Tuberculosis treatment

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

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

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. 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.

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 and EMB are bacteriostatic (they stop the bacteria replicating, but do not kill them); RMP is bacteriocidal (it actually kills bacteria).

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, with a relapse rate of less than 3% after two years. 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 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 and in TB of the spine,  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; the rate of resolution of the abnormality bears no correlation with clinical progress or outcome, 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.

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 is 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, please see Thwaites, 2004 ). 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.

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 problems 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, or antacids. 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). 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 but one study showed no difference. There is a small effect of food on the absorption of PZA and of EMB that is probably not clinically important.

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 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: 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:
 * INH 0.49 per hundred patient months
 * RMP 0.43
 * EMB 0.07
 * PZA 1.48
 * All drugs 2.47
 * 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. 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.

Drug-induced hepatitis
The single biggest problem with TB treatment is drug-induced hepatitis, which has a mortality rate of around 5%. Three drugs can induce hepatitis: PZA, INH and RMP (in decreasing order of frequency). It is not possible to distinguish between these three causes based purely on of signs and symptoms. Test dosing must be carried out to determine which drug is responsible (this is discussed in detail below).

Liver function tests (LFTs) should be checked at the start of treatment, but, if normal, need not be checked again; the patient need only be warned of the symptoms of hepatitis. Some clinicians insist on regular monitoring of LFT's while on treatment, and in this instance, tests need only be done two weeks after starting treatment and then every two months thereafter, unless any problems are detected.

Elevations in bilirubin must be expected with RMP treatment (RMP blocks bilirubin excretion) and usually resolve after 10 days (liver enzyme production increases to compensate). Isolated elevations in bilirubin can be safely ignored.

Elevations in liver transaminases (ALT and AST) are common in the first three weeks or treatment. If the patient is asymptomatic and the elevation is not excessive then no action need be taken; some experts suggest a cut-off of four times the upper limit of normal, but there is no evidence to support this particular number over and above any other number. Some experts consider that treatment should only be stopped if jaundice becomes clinically evident.

If clinically significant hepatitis occurs while on TB treatment, then all the drugs should be stopped until the liver transaminases return to normal. If the patient is so ill that TB treatment cannot be stopped, then STM and EMB should be given until the liver transaminases return to normal (these two drugs are not associated with hepatitis).

Fulminant hepatitis can occur in the course of TB treatment, but is fortunately rare; emergency liver transplantation may be necessary and deaths do occur.

Test dosing for drug-induced hepatitis
Drugs should be re-introduced individually. This cannot be done in an outpatient setting, and must be done under close observation. A nurse must be present to take patient's pulse and blood pressure at 15 minutes intervals for a minimum or four hours after each test dose is given (most problems will occur within six hours of test dosing, if they are going to occur). Patients can become very suddenly unwell and access to intensive care facilities must be available. The drugs should be given in this order: No more than one test dose per day should be given, and all other drugs should be stopped while test dosing is being done. So on day 4, for example, the patient only receives RMP and no other drugs are given. If the patient completes the nine days of test dosing, then it is reasonable to assume that PZA has caused the hepatitis and no PZA test dosing need be done.
 * Day 1: INH at 1/3 or 1/4 dose
 * Day 2: INH at 1/2 dose
 * Day 3: INH at full dose
 * Day 4: RMP at 1/3 or 1/4 dose
 * Day 5: RMP at 1/2 dose
 * Day 6: RMP at full dose
 * Day 7: EMB at 1/3 or 1/4 dose
 * Day 8: EMB at 1/2 dose
 * Day 9: EMB at full dose

The reason for using the order for testing drugs is because the two most important drugs for treating TB are INH and RMP, so these are tested first: PZA is the most likely drug to cause hepatitis and is also the drug that can be most easily omitted. EMB is useful when the sensitivity pattern of the TB organism are not known and can be omitted if the organism is known to be sensitive to INH. Regimens omitting each of the standard drugs are listed below.

The order in which the drugs are tested can be varied according to the following considerations:
 * 1) The most useful drugs (INH and RMP) should be tested first, because the absence of these drugs from a treatment regimen severely impairs its efficacy.
 * 2) The drugs most likely to be causing the reaction should be tested as late as possible (and possibly need not be tested at all). The avoids rechallenging patients with a drug to which they have already had a (possibly) dangerous adverse reaction.

