Treatment

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Revision as of 10:51, 27 August 2008

Active tuberculosis will kill about two of every three people affected if left untreated. Treated tuberculosis has a mortality rate of less than 5% (or less in developed countries where intensive supportive measures are available).

The standard "short" course treatment for tuberculosis (TB), if it is active, is isoniazid, rifampicin, pyrazinamide, and ethambutol for two months, then isoniazid and rifampicin alone for a further four months. The patient is considered cured at six months (although there is still a relapse rate of 2 to 3%). For latent tuberculosis, the standard treatment is six to nine months of isoniazid alone.

If the organism is known to be fully sensitive, then treatment is with isoniazid, rifampicin, and pyrazinamide for two months, followed by isoniazid and rifampicin for four months. Ethambutol need not be used.

Drugs

All first-line anti-tuberculous drug names have a standard three-letter and a single-letter abbreviation:

• ethambutol is EMB or E,
• isoniazid is INH or H,
• pyrazinamide is PZA or Z,
• rifampicin is RMP or R,
• streptomycin is STM or S.

The US commonly uses abbreviations and names that are not internationally recognised: rifampicin is called rifampin and abbreviated RIF; streptomycin is commonly abbreviated SM.

Drug regimens are similarly abbreviated in a standardised manner. The drugs are listed using their single letter abbreviations (in the order given above, which is roughly the order of introduction into clinical practice). A prefix denotes the number of months the treatment should be given for; a subscript denotes intermittent dosing (so ₃ means three times a week) and no subscript means daily dosing. Most regimens have an initial high-intensity phase, followed by a continuation phase (also called a consolidation phase or eradication phase): the high-intensity phase is given first, then the continuation phase, the two phases divided by a slash.

So,

2HREZ/4HR₃

means isoniazid, rifampicin, ethambutol, pyrazinamide daily for two months, followed by four months of isoniazid and rifampicin given three times a week.

These standard abbreviations are used in the rest of this article.

There are six classes of second-line drugs (SLDs) used for the treatment of TB. A drug may be classed as second-line instead of first-line for one of two possible reasons: it may be less effective than the first-line drugs (e.g., p-aminosalicylic acid); or, it may have toxic side-effects (e.g., cycloserine); or it may be unavailable in many developing countries (e.g., fluoroquinolones):

• aminoglycosides: e.g., amikacin (AK), kanamycin;
• polypeptides: e.g., capreomycin, viomycin, enviomycin;
• fluoroquinolones: e.g., ciprofloxacin (CIP), levofloxacin, moxifloxacin (MXF);
• thioamides: e.g. ethionamide, prothionamide
• cycloserine (the only antibiotic in its class);
• p-aminosalicylic acid (PAS or P).

Other drugs that may be useful, but are not on the WHO list of SLDs:

• rifabutin
• macrolides: e.g., clarithromycin (CLR);
• linezolid (LZD);
• thioacetazone (T);
• thioridazine;
• arginine;
• vitamin D;
• R207910.

These drugs may be considered "third-line drugs" and are listed here either because they are not very effective (e.g., clarithromycin) or because their efficacy has not been proven (e.g., linezolid, R207910). Rifabutin is effective, but is not included on the WHO list because for most developing countries, it is impractically expensive.

