Tuberculosis management

Because of the complexity of drug regimens, drug toxicity and the need for adherence, patients with tuberculosis (TB) are best managed by a multidisciplinary team comprising doctors with training and expertise in the management of TB, specialist nurses, microbiologists and pharmacists[1].

The aim of TB treatment is to cure the patient of disease without relapse, thereby preventing death, the emergence of drug resistance and transmission of the disease to other people[1].

Drug-sensitive TB

For most adults and children a six-month course of isoniazid plus rifampicin is recommended, supplemented with pyrazinamide and ethambutol for the first two months,1 using the recommended doses listed in the British National Formulary and BNF for Children. Adherence to treatment is crucial (see Box 1).

This regimen should be prescribed for patients with respiratory and non-respiratory TB[1]. However, for patients with central nervous system TB, it is recommended that treatment is extended to 12 months — ie, 12 months of isoniazid plus rifampicin, supplemented with pyrazinamide and ethambutol for the first two months[1].

TB meningitis is associated with higher morbidity and mortality. Treatment with corticosteroids has been shown to reduce mortality, but not morbidity, of patients with TB meningitis[5,6]. The British Infection Society recommends: dexamethasone 0.4mg/kg/day as a reducing course over six to eight weeks for adults; and prednisolone 4mg/kg/day for four weeks followed by a four-week reducing regimen for children[7]. However, the National Institute for Health and Care Excellence recommends using prednisolone at a starting dosage of 20–40mg daily for adults and 1–2mg/kg/day for children[1].

Corticosteroids are also recommended in the treatment of pericardial TB (prednisolone 60mg daily for adults; 1mg/kg/day for children)[1].

Drug-resistant TB

The treatment of drug-resistant TB is highly complex and there is a paucity of randomised controlled trials to guide regimen choice. Second-line anti-TB drugs are generally less effective and have more adverse effects than first-line options. NICE has therefore recommended that only specialist doctors with experience of treating drugresistant TB should manage these cases[1].

The main causes of drug-resistant TB include: nonadherence to treatment; failure to complete the prescribed course; unsuitable treatment regimens; or lack of availability of high-quality drugs (eg, use of sub-quality medicines or treatment interruptions caused by supply problems).

The degree of drug-resistance varies and the different types of drug-resistant TB are[8]:

• Mono-drug-resistant TB — resistance to one anti-TB medicine
• Multi-drug-resistant TB (MDRTB) — resistance to isoniazid and rifampicin, at least
• Extensive drug resistance (XDRTB) — resistance to a fluoroquinolone and at least one injectable second-line option, in addition to multi-drug resistance.

Although NICE provides guidance for the management of mono-drug-resistant TB[1], there are no guidelines on the treatment of MDRTB in the UK and practice is based on recommendations from the World Health Organization[9]. UK clinicians can access expert advice from the British Thoracic Society’s MDRTB clinical advice service — an internet forum available on its website[10]. This multidisciplinary service provides advice from respiratory, infectious disease and public health clinicians, microbiologists, paediatricians, a surgeon, TB specialist nurse and a pharmacist. Additional resources, due to be made available in autumn 2013, include drug monographs, case studies and frequently asked questions.

The WHO categorises anti-TB drugs into five groups (see Box 2) according to efficacy, experience of use and drug class; this aids decision-making in the management of MDRTB. Treatment is tailored to individual patients and is largely based on drug sensitivity findings and previous treatment. Patients should be started on a regimen made up of five different anti-TB medicines. Initial treatment usually comprises[9]:

• Pyrazinamide (unless resistant)
• A fluoroquinolone (usually moxifloxacin)
• A parenteral anti-TB medicine
• Two oral bacteriostatic medicines (usually prothionamide and cycloserine, or p-aminosalicylic acid if cycloserine cannot be used)
• Adding ethambutol to the initial five-drug regimen.

If a total of five options cannot be drawn from groups 1 to 4 (see Box 2), a drug from group 5 can be used — however, these drugs are considered to represent half a drug in the regimen because there is a lack of evidence on their efficacy.