A similar scheme may be used for other adverse effects (such as fever and rash), using similar principles.

Deviations from the standard regimen
There is evidence supporting some deviations from the standard regimen when treating pulmonary TB. Sputum culture positive patients who are smear negative at the start of treatment do well with only 4 months of treatment (this has not been validated for HIV-positive patients); and sputum culture negative patients do well on only 3 months of treatment (possibly because some of these patients never had TB at all). It is unwise to treat patients for only three or four months, but all TB physicians will have patients who stop their treatment early (for whatever reason), and it can be re-assuring to know that sometimes retreatment is unnecessary. Elderly patients who are already taking a large number of tablets may be offered 9HR, omitting PZA which is the bulkiest part of the regimen.

It may not always be necessary to treat with four drugs from the beginning. An example might be a close contact of a patient known to have a fully-sensitive strain of tuberculosis: in this case, it is acceptable to use 2HRZ/4HR (omitting EMB and STM) in the expectation that their strain will be INH susceptible also. Indeed, this was previously the recommended standard regimen in many countries until the early 1990s, when isoniazid-resistance rates increased.

TB involving the brain or spinal cord (meningitis, encephalitis, etc.) is currently treated with 2HREZ/10HR (12 months of treatment in total), but there is no evidence to say that this is superior to 2HREZ/4HR, it is merely that no-one has been brave enough to do the clinic trial that answers the question if the short course is equivalent.

Regimens omitting isoniazid
Isoniazid resistance in the UK accounts for approximately 6 to 7% of isolates at time of writing (25 Feb 2006). Worldwide, it is the most common type of resistance encountered, hence the current recommendation of using HREZ at the beginning of treatment until sensitivities are known. It is useful to know of current reported outbreaks (like the current outbreak of INH-resistant TB in London).

If a patient is discovered to be infected with an isoniazid-resistant strain of TB having completed 2 months of HREZ, then he should be changed to RE for a further 10 months. If the patient is intolerant to isoniazid, then a reasonable regimen is 2REZ/10RE (although 2REZ/7RE may be acceptable if the patient is well supervised). The US recommendation is 6RZE with the option of adding a quinolone such as moxifloxacin. The level of evidence for all these regimens is poor, and there is little to recommend one over the other.

Regimens omitting rifampicin
It is rare for TB strains to be resistant to rifampicin without being resistant to isoniazid, but rifampicin intolerance is not uncommon (hepatitis or thrombocytopaenia being the most common reasons for stopping rifampicin). Of the first-line drugs, rifampicin is also the most expensive, and in the poorest countries, regimens omitting rifampicin are therefore often used. Rifampicin is the most potent sterilising drug available for the treatment of tuberculosis and all treatment regimens that omit rifampicin are significantly longer than the standard regimen.

The UK recommendation is 18HE or 12HEZ. The US recommendation is 9 to 12HEZ, with option of adding a quinolone (for example, MXF).

Regimens omitting pyrazinamide
PZA is a common cause of rash, hepatitis and of painful arthralgia in the HREZ regimen, and can be safely stopped in those patients who are intolerant to it. Isolated PZA resistance is uncommon in M. tuberculosis, but M. bovis is innately resistant to PZA. PZA is not crucial to the treatment of fully-sensitive TB, and its main value is in shortening the total treatment duration from nine months to six.

There is good evidence from UK trials that a regimen of 9HR is adequate for M. tuberculosis; this is also the first-line regimen used to treat M. bovis.

Regimens omitting ethambutol
EMB intolerance or resistance is rare. If a patient is truly intolerant or is infected with TB that is resistant to EMB, then 2HRZ/4HR is a perfectly acceptable regimen. EMB has no part to play in the treatment of TB that is sensitive to both INH and RMP, and the only reason for including it in the initial regimen is because of increasing rates of INH resistance. If INH resistance rates are known to be low, or if the infecting TB strain is known to be INH-sensitive, then there is no need to use EMB anyway.

