Drug Resistance Tuberculosis
Drug Resistance Tuberculosis
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- No visible clinical improvement inspite of regular and adequate chemotherapy for t=3 months.
- Presence of multiple or giant cavities
- Serial X-ray showing detoriation or no improvement after 3 months of therapy
- Sputum is positive by direct smear even after 5 months of adequate therapy
- Culture and sensitivity test of bacilli by slide culture, use of egg enriched sheep blood media (EESBM). Bactac system of radiometric detection of mycobacterial growth. Luciferace reporter Myco-bacteriophage test (LRM test)
Recommended Dose
The recommended dose of bedaquiline for the treatment of pulmonary MDR in adults is:
- Weeks 1 – 2: 400 mg (4 tablets of 100 mg) given orally, once daily
- Weeks 3 – 24: 200 mg (2 tablets of 100 mg) three times per week, for a total dose of 600 mg per week
Initiation and Discontinuation
Bedaquiline is to be used for a period of 24 weeks.
- Bedaquiline may be used on a case-by-case basis for durations longer than 24 weeks when treatment options are limited.
This drug has a half-life of 4-5 months. Consider discontinuing bedaquiline 4–5 months prior to discontinuing other drugs in the treatment regimen to reduce or avoid an extended period of exposure to low levels of bedaquiline as a single drug and subsequent acquired resistance.
Administration
All doses should be used in combination with at least three other anti-TB drugs to which the patient’s MDR TB isolate has been shown to be susceptible through laboratory testing.
Each dose should only be given by directly observed therapy (DOT) and with case management strategies to ensure treatment adherence. Each dose should be taken with food to maximize drug absorption.
Missed Doses
Adverse Reactions
To date, adverse drug reactions associated with bedaquiline include:
- Nausea / Vomiting
- Dizziness
- Headache
- Hemoptysis
- Increased blood amylase
- Increased serum transaminases
- Rash
- Arthralgia (joint pain) / Myalgia (muscle pain)
- Chest pain
- Anorexia, fatigue, dark or cola-colored urine, jaundice
Patient Counseling
Patients should be advised:
- To eat food before taking bedaquiline
- To abstain from alcohol and other hepatotoxic drugs
- To report any signs and symptoms of adverse drug reactions to their health care provider
- Of the potential benefits and harms of bedaquiline
- That treatment non-adherence could result in treatment failure, relapse, or acquired drug resistance
Drug Interactions
Bedaquiline is metabolized through the cytochrome P450 (CYP) system. Co-administration with rifamycins (e.g., rifampin, rifapentine, and rifabutin) or other strong CYP3A4 inducers should be avoided. Among the limited studies to date, no significant pharmacokinetic interactions have been observed between bedaquiline and the anti-TB drugs isoniazid, pyrazinamide, ethambutol, kanamycin, ofloxacin, or cycloserine.
Patient Monitoring
Monitoring for Cardiac Toxicity
Bedaquiline can affect the heart’s electrical activity, which could lead to an abnormal and potentially fatal heart rhythm. Patients should be monitored for symptoms of cardiac toxicity and by electrocardiogram (ECG).
- Serum potassium, calcium, and magnesium should be obtained at baseline and whenever clinically indicated, especially if QTcF prolongation is detected.
- ECG should be obtained at baseline and repeated at least 2, 12, and 24 weeks after treatment is started.
- Weekly ECGs are recommended for persons prescribed bedaquiline and (1) other QTcF prolonging drugs including fluorquinolones, macrolide antibacterial drugs, and clofazimine; (2) have a history of Torsade de Pointes, congenital long QTcF syndrome, hypothyroidism and bradyarrhythmias, or uncompensated heart failure; or (3) have serum calcium, magnesium, or potassium levels below the lower limits of normal.
- If syncope occurs, obtain an ECG to evaluate for QTcF prolongation.
Monitoring for Hepatotoxicity
Monitoring for Renal Toxicity
Therapeutic Drug Monitoring
Microbiologic Monitoring
Monitoring for Additional Side Effects
Bedaquiline may cause serious or life-threatening changes in your heart rhythm. You will need to have an electrocardiogram (ECG; a test that measures the electrical activity of the heart) before your treatment and several times during your treatment to see how this medication affects your heart rhythm. Tell your doctor if you or anyone in your family has prolonged QT syndrome (a rare heart problem that may cause irregular heartbeat, fainting, or sudden death) and if you have or have ever had a slow or irregular heartbeat, an underactive thyroid gland, low levels of calcium, magnesium, or potassium in your blood, heart failure, or a recent heart attack. Tell your doctor and pharmacist if you are taking any of the following medications: azithromycin (Zithromax), ciprofloxacin (Cipro), clarithromycin (Biaxin), clofazimine (Lamprene), erythromycin (E.E.S, E-Mycin, Erythrocin), gemifloxacin (Factive), levofloxacin (Levaquin), moxifloxacin (Avelox), and telithromycin (Ketek). If you develop a fast or irregular heartbeat or if you faint, call your doctor immediately.
Your doctor or pharmacist will give you the manufacturer's patient information sheet (Medication Guide) when you begin treatment with bedaquiline and each time you refill your prescription. Read the information carefully and ask your doctor or pharmacist if you have any questions. You can also visit the Food and Drug Administration (FDA) website
Talk to your doctor about the risks of taking bedaquiline.
If you or your child are unable to swallow the 20 mg tablet whole, you may break them in half on the score mark.
If you or your child are unable to swallow the 20 mg tablets whole or in half, the tablets can be dissolved in 1 teaspoon (5 mL) of water in a drinking cup (no more than 5 tablets). You can drink this mixture immediately or to make taking it easier, add at least 1 teaspoon (5 mL) of additional water, milk product, apple juice, orange juice, cranberry juice, or a carbonated beverage, or alternatively, a soft food may be added. Then, swallow the entire mixture immediately. After taking the dose, rinse the cup with a small amount of additional liquid or soft food and take it immediately to be sure that you receive the entire dose. If you need more than five 20 mg-tablets of bedaquiline, repeat the steps above until you reach your prescribed dose.
Alternatively, to make it easier to swallow, you can also crush the 20 mg tablets and add to a soft food such as yogurt, applesauce, mashed banana, or oatmeal and swallow the entire mixture immediately. After taking the dose, add a small amount of additional soft food and take it immediately to be sure that you receive the entire dose.
If you have a nasogastric (NG) tube, your doctor or pharmacist will explain how to prepare bedaquiline to give through an NG tube.
Continue to take bedaquiline until you finish the prescription and do not miss doses, even if you feel better. If you stop taking bedaquiline too soon or skip doses, your infection may not be completely treated and the bacteria may become resistant to antibiotics. This will make your infection harder to treat in the future. To make it easier for you to take all of your medication as directed, you may participate in a directly observed therapy program. In this program, a healthcare worker will give you each dose of medication and will watch as you swallow the medication.
- Peripheral neuropathy
- Spontaneous tendon rupture and tendonitis.
- Hepatitis
- Psychiatric effects (hallucinations, depression),
- Torsades de pointes
- Stevens=Johnson syndrome
- Clostridium difficile associated disease, and
- photosensitivity/phototoxicity reactions.
- Several reports suggest the use of moxifloxacin may lead to Uveitis.
- Non Steroidal anti-inflammatory drugs (NSAIDs): Although not observed with moxifloxacin in preclinical and clinical trials, the concomitant administration of a nonsteroidal anti-inflammatory drug with a fluoroquinolone may increase the risks of CNS stimulation and convulsions."
- "Moxifloxacin is contraindicated in persons with a history of hypersensitivity to moxifloxacin, any member of the quinolone class of antimicrobial agents, or any of the product components. Moxifloxacin should be used with caution in patients with diabetes, as glucose regulation may be significantly altered.Moxifloxacin is also considered to be contraindicated within the pediatric population, pregnancy, nursing mothers, patients with a history of tendon disorder, patients with documented QT prolongation, and patients with epilepsy or other seizure disorders. Coadministration of moxifloxacin with other drugs that also prolong the QT interval or induce bradycardia (e.g., beta-blockers, amiodarone) should be avoided. Careful consideration should be given in the use of moxifloxacin in patients with cardiovascular disease, including those with conduction abnormalities.
