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 50 mg 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 10 mg 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 drug-induced hepatitis, from tb treatment, 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 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 of 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-minute intervals for a minimum of four hours after each test dose is given (most problems will occur within six hours of test dosing, if they are going to occur at all). patients can become very suddenly unwell and access to intensive care facilities must be available. the drugs should be given in this order: 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 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. 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: 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. the drugs most likely to be causing the reaction should be tested as late as possible (and possibly need not be tested at all). this 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. dysbiosis caused by hrze antibiotic treatment tuberculosis treatment results in changes to the structure of the gut microbiome both during and after treatment in mice and humans. it is currently unknown what the long term effects of this dysbiosis are on systemic immunity. 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); 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 reassuring 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. there is no difference in relapse rates amongst those who are treated with 6 months or longer period of time. however, more well-designed studies are needed to answer this question. regimens omitting isoniazid isoniazid resistance accounts 6.9% of isolates in the uk (2010). 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 patients are discovered to be infected with an isoniazid-resistant strain of tb having completed 2 months of hrez, then they should be changed to re for a further 10 months, and the same thing if the patient is intolerant to isoniazid (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 the uk prevalence of rifampicin (rmp) resistance is 1.4%. it is rare for tb strains to be resistant to rmp without also being resistant to inh, which means that rifampicin-resistance usually means resistance to inh as well (that is, mdr-tb). however, rmp 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 the 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. an alternative regimen is 2hre/7hr, for which there is excellent clinical trial evidence. the 1994 us cdc guidelines for tuberculosis erroneously cite slutkin as evidence that a nine-month regimen using only isoniazid and rifampicin is acceptable, but almost all of the patients in that study received ethambutol for the first two to three months (although this is not obvious from the abstract of that article). this mistake was rectified in the 2003 guidelines. this regimen (2hre/7hr) is the first-line regimen used to treat m. bovis, since m. bovis is intrinsically resistant to pyrazinamide. 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 an acceptable regimen. the main motivator for including emb in the initial two months is because of increasing rates of inh resistance. tuberculosis and other conditions liver disease people 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. there are broadly two categories of treatment: a) cirrhotic patients with essentially normal baseline liver function tests (childs a cirrhosis). such patients may be treated with standard 4 drug regime for 2 months followed by 2 drugs for remaining 4 months (total 6-month treatment). b) cirrhotic patients altered baseline liver function tests (childs b & c). according to 2010