Special Situations in the Treatment of MDR TB

Dr. Ashraf AbdulhaseebChest Diseases Consultant

Chief of DR-TB center, Abbassia Chest Hospital

MDR-TB and children • When DST is available, it should be used to guide

therapy.

• Every effort should be made to confirm DR-TB bacteriologically by DST and to avoid exposing children unnecessarily to toxic drugs.

• Culture negative children with clinical evidence and history of contact to confirmed DR-TB index case should be guided by the DST results and treatment history of the index case.

MDR-TB and children • DR-TB is life-threatening, and no anti-tuberculosis drugs are

absolutely contraindicated in children.

• Benefit of Fluoroquinolone in treating DR-TB in children outweighs any risk.

• Anti-tuberculosis drugs should be dosed according to body weight.

• All drugs, except Ethambutol, should be dosed at the higher end of the recommended ranges whenever possible.

• In children, weight loss or, more commonly, failure to gain weight adequately, maybe one of the first (or only) signs of treatment failure

Pediatric dosing of second-line anti-tuberculosis drugs

Swanson DS, Starke JR. Drug resistant tuberculosis in pediatrics. Pediatric Clinics of North America, 1995, 42(3):553–581Siberry GK, Iannone R, eds. The Harriet Lane handbook, 15th ed. Baltimore, Mosby, 2000.

Cultures in children• Older children (older than 5 years) can

sometimes produce sputum by induction with hypertonic nebulized saline and careful coaching.

• For very young children with pulmonary TB, aspiration of gastric contents, first thing in the morning, worth trial, but +ve culture yield is 50%.

• Bronchoalveolar lavage (BAL) specimens have a slightly lower yield than gastric aspirate specimens.

Drug Administration in children• Very few anti-tuberculosis drugs are available in liquid

preparations or in chewable tablets appropriate for pediatric dosing.

• Fluoroquinolone are available in suspension form.

• Approximate doses of medications are adequate.

• Cut tablets into approximate fragments. Crush fragments for smaller children.

Drug Administration in children• If the child’s dose is 100 mg and the drug comes as a 250 mg

tablet, 2 tablets will supply 5 doses. Any small discrepancy in dosing will even out over time.

• Shake capsules open and approximate fractions for serial doses.

• Mix crushed tablets or capsule contents into a small amount of vehicle.

• Immediately after the medication is given, give good drink to clear the palate.

• Give lots of praise and incentives.

MDR-TB in pregnancy• All female patients of childbearing age should be tested for

pregnancy upon initial evaluation

• Birth control is strongly recommended for all non-pregnant women receiving therapy for DR-TB

• Pregnancy is not a contraindication for treatment of active DR-TB

• Pregnant patients should be carefully evaluated, taking into consideration gestational age and severity of the DR-TB

MDR-TB in pregnancy• Start treatment of drug resistance in second trimester or sooner

if condition of patient is severe.

• When therapy is started, three or four oral drugs with demonstrated efficacy against the infecting strain should be used.

• • Reinforcement with an injectable agent and possibly other drugs

immediately postpartum.

• Avoid injectable agents during pregnancy; can be particularly toxic to the developing fetal ear

MDR-TB in pregnancy• Capreomycin may although carry a risk of ototoxicity but is the

injectable drug of choice if an injectable agent cannot be avoided

• Avoid Ethionamide if possible; Ethionamide can increase the risk of nausea and vomiting of pregnancy, and teratogenic effects have been observed in animal studies.

• One series reported 200 women exposed to Fluoroquinolone in the first trimester and none of the babies suffered musculoskeletal abnormalities.

• (WHO) and (IUATLD) do recommend routine use of Pyrazinamide during pregnancy

MDR-TB in pregnancy• Isoniazid, Rifampicin, and Ethambutol have not been associated with

teratogenic effects.

• Rifabutin, Cycloserine, and PAS have not been extensively studied, but animal models and human reports have not shown toxicity.

• Clofazimine; Use with caution when essential; drug appears to be safe during pregnancy when used at lower doses for leprosy, but experience is limited

• Clarithromycin; Avoid use if possible. May be teratogenic

• Amoxicillin/Clavulanate; Experience in gravid patients suggests safety

MDR-TB & the newborn & breast feeding

• Management of the infant born to a mother with TB disease includes 2 major issues:

1. Is the baby already infected with TB (congenital TB)?

2. How can we prevent the baby from becoming infected with TB?

Congenital TB• Fortunately, exceedingly rare.• Congenital TB is usually diagnosed in the first weeks to

months of life.• findings include: Fever– irritability– Poor feeding– Skin lesions– Liver and/or spleen enlargement– enlarged lymph nodes– Cough or increased work of breathing– Various chest radiographic abnormalities

Diagnosis • gastric aspirate collection.• Lumbar puncture for cell count, protein, glucose, bacterial and

acid-fast bacilli (AFB) smear and culture should be performed.• Culture of blood, skin lesions, and ear discharge are also

sometimes helpful.• Granulomata in the placenta increases the likelihood that the

baby is infected.

