Linezolid for treatment of chronic XDR journal presentation

Title Linezolid for Treatment of Chronic

Extensively Drug-Resistant Tuberculosis

The New England Journal of Medicine367;16 nejm.1508 org october 18, 2012

Guide: Dr. Akhil Goel Sir

Introduction• World-wide, increasing incidence of multi-drug

resistant tuberculosis (MDR-TB) and extensively drug-resistant TB (XDR-TB).

• Effective drug treatment options - sub-optimal or non-existent.

• Multidrug-resistant TB (MDR-TB) is caused by mycobacteria that are resistant to the most effective anti-TB drugs

(isoniazid and rifampicin). • The term XDR TB is defined as MDR TB plus

resistance to any fluoroquinolone and at least 1 of 3 injectable second-line anti-TB drugs

(capreomycin, kanamycin, and amikacin).

Burden of MDR and XDR TB

In World: As of 2013, 3.7% of new tuberculosis cases have MDR-TB. About 20% in retreatment cases. In India: MDR TB levels of about 3% in new cases and around 12- 17% in retreatment cases. Exact prevalence of XDR unknown.

By March 2013, 84 countries had reported at least one XDR-TB case.

Used to treat infections, including pneumonia, infections of the skin, and infections caused by a resistant bacterium (Enterococcus faecium).Is a reversible monoamine oxidase inhibitor (MAOI).

TB drugs used to treat drug resistant TB according to group (class)Group 1 drugs : First Line Oral Agents Pyrazinamide, Ethambutol, Rifabutin

Group 2 drugs : Injectable Agents Kanamycin, Amikacin, Capreomycin, Streptomycin

Group 3 drugs : Fluoroquinolones Levofloxacin, Moxifloxacin, Ofloxacin

Group 4 drugs : Oral Bacteriostatic Second Line Agents Para–aminosalicylic acid, Cycloserin, Eterizidon, Ethionamide, Protionamide

Group 5 drugs : Agents with an unclear role Clofazimine, Linezolid, Amoxicillin/clavulanate, Thioacetazone, Imipenem/Cilastatin, High dose isoniazid, clarithromycin

• Category IV regimen • RNTCP will be using a Standardised Treatment Regimen (Cat IV) for the

treatment of MDR-TB cases (and • those with rifampicin resistance) under the programme. Cat IV regimen

comprises of 6 drugs- kanamycin, • ofloxacin (levofloxacin)†• , ethionamide, pyrazinamide, ethambutol and cycloserine during 6-9

months of the • Intensive Phase and 4 drugs- ofloxacin (levofloxacin), ethionamide,

ethambutol and cycloserine during the 18 • months of the Continuation Phase. p-aminosalicylic acid (PAS) is included in

the regimen as a substitute drug • if any bactericidal drug (K, Ofl, Z and Eto) or 2 bacteriostatic (E and Cs)

drugs are not tolerated

• • Multidrug-resistant TB (MDR-TB) is caused by organisms that are resistant to the most effective anti-TB drugs

• (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 TB (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).• •

Methodology

1. Place and Time of the study:

2. Study Patients: a. Inclusion Criteria b. Exclusion Criteria3. Sample Size:4. Randomization: 5. Primary End Point:6. Second

Randomization:7. Adherence to drug

treatment: 8. Adverse Events

Monitoring:

Phase 2a, randomized, two-group study at in Changwon and in Seoul, South Korea.

Enrollment Of Study Participants: From December 2008 through May 2011.

1. Place and Time of the study:

Study Design: Allocation: RandomizedEndpoint Classification: Efficacy StudyIntervention Model: Parallel AssignmentMasking: Open LabelPrimary Purpose: Treatment

Methodology

1. Place and time of study :




Monitoring:

1. Study Participants: a. Inclusion Criteria

Adults, 20 years of age or older chronic XDR PTB (positive sputum smear and culture) and with confirmed genotypic or phenotypic resistance to isoniazid, rifampin, kanamycin, ofloxacin, and moxifloxacin or a documented non-response to treatment, despite test results showing drug susceptibility. On unchanged, failing regimen for 6 months or more before enrollment.

Methodology





Monitoring:

b. Exclusion Criteria 1) Previous treatment with linezolid2) Anticipated surgical treatment3) Positive test result for HIV4) Specific baseline laboratory

abnormalities,5) Moderate-to-severe peripheral or optic

neuropathy, 6) and need for treatment with

contraindicated drugs.

