Federico Pea - Academia.edu (original) (raw)

Papers by Federico Pea

Research paper thumbnail of Population Pharmacokinetic and Pharmacodynamic Analysis of Dalbavancin for Long-Term Treatment of Subacute and/or Chronic Infectious Diseases: The Major Role of Therapeutic Drug Monitoring

Antibiotics

A population pharmacokinetic analysis of dalbavancin was conducted in patients with different inf... more A population pharmacokinetic analysis of dalbavancin was conducted in patients with different infection sites. Non-linear mixed effect modeling was used for pharmacokinetic analysis and covariate evaluation. Monte Carlo simulations assessed the probability of target attainment (PTA) of total dalbavancin concentration ≥ 8.04 mg/L over time (associated with ≥90% probability of optimal pharmacodynamic target attainment of fAUC24h/MIC > 111.1 against S. aureus) associated with a single or double dosage, one week apart, of 1000 or 1500 mg in patients with different classes of renal function. Sixty-nine patients with 289 concentrations were included. Most of them (53/69, 76.8%) had bone and joint infections. A two-compartment model adequately fitted dalbavancin concentration–time data. Creatinine clearance (CLCR) was the only covariate associated with dalbavancin clearance. Monte Carlo simulations showed that, in patients with severe renal dysfunction, the 1000 mg single or double one ...

Research paper thumbnail of Physiological Manifestations of Critical Illness

Antibiotic Pharmacokinetic/Pharmacodynamic Considerations in the Critically Ill, 2017

Critical illness is a condition that may greatly affect the pharmacokinetic behavior of antibioti... more Critical illness is a condition that may greatly affect the pharmacokinetic behavior of antibiotics. It is characterized by several manifestations that may occur because of different underlying diseases. These manifestations, by altering mainly the volume of distribution (Vd) and the clearance (CL) of a given antibiotic, are expected to cause drug overexposure or underexposure when standard doses of antibiotics are administered to critically ill patients. From a clinical standpoint, critically ill patients are very different from stable patients with normal renal function or even from healthy volunteers. This means that the dose of many antibiotics and the mode of administering them should be different in order to ensure adequate treatment. 3.2 Physicochemical Properties of Antibiotics and Critical Illness As a rule, the influence that critical illness may exert on antibiotic pharmacokinetics may significantly differ according to the physicochemical properties of the antibiotics (Table 3.1). In this regard, it's very useful to split antibiotics into two major categories, namely hydrophilic and lipophilic agents [1].

Research paper thumbnail of Assessment of a PK/PD Target of Continuous Infusion Beta-Lactams Useful for Preventing Microbiological Failure and/or Resistance Development in Critically Ill Patients Affected by Documented Gram-Negative Infections

Antibiotics, 2021

Background: Emerging data suggest that more aggressive beta-lactam PK/PD targets could minimize t... more Background: Emerging data suggest that more aggressive beta-lactam PK/PD targets could minimize the occurrence of microbiological failure and/or resistance development. This study aims to assess whether a PK/PD target threshold of continuous infusion (CI) beta-lactams may be useful in preventing microbiological failure and/or resistance development in critically ill patients affected by documented Gram-negative infections. Methods: Patients admitted to intensive care units from December 2020 to July 2021 receiving continuous infusion beta-lactams for documented Gram-negative infections and having at least one therapeutic drug monitoring in the first 72 h of treatment were included. A receiver operating characteristic (ROC) curve analysis was performed using the ratio between steady-state concentration and minimum inhibitory concentration (Css/MIC) ratio as the test variable and occurrence of microbiological failure as the state variable. Area under the curve (AUC) and 95% confidence...

Research paper thumbnail of Antimicrobial Dose Reduction in Continuous Renal Replacement Therapy: Myth or Real Need? A Practical Approach for Guiding Dose Optimization of Novel Antibiotics

Clinical Pharmacokinetics, 2021

Acute kidney injury represents a common complication in critically ill patients affected by septi... more Acute kidney injury represents a common complication in critically ill patients affected by septic shock and in many cases continuous renal replacement therapy (CRRT) may be required. In this scenario, antimicrobial dose optimization is highly challenging as the extracorporeal circuit may cause several pharmacokinetic alterations, which add up to volume of distribution and clearance variations resulting from sepsis. Variations in CRRT settings (i.e. modality of solute removal, type of filter material, blood flow rate and effluent flow rate), coupled with the presence of residual and/or recovering renal function, may cause dynamic variations in the clearance of hydrophilic antimicrobials. This means that dose reduction may not always be needed. Nowadays, the lack of pharmacokinetic data for novel antimicrobials during CRRT limits evidence-based dose recommendations for critically ill patients in this setting, thus making available evidence hardly applicable in real-world scenarios. This review aims to summarize the major determinants involved in antimicrobial clearance, and the available pharmacokinetic studies performed during CRRT involving novel antibiotics used for the management of multidrug-resistant Gram-positive and Gram-negative infections (namely ceftolozane-tazobactam, ceftazidime-avibactam, cefiderocol, imipenem-relebactam, meropenem-vaborbactam, ceftaroline, ceftobiprole, dalbavancin, and fosfomycin), providing a practical approach in guiding dose optimization in this special population.

