Antimicrobial Chemotherapy, 5th Edition

Part 4 - Therapeutic Use of Antimicrobial Agents

Chapter 25

Mycobacterial Disease

Tuberculosis

Tuberculosis (TB) is one of the most widespread human infections. The World Health Organization (WHO) estimate that a third of the world's population harbour Mycobacterium tuberculosis, and every year more than eight million people develop new clinical disease. The pulmonary form was described by Hippocrates, and characteristic lesions of TB of the spine have been demonstrated in the mummies of ancient Egypt. The disease attacks both man and animals, affects all ages and every organ in the body, and ranges from latent to hyperacute (the ‘galloping consumption’ of Victorian times), killing young and old alike, the famous and the unknown. This reservoir of infected persons is made up of those with infectious pulmonary TB (sputum-smear positive) who can infect between 10 and 15 people every year. Co-infection with human immunodeficiency virus (HIV) is the most potent risk factor for the development of active TB: according to the WHO over 40 million people are co-infected.

The last 60 years have seen enormous progress in the understanding of the epidemiology, prevention, and treatment of TB and, although far from eradicated, this age-old killer of man has become a preventable and curable disease. The prevalence in a population is linked to a number of socio-economic factors, notably poverty, malnutrition, social exclusion, and poor health services. Furthermore, the HIV pandemic has magnified the impact of TB, particularly in sub-Saharan Africa, where co-infection rates are greatest. The control of TB is a global healthcare priority and cannot be successful unless HIV prevention and control become parallel priorities.

Immune response

Immunity in TB is cell mediated; the key to restriction of intracellular growth of the bacillus is co-operation between macrophages and sensitized lymphocytes. Humoral reactions are thought to play little part. The generation of clones of antigen-specific T cells initiates the immune response, which is depressed in HIV-positive patients. T-cell clones may facilitate elimination of the pathogen by macrophage activation and granuloma formation or by cytotoxic action; or they may interact with B cells to produce specific antibodies, which, in conjunction with phagocytic cells or complement, also act as an effector arm. The mechanism by which mycobacteria survive inside activated macrophages is unknown and may be oxygen dependent or oxygen independent. A genetic predisposition to tuberculous disease has been sought. Certain HLA-haplotypes have been associated with heightened susceptibility.

Principles of management

TB can affect many organs and tissues (Table 25.1). However, the pulmonary form of the disease is most common (65%) and accounts for its spread. The effective management of pulmonary TB therefore remains the greatest priority in controlling this disease. The key components of management are:

  • rapid detection of active disease;
  • reliable microbiological diagnosis;
  • supervised treatment with combination chemotherapy;
  • notification of cases and contact tracing;
  • monitoring for drug-resistant disease;
  • continuous reporting and surveillance.

Vaccination is included in this strategy by some countries, including the UK. The vaccine is based on a laboratory-modified strain of M. bovis, which is administered as BCG (bacille Calmette-Guérin—named after the two French originators of the vaccine). However, the efficacy of this vaccine has proved highly variable in published studies. Furthermore, it requires pre-immunization Mantoux test screening of the recipients using tuberculin (an extract of M. tuberculosis) to distinguish between previously infected (positive tuberculin test) and non-infected (negative tuberculin test) persons. Because of the logistics of testing, and the occasional difficulty in interpreting the skin test outcome, together with the fact that the vaccine sensitizes recipients to tuberculin thus reducing its value in skin testing to identify at-risk persons, many countries have not adopted this approach. In the UK BCG immunization is now restricted to babies and older people who are most at risk of TB, such as those living in areas with a high rate of TB or whose parents or grandparents were born in countries with a high prevalence of the disease.

Table 25.1 Tuberculosis: presenting infections

Common

Less common

Uncommon

Pulmonary

Meningitis

Pericardial

Lymph node

Intra-abdominal

Skin

Genito-urinary

Bone

 

Clinical diagnosis

Symptoms of persistent cough, often with minimal sputum production, occasional coughing up of blood (haemoptysis), weight loss, and sweats (often at night) should all raise suspicions for pulmonary TB. A chest X-ray will often show evidence of diffuse upper lobe streaking and consolidation. More advanced disease results in cavity formation.

