), which means that the drugs are administered under the supervision of a nurse. In order for the service to have optimum effect there must never be an interruption of stocks, the service must be good, must be easily accessible and the care providers should take responsibility for real care.

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Example:

• Basic 6 month therapy: 2 months INH (H) + RMP (R) + PZA (Z) + EMB (E), followed by a further 4 months INH + RMP
• In case of relapse with sputum positive: 8 month therapy: 2 months SHRZE, 1 month HRZE, 5 months HRE

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• Pregnancy: INH + EMB + RMP, no streptomycin, PZA unknown (probably safe)
• Breast feeding: normal therapy for mother, INH-prophylaxis and then BCG for the child
• Liver disease: if not a consequence of the medication, no special adjustment necessary. It is advisable to avoid PZA in alcoholic liver disease.
• Renal insufficiency: normal dose of INH + RMP, half dose of EMB, 3/4 dose of PZA, no streptomycin
• AIDS: normal dosages if no antiretroviral therapy, no thiosemicarbazone (risk of exfoliative dermatitis)
• Tuberculosis of the spine with threatened paraplegia: surgical consultation is indicated (decompression, possibly spinal fusion with bone grafts) and bed rest.

The development of tuberculostatic therapy has made it possible in theory to cure almost every tuberculosis patient. Nevertheless practice proves otherwise. This is because continued compliance with the therapy is essential for a complete and definitive recovery. Problems with therapy compliance are not confined to developing countries; not all patients do fully comply with their therapy in industrialised countries either. It is estimated that 33% of the patients in the "developed" world do not follow the medical instructions correctly. Treatment which is administered irregularly or stopped too soon has serious consequences, not only for the patient but also for the whole community.

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How do we know whether a patient takes the prescribed medication? By asking the patient, of course, but this does not always lead to reliable data. Some forget, or refuse to state that they have not taken the prescribed doses. Rifampicin stains the urine and other bodily fluids orange-red and can thus be easily recognised. Using a simple urine stick, isoniazide can be traced, but this test material is usually not available in developing countries. Patients may also refuse to give a urine sample.

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Why does a patient refuse to take medicines which can prevent him or her dying from tuberculosis? There are various reasons. Tuberculosis requires long-term uninterrupted treatment, in which several pills have to be taken every day. The side effects may be unpleasant. The symptoms of the disease subside very quickly. Once the symptoms have disappeared, the patient might think that further treatment is unnecessary. If the symptoms continue for longer than expected, the patient thinks that he is being given the wrong treatment and therefore interrupts the therapy. The patient may be struggling with other problems, such as debts and hunger, which demand more attention than the illness "which after all is getting better".

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To prevent poor therapy compliance it is of great importance to convince the patient that the dangers of tuberculosis are real and to explain the limitations of the treatment. Poor therapy compliance is difficult to predict for each patient, except those patients who have previously proved to have little discipline. Nevertheless even well-meaning patients may be in material, psychological or socio-economic circumstances which may lead to poor therapy compliance. Examples are extra physical or mental stress, misunderstanding, behavioural disorders, homelessness, unemployment, low income, transport problems, lack of familial or social support, migration. In such cases extra attention and supervision are needed from the health worker. The requirement for therapy compliance is an integral part of the treatment.

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• Therapy compliance can be assisted by shortening the treatment. As well as the advantage of reducing the total treatment period to 6 months (short course) this also leads to a reduction in costs. Therapy compliance can also be improved by combining several drugs in one pill, or administering them as an injection. Adaptations to the packaging of the pills may help the patient to remember when the medication must be taken and whether the medicines have already been taken on a certain day.
• A small present (a reward or encouragement) to motivate the patient to what is asked. The use of such incentives has a symbolic value. It is not so much what the patient receives, but it is the thought that counts. This is usually food or money. Sometimes an incentive only serves to make a patient prepared to come to the dispensary or hospital. Such a policy should be considered in consultation with other health authorities in the region. Social contact can also have the effect of an incentive. Many patients are very pleased when a nurse calls at their home and gets to know the family.
• Instruction is generally given in combination with other measures. Information alone is not sufficient. Patients must be convinced that they have to adjust or change their behaviour. Individual messages must be adjusted to suit the language and culture of the patient.
• Taking medication under supervision means that the nurse ensures that the patient swallows the tablets. In a rural area this is difficult, but in towns and cities or slum areas it is possible. To ensure full therapy compliance, supervision should be maintained for the full duration of the treatment. In particular, patients with positive sputum and also those having repeat treatment, are eligible for supervised ingestion of medication. Hospitalisation is an alternative.
• Drawing on local health workers is an essential element of an efficient tuberculosis eradication programme. They usually belong to the same community as the patient.