Research paper thumbnail of Antimicrobial therapeutic drug monitoring in critically ill adult patients: a Position Paper#

Intensive Care Medicine, 2020

Purpose: This Position Paper aims to review and discuss the available data on therapeutic drug mo... more Purpose: This Position Paper aims to review and discuss the available data on therapeutic drug monitoring (TDM) of antibacterials, antifungals and antivirals in critically ill adult patients in the intensive care unit (ICU). This Position Paper also provides a practical guide on how TDM can be applied in routine clinical practice to improve therapeutic outcomes in critically ill adult patients. Methods: Literature review and analysis were performed by Panel Members nominated by the endorsing organisations,

Research paper thumbnail of Proactive therapeutic drug monitoring (TDM) may be helpful in managing long-term treatment with linezolid safely: findings from a monocentric, prospective, open-label, interventional study

Journal of Antimicrobial Chemotherapy, 2019

BackgroundThrombocytopenia may be a dose-dependent adverse effect of linezolid therapy.Objectives... more BackgroundThrombocytopenia may be a dose-dependent adverse effect of linezolid therapy.ObjectivesTo assess whether proactive therapeutic drug monitoring (TDM) could be helpful in preventing and/or in recovering from the occurrence of linezolid-induced thrombocytopenia during long-term treatment.MethodsThis was a monocentric, prospective, open-label, interventional study conducted between June 2015 and December 2017 among adult patients receiving >10 days of linezolid therapy and undergoing proactive TDM (desired trough level 2–8 mg/L) and platelet count assessment at day 3–5 and then once weekly up to the end of treatment.ResultsSixty-one patients were included. Twenty-eight (45.9%) always had desired trough level (group A) and 33 (54.1%) experienced linezolid overexposure (group B) [29/33 transiently (subgroup B1) and 4/33 persistently (subgroup B2)]. No patient experienced linezolid underexposure. Median duration of treatment for the different groups ranged between 19 and 54 da...

Research paper thumbnail of Clinical and pharmacokinetic drug evaluation of delafloxacin for the treatment of acute bacterial skin and skin structure infections

Expert opinion on drug metabolism & toxicology, 2017

In the era of multi-drug resistant pathogens, the adequate treatment of skin and skin structure i... more In the era of multi-drug resistant pathogens, the adequate treatment of skin and skin structure infections remains a challenge for clinicians. Delafloxacin, with its broad spectrum against Gram-positive, Gram-negative and anaerobic organisms, represents a new therapeutic option in this setting, especially when coverage of methicillin-resistant Staphylococcus aureus is required in the empirical or targeted approach. Areas covered: In this drug evaluation, the Authors have reviewed the pharmacokinetic and pharmacodynamic characteristics of delafloxacin. In addition, recent data on clinical efficacy and safety from clinical trials have been included. Expert opinion: Delafloxacin represents an attractive therapeutic option due to a broad antimicrobial and favorable pharmacokinetic and pharmacodynamic profile. Several in vitro studies have demonstrated the low potential for resistance selection if used in empirical regimens. Delafloxacin is a promising candidate for the treatment of Gram...

Research paper thumbnail of Ceftolozane/tazobactam: place in therapy

Expert review of anti-infective therapy, Apr 1, 2018

Ceftolozane/tazobactam (C/T) is a new antibiotic resulting from the combination of a novel cephal... more Ceftolozane/tazobactam (C/T) is a new antibiotic resulting from the combination of a novel cephalosporin, structurally similar to ceftazidime, with tazobactam, a well-known beta-lactamase inhibitor. C/T remains active against extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae and multi-drug resistant (MDR) P. aeruginosa, and has been recently approved for the treatment of complicated intra-abdominal infections (cIAI) and complicated urinary infections (cUTI). A trial on hospital-acquired pneumonia is ongoing. Areas covered: The place in therapy of C/T is delineated by addressing the following main topics: (i) antimicrobial properties; (ii) pharmacological properties; (iii) results of clinical studies. Expert commentary: C/T is approved for cIAI and cUTI. However, the drug has a special value for clinicians in any kind of infectious localization for two main reasons. The first is that C/T is especially valuable in suspected or documented severe infections due to MDR P....

Research paper thumbnail of A 10-Year Experience of Therapeutic Drug Monitoring (TDM) of Linezolid in a Hospital-wide Population of Patients Receiving Conventional Dosing: Is there Enough Evidence for Suggesting TDM in the Majority of Patients?