Microbiological diagnosis

Specimens, notably sputum from patients with suspected pulmonary TB, should be examined microscopically using either a fluorescent stain (auramine) or the more traditional Ziehl-Neelsen stain. The microscopic detection of bacilli with the typical appearances of M. tuberculosispermits early diagnosis. Such a patient is classified as ‘smear-positive’ and managed as if they have ‘open’ (contagious) TB.

Other samples for diagnosis include biopsy material (lymph node, bone marrow, other tissues). Culture of M. tuberculosis is slow and may take 3-6 weeks to confirm the diagnosis. Susceptibility testing of anti-TB drugs adds to the length of this process. Rapid methods of identification are becoming more widely available, including rapid tests of susceptibility to isoniazid and rifampicin.

Treatment

The chemotherapy of human TB has depended almost entirely on large prospective controlled trials of different regimens, which have helped define the current recommendations for the treatment and prevention of the disease. There is still no in-vitro or animal model that can reliably predict the response to treatment in man.

Standard first-line treatment for TB requires compliance with a multidrug regimen for a minimum period of 6 months. Rifampicin and isoniazid are potent anti-TB agents and are administered throughout the 6 months. Pyrazinamide is added for the initial 2 months. A further drug, such as ethambutol is also included for the first 2 months if there are concerns about drug-resistant disease, with streptomycin as a further alternative (Table 25.2).

 

The rationale for this multidrug regimen is to provide effective therapy while avoiding the emergence of naturally occurring low frequency drug-resistant mutant strains of M. tuberculosis, which may cause relapse of the disease following the eradication of the susceptible strains. The initial 3-4 drug regimen is effective in preventing this from happening. Under normal circumstances, culture and sensitivity information should be available by 2 months to permit the safe transfer to rifampicin and isoniazid for the final 4 months of treatment.

Multidrug-resistant TB, defined as resistance to both isoniazid and rifampicin, is increasing worldwide. It currently accounts for less than 5% of isolates in the UK but has reached very high levels (> 35%) in parts of Russia and some eastern European countries. This is of major concern since laboratory facilities to support the clinical management of TB in resource poor countries are often inadequate and coincide with highest incidence rates of disease, including that caused by multiresistant TB. Second-line agents for treating TB (Table 25.3) are not only less active but often more toxic than first-line drugs. Treatment must also be prolonged for periods of up to 18-24 months.

Treatment of TB requires close supervision and should be under the direction of a specialist in respiratory medicine or infectious diseases and supporting staff. The key factors to a successful outcome are compliance with the regimen, an assured supply of medication, avoidance of interactions with any other concomitant medicines, early detection of drug toxicity and dose adjustment for weight and renal function, since these may alter during the period of treatment.

Table 25.2 Recommended first line treatment regimens for tuberculosis in adults

Drug

Initial phase (2 months)

Continuation phase (4 months)

Major side effects

Standard regimen

Rifampicin

10 mg/kg/day (450-600 mg/day)

10 mg/kg/day (450-600 mg/day)

Hepatitis; gastrointestinal upsets

Isoniazida

5 mg/kg/day (200-300 mg/day)

5 mg/kg/day (200-300 mg/day)

Peripheral neuropathy; hepatitis

Pyrazinamide

30 mg/kg/day (1.5-2 g/day)

   

Gastrointestinal upsets; gout

Ethambutol

15-25 mg/kg/day

   

Retrobulbar neuritis

Intermittent regimen (3 times weekly)

Rifampicin

10 mg/kg

10 mg/kg

}

As above

Isoniazid

15 mg/kg

15 mg/kg

Pyrazinamide

50 mg/kg

50 mg/kg

Or streptomycin (15 mg/kg/day or 0.75-1 g/day for 2 months if resistant to isoniazid).

TB is a notifiable disease in many countries. This ensures that there is not only close supervision of the infected person but that household and other contacts can be assessed for evidence of infection (a positive tuberculin skin test) or active disease based on symptoms and a positive chest X-ray. Outbreaks continue to occur, emphasizing the importance of notification and contact tracing.