The intensive phase of treatment should last eight months, after which the parenteral medicine is usually stopped and the remaining drugs are continued for a total of 20 months. If the regimen appears to be failing (often an indicator of poor adherence or increased resistance) at least two new drugs should be started, because adding a single drug is likely to result in resistance to it.

Latent TB infection

Treatment for latent TB infection (LTBI) is recommended for certain groups of people after active TB disease is excluded, such as those aged 35 years or younger, those who are immunocompromised owing to medication or disease, healthcare workers and patients on the waiting list for renal transplantation[1,11]. Treating people with LTBI who are contacts of patients with infectious MDRTB is not recommended due to the lack of data demonstrating efficacy of any potential regimen.

• People requiring treatment for LTBI should receive one of the following regimens[1]:
• People not known to have HIV — either six months of isoniazid or three months of rifampicin plus isoniazid
• People who have HIV — six months of isoniazid
• People who are contacts of patients with isoniazidresistant TB — six months of rifampicin.

Adverse effects of anti-TB drugs

The treatment of TB requires patients to take multiple medicines for prolonged periods and adverse drug reactions are common. At the time TB treatment is started, all patients should be educated on the common side effects of treatment and how to manage them.

Patients started on standard anti-TB medicines for drug-sensitive TB should be advised that they may experience the following:

• 
  Body secretions, such as urine, saliva, sweat and tears, may turn orange/red — this is normal (due to rifampicin) and harmless
• Stomach upset, nausea, vomiting or diarrhoea — nausea is common initially but is usually mild; if severe nausea or vomiting occurs an antiemetic may be required
• Skin rashes and itch — mild rashes and itching are usually temporary but may require antihistamines; if severe, treatment may need to be discontinued
• Pins and needles in the fingers or toes — peripheral neuropathy is a rare side effect of isoniazid and is more common in patients who are malnourished, immunocompromised, diabetic, elderly, alcoholic or renally impaired; at-risk groups should be prescribed supplemental pyridoxine 10–50mg once a day; if symptomatic, larger doses may be required
• Rarely jaundice (characterised by yellowing of the skin or eyes) — rifampicin, isoniazid and pyrazinamide are all potentially hepatotoxic; patients who become jaundiced should stop treatment immediately and contact their doctor or TB nurse urgently to arrange a clinical assessment and liver function tests (LFTs)
• Visual disturbances (blurred vision or red/green colour disturbance) — rarely ethambutol can cause optic neuritis, and visual acuity should be checked at the start of treatment.

Some of the common adverse effects associated with second-line anti-TB medicines are listed in Box 3.

Managing TB with liver dysfunction

Whereas many national guidelines advise only to check LFTs when starting anti-TB medicines and repeating only if symptomatic[1], many centres monitor LFTs routinely during the initial two months of treatment. If transaminases rise greater than five times the upper limit of normal, or greater than three times normal and the patient is symptomatic, all potentially hepatotoxic drugs (namely rifampicin, isoniazid and pyrazinamide) should be stopped immediately.

Liver function should be monitored closely and the advice of a liver specialist sought if necessary. If the patient is well and sputum-smear-negative (ie, noninfectious) no treatment is required until after LFTs return to normal. However, if the patient is unwell, or sputum-smear-positive, TB treatment must continue using streptomycin and ethambutol, providing that there are no contraindications or drug resistance[12].

Once liver function has returned to normal, the firstline anti-TB drugs can be reintroduced sequentially while rechecking LFTs twice a week. Isoniazid is commenced first at a dose of 50mg daily and increased gradually to 300mg daily over two to three days and then continued. If no adverse reaction occurs, rifampicin can be started at a dose of 75mg daily, then increased gradually to 450mg (for patients <50kg) or 600mg (for patients >50kg) and then continued. If there is still no adverse reaction, pyrazinamide can be restarted at a dose of 250mg daily and increased gradually to 1.5g (<50kg) or 2g (>50kg) daily. If the full dose of each drug is achieved with no further hepatotoxicity, streptomycin can be stopped and the standard treatment regimen restarted[2,12].

