Tuberculosis Management

See related articles Tuberculosis and BCG vaccination.

1. Notification. All cases of tuberculosis (TB) must be notified under under the Public Health (Infectious Diseases) Regulations 1988, to provide surveillance data and to initiate contact tracing and nursing input. The doctor suspecting the diagnosis is legally responsible for notification of the consultant in communicable disease control (CCDC).
2. Staff and services. All health authorities should have an integrated policy for prevention and control of TB. Most cases can be managed as outpatients but occasional admission may be needed. Patients with suspected TB should be admitted to a single side-room vented to the outside until they are proven to be non-infectious. Consideration should also be given to the likelihood of multidrug resistance (MDR) and the immune status of the other patients on the ward, as per the guidelines.¹ Only physicians with full training and expertise in management of TB with access to TB nurse specialists and health visitors should be responsible for patients with respiratory TB.
3. Compliance. Compliance is a major determinant of the success of drug treatment as it is essential to prevent treatment failure and acquisition of drug resistance. A patient should always be aware of their diagnosis and be prepared for a long course of treatment. Supervised therapy can improve compliance in some treatment groups. NICE has identified improved adherence as a key area for implementation.¹ NICE recommends that all patients should have a risk assessment for adherence to treatment.
4. Supervised treatment. The World Health Organisation (WHO) strongly recommends the use of directly observed therapy (DOT) to improve compliance and prevent the emergence of drug resistance by ensuring that monotherapy is avoided.² A healthcare worker or other trained personnel must observe ingestion of every single drug dose. Most DOT programmes have shown high success rates.³ DOT is only recommended in the UK for patients who are unlikely to comply with unsupervised daily administration of antituberculous medication. Such patients may include drug abusers, homeless or mentally ill patients.¹ The TB service should ensure each patient with TB has a key worker to help with education and adherence. DOT programmes may be based at a chest clinic, hospital or pharmacy. Intermittent regimens are often more convenient for DOT than daily dosing and schemes may include incentives for co-operation and rewards such as food, childcare or repayment of transport costs.⁴
5. Contact tracing. See below.
6. New entrant screening. NICE has recently highlighted new entrant screening as a priority for implementation.¹ New entrants should be identified:
   • From Port of Arrival reports
   • On newly registering in primary care
   • At entry to educational establishments
   • From links with statutory and voluntary groups working with new entrants
7. BCG vaccination. Another key area for implementation identified by NICE.¹ At-risk neonates should be identified and BCG vaccination discussed with parents. In areas where there is a high incidence of TB (more than 40 cases per 100,000 per year), BCG might be offered to all neonates.

A combination of drugs is used to accelerate the response of the infection to treatment and shorten the length of therapy needed for cure.⁴Drug treatment usually lasts for 6 months. The choice of treatment regimen depends on:

• Organ/system affected:
  • Respiratory TB (TB affecting lungs, pleural cavity, mediastinal lymph nodes or larynx). Usually 4 drugs for 2 months, followed by 2 drugs for 4 months or until susceptibility reports if sputum culture is positive. Nine months are needed if pyrazinamide is not prescribed or not tolerated. NICE¹ now lists the standard regimen of 6 months' treatment as:
    • 4 drugs initially (isoniazid, rifampicin, ethambutol and pyrazinamide) for 2 months.
    • Then 4 months of 2 drugs (isoniazid and rifampicin).
    • Use as first choice fixed-dose combination tablets.
    • Use as first choice daily dosing.
    • NICE considers this standard regimen should be used for:
      • Fully drug-susceptible TB at all sites except for the central nervous system (CNS) (see below).
      • All ages, children and adults.
      • Patients with negative and positive HIV status.
    Where DOT is employed this should incorporate thrice-weekly regimens (but not twice-weekly).¹
  • Peripheral lymph node TB (non-respiratory TB). 6 months are as effective as 9. NICE recommend the standard 6 month regimen even if an affected lymph node has been surgically removed.¹ Stop after 6 months regardless of new nodes appearing, persistent nodes or draining sinuses.¹
  • Bones and joints. The spine is the most common site. First choice is the standard 6 months' regimen as for respiratory TB.¹
  • Pericarditis. First choice is the standard 6 months' regimen.¹ Corticosteroids are recommended by NICE at doses as for meningeal TB (see below). Corticosteroids are particularly necessary in acute constrictive tuberculous pericarditis.
  • Meningitis. Lack of trial evidence, but experience suggests 12-month regimens. NICE¹ lists as a key priority the treatment of active meningeal TB with:
    • 12 months of treatment.
    • 2 months of 4 drugs as above, followed by 2 drugs for 10 months (isoniazid and rifampicin).
    • A glucocorticoid with the dose reduced after 2 to 3 weeks. Adults starting on prednisolone 20-40 mg (if on rifampicin) otherwise 10-20 mg. Children 1- 2 mg/kg up to maximum of 40 mg.
    No evidence of need for intrathecal streptomycin.
  • Disseminated TB. First choice is the standard 6-month regimen.¹ However the 12-month regimen should be used if there is CNS involvement (exclude with CT or MRI scan, with or without lumbar puncture).
  • Other sites. Generally 6 months of treatment.
• Drug resistance profile - drug resistance increases the risks of treatment failure and development of further resistance. Approximately 6% of M. tuberculosis is resistant to at least one antituberculous drug in the UK. Acquired resistance is usually due to inadequate treatment.
• Risk factors for resistance¹ include:
  • Previous treatment for TB
  • Prior failure of TB treatment
  • Contact with a known case of drug-resistant TB
  • Immigration from areas of high resistance
  • HIV-positive status
  • Residence in London
  • Age profile (highest rates are between ages 25 and 44)
  • Male gender
• Compliance
• Drug intolerance
• Immune status

