BACKGROUND: Invasive fungal diseases are important causes of morbidity and mortality. Clarity and uniformity in defining these infections are important factors in improving the quality of clinical studies. A standard set of definitions strengthens the consistency and reproducibility of such studies. METHODS: After the introduction of the original European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group definitions, advances in diagnostic technology and the recognition of areas in need of improvement led to a revision of this document. The revision process started with a meeting of participants in 2003, to decide on the process and to draft the proposal. This was followed by several rounds of consultation until a final draft was approved in 2005. This was made available for 6 months to allow public comment, and then the manuscript was prepared and approved. RESULTS: The revised definitions retain the original classifications of "proven," "probable," and "possible" invasive fungal disease, but the definition of "probable" has been expanded, whereas the scope of the category "possible" has been diminished. The category of proven invasive fungal disease can apply to any patient, regardless of whether the patient is immunocompromised, whereas the probable and possible categories are proposed for immunocompromised patients only. CONCLUSIONS: These revised definitions of invasive fungal disease are intended to advance clinical and epidemiological research and may serve as a useful model for defining other infections in high-risk patients.

http://bibliotecadigital.udea.edu.co/bitstream/10495/24087/1/RestrepoAngela_2008_DefinitionsInvasiveCancer.pdf

Revised Definitions of Invasive Fungal Disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group

To provide an update to “Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012”. A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict-of-interest (COI) policy was developed at the onset of the process and enforced throughout. A stand-alone meeting was held for all panel members in December 2015. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. The panel consisted of five sections: hemodynamics, infection, adjunctive therapies, metabolic, and ventilation. Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Each subgroup generated a list of questions, searched for best available evidence, and then followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence from high to very low, and to formulate recommendations as strong or weak, or best practice statement when applicable. The Surviving Sepsis Guideline panel provided 93 statements on early management and resuscitation of patients with sepsis or septic shock. Overall, 32 were strong recommendations, 39 were weak recommendations, and 18 were best-practice statements. No recommendation was provided for four questions. Substantial agreement exists among a large cohort of international experts regarding many strong recommendations for the best care of patients with sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for these critically ill patients with high mortality.

https://link.springer.com/content/pdf/10.1007%2Fs00134-017-4683-6.pdf

Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016

The aim of broth and agar dilution methods is to determine the lowest concentration of the assayed antimicrobial agent (minimal inhibitory concentration, MIC) that, under defined test conditions, inhibits the visible growth of the bacterium being investigated. MIC values are used to determine susceptibilities of bacteria to drugs and also to evaluate the activity of new antimicrobial agents. Agar dilution involves the incorporation of different concentrations of the antimicrobial substance into a nutrient agar medium followed by the application of a standardized number of cells to the surface of the agar plate. For broth dilution, often determined in 96-well microtiter plate format, bacteria are inoculated into a liquid growth medium in the presence of different concentrations of an antimicrobial agent. Growth is assessed after incubation for a defined period of time (16-20 h) and the MIC value is read. This protocol applies only to aerobic bacteria and can be completed in 3 d.

Agar and broth dilution methods to determine the minimal inhibitory concentration (MIC) of antimicrobial substances

Infectious Diseases Society of America.

This document updates and expands the initial Infectious Diseases Society of America (IDSA) Fever and Neutropenia Guideline that was published in 1997 and first updated in 2002. It is intended as a guide for the use of antimicrobial agents in managing patients with cancer who experience chemotherapy-induced fever and neutropenia. Recent advances in antimicrobial drug development and technology, clinical trial results, and extensive clinical experience have informed the approaches and recommendations herein. Because the previous iteration of this guideline in 2002, we have a developed a clearer definition of which populations of patients with cancer may benefit most from antibiotic, antifungal, and antiviral prophylaxis. Furthermore, categorizing neutropenic patients as being at high risk or low risk for infection according to presenting signs and symptoms, underlying cancer, type of therapy, and medical comorbidities has become essential to the treatment algorithm. Risk stratification is a recommended starting point for managing patients with fever and neutropenia. In addition, earlier detection of invasive fungal infections has led to debate regarding optimal use of empirical or preemptive antifungal therapy, although algorithms are still evolving. What has not changed is the indication for immediate empirical antibiotic therapy. It remains true that all patients who present with fever and neutropenia should be treated swiftly and broadly with antibiotics to treat both gram-positive and gram-negative pathogens. Finally, we note that all Panel members are from institutions in the United States or Canada; thus, these guidelines were developed in the context of North American practices. Some recommendations may not be as applicable outside of North America, in areas where differences in available antibiotics, in the predominant pathogens, and/or in health care-associated economic conditions exist. Regardless of venue, clinical vigilance and immediate treatment are the universal keys to managing neutropenic patients with fever and/or infection.

