Invasive Fungal Diseases in Adult Patients in Intensive Care Unit (FUNDICU): 2024 consensus definitions from ESGCIP, EFISG, ESICM, ECMM, MSGERC, ISAC, and ISHAM.

PURPOSE: The aim of this document was to develop standardized research definitions of invasive fungal diseases (IFD) in non-neutropenic, adult patients without classical host factors for IFD, admitted to intensive care units (ICUs). METHODS: After a systematic assessment of the diagnostic performance for IFD in the target population of already existing definitions and laboratory tests, consensus definitions were developed by a panel of experts using the RAND/UCLA appropriateness method. RESULTS: Standardized research definitions were developed for proven invasive candidiasis, probable deep-seated candidiasis, proven invasive aspergillosis, probable invasive pulmonary aspergillosis, and probable tracheobronchial aspergillosis. The limited evidence on the performance of existing definitions and laboratory tests for the diagnosis of IFD other than candidiasis and aspergillosis precluded the development of dedicated definitions, at least pending further data. The standardized definitions provided in the present document are aimed to speed-up the design, and increase the feasibility, of future comparative research studies.

Posterior Dislocation of the Shoulder: The Light-Bulb Sign.

Posterior dislocation is a rather rare injury, often misdiagnosed. The current report offers valuable insights regarding the anatomical background of this clinical entity and emphasizes the 'light-bulb sign,' which can be observed in anterior-posterior shoulder X-rays when there is a posterior dislocation. It is crucial for healthcare professionals, including emergency department physicians, radiologists, general practitioners, orthopedic surgeons, and other relevant medical experts, to be well-acquainted with this sign and maintain a heightened awareness when encountering such cases. A 57-year-old male presented to the Emergency Department due to right shoulder pain immediately after an epileptic seizure. His arm was locked in internal rotation, while the initial X-rays, although did not reveal evident malalignment, showed the light-bulb sign. Further imaging with a computer tomography (CT) scan exhibited a large (50%) reverse Hill-Sachs defect. The patient was treated surgically with hemiarthroplasty. The light-bulb sign should be a red flag for physicians who evaluate these patients or these X-rays. The patient's history, such as epileptic seizures and examination, especially the locked arm in internal rotation, are of paramount importance for not misdiagnosing these cases.

Antimicrobial Stewardship in the Hospital Setting: A Narrative Review.

The increasing global threat of antibiotic resistance, which has resulted in countless fatalities due to untreatable infections, underscores the urgent need for a strategic action plan. The acknowledgment that humanity is perilously approaching the "End of the Miracle Drugs" due to the unjustifiable overuse and misuse of antibiotics has prompted a critical reassessment of their usage. In response, numerous relevant medical societies have initiated a concerted effort to combat resistance by implementing antibiotic stewardship programs within healthcare institutions, grounded in evidence-based guidelines and designed to guide antibiotic utilization. Crucial to this initiative is the establishment of multidisciplinary teams within each hospital, led by a dedicated Infectious Diseases physician. This team includes clinical pharmacists, clinical microbiologists, hospital epidemiologists, infection control experts, and specialized nurses who receive intensive training in the field. These teams have evidence-supported strategies aiming to mitigate resistance, such as conducting prospective audits and providing feedback, including the innovative 'Handshake Stewardship' approach, implementing formulary restrictions and preauthorization protocols, disseminating educational materials, promoting antibiotic de-escalation practices, employing rapid diagnostic techniques, and enhancing infection prevention and control measures. While initial outcomes have demonstrated success in reducing resistance rates, ongoing research is imperative to explore novel stewardship interventions.

Modified Anterolateral Minimally Invasive Surgery (ALMIS) for Total Hip Replacement: Anatomical Considerations, Range of Motion and Clinical Outcomes.

