Ignite Creation Date:
2024-10-26 @ 3:39 PM
Last Modification Date:
2024-10-26 @ 3:39 PM
Study NCT ID:
NCT06583642
Status:
NOT_YET_RECRUITING
Last Update Posted:
None
First Post:
2024-09-01
Brief Title:
Antimicrobial Therapeutic Drug Monitoring During Lung Transplant Perioperative Phase
Sponsor:
None
Organization:
None
Study Overview
Official Title:
Antimicrobial Therapeutic Drug Monitoring During Lung Transplant Perioperative Phase
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Background Post-LUTX pneumonia represents a leading cause of death along the first month after LUTX Donor-derived transmission of pathogenic species occurs up to 25 of recipients receiving a graft with a positive BAL culture despite in-vitro adequate antimicrobial prophylaxis
Hypothesis LUTX recipients are either exposed to suboptimal antimicrobial doses or antimicrobial penetration into the lug parenchyma is altered either due to surgery absence of bronchial anastomoses or to the hyperinflammatory state
Methods LUTX recipients admitted to the intensive care unit at the Fondazione IRCCS Ca Granda Policlinico Hospital According to the institutional perioperative prophylaxis protocol and the donorrecipient ecology the most frequent antimicrobial molecules administered will be cefepime vancomycin and meropenem Antimicrobial pharmacokinetics will be investigated at three timepoints Plasma levels of the ongoing antimicrobial molecule will be assessed at ICU admission on postoperative day 1 and on postoperative day 3 Bronchoalveolar lavage BAL samples for the measurement of BAL antimicrobial levels will be collected during the BAL performed for clinical indication on postoperative day 1 and on postoperative day 3
Absolute plasma and BAL antimicrobial levels will be assessed The ratio of BAL to plasma dosage of antimicrobial will be assessed to evaluate antimicrobial penetration within the target tissue Correlation between both plasma and BAL antimicrobial dosage and recipients postoperative fluid balance body weight vasopressor requirement renal function will be performed
Hypothesis LUTX recipients are either exposed to suboptimal antimicrobial doses or antimicrobial penetration into the lug parenchyma is altered either due to surgery absence of bronchial anastomoses or to the hyperinflammatory state
Methods LUTX recipients admitted to the intensive care unit at the Fondazione IRCCS Ca Granda Policlinico Hospital According to the institutional perioperative prophylaxis protocol and the donorrecipient ecology the most frequent antimicrobial molecules administered will be cefepime vancomycin and meropenem Antimicrobial pharmacokinetics will be investigated at three timepoints Plasma levels of the ongoing antimicrobial molecule will be assessed at ICU admission on postoperative day 1 and on postoperative day 3 Bronchoalveolar lavage BAL samples for the measurement of BAL antimicrobial levels will be collected during the BAL performed for clinical indication on postoperative day 1 and on postoperative day 3
Absolute plasma and BAL antimicrobial levels will be assessed The ratio of BAL to plasma dosage of antimicrobial will be assessed to evaluate antimicrobial penetration within the target tissue Correlation between both plasma and BAL antimicrobial dosage and recipients postoperative fluid balance body weight vasopressor requirement renal function will be performed
Detailed Description:
1 BACKGROUND
Lung Transplantation LUTX is the curative treatment for selected patients with end-stage lung disease Despite continuous optimization of recipients perioperative phase morbidity and mortality remain about 20 Bacterial infections are a leading cause of death in the early post-transplant period
Donor-recipient transmission of pathogens plays an actual role in worsening graft function The rate of donor with bacterial growth on the pre-LUTX bronchoalveolar lavage BAL is high 36Furthermore among uncolonized recipients receiving a graft with a positive BAL carries the risk of developing a donor-derived infection DDI in almost one quarter of cases affecting early graft function despite recipients were already treated with an in-vitro appropriate antibiotic therapy In this scenario the adequacy of perioperative antimicrobial prophylaxis might play a major in preventing either donor derived pulmonary or surgical site infections
Aim of the present study is to describe the PK of the most frequently used perioperative antimicrobials ie cefepime meropenem and vancomycin in plasma and in the bronchoalveolar lavage of patients undergoing double LUTX during the immediate postoperative phase
