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

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

Clinically Significant Drug Interactions Between Psychotropic Agents and Repurposed COVID-19 Therapies

As many patients with underlying psychiatric disorders may be infected with COVID-19, and COVID-19-affected subjects may frequently experience a new onset of psychiatric manifestations, concomitant use of psychotropic medications and COVID-19 therapies is expected to be highly likely and raises concerns of clinically relevant drug interactions. In this setting, four major mechanisms responsible for drug interactions involving psychotropic agents and COVID-19 therapies may be identified: (1) pharmacokinetic drug–drug interactions mainly acting on cytochrome P450; (2) pharmacodynamic drug–drug interactions resulting in additive or synergistic toxicity; (3) drug–disease interactions according to stage and severity of the disease; and (4) pharmacogenetic issues associated with polymorphisms of cytochrome P450 isoenzymes. In this review, we summarise the available literature on relevant drug interactions between psychotropic agents and COVID-19 therapies, providing practical clinical recommendations and potential management strategies according to severity of illness and clinical scenario

An evidence-based multidisciplinary approach focused at creating algorithms for targeted therapy of bsis, cutis, and ciais caused by enterobacterales in critically ill adult patients

Prompt implementation of appropriate targeted antibiotic therapy represents a valuable approach in improving clinical and ecological outcome in critically septic patients. This multidisciplinary opinion article focused at developing evidence-based algorithms for targeted antibiotic therapy of bloodstream (BSIs), complicated urinary tract (cUTIs), and complicated intrabdominal infections (cIAIs) caused by Enterobacterales. The aim was to provide a guidance for intensive care physicians either in appropriately placing novel antibiotics or in considering strategies for sparing the broadest-spectrum antibiotics. A multidisciplinary team of experts (one intensive care physician, one infectious disease consultant, one clinical microbiologist and one MD clinical pharmacologist), performed several rounds of assessment to reach agreement in developing six different algorithms according to the susceptibility pattern (one each for multi-susceptible, extended-spectrum beta-lactamase-producing, AmpC beta-lactamase-producing, Klebsiella pneumoniae carba-penemase (KPC)-producing, OXA-48-producing, and Metallo-beta-lactamase (MBL)-produ-cing Enterobacterales). Whenever multiple therapeutic options were feasible, a hierarchical scale was established. Recommendations on antibiotic dosing optimization were also pro-vided. In order to retrieve evidence-based support for the therapeutic choices proposed in the algorithms, a comprehensive literature search was performed by a researcher on PubMed-MEDLINE from inception until March 2021. Quality and strength of evidence was established according to a hierarchical scale of the study design. Only articles published in English were included. It is expected that these algorithms, by allowing prompt revision of antibiotic regimens whenever feasible, appropriate place in therapy of novel beta-lactams, implementation of strategies for sparing the broadest-spectrum antibiotics, and pharmacoki-netic/pharmacodynamic optimization of antibiotic dosing regimens, may be helpful either in improving clinical outcome or in containing the spread of antimicrobial resistance

Media Interaktif e-Modul Materi Virus Sebagai Penunjang Pembelajaran Daring di MAN 3 Jombang

Pandemi covid-19 berdampak pada pembelajaran di sekolah. Hal ini juga terjadi di MAN 3 Jombang, pembelajaran yang dilakukan adalah pembelajaran daring. Berdasarkan analisis kebutuhan, pembelajaran daring membuat peserta didik kurang memahami materi yang disampaikan karena guru hanya memberikan materi melalui ppt dan media yang digunakan hanya buku pegangan siswa dan LKS saja. Tujuan dari penelitian ini adalah mengembangkan media pembelajaran berupa e-modul materi virus sebagai pendukung pembelajaran daring di MAN 3 Jombang dengan melihat. Rumusan masalah dalam penelitian ini Bagaimana desain dan kelayakan media pembelajaran e-modul untuk pembelajaran biologi materi virus. Instrumen pengumpulan data berupa lembar validasi ahli media, lembar validasi ahli materi dan angket respon siswa. Berdasarkan penelitian yang dilakukan maka dapat disimpulkan e-modul materi virus yang dikembangkan layak digunakan dengan revisi dengan presentase rata-rata yang diberikan oleh validator sebesar 80,43%.Keseluruhan peserta didik memberikan respon sangat baik dengan presentase rata-rata sebesar 88,83% terhadap e-modul materi virus yang dikembangkan dapat mendukung pembelajaran secara daring

A descriptive pharmacokinetic/pharmacodynamic analysis of continuous infusion ceftazidime-avibactam for treating DTR gram-negative infections in a case series of critically ill patients undergoing continuous veno-venous haemodiafiltration (CVVHDF)