Background and Objectives: In the modified anterolateral minimally invasive surgery (ALMIS) for total hip arthroplasty (THA), the intermuscular plane between the tensor fasciae latae and the gluteus maximus (GM) is exposed, while the anterior » of the GM is detached. There are scarce data regarding this surgical approach. The purpose of the present study is to thoroughly describe this approach, encompassing the anatomical background, and to present the results of a retrospective two-center study of 603 patients. Materials and Methods: The present study includes a two-center retrospective observational cohort of 603 patients undergoing the ALMIS technique with minimum 5-year follow-up. Demographics were recorded, while range of motion (ROM) of the hip joint and the Harris Hip Score (HHS) were evaluated preoperatively, at 1, 3 and 12 months postoperatively and at the final follow-up (>5 years). Surgery-related complications were also recorded. Results: The studied population's mean age was 69.4 years, while most of them were females (397; 65.8%). The mean follow-up was 6.9 years. The median HHS at the 1-month follow-up was 74, compared to the 47 preoperatively (p-value < 0.0001). At the final follow-up, median HHS was 94. At the 1-month follow-up, mean adduction was 19.9° (compared to 15.4° preoperatively; p < 0.0001), mean abduction 24.3° (18.2° preoperatively; p < 0.0001), mean flexion 107.8° (79.1° preoperatively; p < 0.0001), mean external rotation 20.1° (12.1° preoperatively; p < 0.0001) and mean internal rotation 15.3° (7.2° preoperatively; p < 0.0001). ROM further improved until the final follow-up; mean adduction reached 22°, mean abduction 27.1°, mean flexion 119.8°, mean external rotation 24.4° and mean internal rotation 19.7°. Regarding complications, 1.3% of the sample suffered anterior traumatic dislocation, in 1.8% an intraoperative femoral fracture occurred, while 1.2% suffered periprosthetic joint infection. Conclusions: The modified ALMIS technique exhibited excellent clinical outcomes at short-, mid- and long-term follow-up, by significantly improving hip ROM and the HHS. Careful utilization of this technique, after adequate training, should yield favorable outcomes, while minimal major complications should be expected.

High-Dose Nebulized Colistin Methanesulfonate and the Role in Hospital-Acquired Pneumonia Caused by Gram-Negative Bacteria with Difficult-to-Treat Resistance: A Review.

Hospital-acquired pneumonia, including ventilator-associated pneumonia (VAP) due to difficult-to-treat-resistant (DTR) Gram-negative bacteria, contributes significantly to morbidity and mortality in ICUs. In the era of COVID-19, the incidences of secondary nosocomial pneumonia and the demand for invasive mechanical ventilation have increased dramatically with extremely high attributable mortality. Treatment options for DTR pathogens are limited. Therefore, an increased interest in high-dose nebulized colistin methanesulfonate (CMS), defined as a nebulized dose above 6 million IU (MIU), has come into sight. Herein, the authors present the available modern knowledge regarding high-dose nebulized CMS and current information on pharmacokinetics, clinical studies, and toxicity issues. A brief report on types of nebulizers is also analyzed. High-dose nebulized CMS was administrated as an adjunctive and substitutive strategy. High-dose nebulized CMS up to 15 MIU was attributed with a clinical outcome of 63%. High-dose nebulized CMS administration offers advantages in terms of efficacy against DTR Gram-negative bacteria, a favorable safety profile, and improved pharmacokinetics in the treatment of VAP. However, due to the heterogeneity of studies and small sample population, the apparent benefit in clinical outcomes must be proven in large-scale trials to lead to the optimal use of high-dose nebulized CMS.

In vitro activities of omadacycline, eravacycline, cefiderocol, apramycin, and comparator antibiotics against Acinetobacter baumannii causing bloodstream infections in Greece, 2020-2021: a multicenter study.

Resistance of Acinetobacter baumannii to multiple clinically important antimicrobials has increased to very high rates in Greece, rendering most of them obsolete. The aim of this study was to determine the molecular epidemiology and susceptibilities of A. baumannii isolates collected from different hospitals across Greece. Single-patient A. baumannii strains isolated from blood cultures (n = 271), from 19 hospitals, in a 6-month period (November 2020-April 2021) were subjected to minimum inhibitory concentration determination and molecular testing for carbapenemase, 16S rRNA methyltransferase and mcr gene detection and epidemiological evaluation. 98.9% of all isolates produced carbapenemase OXA-23. The vast majority (91.8%) of OXA-23 producers harbored the armA and were assigned mainly (94.3%) to sequence group G1, corresponding to IC II. Apramycin (EBL-1003) was the most active agent inhibiting 100% of the isolates at ≤16 mg/L, followed by cefiderocol which was active against at least 86% of them. Minocycline, colistin and ampicillin-sulbactam exhibited only sparse activity (S <19%), while eravacycline was 8- and 2-fold more active than minocycline and tigecycline respectively, by comparison of their MIC50/90 values. OXA-23-ArmA producing A. baumannii of international clone II appears to be the prevailing epidemiological type of this organism in Greece. Cefiderocol could provide a useful alternative for difficult to treat Gram-negative infections, while apramycin (EBL-1003), the structurally unique aminoglycoside currently in clinical development, may represent a highly promising agent against multi-drug resistant A. baumanni infections, due to its high susceptibility rates and low toxicity.