/pdf/clinical-practice-guideline-for-the-use-of-antimicrobial-1cdrjevze2.pdf

Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer: 2010 Update by the Infectious Diseases Society of America

/pdf/does-the-use-in-animals-of-antimicrobial-agents-including-cn942ncdkj.pdf

Does the use in animals of antimicrobial agents, including glycopeptide antibiotics, influence the efficacy of antimicrobial therapy in humans?

Twenty-eight neutropenic (<500 granulocytes/µl) adults with microbiologically or histologically proven systemic mycosis were randomly assigned to receive either amphotericin B alone (0.5 mg/kg/day; n=14) or amphotericin B (0.5 mg/kg/day) plus 5-flucytosine (150 mg/kg/day; n=14) intravenously. Therapy was given for an average duration of 10 days in both groups, amounting to a total dose of amphotericin B of 338 mg and 308 mg, respectively. The mean duration of granulocytopenia was 18 days in the amphotericin B group and 20 days in the combination group. Only two patients treated with amphotericin B alone and three given the combination survived. Adverse events were similiar in both groups with an elevation of the serum creatinine in six cases during the administration of amphotericin B alone and in seven cases treated with the combination. No other serious adverse events were encountered. Treatment with both regimens was disappointing partly because mycosis was too far advanced by the time therapy was begun and neutrophils were recovered in only half the patients.

Amphotericin B versus amphotericin B plus 5-flucytosine: Poor results in the treatment of proven systemic mycoses in neutropenic patients

In a prospective randomized study, 120 febrile, granulocytopenic patients received as initial therapy ceftazidime with or without teicoplanin. At the onset of fever, patients had no obvious infectious focus. For 103 assessable episodes, initial bacteremias were detected in 18 of 51 patients (35%) given ceftazidime and 20 of 52 patients (38%) given the combination; 13 and 17 bacteremias caused by gram-positive bacteria occurred in these groups, respectively. There was no difference in terms of the final response (25 of 51 patients [49%] treated with ceftazidime alone versus 33 of 52 patients [63%] given the combination), and the morbidity was comparable for both treatment groups. The duration of fever and of total antibiotic therapy were similar in both groups. Initial therapy was modified in 26 patients (51%) treated with ceftazidime, with 20 surviving the infection, and in 19 patients (37%) treated with the combination, with 15 surviving. Persistent fever was the main reason for changing treatment, and no patient died of a gram-positive infection. Subsequent infective events occurred in 16 patients (31%) given ceftazidime and in 25 patients (48%) given the combination. Lung infiltrates developed in 12 and 13 patients, respectively, but more new infections occurred in the combination group. Allergic skin reactions were also more frequent in this group. Thus, while teicoplanin provides simple, reliable, and safe treatment of patients with presumed gram-positive infections, it is not useful when given empirically to this patient population, and treatment may result in more infective complications and adverse events.

Ceftazidime as monotherapy or combined with teicoplanin for initial empiric treatment of presumed bacteremia in febrile granulocytopenic patients.

Susceptibility testing of fungi and development of interpretative breakpoints has become increasingly important due to the growing incidence of invasive fungal infections, the number and classes of antifungals, and the emerging reports of acquired resistance. The subcommittee on antifungal susceptibility testing of the European Committee on Antibiotic Susceptibility Testing (EUCAST) has developed standards for susceptibility testing of fermentative yeasts and molds as well as proposing breakpoints for fluconazole and voriconazole against Candida. The aim of this work is to describe the EUCAST process of setting breakpoints for antifungals. Five aspects are evaluated during the process of developing breakpoints: 1) the most common dosage used in each European country, 2) the definition of the wild-type population for each target microorganism at the species level and the determination of epidemiological cutoffs, 3) the drug's pharmacokinetics and 4) pharmacodynamics, including Monte Carlo simulations, and 5) the correlation of MICs with clinical outcome of patients treated with the compound. When insufficient data are available (e.g., due to lack of information on the clinical outcome of infections caused by isolates with an elevated MIC), epidemiological cutoff values, rather than breakpoints, are recommended until the necessary information becomes available.

J.P. Donnelly

Papers

Does the use in animals of antimicrobial agents, including glycopeptide antibiotics, influence the efficacy of antimicrobial therapy in humans?

Amphotericin B versus amphotericin B plus 5-flucytosine: Poor results in the treatment of proven systemic mycoses in neutropenic patients

Ceftazidime as monotherapy or combined with teicoplanin for initial empiric treatment of presumed bacteremia in febrile granulocytopenic patients.

EUCAST breakpoints for antifungals.

Oral ketoconazole and amphotericin B for the prevention of yeast colonization in patients with acute leukaemia.