Basic & Clinical Pharmacology & Toxicology, 2017

A retrospective study was conducted to assess our 10-year experience of therapeutic drug monitori... more A retrospective study was conducted to assess our 10-year experience of therapeutic drug monitoring (TDM) of linezolid in a large patient population to establish whether conventional dosing may result in adequate drug exposure in the majority of patients. Patients included in this study underwent TDM of linezolid trough concentration (C min) during treatment with conventional doses of 600 mg every 12 hr in the period between January 2007 and June 2016. The desired range of C min was set between 2 and 7 mg/L (underexposure, C min < 2 mg/L; overexposure, C min > 7 mg/L). Multivariate logistic regression analysis investigated variables potentially correlated with linezolid C min. One thousand and forty-nine patients had 2484 linezolid C min assessed during treatment with conventional doses. Median (IQR) linezolid C min was 5.08 mg/L (2.78-8.52 mg/L). Linezolid C min was within the desired range in 50.8% of cases (1262/2484). Overexposure (n = 821; 33%) occurred much more frequently than underexposure (n = 401; 16.2%) and was severe (>20 mg/L) in 3.9% of cases (98/2484). Linezolid overexposure was significantly associated with CrCL C-G estimates ≤40 mL/min. (OR 1.463; 95% CI 1.124-1.904, p = 0.005). Linezolid underexposure was significantly associated with CrCL C-G estimates >100 mL/min. (OR 3.046; 95% CI 2.234-4.152, p < 0.001). Linezolid C min was not correlated linearly with CrCL C-G (R 2 = 0.061). Variability in renal function explained only partially the very wide interindividual linezolid C min variability. Our study suggests that TDM could represent a valuable approach in optimizing linezolid exposure in the majority of patients.

Research paper thumbnail of A 1 year retrospective audit of quality indicators of clinical pharmacological advice for personalized linezolid dosing: one stone for two birds?

British Journal of Clinical Pharmacology, 2015

This study explored the clinical and economic impact of clinical pharmacological advice (CPA) (ba... more This study explored the clinical and economic impact of clinical pharmacological advice (CPA) (based on therapeutic drug monitoring [TDM] results, and on patients' characteristics and co-medications) on personalized linezolid therapy in a tertiary care hospital.

Research paper thumbnail of The effect of pathophysiology on pharmacokinetics in the critically ill patient--concepts appraised by the example of antimicrobial agents

Advanced drug delivery reviews, Jan 20, 2014

Critically ill patients are at high risk for development of life-threatening infection leading to... more Critically ill patients are at high risk for development of life-threatening infection leading to sepsis and multiple organ failure. Adequate antimicrobial therapy is pivotal for optimizing the chances of survival. However, efficient dosing is problematic because pathophysiological changes associated with critical illness impact on pharmacokinetics of mainly hydrophilic antimicrobials. Concentrations of hydrophilic antimicrobials may be increased because of decreased renal clearance due to acute kidney injury. Alternatively, antimicrobial concentrations may be decreased because of increased volume of distribution and augmented renal clearance provoked by systemic inflammatory response syndrome, capillary leak, decreased protein binding and administration of intravenous fluids and inotropes. Often multiple conditions that may influence pharmacokinetics are present at the same time thereby excessively complicating the prediction of adequate concentrations. In general, conditions leadi...

Research paper thumbnail of An international, multicentre survey of  -lactam antibiotic therapeutic drug monitoring practice in intensive care units

Journal of Antimicrobial Chemotherapy, 2014

Emerging evidence supports the use of therapeutic drug monitoring (TDM) of b-lactams for intensiv... more Emerging evidence supports the use of therapeutic drug monitoring (TDM) of b-lactams for intensive care unit (ICU) patients to optimize drug exposure, although limited detail is available on how sites run this service in practice. This multicentre survey study was performed to describe the various approaches used for b-lactam TDM in ICUs. Methods: A questionnaire survey was developed to describe various aspects relating to the conduct of b-lactam TDM in an ICU setting. Data sought included: b-lactams chosen for TDM, inclusion criteria for selecting patients, blood sampling strategy, analytical methods, pharmacokinetic (PK)/pharmacodynamic (PD) targets and dose adjustment strategies. Results: Nine ICUs were included in this survey. Respondents were either ICU or infectious disease physicians, pharmacists or clinical pharmacologists. Piperacillin (co-formulated with tazobactam) and meropenem (100% of units surveyed) were the b-lactams most commonly subject to TDM, followed by ceftazidime (78%), ceftriaxone (43%) and cefazolin (43%). Different chromatographic and microbiological methods were used for assay of b-lactam concentrations in blood and other biological fluids (e.g. CSF). There was significant variation in the PK/PD targets (100% fT .MIC up to 100% fT .4×MIC) and dose adjustment strategies used by each of the sites. Conclusions: Large variations were found in the type of b-lactams tested, the patients selected for TDM and drug assay methods. Significant variation observed in the PK/PD targets and dose adjustment strategies used supports the need for further studies that robustly define PK/PD targets for ICU patients to ensure a greater consistency of practice for dose adjustment strategies for optimizing b-lactam dosing with TDM.

Research paper thumbnail of High vancomycin dosage regimens required by intensive care unit patients cotreated with drugs to improve haemodynamics following cardiac surgical procedures

Journal of Antimicrobial Chemotherapy, 2000

Research paper thumbnail of Successful Long-Term Treatment of Cerebral Nocardiosis with Unexpectedly Low Doses of Linezolid in an Immunocompromised Patient Receiving Complex Polytherapy

Antimicrobial Agents and Chemotherapy, 2012

Cerebral nocardiosis is a severe infection that carries the highest mortality rate among all bact... more Cerebral nocardiosis is a severe infection that carries the highest mortality rate among all bacterial cerebral abscesses. We report on a case in an immunocompromised patient which was successfully treated with unexpectedly low doses of linezolid. Therapeutic drug monitoring was very helpful in highlighting issues of poor compliance and of drug-drug interactions.