Treatment and diagnosis of severe KPC-producing Klebsiella pneumoniae infections: a perspective on what has changed over last decades.

Antimicrobial resistance is a global health threat. Among Gram-negative bacteria, resistance to carbapenems, a class of ß-lactam antibiotics, is usually a proxy for difficult-to-treat resistance, since carbapenem-resistant organisms are often resistant to many classes of antibiotics. Carbapenem resistance in the Gram-negative pathogen Klebsiella pneumoniae is mostly due to the production of carbapenemases, enzymes able to hydrolyze carbapenems, and K. pneumoniae carbapenemase (KPC)-type enzymes are overall the most prevalent carbapenemases in K. pneumoniae. In the last decade, the management of severe infections due to KPC-producing K. pneumoniae (KPC-Kp) in humans has presented many peculiar challenges to clinicians worldwide. In this perspective, we discuss how the treatment of severe KPC-Kp infections has evolved over the last decades, guided by the accumulating evidence from clinical studies, and how recent advances in diagnostics have allowed to anticipate identification of KPC-Kp in infected patients.KEY MESSAGESIn the last decade, the management of severe infections due to KPC-Kp has presented many peculiar challenges to clinicians worldwideFollowing the introduction in clinical practice of novel ß-lactam/ß-lactamase inhibitor combinations and novel ß-lactams active against KPC-producing bacteria, the management of severe KPC-Kp infections has witnessed a remarkable evolutionTreatment of severe KPC-Kp infections is a highly dynamic process, in which the wise use of novel antimicrobials should be accompanied by a continuous refinement based on evolving clinical evidence and laboratory diagnostics.

The Insertion of Threaded Acetabulum Components: Indications According to Specific Acetabulum Anatomy and Methods to Avoid Pitfalls.

New-generation threaded acetabulum components have been used in total hip arthroplasty (THA) with good outcomes. We have extensively used the EcoFit® SC cup (Implantcast, Buxtehude, Germany) in our practice. In this report, we present some major complications related to the use of this implant, as well as insights regarding the surgical technique to avoid such adverse effects. Furthermore, we attempt to describe certain contraindications for using threaded cups in THA, taking into account specific patient anatomy and intraoperative acetabulum preparation. We have observed acetabulum roof and posterior wall fractures, as well as incomplete placement of the component. Ensuring the meticulous preparation of the peripheral rim of the acetabulum is crucial to prevent incomplete placement since threaded components have a larger diameter than that of the reamers used to prepare the acetabulum. Additionally, when dealing with the acetabula where the posterior or anterior walls have thinned, it is advisable to refrain from using a threaded cup to avoid the risk of intraoperative fractures caused by the torque forces exerted during implant insertion.

Current and Potential Therapeutic Options for Infections Caused by Difficult-to-Treat and Pandrug Resistant Gram-Negative Bacteria in Critically Ill Patients.

Carbapenem resistance in Gram-negative bacteria has come into sight as a serious global threat. Carbapenem-resistant Gram-negative pathogens and their main representatives Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa are ranked in the highest priority category for new treatments. The worrisome phenomenon of the recent years is the presence of difficult-to-treat resistance (DTR) and pandrug-resistant (PDR) Gram-negative bacteria, characterized as non-susceptible to all conventional antimicrobial agents. DTR and PDR Gram-negative infections are linked with high mortality and associated with nosocomial infections, mainly in critically ill and ICU patients. Therapeutic options for infections caused by DTR and PDR Gram-negative organisms are extremely limited and are based on case reports and series. Herein, the current available knowledge regarding treatment of DTR and PDR infections is discussed. A focal point of the review focuses on salvage treatment, synergistic combinations (double and triple combinations), as well as increased exposure regimen adapted to the MIC of the pathogen. The most available data regarding novel antimicrobials, including novel ß-lactam-ß-lactamase inhibitor combinations, cefiderocol, and eravacycline as potential agents against DTR and PDR Gram-negative strains in critically ill patients are thoroughly presented.

