Artifacts in Nuclear Medicine with Identifying and resolving artifacts.
Linezolid for treatment of chronic XDR journal presentation
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.
14.
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.
18.
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
22.
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,
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.
Editor's Notes
According to CONSORT guidelines, identification as a randomized trial in the title.Rationale of the study:Despite these characteristics, a number of case reports and retrospective studies suggest that linezolid may be effective in treating MDR and XDR tuberculosis.15-21 These studies all have important limitations, including a retrospective design, small numbers, the use of linezolid with multiple other active agents, no controls, and limited follow-up. This apparent discrepancy between preclinical data and clinical observations prompted us to undertake a prospective, randomized trial of linezolid in patients with chronic XDR tuberculosis who did not have a response to all other available chemotherapeutic options.This study, conducted in Masan and Seoul, South Korea, will investigate the effectiveness of linezolid (LZD) in treating patients with extensively drug resistant tuberculosis (XDR TB). Because regular medicines do not work well against XDR TB, many more people die from it than from regular TB, which can be successfully treated by taking TB medication for 6 months. Linezolid has been used to treat other kinds of infections, but has not been well studied for TB. This study will look at the side effects and effectiveness of prolonged treatment with linezolid at two different doses.
World-wide, there is an increasing incidence of multi-drug resistant tuberculosis (MDR-TB) and extensively drug-resistant TB (XDR-TB). For patients diagnosed with either of these deadly diseases, effective drug treatment options are sub-optimal or non-existent.
MDR-TB results from either infection with organisms which are already drug-resistant ormay develop in the course of a patient's treatment.Last sentence: These forms of TB do not respond to the standard six month treatment with first-line anti-TB drugs and can take twoyears or more to treat with drugs that are less potent, more toxic and much more expensive.
WHO estimates that there were about 0.5 million new MDR-TB cases in the world in 2011. About 60% of these cases occurred in Brazil, China, India, the Russian Federation and South Africa alone.
RNTCP CATEGORY IV REGIMEN: 6 (9) Km Ofx (Lvx) Eto Cs Z E / 18 Ofx (Lvx)Eto Cs E
. • Proportion of TB cases with drug resistance: about 3.7% of new tuberculosis (TB) patients in the world have multidrug-resistant strains (MDRTB). Levels are much higher in those previously treated – about 20%. The Estimates of MDR-TB burden 2011* New Retreatment% of TB cases with MDR-TB 2.1 (1.5–2.7) 15 (13–16)MDR-TB cases among notified pulmonaryTB cases 21 000 (15 000–27 000) 45 000 (40 000–50 000)frequency of MDR-TB varies substantially between countries. About 9% of MDR-TB cases also have resistance to two other classes of drugs, or extensively drug-resistant TB (XDR-TB). By March 2013, 84 countries had reported at least one XDR-TB case.
This was study done to know effect of linezolid 600 mg in xdr patients refractory to other treatments. They made two groups for this One in which they started linezolid immediately.People 20 years of age and older who have XDR TB may be eligible for this 3-year study.This drug should not be used with the following medications because very serious interactions may occur: atomoxetine, bethanidine, bupropion, buspirone, carbamazepine, cyclobenzaprine, dextromethorphan, certain antihistamines (azatadine, carbetapentane, chlorpheniramine), certain eye drops (apraclonidine, brimonidine), herbal products (e.g., ephedra/ma huang), maprotiline, methyldopa, certain narcotic pain relievers (fentanyl, meperidine, methadone, tapentadol), papaverine, drugs for Parkinson's disease (such as entacapone, tolcapone), sympathomimetics (e.g., ephedrine, methylphenidate), tetrabenazine, tricyclic antidepressants (such as amitriptyline, doxepin).Avoid taking other MAO inhibitors (isocarboxazid, methylene blue, moclobemide, phenelzine, procarbazine, rasagiline, selegiline, tranylcypromine) within 2 weeks before, during, and after treatment with this medication.If you are currently using any of these medications listed above, tell your doctor or pharmacist before starting linezolid.The risk of serotonin syndrome/toxicity increases if you are also taking other drugs that increase serotonin. Examples include street drugs such as MDMA/"ecstasy," St. John's wort, certain antidepressants (including mirtazapine, trazodone, SSRIs such as fluoxetine/paroxetine, SNRIs such as duloxetine/venlafaxine), tramadol, "triptans" used to treat migraine headaches (such as eletriptan, sumatriptan), tryptophan, among others. The risk of serotonin syndrome/toxicity may be more likely when you start or increase the dose of these drugs.Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: bethanidine, indoramin, levodopa, rifampin, other drugs which depress the bone marrow (e.g., cancer chemotherapy), other herbals (such as ginseng).Check the labels on all your medicines (e.g., cough-and-cold products, diet aids) because they may contain ingredients that could increase your heart rate or blood pressure. Avoid these products while taking this medication. Ask your pharmacist for additional information.Limit your tyramine intake while using this medication and for 2 days after stopping treatment. Also avoid foods or drinks with high tyramine content during use because the combination may cause a serious rise in your blood pressure.