Table 25.3 Second-line drugs for the treatment of tuberculosis in adults

Drug

Usual adult dose

Toxicity

Thiacetazone

150 mg daily

Gastrointestinal intolerance, Stevens-Johnson syndrome, bone marrow depression, ototoxicity, hepatitis

Ethionamide (protionamide)

0.5-1.0 g/day (divided dose)

Gastrointestinal intolerance, hepatitis, hypersensitivity, convulsions, depression, alopecia

Cycloserine

250 mg every 12 h or every 8 h

Seizures, psychoses, various central nervous system effects

Amikacin

7.5 mg/kg every 12 ha

Nephrotoxicity, ototoxicity, rash, neuromuscular blockade, eosinophilia

Capreomycin

1 g/day

Nephrotoxicity, ototoxicity, hypersensitivity

Kanamycin

15 mg every 12 ha

Nephrotoxicity, ototoxicity, hypersensitivity

Ciprofloxacinb

750 mg every 12 h

Gastrointestinal intolerance, crystaluria, tremor, convulsions, rash, hepatitis, renal failure

Para-aminosalicylic acid

12 g/day (divided doses)

Gastrointestinal intolerance, hypersensitivity, hypothyroidism, crystaluria

Peak drug levels should be less than 3 mg/dl (30 mg/l) and trough less than 1 mg/dl (10 mg/l).

Alternatives include: moxifloxacin and levofloxacin.

 

Factors involved in the response to chemotherapy

In pulmonary TB, most of the tubercle bacilli are found on the walls of cavities in the lungs open to the bronchi. Here the pH is relatively high, at least on the alkaline side of neutrality. The oxygen tension is also high and the bacilli are actively multiplying. In addition, there is another smaller population of bacilli, dormant in closed cavities, or in caseating tissue, or inside macrophages, where the pH and oxygen tension are both low, and bacterial multiplication is slow.

The drugs available for the treatment of TB differ in their activity against tubercle bacilli under different conditions. For example, rifampicin acts against both extracellular and intracellular organisms, and also on those dormant in caseous nodules, while streptomycin and isoniazid are bactericidal against actively multiplying bacteria under alkaline conditions. Pyrazinamide acts largely on intracellular organisms in an acid medium. Bactericidal activity against actively multiplying bacteria largely determines the early response of the sick patient to chemotherapy, while sterilizing activity against the dormant ‘persisters’ in the bacterial population is most important when considering the risk of relapse after cessation of treatment.

First-line antituberculosis drugs

Isoniazid (isonicotinic acid hydrazide; INH)

Isoniazid is an important anti-TB drug being highly potent and bactericidal. Primary resistance in M. tuberculosis in the UK is uncommon (< 5%) but increasing. However, resistance develops quickly with single-drug therapy and is avoided by a combined drug regimen. Together with rifampicin, isoniazid is the most widely used drug in the treatment of TB. It penetrates rapidly into all tissues and lesions and, its activity is not affected by pH. It is also well tolerated and cheap. It is given as a single daily oral dose as it is more important to achieve a high peak concentration than it is to maintain a continuously inhibitory level. Following oral absorption, plasma concentrations are good and cerebrospinal fluid (CSF) penetration is about 50-80% of the serum levels. Urinary concentrations are high. In intermittent regimens, increased doses can be used and higher peak levels attained.

Isoniazid is metabolized mainly by acetylation in the liver, at a rate which is genetically determined. Patients can be divided into two groups—rapid and slow inactivators. This is usually of little clinical importance in patients treated daily, or even twice weekly, but with intermittent regimens in which the drug is given only once a week, rapid inactivators (within 1 h) fare less well than slow inactivators (within 3 h), and there is some practical value in determining to which group a patient belongs when an intermittent regimen is contemplated.

Adverse reactions are uncommon but include hypersensitivity rashes and hepatitis (0.1%). The latter is potentially serious and the risk increases with age. It can be easily managed by prompt withdrawal of treatment. A sharp rise in serum transaminases at the outset of treatment, is relatively common and may be enhanced by the concomitant use of rifampicin, but is usually of little significance. Liver function tests should be checked before starting treatment as a yardstick to measure any subsequent adverse reactions. Isoniazid interferes competitively with pyridoxine metabolism by inhibiting the formation of the active form of the vitamin and hence often results in peripheral neuropathy, which can be prevented by co-administration of pyridoxine. It also tends to raise plasma concentrations of warfarin, diazepam, phenytoin, and carbamazepine by inhibiting their metabolism in the liver. Overdosage may give rise to vomiting, dizziness, blurred vision, and slurring of speech.

