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| THE VARIABLES - THE CONFOUNDING FACTORS |
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| Year : 2017 | Volume
: 4
| Issue : 2 | Page : 100-107 |
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Tuberculosis in special situations: Co-morbid conditions, physiological states and contraception
Harjit Dumra
Consultant Pulmonologist and Critical Care Specialist, “Sparsh” Chest Diseases Centre, Ahmedabad, Gujarat, India
| Date of Web Publication | 30-Nov-2017 |
Correspondence Address:
Harjit Dumra
Consultant Pulmonologist and Critical Care Specialist, “Sparsh” Chest Diseases Centre, Ahmedabad, Gujarat
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/astrocyte.astrocyte_64_17
Till date we believed that multidrug-resistant and extensively drug resistant were our deadliest foes when dealing with tuberculosis. However, conditions commonly encountered in daily practice such as diabetes, liver, renal, psychiatric disorders, and pregnancy tend to frequently overlap with tuberculosis. These multimorbid conditions prove to be equally challenging for an average medical practitioner. Inappropriate prescriptions in the above situations prove to be a significant impediment to the overall control of tuberculosis in the community at large. The advent of solid organ transplantation and aggressive use of immunosuppressive medication for malignancies and chronic inflammatory disorders has added a new dimension to the already preexisting challenges faced by practicing clinicians, particularly in the context of treating tuberculosis in the immunocompromised and drug-drug interactions. This is another area which needs special attention. Pediatric multidrug resistant tuberculosis is a growing menace and needs to be controlled before it becomes an insurmountable problem. In addition, the emerging epidemics of metabolic syndrome, substance abuse, and drug dependence have only compounded the problem. Tuberculosis in the above populations, particularly if drug resistant can be one of the worst nightmares for the treating clinician. This article tries to highlight these prevalent issues and offers practical and evidence-based solutions to help clinicians in their endeavor to achieve a tuberculosis free world.
Keywords: Diabetes, liver disease, renal failure, special situations, tuberculosis
How to cite this article:
Dumra H. Tuberculosis in special situations: Co-morbid conditions, physiological states and contraception. Astrocyte 2017;4:100-7 |
| Introduction | |  |
Tuberculosis (TB) in India has long been a scourge which has frustrated all efforts to bring it under control. There are several reasons behind this, the important ones being poorly understood complex biology and pathogenesis of Mycobacterium tuberculosis infection, potential long latency periods, unrecognized primary and re-infections, and relatively symptom free disease onset leading to transmission for several months before most patients present for clinical care, which is a huge unrecognized reservoir of latent TB infections compounded by a limited repertoire of cheap and safe TB drugs, lengthy treatment with multiple drugs leading to poor adherence, particularly so for treatment of drug-resistant TB.[1],[2]
If this was not enough, TB tends to afflict, not uncommonly, people who are already crippled by chronic diseases. This makes managing this dreaded disease even more challenging. Although the basic principles of managing TB in these situations remain the same, special attention needs to be given to dosages, duration, number, and categories of anti-TB drugs used. The commonly encountered conditions where treatment needs require a more focused approach include diabetes, chronic renal failure, liver disease, pregnancy, lactation, patients who are immunocompromised because of diseases or drugs, and lastly pediatric and geriatric age groups. This article in brief would address the issues frequently encountered in managing tuberculosis in these complex situations.
| Diabetes Mellitus | | |
We already know that there is increased risk of progression to active TB among persons with latent TB infection (LTBI) and diabetes. However, it has only recently come to light that outcomes for patients who have both TB and diabetes are poorer than for TB patients without diabetes.[3] Although the role of diabetes mellitus (DM) in furthering drug resistance has remained controversial, new evidence is coming up which indicates that diabetes does increase the risk of drug-resistant TB.[4] The emergence of the epidemic of diabetes in the developing world has led to a renewed focus on this important syndemic.
