Bench-to-bedside review: Appropriate antibiotic therapy in severe sepsis and septic shock – does the dose matter?

Appropriate antibiotic therapy in patients with severe sepsis and septic shock should mean prompt achievement and maintenance of optimal exposure at the infection site with broad-spectrum antimicrobial agents administered in a timely manner. Once the causative pathogens have been identified and tested for in vitro susceptibility, subsequent de-escalation of antimicrobial therapy should be applied whenever feasible. The goal of appropriate antibiotic therapy must be pursued resolutely and with continuity, in view of the ongoing explosion of antibiotic-resistant infections that plague the intensive care unit setting and of the continued decrease in new antibiotics emerging. This article provides some principles for the correct handling of antimicrobial dosing regimens in patients with severe sepsis and septic shock, in whom various pathophysiological conditions may significantly alter the pharmacokinetic behaviour of drugs

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

Disseminate Fungal Infection after Acute Pancreatitis in a Simultaneous Pancreas-Kidney Recipient

Fungal infections after kidney transplantation are a major cause of morbidity and mortality, and Candida infection of the pancreas is considered an infrequent but important agent in necrotizing pancreatitis. We report the case of a 43-year-old Caucasian patient who underwent simultaneous pancreas-kidney transplantation because of diabetes type I, and chronic renal failure with peritoneal dialysis. The postoperative course was complicated by acute pancreatitis due to the thrombosis of the splenic artery of the graft, the subsequent acute rupture of the external iliac artery caused by fungal arteritis (Candida glabrata), and peritonitis a few days later caused by sigmoid perforation with detection of Candida glabrata infection of the resected intestinal tract. The present case remarks that awareness and prevention of fungal infection are major issues in the transplant field. Important information can be added by systematic culture of conservation perfusates but, probably, the best way for early recognition of a critical level of infectious risk remains the routine application of the colonization index screening. In cases of positive results, preemptive antifungal therapy could be warranted

Cost-effectiveness analysis of initial HIV treatment under Italian guidelines

INTRODUCTION: Since the mid-1990s, highly active antiretroviral therapy (HAART) has modified the clinical course of human immunodeficiency virus (HIV) infection, reducing the rate of disease progression, the incidence of opportunistic infections, and mortality. The authors of this paper performed an economic analysis to estimate the cost-effectiveness of the HAART regimens in Italy for managing HIV-infected patients according to national guidelines. PATIENTS AND METHODS: The incremental cost-effectiveness analysis was carried out by means of a Markov model, which through a decision-analytic approach, made it possible to compare the studied antiretroviral regimens. The population considered in the model consisted of adult subjects with HIV who received antiretroviral HAART treatment for the first time. The population considered in the analysis reflects the patients' characteristics according to one of the regional surveillance systems HIV/AIDS infection report currently operating in Italy. The analysis was carried out from the point of view of the Italian health care system. The considered outcome measures were quality-adjusted life years (QALYs) and direct health costs calculated for the year 2010. Both the outcomes (QALYs) and the costs were discounted by 3.5%. The time horizon adopted in the model was 10 years. RESULTS: The model shows, in terms of cost per gained QALY, single tablet regimen (STR) appeared to be the most cost-effective therapeutic choice (22,017), followed by tenofovir (TDF) + lamivudine + efavirenz (EFV) (24,526), and TDF/emtricitabine (FTC) + nevirapine (26,416), and TDF + FTC + EFV (26,558); the remaining strategies have an incremental cost-effectiveness ratio (ICER) value varying from 28,000 to 41,000 per QALY. The sensitivity analysis on the main variables confirmed the validity of the base case scenario. CONCLUSION: STR is the most cost-effective treatment strategy, compared with the other therapeutic regimens recommended by the Italian guidelines. All the ICER values of the various regimens considered by the Italian guidelines were lower than the threshold value of 50,000 commonly accepted at the international level. The model developed represents a tool for policy makers and health care professionals to make short- and long-term cost projections and thus evaluate their impact on the available budgets for HIV patients

Population Pharmacokinetic and Pharmacodynamic Analysis for Maximizing the Effectiveness of Ceftobiprole in the Treatment of Severe Methicillin-Resistant Staphylococcal Infections

