It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.

Background Invasive fungal diseases (IFDs) remain important causes of morbidity and mortality. The consensus definitions of the Infectious Diseases Group of the European Organization for Research and Treatment of Cancer and the Mycoses Study Group have been of immense value to researchers who conduct clinical trials of antifungals, assess diagnostic tests, and undertake epidemiologic studies. However, their utility has not extended beyond patients with cancer or recipients of stem cell or solid organ transplants. With newer diagnostic techniques available, it was clear that an update of these definitions was essential. Methods To achieve this, 10 working groups looked closely at imaging, laboratory diagnosis, and special populations at risk of IFD. A final version of the manuscript was agreed upon after the groups’ findings were presented at a scientific symposium and after a 3-month period for public comment. There were several rounds of discussion before a final version of the manuscript was approved. Results There is no change in the classifications of “proven,” “probable,” and “possible” IFD, although the definition of “probable” has been expanded and the scope of the category “possible” has been diminished. The category of proven IFD can apply to any patient, regardless of whether the patient is immunocompromised. The probable and possible categories are proposed for immunocompromised patients only, except for endemic mycoses. Conclusions These updated definitions of IFDs should prove applicable in clinical, diagnostic, and epidemiologic research of a broader range of patients at high-risk.

It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.

Blood cultures are limited for diagnosing invasive candidiasis by poor sensitivity and slow turn-around time. New diagnostics are needed to complement cultures, in particular to identify the "missing 50%" of patients who are blood culture-negative. Mannan/anti-mannan immunoglobulin G, β-D-glucan (BDG) and polymerase chain reaction (PCR) assays can diagnose candidemia before blood cultures and show promising sensitivity/specificity, but they are not widely investigated in blood culture-negative, deep-seated candidiasis. In a recent study, BDG and PCR were superior to blood cultures in deep-seated candidiasis, suggesting they may identify currently undiagnosed patients and expand our understanding of disease spectrum. Positive predictive values of nonculture tests are limited by the low prevalence of invasive candidiasis, which mandates that results be interpreted judiciously. When used as biomarkers that assess a patient's risk of having invasive candidiasis, tests will facilitate preemptive antifungal strategies. Because negative predictive values are excellent, tests will also be useful for ruling out invasive candidiasis and discontinuing unnecessary antifungal therapy.

Purpose: Invasive pulmonary aspergillosis is increasingly reported in patients with influenza admitted to the intensive care unit (ICU). Classification of patients with influenza-associated pulmonary aspergillosis (IAPA) using the current definitions for invasive fungal diseases has proven difficult, and our aim was to develop case definitions for IAPA that can facilitate clinical studies. Methods: A group of 29 international experts reviewed current insights into the epidemiology, diagnosis and management of IAPA and proposed a case definition of IAPA through a process of informal consensus. Results: Since IAPA may develop in a wide range of hosts, an entry criterion was proposed and not host factors. The entry criterion was defined as a patient requiring ICU admission for respiratory distress with a positive influenza test temporally related to ICU admission. In addition, proven IAPA required histological evidence of invasive septate hyphae and mycological evidence for Aspergillus. Probable IAPA required the detection of galactomannan or positive Aspergillus culture in bronchoalveolar lavage (BAL) or serum with pulmonary infiltrates or a positive culture in upper respiratory samples with bronchoscopic evidence for tracheobronchitis or cavitating pulmonary infiltrates of recent onset. The IAPA case definitions may be useful to classify patients with COVID-19-associated pulmonary aspergillosis (CAPA), while awaiting further studies that provide more insight into the interaction between Aspergillus and the SARS-CoV-2-infected lung.

Background This guidance document provides recommendations to clinicians for the treatment of infections caused by extended-spectrum β-lactamase producing Enterobacterales (ESBL-E), carbapenem-resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with difficult-to-treat resistance (DTR-P. aeruginosa). Antimicrobial resistant infections are commonly encountered in United States hospitals, result in significant morbidity and mortality. Methods A panel of six infectious diseases specialists with expertise in managing antimicrobial resistant infections formulated common questions about the treatment of ESBL-E, CRE, and DTR-P. aeruginosa infections. Based on review of the published literature and clinical experience, the panel provides recommendations and associated rationale for each recommendation. The document is framed so that each question can stand on its own. Because of significant differences in the molecular epidemiology of resistance and availability of specific anti-infectives globally, the document focuses on treatment of antimicrobial resistant infections in the United States. Results Approaches to empiric treatment selection, duration of therapy, and other management considerations are briefly discussed. The majority of guidance focuses on preferred and alternative treatment recommendations for antimicrobial resistant infections, assuming that the causative organism has been identified and antibiotic susceptibility testing results are known. Treatment recommendations apply to both adult and pediatric populations. Conclusions The field of antimicrobial resistance is dynamic and rapidly evolving, and the treatment of antimicrobial resistant infections will continue to challenge clinicians. This guidance document is current as of September 17th, 2020. Updates to this guidance document will occur periodically as new data emerge. Furthermore, the panel will expand recommendations to include other problematic Gram-negative pathogens in future versions. The most current version of the guidance including the date of publication can be found at www.idsociety.org/practice-guideline/amr-guidance/.