A recent study from Taiwan included 192 patients (60 with DM and TB, 132 with TB only) who were treated for a full course of anti-TB medication and were prospectively followed for over 1 year. The DM and TB patients had higher treatment failure rates (17% vs. 2%) and longer time to clearance of Mycobacteria from sputum (2.5 months vs. 1.6 months) than did the TB only patients. After 1 year, 3 DM and TB patients (5.0%) and one TB-only patient (0.8%) had multidrug-resistant (MDR)-TB.[4]
An important reason cited for poor outcomes and acquired drug resistance has been linked to suboptimal drug levels, particularly of rifampicin (RIF). This was initially described in diabetic patients in an Indonesian cohort with higher body mass index and TB. More recently, researchers at the University of Virginia have reported on the results of therapeutic drug monitoring (TDR) for first-line drugs in patients who were slow to respond to therapy, defined as no improvement in symptoms, or were persistently smear positive at 6 weeks of treatment. Diabetic patients were 6.3 times more likely to be slow responders when adjusted for age, gender, country of origin, prior TB cavitory disease, HIV, and alcohol and tobacco use. They found that 82% of these slow responders had low levels of either isoniazid (INH) or RIF, with statistically significantly lower serum RIF levels.
In addition, there is also reasonable evidence indicating that once patients with DM and TB have MDR-TB, outcomes of treatment are poor. A recent Korean study examined 1,407 patients with MDR-TB treated between 2000 and 2002 and followed them for 8–11 years. Diabetes was present in 239 of these (17%). Patients with MDR-TB and DM had a significantly lower treatment success rate than those without DM (36.0% vs. 47.2%). DM was a significant predictor of poor long-term survival in multivariate analyses.[4]
In addition, patients with diabetes and MDR-TB may be at an increased risk of adverse events because many anti-TB drugs have side effects that place diabetic patients at special risk. Patients with long-standing diabetes are prone to renal impairment that can be worsened by the second-line injectable drugs used in MDR-TB. Neuropathy, not an uncommon complication of diabetes, can be worsened by several drugs used to treat MDR-TB such as high-dose INH, cycloserine (CS), linezolid (LZD), aminoglycosides, and ethionamide. Patients with diabetes may have decreased gastric motility (gastroparesis) and may be at an increased risk of nausea and vomiting with medications such as ethionamide and PAS and other MDR-TB medications.[4]
Hence, it would be prudent to follow certain basic principles while managing TB with diabetes. These include monitoring renal functions regularly and intermittent dosing for injectable drugs if there is pre-existing or newly developing renal impairment. Gastroparesis should be treated aggressively with gastric motility agents such as metoclopramide. If neuropathy develops, the offending drug should be changed, if possible. Dosage of vitamin, if that cannot be done safely, consider use of agents such as tricyclic antidepressants, gabapentin, and/or adding or increasing the dosage of vitamin B6. TDM should be considered in case of delayed, slow, or lack of response.
A common misconception is that oral hypoglycemic agents are contraindicated during the treatment of drug-resistant TB. Control of diabetes is the foremost target, with oral drugs or insulin being secondary. However, a precaution which needs to be exercised when using oral hypoglycemics is to modify the dosage as the use of ethionamide or prothionamide may make it more difficult to control insulin levels.
| Liver Disease | | |
Most of the first-line TB drugs and some of the second-line drugs have the potential to cause hepatotoxicity, and their use must be contemplated with care in the setting of severe liver dysfunction. The following is a list of anti-TB medications and their effect on the liver [Table 1].[4]
Patients with history of liver disease and susceptible TB can receive the usual anti-TB drug regimens provided there is no clinical evidence of severe chronic liver disease, hepatitis virus carriage, and recent history of acute hepatitis or excessive alcohol consumption. However, hepatotoxic reactions to anti-TB drugs may be more common in these patient groups and should be anticipated. In general, in patients with chronic liver disease pyrazinamide should be avoided. All other drugs can be used but close monitoring of liver enzymes is advised. If significant aggravation of liver inflammation occurs, the drugs responsible may have to be stopped. One should always remember that sometimes in such cases hepatitis could be secondary to non-TB drugs being used for other comorbid disorders. MDR-TB patients having deranged liver function test (LFT) during pretreatment evaluation should be strictly monitored through monthly LFTs while on treatment. However, routine LFT is not recommended in all cases.