A Wide Database for a Multicenter Study on Pneumocystis jirovecii Pneumonia in Intensive Care Units.

Pneumocystis jirovecii pneumonia (PJP) is an opportunistic fungal infection that may affect patients with immunosuppression. In order to improve the diagnosis accuracy for PJP, facilitating the collection of data across Europe to reliably assess the performance of diagnostic tests for PJP is essential to improve the care of critically ill patients developing this severe condition. Such large data can be collected thanks to the contribution of several European hospitals in the compilation of a dedicated electronic Case Report Form (eCRF). The main focus of this work is to create an interface with high ergonomics both in the compilation and in the subsequent validation of the records.

Pulmonary and systemic pharmacokinetics of colistin methanesulfonate (CMS) and formed colistin following nebulisation of CMS among patients with ventilator-associated pneumonia.

There has been accumulating interest in nebulised colistin methanesulfonate (CMS) for the treatment of ventilator-associated pneumonia (VAP). In this study, pulmonary and systemic pharmacokinetics following nebulisation of CMS at a dose of 3 MIU and 5 MIU, using a vibrating mesh nebuliser, for VAP caused by extensively drug-resistant Gram-negative pathogens was assessed. Blood samples and mini-bronchoalveolar lavage (mini-BAL) was performed post-dose at 1, 4 and 8 h. Concentrations of CMS and formed colistin in mini-BAL and plasma were determined by liquid chromatography-tandem mass spectrometry, and pharmacokinetic analysis was conducted using a population approach. The study population included three groups (n = 10 per group): (A) intravenous CMS and concomitantly nebulised CMS at a dose of 3 MIU (30 min duration); (B) nebulised CMS at a dose of 3 MIU (30 min duration) as monotherapy; and (C) nebulised CMS 5 MIU (45 min duration) as monotherapy. Mean plasma formed colistin concentrations were <1 mg/L following CMS nebulisation as monotherapy (groups B and C). Predicted trough concentrations of formed colistin in the epithelial lining fluid (ELF) following 24-h dosing of 3 MIU and 5 MIU nebulised CMS were 120.4 mg/L and 200.7 mg/L, respectively. The model predicted that concomitant intravenous CMS (group A) had minimal impact on the formed colistin concentration in ELF. This study demonstrated high ELF formed colistin concentrations following nebulised CMS (constantly above colistin MICs), while plasma concentrations were lower than those associated with nephrotoxicity. Our results provide important information for optimisation of nebulised colistin therapy.

Carbapenemase producing Klebsiella pneumoniae: implication on future therapeutic strategies.

INTRODUCTION: The emergence of carbapenemase resistant Gram-negative is designated as an 'urgent' priority of public health. Carbapenemase producing Klebsiella pneumoniae (CPKP) is linked with significant mortality. Conventionally used antibiotics (polymyxins, tigecycline, aminoglycosides, etc.) are associated with poor efficacy and toxicity profiles are quite worrisome. AREAS COVERED: This article reviews mechanism of resistance and evidence regarding novel treatments of infections caused by CPKP, focusing mainly on currently approved new therapies and implications on future therapeutic strategies. A review of novel ß-lactam/ß-lactamase inhibitors (BLI) recently approved and in clinical development as well as cefiderocol, eravacycline and apramycin are discussed. EXPERT OPINION: Newly approved and forthcoming antimicrobial agents are promising to combat infections caused by CPKP. Ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-cilastatin-relebactam are novel agents with favorable outcome and associated with improved mortality in KPC-producing K. pneumoniae infections. However, are inactive against metallo-ß-lactamases (MBL). Novel BLI in later stage of development, i.e. aztreonam-avibactam, cefepime-zidebactam, cefepime-taniborbactam, and meropenem-nacubactam as well as cefiderocol are active in vitro against both KPC and MBL. Potential expectations of future therapeutic strategies are improved potency against CPKP, more tolerable safety profile, and capability of overcoming current resistance mechanism of multidrug-resistant K. pneumoniae.