Ceftazidime-avibactam is a novel ␤-lactam/␤-lactamase inhibitor with activity against carbapenem-resistant Enterobacteriaceae (CRE) that produce Klebsiella pneumoniae carbapenemase (KPC). We report the first cases of ceftazidimeavibactam resistance to develop during treatment of CRE infections and identify resistance mechanisms. Ceftazidime-avibactam-resistant K. pneumoniae emerged in three patients after ceftazidime-avibactam treatment for 10 to 19 days. Wholegenome sequencing (WGS) of longitudinal ceftazidime-avibactam-susceptible and -resistant K. pneumoniae isolates was used to identify potential resistance mechanisms. WGS identified mutations in plasmid-borne bla KPC-3 , which were not present in baseline isolates. bla KPC-3 mutations emerged independently in isolates of a novel sequence type 258 sublineage and resulted in variant KPC-3 enzymes. The mutations were validated as resistance determinants by measuring MICs of ceftazidime-avibactam and other agents following targeted gene disruption in K. pneumoniae, plasmid transfer, and bla KPC cloning into competent Escherichia coli. In rank order, the impact of KPC-3 variants on ceftazidime-avibactam MICs was as follows: D179Y/T243M double substitution Ͼ D179Y Ͼ V240G. Remarkably, mutations reduced meropenem MICs Ն4-fold from baseline, restoring susceptibility in K. pneumoniae from two patients. Cefepime and ceftriaxone MICs were also reduced Ն4-fold against D179Y/T243M and D179Y variant isolates, but susceptibility was not restored. Reverse transcription-PCR revealed that expression of bla KPC-3 encoding D179Y/T243M and D179Y variants was diminished compared to bla KPC-3 expression in baseline isolates. In conclusion, the development of resistance-conferring bla KPC-3 mutations in K. pneumoniae within 10 to 19 days of ceftazidime-avibactam exposure is troubling, but clinical impact may be ameliorated if carbapenem susceptibility is restored in certain isolates.

Thirty-seven carbapenem-resistant Enterobacteriaceae (CRE)-infected patients were treated with ceftazidime-avibactam. Clinical success and survival rates at 30 days were 59% (22/37) and 76% (28/37), respectively. In 23% (5/22) of clinical successes, CRE infections recurred within 90 days. Microbiologic failure rate was 27% (10/37). Ceftazidime-avibactam resistance was detected in 30% (3/10) of microbiologic failures.Keywords. ceftazidime-avibactam resistance; carbapenemresistant Enterobacteriaceae; Klebsiella pneumoniae carbapenemase.Ceftazidime-avibactam is a novel β-lactam/β-lactamase inhibitor combination that was recently approved by the US Food and Drug Administration for the treatment of complicated intraabdominal and complicated urinary tract infections [1]. The agent demonstrates in vitro activity against carbapenem-resistant Enterobacteriaceae (CRE) that produce Klebsiella pneumoniae carbapenemase (KPC), but not metallo-β-lactamases such as New Delhi MBL (NDM), Verona integron-encoded MBL (VIM), or imipenemase (IMP) [2]. Ceftazidime-avibactam may offer a significant advance over previously developed antimicrobials with in vitro activity against CRE, such as colistin, gentamicin, and tigecycline, which are limited by concerns over efficacy and/or toxicity. Our objective in this study was to describe our initial clinical experience with ceftazidimeavibactam against CRE infections. METHODSWe conducted a retrospective study of patients with CRE infection who were treated with ceftazidime-avibactam at the University of Pittsburgh Medical Center between April 2015 and February 2016. CRE was defined by current Centers for Disease Control and Prevention criteria as resistance to any carbapenem [3]. A standard dosage of 2.5 g intravenously (IV) every 8 hours was used, with adjustments for renal impairment made according to manufacturer recommendations [1]. Types of CRE infection were classified according to National Healthcare Safety Network criteria [4]. Clinical success was defined as survival and absence of recurrence at 30 days following the onset of infection, resolution of signs and symptoms of infection, and sterilization of site-specific cultures within 7 days of treatment initiation. Microbiologic failure was defined as isolation of CRE following ≥7 days of ceftazidime-avibactam treatment. Recurrences within 90 days of onset were defined by microbiologic failure and concomitant signs of infection. Minimum inhibitory concentrations (MICs) were determined using reference Clinical and Laboratory Standards Institute broth microdilution methods; avibactam was tested at a fixed concentration of 4 µg/mL [2]. Isolates were tested for the presence of β-lactamases as described previously [5,6]. Comparisons between groups were made using Fisher exact test (categorical variables) and Mann-Whitney U (continuous variables). Significance was defined as P ≤ .05 (2-tailed). RESULTSThirty-seven consecutive patients treated for 3 days or longer with ceftazidime-avibactam were evaluated. Median age was 64 years (range, 26-...