Methodology





Monitoring:

3. Sample Size:

culture conversion rate of more than 90% with linezolid during the first 4 months of therapy, And on the basis of historical data, it was assumed that less than 10% of patients would have spontaneous culture conversion without having received linezolid.Thus, a sample of 16 patients per group would provide 92% power, assuming a two-sided type 1 error rate of 0.05 and a 10% discontinuation rate. Recruited 20 patients per group to allow for additional loss to follow-up and death.

Methodology





Monitoring:

3. Randomization:

Permuted block randomization to receive linezolid, at a dose of 600 mg per day, in addition to their existing regimen, in two groups:Immediately or after a 2-month delay. Stratification according to status with regard to diabetes mellitus (types 1 and 2 included). All patients continued their existing regimen and were hospitalized from the time of enrollment until sputum-culture conversion.

ALLOCATION CONCEALMENTAllocation concealment is a different concept to blinding. It means that the person randomising the patient does not know what the next treatment allocation will be. It is important as it prevents selection bias affecting which patients are given which treatment (the bias randomisation is designed to avoid).Allocation concealment is possible with all types of trial, including unblinded trials, and is therefore universally recommended. The best way of ensuring allocation concealment is to use a centralised service, since this cannot be subverted by investigators and provides independent verification that it was not possible for the investigators to know the allocation sequence in advance. Read about the problems of not using centralised randomisation.Note that using patient date of birth (e.g. odd/even) or alternating treatments as the randomisation scheme means that the allocation is not concealed but is open to all. The treatment allocation may then be subject to selection bias since patients expected to have a worse outcome may be selectively excluded from the active treatment group.

MinimizationAn assignment strategy, similar in intention to stratification, that ensures excellent balance between intervention groups for specified prognostic factors. The next participant is assigned to whichever group would minimize the imbalance between groups on specified prognostic factors.

Minimization is an acceptable alternative to random assignment.

http://www.sealedenvelope.com/randomisation/real-envelopes/






50 Patients underwent screening

41 underwent Randomization

21 were assigned to Immediate treatment to receive Linezolid 600 mg daily

20 were assigned to delayed treatment with Linezolid 600 mg daily

Methodology





Monitoring:

3. Primary End Point:

Sputum-culture conversion, with data censored at 4 months. Conversion was defined as negative sputum samples on solid (L.J.) medium for 3 consecutive weeks; Patients continued taking linezolid at a dose of 600 mg per day until they had negative sputum smears (ZN staining) for 2 consecutive weeks or until they had received 4 months of linezolid treatment, whichever came first.

Methodology





Monitoring:

3. Second Randomization:

Patients underwent a second randomization, stratified according to diabetes mellitus status, either to continue receiving linezolid at a dose of 600 mg per day or to receive a lower dose, 300 mg per day, for an additional 18 months or until therapy was stopped owing to side effects or laboratory abnormalities.

Methodology





Monitoring:

7. Adherence to drug treatment:

videophone ortelephone pill counts monthly. Blood for pharmacokinetic analysis.

Methodology





Monitoring: 8. Adverse Events

Monitoring:

Baseline and serial safety evaluations weekly until 16 weeks, every 2 weeks from 17 through 24 weeks, and then monthly thereafter.

NCV by neurologist at baseline.

The Subjective Peripheral Neuropathy Screen, and clinical neurologic examinations by the study staff at baseline and monthly thereafter.

To monitor patients for linezolid-induced optic neuropathy, testing for visual acuity, contrast sensitivity, and color vision Patients with any symptoms or abnormal findings were referred to an ophthalmologist.

Results:

1. Study Patients:2. Primary Outcome: 3. Safety (Adverse

Effects:4. Drug Resistance:

5. Pharmacokinetics:

1. Study Patients: 39 patients were predominantly men (72%), with a mean age of 41.2 years (range, 20 to 64), and 36% of the patients had diabetes mellitus77% of the patients were classified as having “far advanced” tuberculosis

Results:






8. Adverse Events Monitoring:

2. Primary Outcome:

The primary outcome was the time to sputum culture conversion, with data censored at 4 months. By 4 months, 15 of the 19 patients (79%) in the immediate-start group and 7 of the 20 (35%) in the delayed-start group had conversion to negative sputum cultures on solid medium (P = 0.001)

Figure 2. Kaplan–Meier Curves for Culture ConversionAccording to Time since Randomization.Panel A shows the results for solid culture medium

Results:

1. Study Patients:2. Primary Outcome: 3. Sample Size:4. Randomization: 5. Primary End Point:6. Second



Monitoring:

2. Primary Outcome:

Figure 2. Kaplan–Meier Curves for Culture ConversionAccording to Time since Randomization.Panel B the results for liquid culture medium.