The combination of corticosteroids and moxifloxacin has increased potential to result in tendonitis and disability.
Moxifloxacin is not believed to be associated with clinically significant drug interactions due to inhibition or stimulation of hepatic metabolism. Thus, it should not, for the most part, require special clinical or laboratory monitoring to ensure its safety. Moxifloxacin has a potential for a serious drug interaction with NSAIDs.
"In the event of acute overdose, the stomach should be emptied and adequate hydration maintained. ECG monitoring is recommended due to the possibility of QT interval prolongation. The patient should be carefully observed and given supportive treatment. The administration of activated charcoal as soon as possible after oral overdose may prevent excessive increase of systemic moxifloxacin exposure. About 3% and 9% of the dose of moxifloxacin, as well as about 2% and 4.5% of its glucuronide metabolite are removed by continuous ambulatory peritoneal dialysis and hemodialysis, respectively."
Like nearly all antibiotics, linezolid has been associated with Clostridium difficile-associated diarrhea (CDAD) and pseudomembranous colitis, although the latter is uncommon, occurring in about one in two thousand patients in clinical trials. C. difficile appears to be susceptible to linezolid in vitro, and linezolid was even considered as a possible treatment for CDAD.
Long-term use
Long-term use of linezolid has also been associated with chemotherapy -induced peripheral neuropathy, a progressive and enduring often irreversible tingling numbness, intense pain, and hypersensitivity to cold, beginning in the hands and feet and sometimes involving the arms and legs. Chemotherapy drugs associated with CIPN include thalidomide, the epothilones such as ixabepilone. the vinca alkaloids vincristine and vinblastine, the taxanes paclitaxel and docetaxel, the proteasome inhibitors such as bortezomib, and the platinum-based drugs cisplatin, oxaliplatin and carboplatin . and optic neuropathy , which is most common after several months of treatment and may also be irreversible. Although the mechanism of injury is still poorly understood, mitochondrial toxicity has been proposed as a cause; linezolid is toxic to mitochondria, probably because of the similarity between mitochondrial and bacterial ribosomes. Lactic acidosis, a potentially life-threatening buildup of Lactic acid in the body, may also occur due to mitochondrial toxicity. Because of these long-term effects, the manufacturer recommends weekly complete blood counts during linezolid therapy to monitor for possible bone marrow suppression, and recommends that treatment last no more than 28 days. A more extensive monitoring protocol for early detection of toxicity in seriously ill patients receiving linezolid has been developed and proposed by a team of researchers in Melbourne, Australia. The protocol includes twice-weekly blood tests and liver function tests measurement of serum lactate levels, for early detection of lactic acidosis; a review of all medications taken by the patient, interrupting the use of those that may interact with linezolid; and periodic eye and neurological exams in patients set to receive linezolid for longer than four weeks.
The adverse effects of long-term linezolid therapy were first identified during postmarketing surveillance. Bone marrow suppression was not identified during Phase III trials, in which treatment did not exceed 21 days. Although some participants of early trials did experience thrombocytopenia, it was found to be reversible and did not occur significantly more frequently than in controls (participants not taking linezolid). There have also been postmarketing reports of seizures , and, as of 2009, a single case each of Bell's palsy (paralysis of the facial nerve) and kidney toxicity. Evidence of protein synthesis inhibition in mammalian cells by linezolid has been published.
Linezolid is a weak, non-selective, reversible monoamine oxidase inhibitor (MAOI), and should not be used concomitantly with other MAOIs, large amounts of tyramine-rich foods (such as pork, aged cheeses, alcoholic beverages, or smoked and pickled foods), or serotonergic drugs. There have been postmarketing reports of serotonin syndrome when linezolid was given with or soon after the discontinuation of serotonergic drugs, particularly selective serotonin reuptake inhibitors (SSRIs) such as paroxetine and sertraline. It may also enhance the blood pressure-increasing effects of sympathomimetic drugs such as pseudoephedrine or phenylpropanolamine. It should also not be given in combination with pethidine (meperidine) under any circumstance due to the risk of serotonin syndrome..