Liver disease
It should be noted that patients with alcoholic liver disease are at an increased risk of tuberculosis. The incidence of tuberculous peritonitis is particularly high in patients with cirrhosis of the liver.

No dosing change needs to be made in the dosing of patients with known liver disease, unless the liver disease is thought to have been caused by TB treatment. Some authorities recommend avoiding PZA in patients with known liver disease, because of the five first-line drugs, PZA has the highest risk of producing drug-induced hepatitis.

Patients with pre-existing liver disease should have their liver function tests monitored regularly throughout TB treatment.

Drug-induced hepatitis is discussed in a separate section above.

Pregnancy
Pregnancy itself is not a risk factor for TB.

Rifampicin makes hormonal contraception less effective, so additional precautions need to be taken for birth control during tuberculosis treatment.

Untreated TB in pregnancy is associated with an increased risk of miscarriage and major foetal abnormality, and treatment of pregnant women. The US guidelines recommend omitting PZA when treating TB in pregnancy; the UK and WHO guidelines make no such recommendation. There is extensive experience with the treatment of pregnant women with TB and no toxic effect of PZA in pregnancy has ever been found. High doses of RMP (much higher than used in humans) causes neural tube defects in animals, but no such effect has ever been found in humans. There may be an increased risk of hepatitis in pregnancy and during the puerperium. It is prudent to advise all women of child-bearing age to avoid getting pregnant until TB treatment is completed.

Aminoglycosides (STM, capreomycin, amikacin) should be used with caution in pregnancy, because they may cause deafness in the unborn child. The attending physician must weigh the benefits of treating the mother against the potential harm to the baby, and good outcomes have been reported in children whose mothers were treated with aminoglycosides.

Kidney disease
Patients with renal failure have a 10 to 30-fold increase in risk of getting TB. Patients with kidney disease who are being given immunosuppressive drugs or are being considered for transplant should be considered for treatment of latent tuberculosis if appropriate.

Aminoglycosides (STM, capreomycin and amikacin) should be avoided in patients with mild to severe kidney problems because of the increased risk of damage to the kidneys. If the use of aminoglycosides cannot be avoided (e.g., in treating drug-resistant TB) then serum levels must be closely monitored and the patient warned to report any side-effects (deafness in particular). If patient have end-stage renal failure and have no useful remaining kidney function, then aminoglycosides can be used, but only if drug levels can be easily measured (often only amikacin levels can be measured).

In mild renal impairment, no change needs to be made in dosing any of the other drugs routinely used in the treatment of TB. In severe renal insufficiency (GFR<30), the EMB dose should be halved (or avoided altogether). The PZA dose is 20mg/kg/day (UK recommendation) or three-quarters the normal dose (US recommendation), but not much published evidence is available to support this.

When using 2HRZ/4HR in patients on dialysis, the drugs should be given daily during the initial high-intensity phase. In the continuation phase, the drugs should be given at the end of each haemodialysis session and no dose should be taken on non-dialysis days.

HIV
In patients with HIV, treatment for the HIV should be delayed until TB treatment is completed, if possible.

The current UK guidance (provided by the British HIV Association) is
 * CD4 count over 200&mdash;delay treatment until the six months of TB treatment are complete.
 * CD4 count 100 to 200&mdash;delay treatment until the initial two month intensive phase of therapy is complete
 * CD4 count less than 100&mdash;the situation is unclear and patients should be enrolled in clinical trials examining this question. There is evidence that if these patients are managed by a specialist in both TB and HIV then outcomes are not compromised for either disease.

If HIV treatment has to be started while a patient is still on TB treatment, then the advice of a specialist HIV pharmacist should be sought. In general, there is no significant interactions with the NRTI's. Nevirapine should not be used with rifampicin. Efavirenz may be used, but dose used depends on the patient's weight (600mg daily if weight less than 50kg; 800mg daily if weight greater than 50kg). Efavirenz levels should be checked early after starting treatment (unfortunately, this is not a service routinely offered in the US, but is readily available in the UK). The protease inhibitors must be avoided if at all possible.

Thioacetazone must not be used because the risk of potentially fatal exfoliative dermatitis.

Epilepsy
INH may be associated with an increased risk of seizures. Pyridoxine 10mg daily should be given to all epileptics taking INH. There is no evidence that INH causes seizures in patients who are not epileptic.

