Linezolid Experience Among MDR TB Patients in Mumbai€¦ · 08.02.2018 · Duration of Treatment...
Transcript of Linezolid Experience Among MDR TB Patients in Mumbai€¦ · 08.02.2018 · Duration of Treatment...
Duration of Treatment by Dose of Linezolid
Many participants started with 600mg but transitioned to 300mg daily.
Higher initial dose was significantly associated with earlier time to dose adjustment (p=0.0016), but not
total with shorter total duration of linezolid therapy (p=0.289).
Treatment Associated Side Effects Among Participants Receiving Linezolid, N (%)
Neuropathy and hematologic side effects were most associated with linezolid
Time to Neuropathy and Marrow Suppression During Linezolid
Time to Neuropathy and Hematologic Side Effects Duration of Treatment and Time to Side Effect
There was no significant association between first dose or total linezolid duration and time to side effect.
Tuberculosis (TB) is the #1 infectious disease killer worldwide, and 26% of cases occur in India. The
city of Mumbai is particularly affected, with 12% of India’s Multidrug-Resistant TB (MDR-TB, TB
resistant to isoniazid and rifampin).
MDR-TB, Pre-XDR-TB (resistant to isoniazid, rifampin, and either a quinolone or a second-line
injectable drug), and Extensively Drug Resistant TB (XDR-TB, resistant to isoniazid, rifampin, a
quinolone, and a second-line injectable drug) require longer treatment than drug susceptible TB, and
rely on less-effective and more toxic drugs, causing significant morbidity.
Linezolid is a repurposed bacteriostatic drug that is associated with increased rates of culture-
conversion (Lee M, et al. NEJM 2013) and is being used in novel treatment regimens trials including
the Nix-TB trial (Conradie F, et al. CROI Abstract 2017). Unfortunately, linezolid is also associated
with significant toxicities including painful peripheral neuropathy and bone marrow suppression.
We reviewed the data from a prospective observation cohort of MDR, Pre-XDR, and XDR-TB patients
in Mumbai to document our experience of the safety and efficacy of linezolid in India.
Linezolid Experience Among MDR-TB Patients in Mumbai Jeffrey A Tornheim,
1 Shashank Ganatra,
2 Andrea DeLuca,
3 Radhika Banka,
2
Camilla Rodrigues,2 Amita Gupta,
1 Zarir F Udwadia
2
1Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USA
2PD Hinduja National Hospital and Medical Research Center, Mumbai, India
3Division of Global Disease Epidemiology and Control, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
BACKGROUND
MDR-TB patients seeking care at the Outpatient Chest Clinic at PD Hinduja National Hospital and
Medical Research Centre were recruited by a research clinician, and consented to enrollment into a
prospective observational cohort. Participants had TB history, prescriptions, labs, and imaging
reviewed and entered into a Microsoft Access database. Date were cleaned and analyzed in R.
The impact of linezolid was evaluated by the following variables:
Linezolid treatment exposure (including prescriptions prior to enrollment) was categorized as follows:
Wilcoxon rank sum tests identified differences in times. Univariate logistic regressions were generated
to calculate odds of each side effect. Linear regressions calculated the impact of exposure on time to
each event (as a continuous variable). Multivariate analysis including disease profile (MDR-, Pre-XDR-,
and XDR-TB), pulmonary vs. extrapulmonary disease, and concurrent receipt of other drugs.
METHODS
In a cohort of MDR-TB patients with complex drug resistance, use of linezolid was common and rates
of linezolid resistance were low.
Linezolid dosing was highly variable, with higher initial doses frequently adjusted early in treatment.
Median duration before dose adjustment was 4.5 months (600mg) and 6.8 months (300mg, p=0.04).
Neuropathy and hematologic side effects were common and occurred well before dose adjustments
Linezolid was associated with improvement in cavitary lung disease culture conversion.
Use of linezolid was associated with increased odds of neuropathy, but not with hematologic events
after controlling for drug resistance and co-administered drugs.
Linezolid doses (>10mg / kg or >15 mg / kg) were not associated with improved radiographic or
microbiologic improvement
CONCLUSIONS
RESULTS—Experience with Linezolid
Odds of Treatment Outcomes and Associated Side Effects
Use of linezolid was associated with significant improvement in cavitary lung disease measured by
Ralph score (% lung involvement + 40 for the presence of a cavity). Odds of culture conversion increased with duration of therapy, as did odds of anemia. Odds of neuropathy was associated with ever having taken linezolid but not duration of therapy.
No significant associations were identified between treatment, dose in mg or mg / kg, or duration and
improved chest X-ray % involvement or odds of leukopenia, thrombocytopenia, or severe anemia.
RESULTS—Linezolid and Outcomes
This work was graciously supported by the Paul S. Leitman Global Travel Grant, the UJMT Fogarty Global Health Fellows
Program (R25TW009340), The Frederick Mulder Foundation, the Pogge Tong Foundation, NIH/NIAID (UM1AI069465),
NIH/DBT RePORT India Consortium, the Ujala Foundation, Gilead Foundation, and Wyncote Foundation.
ACKNOWLEDGEMENTS
441 MDR-TB patients were enrolled between October 20, 2015 and August 26, 2017 (22 months).
241 (54.6%) participants received linezolid and 158 (35.8%) currently receive linezolid. Linezolid
prescription was significantly associated with drug resistance (p<0.001).
