Management of drug toxicity in MDR/XDR-TB treatment

HS Schaaf

Desmond Tutu TB CentreDepartment of Paediatrics and Child Health

Stellenbosch University

Introduction

• Second-line drugs in general are more toxic than first-line drugs

• HCWs should know the common adverse effects of drugs used, need to warn patients and screen regularly

• With many drugs given inMDR/XDR-TB regimens, often administered with other drugs, such as ARVs, it could be difficult to determine the culprit drug

Introduction• Assessing adverse effects (AEs) in children is more

difficult in children than in adults

• Overall, AEs are less frequent than in adults

• Baseline assessment for some AEs is important, as problems may exist before start of treatment (e.g. hearing assessment, thyroid function tests)

• Limit AEs by prescribing and dispensing the correct dosage of each drug

• Not all AEs are serious and few require considering stopping or changing of drugs

• Some AEs are common and occur with many drugs (e.g. skin rashes, nausea and vomiting)

Absence of child-friendly drugs and dosages

Overdosing or underdosing can easily occur

Under- or overdosing may also occur becauseof lack of paediatricpharmacokinetic data onsecond-line anti-TB drugs

WHO MDR-TB drug grs Recommended doses

Gr. A Fluoroquinolones

Levofloxacin

Moxifloxacin

15-20 mg/kg (higher?)

10 mg/kg (PK studies)

Gr. B 2nd-line Inject

Km/Am/Cm

15-20 mg/g

Gr. C: Other core

2nd-line drugs

Ethionamide /Pto

Cycloserine / Tzd

Linezolid

Clofazimine

15-20 mg/kg

15-20 mg/kg

<10 yrs: 10mg/kg bd

>10 yrs: 300-600mg/day

2-5 mg/kg; max 100mg

(alternate day dosing?)

MDR-TB drug groups Recommended dose

Group D: Add-ons D1:

Pyrazinamide

Ethambutol

High-dose INH

D2: Bedaquiline

Delamanid

D3: PAS

Amox/Clav used with

imipenem /meropenem)

30-40 mg/kg

20-25 mg/kg

15-20 mg/kg (400mg)

>12 yrs >33kg as in adults

>6yrs/>20kg - 50mg bd

>12yrs/>35kg - 100mg bd

150-200 mg/kg/day

25-30mg/kg tds

Alphabetical Toxicity list – which drug causes what?

• Arthralgia/arthritis: FQNs/PZA/RFB

• Blood dyscrasias: INH/RIF/PZA/LZD/FQNs/PAS and more

• Central nervous system toxicity: headache, drowsiness, seizures, weakness, insomnia, hallucinations: FQNs

• Depression/Psychosis: INH/ETO/TZD

• Endocrine effects – hypothyroidism: PAS/ETOgynaecomastia: ETO/INH

• Flu-like syndrome: RIF/RFB/PAS

• GIT disturbances – nausea, vomiting, abdominal pain, diarrhoea: Many! ETO/PAS/FQNs/CFZ/LZD/BDQ

Expert Opinion Drug Safety 2016 – Schaaf et al

Alphabetical Toxicity List – which drug does what?

• Hearing impair/ototoxicity: AM/KM/CM Hair loss (alopecia): INH/ETO

• Idiopathic intracranial pressure: FQNs

• Jaundice/hepatotoxicity: PZA/INH/RIF/ETO/PAS/MFX

• K+ decrease: Electrolyte disturbance : CM/PAS

• Lactic acidosis: LZD

• Myelosuppression: LZD

• Nephrotoxicity: AM/KM/CM/SM

• Optic neuritis/vision disturbance/colour blindness: EMB/LZD/INH/ETO/PAS

Expert Opinion Drug Safety 2016 – Schaaf et al

Alphabetical Toxicity list – which drug causes what?