2 HYPOTHESIS of the study
Hypothesis of the study is that LUTX recipients are either exposed to suboptimal antimicrobial doses or antimicrobial penetration into the lug parenchyma is altered either due to surgery absence of bronchial anastomoses or to the hyperinflammatory state
Objective of the study is to describe and model the PK of cefepime meropenem and vancomycin in adult patients undergone primary double LUTX
3 METHODS
Prospective observational single-center pharmacological biological no-profit study
31 Primary Endpoints PKPD of cefepime vancomycin and meropenem in adult patients undergone primary double lung transplant
32 Secondary Endpoints
1 To measure the ratio between BAL fluid and plasma antibiotic level of antimicrobials in order to quantify the antimicrobial penetration into the lung tissue
2 To identify the clinical factors correlated to subtherapeutic suboptimal exposure of antimicrobials in LUTX recipients perioperative phase
33 Setting The study will be carried out in the Institutional ICU General Intensive Care Unit EVecla as well as the thoracic surgery and pneumology unit
4 PROCEDURES
Participation in the study will not change the standard enlistment protocol the surgery procedure or anesthesiologic management
41 Drug Administration
All the patients will be treated as per standard clinical management In particular vancomycin cefepime and meropenem will be provided to the patients as per their international approved and Italian Agenzia Italiana del Farmaco indications following their drug information leaflet at discretion of the caring physician
In particular
Cefepime represents the Institutional molecule of choice for perioperative prophylaxis A loading dose of 2g is administered before surgical incision and repeated every 4 hours along surgery Additional 1g dose is administered whenever severe bleeding 15Lt occurs or ECMO support is required Postoperatively at ICU admission a continuous infusion of 6gday is started and then prosecuted stopped or modified according to the result of the mPCR on BAL performed on the 3rd postoperative day Dose adjustment will be performed by the treating physician according to daily measured patients creatinine clearance
Vancomycin is administered before surgical incision at a dose 15mgKg and not repeated throughout surgery Whenever either donor or recipient BAL will test positive for methicillin resistant staphylococcus aureus Vancomycin treatment will be started at a dose of 25mgkg loading dose followed by continuous infusion of 20mgkg Daily plasma level will be assessed by the treating physician and dose adjustment will be performed accordingly
Meropenem will be started whenever either the donor or the recipients BAL will test positive for CTX-M mechanism of antimicrobial resistance Meropenem will be administered with a loading dose of 2g followed by a continuous infusion of 6gday Dose adjustment will be performed by the treating physician according to daily measured patients creatinine clearance
42 Study Procedures
Once admitted to the Intensive Care Unit patients a continuous infusion of cefepime 6gday will be started A 4 ml blood sample remnant from the daily blood lab tests performed in the ICU will be collected for the measurement of antimicrobial plasma level immediately after surgery The blood sample will be centrifuged at 4C 3000 rpm for 15 min Plasma sample collected in a deidentified cryovial will be stored at -80C in a refrigerator located in the Intensive Care Unit Simultaneously measurement of patient weight arterial and venous blood gas analysis to calculate intrapulmonary shunt and lung mechanics ie static lung compliance will be performed
Similarly the first morning and at 72h after LUTX the thoracic surgeon will perform a bronchoscopy to check for the integrity of bronchial anastomosis and will perform a surveillance BAL which will be processed for both fast and standard microbiological tests At each BAL performed 4 mL of discard BAL sample will be collected for the measurement of BAL antimicrobial level Simultaneously to the BAL a 4 ml blood sample remnant from the daily blood lab tests performed in the ICU will be collected for the measurement of antimicrobial plasma level The blood sample will be centrifuged at 4C 3000 rpm for 15 min Plasma sample collected in a deidentified cryovial will be stored at -80C in a refrigerator located in the Intensive Care Unit Simultaneously measurement of patient weight arterial and venous blood gas analysis to calculate intrapulmonary shunt and lung mechanics ie static lung compliance will be performed Renal function ie creatinine clearance and fraction of excreted urea and sodium measured daily in the Intensive Care Unit will be collected A chest X-Ray performed per clinical practice to grade Primary graft dysfunction at 24 and 72 hours after LUTX will be collected