Research paper thumbnail of Therapeutic Drug Monitoring of Linezolid: a Retrospective Monocentric Analysis

Antimicrobial Agents and Chemotherapy, 2010

The objective of the present retrospective observational study carried out in patients receiving ... more The objective of the present retrospective observational study carried out in patients receiving a standard dosage of linezolid and undergoing routine therapeutic drug monitoring (TDM) was to assess the interindividual variability in plasma exposure, to identify the prevalence of attainment of optimal pharmacodynamics, and to define if an intensive program of TDM may be warranted in some categories of patients. Linezolid plasma concentrations (trough [ C min ] and peak [ C max ] levels) were analyzed by means of a high-performance liquid chromatography (HPLC) method, and daily drug exposure was estimated (daily area under the plasma concentration-time curve [AUC 24 ]). The final database included 280 C min and 223 C max measurements performed in 92 patients who were treated with the fixed 600-mg dose every 12 h (q12h) intravenously ( n = 58) or orally ( n = 34). A wide variability was observed (median values [interquartile range]: 3.80 mg/liter [1.75 to 7.53 mg/liter] for C min , 14...

Research paper thumbnail of Dosing Nomograms for Attaining Optimum Concentrations of Meropenem by Continuous Infusion in Critically Ill Patients with Severe Gram-Negative Infections: a Pharmacokinetics/Pharmacodynamics-Based Approach

Antimicrobial Agents and Chemotherapy, 2012

The worrisome increase in Gram-negative bacteria with borderline susceptibility to carbapenems an... more The worrisome increase in Gram-negative bacteria with borderline susceptibility to carbapenems and of carbapenemase-producing Enterobacteriaceae has significantly undermined their efficacy. Continuous infusion may be the best way to maximize the time-dependent activity of meropenem. The aim of this study was to create dosing nomograms in relation to different creatinine clearance (CL Cr ) estimates for use in daily clinical practice to target the steady-state concentrations ( C ss s) of meropenem during continuous infusion at 8 to 16 mg/liter (after the administration of an initial loading dose of 1 to 2 g over 30 min). The correlation between meropenem clearance (CL m ) and CL Cr was retrospectively assessed in a cohort of critically ill patients (group 1, n = 67) to create a formula for dosage calculation to target C ss . The performance of this formula was validated in a similar cohort (group 2, n = 56) by comparison of the observed and the predicted C ss s. A significant relatio...

Research paper thumbnail of Expert clinical pharmacological advice may make an antimicrobial TDM program for emerging candidates more clinically useful in tailoring therapy of critically ill patients

Critical Care

Background Therapeutic drug monitoring (TDM) may represent an invaluable tool for optimizing anti... more Background Therapeutic drug monitoring (TDM) may represent an invaluable tool for optimizing antimicrobial therapy in septic patients, but extensive use is burdened by barriers. The aim of this study was to assess the impact of a newly established expert clinical pharmacological advice (ECPA) program in improving the clinical usefulness of an already existing TDM program for emerging candidates in tailoring antimicrobial therapy among critically ill patients. Methods This retrospective observational study included an organizational phase (OP) and an assessment phase (AP). During the OP (January–June 2021), specific actions were organized by MD clinical pharmacologists together with bioanalytical experts, clinical engineers, and ICU clinicians. During the AP (July–December 2021), the impact of these actions in optimizing antimicrobial treatment of the critically ill patients was assessed. Four indicators of performance of the TDM-guided real-time ECPA program were identified [total T...

Research paper thumbnail of Pharmacokinetic Aspects of Treating Infections in the Intensive Care Unit: Focus on Drug Interactions

Clinical Pharmacokinetics, 2001

Research paper thumbnail of Hyperlactacidemia Potentially Due to Linezolid Overexposure in a Liver Transplant Recipient

Clinical Infectious Diseases, 2006

Research paper thumbnail of Ceftazidime in Acute Myeloid Leukemia Patients with Febrile Neutropenia: Helpfulness of Continuous Intravenous Infusion in Maximizing Pharmacodynamic Exposure

Antimicrobial Agents and Chemotherapy, 2005

The pharmacokinetic-pharmacodynamic profile of a fixed 6-g daily continuous intravenous infusion ... more The pharmacokinetic-pharmacodynamic profile of a fixed 6-g daily continuous intravenous infusion of ceftazidime was assessed in 20 febrile neutropenic patients with acute myeloid leukemia. Mean steady-state ceftazidime concentrations averaging 40 mg/liter from day 2 on ensured maximized pharmacodynamic exposure (values close to four to five times the MIC breakpoint against Pseudomonas aeruginosa). However, large intra-and interindividual pharmacokinetic variability was documented throughout the study period.