Evaluation of the newborn for neonatal sepsis and other congenital infections should also be considered, given the rarity of congenital TB.

Treatment

• Treatment should be based on the mother’s TB isolate susceptibility pattern in consultation with a pediatric TB expert.

Prevention of Infection in the Newborn

• If the mother is still infectious with DR-TB, mother and baby should be separated until the mother is not infectious.

• it is recommended to provide infant formula options as an alternative to breastfeeding.

• Care of the infant should be left to family members until she becomes sputum smear-negative, if feasible.

• A surgical mask or an N-95 respirator can be used until mother becomes sputum smear-negative.

Breast feeding• Most TB drugs are secreted in breast milk at low concentrations.

• The doses of TB drugs that babies receive via breast milk are insufficient to treat or prevent TB in the infant.

• Effects on infants of such exposure during the full course of DR-TB treatment have not been established.

• Mothers receiving INH, Cycloserine and Ethionamide, their breastfed infants should be supplemented with vitamin B6 (pyridoxine).

• The risk of Fluoroquinolone should discussed with the family

Contraception & DR-TB• There is no contraindication to the use of oral

contraceptives with the non-Rifampicin containing regimens.

• vomit directly after taking an oral contraceptive can be at risk of decreased efficacy.

• A barrier method of contraception can be used until a full month of the contraceptive tablets can be tolerated.

Contraception and DR-TB, cont.

• With rifampicin, oral contraceptive pill containing a higher dose of estrogen (50 μg) or another form of contraception is recommended.

Diabetes mellitus• Diabetic patients with MDR-TB are at risk for poor outcomes if not well

controlled.

• DM may potentiate the adverse effects of anti-tuberculosis drugs, especially renal dysfunction and peripheral neuropathy.

• Oral hypoglycemic may require the patient to increase the dosage.

• ethionamide or protionamide may make it more difficult to control insulin levels.

• Creatinine and potassium levels should be monitored more frequently, often weekly for the first month and then at least monthly thereafter.

Renal insufficiency

• Dose and/or the interval between dosing should be adjusted according creatinine clearance

• The formula to calculate the creatinine clearance (CrCl) or the glomerular filtration rate (GFR) is:

General considerations

• The medications should be given after hemodialysis on the day of hemodialysis (this also allows for the easy administration of DOT three times per week).

• Monitoring of serum drug concentrations should be considered to ensure adequate drug absorption, without excessive accumulation,

• Caution should be used with the injectable agents in patients with renal function impairment because of the increased risk of both ototoxicity and nephrotoxicity.

• Cycloserine 250 mg daily doses has not been established, careful monitoring for evidence of neurotoxicity, measure serum concentrations and adjust accordingly.

• Sodium salt formulations of PAS may result in an excessive sodium load and should be avoided in patients with renal insufficiency.

General considerations

Specific TB DrugsEthambutol• Up to 80% cleared by the kidney• Incompletely dialyzed, there may be an increased risk of accumulation

& eye toxicity.• Drug levels may be helpful in cases where EMB is important for the

regimen• Little data are available regarding anti-tuberculosis drug dosing for

patients on continuous ambulatory peritoneal dialysis (CAPD); however, a dose of 15 mg/kg/dose every 48 hours has been used successfully

• Peak serum concentrations (2 to 3 hours post-dose) generally should be maintained within the normal range of 2 to 6 mcg/ml

• The initial dose of EMB should be based on ideal body weight rather than total body weight if the patient is above ideal body weight

• Monitor carefully for red-green color discrimination and visual changes

Specific TB Drugs

• There may be some accumulation of drug and this might increase the risk of ototoxicity.

• These patients should be monitored closely for ototoxicity (both hearing loss and vestibular dysfunction).

• Serum drug concentrations can be used to verify that adequate peak concentrations are achieved (for efficacy).

Levofloxacin• Cleared more extensively by the kidney than is

Moxifloxacin.

• A dose of 750 to 1000 mg/dose 3 times weekly (not daily) is recommended for treatment of TB.