In summary to carry out the PK study we will collect a total amount of 12 mL of blood and 8 mL of bronchoalveolar lavage Those samples will be transferred to the collaborating center Ospedale Luigi Sacco and analyzed for PK study as follows
Blood samples will be collected at ICU admission the first morning after LuTx and at 72h after LUTX Each blood sample 4 mL will be centrifuged and plasma samples stored at -20C until analysis
Bronchoalveolar lavage samples will be collected exclusively first morning after LuTx and at 72h after LUTX Each BAL sample 4 mL will be centrifuged and supernatant samples stored at -20C until analysis
Thus cryopreserved samples will be shipped to the collaborating center ASST Fatebenefratelli Sacco University Hospital Milan Italy at the end of the recruitment period and thus tests will be performed The antibiotic concentrations will be determined using an ultra-performance liquid chromatography-tandem mass spectrometry method LC-MSMS After purification through precipitation and dilution with a solution of methanol acetonitrile and water with 01 formic acid 1µL will be injected The chromatographic separation will be achieved using a gradient acetonitrile and water with formic acid 01 on a reversed-phase analytical column acuity UPLC BEH C18 170lm2150mm Waters Milan Italy For quantification the analysis will be performed in ESI-positive mode Then PK modeling will be carried out as previously done by the collaborating center
Lung Transplantation LUTX is the curative treatment for selected patients with end-stage lung disease Despite continuous optimization of recipients perioperative phase morbidity and mortality remain about 20 Bacterial infections are a leading cause of death in the early post-transplant period
Donor-recipient transmission of pathogens plays an actual role in worsening graft function The rate of donor with bacterial growth on the pre-LUTX bronchoalveolar lavage BAL is high 36Furthermore among uncolonized recipients receiving a graft with a positive BAL carries the risk of developing a donor-derived infection DDI in almost one quarter of cases affecting early graft function despite recipients were already treated with an in-vitro appropriate antibiotic therapy In this scenario the adequacy of perioperative antimicrobial prophylaxis might play a major in preventing either donor derived pulmonary or surgical site infections
Aim of the present study is to describe the PK of the most frequently used perioperative antimicrobials ie cefepime meropenem and vancomycin in plasma and in the bronchoalveolar lavage of patients undergoing double LUTX during the immediate postoperative phase
2 HYPOTHESIS of the study
Hypothesis of the study is that LUTX recipients are either exposed to suboptimal antimicrobial doses or antimicrobial penetration into the lug parenchyma is altered either due to surgery absence of bronchial anastomoses or to the hyperinflammatory state
Objective of the study is to describe and model the PK of cefepime meropenem and vancomycin in adult patients undergone primary double LUTX
3 METHODS
Prospective observational single-center pharmacological biological no-profit study
31 Primary Endpoints PKPD of cefepime vancomycin and meropenem in adult patients undergone primary double lung transplant
32 Secondary Endpoints
1 To measure the ratio between BAL fluid and plasma antibiotic level of antimicrobials in order to quantify the antimicrobial penetration into the lung tissue
2 To identify the clinical factors correlated to subtherapeutic suboptimal exposure of antimicrobials in LUTX recipients perioperative phase
33 Setting The study will be carried out in the Institutional ICU General Intensive Care Unit EVecla as well as the thoracic surgery and pneumology unit
4 PROCEDURES
Participation in the study will not change the standard enlistment protocol the surgery procedure or anesthesiologic management
41 Drug Administration
All the patients will be treated as per standard clinical management In particular vancomycin cefepime and meropenem will be provided to the patients as per their international approved and Italian Agenzia Italiana del Farmaco indications following their drug information leaflet at discretion of the caring physician
In particular