Rifampicin and other rifamycins

Rifampicin is one of the most important of the anti-TB drugs, possessing high potency and efficacy in the treatment of primary and relapsing infection. It has been successfully used for decades in TB. Resistance rates remain low in the UK but are increasing. However, resistance rates of 10-20% are found in certain parts of the world, notably Thailand, the Dominican Republic, and some countries of the former USSR; such strains may be multiresistant. Rifampicin may be given daily or as part of an intermittent regimen. However, rifampicin is not available in some developing countries because it is expensive.

Side effects such as hepatitis and cutaneous reactions require expert supervision. Curiously, side effects are more common on intermittent regimens than when the drug is taken daily. They typically begin 2-3 h after the single morning dose when symptoms described as ‘flu-like’ develop. Once-weekly regimens are more toxic than twice-weekly ones. With daily regimens, side effects are uncommon and often trivial. An exception is the occurrence of purpura, which is an indication to stop the drug and not give it again. Drug interactions with rifampicin are common and require careful management.

Rifampicin is also key to the drug treatment of leprosy (see later) and is sometimes used in the treatment of life-threatening staphylococcal infections and in the prophylaxis of meningococcal and Haemophilus influenzae meningitis. There is no evidence that these occasional uses of rifampicin have jeopardized the value of its use in the treatment of TB.

Three other rifamycins—rifabutin, rifapentine, and benzoxazinorifamycin—are active against M. tuberculosis. They are somewhat more active than rifampicin, accumulate within macrophages and exhibit longer half-lives, but have not achieved widespread use in the treatment of TB.

Pyrazinamide

Pyrazinamide is particularly effective against intracellular tubercle bacilli in acid conditions and has therefore found an important place in short-course chemotherapy to prevent relapse at the end of treatment. It is given orally, produces high serum levels and penetrates freely into CSF. Adverse reactions are rare, but include anorexia, nausea, and flushing; hepatic toxicity has been a problem; hypersensitivity reactions and photosensitivity of the skin also occur.

Treatment for longer than 2 months is not recommended. Drug interactions occur with allopurinol, causing hyperuricaemia with attacks of gout, and with oral antidiabetic agents, causing a further fall in blood sugar. The dose should be reduced in renal impairment and avoided in patients with severe liver damage or a history of gout.

Ethambutol

Ethambutol is active against M. tuberculosis and many atypical mycobacteria. It has a primarily bacteristatic action on proliferating bacteria. Resistance develops slowly during therapy, but primary resistance occurs in less than 4% of strains of M. tuberculosis. It is rapidly absorbed after oral administration and high serum levels are found after 2 h, with even higher levels inside erythrocytes. Adequate levels are found in the CSF. Ethambutol is excreted in the urine both unchanged and as inactive metabolites.

Dose-dependent optic (retrobulbar) neuritis can result in impairment of visual acuity and colour vision. Early changes are usually reversible, but blindness can occur if treatment is not discontinued promptly. It is unusual at currently recommended doses, but it is recommended that the patient's visual acuity be tested before ethambutol is first prescribed and monitored during treatment.

Streptomycin

This was the first effective drug against human TB. Like all aminoglycosides it is not absorbed when given orally, and must be administered as an intramuscular injection. It is more bactericidal during the proliferative phase than in the resting phase of bacterial growth. Adequate concentrations are attained in lung, muscle, uterus, intestinal mucosa, adrenals, and lymph nodes. Diffusion into bone, brain, and aqueous humour is poor. Little normally enters the CSF, although penetration increases when the meninges are inflamed. The deep intramuscular injections are painful and must be administered daily for up to 2 months.

Ototoxicity is the most serious adverse reaction. Vestibular damage occurs in about 30% of cases while cochleotoxicity is less common. The plasma half-life is normally 2-3 h, but is considerably extended in the newborn, in the elderly, and in patients with severe renal impairment. Serum levels need to be monitored in patients over 40 years of age. The dose is adjusted for age and renal function. Hypersensitivity reactions in the form of fever and skin rashes may develop.

Second-line drugs

Thiacetazone

Thiacetazone is one of the earliest anti-TB drugs, and is cheap to manufacture. It is bacteristatic against M. tuberculosis and is sometimes used in combination with isoniazid to inhibit the emergence of resistance, particularly in the continuation phase of long-term regimens. It is well absorbed from the gastrointestinal tract and plasma levels are sustained for long periods of time. Side effects include nausea, vomiting, diarrhoea, skin rashes, and bone marrow depression. Rare cases of fatal exfoliative dermatitis and acute hepatitis failure have been reported.