• Drug concentration monitoring might be beneficial and general toxicity monitoring is imperative.

Specific TB Drugs

Moxifloxacin• In one small study, Moxifloxacin clearance was unaltered in the

presence of renal insufficiency following single oral doses.

• Another recent study found that Moxifloxacin pharmacokinetics in critically ill patients who had acute renal failure and were undergoing dialysis were similar to those in healthy subjects without renal impairment.

• Therefore, Moxifloxacin dosage should not be altered in patients with renal disease.

Specific TB Drugs

Para-aminosalicylate (PAS)• Metabolized in the gastrointestinal (GI) tract and liver, but its

inactive metabolite acetyl-PAS is eliminated renally. • No specific toxicity of the metabolite is known. • The manufacturer does not recommend its use in end-stage renal

failure. • However, in a well-performed study, clearance of the metabolite

(and PAS) by dialysis was documented.• In several case reports, PAS was used after dialysis.• The American Thoracic Society (ATS) recommends using the usual

daily dose and dosing after dialysis. • There are few data regarding use of PAS in patients with renal

failure not yet on dialysis, but no clear evidence of toxicity.

Specific TB Drugs

Liver disordersRifampicin Less likely to cause hepatocellular

damage; causes cholestasis.

Pyrazinamide The most hepatotoxic first line drug, less frequent than INH but episode is severe and prolonged.

Isoniazid The most likely to cause hepatitis first line drug.

Ethionamide, Protionamide and PAS

Can also be hepatotoxic but less than any of the first line drugs.

Fluoroquinolones Rarely hepatotoxic.

• Patients with past history of liver disease can receive the usual anti-TB treatment, with close observation of liver enzymes.

• Patients with chronic liver disease should not receive Pyrazinamide.

• Other drugs can be used, but close monitoring of liver enzymes is advised.

• Patient with TB may have concurrent acute hepatitis that (not drug induced), postpone treatment until resolved but if necessary use combination of four non-hepatotoxic drugs. (levofloxacin, EMB, an aminoglycoside, and Cycloserine), if appropriate.

Liver disorders, cont.

Drug-Resistant Central Nervous System TB

• Several reports detail poor outcomes of DR-TB meningitis.

• Most of the patients were HIV-infected and developed meningitis while already on treatment.

• Mortality in 2 series from South Africa, 1 in adults and 1 in children, ranged from 57% to 88%.

• Isoniazid (INH) is the most important drug in the treatment of TB meningitis.

TB Drugs and their CNS PenetrationINH diffuses into CSF, independent of meningeal

inflammation due to its small sizeand lipophilic nature

Rifampin, rifabutin, Ethambutol, Para-aminosalicylate, Aminoglycosides

penetrate poorly into the CSF with non-inflamed meninges

Pyrazinamide crosses freely into the CSF

Ethionamide, Cycloserine have good CNS penetration, one study showed, 20 mg/kg/day should be used in order to achieve useful levels in the CSF

Fluoroquinolones Have variable CSF penetration.Levofloxacin levels in the CSF are about 15% to 30% that of serum Moxifloxacin has shown good CSF penetration in several animal studies

Seizure disorders • Patient my have previous or current medical history of a seizure

disorder.

• Evaluate whether seizure disorder is under control.

• If not initiation or adjustment of anti-seizure medication will be needed before the start of DR-TB therapy.

• Cycloserine, if crucial, can be given and the anti-seizure medication adjusted as needed to control the seizure disorder.

• In mono & poly-resistance, Isoniazid and Rifampicin may interfere with many of the anti-seizure medications.

Psychiatric disorders• Should be evaluated by psychiatric or trained health worker

before starting treatment.

• Any psychiatric illness identified at the start of or during treatment should be fully addressed.

• Treatment with psychiatric medication, individual counseling and/or group therapy may be necessary to manage the patient

• The use of Cycloserine is not absolutely contraindicated for the psychiatric patient.

• Close monitoring is recommended

Childhood DR-TB, case presentation

• Female child, 7 years old• Received Cat I in October, 2007 and failed. • DST was done and she proved to be resistant

to the 4 drugs• She was contact to her father who proved to

be an MDR-TB case also.• She was admitted to hospital and her father

and started Cat IV treatment in January 2009.

• She received Km, Ofx, Cs, Eto, and PAS• She converted Sputum in the first month• She developed peripheral neuritis and gastritis

as adverse effects. • She is cured now.

Childhood MDR-TB Case presentation

At the end of treatmentInitial x-ray