DRUG RESISTANT TUBERCULOSIS

Harsha Lochan

Red Cross Children’s Hospital

22 August 2012

INTRODUCTION

WHO GLOBAL TUBERCULOSIS REPORT 2011

Estimated no of cases Estimated no of deaths

All forms of tuberculosis (TB) 8.7 million 1 million

HIV associated TB 1.1 million 430 000

MDR TB 630 000

MDR CASES

XDR CASES

SOUTH AFRICA IN 2011

• South Africa is among the high burden TB and MDR- TB countries worldwide

• 343 715 new cases were notified • 45 915 were notified as re-treatment • 10,085 MDR-TB patients were diagnosed (lab

confirmed) and 5643 MDR-TB initiated on treatment

• 1.8 % of new cases were MDR-TB • 6.7 % of retreatment cases were MDR-TB • 609 confirmed XDR-TB patients

www.who.int/tb/data

IN CHILDREN

• At least half a million children became ill with TB and an estimated 64 000 children died of TB in 2011 worldwide

• The extent of drug resistant tuberculosis in this population is not clearly defined

• In 2009, it was estimated that childhood TB represents 10-20% of the TB burden

• The risk for TB disease after infection is high in children <3 years of age and the HIV infected

• A prospective surveillance of children at Tygerberg Hospital 2007-2009

• 294 children with culture confirmed TB

• Drug-susceptibilty was available in 292

• 41 (14%) were INH resistant

• 26 (8.9%) had MDR TB

• 4 (1.4%) had Rifampicin mono-resistance

• 50% of MDR TB cases had Ethambutol resistance

Seddon, Hesseling, et al. Int J Tuberc Lung Dis. 2012

DEFINITIONS

• Monoresistant tuberculosis – resistance to either isoniazid or rifampicin

• Multidrug-resistant tuberculosis (MDR-TB) is caused by organisms that are resistant to isoniazid and rifampicin. MDR-TB results from either infection with organisms which are already drug-resistant or may develop in the course of a patient's treatment.

Extensively-drug resistant tuberculosis (XDR-TB)

is a form of TB caused by organisms that are resistant to isoniazid and rifampicin (i.e. MDR-TB) as well as any fluoroquinolone and any of the second–line anti-TB injectable drugs (amikacin, kanamycin or capreomycin).

TRANSMISSION OF RESISTANCE

• Children with drug-resistant TB usually have transmitted resistance – child is infected by an organism with established resistance.

• Paucibacillary disease – small organism loads

• Adolescents – can have adult-type disease

• Adults – drug resistance is result of transmission and acquisition –susceptible organisms developing resistance due to inadequate treatment

RESISTANT STRAINS

Rifampicin resistant strains

> 95% Rif resistance is due to mutations in the 81 bp core region of the rpoB gene

Isoniazid resistant strains

Most (70-80%) INH resistance due to mutations in the inhA promoter region or the katG gene

Presence of katG predicts high level resistance

Presence of InhA predicts low level resistance

InhA also predicts Ethionamide resistant (50-80%)

DIAGNOSIS

WHEN TO SUSPECT DRUG RESISTANT TUBERCULOSIS

• If a child on standard TB regime is not responding to treatment despite adequate adherence – deterioration in clinical condition, remaining sputum positive after 2 months

• A history of a close contact with confirmed drug resistant TB

• Retreatment patients are at higher risk

• Multidrug-resistant tuberculosis is under detected in children

• Diagnosis of drug resistance requires mycobacterial culture and drug susceptibility testing (DST)

• In children difficulty in obtaining respiratory (sputum or gastric aspirates) or extra pulmonary specimens

• Smear and culture of 2 induced sputa increases the diagnostic yield of pulmonary TB by 22%*

*Moore, Apolles. Int J Tuberc Lung 2011

Delays in diagnosis and initiation of appropriate treatment due to :

• Requirements for microbiological confirmation of drug resistance

• Insufficient recognition of the adult contact DST patterns

Delays • Progression of disease • risk of infectiousness in children • Greater risk of complications eg. TBM • Higher rates of morbidity and mortality

Ettehad, Schaaf, Sneddon, et al. Lancet 2012

TESTING FOR DRUG RESISTANT TUBERCULOSIS

Phenotypic testing Smear microscopy – can not detect

resistance

Culture of the organism is the gold standard

Does the organism grow in the presence of the antibiotic

Solid or liquid culture (MGIT)

Different concentrations of antibiotics – Rifampicin, Isoniazid, aminoglycosides, quinolones, ethambutol, ethionamide

Genotypic testing

Looks for mutations that confer resistance

Line probe assays

Gene Xpert – PCR

CULTURE-BASED METHODS

Conventional culture

• 3-4 weeks (up to 8 weeks)are required to identify drug-resistant organisms on solid media (Lowenstein-Jensen medium)

• Assess inhibition of M. tuberculosis growth in the presence of antibiotics to differentiate between susceptible and resistant strains

Liquid-based culture

• More sensitive than solid media

• Decreased turnaround time: 1-2 weeks (up to 6 weeks)

• Higher cost

• BACTEC 460 TB

• Mycobacteria Growth Indicator Tube (MGIT) system

LINE PROBE ASSAYS – MOLECULAR GENETIC TESTING

• Looks for mutations that confer resistance

• Works if the mutations are known

• Quicker, results are available in hours

• Can be processed on smear positive or smear negative specimens

• Results are best with smear positive or cultured specimens

• It allows the simultaneous detection of the Mycobacterium complex and relevant mutations in the rpoB gene associated with resistance to rifampicin and the important mutations in the katG and inhA genes associated with resistance to isoniazid.

AVAILABLE AND IN USE PRODUCTS

• MTBDRplus (Hain Life Sciences)

Detection of rifampicin and isoniazid resistance in M. tb

rpoB gene (Rifampicin) and either katG or inhA (Isoniazid)

• MTBDRsl (Hain Life Sciences)

Detects resistance to fluoroquinolones, injectable agents and ethambutol

It uses DNA strip technology

The Mycobacterial DNA is extracted from the specimen, specifically amplified via PCR and detected on a membrane strip using reverse hybridisation and enzymatic colour reaction

Line Probe assays detects

• > 98% Rif resistant strains

• 70 – 90% of INH resistant strains

katG mutution predicts high level INH resistance (80-92%)

inhA mutuation predicts low-level INH resistance (78-90%)

GENE XPERT (XPERT MTB/RIF(CEPHEID))

• Real time PCR

• Can detect M. tuberculosis DNA and rifampicin resistance

• Amplifies the portion of the rpoB gene most commonly linked to mutations in rifampicin resistance

• Rapid diagnosis within 2 hours

GENE XPERT

RESULTS OF GENEXPERT

• Sensitivity - 98% in patients with smear + TB

- 72% in patients with smear – TB

• Specificity – 99% in patients without TB

• Correctly identified 97% of patients with Rif-resistant isolates

and 98% of patients with Rif-susceptible isolates

Boheme, Nabeta, Hilleman. NEJM 2010

GENEXPERT MTB/RIF IN CHILDREN

• Xpert done on two induced sputum specimens detected approximately 75% of culture confirmed cases ( 38% with smear microscopy)

• The yield from two nasopharyngeal (NPA) specimens detected almost 70% of culture confirmed cases.

• Recently Xpert done on gastric lavage specimens reported a sensitivity of 69% for culture confirmed cases

Nicol, Workman, Isaacs, et al. Lancet InfectDis 2011

Zar, Workman, Isaacs, et al. Clin Infect Dis 2012 Bates, O’Grady, Maeurer, et al. Lancet Infect Dis 2012

• Rif susceptible on Xpert – INH mono-resistant strains may be missed

• Xpert Rif resistant – confirmed with LPA or with culture. 2nd line DST is carried out

• Xpert negative but culture positive – LPA for Rif and INH

TREATMENT

CHALLENGES IN CHILDREN

• MDR and XDR TB do not respond to the standard 6 months of therapy with first line drugs

• Treatment duration: 18-24 months

• 2nd line drugs are rarely available in paediatric formulations

• Dosing may be inadequate due to crushing or grinding of tablets

• Taste of medication for children

• Adverse events associated with the medication – diarrhoea and vomiting, hypothyroidism, sensori-neural hearing loss

• Pill burden

• Most children will require inpatient care (especially while receiving injectables) and thereafter directly observed therapy

MEDICATION FOR THE TREATMENT OF DRUG RESISTANT TUBERCULOSIS

1. First line oral agents Isoniazid Rifampicin Pyrazinamide Ethambutol 2. Injectable agents Amikacin Kanamycin Capreomycin Streptomycin 3. Fluoroquinolones Ofloxacin Levofloxacin Ciprofloxacin Moxifloxacin

4. Oral bacteriostatic 2nd line agents

Ethionamide Terizidone Para-aminosalicyclic acid

(PAS) 5. Agents with unclear efficacy Clofazimine Linezolid Co-amoxiclav

Clarithromycin Thiacetazone

PRE-INITIATION OF DRUG RESISTANT TB TREATMENT

• Complete history and medical examination • Exclude HIV infection • Bacteriological confirmation of the diagnosis if

possible • Radiological confirmation • Contact tracing • Baseline investigations – full blood count, urea

and creatinine, liver function tests, thyroid function tests.