Some guidelines advise against reintroducing pyrazinamide if the hepatotoxic reaction was particularly severe and prolonged, and suggest continuing with just rifampicin and isoniazid and extending the course duration to nine months[13].

Pharmacist input

Tuberculosis management is an area where pharmacists can form an important part of the multidisciplinary team.

TB specialist nurses have been involved in community outreach programmes attached to hospitals for many years. Pharmacists in clinics and wards can provide patient education on anti-TB medicines, the identification and management of side effects, adherence counselling and managing drug supply, as well as practising as independent prescribers.

In TB/HIV co-infection (see Box 4), pharmacists have a key role to play in educating and advising on practical approaches to managing co-infection, drug-drug interactions, treatment regimen design and therapeutic drug monitoring of antiretrovirals and anti-TB drugs.

It is important to recognise that, since a large proportion of the UK TB population comprises patients who were not born in the UK, language may be a significant barrier to understanding both TB and the anti-TB drug regimens. Simple patient information leaflets, available in 21 different languages, are available from the TB Alert charity website (www.tbalert.org).

Additionally, patient-specific drug information and diary cards to support patient education and adherence can be produced at www.tbtreatmentguide.com — a website run by TB Alert.

References

1. National Institute for Health and Care Excellence. Tuberculosis: clinical diagnosis and management of tuberculosis, and measures for its prevention and control. March 2011. www.nice.org.uk/guidance/cg117 (accessed 10 July 2013).
2. Pozniak AL, Coyne KM, Miller RF, et al. British HIV Association guidelines for the treatment of TB/HIV coinfection. HIV Medicine 2011;12:517–24.
3. Bangalore S, Kamalakkannan G, Parkar S, et al. Fixed-dose combinations improve medication compliance: a meta-analysis. American Journal of Medicine 2007;120:713–9.
4. Department of Health. The National Health Service Act 2006: The Pharmaceutical Services Directions (advanced and enhanced services, England). London: 2011; The Department.
5. Prasad K, Singh MB. Corticosteroids for managing tuberculous meningitis. Cochrane Database of Systematic Reviews 2008, issue 1.
6. Thwaites GE, Nguyen HD, Hoang TQ, et al. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. New England Journal of Medicine 2004;351:1741–51.
7. Thwaites GE, Fisher M, Hemingway, et al. British Infection Society guidelines for the diagnosis and treatment of tuberculosis of the central nervous system in adults and children. Journal of Infection 2009;59:167–87
8. World Health Organization. Guidelines for the programmatic management of drug-resistant tuberculosis: Emergency update 2008. www.who.int (accessed 10 July 2013).
9. World Health Organization. Guidelines for the programmatic management of drug-resistant tuberculosis: 2011 update. www.who.int (accessed 10 July 2013).
10. Jordan TS, Cullen D, Davies PD. A centralised electronic multidrugresistant tuberculosis advisory service: the first 2 years. International Journal of Tuberculosis and Lung Disease 2012;16:950–4.
11. Milburn H, Ashman N, Davies P. Guidelines for the prevention and management of Mycobacterium tuberculosis infection and disease in adult patients with chronic kidney disease. Thorax 2010;65:559–70.
12. Ormerod LP, Skinner C, Wales J. Hepatotoxicity of antituberculosis drugs. Thorax 1996;51:111–3.
13. Saukkonen JL, Cohn DL, Jasmer RM, et al. An official American Thoracic Society statement: hepatotoxicity of antituberculosis therapy. American Journal of Respiratory and Critical Care Medicine 2006;174:935–52.
14. Abdool Karim SS, Naidoo K, Grobler A, et al. Timing of initiation of antiretroviral drugs during tuberculosis therapy. New England Journal of Medicine 2010;362:697–706.
15. Williams I, Churchill D, Anderson J, et al. British HIV association guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy. HIV Medicine 2012;13(supp 2):1–85.
16. Lopez-Cortes LF, Ruiz-Valderas R, Viciana P, et al. Pharmacokinetic interactions between efavirenz and rifampicin in HIV-infected patients with tuberculosis. Clinical Pharmacokinetics 2002;41:681–90.