Ethionamide and protionamide

Because of its gastrointestinal side effects—anorexia, salivation, nausea, abdominal pain, and diarrhoea—ethionamide is one of the most unpleasant of all anti-TB drugs to take and is no longer recommended. Protionamide is closely related in structure, and is better tolerated. It is absorbed quickly when given by mouth with good tissue and CSF levels. It is bacteristatic at therapeutic concentrations but bactericidal at higher concentrations. Contra-indications include pregnancy, severe liver damage, and gastric complaints; care should be exercised in epilepsy and in psychotic patients. Combinations with isoniazid, cycloserine, or alcohol should be avoided.

Cycloserine, amikacin, kanamycin, and capreomycin

These are four rather weak drugs used as reserves for the treatment of TB resistant to the first-line agents. Capreomycin, amikacin, and kanamycin all need to be given by injection. Primary resistance is rare but resistance can develop rapidly.

Fluoroquinolones

Several fluoroquinolones are active against M. tuberculosis. They include ciprofloxacin, ofloxacin, levofloxacin and moxifloxacin. They are bactericidal, orally administered, and well tolerated. They are increasingly being used in the treatment of drug-resistant TB.

p-Aminosalicylic acid

This was formerly used in combination regimens to prevent the emergence of drug-resistant organisms. Up to 10-12 g a day were given orally, in two or three doses. The drug tastes most unpleasant, and gastrointestinal intolerance was common. p-Aminosalicylic acid is no longer used and is included here for historical reasons only.

Short course and intermittent therapy

The discovery that both pyrazinamide and rifampicin are active against dormant as well as actively dividing tubercle bacilli prompted the investigation of shorter periods of treatment. Based on clinical trials, it has been shown that all regimens containing two of the three drugs, isoniazid, pyrazinamide, and rifampicin cure more than 90% of patients in 6 months and virtually all in 9 months. The limitations of treatment are those of cost and of patient compliance. In developing countries, short course intermittent therapy permits supervised mass treatment at a cost the communities can afford.

Affluent countries have slightly different aims. These countries require highly effective unsupervised regimens for use where patient motivation is high and compliance good. The standard regimen of treatment recommended by the British Thoracic Society is an initial phase of 2 months treatment with rifampicin, isoniazid, plus pyrazinamide and ethambutol, then a continuation phase of treatment with isoniazid and rifampicin for a further 4 months (Table 25.2). The regimen of three or four drugs during the initial intensive phase of treatment is important in bringing the acute illness under control as rapidly as possible.

Intermittent regimens have become popular in developing countries for ease of administration. Rifampicin in standard dose, together with isoniazid and pyrazinamide at doses higher than the standard regimen are given on 3 days of the week, again for a total of 6 months (Table 25.2).

 

Directly observed therapy

To ensure compliance with medication and to avoid the risk of relapsing disease and drug-resistant TB, directly observed therapy, whereby a healthcare provider or other responsible person observes the ingestion of medication, has been employed. This policy is widely adopted in many developing countries and can be used selectively in developed countries where there are concerns over compliance. Supervised treatment can be given in the patient's home, place of employment or school. It is effective in improving clinical cure rates and in decreasing rates of drug resistance. Use of fixed drug combinations (e.g. Rifinah: rifampicin + isoniazid; Rifater: rifampicin + isoniazid + pyrazinamide) reduces the risk of inappropriate monotherapy. Although such combinations may not contain exactly the same concentration as individual drugs, clinical results are favourable. It is important not to make mistakes in prescribing and dispensing because of the similarity of names.

Effective chemotherapy rapidly reduces the population of viable bacilli (sputum smears may be positive but cultures remain negative) and consequently reduces the risk of transmission, often within 2 weeks. Hospital care should be kept as short as possible since most patients can be managed in the community.

Non-antimicrobial treatment

Steroids have a limited place in the routine management of TB, but are of value in treating patients with pericarditis, pleural effusion, tuberculous meningitis, and severe miliary TB with dyspnoea when administered as short courses.

Surgical resection is rarely necessary except for rare situations such as severe repeated haemoptysis or resection of extensive disease of a lobe or lung in those with multidrug-resistant or poorly responsive TB.