Ceftobiprole is a fifth-generation cephalosporin used for different Gram-positive bacterial infections. A population pharmacokinetic analysis was conducted in real-life clinical patients to assess the adequacy of current dosages. Population pharmacokinetics was conducted using non-linear mixed effect modeling. Monte Carlo simulations were performed to determine the probability of target attainment (PTA) of free trough or steady-state concentration over MIC (fCtrough/MIC or fCss/MIC) >= 1 or >= 4 associated with both the standard and intensified dosing regimens adjusted for renal function. Cumulative fraction of response (CFR) against methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE) were also calculated. A total of 132 patients with 503 concentrations were included. Most of them (107/132, 81.1%) had hospital- or community-acquired pneumonia, endocarditis, and bacteremia. A three-compartment model adequately fitted ceftobiprole concentration-time data. Estimated glomerular filtration rate significantly affected drug clearance. Monte Carlo simulations showed that the optimal target of fCtrough/MIC or fCss/MIC >= 4 is achieved only with the use of the standard dosages administered by continuous infusion (CI) against MRSA infections in patients with preserved renal function. Intensified dosages administered by CI are needed in patients with impaired renal function and/or augmented renal clearance against MRSA and in patients with preserved renal functions against MRSE

Successful Treatment of Bloodstream Infection due to a KPC-Producing Klebsiella Pneumoniae Resistant to Imipenem/Relebactam in a Hematological Patient

Novel carbapenem-β-lactamase inhibitor combination, imipenem/relebactam (IMI-REL), has been recently approved for treatment of infections with limited or no alternative treatment options. In this study, we described the emergence of the IMI-REL-resistance in a KPC-producing Klebsiella pneumoniae (KPC-Kp) strain collected from a hematological patient with no evidence of prior colonization. Interestingly, IMI-REL-resistance was associated with meropenem/vaborbactam (MER-VAB) cross-resistance but was not associated with cross-resistance to ceftazidime/avibactam (CAZ-AVI). Although treatment with CAZ-AVI and gentamicin completely eradicated the infection due KPC-Kp cross-resistance to IMI-REL and MER-VAB, the patient became colonized subsequently by KPC-Kp strains susceptible to IMI-REL and MER-VAB. Whole-genome sequencing performed by hybrid approach using Illumina and Oxford Nanopore platforms demonstrated that all KPC-Kp strains isolated from hematological patient belonged to the ST512 and were clonally related. Analysis of antimicrobial and porins genes demonstrated that cross-resistance to IMI-REL and MER-VAB was associated with increased blaKPC-3 copy number and truncated OmpK35 and OmpK36 with GD134-135 insertion. Phylogenetic analysis demonstrated that KPC-Kp cross-resistance to IMI-REL and MER-VAB was clonally related to a KPC-Kp resistant to IMI-REL as previously described, demonstrating the spread of this multidrug resistant clone in the hematological unit. In conclusion, the results presented in this study reported the emergence of cross-resistance to MER-VAB and IMI-REL in a KPC-Kp strain isolated from a hematological patient and highlight the potential development and diffusion of new multidrug resistance traits

Prospective role of cefiderocol in the management of carbapenem-resistant Acinetobacter baumannii infections: Review of the evidence

Carbapenem-resistant Acinetobacter baumannii (CRAB) has been classified by the World Health Organization as being in the critical category of pathogens requiring urgent new antibiotic treatment options. Cefiderocol, the first approved siderophore cephalosporin, was designed for the treatment of carbapenem-resistant Gram-negative pathogens, particularly the non-fermenting species A. baumannii and Pseudomonas aeruginosa. Cefiderocol is mostly stable against hydrolysis by serine β-lactamases and metallo-β-lactamases, which are leading causes of carbapenem resistance. This review collates the available evidence on the in vitro activity, pharmacokinetics/pharmacodynamics, and efficacy and safety of cefiderocol, and outlines its current role in the management of CRAB infections. In vitro surveillance data show susceptibility rates of \u3e90% for cefiderocol against CRAB isolates as well as in vitro synergism with a variety of antibiotics recommended in guidelines. Clinical efficacy of cefiderocol monotherapy against CRAB infections has been demonstrated in the descriptive, open-label CREDIBLE-CR and the non-inferiority, double-blind APEKS-NP randomised clinical trials as well as in real-world cases in patients with underlying health problems. To date, the frequency of on-therapy development of cefiderocol resistance in A. baumannii appears to be low, but monitoring is highly recommended. Within current treatment guidelines for moderate-to-severe CRAB infections, cefiderocol is recommended for infections in which other antibiotics failed and in combination with other active antibiotics. In vivo pre-clinical data support the combination of sulbactam or avibactam with cefiderocol to enhance efficacy and to suppress the emergence of cefiderocol resistance. The benefit of combination therapy in the clinical setting is yet to be determined in prospective studies