Uncommonly, a patient with TB may have concurrent acute hepatitis that is unrelated to TB or anti-TB treatment (ATT); and here, clinical judgment becomes necessary. In some cases, it is possible to defer anti-TB treatment until the acute hepatitis has been resolved. In other cases when it is necessary to treat, particularly in settings of drug-resistant TB, the combination of four nonhepatotoxic drugs is the safest option.
If serum alanine aminotransferase levels are more than three times the normal before the initiation of treatment, the following regimens can be considered.
Containing two hepatotoxic drugs
- 2 months of INZ, RIF, EMB, and a higher floroquinolone in the intensive phase, and then 7 months of INZ, RIF, and EMB
- Streptomycin can be used instead of the higher fluoroquinolone in the intensive phase of the above regime, if streptomycin sensitivity is confirmed from a reliable laboratory
- 2 months of RIF, PZA, EMB, and a higher floroquinolone in the intensive phase, and then 4–7 months of RIF, PZA, and EMB
Containing one hepatotoxic drug
Two months of RIF, EMB, higher quinolone and streptomycin, followed by 10 months of RIF and EMB.
Containing no hepatotoxic drugs
Eighteen to twenty-four months of streptomycin, EMB, and a fluoroquinolone.[5] Creatinine should be checked every 2 weeks all through. Streptomycin sensitivity should be confirmed.
Rechallenge regimen in drug-induced hepatitis in the absence of liver disease
All first-line drugs – INZ, RIF, and PZA – are associated with hepatotoxicity. Of the three, RIF is least likely to cause hepatocellular damage, although it is associated with cholestatic jaundice. The hepatotoxic effects of RIF and INZ are additive. PZA is the most hepatotoxic of the three first-line drugs and hepatic damage is dose and duration related.[3]
In view of the significant advantages of the core first-line drugs in the treatment of TB, a rechallenge is usually the norm in patients with anti-tubercular therapy (ATT)-induced hepatitis. The following principals can be followed during rechallenge:
– Background therapy: Streptomycin, EMB, moxifloxacin
– Day 1: RIF 450 or 600 mg daily depending on the weight
– Day 3: Check ALT, if normal
– Day 4: Add INH 300 mg daily
– Day 7: Check ALT, if normal
– Day 8: Add PZA 25 mg/kg/day
– Day 10: Check ALT.
Usually, patients tolerate first-line drugs the second time without developing hepatitis when these drugs are added one after the other. Monitor ALT three times per week during rechallenge.[6]
Rechallenge is preferably avoided in patients who have had fulminant hepatitis (defined as Hepatic encephalopathy with coagulopathy).
| Renal Failure | | |
Patients with chronic renal failure undergoing hemodialysis are at a 10–25-fold increased risk of developing TB disease once infected compared to the general population. These patients require careful monitoring for treatment of TB and drug-resistant TB in particular.
Furthermore, renal insufficiency can be caused by longstanding TB infection itself or previous use of aminoglycosides. Great care should be taken in the administration of second-line drugs in patients with renal insufficiency, and the dose and/or the interval between dosing should be adjusted according to the patient's creatinine clearance.
Dosing recommendations for adult patients with reduced renal function and for adult patients receiving hemodialysis [Table 2]:[4] | Table 2: Recommended Doses of Anti-TB Drugs in Patients with Renal Failure
Click here to view |
Most regarding the dosing of anti-TB drugs is best documented for patients with creatinine clearance less than 30 mL/min or for those undergoing hemodialysis. Data for individuals with mild renal failure or undergoing peritoneal dialysis is scarce. In addition to the effects on drug clearance, the diseases that cause renal failure and concomitant treatments can also impact drug levels (by altering absorption or through drug interactions).
Although there are recommendations for giving large doses before dialysis and supplementary doses after dialysis, the practical method is to give the medications immediately following hemodialysis to avoid premature removal of drugs. In general, the doses of the anti-TB medications should not be reduced but rather the interval should be increased.