Monitoring the therapeutic response

Inadequate compliance is by far the most important cause of therapeutic failure. Most cases of chronic or relapsing TB are the result of irregular, inadequate administration of prescribed drugs or the use of less potent regimens, and often result in the selection of resistant strains. The clinical response to treatment requires monitoring weight changes, fever, and symptoms of cough and shortness of breath. Where resources permit, cultures and smears can be examined for acid-fast bacilli. Fixed-dose combinations that include rifampicin can be detected by observing the red-orange discoloration of body fluids, especially urine.

Pregnancy and lactation

Treatment should not be interrupted or postponed if TB is diagnosed during pregnancy. Because of risk to the fetus, aminoglycosides such as streptomycin and fluoroquinolones should be avoided. Patients can breast feed normally while taking anti-TB drugs.

Tuberculosis and HIV infection

HIV infection results in progressive depletion and dysfunction of CD4 lymphocytes and impaired macrophage and monocyte function. Because CD4 cells and macrophages are essential to the host response to TB, HIV exerts an enormous influence on M. tuberculosis infection. Higher rates of reactivation disease occur (7-10% per year, compared with 5-8% per lifetime for HIV-negative patients). There are also much higher rates of acute disease (including extrapulmonary TB), skin anergy (producing a false-negative TB test), and possible malabsorption of anti-TB medications owing to enteropathy. The presenting features of pulmonary TB also differ according to the stage of HIV infection. In early disease, conventional presentations with cavitation are usual. However, in advanced disease chest X-ray changes may be atypical or absent. Serious drug-drug interactions can occur, especially between rifamycins, protease inhibitors and non-nucleoside reverse transcriptase inhibitors used to treat HIV.

The treatment of TB in HIV-positive patients is therefore problematic and requires expert knowledge of both anti-TB and antiretroviral drugs. Treatment regimens may need to be prolonged. Multiresistant strains are more common in AIDS patients; in parts of Africa resistance to all first-line drugs is not uncommon. The microbiological diagnosis of TB in HIV-positive individuals may also be difficult, owing to concurrent infection with Pneumocystis carinii (P. jiroveci), cytomegalovirus or fungi. Atypical mycobacteria (see below) are also more frequent.

Chemoprophylaxis against tuberculosis

Chemoprophylaxis of HIV-infected persons who are found to be tuberculin skin test positive is widely practised in the USA but is less commonly used in the UK. Isoniazid is used alone as prophylaxis because it is effective, cheap, acceptable, and has few side effects. Fears that isoniazid-resistant organisms would emerge have so far proved unfounded and largely reflects the lower bacillary load compared with that associated with clinical disease.

Drug-resistant tuberculosis

Current recommended drug regimens are designed to prevent the emergence of drug resistance. However, control of TB is threatened by the worldwide emergence of drug resistance in M. tuberculosis. Outbreaks of multiresistant TB have occurred in hospitals, centres for the care of patients with AIDS, and prisons, posing considerable clinical and public health problems. In the UK, the incidence of resistance to isoniazid alone is presently below 6%; resistance to isoniazid and rifampicin (with or without resistance to other drugs) is less than 1.5% but has been increasing steadily. However, with the emergence of multidrug resistance in other parts of the world, enhanced surveillance is required.

Molecular genetic methods that allow the rapid detection of isoniazid- and rifampicin-resistant strains are available in reference centres and are helpful in modifying therapy or prompting patient isolation (see below). Likewise, genotyping helps to differentiate re-infection from reactivation and can be used to characterize cross-infection among close contacts of infectious cases.

Hospital transmission of multiresistant M. tuberculosis

Healthcare workers are at risk from TB from patients with unsuspected pulmonary TB, or during the period required for chemotherapy to render them non-infectious.

Infection control measures require early detection of patients with smear positive TB, especially those with multiresistant M. tuberculosis.They should be cared for in isolation rooms. Negative air pressures should be maintained in these rooms. To prevent transmission, high-efficiency particulate air (HEPA) filters may have to be fitted if there is difficulty in exhausting contaminated air from buildings. Filter masks should be worn by staff and visitors to reduce the risk of inhaling infectious airborne particles.

Extrapulmonary tuberculosis

Tuberculous meningitis

This form of tuberculous infection is invariably fatal if untreated, and appropriate chemotherapy is vital. It is a frequent complication of untreated miliary TB, and may vary from an abrupt and severe illness resembling other acute bacterial meningitis to a subtle and chronic disease extending over several weeks. The diagnosis is made on the basis of CSF examination.