Linezolid drug susceptibility testing was performed in MGIT at 1µg/mL for 210 participants. 16 (7.6%)
were resistant. All subsequent analysis only includes the 194 participants with documented linezolid
susceptibility.
RESULTS—Description of Cohort
Participant Demographics N (%) Female 272 (61.7)
Students 110 (24.9)
Professionals 57 (12.9)
Current or Former Smoker 34 (7.9)
Left Work or School for TB 203 (46.0)
Median Age (IQR) 27 (22.0—34.0)
Median BMI (IQR) 19.8 (16.7—23.0)
Clinical Characteristics N (%) Pulmonary TB 326 (73.9)
Culture Positive 367 (83.2)
Smear Positive 295 (66.9)
HIV Positive 1 (0.2)
Diabetes 37 (8.4)
Prediabetes 34 (7.7)
Anemia ( Any Severity) 332 (75.3)
Patient Reported Side Effects
Hearing Loss Vertigo Tinnitus Vision Change
Tingling, Burning, or Numbness Headache Tremor Taste Changes
Self-Reported Seizure Psychosis Anxiety Insomnia
Self-Reported Depression Syncope Other Cognitive Changes
Nausea Anorexia Weight Loss Other GI Symptoms
Joint Pain Calf Pain Muscle Cramps Back Pain
Chest Pain Palpitations Peripheral Edema Persistent Dyspnea
Skin Discoloration Rash Oral Ulcers Hair Loss
Subjective Fever Hemoptysis Dysmenorrhea Earache
Objective Side Effects:
Kidney Injury (Creatinine >1.1) Thyroid Dysfunction (TSH >4.0)
Anemia (WHO Classification) Thrombocytopenia (<150,000) Leukopenia (<4,000)
Liver Injury (SGOT/SGPT greater than the upper limit of normal (“ULN”), 3x ULN, 10x ULN)
QTc Prolongation (>450ms, >500 ms)
Treatment Outcomes
Culture Conversion X-ray Improvement (% Lung Involvement, Ralph Score)
Resistance Profile Received Linezolid
N (%)
Did Not Receive Linezolid
N (%)
All Participants
N (%) MDR-TB 26 (10.8) 135 (67.5) 161 (36.5)
Pre-XDR-TB 129 (53.5) 63 (31.5) 192 (43.5)
XDR-TB 86 (35.7) 2 (1.0) 88 (20.0)
All Patients 241 (100) 200 (100) 441 (100)
Dose in mg First Dose
N (Valid %) Months Before
Changing Dose
Median (IQR)
Current Dose
N (Valid %)
Total Months of
Linezolid
Median (IQR)
300mg 29 (22.5) 5.8 (6.9) 44 (50.0) 8.1 (7.7)
600mg 93 (72.1) 4.1 (4.4) 44 (50.0) 6.2 (5.2)
1200mg 6 (4.7) 1.4 (3.2) 0 (0) —
1800mg 1 (0.8) 6.7 (NA) 0 (0) —
Unknown 65 (NA) — 2 (NA) —
Any Dose 194 (100) 4.3 (5.1) 90 (100) 5.9 (7.2)
Ever on Linezolid Currently on Linezolid Months of Linezolid
Outcome of Interest Univariate
Estimate Multivariate
Estimate
Univariate
Estimate
Multivariate
Estimate
Univariate
Estimate
Multivariate
Estimate
Ralph Score Reduction 5.1 (0.454) 10.6 (0.204) 13.3 (0.039) 15.67 (0.022) -0.394 (0.575) -0.35 (0.629)
Odds of Culture Conversion 1.45 (0.268) 1.59 (0.278) 0.57 (0.839) 0.72 (0.331) 1.08 (0.029) 1.09 (0.027)
Odds of Neuropathy 5.36 (0.001) 7.49 (0.028) 1.145 (0.696) 0.92 (0.871) 1.03 (0.410) 1.12 (0.157)
Odds of Hg<11 0.63 (0.362) 2.55 (0.490) 0.595 (0.240) 0.16 (0.093) 1.07 (0.218) 1.46 (0.035)
Receipt of linezolid (ever or currently) Dose prescribed (mg per dose, mg daily, and mg/kg)
Cumulative exposure (mg) Duration of treatment (at initial dose and at any dose)
Moderate or Severe Anemia (Hg<11)—37 (19.1%) Severe Anemia (Hg<8)—9 (4.6%)
Leukopenia (WBC<4)—8 (4.1%) Thrombocytopenia (Plt<150)—7 (3.6%)
Any Hematologic Side Effect—40 (20.6%) Neuropathy—48 (24.7%)
Event Color Median (IQR)
Platelets <150,000 83 (116)
White Blood Cells <4,000 84 (112)
Hemoglobin <11 118 (104)
Hemoglobin <8 146 (121)
Neuropathy 90 (135)
Event Color Median (IQR)
First Hematologic Event
(Hg<11, WBC<4,000, or Platelets <150,000)
105 (115)
Neuropathy 90 (135)
Total Duration of Linezolid Treatment 178 (217)
First Linezolid Dose Reduced or Discontinued 129 (152)
Event Color Median (IQR)
300mg Daily 174 (207)
600mg Daily 124 (131)
1200mg Daily 40.5 (96)