Explain what is genotypic and phenotypic resistance?The primary objective of this study is to evaluate the efficacy of LZD therapy, as measured by sputum culture conversion. Secondary aims of this study include: investigation of the pharmacokinetic and pharmacodynamic profiles of LZD in blood; tolerability and toxicity of prolonged LZD administration at doses of 300 mg and 600 mg daily; the rate of change of radiological findings by computed tomography (CT); the rate of relapse 12 months after discontinuation of therapy; the rate of development of drug resistance to LZD; changes in immunologic and bacterial lipid markers during LZD therapy; the correlation of whole-blood killing assays with response to LZD therapy; and effects of LZD on mitochondrial function, a potential early indicator of LZD toxicity. In a substudy, we aim to investigate the changes in lung architecture and cellular activity during treatment using F-fluoro-2-deoxy-D-glucose - positron emission tomography-computed tomography (FDG-PET-CT) of 20 subjects on LZD therapy. Estimated total study duration for each subject will be approximately 3 years.
Base line investigations hide.Why they are excluding HIV. Hiv cases Art may have drug interaction with this one and resistance pattern may differ.We have increase the sampel size to show impact
FormulaFrom prior case studies, it was estimated Page no 86 of Hulley design clinical research
A 2-month delay was used to minimize the possibility that study effects other than linezolid could accountfor observed improvement.Block size and allocation ratio is not specified.Allocation concealment methods not specified in the article.No mention of blinding . Only microbiological staff were not aware of the intervention during the whole study.
Between December 2008 and May 2011, a total of 50 patients were screened for eligibility and 41 underwent randomization. Two patients were subsequently withdrawn owing to preexisting peripheral neuropathy that was discovered during the baseline examination; the remaining 39 patients were included in the modified intention-to-treat analysis. Two other patients who withdrew before culture conversion were considered to have treatment failure: 1 patient, who had an adverse event requiring a drug holiday, was withdrawn 79 days after starting treatment with linezolid because the drug holiday exceeded the protocol-specified window (28 days before sputum-culture conversion and 42 days after sputum-culture conversion); the other patient was withdrawn 32 days after study entry because of a diagnosis of advanced colon cancer (this patient was in the delayed-start group and had not received any linezolid).
EFFICACY The extent to which a specifi c intervention, procedure, regimen, or serviceproduces a beneficial result under ideal conditions; the benefi t or utility to the individualor the population of the service, treatment regimen, or intervention. Ideally, thedetermination of efficacy is based on the results of a randomized controlled trial.EFFICIENCY1. The effects or end results achieved in relation to the effort expended in terms ofmoney, resources, and time. The extent to which the resources used to providea specific intervention, procedure, regimen, or service of known efficacy andeffectiveness are minimizedIn statistics, the relative precision with which a particular study design or estimatorwill estimate a parameter of interest. statistical efficiency is the extent to which a study design maximizes the precision ofeffect estimates obtained from a given number of subjects or given amount of person-time.study efficiency is the value of information obtained from a study in relation to thenumber of subjects (or person-time) and/or to the monetary and other costs of the study.
culture on liquid medium was performed with the use of the MB/BacT automated mycobacterial culture system. Censoring Definition: wait for mail.Sampling collection weekly or what time.Try to diagramatically demonstrate.Loss or attrition of subjects from a follow-up study; the occurrence of the event ofinterest among such subjects is uncertain after a specified time when it was known thatthe event of interest had not occurred; it is not known, however, if or when the event ofinterest occurred subsequently. Such subjects are described as censored. For example, ina follow-up study with myocardial infarction as the outcome of interest, a subject whohas not had an infarct but is killed in a traffi c crash in year 6 is described as censoredas of year 6, since it cannot be known when, if ever, he might have had an infarct at alater year of follow-up. This is censoring by competing risk; other varieties include lossto follow-up and termination of the study. Examination of data for censoring requiresthe use of special analytical methods, such as life table analysis. Observations with unknown values from one end or a particular interval of afrequency distribution.
STRATIFICATION The process of or result of separating a sample into several subsamplesaccording to specified criteria, such as age groups, socioeconomic status, etc. Theeffect of confounding variables may be controlled by stratifying the analysis of results.For example, lung cancer is known to be associated with smoking. To examine the possibleassociation between urban atmospheric pollution and lung cancer, controlling forsmoking, the population may be divided into strata according to smoking status. Theassociation between air pollution and cancer can then be appraised separately withineach stratum. Stratification is used not only to control for confounding effects but alsoas a way of detecting modifying effects. In this example, stratification makes it possibleto examine the effect of smoking on the association between atmospheric pollution andlung cancer. See also adjustment; effect modification; standardization.
