Relevant BNF section: 5.1
Notifications of tuberculosis in England and Wales declined steadily until 1987, when about 5100 cases were reported.1 Since then numbers have begun to rise, reaching a provisional figure of about 5700 in 1994.2 The proportion of isolates of Mycobacterium tuberculosis resistant to one or more conventional first-line antituberculosis drugs has remained steady at about 10%.3 The incidence of tuberculosis is also rising in other countries, but the speed of increase and the proportion of infections that are drug resistant vary. In this article we discuss drug-resistant tuberculosis in the UK and consider its prevention, treatment and control.
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Relevant BNF section: 5.1
Incidence of infection
In England and Wales (and figures are likely to be similar throughout the UK) about 5 per 100 000 of the white population contract tuberculosis.4 Among immigrants from the Indian subcontinent the notification rate is much higher (about 120 per 100 000 overall, and over 500 per 100 000 recent immigrants).4 Among patients with AIDS the incidence of tuberculosis is about 5%.5 Poverty probably increases the risk independently of other known risk factors.6
In the UK about 3% of isolates are resistant to isoniazid alone and 0.6% to both isoniazid and rifampicin.3 Drug-resistant tuberculosis can be acquired from a patient infected with a resistant strain (primary resistance) or can develop in an infected patient when inadequate drug treatment eliminates sensitive strains, leaving resistant ones, which arise through random mutations, to multiply (secondary resistance).
Patients who harbour resistant strains may pass drug-resistant disease to contacts, including health care workers.7,8 Even with treatment based on in-vitro sensitivities and lasting 2 years, over a third of patients with drug-resistant tuberculosis do not improve, and nearly half of those in whom treatment is unsuccessful die of the disease.9
Risk factors for resistance
Resistant infections are commonest in patients who have had previous antituberculosis treatment,10 especially those who have been given inadequate treatment or have not completed the course.11,12 Homelessness puts health provision at risk and so leads to inadequate treatment and thus to increased risk of resistance.13
The standard approach to minimising the risk of resistance developing in a previously untreated patient is to give a combined preparation containing isoniazid + rifampicin + pyrazinamide for the first 2 months, followed by a combined preparation of isoniazid + rifampicin for a further 4 months.14,15 In the UK treatment is usually coordinated through a chest clinic. The problem, however, is how to ensure that treatment is continued for the full 6 months. Patients who take the medicines unsupervised should have their adherence to treatment checked with monthly pill counts and urine tests for rifampicin (which changes the colour to dark orange) or isoniazid (INH dipstick test).14 If poor adherence is suspected the patient should be asked to attend the treatment centre three times a week to be given the medicines under direct observation.14 For intermittent treatment drug doses will need to be higher.15
To be successful, the treatment centre should have a warm, welcoming atmosphere. Moreover the staff need to be dedicated and prepared to seek out non-attenders in hostels, prisons or shelters.16 In New York City, a 25% fall in notifications of multiresistant tuberculosis in 1994, compared with a 7% fall in all tuberculosis notifications, has been ascribed largely to directly observed treatment.17 The system has also worked well in an area of Texas where the prevalence of risk factors for resistance (e.g. homelessness) has increased.18
Treatment of resistant infections
Patients with drug-resistant tuberculosis should be treated by a chest physician experienced in the management of such cases.14 Tubercle bacilli grow slowly in culture, so drug resistance cannot be detected for several weeks and appropriate treatment may be delayed. For patients suspected of having resistant tuberculosis it is best to start with isoniazid + rifampicin + pyrazinamide + ethambutol; this regimen should be continued for 2 months, or until sensitivities are known.14
Where microbiology shows isoniazid resistance, isoniazid should be withdrawn and treatment continued with rifampicin and ethambutol for at least 12 months.14 If isoniazid resistance is known before treatment starts, streptomycin + pyrazinamide + rifampicin + ethambutol should be given for the first 2 months, then rifampicin and ethambutol for a further 7 months.14 If treatment fails or if microbiology shows multiple drug resistance (including isoniazid and rifampicin resistance) the choice of drugs will depend on the sensitivities of isolates. At least three of the following second-line drugs should be given until sputum cultures become negative, then two drugs for a minimum of 9 months.11,14,15 Paraminosalicylic acid and ethionamide (neither licensed in the UK) both cause gastrointestinal symptoms, and few patients can tolerate the two together. Cycloserine is effective but neurotoxic. Streptomycin is given by injection, which could be seen as an advantage because it brings the patient to the clinic for supervised chemotherapy. However, streptomycin is ototoxic; and because it is excreted through the kidneys it should be used cautiously in elderly patients and those with impaired renal function. Amikacin, kanamycin and capreomycin also have to be given by injection. The fluoroquinolones, such as ofloxacin and ciprofloxacin, have also been used successfully to treat and retreat tuberculosis.19,20 Another alternative is thiacetazone (not licensed in the UK), but it can cause severe rash in HIV-infected patients. 11 Surgical resection should be considered for patients with localised disease and a good respiratory reserve.11
Special precautions are needed to prevent the spread of multiresistant strains. Patients with multiresistant tuberculosis should be nursed in single rooms vented to the outside, ideally until sputum smears are negative.21 The value of masks for patients and contacts is unclear.8,21,22 Chemoprophylaxis for contacts in whom tuberculin skin tests convert from negative to positive depends on the sensitivity profile of strains isolated from the source of the infection.
The efficacy of BCG vaccination depends on the potency of the vaccine and previous infection with non-tuberculous mycobacteria and varies from patient to patient. In a meta-analysis of the results of 14 prospective trials and 12 case-control studies BCG vaccine reduced the risk of pulmonary tuberculosis by 50% overall, but the results of individual trials varied widely.23 In the UK, BCG vaccination appears to reduce the risk of acquiring tuberculosis by at least 75%.24 Although advice from the Department of Health is that BCG should be offered to all children aged 10-1325, we have learnt that this is not universally applied. BCG should also be given to newborn infants and small children of families of recent immigrants from areas where tuberculosis is common (e.g. India, Pakistan), children of families with a history of tuberculosis and tuberculin-negative people travelling to areas of high incidence. Tuberculosis screening and BCG vaccination for tuberculin-negative people should be offered to all health care workers and all staff working in institutions such as hostels for AIDS patients and the homeless.21
The incidence of tuberculosis is rising in the UK but there is no evidence yet of altered bacterial resistance. It is very important to ensure that infected patients are fully treated and that programmes for preventing infection and transmission are fully implemented. For patients who do not reliably take their medicines, intermittent supervised treatment, organised through a chest clinic, is probably the most effective means of treating and controlling transmission of the disease, including infection with resistant strains. Initial quadruple therapy, with isoniazid, rifampicin, pyrazinamide and ethambutol, should be considered for patients in whom a resistant infection is suspected. BCG vaccination, which is currently offered to children aged 10-13, should also be available for newborn infants and young children in high-risk groups.
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