TB treatment involves numerous drug interactions with anti-epileptic drugs and serum drug levels should be closely monitored. There are serious interactions between rifampicin and carbamazepine, rifampicin and phenytoin, and rifampicin and sodium valproate. The advice of a pharmacist should always be sought.

Definitions
Multi-drug resistant tuberculosis (MDR-TB) is defined as TB that is resistant at least to INH and RMP. Isolates that are multiply-resistant to any other combination of anti-TB drugs but not to INH and RMP are not classed as MDR-TB.

As of Oct 2006, "Extensively drug-resistant tuberculosis" (XDR-TB) is defined as MDR-TB that is resistant to quinolones and also to any one of kanamycin, capreomycin, or amikacin. The old case definition of XDR-TB is MDR-TB that is also resistant to three or more of the six classes of second-line drugs. This definition should no longer be used, but is included here because many older publications refer to it.

The principles of treatment for MDR-TB and for XDR-TB are the same. The main difference is that XDR-TB is associated with a much higher mortality rate than MDR-TB, because of a reduced number of effective treatment options. The epidemiology of XDR-TB is currently not well studied, but it is believed that XDR-TB does not transmit easily in healthy populations, but is capable of causing epidemics in populations which are already stricken by HIV and therefore more susceptible to TB infection.

Epidemiology of drug-resistant TB
A 1997 survey of 35 countries found rates above 2% in about a third of the countries surveyed. The highest rates were in the former USSR, the Baltic states, Argentina, India and China, and was associated with poor or failing national Tuberculosis Control programmes. Likewise, the appearance of high rates of MDR-TB in New York city the early 1990s was associated with the dismantling of public health programmes by the Reagan administration.

MDR-TB can develop in the course of the treatment of fully sensitive TB and this is always the result of patients missing doses or failing to complete a course of treatment.

Thankfully, MDR-TB strains appear to be less fit and less transmissible. It has been known of many years that INH-resistant TB is less virulent in guinea pigs, and the epidemiological evidence is that MDR strains of TB do not dominate naturally. A study in Los Angeles found that only 6% of cases of MDR-TB were clustered. This should not be a cause for complacency: it must be remembered that MDR-TB has a mortality rate comparable to lung cancer. It must also be remembered that people who have weakened immune systems (because of diseases such as HIV or because of drugs) are more susceptible to catching TB.

There is currently an epidemic of XDR-TB South Africa. The outbreak was first reported as a cluster of 53 patients in a rural hospital in KwaZulu-Natal of whom 52 died. What was particularly worrying was that the mean survival from sputum specimen collection to death was only 16 days and that the majority of patients had never previously received treatment for tuberculosis. This is the epidemic for which the acronym XDR-TB was first used, although TB strains that fulfil the current definition have been identified retrospectively, this was the largest group of linked cases ever found. Since the initial report in September 2006, cases have now been reported in most provinces in South Africa. As of 16 March 2007, there were 314 cases reported, with 215 deaths. It is clear that the spread of this strain of TB is closely associated with a high prevalence of HIV and poor infection control; in other countries where XDR-TB strains have arisen, drug-resistance has arisen from mismanagement of cases or poor patient compliance with drug treatment instead of being transmitted from person to person. This strain of TB does not respond to any of the drugs currently available in South Africa for first- or second-line treatment. It is now clear that the problem has been around for much longer than health department officials have suggested, and is far more extensive. By 23 Nov 2006, 303 cases of XDR-TB had been reported, of which 263 were in KwaZulu-Natal. Serious thought has been put to isolation procedures that may deny some patients their human rights, but which may be necessary to prevent further spread of this strain of TB.

Treatment of MDR-TB
The treatment and prognosis of MDR-TB are much more akin to that for cancer than to that for infection. It has a mortality rate of up to 80%, which depends on a number of factors, including
 * 1) How many drugs the organism is resistant to (the fewer the better),
 * 2) How many drugs the patient is given (Patients treated with five or more drugs do better),
 * 3) Whether an injectable drug is given or not (it should be given for the first three months at least),
 * 4) The expertise and experience of the physician responsible,
 * 5) How co-operative the patient is with treatment (treatment is arduous and long, and requires persistence and determination on the part of the patient),
 * 6) Whether the patient is HIV positive or not (HIV co-infection is associated with an increased mortality).

