who guidelines: depending on the severity of the disease and degree of decompensation, the following regimen can be used, by altering the number of hepatotoxic drugs. one or two hepatotoxic drugs may be used in moderately severe disease (e.g., childs b cirrhosis) whereas hepatotoxic drugs are completely avoided in decompensated child c cirrhosis. • two hepatotoxic drugs – 9 months of isoniazid, rifampin and ethambutol (until or unless isoniazid susceptibility is documented) – 2 months of isoniazid, rifampin, ethambutol and streptomycin followed by 6 months of isoniazid and rifampin • one hepatotoxic drug – 2 months of isoniazid, ethambutol & streptomycin followed by 10 months of isoniazid and ethambutol • no hepatotoxic drugs – 18–24 months of streptomycin, ethambutol and quinolones. patients with liver disease should have their liver function tests monitored regularly throughout tb treatment. 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 while tuberculosis treatment. untreated tb in pregnancy is associated with an increased risk of miscarriage and major fetal 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, and pza is commonly used in pregnancy. 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. experience in peru shows that treatment for mdr-tb is not a reason to recommend termination of pregnancy, and that good outcomes are possible. kidney disease people with kidney failure have a 10 to 30-fold increase in risk of getting tb. people with kidney disease who are being given immunosuppressive medications 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 a person has end-stage kidney disease and has 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 kidney impairment, no change needs to be made in dosing any of the other drugs routinely used in the treatment of tb. in severe chronic kidney disease (gfr<30), the emb dose should be halved (or avoided altogether). the pza dose is 20 mg/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—delay treatment until the six months of tb treatment are complete. cd4 count 100 to 200—delay treatment until the initial two-month intensive phase of therapy is complete cd4 count less than 100—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 (600 mg daily if weight less than 50 kg; 800 mg daily if weight greater than 50 kg). 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 should be avoided if at all possible: patients on rifamycins and protease inhibitors have an increased risk of treatment failure or relapse. the world health organization (who) warns against using thioacetazone in patients with hiv, because of the 23% risk of potentially fatal exfoliative dermatitis. according to caprisa 003 (sapit) study the mortality in patients who were started on anti-retrovirals during tb treatment was 56% lower than those started after tb treatment was completed (hazard ratio 0.44 (95% ci: 0.25 to 0.79); p=0.003). epilepsy inh may be associated with an increased risk of seizures. pyridoxine 10 mg 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. covid- 19 tb and covid-19 are a "cursed duet" and need immediate attention. tb should be considered a risk factor for severe covid disease and patients with tb should be prioritised for covid-19 preventative efforts, including vaccination. drug-resistance main articles: multi-drug-resistant tuberculosis and extensively drug-resistant tuberculosis definitions multi-drug resistant tuberculosis (mdr-tb) is defined as tb that is resistant at least to inh and rmp. isolates that are multi-resistant to any other combination of anti-tb drugs but not to inh and rmp are not classed as mdr-tb. as of october 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 of drug-resistant tb 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. paul farmer points out that the more expensive a treatment, the harder it is for poor countries to get. farmer sees this as verging on denial of basic human rights. africa is low in quality of treatment partly because many african cultures lack the 'concept of time' essential to the schedule of 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. children represent a susceptible population with increasing rates of mdr and xdr-tb. since diagnosis in pediatric patients is difficult, large number of cases are not properly reported. cases of pediatric xdr-tb have been reported in most countries including the united states. in 2006 an outbreak of xdr-tb south africa was first reported as a cluster of 53 patients in a rural hospital in kwazulu-natal, with all but one dying. 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 november 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 how many drugs the organism is resistant to (the fewer the better), how many drugs the patient is given (patients treated with five or more drugs do better), whether an injectable drug is given or not (it should be given for the first three months at least), the expertise and experience of the physician responsible, how co-operative the patient is with treatment (treatment is arduous and long, and requires persistence and determination on the part of the patient), whether the patient is hiv positive or not (hiv co-infection is associated with an increased mortality). treatment courses are a minimum of 18 months and may last years; it may require surgery, though death rates remain high despite optimal treatment. that said, good outcomes are still possible. treatment courses that are at least 18 months long and which have a directly observed component can increase cure rates to 69%. 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 elevated compared to those patients treated in specialist centres. in addition to the obvious risks (e.g., 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