Thirty-three patients underwent the second randomization; 17 patients were randomly assigned to continue receiving linezolid at a dose of 600 mg per day, and 16 to receive the reduced dose of 300 mg per day. The 6 patients who did not undergo the second randomization included 4 who had dose reductions due to adverse events before culture conversion and the 2 withdrawn patients mentioned above who were included in the modified intention-to-treat analysis as having treatment failure.
Patients were treated for at least 18 months after sputum-culture conversion and were followed for an additional 12 months after completing the treatment.
(including complete blood counts, blood chemical measurements, and liver-functiontests) a screening tool used in thetreatment of HIV infection (Supplementary Material2 in the Supplementary Appendix),(using the Han test, which is similarto the Snellen chart)and wasavailable for repeat consultation if any peripheralneuropathy developed.the study staff performed
There were no significant between-group differences. BCG denotes bacilleCalmette–Guérin.† The body-mass index is the weight in kilograms divided by the square of the height in meters.‡ Far advanced tuberculosis was defined according to the guidelines of the Korea Centers for Disease Control andPrevention26 as the presence of disseminated lesions of slight-to-moderate density exceeding the total volume of one lung, or dense and confluent lesions exceeding one third the volume of one lung, or the presence of cavities greater than 4 cm in diameter.§ Drug-susceptibility testing for 15 drugs was performed: isoniazid, para-aminosalicylic acid, streptomycin, ethambutol, rifampin, protionamide, cycloserine, kanamycin, amikacin, ofloxacin, levofloxacin, pyrazinamide, rifabutin, moxifloxacin, and capreomycin.
the gray vertical lines indicate the start of treatment (at 2 months) in the delayed-treatment group and the time of data censoring (at 4 months). Tick marks indicate the censored observations at the time of the last follow-up visit with culture results.
the gray vertical lines indicate the start of treatment (at 2 months) in the delayed-treatment group and the time of data censoring (at 4 months). Tick marks indicate the censored observations at the time of the last follow-up visit with culture results.
according to the duration of linezolid therapy.One patientwithdrew before receiving the study drug, owing to a diagnosis of metastatic colon cancer; data from this person were included in the modified intention- to-treat analysis as a treatment failure.As ofMay 1, 2012, of the 38 patients who received linezolid,17 were still receiving the treatment perprotocol, and 13 had completed treatment, including6 with no relapse during the treatment period,4 with no relapse at the 6-month follow-up, and3 with no relapse at the 12-month follow-up (endof study). Eight patients withdrew early: 4 patientsowing to treatment failure, 1 for personal reasons,and 3 owing to adverse events
Of the 38 patients who received linezolid, 33 (87%) underwent the scheduled second randomization (1 patient had an adverse event requiring withdrawal from the study and 4 had an adverse event requiring dose reduction before undergoing this randomization) (Fig. 1). Seven episodes of myelosuppression, including anemia and neutropenia, which occurred primarily within the first 5 months. In addition, 7 cases of optic neuropathy, 21 cases of peripheral neuropathy, and 1 case of rhabdomyolysis,28 with these events occurring during the first year of treatment.In the second randomization, 17 patients were assigned to continue receiving the 600-mg daily dose, and 16 to receive 300 mg per day. 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.
The minimum inhibitory concentration for these four patients increased by a factor of 8 to a factor of 32, as compared with baseline.The two doses provided proportional exposures, with a mean (±SD) area under the curve of 180.4±89 μg per milliliter per hour for the 600-mg dose and 91.1±43 μg per milliliter per hour for the 300-mg dose. Using Cox regression, we found no association between the time to culture conversion (measured from the date of the start of treatment with linezolid) and either the peak level (P = 0.93) or the trough level (P = 0.92), measured after at least 2 weeks of linezolid treatment.
The two doses provided proportional exposures, with a mean (±SD) area under the curve of 180.4±89 μg per milliliter per hour for the 600-mg dose and 91.1±43 μg per milliliter per hour for the 300-mg dose. Using Cox regression, we found no association between the time to culture conversion (measured from the date of the start of treatment with linezolid) and either the peak level (P = 0.93) or the trough level (P = 0.92), measured after at least 2 weeks of linezolid treatment.
In this analysis involving 39 patients with XDR pulmonary tuberculosis who had not had a response to any standard treatment regimen for 6 months or more
A major concern in undertaking this trial wasthe emergence of acquired resistance to linezolidbecause we were adding a single active drug to afailing regimen.The relatively small numberof clinical isolates with reported linezolidresistance is consistent with this observation.This low frequency of acquisition of resistance may be related to the low rate of observed mutation to linezolid resistance in vitro (estimated at 10−9). The dose of 600 mg per day also maintained linezolid levels above the published mutant-prevention concentration of 0.6 μg per milliliter and may have played a role in reducing the incidence.
The significant beneficial effect of linezolid was tempered, as expected, by the high rates of drug-related adverse events, although almost all events resolved quickly with a reduction in the dose or the temporary cessation of linezolid, and only three patients discontinued the study owing to adverse events.It is worrisome that three of the patients in whom resistance developed had relatively low exposures while receiving the 300-mg dose (Fig. 4B).