• Audiometery

• Confirmed disease should be tailored to the patient’s DST pattern of the strain

• Presumptive diagnosis – directed by the DST of the source case

• If no DST available – treatment decisions should be based on the DST of the drug resistant TB strains in the area

• Need to individualise a regime containing at least 4-5 drugs to which the organism is susceptible

MEDICATION FOR THE TREATMENT OF DRUG RESISTANT TUBERCULOSIS -MDR

1. First line oral agents Isoniazid Rifampicin Pyrazinamide Ethambutol 2. Injectable agents Amikacin Kanamycin Capreomycin Streptomycin 3. Fluoroquinolones Ofloxacin Levofloxacin Ciprofloxacin Moxifloxacin

4. Oral bacteriostatic 2nd line agents

Ethionamide Terizidone Para-aminosalicyclic acid

(PAS) 5. Agents with unclear efficacy Clofazimine Linezolid Co-amoxiclav

Clarithromycin Thiacetazone

MEDICATION FOR THE TREATMENT OF DRUG RESISTANT TUBERCULOSIS - XDR

1. First line oral agents Isoniazid Rifampicin Pyrazinamide Ethambutol 2. Injectable agents Amikacin Kanamycin Capreomycin Streptomycin 3. Fluoroquinolones Ofloxacin Levofloxacin Ciprofloxacin Moxifloxacin

4. Oral bacteriostatic 2nd line agents

Ethionamide Terizidone Para-aminosalicyclic acid

(PAS) 5. Agents with unclear efficacy Clofazimine Linezolid Co-amoxiclav

Clarithromycin Thiacetazone

EXTRA-PULMONARY DRUG RESISTANT TUBERCULOSIS

• Treated using the same medication as for pulmonary TB

• Duration also varies between 18 and 24 months

• If CNS involvement, drugs that have adequate penetration into the CSF are necessary eg. PZA, ethionamide and terizidone

ISONIAZID MONO-RESISTANT

• Diagnosis by culture and DST

• Presumptive treatment based on the DST of the contact

• Rif/PZA/Ethambutol (no INH) for a duration of 8-9 months

• May be consider adding a fluoroquinolone

• Clinical follow-up + sputum microscopy

RIFAMPICIN MONO-RESISTANCE

• If the diagnosis was made using GeneXpert, await laboratory confirmation using DST or LPA

• Treat as for MDR TB

• Include INH in the treatment regime

TREATMENT OUTCOMES

• A systematic review in 2012 included 8 studies

• Successful treatment achieved in 80.1% of patients – cure, completion of treatment or both

• The success was 87.1% if the patients were treated with an injectable agent

• 39% of patients had an adverse event

Ettehad, Schaaf, Sneddon, et al. Lancet 2012

THE MDR-TB EXPOSED CHILD

• Close contacts of MDR-TB patients should be screened and receive clinical follow-up for at least 2 years after exposure if no disease is present

• WHO and the SA NTP guidelines recommend INH as chemoprophylaxis for 6 months

• In the Western Cape

Children < 5 years INH + a fluoroquinolone + ethambutol or ethionamide (based on the adult contact DST)

Older children evaluate for disease and symptomatic follow-up

• Discuss all cases with a TB expert

THE XDR-TB EXPOSED CHILD

• Individuals in contact with patients with XDR-TB may be exposed to strains that are resistant to even more drugs than the MDR-TB strains

• Few treatment options are available

• Close clinical follow-up is essential to monitor if infection progresses to disease

• INH may be used as chemoprophylaxis

Summary

• Young children are at increased risk of TB disease following exposure

• Drug resistant tuberculosis is under-detected in children

• GeneXpert on specimens improves detection of tuberculosis and resistance

• Treatment can be challenging but good outcomes are achievable

• Consult a TB expert

THANK YOU