Cefepime represents the Institutional molecule of choice for perioperative prophylaxis A loading dose of 2g is administered before surgical incision and repeated every 4 hours along surgery Additional 1g dose is administered whenever severe bleeding 15Lt occurs or ECMO support is required Postoperatively at ICU admission a continuous infusion of 6gday is started and then prosecuted stopped or modified according to the result of the mPCR on BAL performed on the 3rd postoperative day Dose adjustment will be performed by the treating physician according to daily measured patients creatinine clearance
Vancomycin is administered before surgical incision at a dose 15mgKg and not repeated throughout surgery Whenever either donor or recipient BAL will test positive for methicillin resistant staphylococcus aureus Vancomycin treatment will be started at a dose of 25mgkg loading dose followed by continuous infusion of 20mgkg Daily plasma level will be assessed by the treating physician and dose adjustment will be performed accordingly
Meropenem will be started whenever either the donor or the recipients BAL will test positive for CTX-M mechanism of antimicrobial resistance Meropenem will be administered with a loading dose of 2g followed by a continuous infusion of 6gday Dose adjustment will be performed by the treating physician according to daily measured patients creatinine clearance
42 Study Procedures
Once admitted to the Intensive Care Unit patients a continuous infusion of cefepime 6gday will be started A 4 ml blood sample remnant from the daily blood lab tests performed in the ICU will be collected for the measurement of antimicrobial plasma level immediately after surgery The blood sample will be centrifuged at 4C 3000 rpm for 15 min Plasma sample collected in a deidentified cryovial will be stored at -80C in a refrigerator located in the Intensive Care Unit Simultaneously measurement of patient weight arterial and venous blood gas analysis to calculate intrapulmonary shunt and lung mechanics ie static lung compliance will be performed
Similarly the first morning and at 72h after LUTX the thoracic surgeon will perform a bronchoscopy to check for the integrity of bronchial anastomosis and will perform a surveillance BAL which will be processed for both fast and standard microbiological tests At each BAL performed 4 mL of discard BAL sample will be collected for the measurement of BAL antimicrobial level Simultaneously to the BAL a 4 ml blood sample remnant from the daily blood lab tests performed in the ICU will be collected for the measurement of antimicrobial plasma level The blood sample will be centrifuged at 4C 3000 rpm for 15 min Plasma sample collected in a deidentified cryovial will be stored at -80C in a refrigerator located in the Intensive Care Unit Simultaneously measurement of patient weight arterial and venous blood gas analysis to calculate intrapulmonary shunt and lung mechanics ie static lung compliance will be performed Renal function ie creatinine clearance and fraction of excreted urea and sodium measured daily in the Intensive Care Unit will be collected A chest X-Ray performed per clinical practice to grade Primary graft dysfunction at 24 and 72 hours after LUTX will be collected
In summary to carry out the PK study we will collect a total amount of 12 mL of blood and 8 mL of bronchoalveolar lavage Those samples will be transferred to the collaborating center Ospedale Luigi Sacco and analyzed for PK study as follows
Blood samples will be collected at ICU admission the first morning after LuTx and at 72h after LUTX Each blood sample 4 mL will be centrifuged and plasma samples stored at -20C until analysis
Bronchoalveolar lavage samples will be collected exclusively first morning after LuTx and at 72h after LUTX Each BAL sample 4 mL will be centrifuged and supernatant samples stored at -20C until analysis
Thus cryopreserved samples will be shipped to the collaborating center ASST Fatebenefratelli Sacco University Hospital Milan Italy at the end of the recruitment period and thus tests will be performed The antibiotic concentrations will be determined using an ultra-performance liquid chromatography-tandem mass spectrometry method LC-MSMS After purification through precipitation and dilution with a solution of methanol acetonitrile and water with 01 formic acid 1µL will be injected The chromatographic separation will be achieved using a gradient acetonitrile and water with formic acid 01 on a reversed-phase analytical column acuity UPLC BEH C18 170lm2150mm Waters Milan Italy For quantification the analysis will be performed in ESI-positive mode Then PK modeling will be carried out as previously done by the collaborating center
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None