With data censored at 4 months, 12 of the 19 patients (63%) in the immediate- start group and 11 of the 20 (55%) in the delayed-start group had culture conversion on liquidmedium (P = 0.07)

Results:

1. Study Patients:2. Primary Outcome: 3. Sample Size:4. Randomization: 5. Primary End Point:6. Second



Monitoring:

2. Primary Outcome:

Figure 2. Kaplan–Meier Curves for Culture ConversionAccording to Time since Randomization.Panel C shows the time to culture conversion on solidmedium (solid line) along with the 95% confidence interval(dashed lines) for the 38 participants who receivedlinezolid,

Combining the two groups, 34 of the 38 patients who received linezolid (89%) had culture conversion on solid medium by 6 months at a median of 75 days after the start of treatment with linezolid.

Results:

1. Study Patients:2. Primary

Outcome: 3. Safety (Adverse



3. Safety (Adverse Effects:

Of the 38 patients who received linezolid, 33 (87%) had clinically significant adverse events; 31 patients (82%) had events that were possibly or probably related to linezolid Most adverse events resolved relatively quickly, And only 3 patients permanently discontinued linezolid owing to drug toxicity (2 patients because of optic neuropathy, and 1 because of anemia).

In the second randomization , of the 17 patients who continued taking 600 mg per day, 15 (88%) had an adverse event related to the study drug. of the 16 patients who received 300 mg per day, 11 (69%) had an adverse event related to the study drug.

A Cox proportional-hazards analysis showed that, after the second randomization, the group receiving the 600-mg dose was 2.7 times (95% confidence interval, 1.1 to 6.5) as likely to have an adverse event as the group receiving the 300-mg dose (P = 0.03)

Results:


Effects:

4. Drug Resistance:




8. Adverse Events Monitoring:

4. Drug Resistance:

Of the four patients who did not have a response to treatment,three (two in the 300-mg group, and one in the 600-mg group) did not have confirmed culture conversion.The fourth patient, who was in the 600-mg group, had a treatment relapse (cultures became negative but turned positive again after 1 year of treatment).

Results:

1. Study Patients:2. Primary

Outcome: 3. Safety (Adverse



5.Pharmacokinetics:

Considering that the plasma protein binding of linezolid is approximately 30%, plasma levels of free linezolid were above the measured minimum inhibitory concentration for each isolate during the entire dosing interval in almost all patients taking 600 mg per day. Among those taking 300 mg per day, the trough level was lower than the mean minimum inhibitory concentration in nine patients, including the two in whom linezolid resistance developed during treatment with that dose.Using Cox regression, no association between the time to culture conversion between two groups.

Discussion:

1. Effect of addition of linezolid on pre-existing regimen:

2. Drug Resistance: 3. Side Effects: 4. Impression of the

authors:


the immediate addition of linezolid at a dose of 600 mg per day to the ongoing background treatment regimen had a significant beneficial effect on the time to sputum-culture conversion on solid medium, as compared with the delayed addition of linezolid at the same dose. During the first 6 months of treatment, 34 of the 39 patients (87%) had confirmed culture conversion, at a median of 76 days.

Discussion:


2. Drug Resistance:3. Side Effects: 4. Impression of the

authors:

2. Drug Resistance: In this study, 4 of the 38 patients who received linezolid for 6 months or more (11%) had apparent acquired resistance.

Discussion:


2. Drug Resistance:

3. Side Effects: 4. Impression of the

authors:

3. Side Effects: •Adverse events were significantly reduced in patients who subsequently received the reduced dose of 300 mg per day.•The pharmacokinetic profile of the 300-mg dose, as compared with the minimum inhibitory concentration of the isolates, showed that this dose was sufficient to maintain serum levels above the minimum inhibitory concentration in most patients,

Overview of the Study:

Discussion:


2. Drug Resistance:

3. Side Effects: 4. Impression of the

authors: 4. Impression of the

authors:

Balancing the long-term risk– benefit ratio of linezolid requires identifying a dose with sufficient potency but less toxicity.

Health & Medicine

Linezolid for treatment of chronic XDR journal presentation