Treatment courses are generally measured in months to years; it may require surgery, and despite that, the death rates remain still high despite optimal treatment. That said, good outcomes are still possible.

The treatment of MDR-TB must be undertaken by a physician experienced in the treatment of MDR-TB. Mortality and morbidity in patients treated in non-specialist centres is significantly inferior to those patients treated in specialist centres.

In addition to the obvious risks (i.e., known exposure to a patient with MDR-TB), risk factors for MDR-TB include male sex, HIV infection, previous incarceration, failed TB treatment, failure to respond to standard TB treatment, and relapse following standard TB treatment.

Treatment of MDR-TB must be done on the basis of sensitivity testing: it is impossible to treat such patients without this information. If treating a patient with suspected MDR-TB, the patient should be started on SHREZ+MXF+cycloserine pending the result of laboratory sensitivity testing.

A gene probe for rpoB is available in some countries and this serves as a useful marker for MDR-TB, because isolated RMP resistance is rare (except when patients have a history of being treated with rifampicin alone). If the results of a gene probe (rpoB) are known to be positive, then it is reasonable to omit RMP and to use SHEZ+MXF+cycloserine. The reason for maintaining the patient on INH is that INH is so potent in treating TB that it is foolish to omit it until there is microbiological proof that it is ineffective (even though isoniazid resistance so commonly occurs with rifampicin resistance).

When sensitivities are known and the isolate is confirmed as resistant to both INH and RMP, five drugs should be chosen in the following order (based on known sensitivities):
 * an aminoglycoside (e.g., amikacin, kanamycin) or polypeptide antibiotic (e.g., capreomycin)
 * PZA
 * EMB
 * a fluoroquinolones: moxifloxacin is preferred to ciprofloxacin or ofloxacin;
 * rifabutin
 * cycloserine
 * a thioamide: prothionamide or ethionamide
 * PAS
 * a macrolide: e.g., clarithromycin
 * linezolid
 * high-dose INH (if low-level resistance)
 * interferon-γ
 * thioridazine

Drugs are placed nearer the top of the list because they are more effective and less toxic; drugs are placed nearer the bottom of the list because they are less effective or more toxic, or more difficult to obtain.

Resistance to one drug within a class generally means resistance to all drugs within that class, but a notable exception is rifabutin: rifampicin-resistance does not always mean rifabutin-resistance and the laboratory should be asked to test for it. It is only possible to use one drug within each drug class. If it is difficult finding five drugs to treat then the clinician can request that high level INH-resistance be looked for. If the strain has only low level INH-resistance (resistance at 1.0mg/l INH, but sensitive at 0.2mg/l INH), then high dose INH can be used as part of the regimen. When counting drugs, PZA and interferon count as zero; that is to say, when adding PZA to a four drug regimen, you must still choose another drug to make five. It is not possible to use more than one injectable (STM, capreomycin or amikacin), because the toxic effect of these drugs is additive: if possible, the aminoglycoside should be given daily for a minimum of three months (and perhaps thrice weekly thereafter). Ciprofloxacin should not be used in the treatment of tuberculosis if other fluoroquinolones are available.

There is no intermittent regimen validated for use in MDR-TB, but clinical experience is that giving injectable drugs for five days a week (because there is no-one available to give the drug at weekends) does not seem to result in inferior results. Directly observed therapy certainly helps to improve outcomes in MDR-TB and should be considered an integral part of the treatment of MDR-TB.

Response to treatment must be obtained by repeated sputum cultures (monthly if possible). Treatment for MDR-TB must be given for a minimum of 18 months and cannot be stopped until the patient has been culture-negative for a minimum of nine months. It is not unusual for patients with MDR-TB to be on treatment for two years or more.