Virological and histological evaluation of intestinal samples in COVID-19 patients

BACKGROUNDSevere acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the pathogen responsible for pandemic coronavirus disease 2019 (COVID-19). It is a highly contagious virus which primarily affects the respiratory tract, nevertheless, the lungs are not the only target organs of the virus. The intestinal tract could represent an additional tropism site for SARS-CoV-2. Several observations have collectively suggested that enteric infections can occur in COVID-19 patients. However, the detection of viral RNA in gastrointestinal (GI) tissue samples has not been adequately investigated and results are conflicting.AIMTo detect the presence of SARS-CoV-2 RNA in intestinal mucosa samples and to evaluate histological features.METHODSThe COVID-19 patients hospitalized at an Italian tertiary hospital from April 2020 to March 2021 were evaluated for enrollment in an observational, monocentric trial. The study population was composed of two groups of adult patients. In the first group (biopsy group, 30 patients), patients were eligible for inclusion if they had mild to moderate disease and if they agreed to have a rectal biopsy; in the second group (surgical specimen group, 6 patients), patients were eligible for inclusion if they underwent intestinal resection during index hospitalization. Fifty-nine intestinal mucosal samples were analyzed.RESULTSViral RNA was not detectable in any of the rectal biopsies performed (0/53). Histological examination showed no enterocyte damage, but slight edema of the lamina propria with mild inflammatory lymphoplasmacytic infiltration. There was no difference in inflammatory infiltrates in patients with and without GI symptoms. SARS-CoV-2 RNA was detected in fecal samples in 6 cases out of 14 cases examined (42.9%). In the surgical specimen group, all patients underwent emergency intestinal resection. Viral RNA was detected in 2 surgical specimens of the 6 examined, both of which were from patients with active neoplastic disease. Histological examination also pointed out abundant macrophages, granulocytes and plasma cells infiltrating the muscular layer and adipose tissue, and focal vasculitis.CONCLUSIONMild-moderate COVID-19 may not be associated with rectal infection by the virus. More comprehensive autopsies or surgical specimens are needed to provide histological evidence of intestinal infection

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

How much European prescribing physicians know about invasive fungal infections management?

The use of systemic antifungal agents has increased in most tertiary care centers. However, antifungal stewardship has deserved very little attention. Our objective was to assess the knowledge of European prescribing physicians as a first step of an international program of antifungal stewardship. Methods: Staff physicians and residents of 4 European countries were invited to complete a 20-point questionnaire that was based on current guidelines of invasive candidiasis and invasive aspergillosis. Results: 121 physicians (44.6% staff, 55.4% residents) from Spain 53.7%, Italy 17.4%, Denmark 16.5% and Germany 12.4% completed the survey. Hospital departments involved were: medical 51.2%, ICUs 43%, surgical 3.3% and pharmaceutical 2.5%. The mean score of adequate responses (± SD) was 5.8 ± 1.7 points, with statistically significant differences between study site and type of physicians. Regarding candidiasis, 69% of the physicians clearly distinguished colonization from infection and the local rate of fluconazole resistance was known by 24%. The accepted indications of antifungal prophylaxis were known by 38%. Regarding aspergillosis, 52% of responders could differentiate colonization from infection and 42% knew the diagnostic value of galactomannan. Radiological features of invasive aspergillosis were well recognized by 58% of physicians and 57% of them were aware of the antifungal considered as first line treatment. However, only 37% knew the recommended length of therapy. Conclusions: This simple, easily completed questionnaire enabled us to identify some weakness in the knowledge of invasive fungal infection management among European physicians. This survey could serve as a guide to design a future tailored European training program