Research paper thumbnail of Population Pharmacokinetic and Pharmacodynamic Analysis of Dalbavancin for Long-Term Treatment of Subacute and/or Chronic Infectious Diseases: The Major Role of Therapeutic Drug Monitoring

Antibiotics

A population pharmacokinetic analysis of dalbavancin was conducted in patients with different inf... more A population pharmacokinetic analysis of dalbavancin was conducted in patients with different infection sites. Non-linear mixed effect modeling was used for pharmacokinetic analysis and covariate evaluation. Monte Carlo simulations assessed the probability of target attainment (PTA) of total dalbavancin concentration ≥ 8.04 mg/L over time (associated with ≥90% probability of optimal pharmacodynamic target attainment of fAUC24h/MIC > 111.1 against S. aureus) associated with a single or double dosage, one week apart, of 1000 or 1500 mg in patients with different classes of renal function. Sixty-nine patients with 289 concentrations were included. Most of them (53/69, 76.8%) had bone and joint infections. A two-compartment model adequately fitted dalbavancin concentration–time data. Creatinine clearance (CLCR) was the only covariate associated with dalbavancin clearance. Monte Carlo simulations showed that, in patients with severe renal dysfunction, the 1000 mg single or double one ...

Research paper thumbnail of Physiological Manifestations of Critical Illness

Antibiotic Pharmacokinetic/Pharmacodynamic Considerations in the Critically Ill, 2017

Critical illness is a condition that may greatly affect the pharmacokinetic behavior of antibioti... more Critical illness is a condition that may greatly affect the pharmacokinetic behavior of antibiotics. It is characterized by several manifestations that may occur because of different underlying diseases. These manifestations, by altering mainly the volume of distribution (Vd) and the clearance (CL) of a given antibiotic, are expected to cause drug overexposure or underexposure when standard doses of antibiotics are administered to critically ill patients. From a clinical standpoint, critically ill patients are very different from stable patients with normal renal function or even from healthy volunteers. This means that the dose of many antibiotics and the mode of administering them should be different in order to ensure adequate treatment. 3.2 Physicochemical Properties of Antibiotics and Critical Illness As a rule, the influence that critical illness may exert on antibiotic pharmacokinetics may significantly differ according to the physicochemical properties of the antibiotics (Table 3.1). In this regard, it's very useful to split antibiotics into two major categories, namely hydrophilic and lipophilic agents [1].

Research paper thumbnail of Assessment of a PK/PD Target of Continuous Infusion Beta-Lactams Useful for Preventing Microbiological Failure and/or Resistance Development in Critically Ill Patients Affected by Documented Gram-Negative Infections

Antibiotics, 2021

Background: Emerging data suggest that more aggressive beta-lactam PK/PD targets could minimize t... more Background: Emerging data suggest that more aggressive beta-lactam PK/PD targets could minimize the occurrence of microbiological failure and/or resistance development. This study aims to assess whether a PK/PD target threshold of continuous infusion (CI) beta-lactams may be useful in preventing microbiological failure and/or resistance development in critically ill patients affected by documented Gram-negative infections. Methods: Patients admitted to intensive care units from December 2020 to July 2021 receiving continuous infusion beta-lactams for documented Gram-negative infections and having at least one therapeutic drug monitoring in the first 72 h of treatment were included. A receiver operating characteristic (ROC) curve analysis was performed using the ratio between steady-state concentration and minimum inhibitory concentration (Css/MIC) ratio as the test variable and occurrence of microbiological failure as the state variable. Area under the curve (AUC) and 95% confidence...

Research paper thumbnail of Antimicrobial Dose Reduction in Continuous Renal Replacement Therapy: Myth or Real Need? A Practical Approach for Guiding Dose Optimization of Novel Antibiotics

Clinical Pharmacokinetics, 2021

Acute kidney injury represents a common complication in critically ill patients affected by septi... more Acute kidney injury represents a common complication in critically ill patients affected by septic shock and in many cases continuous renal replacement therapy (CRRT) may be required. In this scenario, antimicrobial dose optimization is highly challenging as the extracorporeal circuit may cause several pharmacokinetic alterations, which add up to volume of distribution and clearance variations resulting from sepsis. Variations in CRRT settings (i.e. modality of solute removal, type of filter material, blood flow rate and effluent flow rate), coupled with the presence of residual and/or recovering renal function, may cause dynamic variations in the clearance of hydrophilic antimicrobials. This means that dose reduction may not always be needed. Nowadays, the lack of pharmacokinetic data for novel antimicrobials during CRRT limits evidence-based dose recommendations for critically ill patients in this setting, thus making available evidence hardly applicable in real-world scenarios. This review aims to summarize the major determinants involved in antimicrobial clearance, and the available pharmacokinetic studies performed during CRRT involving novel antibiotics used for the management of multidrug-resistant Gram-positive and Gram-negative infections (namely ceftolozane-tazobactam, ceftazidime-avibactam, cefiderocol, imipenem-relebactam, meropenem-vaborbactam, ceftaroline, ceftobiprole, dalbavancin, and fosfomycin), providing a practical approach in guiding dose optimization in this special population.