Patients with MDR-TB should be isolated in negative-pressure rooms, if possible. Patients with MDR-TB should not be accommodated on the same ward as immunosuppressed patients (HIV infected patients, or patients on immunosuppressive drugs). Careful monitoring of compliance with treatment is crucial to the management of MDR-TB (and some physicians insist on hospitalisation if only for this reason). Some physicians will insist that these patients are isolated until their sputum is smear negative, or even culture negative (which may take many months, or even years). Keeping these patients in hospital for weeks (or months) on end may be a practical or physical impossibility and the final decision depends on the clinical judgement of the physician treating that patient. The attending physician should make full use of therapeutic drug monitoring (particularly of the aminoglycosides) both to monitor compliance and to avoid toxic effects.

Some supplements may be useful as adjuncts in the treatment of tuberculosis, but the for the purposes of counting drugs for MDR-TB, they count as zero (if you already have four drugs in the regimen, it may be beneficial to add arginine or vitamin D or both, but you still need another drug to make five).
 * arginine (peanuts are a good source)
 * Vitamin D

The drugs listed below have been used in desperation and it is uncertain whether they are effective at all. They are used when it is not possible to find five drugs from the list above.
 * imipenem
 * co-amoxiclav
 * clofazimine
 * prochlorperazine
 * metronidazole

The follow drugs are experimental compounds that are not commercially available, but which may be obtained from the manufacturer as part of a clinical trial or on a compassionate basis. Their efficacy and safety are unknown:
 * PA-824 (manufactured by PathoGenesis Corporation, Seattle, Washington)
 * R207910 (under development by Johnson & Johnson)

In extremely resistant disease, surgery is sometimes the last port of call. The centre with the largest experience in this is the National Jewish Medical and Research Center in Denver, Colorado. In 17 years of experience, they have performed 180 operations; of these, 98 were lobectomies, 82 were pneumonectomies. There is a 3.3% operative mortality, with an additional 6.8% dying following the operation; 12% experienced significant morbidity (particularly extreme breathlessness). Of 91 patients who were culture positive before surgery, only 4 were culture positive after surgery.


 * See Modern surgical management

Patients who fail treatment
Patients who respond to treatment and appear to be cured after completing a course of TB treatment are not classed as treatment failures, but as relapses and are discussed in a separate section below.

Patients are said to have failed treatment if (1) they fail to respond to treatment (cough and sputum production persisting throughout the whole of treatment), or (2) who only experience a transient response to treatment (the patient gets better at first, but then get worse again, all the while on treatment). Patients who fail treatment must be distinguished from patients who relapse. A patient is said to relapse if he gets better while on treatment and only gets worse again after stopping treatment; patients who relapse are discussed in a separate section below.

It is very uncommon for patients not to respond to TB treatment at all (even transiently), because this implies resistance at base-line to all of the drugs in the regimen. Patients who fail to get any response at all while on treatment should first of all be questioned very closely about whether or not they have been taking their medicines, and perhaps even be admitted to hospital to be observed taking their treatment. Blood or urine samples may be taken to check for malabsorption of TB drugs. If it can be shown that they are fully compliant with their medication, then the probability that they have another diagnosis (perhaps in addition to the diagnosis of TB) is very high. These patients should have their diagnosis carefully reviewed and specimens obtained for TB culture and sensitivity testing. Patients who get better and then get worse again should likewise be question very closely about adherence to treatment. If adherence is confirmed then they should be investigated for resistant TB (including MDR-TB), even if a specimen has already been obtained for microbiology before commencing treatment.

Prescription or dispensing errors will account for a proportion of patients who fail to respond to treatment. Immune defects are a rare cause of non-response. In a tiny proportion of patients, treatment failure is a reflection of extreme biological variation and no cause is found.

Patients who relapse
A patient is said to relapse, if he improves while on treatment, but becomes ill again after stopping treatment. Patients who experience only a transient improvement while on treatment, or who never respond to treatment are said to have failed treatment and are discussed above.

There is a small relapse rate associated with all treatment regimens, even if the treatment has been taken religiously with 100% compliance (the standard regimen 2HREZ/4HR has a relapse rate of 2 to 3%). The majority of relapses occur within 6 months of finishing treatment. Patients who are more likely to relapse are those who took their medication in an unreliable and irregular fashion.