• Peripheral neuropathy: INH/ETO/LZD/TZD Pancreatitis: LZD

• QTc interval prolongation: FQN/CFZ/CLA/BDQ/DLM

• Rashes: PZA/FQNs/TZD/PAS and many other

• Skin discolouration – red skin: CFZ

• Tendinitis/tendonopathy: FQNs

• Uveitis: RFB

• Vestibular toxicity: AM/KM/CM/SM

Expert Opinion Drug Safety 2016 – Schaaf et al

Group A - Fluoroquinolones

• MANY AEs, but far less common than originally anticipated! (and mostly non-severe AEs)

• Arthralgia/arthritis – biggest concern, but very rare(tendon rupture almost exclusively in adults)

• NO LONG-TERM EFFECTS AFTER 5 YEARS IN 1340 CHILDREN ON LEVOFLOXACIN (Bradley et al. Pediatrics 2014)

• GIT adverse effects: Most common AE. Nausea and vomiting (commonest – 5-10%), abdominal discomfort/pain/dyspepsia (<3%), anorexia and diarrhoea (<3%).

Group A - Fluoroquinolones

• CNS/Neurological AEs have been described – Insomnia (sleeplessness)

– Hallucinations (overdose)

– Headache, dizziness, drowsiness

– Agitation, anxiety, restlessness, nervousness, tremors

• QTc-interval prolongation– Not yet reported in children

in some small studies available.

– Mainly moxifloxacin. Most likely not necessary to screen or monitor with ECGs routinely

Group A - Fluoroquinolones

• Dermatological (<0,5%)

– Rash, erythema, pruritis, urticaria, angioedema, anaphylactic reactions, vasculitis (rare)

– Stevens-Johnson syndrome, Toxic epidermal necrolysis

– Photosensitivity (rare)

• Ophthalmological

– Ocular irritation/discomfort, tearing, pruritus, keratitis, conjunctival hyperaemia, decreased visual acuity, dry eye and ocular pain – very rare

– Idiopathic Intracranial Pressure (withpapiloedema)

Group A - Fluoroquinolones

• What to do?Assessment of these adverse effects may be difficult in children

• Arthralgia/arthritis and other serious AEs – withdraw the fluoroquinolone and opt for alternative drug if available

• Non-serious AEs – can evaluate response to lowered dose, but often not necessary to change dose, as AEs may clear with time (insomnia, nausea, etc)

Group B – 2nd-line injectables• All have similar AEs (Km, Am, Cm)

• Nephrotoxicity and electrolyte disturbances (decrease in potassium levels) are uncommon in children, but creatinine and K+ levels should be checked regularly

• Ototoxicity: Hearing loss common – Up to 50% in adults and 25% in children

– Sensorineural hearing loss: may continue after stopping the drug (up to 6 months)

– High frequency hearing loss most common

– Can be acute with severe hearing loss

– Some genetic markers, but these are uncommon

– Vestibular (balance/tinnitus) not well studied in children

Ototoxicity (cont.)• How to assess

- Pure tone audiometry (mainly older children)- Otoacoustic Emission (OAE) (ensure it can test high frequencies)

• Assess middle ear via tympanometry and/or otoscopy(conductive hearing loss)- Interpret OAE/pure tone in light of these results.

• Routinely screen for hearing abnormality- Cannot rely on subjective report of hearing loss- Baseline, then monthly- If abnormal then more frequent

Case

• 3-yr-old girl with confirmed MDR-TB and extensive pulmonary infiltrates.

• On treatment hd-INH, PZA, ETO, TZD, LFX, EMB and AM (injectable) – now month 3 and 2nd culture at month 1 still positive

• Otoacoustic Emission (OAE) demonstrates high-frequency HL at 6000-8000 Hz bilaterally. Baseline OAE was normal.

• No other AEs of importance found

• How are you going to manage this case?

How are you going to manage this case?(for participants to answer)

1) Tell the mother child is better off deaf than dead

2) See if there is an alternative drug available to exchange with amikacin, e.g. PAS or linezolid

3) Stop amikacin injections irrespective of culture results or improvement of child’s TB

4) Continue amikacin injections irrespective of culture results or improvement of child’s TB

5) You should not have started the child on amikacin in the first place

Case - discussion• Better deaf than dead? Not ideal either way!

• Look at clinical progress of the child, did the CXR improve markedly? Any negative culture results now at month 2?

• Are there any other “good” anti-TB drugs available, e.g. PAS or linezolid – soon to consider new drugs also?