The recommendations for treatment of TB, either pulmonary or extrapulmonary, in renal failure remain the same, albeit with dose interval modifications where appropriate. INZ and RIF are eliminated by biliary excretion, hence, no change in dosing is necessary. There is significant renal excretion of EMB and doses should therefore be adjusted. For patients with stages 4 and 5 chronic renal disease and on hemodialysis, dosing intervals should be increased to three times weekly for EMB and aminoglycosides. The doses remain the same as the ones used in daily regimens.
Until a few years ago, the effect of chronic kidney disease (CKD) on Pyrazinamide (Z) kinetics was not fully studied and various authors had recommended either to avoid Z in CKD or to use it in reduced dosage of 12–20 mg/kg/day or 40–60 mg/kg/thrice or twice a week. Now most of the guidelines, including the WHO recommendations, approve normal dosage of Z in CKD patients.[1]
Treatment of MDR-TB in patients with renal insufficiency also requires several modifications. MDR-TB patients require aminoglycosides for 6 months or more. In patients with mild renal impairment, the dose of aminoglycosides may be reduced. In the presence of severe renal failure, the aminoglycoside therapy should be discontinued and replaced with other potent non-nephrotoxic anti-TB drugs. Other drugs, which also might require dose or interval adjustment in presence of mild to moderate renal impairment, are quinolones, cycloserine, and PAS.
PAS is a relatively weak drug, and the therapeutic window is too narrow. Gastrointestinal upset and vomiting due to PAS can worsen acidosis in patients of CRF. Hence, it should be avoided in CRF patients. On the contrary, ethionamide and prothionamide are relatively safe drugs in CRF.
While receiving INZ, patients with severe renal insufficiency should also be given pyridoxine in order to prevent peripheral neuropathy.
| Pregnancy and Breastfeeding | | |
Successful management of TB during pregnancy has important implications both for the mother and newborn. Because of the risk of TB to the fetus, treatment of TB in pregnant women should always be pursued aggressively. In a patient with drug-susceptible TB, the initial treatment regimen should consist of INH, RIF, EMB, and PZA. Although all drugs cross the placenta, they do not appear to have teratogenic effects. Teratogenicity data for PZA is scarce, however, it can probably be used safely during pregnancy and is recommended by WHO. Streptomycin is documented to have harmful effects on the human fetus (congenital deafness) and should not be used. Pyridoxine must be given to pregnant patients receiving TB treatment.
Several medications used to treat drug-resistant TB are either teratogenic or their safety during pregnancy is unknown. Consequently, treatment of drug-resistant TB during pregnancy is very challenging. Hence, birth control is strongly recommended for all nonpregnant sexually active women receiving therapy for drug-resistant TB.
Management of MDR-TB patients who are pregnant prior to initiation of treatment or while on treatment is based on the duration of pregnancy. If the duration of pregnancy is <20 weeks, the patient should be advised to opt for a medical termination of pregnancy (MTP) in view of the potential severe risk to both the mother and fetus, following which treatment can be initiated (if the patient has not started treatment) or continued (if the patient is already on treatment).
For patients who are unwilling for MTP or have pregnancy of >20 weeks (making them ineligible for MTP), the risk to the mother and fetus need to be explained clearly and a modified Regimen for MDR-TB should be started.[5]
Some general principles to consider when treating pregnant women with MDR TB [3],[4],[5]
- Weigh the benefits versus risks before initiation of treatment. Most pregnant patients should be started on treatment as early as the diagnosis is made because any delay can lead to rapid progression of TB. However, because the majority of teratogenic effects occur in the first trimester, treatment may be delayed until the second trimester provided the patient is stable and with minimum disease in noncritical extrapulmonary site, e.g. cervical lymph node. A decision to start treatment or to postpone until after the first trimester should be agreed to by at least the patient and the doctor after analyzing the risks and benefits.