The probability of resistance is higher in those patients who relapse and every effort must be made to obtain a specimen that can be cultured for sensitivities. That said, most patients who relapse do so with a fully sensitive strain and it is possible that these patients have not relapsed, but have instead been re-infected; these patients can be re-treated with the same regimen as before (no drugs need to be added to the regimen and the duration need not be any longer).

The WHO recommends a regimen of 2SHREZ/6HRE when microbiology is not available (the majority of countries where TB is highly endemic). This regimen was designed to provide optimal treatment for fully-sensitive TB (the most common finding in patients who have relapsed) as well as to cover the possibility of INH-resistant TB (the most common form of resistance found).

Because of the life-long risk of relapse, all patients should be warned of the symptoms of TB relapse upon finishing treatment and given strict instructions to return to their doctor if symptoms recur.

Trial of TB treatment
In areas where TB is highly endemic, it is not unusual to encounter patient with a fever, but in whom no source of infection is found. The physician may then, after extensive investigation has excludes all other diseases, resort to a trial of TB treatment. The regimen used is HEZ for a minimum of three weeks; RMP and STM are omitted from the regimen because they are broad spectrum antibiotics, whereas the other three first-line drugs treat only mycobacterial infection. Resolution of the fever after three weeks of treatment is good evidence for occult TB and the patient should then be changed to conventional TB treatment (2HREZ/4HR). If the fever does not resolve after three weeks of treatment then it is reasonable to conclude that the patient has another cause for his fever.

Surgical treatment
Surgery has played an important part in the management of tuberculosis since the 1940s.

Historical surgical management
The first successful treatments for tuberculosis were all surgical. They were based on the observation that healed tuberculous cavities were all closed. Surgical management was therefore directed at closing open cavities in order to encourage healing. These procedures were all used in the pre-antibiotic era. There exists a myth that surgeons believed that the purpose was to deprive the organism of oxygen: it was however well known that the organism survives anaerobic conditions. Although these procedures may be considered barbaric by today's standards, it must be remembered that these treatments represented a potential cure for a disease that at the time had a mortality at least as bad as lung cancer today.


 * Recurrent or persistent pneumothorax
 * The simplest and earliest procedure was to introduce air into the pleural space so as to collape the affected lung and therefore the open cavity. There was always spontaneous resolution of the pneumothorax and the procedure had to be repeated every few weeks.


 * Phrenic nerve crush
 * The phrenic nerve (which supplies the diaphragm) was cut or crushed so as to permanently paralyse the diaphragm on that side. The paralysed diaphragm would then rise up and the lung on that side would collapse, thus closing the cavity.


 * Thoracoplasty
 * When the cavity was located in the apex of the lung, thoracoplasty could be performed. Six to eight ribs were broken and pushed into the thoracic cavity to collapse the lung beneath. This was a disfiguring operation, but it avoided the need for repeated procedures.


 * Plombage
 * Plombage reduced the need for a disfiguring operation. It involved inserting porcelain balls into the thoracic cavity to collapse the lung underneath.

Surgical resection of infected lung was not possible in the 1940s and 1950's, because the science of anaesthesia at the time was not sufficiently advanced to permit surgery on the lungs of an anaesthetised patient.

Modern surgical management
In modern times, the surgical treatment of tuberculosis is confined to the management of multi-drug resistant TB. A patient with MDR-TB who remains culture positive after many months of treatment may be referred for lobectomy or pneumonectomy with the aim of cutting out the infected tissue. In addition, some complications of treated tuberculosis like recurrent hemoptysis, destroyed or bronchiectaic lungs and empyema (a collection of pus in the pleural cavity) are also amenable to surgical therapy

In extrapulmonary TB, surgery is often needed to make a diagnosis (rather than to effect a cure): surgical excision of lymph nodes, drainage of abscesses, tissue biopsy, etc. are all examples of this. Samples taken for TB culture should be sent to the laboratory in a sterile pot with no additive (not even water or saline) and must arrive in the laboratory as soon as possible. Where facilities for liquid culture are available, specimens from sterile sites may be inoculated directly following the procedure: this may improve the yield. In spinal TB, surgery is indicated for spinal instability (when there is extensive bony destriction) or when the spinal cord is threatened. Therapeutic drainage of tuberculous abscesses or collections is not routinely indicated and will resolve with adequate treatment. In TB meningitis, hydrocephalus is a potential complication and may necessitate the insertion of a ventricular shunt or drain.