Treatment should be given promptly and include isoniazid and rifampicin. During the first intensive phase, these drugs should be accompanied by pyrazinamide and ethambutol. After about 2 months, these can be discontinued, but the isoniazid and rifampicin should be continued for at least a further 10 months. Intrathecal antibiotics are unnecessary, but additional treatment with corticosteroids should be used in severe cases especially in those with raised intracranial pressure or cranial nerve palsies.

Other forms of tuberculosis

TB can affect any system in the body including, in decreasing order of frequency, superficial lymph nodes, bone and joints, the genito-urinary tract, the abdomen, the breast, and skin. Patients with non-respiratory TB can be regarded as non-infectious. Generally, the principles described for the treatment of pulmonary TB are also appropriate for the treatment of other forms, although few regimens have been subject to controlled clinical trials. Surgical intervention is sometimes necessary to establish the diagnosis, or to drain large abscesses, relieve pressure from tuberculous masses, or repair damage from scar tissue, but is no longer the mainstay of treatment.

Opportunistic (atypical) mycobacteria

The so-called opportunistic or ‘atypical’ species of mycobacteria, also known as ‘mycobacteria other than TB’, that can cause human disease include M. kansasii, M. marinum, M. avium, M. intracellulare, M. fortuitum, and several others. The isolation of atypical mycobacteria does not prove that disease is present unless the organism is isolated from a normally sterile body site; colonization with these organisms is not uncommon. Nevertheless, disease caused by these organisms may be indistinguishable from true TB. Atypical mycobacteria are usually more resistant to the standard anti-TB agents than is M. tuberculosis.

Atypical mycobacteria of the M. avium complex have also come into prominence since the appearance of AIDS. Patients with AIDS seem particularly prone to develop infection with these mycobacteria, and the disease may be associated with a severe ‘wasting syndrome’. These mycobacteria are also usually highly resistant to the common anti-TB drugs and alternative regimens are recommended (see p. 406).

Leprosy

This is a chronic communicable tropical disease caused by infection with M. leprae, which mainly affects the skin and peripheral nerves causing anaesthesia, muscle weakness, paralysis, and consequent injury and deformity. Currently, the disease is restricted to some six countries as a result of a WHO eradication programme. Over the centuries, those with leprosy have often been ostracized and excluded from society, despite the fact that it is not very contagious. Transmission is caused by respiratory droplet spread from close contact. There is a spectrum of disease determined by the extent of cell-mediated immune response by the host. This not only distinguishes the major types of the disease but also has implications for treatment (Fig. 25.1).

Two major types are described: lepromatous and tuberculoid leprosy. In lepromatous leprosy there is diffuse involvement of skin and mucous membranes, with ulceration, iritis, and keratitis; scrapings of skin or mucous membranes contain numerous acid-fast bacilli. The tuberculoid form is more localized, but nerve involvement occurs early; only scanty bacilli are present. In both forms, progress of the disease is slow. The tuberculoid form may heal spontaneously in a few years. Death is usually due to other causes.

The approach to leprosy control includes early case detection, adequate treatment with a combination of dapsone, rifampicin, and clofazimine, and the prevention of disabilities and rehabilitation of sufferers. Paucibacillary (tuberculoid) disease is cured in 6 months with dapsone and rifampicin while multibacillary (lepromatous) disease requires 2 years' treatment with dapsone, clofazimine, and rifampicin. Dapsone (diaminodiphenylsulphone) resistance is avoided by the use of triple therapy. Rifampicin is more rapidly bactericidal than dapsone, but resistance may arise if it is used alone. Clofazimine is effective, but some patients develop discoloration of the skin that may prove unacceptable.

With such long and complicated regimens, patient compliance is naturally a problem, particularly in areas of the world where leprosy is most prevalent. Second-line agents include minocycline, ofloxacin, and clarithromycin.


Furthermore, a single-dose triple combination of rifampicin, ofloxacin, and minocycline has been successful in lepromatous leprosy and provides a further alternative. If confirmed, this offers an attractive regimen for use in endemic areas.

 

Fig. 25.1 The spectrum of leprosy as determined by host response and bacillary load and its implications for treatment. LL, lepromatous leprosy; BL, borderline lepromatous; BB, borderline leprosy; BT, borderline tuberculoid; TT, tuberculoid leprosy.

It should be remembered that patients with leprosy might also have TB; regimens used for leprosy treatment are inadequate for treating TB.