The standard regimen

Rationale and evidence for the standard regimen

Tuberculosis has been treated with combination therapy for over fifty years. Drugs are not used singly (except in latent TB or chemoprophylaxis), and regimens that use only single drugs result in the rapid development of resistance and treatment failure.<ref name="MRC1948">Medical Research Council Streptomycin in Tuberculosis Trials Committee (1948). "Streptomycin treatment for pulmonary tuberculosis". Brit Med J ii: 769–82. </ref><ref name="Wang2006">Wang J-Y, Hsueh P-R, Jan I-S, et al. (2006). "Empirical treatment with a fluoroquinolone delays the treatment for tuberculosis and is associated with a poor prognosis in endemic areas". Thorax 61: 903–8. doi:10.1136/thx.2005.056887. PMID 16809417. </ref> The rationale for using multiple drugs to treat TB are based on simple probability. The frequency of spontaneous mutations that confer resistance to an individual drug are well known: 1 in 10⁷ for EMB, 1 in 10⁸ for STM and INH, and 1 in 10¹⁰ for RMP.<ref name="David1970">David H. L. (1970). "Probability Distribution of Drug-Resistant Mutants in Unselected Populations of Mycobacterium tuberculosis". Appl Microbiol 20 (5): 810–4. PMID 4991927. </ref> A patient with extensive pulmonary TB has approximately 10¹² bacteria in his body, and therefore will probably be harboring approximately 10⁵ EMB-resistant bacteria, 10⁴ STM-resistant bacteria, 10⁴ INH-resistant bacteria and 10² RMP-resistant bacteria. Resistance mutations appear spontaneously and independently, so the chances of him harbouring a bacterium that is spontaneously resistant to both INH and RMP is 1 in 10⁶, and the chances of him harbouring a bacterium that is spontaneously resistant to all four drugs is 1 in 10¹¹. This is, of course, an oversimplification, but it is a useful way of explaining combination therapy.

There are other theoretical reasons for supporting combination therapy. The different drugs in the regimen have different modes of action. INH are bacteriocidal against replicating bacteria. EMB is bacteriostatic at low doses, but is used in TB treatment at higher, bactericidal doses. RMP is bacteriocidal and has a sterilizing effect. PZA is only weakly bactericidal, but is very effective against bacteria located in acidic environments, inside macrophages, or in areas of acute inflammation.

All TB regimens in use were 18 months or longer until the appearance of rifampicin. In 1953, the standard UK regimen was 3SPH/15PH or 3SPH/15SH₂. Between 1965 and 1970, EMB replaced PAS. RMP began to be used to treat TB in 1968 and the BTS study in the 1970s showed that 2HRE/7HR was efficacious. In 1984, a BTS study showed that 2HRZ/4HR was efficacious,<ref name="BTS1984">British Thoracic Society (1984). "A controlled trial fo six months' chemotherapy in pulmonary tuberculosis. Final report: results during the 36 months after the end of chemotherapy and beyond". Brit J Diseases Chest 78 (4): 330–36. PMID 6386028. </ref> with a relapse rate of less than 3% after two years.<ref name="Ormerod1987">Ormerod LP, Horsfield N (1987). "Short-course antituberculous chemotherapy for pulmonary and pleural disease: five years' experience in clinical practice". Brit J Diseases Chest 81 (3): 268–71. doi:10.1016/0007-0971(87)90160-4. </ref> In 1995, with the recognition that INH resistance was increasing, the BTS recommended adding EMB or STM to the regimen: 2HREZ/4HR or 2SHRZ/4HR, which are the regimens currently recommended. The WHO also recommend a six month continuation phase of HR if the patient is still culture positive after 2 months of treatment (approximately 15% of patients with fully-sensitive TB) and for those patients who have extensive bilateral cavitation at the start of treatment.

Monitoring and DOTS

DOTS stands for "Directly Observed Therapy, Short-course" and is a major plank in the WHO global TB eradication programme. The WHO advises that all TB patients should have at least the first two months of their therapy observed (and preferably the whole of it observed): this means an independent observer watching tuberculosis patients swallow their anti-TB therapy. The independent observer is often not a healthcare worker and may be a shopkeeper or a tribal elder or similar senior person within that society. DOTS is used with intermittent dosing (thrice weekly or 2HREZ/4HR₃). Twice weekly dosing is effective<ref> "A 62-dose, 6 month therapy for pulmonary and extrapulmonary tuberculosis: A twice-weekly, directly observed, and cost-effective regimen" (1990). Ann Intern Med 112 (6): 407–415. PMID 2106816. </ref> but not recommended by the WHO, because there is no margin for error (accidentally omitting one dose per week results in once weekly dosing, which is ineffective).

Treatment with properly implemented DOTS has a success rate exceeding 95% and prevents the emergence of further multi-drug resistant strains of tuberculosis.