Anterolateral Minimally Invasive Total Hip Arthroplasty: Pitfalls During the Learning Curve and Clinical Outcomes.

Introduction:To report outcomes and complications from a modified anterolateral minimal invasive surgery (ALMIS) approach for total hip arthroplasty (THA). Patients and methods: All patients undergoing THA through ALMIS approach during a seven-year period were retrospectively evaluated. Results:One hundred fifty-four patients with a mean follow-up of 4.6 years were studied. The mean Harris hip score was found to be 91.1. A number of complications were recorded, including two cases (1.3%) of greater avulsion trochanter, one case (0.6%) of femur fractures, 12 (7.8%) cases of Trendelenburg sign and 12 cases of heterotopic ossification. Conclusions: This approach offers good visualization during acetabulum and femur preparation and excellent clinical results during mid-term follow-up.

Multidrug-resistant Klebsiella pneumoniae: mechanisms of resistance including updated data for novel ß-lactam-ß-lactamase inhibitor combinations.

Introduction: Multi-drug-resistant Klebsiella pneumoniae is currently one of the most pressing emerging issues in bacterial resistance. Treatment of K.pneumoniae infections is often problematic due to the lack of available therapeutic options, with a relevant impact in terms of morbidity, mortality and healthcare-associated costs. Soon after the launch of Ceftazidime-Avibactam, one of the approved new ß-lactam/ß-lactamase inhibitor combinations, reports of ceftazidime-avibactam-resistant strains developing resistance during treatment were published. Being a hospital-associated pathogen, K.pneumoniae is continuously exposed to multiple antibiotics resulting in constant selective pressure, which in turn leads to additional mutations that are positively selected.Areas covered: Herein the authors present the K.pneumoniae mechanisms of resistance to different antimicrobials, including updated data for ceftazidime-avibactam.Expert opinion: K.pneumoniae is a nosocomial pathogen commonly implicated in hospital outbreaks with a propensity for antimicrobial resistance toward mainstay ß-lactam antibiotics and multiple other antibiotic classes. Following the development of drug resistance and understanding the mechanisms involved, we can improve the efficacy of current antimicrobials, by applying careful stewardship and rational use to preserve their potential utility. The knowledge on antibiotic resistance mechanisms should be used to inform the design of novel therapeutic agents that might not be subject to, or can circumvent, mechanisms of resistance.

Performance of Existing Definitions and Tests for the Diagnosis of Invasive Fungal Diseases other than Invasive Candidiasis and Invasive Aspergillosis in Critically Ill, Adult Patients: A Systematic Review with Qualitative Evidence Synthesis.

The Fungal Infections Definitions in Intensive Care Unit (ICU) patients (FUNDICU) project aims to provide standard sets of definitions for invasive fungal diseases (IFDs) in critically ill, adult patients, including invasive aspergillosis (IA), invasive candidiasis (IC), Pneumocystis jirovecii pneumonia (PJP), and other non-IA, non-IC IFDs. The first step of the project was the conduction of separated systematic reviews of the characteristics and applicability to critically ill, adult patients outside classical populations at risk (hematology patients, solid organ transplant recipients) of available definitions and diagnostic tests for IFDs. We report here the results of two systematic reviews exploring the performance of available definitions and tests, for PJP and for other non-IA, non-IC IFDs. Starting from 2585 and 4584 records for PJP and other IFDs, respectively, 89 and 61 studies were deemed as eligible for full-text evaluation. However, only two studies for PJP and no studies for other IFDs met the FUNDICU protocol criteria for inclusion in qualitative synthesis. Currently, there is no sufficient solid data for directly evaluating the performance of existing definitions and laboratory tests for the diagnosis of PJP and other non-IA, non-IC IFDs in critically ill adult patients outside classical populations at risk.

Evolution of epidemiological characteristics of infective endocarditis in Greece.