Research paper thumbnail of Antimicrobial therapeutic drug monitoring in critically ill adult patients: a Position Paper#

Intensive Care Medicine, 2020

Purpose: This Position Paper aims to review and discuss the available data on therapeutic drug mo... more Purpose: This Position Paper aims to review and discuss the available data on therapeutic drug monitoring (TDM) of antibacterials, antifungals and antivirals in critically ill adult patients in the intensive care unit (ICU). This Position Paper also provides a practical guide on how TDM can be applied in routine clinical practice to improve therapeutic outcomes in critically ill adult patients. Methods: Literature review and analysis were performed by Panel Members nominated by the endorsing organisations,

Research paper thumbnail of Proactive therapeutic drug monitoring (TDM) may be helpful in managing long-term treatment with linezolid safely: findings from a monocentric, prospective, open-label, interventional study

Journal of Antimicrobial Chemotherapy, 2019

BackgroundThrombocytopenia may be a dose-dependent adverse effect of linezolid therapy.Objectives... more BackgroundThrombocytopenia may be a dose-dependent adverse effect of linezolid therapy.ObjectivesTo assess whether proactive therapeutic drug monitoring (TDM) could be helpful in preventing and/or in recovering from the occurrence of linezolid-induced thrombocytopenia during long-term treatment.MethodsThis was a monocentric, prospective, open-label, interventional study conducted between June 2015 and December 2017 among adult patients receiving >10 days of linezolid therapy and undergoing proactive TDM (desired trough level 2–8 mg/L) and platelet count assessment at day 3–5 and then once weekly up to the end of treatment.ResultsSixty-one patients were included. Twenty-eight (45.9%) always had desired trough level (group A) and 33 (54.1%) experienced linezolid overexposure (group B) [29/33 transiently (subgroup B1) and 4/33 persistently (subgroup B2)]. No patient experienced linezolid underexposure. Median duration of treatment for the different groups ranged between 19 and 54 da...

Research paper thumbnail of Clinical and pharmacokinetic drug evaluation of delafloxacin for the treatment of acute bacterial skin and skin structure infections

Expert opinion on drug metabolism & toxicology, 2017

In the era of multi-drug resistant pathogens, the adequate treatment of skin and skin structure i... more In the era of multi-drug resistant pathogens, the adequate treatment of skin and skin structure infections remains a challenge for clinicians. Delafloxacin, with its broad spectrum against Gram-positive, Gram-negative and anaerobic organisms, represents a new therapeutic option in this setting, especially when coverage of methicillin-resistant Staphylococcus aureus is required in the empirical or targeted approach. Areas covered: In this drug evaluation, the Authors have reviewed the pharmacokinetic and pharmacodynamic characteristics of delafloxacin. In addition, recent data on clinical efficacy and safety from clinical trials have been included. Expert opinion: Delafloxacin represents an attractive therapeutic option due to a broad antimicrobial and favorable pharmacokinetic and pharmacodynamic profile. Several in vitro studies have demonstrated the low potential for resistance selection if used in empirical regimens. Delafloxacin is a promising candidate for the treatment of Gram...

Research paper thumbnail of Ceftolozane/tazobactam: place in therapy

Expert review of anti-infective therapy, Apr 1, 2018

Ceftolozane/tazobactam (C/T) is a new antibiotic resulting from the combination of a novel cephal... more Ceftolozane/tazobactam (C/T) is a new antibiotic resulting from the combination of a novel cephalosporin, structurally similar to ceftazidime, with tazobactam, a well-known beta-lactamase inhibitor. C/T remains active against extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae and multi-drug resistant (MDR) P. aeruginosa, and has been recently approved for the treatment of complicated intra-abdominal infections (cIAI) and complicated urinary infections (cUTI). A trial on hospital-acquired pneumonia is ongoing. Areas covered: The place in therapy of C/T is delineated by addressing the following main topics: (i) antimicrobial properties; (ii) pharmacological properties; (iii) results of clinical studies. Expert commentary: C/T is approved for cIAI and cUTI. However, the drug has a special value for clinicians in any kind of infectious localization for two main reasons. The first is that C/T is especially valuable in suspected or documented severe infections due to MDR P....

Research paper thumbnail of A 10-Year Experience of Therapeutic Drug Monitoring (TDM) of Linezolid in a Hospital-wide Population of Patients Receiving Conventional Dosing: Is there Enough Evidence for Suggesting TDM in the Majority of Patients?

