to know how to present a journal article

1. Title
Linezolid for Treatment of Chronic
Extensively Drug-Resistant
Tuberculosis
The New England Journal of Medicine
367;16 nejm.1508 org october 18, 2012
Guide: Dr. Akhil Goel Sir

2. 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.

3. • 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).

4. 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).

5. 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

6. • 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

7. • • 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).
• •

8. Methodology
1. Place and Time of
the study:
2. Study Patients:
a. Inclusion Criteria
b. Exclusion Criteria
3. 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: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment

9. Methodology
1. Place and time of
study :
2. Study Patients:
a. Inclusion Criteria
b. Exclusion Criteria
3. Sample Size:
4. Randomization:
5. Primary End Point:
6. Second
Randomization:
7. Adherence to drug
treatment:
8. Adverse Events
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.

10. Methodology
1. Place and time of
study :
2. Study Patients:
a. Inclusion Criteria
b. Exclusion Criteria
3. Sample Size:
4. Randomization:
5. Primary End Point:
6. Second
Randomization:
7. Adherence to drug
treatment:
8. Adverse Events
Monitoring:
b. Exclusion Criteria 1) Previous treatment with linezolid
2) Anticipated surgical treatment
3) Positive test result for HIV
4) Specific baseline laboratory
abnormalities,
5) Moderate-to-severe peripheral or optic
neuropathy,
6) and need for treatment with
contraindicated drugs.

11. Methodology
1. Place and time of
study :
2. Study Patients:
a. Inclusion Criteria
b. Exclusion Criteria
3. Sample Size:
4. Randomization:
5. Primary End Point:
6. Second
Randomization:
7. Adherence to drug
treatment:
8. Adverse Events
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.

12. Methodology
1. Place and time of
study :
2. Study Patients:
a. Inclusion Criteria
b. Exclusion Criteria
3. Sample Size:
4. Randomization:
5. Primary End Point:
6. Second
Randomization:
7. Adherence to drug
treatment:
8. Adverse Events
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.

13. ALLOCATION CONCEALMENT
Allocation 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.
Minimization
An 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.

15. 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

16. Methodology
1. Place and time of
study :
2. Study Patients:
a. Inclusion Criteria
b. Exclusion Criteria
3. Sample Size:
4. Randomization:
5. Primary End Point:
6. Second
Randomization:
7. Adherence to drug
treatment:
8. Adverse Events
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.

17. Methodology
1. Place and time of
study :
2. Study Patients:
a. Inclusion Criteria
b. Exclusion Criteria
3. Sample Size:
4. Randomization:
5. Primary End Point:
6. Second
Randomization:
7. Adherence to drug
treatment:
8. Adverse Events
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.

19. Methodology
1. Place and time of
study :
2. Study Patients:
a. Inclusion Criteria
b. Exclusion Criteria
3. Sample Size:
4. Randomization:
5. Primary End Point:
6. Second
Randomization:
7. Adherence to drug
treatment:
8. Adverse Events
Monitoring:
7. Adherence to drug
treatment:
videophone or
telephone
pill counts monthly.
Blood for pharmacokinetic analysis.

20. Methodology
1. Place and time of
study :
2. Study Patients:
a. Inclusion Criteria
b. Exclusion Criteria
3. Sample Size:
4. Randomization:
5. Primary End Point:
6. Second
Randomization:
7. Adherence to drug
treatment:
8. Adverse Events
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.

21. 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
mellitus
77% of the patients were classified as having
“far advanced” tuberculosis

23. Results:
1. Study Patients:
2. Primary Outcome:
3. Safety (Adverse
Effects:
4. Drug Resistance:
5. Pharmacokinetics:
6. Second
Randomization:
7. Adherence to drug
treatment:
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 Conversion
According to Time
since
Randomization.
Panel A shows the
results for solid
culture medium

24. Results:
1. Study Patients:
2. Primary Outcome:
3. Sample Size:
4. Randomization:
5. Primary End Point:
6. Second
Randomization:
7. Adherence to drug
treatment:
8. Adverse Events
Monitoring:
2. Primary Outcome:
Figure 2. Kaplan–
Meier Curves for
Culture Conversion
According 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 liquid
medium (P = 0.07)

25. Results:
1. Study Patients:
2. Primary Outcome:
3. Sample Size:
4. Randomization:
5. Primary End Point:
6. Second
Randomization:
7. Adherence to drug
treatment:
8. Adverse Events
Monitoring:
2. Primary Outcome:
Figure 2. Kaplan–
Meier Curves for
Culture Conversion
According to Time
since Randomization.
Panel C shows the
time to culture
conversion on solid
medium (solid line)
along with the 95%
confidence interval
(dashed lines) for
the 38 participants
who received
linezolid,
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.

26. Results:
1. Study Patients:
2. Primary
Outcome:
3. Safety (Adverse
Effects:
4. Drug Resistance:
5. Pharmacokineti
cs:
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)

27. Results:
1. Study Patients:
2. Primary Outcome:
3. Safety (Adverse
Effects:
4. Drug Resistance:
5. Pharmacokineti
cs:
6. Second
Randomization:
7. Adherence to
drug treatment:
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).

28. Results:
1. Study Patients:
2. Primary
Outcome:
3. Safety (Adverse
Effects:
4. Drug Resistance:
5. Pharmacokineti
cs:
5.Pharmacokinetic
s:
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.

29. Discussion:
1. Effect of addition
of linezolid on
pre-existing
regimen:
2. Drug Resistance:
3. Side Effects:
4. Impression of the
authors:
1. Effect of addition
of linezolid on
pre-existing
regimen:
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.

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

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

32. Overview of the Study:

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