Daily versus two or three times per week regimens

Unsupervised treatment involves daily dosing, whereas supervised treatment was often given 2 and 3 times per week. Only thrice-weekly regimens are now recommended.¹

Combination preparations

Combinations should be used whenever possible to improve compliance and prevent accidental monotherapy. Care must be taken when prescribing as many different compounds have similar trade names, e.g. Rifinah®, Rimactazid®, Rifater®.

First-line drugs⁵

• Isoniazid is the most potent bactericidal drug. It has good penetration of tuberculous lesions and is excreted by the kidneys.
• Rifampicin is a potent mycobacterial RNA polymerase inhibitor. It has good tissue penetration and gives an orange discoloration to body fluids. It is metabolised by the liver and excreted in urine and bile. Rifampicin is a cytochrome P450 enzyme inducer and therefore interacts with the effects of other drugs.
• Pyrazimamide is bacteriostatic against semi-dormant, intracellular mycobacteria and is excreted by the kidneys.
• Ethambutol gradually inhibits mycobacterial growth and is excreted in urine and faeces.

Treatment is divided into an initial phase and a continuation phase. Occasionally, extended regimens are used.

Second-line drugs

Second-line agents are used by specialists in certain situations (for example resistance and intolerance) and include: amikacin, capreomycin, cycloserine, macrolides (azithromycin, clarithromycin) and quinolones (moxifloxacin, levofloxacin).
Streptomycin is unlicensed and now rarely used in the UK.

Alternative low-cost regimes

There are several alternative cheaper regimes for use in countries with low per capita income. See the National Tuberculosis Programmes (NTPs) for the particular country.

Drug reactions occur in 10% of patients treated for TB, with a high proportion requiring modification of treatment. Such reactions are more common in those who are on non-standard treatments or who are HIV-positive. Serious complications include (see individual drugs for full list):

• Isoniazid can cause peripheral neuropathy. It is recommended that patients at increased risk be given prophylactic pyridoxine. This includes diabetics, alcoholics, malnourished and HIV-positive patients, and those with chronic renal failure.
• Rifampicin can cause shock, acute renal failure and thrombocytopenic purpura. If these occur, rifampicin must be immediately withdrawn and not reintroduced. Rifampicin accelerates the metabolism of corticosteroids, protease inhibitors, sulphonylureas, anticoagulants, the combined oral contraceptive pill (COCP) and other medications. These drug doses should be adjusted accordingly and alternative contraceptive advice offered.
• Ethambutol can cause rare but serious visual disturbances, including reduced visual acuity (VA), colour blindness and restriction of visual fields. For this reason it is best avoided in those <3 years of age when VA cannot be measured, except in resistant cases where sensitivity is proven. The risk is increased with higher doses and renal impairment. Patients should discontinue treatment immediately if they notice visual deterioration. Sight is usually recovered after treatment cessation.

Renal function must be checked before treatment with ethambutol or streptomycin. These drugs are best avoided if renal function is impaired but, if they are necessary, reduced dosages are used and serum drug concentrations must be closely monitored. Isoniazid, rifampicin and pyrazinamide can be given in standard doses in renal impairment.
Liver function tests (LFTs) must be performed before treatment, as isoniazid, rifampicin and pyrazinamide are all potentially hepatotoxic. Note, however, that modest elevation of pre-treatment transaminases is not uncommon in TB patients. If baseline LFTs are normal and there is no evidence of chronic liver disease then further monitoring is not required. Otherwise, weekly or fortnightly monitoring of LFTs is necessary. Treatment should be stopped and LFTs rechecked if:

• There is fever, malaise, vomiting, unexplained deterioration or jaundice
• Transaminases are 5 x normal
• Rising bilirubin level

If the patient is unwell or TB is still infectious then admission is needed for treatment with second-line drugs. When LFTs are back to normal, first-line drugs can be cautiously reintroduced.
VA should be measured using a Snellen chart prior to ethambutol use. Ethambutol should only be used in patients who can appreciate and report visual deterioration. It is therefore not recommended in children under 5 and should be used cautiously in unconscious patients.

