Defining standards of CARE for invasive fungal diseases in the ICU.

The aim of this article is to review the current recommendations for the diagnosis and treatment of invasive fungal infection in the ICU setting and to explore whether there are standards of care for this patient population. The text focuses mainly on the two most common invasive fungal diseases that afflict non-neutropenic patients: candidaemia and invasive candidosis (IC), and invasive pulmonary aspergillosis (IPA).

Contamination of Ambient Air with Acinetobacter baumannii on Consecutive Inpatient Days.

Acinetobacter-positive patients had their ambient air tested for up to 10 consecutive days. The air was Acinetobacter positive for an average of 21% of the days; the rate of contamination was higher among patients colonized in the rectum than in the airways (relative risk [RR], 2.35; P = 0.006). Of the 6 air/clinical isolate pairs available, 4 pairs were closely related according to rep-PCR results.

Evaluation of an early step-down strategy from intravenous anidulafungin to oral azole therapy for the treatment of candidemia and other forms of invasive candidiasis: results from an open-label trial.

BACKGROUND: Hospitalized patients are at increased risk for candidemia and invasive candidiasis (C/IC). Improved therapeutic regimens with enhanced clinical and pharmacoeconomic outcomes utilizing existing antifungal agents are still needed. METHODS: An open-label, non-comparative study evaluated an intravenous (i.v.) to oral step-down strategy. Patients with C/IC were treated with i.v. anidulafungin and after 5 days of i.v. therapy had the option to step-down to oral azole therapy (fluconazole or voriconazole) if they met prespecified criteria. The primary endpoint was the global response rate (clinical + microbiological) at end of treatment (EOT) in the modified intent-to-treat (MITT) population (at least one dose of anidulafungin plus positive Candida within 96 hours of study entry). Secondary endpoints included efficacy at other time points and in predefined patient subpopulations. Patients who stepped down early (≤ 7 days' anidulafungin) were identified as the "early switch" subpopulation. RESULTS: In total, 282 patients were enrolled, of whom 250 were included in the MITT population. The MITT global response rate at EOT was 83.7% (95% confidence interval, 78.7-88.8). Global response rates at all time points were generally similar in the early switch subpopulation compared with the MITT population. Global response rates were also similar across multiple Candida species, including C. albicans, C. glabrata, and C. parapsilosis. The most common treatment-related adverse events were nausea and vomiting (four patients each). CONCLUSIONS: A short course of i.v. anidulafungin, followed by early step-down to oral azole therapy, is an effective and well-tolerated approach for the treatment of C/IC. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00496197.

Higher clinical success in patients with ventilator-associated pneumonia due to methicillin-resistant Staphylococcus aureus treated with linezolid compared with vancomycin: results from the IMPACT-HAP study.

INTRODUCTION: Controversy exists regarding optimal treatment for ventilator-associated pneumonia (VAP) due to methicillin-resistant Staphylococcus aureus (MRSA). The primary objective of this study was to compare clinical success of linezolid versus vancomycin for the treatment of patients with MRSA VAP. METHODS: This was a multicenter, retrospective, observational study of patients with VAP (defined according to Centers for Disease Control and Prevention criteria) due to MRSA who were treated with linezolid or vancomycin. MRSA VAP was considered when MRSA was isolated from a tracheal aspirate or bronchoalveolar lavage. Clinical success was evaluated by assessing improvement or resolution of signs and symptoms of VAP by day 14. After matching on confounding factors, logistic regression models were used to determine if an association existed between treatment arm and clinical success. RESULTS: A total of 188 patients were evaluated (101 treated with linezolid and 87 with vancomycin). The mean ± standard deviation Acute Physiology and Chronic Health Evaluation (APACHE) II score was 21 ± 11 for linezolid- and 19 ± 9 for vancomycin-treated patients (P = 0.041). Clinical success occurred in 85% of linezolid-treated patients compared with 69% of vancomycin-treated patients (P = 0.009). After adjusting for confounding factors, linezolid-treated patients were 24% more likely to experience clinical success than vancomycin-treated patients (P = 0.018). CONCLUSIONS: This study adds to the evidence indicating that patients with MRSA VAP who are treated with linezolid are more likely to respond favorably compared with patients treated with vancomycin.