Some people recommend monthly surveillance until cultures convert to negative; this does not form any part of the UK or WHO recommendations for TB. If cultures are positive or symptoms do not resolve after three months of treatment, it is necessary to re-evaluate the patient for drug-resistant disease or nonadherence to drug regimen. If cultures do not convert to negative despite three months of therapy, consider initiating directly observed therapy.

Extra-pulmonary tuberculosis

Tuberculosis not affecting the lungs is called extra-pulmonary tuberculosis. Disease of the central nervous system is specifically excluded from this classification.

The UK and WHO recommendation is 2HREZ/4HR; the US recommendation is 2HREZ/7HR. There is good evidence from randomised-controlled trials to say that in tuberculous lymphadenitis<ref>Campbell IA, Ormerod LP, Friend JA, Jenkins PA, Prescott RJ. (1993). "Six months versus nine months chemotherapy for tuberculosis of lymph nodes: final results". Respir Med. 87 (8): 621–3. doi:10.1016/S0954-6111(05)80265-3. PMID 8290746. </ref> and in TB of the spine,<ref>Upadhyay SS, Saji MJ, Yau AC. (1996). "Duration of antituberculosis chemotherapy in conjunction with radical surgery in the management of spinal tuberculosis". Spine 21 (16): 1898–1903. doi:10.1097/00007632-199608150-00014. </ref><ref>Medical Research Council Working Party on tuberculosis of the spine.. "Five-year assessment of controlled trials of chort-course chemotherapy regimens of 6, 9 or 18 months' duration for spinal tuberculosis in patients ambulatory from the start or undergoing radical surgery". Int Orthopaed 23 (2): 73–81. </ref><ref>Parthasarathy R, Sriram K, Santha T, et al. (1999). "Short-course chemotherapy for tuberculosis of the spine: a comparison between ambulant treatment and radical surgery—ten-year report". J Bone Joint Surg Brit Vol 81B (3): 464–71. doi:10.1302/0301-620X.81B3.9043. PMID 10872368. </ref> the six month regimen is equivalent to the nine month regimen; the US recommendation is therefore not supported by the evidence.

Up to 25% of patients with TB of the lymph nodes (TB lymphadenitis) will get worse on treatment before they get better and this usually happens in the first few months of treatment. A few weeks after starting treatment, lymph nodes often start to enlarge, and previously solid lymph nodes may become fluctuant. This should not be interpreted as failure of therapy and is a common reason for patients (and their physicians) to panic unnecessarily. With patience, two to three months into treatment the lymph nodes start to shrink again and re-aspiration or re-biopsy of the lymph nodes is unnecessary: if repeat microbiological studies are ordered, they will show the continued presence of viable bacteria with the same sensitivity pattern, which further adds to the confusion: physicians inexperienced in the treatment of TB will then often add second-line drugs in the belief that the treatment is not working. In these situations, all that is required is re-assurance. Steroids may be useful in resolving the swelling, especially if it is painful, but they are unnecessary. Additional antibiotics are unnecessary and the treatment regimen does not need to be lengthened.

Tuberculosis of the central nervous system

Tuberculosis may affect the central nervous system (meninges, brain or spinal cord) in which case it is called TB meningitis, TB cerebritis, and TB myelitis respectively; the standard treatment is 12 months of drugs (2HREZ/10HR) and steroid are mandatory. Diagnosis is difficult as CSF culture is positive in less than half of cases, and therefore a large proportion of cases are treated on the basis of clinical suspicion alone. PCR of CSF does not significantly improve the microbiology yield; culture remains the most sensitive method and a minimum of 5 ml (preferably 20 ml) of CSF should be sent for analysis. TB cerebritis (or TB of the brain) may require brain biopsy in order to make the diagnosis, because the CSF is commonly normal: this is not always available and even when it is, some clinicians would debate whether it is justified putting a patient through such an invasive and potentially dangerous procedure when a trial of anti-TB therapy may yield the same answer; probably the only justification for brain biopsy is when drug-resistant TB is suspected. It is possible that shorter durations of therapy (e.g. six months) may be sufficient to treat TB meningitis, but no clinical trial has addressed this issue. The CSF of patients with treated TB meningitis is commonly abnormal even at 12 months;<ref name="Kent1993">Kent SJ, Crowe SM, Yung A, Lucas CR, Mijch AM. "Tuberculous Meningitis: A 30-Year Review". Clin Infect Dis 17: 987–94. PMID 8110957. </ref> the rate of resolution of the abnormality bears no correlation with clinical progress or outcome,<ref name="Teoh1986">Teoh R, O'Mahony G, Yeung VTF (1986). "Polymorphonuclear pleocytosis in the cerebrospinal fluid during chemotherapy for tuberculous meningitis". J Neurol 233 (4): 237–41. doi:10.1007/BF00314027. </ref> and is not an indication for extending or repeating treatment; repeated sampling of CSF by lumbar puncture to monitor treatment progress should therefore not be done.