Multidrug-resistant tuberculosis

In England 1% of M. tuberculosis is described as multidrug-resistant - having resistance to isoniazid and rifampicin, regardless of resistance to other drugs. Rates have increased slightly in the UK in recent years but remain low compared with overseas.

• The treatment of multidrug-resistant TB (MDR-TB) takes longer and is much more difficult.⁶
• Current optimal drug therapy for MDR-TB only offers a 60-70% cure rate.²
• Management is specialised, complex and expensive and should only be undertaken in recognised, experienced centres with isolation facilities.²
• Treatment must be monitored closely because of increased drug toxicity and to ensure compliance.
  • All patients must therefore participate in directly observed therapy (DOT) for the entire treatment course.
  • If MDR-TB is suspected, the patient should be started on 5 or more drugs to which the organism is likely to be susceptible, while the actual sensitivity profiles are investigated.
  • These drugs are continued until sputum cultures are negative and the patient is no longer infectious.
  • When the specific drug resistance is determined, the regime is reduced to 3 or more drugs to which the organism is known to be sensitive, and is continued for a minimum of 9 months. Treatment may even extend beyond 2 years.
• Surgical excision of pulmonary lesions may be useful if the disease is unresponsive to medical therapy.

Immunocompromised patients

TB is an AIDS defining illness and HIV testing should be considered. Patients with a low CD4 count are more likely to have disseminated TB. Patients with advanced disease are more likely to develop disseminated TB and, predictably, TB patients with concurrent HIV infection have a worse prognosis. Patients with HIV show a good response to chemotherapy. Patients should be prescribed the standard treatment unless MDR-TB is suspected but treatment may be prolonged.

Pregnancy

Women must be aware of the reduced efficacy of the COCP with rifampicin-based chemotherapy. No first-line medications have been shown to be teratogenic and conception whilst on treatment is therefore not an indication for termination of pregnancy (TOP). Second-line drugs of ethionamide and prothionamide may be teratogenic and are best avoided. Streptomycin and other aminoglycosides should also be avoided during pregnancy, as they may be ototoxic to the fetus. Mothers may breast-feed normally while taking antituberculous treatment.²

Renal disease

Rifampicin, isoniazid and pyrazinamide can be given at standard doses, but reduced doses of streptomycin and ethambutol are used (with monitoring of serum levels). Dialysis affects clearance of drugs and requires dose modification.

Children

The management of respiratory and non-respiratory TB is similar to the standard adult regimens. Doses however must be calculated by weight and are generally rounded up for ease of prescribing. Ethambutol is used with caution for fear of visual disturbances. Supplemental pyridoxine is only recommended for breast-fed or malnourished children.²

Corticosteroids

Enzyme induction requires maintainance dose of corticosteroids (taken for accompanying conditions) to be doubled if rifampicin is taken. Corticosteroids are used for:

• Pericarditis
• Meningitis (stages II and III)
• Endobronchial disease in children
• TB affecting ureters
• Pleural effusions
• Extensive pulmonary disease
• Hypersensitivity to antituberculous drugs.

Diabetes

Incidence of TB is increased in diabetes and pulmonary disease is often more extensive. Standard regimens can be used. Sulphonylureas have reduced efficacy with rifampicin.

In the UK, treatment of fully sensitive organisms with good patient compliance has very low failure and relapse rates. If such a patient is well after completion of treatment then no formal follow-up or surveillance is necessary. The patient will be referred back to clinic by his GP should any problems arise. If relapse does occur, the organism is usually fully sensitive and the same treatment regimen can be used.
However, treatment failure or relapse after therapy is usually due to poor patient compliance. This will also increase the risk of drug resistance. Cultures and drug sensitivity profiles must therefore be repeated and consideration given to rapid molecular determination of rifampicin resistance. Further treatment must be fully supervised and is similar to regimens used in MDR-TB.²

New antituberculous drugs

There is global demand for drugs, which would allow shorter treatment courses, improved compatibility with HIV treatment and greater efficacy against MDR and latent TB.⁷ A long-acting rifamycin, rifapentine, which allows less frequent dosing is licensed in the US but concerns regarding high relapse rates have so far prevented its use in the UK. Another rifamycin, rifabutin, may provide a useful alternative to rifampicin for HIV-positive patients on concurrent antiretroviral therapy. Recent studies of novel drug classes have also demonstrated significant antimycobacterial activity of the diarylquinolones, nitroimidazopyrans and oxazolidinones, and various compounds are undergoing further development.⁸

This should be carried out by the multi-disciplinary TB team. Detailed guidance has been outlined by NICE.¹

• It aims to detect people infected with TB but with no clinical evidence of disease (10% of all TB diagnoses).
• It aims to identify BCG vaccination candidates.
• Detect a source patient, e.g. when a child is diagnosed with TB.