• Are 2nd-line DSTs available – not FQN resistant or already 2nd-line injectable resistance?

• Re-evaluate hearing in 2 weeks – same or worse?

• Consider stopping injectable drug if: good improvement and another drug available and no 2nd-line DST resistance. Do not add a single drug to a failing regimen. Individualise EACH CASE

Group C – Other core drugs

• Ethionamide/prothionamide

– GIT disturbances – metallic taste, nausea, vomitingVomiting: May need to split dose or start with lower dose, but vomiting usually stops within 1-2 weeks

– Hepatotoxicity (uncommon)

– Very rare: convulsions, peripheral neuropathy –pyridoxine responsive. We give pyridoxine (Vit B6) to all MDR-TB patients

– Gynaecomastia may occur – stop ethionamide

– Diabetes may be difficult to control when starting ethionamide

Group C – Other core drugs

• Ethionamide/prothionamide (cont.)– Hypothyroidism – do routine thyroid function tests

(TSH & fT4) baseline & 2-monthly

– Symptomatic hypothyroidism uncommon

– Interpret with caution in first 1-2 months of treatment – the TB itself or HIV may affect TFTs

– If primary hypothyroidism (elevated TSH, low fT4), supplement with levothyroxine

– Hypothyroidism reversible - stop levothyroxine once ETH/PAS stopped

Group C – Oral core drugs

• Cycloserine/Terizidone

– Neuropsychiatric AEs: Dose-relatedanxiety, confusion, depression, psychosis also other like convulsions

– Pyridoxine supplementation should be prescribed

– Neurological AEs rare in children

– Reduce the dose or stop the drug if CNS AEs occur

– (we find most depression in children related to chronic illness and social situation rather than the drugs – anti-depressive treatment often helps)

Group C – Other core drugs

• Clofazimine: (Dosing difficult in small children)

– Skin pigmentation Red to reddish-brown (dark) pigmentation of the skin, conjunctiva & cornea

– GIT: diarrhoea, nausea, vomiting, abdominal pain

– Skin: Ichthyosis, a skin disorder with thickened, dry, scaly skin which can be quite distressing to patients

– QT prolongation - possible

Clofazimine – Skin colour months apart

Group C – Oral core drugs

• Linezolid (very effective drug in pre-XDR/XDR-TB)

– Myelosuppression (anaemia, leucocytosis, thrombcytopenia) – lower the dose or stop; may need blood transfusion

– Peripheral neuropathy – it is reversible (lower dose)

– Optic neuritis (vision loss)

– Pancreatitis

– Lactic acidosis

– All of the above rare at currently recommended lower dosages in children (10mg/kg twice daily <10 yrs of age and 300mg/day 10-13 yrs of age)

Group D1 – Add-on drugs

• High-dose INH: (15-20mg/kg max dose 400mg)

– May still have effect in low-level INH resistance

– Hepatotoxicity: most serious AE – stop all hepatotoxic drugs (can be reintroduced)

– Dose-related neurotoxicity, such as peripheral neuropathy, seizures, psychosis, ataxia and optic neuritis is rare in children - can be prevented by adding pyridoxine to the regimen

– Very rare haematological AEs, also responsive to pyridoxine, are sideroblastic anaemia, haemolytic anaemia, thrombocytopenia and aplastic anaemia

– Skin rashes are common; in adolescents acneiformerruptions are common; Hair loss possible

Ethambutol and pyrazinamide often used in MDR-TB Rx

• Ethambutol

– Optic neuritis: Uncommon to very rare as long as remain within acceptable dose/kg, as is drug dose related

– Vision acuity and colour vision (reversible if stopped early)

– Use with caution in patients with renal impairment

Group D1 – Add-on drugs

Group D1 – Add-on drugs

• Pyrazinamide

– Hepatotoxicity: First signs are new onset vomiting and abdominal tenderness. Jaundice late sign. STOP ALL HEPATOTOXIC DRUGS. Can try to reintroduce once liver enzymes normalized

– Arthralgia may occur due to hyperuricaemia – very rarein children but may be more if used with FQNs