- Treat with at least four second-line highly effective anti-TB drugs plus PZA. The regimen should be reinforced with an injectable agent and other drugs as needed immediately postpartum.
- Avoid injectable agents during pregnancy. Aminoglycosides are the only TB drugs that have well-documented teratogenicity and eight nerve toxicity. Among the aminoglycosides, capreomycin is the injectable drug of choice if an injectable agent cannot be avoided. It can be used thrice weekly from the start to decrease drug exposure to the fetus.
- Avoid ethionamide. Ethionamide can increases the risk of gastrointestinal side effects such as nausea and vomiting associated with pregnancy, and teratogenic effects have also been observed in animal studies.
- Despite limited data on safety and long-term use of fluoroquinolones, cycloserine, PAS, and amoxicillin/clavulanate in pregnancy, they are considered the drugs of choice for MDR-TB treatment during pregnancy along with PZA and EMB.
- Linezolid (LZD) is classified as the pregnancy category C drug. Some animal studies have failed to reveal evidence of fetal harm; however, studies using high doses have demonstrated fetotoxicity and teratogenicity. There are no controlled data in human pregnancies. LZD should only be given during pregnancy when benefits outweigh risk. The same rules apply to the use of clofazimine.
- In case teratogenic drugs such as aminoglycosides, ethionamide/prothionamide, or others are withheld because of the pregnancy, they can be added postpartum to make a more complete regimen. There may not be a clear transition between the intensive and continuation phase, and the injectable agent can be given for 3–6 months postpartum even in the middle of the treatment. Alternatively, if the patient is doing well and past the normal 8-month period for the injectable agent, it need not be added. Any addition of drugs should be mindful of the principle of never adding a single drug to failing regimen. The total treatment duration is the same as for MDR-TB treatment
Breastfeeding
Breastfeeding should not be discouraged for women being treated with the first-line anti-TB agents because the small concentrations of these drugs in breast milk do not produce toxicity in the nursing newborn. Conversely, drugs excreted in breast milk should not be considered an effective treatment option for tuberculosis or for latent tuberculosis infection in a nursing infant. Pyridoxine supplementation (25 mg/day) is recommended for all breastfeeding women taking INH, cycloserine, or ethionamide. The amount of pyridoxine in multivitamins is variable but generally less than the needed amount. Although floroquinolones should generally be avoided in breast feeding women, in settings of MDR TB the benefits to the mother far outweigh the risks to the infant and hence should be continued.
In case of drug-resistant TB, if the mother is sputum smear positive, the care of the infant should be left to family members until she becomes sputum smear negative, if this is feasible. If this is practically not possible, when the mother and infant are together, this time should be spent in well-ventilated areas or outdoors. The mother should use a surgical mask until she becomes sputum smear negative.
| Contraception | | |
There is no contraindication to the use of oral contraceptives with non-RIF containing regimens. In case the patient vomits directly after taking an oral contraceptive, the efficacy of the drug can be compromised. These patients should be advised to take their contraceptives apart from times when they may experience vomiting caused by the anti-TB treatment medications. It is preferable to use a barrier method of contraception until a full month of the contraceptive tablets have been tolerated.
For patients on RIF containing regimen, the use of RIF interacts with the contraceptive drugs resulting in decreased efficacy of protection against pregnancy. In such a case one of the two options can be exercised (1) the use of an oral contraceptive pill containing a higher dose of estrogen (50 μg) or (2) the use of another form of contraception. Condoms are a reasonable solution for patients who do not want to take additional pills and/or when protection against sexually transmitted diseases is also needed.
| Children With Drug-Resistant Tuberculosis | | |
Isolation of M. tuberculosis from a child with pulmonary TB is an extremely difficult proposition. Hence, treatment of TB in children essentially relies on the results of drug susceptibility testing of the source case. In cases of suspected drug-resistant TB in a child or when a source case isolate is not available, reliable specimens for microbiological evaluation should be obtained via early morning gastric aspiration, bronchoalveolar lavage, or biopsy.
