Clinical trial NCT03126890: Investigation of the Correlation Between Plasma Concentration of Linezolid Antibiotic and Treatment Response and Adverse Reactions
Official title: Investigation of the Correlation Between Plasma Concentration of Linezolid Antibiotic and Treatment Response and Adverse Reactions
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Myelosuppression
Lactic Acidosis
Peripheral Neuropathy
Keywords: Pharmacokinetics,adverse events
Linezolid
Therapeutic drug monitoring
Myelosuppression
Lactic acidosis
Peripheral neuropathy
Lead sponsor: National Taiwan University Hospital
Sponsor class: OTHER
First posted: 2017-04-25
Enrollment: 1000
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: OTHER
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients with oral or intravenous linezolid

Brief summary: Linezolid is the second line agent in the treatment of MRSA and PRSP infections, and it is also the drug of choice for VRE infections. It can be an alternative option against multidrug resistant tuberculosis and non-tuberculosis mycobacterium. However, Patients who receive more than 2 weeks of treatment duration and who have renal dysfunction or severe cirrhosis may prone to experience anemia, thrombocytopenia, and leukopenia. Long-term use may also result in lactic acidosis, peripheral neuropathy and optic neuropathy due to mitochondrial toxicity. Thus, this study will analysis the medical charts in National Taiwan University Hospital (NTUH) from 2011 to 2016 to get the population demographics who use linezolid and analysis the occurrence rate of myelosuppression, neuropathy and lactic acidosis. Simultaneously, the investigators also use therapeutic drug monitoring (TDM) to prospectively evaluate the association of linezolid blood concentration and clinical efficacy and safety. The result of this study will provide physicians more information to prevent concentration-dependent adverse effects.

Detailed description: The increasing resistance of methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and penicillin-resistant Streptococcus pneumoniae (PRSP) has caused significant medical issue. With limited antimicrobial agents available, it has been an increasing challenge in infection control and disease treatment. Linezolid is the second line antibiotics in the treatment of MRSA and PRSP infections, and it is also the drug of choice for VRE infections. It can be an alternative against multidrug resistant tuberculosis and non-tuberculosis mycobacterium. Linezolid has almost 100% of bioavailability. It has excellent tissue penetration. It metabolized via non-enzymatic oxidation. Two major metabolites, aminoethoxyacetic acid (chemical name) and hydroxyethyl glycine (chemical name), are final forms before excreted through kidneys. Even though the manufacturer does not recommend dosing adjustment for patients with renal or hepatic dysfunction, recent studies demonstrated accumulation of linezolid and 2 metabolites in the body. Patients who receive more than 2 weeks of treatment duration and who have renal dysfunction or severe cirrhosis may present higher plasma linezolid concentration. Patients may experience anemia, thrombocytopenia, and leukopenia under long-term use of linezolid. However, there is lack of study on lactic acidosis, peripheral neuropathy, and optic neuropathy due to mitochondrial toxicity.

This study has two parts. This study will analysis the medical charts in NTUH from 2011 to 2016 to get the population demographics who use linezolid and the occurrence rate of myelosuppression, neuropathy and lactic acidosis. Then, followed by a prospective study which aim is to monitor the plasma peak and trough concentration of linezolid (total and free drug) and 2 metabolites by different sample collecting method (plasma, dry blood spot; DBS). If clinical necessity, the investigators may also monitor tissue fluid concentration. Clinical response and toxicity were monitored by liquid chromatography (LC) analysis. The investigators plan to evaluate the association between plasma concentration and toxicity including bone marrow suppression, peripheral neuropathy, and lactic acidosis. It is important to determine if dose adjustment in patients with renal and/or hepatic dysfunction is required. Simultaneously, the investigators want to develop DBS method which can ease patients' uncomfortable sense and simplify the drug monitor process. The result of this study will provide physicians more information to prevent concentration-dependent adverse effects.

Eligibility criteria: Retrospective study 1. Adults (age \> 20 year old) with linezolid treatment (oral or intravenous) in National Taiwan University hospital medical charts record from 2011 to 2016. 2. Patients with linezolid treatment for 3 days or above Prospective study

1. Adults (age \> 20 year old) are going to start with linezolid treatment (oral or intravenous) due to gram positive infection, multidrug resistant - tuberculosis (MDR-TB) or nontuberculous mycobacterium (NTM) infection.
2. Keeping follow up in National Taiwan University Hospital

Exclusion Criteria:

Retrospective study 1. Patients without baseline complete blood count (CBC) data (RBC or Hb, WBC, platelet) before linezolid treatment. Prospective study

1. Patients with severe disease status (assess by clinicians) might die within 2 days or treatment duration less than 2 days

Primary outcomes:
measure: Clinical efficacy
timeFrame: Observation periods: entire linezolid treatment course until 30 days after the completion of treatment, loss of follow up, death or December 2020 (up to 4 years).
measure: Safety - thrombocytopenia
timeFrame: Observation periods: entire linezolid treatment course until resolution of side effect, loss of follow up, death or December 2020 (up to 4 years).
measure: Safety - anemia
timeFrame: Observation periods: entire linezolid treatment course until resolution of side effect, loss of follow up, death or December 2020 (up to 4 years).
measure: Safety - leukopenia
timeFrame: Observation periods: entire linezolid treatment course until resolution of side effect, loss of follow up, death or December 2020 (up to 4 years).
measure: Safety - lactic acidosis
timeFrame: Observation periods: entire linezolid treatment course until resolution of side effect, loss of follow up, death or December 2020 (up to 4 years).
measure: Safety - peripheral neuropathy
timeFrame: Observation periods: entire linezolid treatment course until resolution of side effect, loss of follow up, death or December 2020 (up to 4 years).
Secondary outcomes:
Other outcomes:
Locations:
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
state: Test2
Study officials:
affiliation: National Taiwan University Hospital
name: Shu-Wen Lin
role: PRINCIPAL_INVESTIGATOR
References: