The Cytokine Release Syndrome and/or the Proinflammatory Cytokines as Underlying Mechanisms of Downregulation of Drug Metabolism and Drug Transport: A Systematic Review of the Clinical Pharmacokinetics of Victim Drugs of this Drug-Disease Interaction Under Different Clinical Conditions

Background and Objective An ever-growing body of evidence supports the impact of cytokine modulation on the patient's phenotypic drug response. The aim of this systematic review was to analyze the clinical studies that assessed the pharmacokinetics of victim drugs of this drug-disease interaction in the presence of different scenarios of cytokine modulation in comparison with baseline conditions. Methods We conducted a systematic review by searching the PubMed-MEDLINE database from inception until February 2022 to retrieve prospective and/or retrospective observational studies, population pharmacokinetic studies, phase I studies, and/or case series/reports that investigated the impact of cytokine modulation on the pharmacokinetic behavior of victim drugs. Only studies providing quantitative pharmacokinetic data of victim drugs by comparing normal status versus clinical conditions with documented cytokine modulation or by assessing the influence of anti-inflammatory biological agents on metabolism and/or transport of victim drugs were included. Results Overall, 26 studies were included. Rheumatoid arthritis (6/26; 23.1%) and sepsis (5/26; 19.2%) were the two most frequently investigated pro-inflammatory clinical scenarios. The victim drug most frequently assessed was midazolam (14/26; 53.8%; as a probe for cytochrome P450 [CYP] 3A4). Cytokine modulation showed a moderate inhibitory effect on CYP3A4-mediated metabolism (area under the concentration-time curve increase and/or clearance decrease between 1.98-fold and 2.59-fold) and a weak-to-moderate inhibitory effect on CYP1A2, CYP2C9, and CYP2C19-mediated metabolism (in the area under the concentration-time curve increase or clearance decrease between 1.29-fold and 1.97-fold). Anti-interleukin-6 agents showed remarkable activity in counteracting downregulation of CYP3A4-mediated activity (increase in the area under the concentration-time curve between 1.75-fold and 2.56-fold). Conclusions Cytokine modulation may cause moderate or weak-to-moderate downregulation of metabolism/transport of victim drugs, and this may theoretically have relevant clinical consequences

Pharmacokinetic/pharmacodynamic issues for optimizing treatment with beta-lactams of Gram-negative infections in critically ill orthotopic liver transplant recipients: a comprehensive review

Orthotopic liver transplant (OLT) represents the standard of care for managing patients affected by end-stage and life-threatening liver diseases. Although a significant improvement in surgical techniques, immunosuppressant regimens, and prompt identification of early post-transplant complications resulted in better clinical outcome and survival in OLT recipients, the occurrence of early bacterial infections still represents a remarkable cause of morbidity and mortality. In this scenario, beta-lactams are the most frequent antimicrobials used in critical OLT recipients. The aim of this narrative review was to provide a comprehensive overview of the pathophysiological issues potentially affecting the pharmacokinetics of beta-lactams and to identify potential strategies for maximizing the likelihood of attaining adequate pharmacokinetic/pharmacodynamic (PK/PD) targets of beta-lactams in critically ill OLT recipients. A literature search was carried out on PubMed-MEDLINE database (until 31st March 2024) in order to retrieve clinical trials, real-world observational evidence, and/or case series/reports evaluating the PK/PD of traditional and novel beta-lactams in settings potentially involving critically ill OLT recipients. Retrieved evidence were categorized according to the concepts of the so-called “antimicrobial therapy puzzle”, specifically assessing a) beta-lactam PK/PD features, with specific regard to aggressive PK/PD target attainment; b) site of infection, with specific regard to beta-lactam penetration in the lung, ascitic fluid, and bile; and c) pathophysiological alterations, focusing mainly on those specifically associated with OLT. Overall, several research gaps still exist in assessing the PK behavior of beta-lactams in critical OLT recipients. The impact of specific OLT-associated pathophysiological alterations on the attainment of optimal PK/PD targets may represent an important field in which further studies are warranted. Assessing the relationship between aggressive beta-lactam PK/PD target attainment and clinical outcome in critical OLT recipients will represent a major challenge in the next future

Ceftriaxone for methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia: a matter of dosages?

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Janus Kinase Inhibitors and Coronavirus Disease (COVID)-19: Rationale, Clinical Evidence and Safety Issues

: We are witnessing a paradigm shift in drug development and clinical practice to fight the novel coronavirus disease (COVID-19), and a number of clinical trials have been or are being testing various pharmacological approaches to counteract viral load and its complications such as cytokine storm. However, data on the effectiveness of antiviral and immune therapies are still inconclusive and inconsistent. As compared to other candidate drugs to treat COVID-19, Janus Kinase (JAK) inhibitors, including baricitinib and ruxolitinib, possess key pharmacological features for a potentially successful repurposing: convenient oral administration, favorable pharmacokinetic profile, multifunctional pharmacodynamics by exerting dual anti-inflammatory and anti-viral effects. Baricitinib, originally approved for rheumatoid arthritis, received Emergency Use Authorization in November 2020 by the Food and Drug Administration in combination with remdesivir for the treatment of COVID-19 in hospitalized patients ≥ 2 years old who require supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation. By July 2021, the European Medicines Agency is also expected to issue the opinion on whether or not to extend its use in hospitalised patients from 10 years of age who require supplemental oxygen. Ruxolitinib, approved for myelofibrosis, was prescribed in patients with COVID-19 within an open-label Emergency Expanded Access Plan. This review will address key milestones in the discovery and use of JAK inhibitors in COVID-19, from artificial intelligence to current clinical evidence, including real world experience, and critically appraise emerging safety issues, namely infections, thrombosis, and liver injury. An outlook to ongoing studies (clinicaltrials.gov) and unpublished pharmacovigilance data is also offered

Real-Time TDM-Based Expert Clinical Pharmacological Advice Program for Attaining Aggressive Pharmacokinetic/Pharmacodynamic Target of Continuous Infusion Meropenem in the Treatment of Critically Ill Patients with Documented Gram-Negative Infections Undergoing Continuous Veno-Venous Hemodiafiltration

: (1) Objectives: to describe the pharmacokinetic/pharmacodynamic (PK/PD) profile of continuous infusion (CI) meropenem in critical patients with documented Gram-negative infections undergoing continuous veno-venous hemodiafiltration (CVVHDF) and to assess the relationship with microbiological outcome. (2) Methods: Data were retrospectively retrieved for patients admitted to the general and the post-transplant intensive care units in the period October 2022-May 2023 who underwent CVVHDF during treatment with CI meropenem optimized by means of a real-time therapeutic drug monitoring (TDM)-based expert clinical pharmacological advice (ECPA) program for documented Gram-negative infections. Steady-state meropenem plasma concentrations were measured, and the free fractions (fCss) were calculated. Meropenem total clearance (CLtot) was calculated at each TDM assessment, and the impact of CVVHDF dose intensity and of residual diuresis on CLtot was investigated by means of linear regression. Optimal meropenem PK/PD target attainment was defined as an fCss/MIC ratio > 4. The relationship between meropenem PK/PD target attainment and microbiological outcome was assessed. (3) Results: A total of 24 critical patients (median age 68 years; male 62.5%) with documented Gram-negative infections were included. Median (IQR) meropenem fCss was 19.9 mg/L (17.4-28.0 mg/L). Median (IQR) CLtot was 3.89 L/h (3.28-5.29 L/h), and median (IQR) CVVHDF dose intensity was 37.4 mL/kg/h (33.8-44.6 mL/kg/h). Meropenem dosing adjustments were provided in 20 out of 24 first TDM assessments (83.3%, all decreases) and overall in 26 out of the 51 total ECPA cases (51.0%). Meropenem PK/PD target attainment was always optimal, and microbiological eradication was achieved in 90.5% of assessable cases. (4) Conclusion: the real-time TDM-guided ECPA program was useful in attaining aggressive PK/PD targeting with CI meropenem in critically ill patients undergoing high-intensity CVVHDF and allowed microbiological eradication in most cases with dosing regimens ranging between 125 and 500 mg q6h over 6 h

Liver Injury with Nintedanib: A Pharmacovigilance-Pharmacokinetic Appraisal

Drug-induced liver injury (DILI) with nintedanib has emerged as an adverse event of special interest in premarketing clinical trials. We characterized DILI with nintedanib in the real world and explored the underlying pharmacological basis. First, we assessed serious hepatic events reported to the Food and Drug Administration's Adverse Event Reporting System by combining the disproportionality approach [reporting odds ratio (ROR) with 95% confidence interval (CI)] with individual case assessment. Demographic and clinical features were inspected (seriousness, onset, discontinuation, dechallenge/rechallenge, concomitant drugs) to implement an ad hoc causality assessment scoring system. Second, we appraised physiochemical and pharmacokinetic parameters possibly predictive of DILI occurrence. Significant disproportionality was found for nintedanib as compared to pirfenidone (N = 91; ROR = 4.77; 95% CI = 3.15-7.39). Asian population, low body weight (59 kg), and rapid DILI onset (13.5 days) emerged as clinical features. Hospitalization and discontinuation were found in a significant proportion of cases (32% and 36%, respectively). In 24% of the cases, at least two potentially hepatotoxic drugs (statins, proton pump inhibitors, antibiotics) were recorded. Causality was at least possible in 92.3% of the cases. High lipophilicity and predicted in silico inhibition of liver transporters emerged as potential pharmacokinetic features supporting the biological plausibility. Although causality cannot be demonstrated, clinicians should consider early monitoring and medication review on a case-by-case basis

Does therapeutic drug monitoring (TDM) of trough concentrations suffice for optimizing preemptive therapy with ganciclovir of cytomegalovirus infections in non-renal solid organ transplant recipients?

Objectives: The aim of this study is to explore the relationship between ganciclovir exposure and clinical efficacy and/or safety in non-renal solid organ transplant (SOT) recipients receiving preemptive therapy with ganciclovir/valganciclovir and undergoing therapeutic drug monitoring (TDM)-guided dosing optimization. Methods: Non-renal SOT recipients admitted to IRCCS Azienda Ospedaliero-Universitaria of Bologna receiving preemptive therapy with ganciclovir or valganciclovir for active cytomegalovirus (CMV) infection and who underwent at least one TDM were included. Desired ganciclovir Cmin range was set at 1-3 mg/L, and average ganciclovir trough concentrations (Cmin ) were calculated for each patient. Reduced CMV viral load below the lower limit of quantification (LLQ) at 30 days and occurrence of myelotoxicity were selected as the primary outcome. Univariate analysis was performed by comparing patients with average Cmin below or above 1 or 3 mg/L. Receiver operating characteristic (ROC) curve analysis was performed to identify the average ganciclovir Cmin cut-off predictive for clinical efficacy or toxicity. Results: Twenty-nine out of 89 retrieved patients met the inclusion criteria, with a median (interquartile [IQR]) baseline CMV viral load of 27,163 copies/mL (IQR 13 159.75-151 340.25 copies/mL). Reduced CMV viral load below the LLQ at 30 days was found in 17 patients (58.6%). No difference was found in the primary outcome between patients showing average Cmin below or above 1 mg/L (100.0% vs. 53.8%; p = .25) and/or 3 mg/L (65.2% vs. 33.3%; p = .20). ROC analysis did not allow to identify an average Cmin cut-off predictive of clinical efficacy or toxicity. Conclusions: No clear relationship between ganciclovir Cmin and neither CMV eradication nor safety issues was identified

Off-Label Use of Dalbavancin for Sequential Treatment of Spondylodiscitis by Methicillin-Resistant Staphylococcus aureus: A Retrospective Single-Centre Experience

Background: Our aim was to describe the clinical outcome and safety of the sequential treatment with off-label dalbavancin in patients with spondylodiscitis that is caused by methicillin-resistant Staphylococcus aureus (MRSA). Methods: We retrospectively included all patients >18 years of age with spondylodiscitis that is caused by MRSA that was treated with dalbavancin from January 2018-January 2021, recording the instances of clinical cure/failure, adverse events, and the need to be re-hospitalized after the initiation of dalbavancin. In 2/15 patients, we performed therapeutic drug monitoring (TDM) for dalbavancin. Results: We included 15 patients, 53.3% of them were females, with a median age of 67.9 years (57.4-78.5); 100% patients reported back pain, while a fever was present only in 2/15 cases. The spondylodiscitis was localized in 86.6% cases at the lumbar level. A median of a 2-week in-hospital intravenous vancomycin was followed by dalbavancin with a median duration of 12 weeks (12-16). All patients reported a clinical cure, except for a woman who is still on a suppressive treatment. No patient needed to be re-hospitalized, access to emergency department, or experienced adverse events. The TDM for dalbavancin showed that more than 90% of the determinations were above the pharmacodynamic target against staphylococci. Conclusions: The results from our unique, even if it was small, cohort demonstrated that dalbavancin can be a safe/effective option as a sequential treatment in patients with serious infections requiring prolonged antibiotic therapy, such as spondylodiscitis

The impact of preservation fluid culture on graft site arteritis: a systematic review and metanalysis

The role of culturing the graft preservation fluid (PF) is controversial and its impact on graft arteritis development remains unclear

Relationship between Pharmacokinetic/Pharmacodynamic Target Attainment and Microbiological Outcome in Critically Ill COVID-19 Patients with Documented Gram-Negative Superinfections Treated with TDM-Guided Continuous-Infusion Meropenem

Objectives: The objective of this study was to explore the relationship between pharmacokinetic/pharmacodynamic (PK/PD) target attainment of continuous-infusion (CI) meropenem and microbiological outcome in critical COVID-19 patients with documented Gram-negative superinfections. Methods: Patients receiving CI meropenem for documented Gram-negative infections at the COVID ICU of the IRCCS Azienda Ospedaliero-Universitaria di Bologna and undergoing therapeutic drug monitoring from January 2021 to February 2022 were retrospectively assessed. Average steady-state meropenem concentrations (C-ss) were calculated and the C-ss/MIC ratio was selected as a pharmacodynamic parameter of meropenem efficacy. The C-ss/MIC ratio was defined as optimal if >= 4, quasi-optimal if between 1 and 4, and suboptimal if <1. The relationship between C-ss/MIC and microbiological outcome was assessed. Results: Overall, 43 critical COVID-19 patients with documented Gram-negative infections were retrieved. Combination therapy was implemented in 26 cases. C-ss/MIC ratios were optimal in 27 (62.8%), quasi-optimal in 7 (16.3%), and suboptimal in 9 cases (20.9%). Microbiological failure occurred in 21 patients (48.8%), with no difference between monotherapy and combination therapy (43.8% vs. 53.8%; p = 0.53). The microbiological failure rate was significantly lower in patients with an optimal C-ss/MIC ratio compared to those with a quasi-optimal or suboptimal C-ss/MIC ratio (33.3% vs. 75.0%; p = 0.01). Conclusion: Suboptimal attainment of meropenem PK/PD targets may be a major determinant impacting on microbiological failure in critical COVID-19 patients with Gram-negative superinfections