In general, treatment of sensitive TB follows the same principles as in adults and is usually associated with good outcomes. In addition, extrapulmonary tuberculosis in children can be treated with the same regimens as pulmonary disease.
However, MDR-TB in children is a life-threatening disease. Although no anti-TB drugs are contraindicated in children, there is limited reported experience in the literature on the use of many of the second-line drugs in children for extended periods. The risks and benefits of each drug should be carefully considered while designing a regimen. For MDR-TB, at least 4–6 likely effective drugs should initially be employed, including a fluoroquinolone and an injectable agent. Children who have received treatment for drug-resistant TB have generally tolerated the second-line drugs well. Although fluoroquinolones have been shown to retard cartilage development in animals, similar effects have not been documented in humans even after long-term use. The benefits of fluoroquinolones in treating drug-resistant TB in children far outweigh any risk. In addition, ethionamide, PAS, and cycloserine have been used effectively in children and are generally well tolerated. There is not extensive experience with the long-term use of linezolid for pediatric TB. For aminoglycosides, most guidelines suggest using an injectable drug for at least 4–6 months from culture conversion.[4],[5]
Anti-TB drugs should be dosed according to body weight with adjustment of doses as children gain weight. There is enough data now to suggest that children metabolize most TB drugs more rapidly than adults and higher weight-based doses are required to achieve the same serum concentrations. However, the same does not hold true for neonates and young infants, and optimum doses are yet to be defined. Expert opinion is that all drugs, except EMB, should be dosed at the higher end of the recommended ranges, whenever possible. EMB should be dosed at 15 mg/kg and not at 25 mg/kg as sometimes used in adults with drug-resistant TB, as it is more difficult to monitor optic neuritis in children.[4],[5]
Very few anti-TB drugs are available in liquid preparations or in chewable tablets appropriate for pediatric dosing, and hence, on many occasions approximate doses construed out of pill fragments/crushed pills are considered optimum. Most often pills need to be mixed with a vehicle either food or liquids. For aminoglycosides, intravenous injections preferably with percutaneous catheters should be attempted. If intramuscular injections are being given, the thigh and gluteal region are preferred for neonates and young infants. Deltoid is an option only for older children. Also, the site of injection should be rotated.[4],[5]
Just as it is extremely difficult to confirm a diagnosis in children, for the very same reasons, it is difficult to monitor a microbiological response to treatment. This makes diagnosing treatment failure in children extremely challenging. Persistent abnormalities on chest radiographs do not necessarily imply a lack of improvement. In children, weight loss or, more commonly, failure to gain weight adequately in the presence of proper nutritional intake is of particular concern and often one of the first (or only) signs of treatment failure. This is another key reason to monitor weight carefully in children.[4],[5]
Early diagnosis, strong social support, parental and family counseling, and a close relationship with the health care providers may help to improve outcomes in children.
| Solid Organ Transplant | | |
The occurrence of TB among solid organ transplant (SOT) recipients varies based on the background rates of TB in the general population. A review of literature indicates that the incidence may be 20–74 times higher than that of the general population and maybe associated with higher mortality.[4]
TB can occur in a person who has received a SOT due to five reasons:
- Reactivation of LTBI
- Relapse of previously treated TB
- Donor-derived reactivation
- Transmission of TB
- Person with active TB requiring urgent transplantation (e.g. drug-induced hepatotoxicity)
The most common scenario is reactivation of LTBI.
Although the reasons for the onset of TB may differ, the time of onset is usually the first 6 months post-transplant. The exception is renal transplant patients where the onset can be later. The diagnosis of TB among persons who have received a SOT can be challenging due to the lack of traditional TB risk factors, atypical symptoms at presentation, and a wide range of radiographic manifestations including focal infiltrate, miliary pattern, pulmonary nodules, and pleural effusions. Although in most SOT patients pulmonary disease is the most common presentation, 16% have extrapulmonary disease and 33% have disseminated TB disease, which also contributes to the difficulty in diagnosis.