Although TB meningitis and TB cerebritis are classified together, the experience of many clinicians is that their progression and response to treatment is not the same. TB meningitis usually responds well to treatment, but TB cerebritis may require prolonged treatment (up to two years) and the steroid course needed is often also prolonged (up to six months). Unlike TB meningitis, TB cerebritis often required repeated CT or MRI imaging of the brain to monitor progress.

CNS TB may be secondary to blood-borne spread: therefore some experts advocate the routine sampling of CSF in patients with miliary TB.<ref name="Chang1998">Chang AB et al (1998). "Central nervous system tuberculosis after resolution of miliary tuberculosis". Pediatr Infect Dis J 17 (6): 519–523. doi:10.1097/00006454-199806000-00019. PMID 9655548. </ref>

The anti-TB drugs that are most useful for the treatment of CNS TB are:

• INH (CSF penetration 100%)
• RMP (10–20%)
• EMB (25–50% inflamed meninges only)
• PZA (100%)
• STM (20% inflamed meninges only)
• LZD (20%)
• Cycloserine (80–100%)
• Ethionamide (100%)
• PAS (10–50%) (inflamed meninges only)

The use of steroids is routine in TB meningitis (see section below).

Steroids

The usefulness of corticosteroids (e.g., prednisolone or dexamethasone) in the treatment of TB is proven for TB meningitis and TB pericarditis. The dose for TB meningitis is dexamethasone 8 to 12mg daily tapered off over six weeks (for those who prefer more precise dosing should refer to Thwaites et al., 2004<ref name="Thwaites2004">Thwaites GE et al. (2004). "Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults". N Engl J Med 351 (17): 1741–51. doi:10.1056/NEJMoa040573. PMID 15496623. </ref>). The dose for pericarditis is prednisolone 60mg daily tapered off over four to eight weeks.

Steroids may be of temporary benefit in pleurisy, extremely advanced TB, and TB in children:

• Pleurisy: prednisolone 20 to 40mg daily tapered off over 4 to 8 weeks
• Extremely advanced TB: 40 to 60mg daily tapered off over 4 to 8 weeks
• TB in children: 2 to 5mg/kg/day for one week, 1mg/kg/day the next week, then tapered off over 5 weeks

Steroids may be of benefit in peritonitis, miliary disease, laryngeal TB, lymphadenitis and genitourinary disease, but the evidence is scant and the routine use of steroids cannot be recommended. Steroid treatment in these patients should be considered on a case by case basis by the attending physician. Thalidomide may be of benefit in TB meningitis and has been used in cases where patients have failed to respond to steroid treatment.<ref name="Roberts2003">Roberts MT, Mendelson M, Meyer P, Carmichael A, Lever AM (2003). "The use of thalidomide in the treatment of intracranial tuberculomas in adults: two case reports". J Infect 47 (3): 251–5. doi:10.1016/S0163-4453(03)00077-X. PMID 12963389. </ref>

Non-compliance

Patients who take their TB treatment in an irregular and unreliable way are at greatly increased risk of treatment failure, relapse and the development of drug-resistant TB strains.