Purpose: To explore pharmacokinetic/pharmacodynamic (PK/PD) profile of continuous infusion (CI) ceftazidime-avibactam for treating difficult-to-treat resistant Gram-negative (DTR-GN) infections in critical patients undergoing continuous venovenous haemodiafiltration (CVVHDF). Materials and methods: Patients treated with CI ceftazidime-avibactam for DTR-GN infections during CVVHDF were retrospectively assessed. Ceftazidime and avibactam concentrations were measured at steady-state and the free fraction (fCss) was calculated. Total clearance (CLtot) of both agents were calculated and the impact of CVVHDF intensity was assessed by linear regression. The joint PK/PD target of ceftazidime-avibactam was defined as optimal when both fCss/MIC≥4 for ceftazidime and fCss/CT > 1 for avibactam were achieved. Relationship between ceftazidime-avibactam PK/PD targets and microbiological outcome was assessed. Results: Eight patients with DTR-GN infections were retrieved. Median fCss were 84.5 (73.7–87.7 mg/L) for ceftazidime and 24.8 mg/L (20.7–25.8 mg/L) for avibactam. Median CLtot was 2.39 L/h (2.05–2.96 L/h) for ceftazidime and 2.56 L/h (2.12–2.98 L/h) for avibactam. Median CVVHDF dose was 38.6 mL/h/kg (35.9–40.0 mL/kg/h). CLtot were linearly correlated with CVVHDF dose (r = 0.53;p = 0.03, and r = 0.64;p = 0.006, respectively). The joint PK/PD targets were optimal granting microbiological eradication in all the assessable cases. Conclusion: CI administration of 1.25–2.5 g q8h ceftazidime-avibactam may allow prompt attainment and maintenance of optimal joint PK/PD targets during high-intensity CVVHDF

A Proof of Concept of the Usefulness of a TDM-Guided Strategy for Optimizing Pharmacokinetic/Pharmacodynamic Target of Continuous Infusion Ampicillin-Based Regimens in a Case Series of Patients with Enterococcal Bloodstream Infections and/or Endocarditis

(1) Objective: To describe the usefulness of a real-time therapeutic drug monitoring (TDM)-based strategy for optimizing pharmacokinetic/pharmacodynamic (PK/PD) target attainment of continuous infusion (CI) ampicillin-based regimens in a case series of patients affected by suspected or documented enterococcal bloodstream infections (BSIs) and/or infective endocarditis (IE). (2) Methods: Patients treated with CI ampicillin-based regimens for documented or suspected enterococcal BSI/IE who underwent real-time therapeutic drug monitoring (TDM)-based expert clinical pharmacological advice (ECPA) between June 2021 and May 2022 were retrospectively assessed. Ampicillin concentrations were determined at steady state, and the free fraction (fC(ss)) was calculated according to a plasma protein binding of 20%. The fC(ss)/MIC ratio was selected as the PD parameter for ampicillin efficacy and was defined as optimal for values between 4 and 8. The requirement for TDM-guided ampicillin dosing adjustments was assessed. (3) Results: Data for 12 patients with documented (n = 10) or suspected (n = 2) enterococcal infections (7 with BSIs and 5 with IE) were retrieved. The ampicillin PK/PD target was optimal over time in all of the 10 documented infections. None of the enterococcal BSIs persisted. Following the first real-time TDM-based ECPA, ampicillin dosage was decreased by >50% in 11 out of 12 patients (91.7%). (4) Conclusions: CI may be helpful in attaining aggressive ampicillin PK/PD targets in patients affected by enterococcal BSIs and/or IE. Administration of CI ampicillin after loading coupled with real-time TDM-based ECPA could be a valuable strategy for managing enterococcal infections

Real-Time TDM-based optimization of continuous-infusion meropenem for improving treatment outcome of febrile neutropenia in oncohaematological patients: Results from a prospective, monocentric, interventional study

Objectives: To assess the role that real-Time therapeutic drug monitoring (TDM)-guided optimization of continuous-infusion (CI) meropenem may have in maximizing empirical treatment and in preventing breakthrough infection and/or colonization with carbapenem-resistant Enterobacteriaceae (CRE) among oncohaematological patients with febrile neutropenia (FN). Methods: A monocentric, interventional, prospective study was conducted. The pharmacodynamic (PD) target was a steady-state meropenem concentration-To-MIC ratio (Css/MIC) of 4-8. The primary endpoint was 14 day all-cause mortality. The secondary endpoint was the prevalence of CRE colonization in rectal swabs of patients rehospitalized within 3months. Results: Among the 75 patients enrolled, most (56%) had AML, almost half (37/75, 49.3%) underwent HSCT and one-Third (32%) received meropenem as monotherapy. Meropenem dosages were adjusted in 30.1% of TDM reassessments. Gram-negative infections were microbiologically documented in 20.0% of patients. All of the 12 patients having infections caused by in vitro meropenem-susceptible pathogens attained the desired PD target and were cured. Three patients had infections caused by in vitro meropenem-resistant pathogens. Two of these achieved a Css/MIC target of 1 and were cured; the other one achieved a suboptimal PD target (0.59) and died. The 14 day all-cause mortality (10.7%) was significantly associated, at multivariate regression, with HSCT (OR 0.086, 95% CI 0.008-0.936, P = 0.044) and with augmented renal clearance (OR 10.846, 95% CI 1.534-76.672, P = 0.017). None of the patients who had hospital readmissions in the 3month follow-up (63/75) had CRE colonization in rectal swabs. Conclusions: Real-Time TDM-guided CI meropenem may be a useful approach for attaining adequate exposure and preventing CRE emergence in FN oncohaematological patients