When using RIF for drug susceptible TB the doses of immunosuppressants needs to be carefully monitored as RIF tends to decrease levels of prednisolone, cyclosporine, tacrolimus, sirolimus, and mycofenolate mofetil. However, RIF has no interactions with azathioprine, and can be used without monitoring.
Treatment of MDR-TB in a person who has received a SOT can be complicated primarily due to the interactions between TB medications and immunosuppressive medications. An important decision which requires close coordination between the TB clinician and the transplant team is to determine whether the dose of immunosuppressant can be safely reduced during MDR TB treatment. Common interactions encountered between MDR-TB drugs and immunosuppressants are summarized in the table below [Table 3]. Due to the occurrence of these interactions, MDR-TB treatment will require close monitoring, consideration of use of intermittent dosing of medications (e.g. aminoglycosides or capreomycin, and linezolid), and TDM of both immunosuppressants and anti-TB drugs to ensure a successful completion of treatment. | Table 3: Interactions between Immunosuppressants and commonly used MDR-TB Medications[4]
Click here to view |
| Seizure Disorders | | |
Some patients requiring treatment for TB will have a previous or current medical history of a seizure disorder. The first step in evaluating such patients is to determine whether the seizure disorder is under control and whether the patient is taking appropriate anti-seizure medication. If the seizures are not under control, initiation or adjustment of anti-seizure medication will be needed before the start of therapy. In addition, any other underlying conditions or causes of seizures such as metabolic or electrolyte imbalances should be corrected.
When treating patients with drug susceptible TB, INZ and RIF tend to cause alteration in drug levels of phenytoin and carbamazepine. INZ increases while RIF decreases the level of the above two drugs. It would be advisable to check the serum levels of anti-convulsants in such a situation. However, where serum levels are not available, levetiracetam would be the drug of choice to use because of the absence of interactions with INZ and RIF.
In case of drug-resistant TB, seizures that present for the first time during anti-TB therapy could be the result of an adverse effect of any one of the anti-TB drugs suh as cycloserine, INH, or fluoroquinolones.[3]
Cycloserine should be avoided in patients with active seizure disorders that are not well controlled with medication. However, in cases where cycloserine is a crucial component of the treatment regimen, it can be given and anti-seizure medication adjusted as needed to control the seizure disorder. In such a situation the anticonvulsant is generally continued until MDR-TB treatment is completed or cycloserine is discontinued.[5]
It is advisable to check creatinine in patients with new onset seizures. A decrease in renal function can result in high blood levels of cycloserine, which can cause seizures. Adjusting the dose of cycloserine might be all that is needed to control the seizures.
High dose INZ also carries an exaggerated risk of seizure and should be avoided in patients with active seizure disorders. Oral pyridoxine (maximum dose of 200 mg per day) can be used in patients with seizure disorders to protect against the neurological adverse effects of INZ or cycloserine.[5]
Floroquinolones are the cornerstone of treatment of MDR-TB. Moxifloxacin is a drug frequently recommended for treatment of CNS TB, clearly indicating the benefits of floroquinolones even in patients at risk of seizures. Hence, the risks benefit ratios of floroquinolone use in a patient with seizures should be assessed on a case-to-case basis.
| Psychiatric Disorders | | |
All medical professionals treating drug-resistant TB should closely work with a psychiatrist and have an organized system for psychiatric emergencies. Psychiatric emergencies include psychosis, suicidal ideation, and any situation involving the patient's being a danger to him/her self or others. Disorders such as psychosis and depression which present during the course of treatment of MDR-TB may be secondary to drugs such as cycloserine, fluoroquinolones, INH, or ethionamide/prothionomide. However other etiologies such as psychosocial stresses, hypothyroidism, illicit drug, and alcohol use should also be actively screened for.