There are variety of reasons why patients fail to take their medication. The symptoms of TB commonly resolve within a few weeks of starting TB treatment and many patients then lose motivation to continue taking their medication. Regular follow-up is important to check on compliance and to identify any problems patients are having with their medication. Patients need to be told of the importance of taking their tablets regularly, and the importance of completing treatment, because of the risk of relapse or drug-resistance developing otherwise.

One of the main complaints is the bulkiness of the tablets. The main offender is PZA (the tablets being the size of horse tablets). PZA syrup may be offered as a substitute, or if the size of the tablets is truly an issue and liquid preparations are not available, then PZA can be omitted altogether. If PZA is omitted, the patient should be warned that this results in a significant increase in the duration of treatment (details of regimens omitting PZA are given below).

The other complaint is that the medicines must be taken on an empty stomach to facilitate absorption. This can be difficult for patients to follow (for example, shift workers who take their meals at irregular times) and may mean the patient waking up an hour earlier than usual everyday just to take medication. The rules are actually less stringent than many physicians and pharmacists realise: the issue is that the absorption of RMP is reduced if taken with fat, but is unaffected by carbohydrate, protein,<ref>Purohit SD, Sarkar SK, Gupta ML, Jain DK, Gupta PR, Mehta YR. (1987). "Dietary constituents and rifampicin absorption". Tubercle 68: 151–2. doi:10.1016/0041-3879(87)90034-1. </ref> or antacids.<ref>Peloquin CA, Namdar R, Singleton MD, Nix DE. (1999). "Pharmacokinetics of rifampin under fasting conditions, with food, and with antacids". Chest 115: 12–18. doi:10.1378/chest.115.1.12. PMID 9925057. </ref> So the patient can in fact have his or her medication with food as long as the meal does not contain fat or oils (e.g., a cup of black coffee or toast with jam and no butter).<ref>Sieger DI, Bryant M, Burley DM, Citron KM. (1974). "Effect of meals on rifampicin absorption". Lancet 2: 197–8. doi:10.1016/S0140-6736(74)91487-1. </ref> Taking the medicines with food also helps ease the nausea that many patients feel when taking the medicines on an empty stomach. The effect of food on the absorption of INH is not clear: two studies have shown reduced absorption with food<ref name="Peloquin1999">Peloquin CA, Namdar R, Dodge AA, Nix DE. (1999). "Pharmacokinetics of isoniazid under fasting conditions, with food, and with antacids". Int J Tuberc Lung Dis 3 (8): 703–10. PMID 10460103. </ref><ref>Joshi MV, Saraf YS, Kshirsagar NA, Acharya VN. (1991). "Food reduces isoniazid bioavailability in normal volunteers". J Assoc Physicians India 39: 470–1. </ref> but one study showed no difference.<ref>Zent C, Smith P. (1995). "Study of the effect of concomitant food on the bioavailability of refampicin, isoniazid, and pyrazinamide". Tubercle Lung Dis 76: 109–13. doi:10.1016/0962-8479(95)90551-0. </ref> There is a small effect of food on the absorption of PZA and of EMB that is probably not clinically important.<ref>Peloquin CA, Bulpitt AE, Jaresko GS, Jelliffe RW, James GT, Nix DE. (1998). "Pharmacokinetics of pyrazinamide under fasting conditions, with food, and with antacids". Pharmacotherapy 18 (6): 1205–11. PMID 9855317. </ref><ref>Peloquin CA, Bulpitt AE, Jaresko GS, Jelliffe RW, Childs JM, Nix DE (1999). "Pharmacokinetics of ethambutol under fasting conditions, with food, and with antacids". Antimicrob Agents Chemother 43 (3): 568–72. PMID 10049268. </ref>

It is possible to test urine for isoniazid and rifampicin levels in order to check for compliance. The interpretation of urine analysis is based on the fact that isoniazid has a longer half-life than rifampicin:

• urine positive for isoniazid and rifampicin patient probably fully compliant
• urine positive for isoniazid only patient has taken his medication in the last few days preceding the clinic appointment, but had not yet taken a dose that day.
• urine positive for rifampicin only patient has omitted to take his medication the preceding few days, but did take it just before coming to clinic.
• urine negative for both isoniazid and rifampicin patient has not taken either medicine for a number of days

In countries where doctors are unable to compel patients to take their treatment (e.g., the UK), some say that urine testing only results in unhelpful confrontations with patients and does not help increase compliance. In countries where legal measures can be taken to force patients to take their medication (e.g., the US), then urine testing can be a useful adjunct in assuring compliance.