Nutrition
It is well known that malnutrition is a strong risk factor for becoming unwell with TB, that TB is itself a risk factor for malnutrition, and that malnourished patients with TB (BMI less than 18.5) are at an increased risk of death even with appropriate antibiotic therapy. Baldwin et al. (2004) underscore the importance of access to nutritional enhancements, which they show in turn interface well with a prevalent ethno-medical worldview that may minimize diagnostic delays, and fortify adherence to requisite TB treatment regimes.

Vitamin D
Vitamin D supplementation appears to have a beneficial effect on the treatment of tuberculosis and appears to enhance immunity to tuberculosis, That vitamin D deficiency appears to impair the body's ability to fight tuberculosis was first noted by Professor Peter Davies in 1985, and genetic differences in the vitamin D receptor in West African, Gujarati and Chinese populations have been noted.

The mechanism by which this happens is not entirely clear. In mice, the mechanism appears to be up-regulation of nitric oxide-mediated killing, but this appears not to be the case in humans. Instead, in humans, vitamin D-mediated killing appears to happen via an antimicrobial peptide called cathelicidin. Indeed, reduced levels of vitamin D may explain the increased susceptibility of African-Americans to tuberculosis, and may also explain why phototherapy is effective for lupus vulgaris (tuberculosis of the skin) (a finding which won Niels Finsen the Nobel Prize in 1903), because skin exposed to sunlight naturally produces more vitamin D.

Latent tuberculosis
The treatment of latent tuberculosis infection (LTBI) is essential to controlling and eliminating TB by reducing the risk that TB infection will progress to disease.

The terms "preventive therapy" and "chemoprophylaxis" have been used for decades and are preferred in the UK because it involves giving medication to people who have no active disease and are currently well, the reason for treatment is primarily to prevent people from becoming unwell. The term "latent tuberculosis treatment" is preferred in the US because the medication does not actually prevent infection: it prevents an existing silent infection from becoming active. The feeling in the US is that the term "treatment of LTBI" promotes wider implementation by convincing people that they are receiving treatment for disease. There are no convincing reasons to prefer one term over the other.

It is essential that assessment to rule out active TB is carried out before treatment for LTBI is started. To give LTBI treatment to someone with active TB is a serious error: the TB will not be adequately treated and there is a risk of developing drug-resistant strains of TB.

There are several treatment regimens available:
 * 9H&mdash;Isoniazid for 9 months is the gold standard and is 93% effective.
 * 6H&mdash;Isoniazid for 6 months might be adopted by a local TB program based on cost-effectiveness and patient compliance. This is the regimen currently recommended in the UK for routine use. The US guidance exclude this regimen from use in children or persons with radiographic evidence of prior tuberculosis (old fibrotic lesions). (69% effective)
 * 6 to 9H2&mdash;A twice-weekly regimen for the above 2 treatment regimens is an alternative if administered under Directly observed therapy (DOT).
 * 4R&mdash;Rifampicin for 4-months is an alternative for those who are unable to take isoniazid or who have had known exposure to isoniazid-resistant TB.
 * 3HR&mdash;Isoniazid and rifampicin may be given for three months.
 * 2RZ&mdash;The two month regimen of rifampicin and pyrazinamide is no longer recommended for treatment of LTBI because of the greatly increased risk of drug-induced hepatitis and death.

Current research
There is currently some evidence from animal and clinical studies that suggests that MXF-containing regimens as short as four months may be as effective as six months of conventional therapy. Bayer is currently running a Phase II trial in collaboration with the TB Alliance to evaluate shorter treatment regimens for TB; encouragingly, Bayer have also promised that if the trials are successful, Bayer will make moxifloxacin affordable and accessible in countries that need it.

The follow drugs are experimental compounds that are not commercially available, but which may be available from the manufacturer as part of a clinical trial or on a compassionate basis. Their efficacy and safety are unknown:
 * PA-824 (manufactured by PathoGenesis Corporation, Seattle, Washington)
 * R207910 (under development by Johnson & Johnson)