Screening is recommended for selected contacts, since the source case has exhibited respiratory symptoms. If this is unknown, contacts during the 3 months preceding the initial diagnosis are screened. Tracing should be extended backwards if necessary.

• Initially, screen people from the same household and any frequent visitors of the index case. If the index case has pulmonary TB, all close contacts should be screened. Screening is not usually necessary for contacts of non-pulmonary TB patients.
• Screening of casual contacts is less fruitful and is only necessary if the index case is highly infectious or the contacts are particularly susceptible, such as young children or immunocompromised adults. Casual contacts include occupational contacts or healthcare workers.

Contacts are assessed, as per BTS guidelines, with regard to:

• Symptoms
• BCG vaccination status
• Tuberculin (Mantoux/Heaf) skin test
• CXR findings

Treatment should be considered if a contact has evidence of:

• Tuberculous disease, i.e. positive skin test with clinical signs and symptoms. Begin one of the standard treatment regimens.
• Tuberculous infection, i.e. positive skin test but asymptomatic and normal CXR, suggesting presence of small numbers of bacteria in the body which may later cause disease
• Ongoing risk of acquiring infection.

Chemoprophylaxis is available for patients with evidence of tuberculous infection but not clinical disease. Although similar drugs are used, chemoprophylaxis therapy is less intense than TB treatment regimens:

• Routine chemoprophylaxis involves isoniazid for 6 months or isoniazid plus rifampicin for 3 months.
• Chemoprophylaxis is not routinely recommended for contacts of MDR-TB because of limited drug options and drug toxicity.
• Patients who are likely to benefit most include:
  • Children under 16 years of age with strongly positive Heaf tests
  • Children under 2 years of age, with close contact with smear-positive (infectious) TB case, including babies of infectious mothers
  • Patients with recent tuberculin conversion
  • HIV-positive close contacts of infectious TB case
• BCG vaccination is recommended for uninfected contacts that fulfil all of the following criteria:
  • Child under 16 years of age
  • Previously unvaccinated
  • Persistently tuberculin negative
  Although unproven, the BCG may confer a small protective effect when given to adults and so can also be offered to older patients, if there are compelling ongoing risk factors for TB.

Follow-up of contacts of sensitive strains of TB is usually unnecessary. If there is no evidence of disease during initial screening then the risk of infection is very low. Patients should be aware of the need to report suspicious symptoms to their GP in future, and their doctor must be informed of past TB contact. It is, however, important to monitor MDR-TB contacts closely in clinic.

NICE has now produced guidelines.¹ These give further details and recommendations on clinical diagnosis, management and prevention of tuberculosis.

1. Tuberculosis, NICE Clinical Guideline (March 2006); Clinical diagnosis and management of tuberculosis and measures for its prevention and control
2. Davies PO; Multi-drug resistant Tuberculosis
3. WHO; World Health Organisation - PDF; 8th WHO Annaul report on Global TB
4. Chan ED, Iseman MD; Current medical treatment for tuberculosis. BMJ. 2002 Nov 30;325(7375):1282-6.
5. Rang HP, Dale MM and Ritter JM. Antibacterial agents. In Pharmacology, Third Edition (1995), pp 718-742. London: Churchill Livingstone
6. DH; Stopping Tuberculosis in England: An action plan from the Chief Medical Officer; 2004
7. TB Alliance; Global Alliance for the development of better TB drugs. A not-for-profit organisation.
8. O'Brien RJ and Nunn PP; The Need for New Drugs against Tuberculosis; Obstacles, Opportunities, and Next Steps. Am. J. Respir. Crit. Care Med., Volume 163, Number 5, April 2001, 1055-1058.
9. BTS Guidelines; Control and prevention of tuberculosis in the United Kingdom: Code of Practice 2000. Joint Tuberculosis Committee of the British Thoracic Society. Thorax 2000;55:887-901.

• WHO; World Health Organization - Tuberculosis
• HPA - TB surveillance statistics. Health Protection Agency.
• Sterling TR, Lehmann HP, Frieden TR; Impact of DOTS compared with DOTS-plus on multidrug resistant tuberculosis and tuberculosis deaths: decision analysis.;BMJ 2003 Mar 15;326(7389):574.
• Gelband H; Regimens of less than six months for treating tuberculosis. Cochrane Database - Full Text.
• Kennedy N; Drugs for difficult bugs.
• Immunisation against infectious disease - 'The Green Book', Department of Health (various dates)
• Guidelines for tuberculosis prevention and control, Health Protection Agency (2008)
• Tuberculosis, Clinical Knowledge Summaries (January 2009)