Linezolid does not inhibit or induce the cytochrome P450 (CYP) system, which is responsible for the metabolism of many commonly used drugs, and therefore does not have any CYP-related interactions.
How and when to take steroid tablets
Take your medicine as instructed by your doctor. They'll explain how much to take and how often.
It's normally best to take steroid tablets with or soon after a meal – usually breakfast – because this can stop them irritating your stomach.
If you miss a dose or take too much
If you forget a dose, take it as soon as you remember. If it's almost time for your next dose, skip the one you missed.
Do not take a double dose to make up for a forgotten dose.
Accidentally taking too many steroid tablets is unlikely to be harmful if it's a one-off. Speak to your doctor or a pharmacist if you're worried.
Taking too many steroid tablets over a long period can make you more likely to get side effects.
Coming off treatment
Do not stop taking your medicine without talking to your doctor.
If you've been taking steroid tablets for more than a few days, you usually need to reduce your dose gradually. Stopping suddenly can cause your adrenal gland, which makes important hormones for the body, to stop working. This is known as adrenal insufficiency.
Symptoms of adrenal insufficiency include:
- feeling extremely tired
- feeling and being sick
- dizziness
- loss of appetite and weight loss
Your original symptoms may also come back suddenly.
Your doctor will be able to provide more advice about how to safely stop taking steroids.
Side effects of steroid tablets
Taking steroid tablets for less than 3 weeks is unlikely to cause any significant side effects. But you may get some side effects if you need to take them for longer or at a high dose.
Side effects of steroid tablets can include:
- indigestion or heart burn
- increased appetite, which could lead to weight gain
- difficulty sleeping
- changes in mood and behavior's, such as feeling irritable or anxious
- an increased risk of infections – especially chickenpox, and shingles measles
- high blood sugar or diabetes
- weakening of the bones (osteoporosis)
- high blood pressure
- Cushing's syndrome - which can cause symptoms such as thin skin that bruises easily, a build-up of fat on the neck and shoulders and a red, puffy, rounded face
- eye conditions, such as glaucoma and cataract
- mental health problems, such as depression or suicidal thoughts ; get an urgent GP appointment or call 111 if this happens
Most side effects will pass once treatment stops. Tell your doctor if they bother you.
- Miliary Tuberculosis
- Tubercular Pneumonia
- Widespread infiltration
- Pleural, pericardial or peritoneal effusion
- Acutely ill patient
- Segmental opacities in primary pulmonary tuberculosis of less than three months duration thereby significantly lowering incidence of bronchiectasis
- Suppression of hypersensitivity reactions of anti tubercular drugs.
- Tubercular meningitis
- Large lymph nodes involving or compressing trachea or bronchi.
- Cavitated lesion in lower lobe or well localized disease resistant to many drugs.
- Tuberculoma larger than 2 cm in diameter.
- Stenosis of bronchus with bronchiectasis.
- Selected case of non-tuberculous myco-bacterial infection.
- Rarely for localized mycetoma complicating previous tuberculosis
- Empyema.
- Cough
- Hemoptysis
- Laryngitis
- Children under 5 years of age because of risk of miliary disease and meningitis.
- Tuberculin positive children and adults up to 35 years of age (who have not have BCG) in close contact with infectious cases.
- Recent tuberculin converters
- Patients on long term corticosteroids or immunosuppressive drug therapy
- Heaf grade iii and iv positive cases.
- Either Isoniazid 5-10mg/kg (maximum 300mg) for 6 months or Rifampicin 10mg/kg and Isoniazid 5-10 mg/kg for 3 months is advised.
- In HIV positive patients with positive tuberculin test (who have not had BCG in past ) Isoniazid 5mg/kg (up 300mg) should be continued indefinitely.
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