OBJECTIVE: The clinical profile, management and outcome of infective endocarditis (IE) may be influenced by socioeconomic issues. METHODS: A nationwide prospective study evaluated IE during the era of deep economic crisis in Greece. Epidemiological data and factors associated with 60-day mortality were analyzed through descriptive statistics, logistic and Cox-regression models. RESULTS: Among 224 patients (male 72.3%, mean age 62.4 years), Staphylococcus aureus (n = 62; methicillin-resistant S. aureus (MRSA) 33.8%) predominated in the young without impact on mortality (p = 0.593), whilst Enterococci (n = 36) predominated in the elderly. Complications of IE were associated with mortality: heart failure [OR 2.415 (95% CI: 1.159-5.029), p = 0.019], stroke [OR 3.206 (95% CI: 1.190-8.632), p = 0.018] and acute kidney injury [OR 2.283 (95% CI: 1.085-4.805), p = 0.029]. A 60-day survival benefit was solely related to cardiac surgery for IE during hospitalization [HR 0.386 (95% CI: 0.165-0.903), p = 0.028] and compliance with antimicrobial treatment guidelines [HR 0.487 (95% CI: 0.259-0.916), p = 0.026]. Compared with a previous country cohort study, history of rheumatic fever and native valve predisposition had declined, whilst underlying renal disease and right-sided IE had increased (p < 0.0001); HIV infection had emerged (p = 0.002). No difference in rates of surgery and outcome was assessed. CONCLUSIONS: A country-wide survey of IE highlighted emergence of HIV, right-sided IE and predominance of MRSA in the youth during a severe socioeconomic crisis. Compliance with treatment guidelines promoted survival.

Emergence of ceftazidime-avibactam resistance through distinct genomic adaptations in KPC-2-producing Klebsiella pneumoniae of sequence type 39 during treatment.

Three ceftazidime-avibactam-resistant KPC-2-producing Klebsiella pneumoniae strains of ST39 were isolated in Greece, from rectal swabs of three patients after 10-15 days of treatment. The patients were treated with ceftazidime-avibactam as monotherapy or in combination with colistin. Two of these strains harbored a D179Y or a D179V substitution in the Ω loop of KPC-2, corresponding to KPC-33, or to the novel KPC-57, respectively. The third strain had a 15 amino acid insertion after position 259 in the KPC-2, corresponding to KPC-44.

Correction: ColistinDose, a Mobile App for Determining Intravenous Dosage Regimens of Colistimethate in Critically Ill Adult Patients: Clinician-Centered Design and Development Study.

[This corrects the article DOI: 10.2196/20525.].

ColistinDose, a Mobile App for Determining Intravenous Dosage Regimens of Colistimethate in Critically Ill Adult Patients: Clinician-Centered Design and Development Study.

BACKGROUND: Determining a suitable dose of intravenous colistimethate is challenging because of complicated pharmacokinetics, confusing terminology, and the potential for renal toxicity. Only recently have reliable pharmacokinetic/pharmacodynamic data and dosing recommendations for intravenous colistimethate become available. OBJECTIVE: The aim of this work was to develop a clinician-friendly, easy-to-use mobile app incorporating up-to-date dosing recommendations for intravenous colistimethate in critically ill adult patients. METHODS: Swift programming language and common libraries were used for the development of an app, ColistinDose, on the iPhone operating system (iOS; Apple Inc). The compatibility among different iOS versions and mobile devices was validated. Dosing calculations were based on equations developed in our recent population pharmacokinetic study. Recommended doses generated by the app were validated by comparison against doses calculated manually using the appropriate equations. RESULTS: ColistinDose provides 3 major functionalities, namely (1) calculation of a loading dose, (2) calculation of a daily dose based on the renal function of the patient (including differing types of renal replacement therapies), and (3) retrieval of historical calculation results. It is freely available at the Apple App Store for iOS (version 9 and above). Calculated doses accurately reflected doses recommended in patients with varying degrees of renal function based on the published equations. ColistinDose performs calculations on a local mobile device (iPhone or iPad) without the need for an internet connection. CONCLUSIONS: With its user-friendly interface, ColistinDose provides an accurate and easy-to-use tool for clinicians to calculate dosage regimens of intravenous colistimethate in critically ill patients with varying degrees of renal function. It has significant potential to avoid the prescribing errors and patient safety issues that currently confound the clinical use of colistimethate, thereby optimizing patient treatment.