Cycloserine may cause severe psychosis and depression leading to suicidal tendencies. However, the use of cycloserine is not absolutely contraindicated for the psychiatric patient. Adverse effects of cycloserine may be more prevalent in the psychiatric patient, but the benefits of using this drug often outweigh the potential higher risk of adverse effects. Close monitoring is recommended if cycloserine is used in patients with psychiatric disorders.[5]
If patient on cycloserine or ethionamide therapy develops depression/psychosis, lowering the dose (500 mg/day) might sometimes be all that is needed. However, if the problems persist, anti-psychotic treatment should be started and the culprit drug should be temporarily suspended. Antidepressants such as amitryptiline or fluoxetine maybe used. Tricyclic antidepressants and selective serotonin reuptake inhibitors should be given together, the exception being patients on linezolid. For pyschotic symptoms, haloperidol can be used. Once symptoms resolve and patient is stabilized, cycloserine/ethionamide therapy may be resumed. Such patients may require anti-psychotic treatment till anti-TB treatment is completed.[5]
| Conclusions | | |
TB in diabetic patients has higher treatment failure rates. TDM should be considered in case of delayed, slow, or lack of response. Patients with chronic liver and renal disorders need modification in regimen to avoid further worsening in organ function. Pyrazinamide in liver failure and aminoglycosides in renal failure are of major concern. Drug-susceptible TB does not need any modification in the standard regimen during pregnancy. Many medications used to treat drug-resistant TB are either teratogenic or their safety during pregnancy is unknown. As a result, birth control is strongly recommended for all nonpregnant sexually active women receiving therapy for drug-resistant TB. Breastfeeding should be preferably avoided in case of mothers being treated for drug-resistant TB till they are culture negative. Treatment of TB in children essentially relies on the results of drug susceptibility testing of the source case. MDR-TB in children is a life-threatening disease and there is limited reported experience in the literature on the use of many of the second-line drugs in children for extended periods. The risks and benefits of each drug should be carefully considered while designing a regimen. Although in most SOT patients pulmonary disease is the most common presentation, extrapulmonary disease and disseminated TB disease are not uncommon. Important decisions are whether drug–drug interactions can have any adverse consequence and whether the dose of immunosuppressants can be safely reduced during MDR-TB treatment. In patients with seizure disorders, TDM of anti-seizure medication is ideal in view of significant drug–drug interactions. However, where serum levels are not available, levetiracetam would be the drug of choice to use because of absence of interactions with INZ and RIF. cycloserine, INH, or fluoroquinolones can cause seizures and should be used cautiously in these patients. Disorders such as psychosis and depression which present during the course of treatment of MDR-TB may be secondary to drugs such as cycloserine, fluoroquinolones, INH, or ethionamide/prothionomide. However, other etiologies such as psychosocial stresses, hypothyroidism, illicit drug, and alcohol use should also be actively screened for.
Last but not the least, astute clinical skills, constant upgradation of knowledge, and a focused approach to prevention of TB seem to be the only solutions in such cases of “TB in special situations.”
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | Singh BS. Management of Tuberculosis in Special Situations. Lung India 2005;22:138-41.  |
| 2. | Petersen E, Maeurer M, Marais B, Migliori G, Mwaba P, Ntoumi F, et al. TB Day 2017: Advances, challenges and opportunities in the “End-TB” era. Int J Infect Dis 2007;56:1-5. |
| 3. | Jaramillo E, Weyer K, Raviglione M, Rich M, et al. Treatment of drug-resistant TB in special conditions and situations. Companion handbook to the WHO guidelines for the programmatic management of drug-resistant tuberculosis. WHO 2014. |
| 4. | Schecter GF, Chitnis AS. Co-morbidities & Special Situations. Drug-resistant tuberculosis: A survival guide for clinicians. 3 rd ed. |
| 5. | Central TB Division, Directorate General Of Health Services, Ministry Of Health and family Welfare, New Delhi, India. www.tbcindia.gov.in. Revised National Tb Control Program. Technical and Operational Guidelines for TB Control in India 2016 chapter 4, part 2. [Last accessed on 2017 Sep 18]. |
| 6. | Saukkonen JJ, Cohn DL, Jasmer RM, Schenker S, Jereb JA, Nolan CM, et al. An official ATS statement: Hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med 2006;174:935-52. [ PUBMED] |
[Table 1], [Table 2], [Table 3]
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