– Skin rashes, flushing and pruritis may occur

– Photosensitivity, thrombocytopenia and anaemia very rare

Cutaneous adverse drug reactions (CADR)• Most common: pruritus, maculopapular exanthema, erythema

multiforme and urticaria

• Less common, still moderate; exfoliative dermatitis, leukocytoclastic vasculitis, lichenoid and fixed drug eruption

• Life threatening severe CADRs (uncommon): involvement of large body surface area and mucous membranes, with blisters and erosions on the skin, increased risk of sepsis, hypovolemia and hypoproteinemia. Includes generalized pustulardermatoses, bullous skin reactions, drug reaction with eosinophila and systemic symptoms (DRESS syndrome), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and acute generalised exanthematous pustulosis (AGEP).

• Almost all anti-TB drugs can cause severe drug reactions. Pyrazinamide most common offending drug?

Case 2

• A 4-yr-old boy on pre-XDR-TB treatment presents with new onset vomiting after 2 months of treatment. Treatment is hd-INH, PZA, EMB, ETO, TZD, LFX, CM & PAS – also on pyridoxine. He is HIV-negative. Although he vomited a few times when he started treatment, this had stopped after one week on treatment. On examination he has no skin rash, no neck stiffness, no diarrhoea, but looks slightly jaundiced with a palpable liver edge

• Diagnosis? How would you manage this child?

How would you manage this child?(Participants to answer)

1) Stop all hepatotoxic drugs immediately

2) Do screening for viral hepatitis

3) Do liver enzyme levels and total/conjugated BR

4) Do abdominal ultrasound if conjugated hyperbilirubinaemia

5) Reintroduce essential drugs one by one once liver enzymes have normalised

6) None of the above

7) All of the above

Case 2 - Discussion

• Hepatitis/Hepatotoxicity

• Signs of hepatotoxicity: new onset vomiting, abdominal pain, jaundice (late)

• Stop all liver-toxic drugs (INH, PZA, ETH, PAS)

• Do liver function tests incl. ALT, AST, total and conjBR. Do abdominal ultrasound if obstructive jaundice suspected (nodal compression)

• Screen for Hepatitis A, C and others as indicated

• Wait until liver enzymes normalise – restart essential drugs one by one checking ALT mainly

Group D2 – New oral drugs

• Delamanid (OPC67683)- Available for compassionate use in children from 6 years/>20kg- dose-finding/safety studies in children ongoing- In adults very safe – minor QTc interval prolongation noted; possible hepatotoxicity (one case)

• Bedaquiline (TMC207)- PK and safety studies starting in children- Adults: increased nausea compared to background MDR-TB treatment & QT-prolongation

• Be aware of other drugs with QT prolongation effect – ECG monitoring/limit other QT prolonging drugs

Group D3 – Other oral drugs

PAS

• GIT disturbances

– Anorexia, diarrhoea, nausea

• Hypothyroidism

– increased risk with ethionamide and in HIV-infected children

• Hepatotoxicity

Group D3

• Amoxicillin/Clavulanate:– Gastrointestinal disturbances; diarrhoea– Skin rashes – Hypersensitivity reactions (both amoxicillin and

clavulanate). Severe hypersensitivity reactions or anaphylaxis should lead to discontinuation of the drug

– Hepatotoxicity – rare

• Carbapenems (Imipenem/Meropenem)– Gastrointestinal: diarrhea, nausea/vomiting– Rash, which are mostly mild – Hypersensitivity (anaphylactic) reactions that may be

severe– Imipenem has been associated with seizures

EXPERT OPINION ON DRUG SAFETY 2016;15:1369-1381

Toxicity and Adherence

• Treatment in hospital and in community needs to be observed – children are ingenious when it comes to making plans how NOT to take their treatment!

• Poor palatability of meds may contribute to adherence problems in some cases

• Adverse effects may also affect adherence – children quickly recognize the culprit drug for nausea and vomiting (and even diarrhoea)!

• Painful injections

• Ask children/caregivers to identify the tablets or capsules and how many of each are taken – can check on dosage and whether omitting some

Thank you!

• Acknowledgement: NRF for financial support