Basic & Clinical Pharmacology & Toxicology, 2017

A retrospective study was conducted to assess our 10-year experience of therapeutic drug monitori... more A retrospective study was conducted to assess our 10-year experience of therapeutic drug monitoring (TDM) of linezolid in a large patient population to establish whether conventional dosing may result in adequate drug exposure in the majority of patients. Patients included in this study underwent TDM of linezolid trough concentration (C min) during treatment with conventional doses of 600 mg every 12 hr in the period between January 2007 and June 2016. The desired range of C min was set between 2 and 7 mg/L (underexposure, C min < 2 mg/L; overexposure, C min > 7 mg/L). Multivariate logistic regression analysis investigated variables potentially correlated with linezolid C min. One thousand and forty-nine patients had 2484 linezolid C min assessed during treatment with conventional doses. Median (IQR) linezolid C min was 5.08 mg/L (2.78-8.52 mg/L). Linezolid C min was within the desired range in 50.8% of cases (1262/2484). Overexposure (n = 821; 33%) occurred much more frequently than underexposure (n = 401; 16.2%) and was severe (>20 mg/L) in 3.9% of cases (98/2484). Linezolid overexposure was significantly associated with CrCL C-G estimates ≤40 mL/min. (OR 1.463; 95% CI 1.124-1.904, p = 0.005). Linezolid underexposure was significantly associated with CrCL C-G estimates >100 mL/min. (OR 3.046; 95% CI 2.234-4.152, p < 0.001). Linezolid C min was not correlated linearly with CrCL C-G (R 2 = 0.061). Variability in renal function explained only partially the very wide interindividual linezolid C min variability. Our study suggests that TDM could represent a valuable approach in optimizing linezolid exposure in the majority of patients.

Research paper thumbnail of A 1 year retrospective audit of quality indicators of clinical pharmacological advice for personalized linezolid dosing: one stone for two birds?

British Journal of Clinical Pharmacology, 2015

This study explored the clinical and economic impact of clinical pharmacological advice (CPA) (ba... more This study explored the clinical and economic impact of clinical pharmacological advice (CPA) (based on therapeutic drug monitoring [TDM] results, and on patients' characteristics and co-medications) on personalized linezolid therapy in a tertiary care hospital.

Research paper thumbnail of The effect of pathophysiology on pharmacokinetics in the critically ill patient--concepts appraised by the example of antimicrobial agents

Advanced drug delivery reviews, Jan 20, 2014

Critically ill patients are at high risk for development of life-threatening infection leading to... more Critically ill patients are at high risk for development of life-threatening infection leading to sepsis and multiple organ failure. Adequate antimicrobial therapy is pivotal for optimizing the chances of survival. However, efficient dosing is problematic because pathophysiological changes associated with critical illness impact on pharmacokinetics of mainly hydrophilic antimicrobials. Concentrations of hydrophilic antimicrobials may be increased because of decreased renal clearance due to acute kidney injury. Alternatively, antimicrobial concentrations may be decreased because of increased volume of distribution and augmented renal clearance provoked by systemic inflammatory response syndrome, capillary leak, decreased protein binding and administration of intravenous fluids and inotropes. Often multiple conditions that may influence pharmacokinetics are present at the same time thereby excessively complicating the prediction of adequate concentrations. In general, conditions leadi...

Research paper thumbnail of An international, multicentre survey of  -lactam antibiotic therapeutic drug monitoring practice in intensive care units

Journal of Antimicrobial Chemotherapy, 2014

Emerging evidence supports the use of therapeutic drug monitoring (TDM) of b-lactams for intensiv... more Emerging evidence supports the use of therapeutic drug monitoring (TDM) of b-lactams for intensive care unit (ICU) patients to optimize drug exposure, although limited detail is available on how sites run this service in practice. This multicentre survey study was performed to describe the various approaches used for b-lactam TDM in ICUs. Methods: A questionnaire survey was developed to describe various aspects relating to the conduct of b-lactam TDM in an ICU setting. Data sought included: b-lactams chosen for TDM, inclusion criteria for selecting patients, blood sampling strategy, analytical methods, pharmacokinetic (PK)/pharmacodynamic (PD) targets and dose adjustment strategies. Results: Nine ICUs were included in this survey. Respondents were either ICU or infectious disease physicians, pharmacists or clinical pharmacologists. Piperacillin (co-formulated with tazobactam) and meropenem (100% of units surveyed) were the b-lactams most commonly subject to TDM, followed by ceftazidime (78%), ceftriaxone (43%) and cefazolin (43%). Different chromatographic and microbiological methods were used for assay of b-lactam concentrations in blood and other biological fluids (e.g. CSF). There was significant variation in the PK/PD targets (100% fT .MIC up to 100% fT .4×MIC) and dose adjustment strategies used by each of the sites. Conclusions: Large variations were found in the type of b-lactams tested, the patients selected for TDM and drug assay methods. Significant variation observed in the PK/PD targets and dose adjustment strategies used supports the need for further studies that robustly define PK/PD targets for ICU patients to ensure a greater consistency of practice for dose adjustment strategies for optimizing b-lactam dosing with TDM.

Research paper thumbnail of High vancomycin dosage regimens required by intensive care unit patients cotreated with drugs to improve haemodynamics following cardiac surgical procedures

Journal of Antimicrobial Chemotherapy, 2000

Research paper thumbnail of Successful Long-Term Treatment of Cerebral Nocardiosis with Unexpectedly Low Doses of Linezolid in an Immunocompromised Patient Receiving Complex Polytherapy

Antimicrobial Agents and Chemotherapy, 2012

Cerebral nocardiosis is a severe infection that carries the highest mortality rate among all bact... more Cerebral nocardiosis is a severe infection that carries the highest mortality rate among all bacterial cerebral abscesses. We report on a case in an immunocompromised patient which was successfully treated with unexpectedly low doses of linezolid. Therapeutic drug monitoring was very helpful in highlighting issues of poor compliance and of drug-drug interactions.