RMP colours the urine and all bodily secretions (tears, sweat, etc.) an orange-pink colour and this can be a useful proxy if urine testing is not available (although this colour fades approximately six to eight hours after each dose).

Adverse effects

For information on adverse effects of individual anti-TB drugs, please refer to the individual articles for each drug.

The relative incidence of major adverse effects has been carefully described:<ref name="Yee2003">Yee D et al. (2003). "Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active tuberculosis". Am J Resp Crit Care Med 167 (11): 1472–7. doi:10.1164/rccm.200206-626OC. PMID 12569078. </ref>

• INH 0.49 per hundred patient months
• RMP 0.43
• EMB 0.07
• PZA 1.48
• All drugs 2.47

This works out to an 8.6% risk that any one patient will need to have his drug therapy changed during the course of standard short-course therapy (2HREZ/4HR). The people identified to be most at risk of major adverse side effects in this study were:

• age >60,
• females,
• HIV positive patients, and
• Asians.

It can be extremely difficult identifying which drug is responsible for which side effect, but the relative frequency of each is known.<ref name="Ormerod1996">Ormerod L. P., Horsfield N. (1996). "Frequency and type of reactions to antituberculosis drugs: observations in routine treatment" 77 (1): 37–42. PMID 8733412. </ref> The offending drugs are given in decreasing order of frequency:

• Thrombocytopaenia: RMP
• Neuropathy: INH
• Vertigo: STM
• Hepatitis: PZA, RMP, INH
• Rash: PZA, RMP, EMB

Thrombocytopaenia is only caused by RMP and no test dosing need be done. Regimens omitting RMP are discussed below. Please refer to the entry on rifampicin for further details.

The most frequent cause of neuropathy is INH. The peripheral neuropathy of INH is always a pure sensory neuropathy and finding a motor component to the peripheral neuropathy should always prompt a search for an alternative cause. Once a peripheral neuropathy has occurred, INH must be stopped and pyridoxine should be given at a dose of 50mg thrice daily. Simply adding high dose pyridoxine to the regimen once neuropathy has occurred will not stop the neuropathy from progressing. Patients at risk of peripheral neuropathy from other causes (diabetes mellitus, alcoholism, renal failure, malnutrition, pregnancy, etc.) should all be given pyridoxine] 10mg daily at the start of treatment. Please refer to the entry on isoniazid for details on other neurological side effects of INH.

Rashes are most frequently due to PZA, but can occur with any of the TB drugs. Test dosing using the same regimen as detailed below for hepatitis may be necessary to determine which drug is responsible.

Itching RMP commonly causes itching without a rash in the first two weeks of treatment: treatment should not be stopped and the patient should be advised that the itch usually resolves on its own. Short courses of sedative antihistamines such as chlorpheniramine may be useful in alleviating the itch.

Fever during treatment can be due to a number of causes. It can occur as a natural effect of tuberculosis (in which case it should resolve within three weeks of starting treatment). Fever can be a result of drug resistance (but in that case the organism must be resistant to two or more of the drugs). Fever may be due to a superadded infection or additional diagnosis (patients with TB are not exempt from getting influenza and other illnesses during the course of treatment). In a few patients, the fever is due to drug allergy. The clinician must also consider the possibility that the diagnosis of TB is wrong. If the patient has been on treatment for more than two weeks and if the fever had initially settled and then come back, it is reasonable to stop all TB medication for 72 hours. If the fever persists despite stopping all TB medication, then the fever is not due to the drugs. If the fever disappears off treatment, then the drugs need to be tested individually to determine the cause. The same scheme as is used for test dosing for drug-induced hepatitis (described below) may be used. The drug most frequently implicated as causing a drug fever is RMP: details are given in the entry on rifampicin.