Research paper thumbnail of Therapeutic Drug Monitoring of Linezolid: a Retrospective Monocentric Analysis

Antimicrobial Agents and Chemotherapy, 2010

The objective of the present retrospective observational study carried out in patients receiving ... more The objective of the present retrospective observational study carried out in patients receiving a standard dosage of linezolid and undergoing routine therapeutic drug monitoring (TDM) was to assess the interindividual variability in plasma exposure, to identify the prevalence of attainment of optimal pharmacodynamics, and to define if an intensive program of TDM may be warranted in some categories of patients. Linezolid plasma concentrations (trough [ C min ] and peak [ C max ] levels) were analyzed by means of a high-performance liquid chromatography (HPLC) method, and daily drug exposure was estimated (daily area under the plasma concentration-time curve [AUC 24 ]). The final database included 280 C min and 223 C max measurements performed in 92 patients who were treated with the fixed 600-mg dose every 12 h (q12h) intravenously ( n = 58) or orally ( n = 34). A wide variability was observed (median values [interquartile range]: 3.80 mg/liter [1.75 to 7.53 mg/liter] for C min , 14...

Research paper thumbnail of Dosing Nomograms for Attaining Optimum Concentrations of Meropenem by Continuous Infusion in Critically Ill Patients with Severe Gram-Negative Infections: a Pharmacokinetics/Pharmacodynamics-Based Approach

Antimicrobial Agents and Chemotherapy, 2012

The worrisome increase in Gram-negative bacteria with borderline susceptibility to carbapenems an... more The worrisome increase in Gram-negative bacteria with borderline susceptibility to carbapenems and of carbapenemase-producing Enterobacteriaceae has significantly undermined their efficacy. Continuous infusion may be the best way to maximize the time-dependent activity of meropenem. The aim of this study was to create dosing nomograms in relation to different creatinine clearance (CL Cr ) estimates for use in daily clinical practice to target the steady-state concentrations ( C ss s) of meropenem during continuous infusion at 8 to 16 mg/liter (after the administration of an initial loading dose of 1 to 2 g over 30 min). The correlation between meropenem clearance (CL m ) and CL Cr was retrospectively assessed in a cohort of critically ill patients (group 1, n = 67) to create a formula for dosage calculation to target C ss . The performance of this formula was validated in a similar cohort (group 2, n = 56) by comparison of the observed and the predicted C ss s. A significant relatio...

Research paper thumbnail of Expert clinical pharmacological advice may make an antimicrobial TDM program for emerging candidates more clinically useful in tailoring therapy of critically ill patients

Critical Care

Background Therapeutic drug monitoring (TDM) may represent an invaluable tool for optimizing anti... more Background Therapeutic drug monitoring (TDM) may represent an invaluable tool for optimizing antimicrobial therapy in septic patients, but extensive use is burdened by barriers. The aim of this study was to assess the impact of a newly established expert clinical pharmacological advice (ECPA) program in improving the clinical usefulness of an already existing TDM program for emerging candidates in tailoring antimicrobial therapy among critically ill patients. Methods This retrospective observational study included an organizational phase (OP) and an assessment phase (AP). During the OP (January–June 2021), specific actions were organized by MD clinical pharmacologists together with bioanalytical experts, clinical engineers, and ICU clinicians. During the AP (July–December 2021), the impact of these actions in optimizing antimicrobial treatment of the critically ill patients was assessed. Four indicators of performance of the TDM-guided real-time ECPA program were identified [total T...

Research paper thumbnail of Pharmacokinetic Aspects of Treating Infections in the Intensive Care Unit: Focus on Drug Interactions

Clinical Pharmacokinetics, 2001

Research paper thumbnail of Hyperlactacidemia Potentially Due to Linezolid Overexposure in a Liver Transplant Recipient

Clinical Infectious Diseases, 2006

Research paper thumbnail of Ceftazidime in Acute Myeloid Leukemia Patients with Febrile Neutropenia: Helpfulness of Continuous Intravenous Infusion in Maximizing Pharmacodynamic Exposure

Antimicrobial Agents and Chemotherapy, 2005

The pharmacokinetic-pharmacodynamic profile of a fixed 6-g daily continuous intravenous infusion ... more The pharmacokinetic-pharmacodynamic profile of a fixed 6-g daily continuous intravenous infusion of ceftazidime was assessed in 20 febrile neutropenic patients with acute myeloid leukemia. Mean steady-state ceftazidime concentrations averaging 40 mg/liter from day 2 on ensured maximized pharmacodynamic exposure (values close to four to five times the MIC breakpoint against Pseudomonas aeruginosa). However, large intra-and interindividual pharmacokinetic variability was documented throughout the study period.