Eighteen years of experience with Acinetobacter baumannii in a tertiary care hospital.

OBJECTIVE: To characterize the descriptive and molecular epidemiology of Acinetobacter baumannii in our hospital. DESIGN: Longitudinal analysis of electronic microbiology laboratory records and isolates. SETTING: A 1,500 bed public teaching hospital in the Miami area. PATIENTS: Consecutive patients with A. baumannii from January 1994 to December 2011. INTERVENTIONS: None MEASUREMENTS AND MAIN RESULTS: : Data on all A. baumannii isolates were clustered at the patient level, and the first isolate per single patient was determined. Yearly trends were analyzed based on carbapenem susceptibilities and originating units for all first isolates and first blood isolates per unique patient. Additionally, carbapenem nonsusceptible isolates frozen in the microbiology laboratory since 1998 were retrieved and evaluated using polymerase chain reaction and randomly amplified polymorphic DNA techniques. A total of 9,334 A. baumannii isolates were detected, of which 4,484 isolates (48%) were identified as first positive isolates per unique patient. Most of the burden of disease was located in the ICUs (odds ratio, 2.64 [95% CI, 2.17-3.22]; p < 0.0001) and in the adult wards (odds ratio, 3.867 [95% CI, 2.71-5.52]; p < 0.0001). Respiratory specimens constituted the most frequent source (49%; odds ratio, 1.619 [95% CI, 1.391-1.884]; p < 0.0001). Of the 4,484 first isolates, 846 isolates (18.9%) were carbapenem nonsusceptible and 3,638 isolates (81.1%) were carbapenem susceptible. Over the years, the number of carbapenem nonsusceptible isolates increased, whereas the number of carbapenem susceptible decreased (p < 0.0001). The trauma ICU had the highest burden of carbapenem nonsusceptible first isolates (205 of 846; 24.2%). Seven clones were discovered among 144 carbapenem nonsusceptible isolates; one of these clones was found from 1999 to 2005. OXA-23 and OXA-40 were identified in 96 and 13 isolates, respectively. One isolate harbored a novel CTX-M-115 enzyme. CONCLUSIONS: This constitutes the largest experience with A. baumannii reported to date from a single center. Half of all isolates were respiratory specimens and were from adult ICUs, especially trauma. Even though this was a polyclonal process, a single clone was identified in the hospital through a 6-year span.

A comparison of microbiology and demographics among patients with healthcare-associated, hospital-acquired, and ventilator-associated pneumonia: a retrospective analysis of 1184 patients from a large, international study.

BACKGROUND: Acceptance of healthcare-associated pneumonia (HCAP) as an entity and the associated risk of infection by potentially multidrug-resistant (MDR) organisms such as methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas and Acinetobacter have been debated. We therefore compared patients with HCAP, hospital-acquired pneumonia (HAP), and ventilator-associated pneumonia (VAP) enrolled in a trial comparing linezolid with vancomycin for treatment of pneumonia. METHODS: The analysis included all patients who received study drug. HCAP was defined as pneumonia occurring < 48 hours into hospitalization and acquired in a long-term care, subacute, or intermediate health care facility; following recent hospitalization; or after chronic dialysis. RESULTS: Data from 1184 patients (HCAP = 199, HAP = 379, VAP = 606) were analyzed. Compared with HAP and VAP patients, those with HCAP were older, had slightly higher severity scores, and were more likely to have comorbidities. Pseudomonas aeruginosa was the most common gram-negative organism isolated in all pneumonia classes [HCAP, 22/199 (11.1%); HAP, 28/379 (7.4%); VAP, 57/606 (9.4%); p = 0.311]. Acinetobacter spp. were also found with similar frequencies across pneumonia groups. To address potential enrollment bias toward patients with MRSA pneumonia, we grouped patients by presence or absence of MRSA and found little difference in frequencies of Pseudomonas and Acinetobacter. CONCLUSIONS: In this population of pneumonia patients, the frequencies of MDR gram-negative pathogens were similar among patients with HCAP, HAP, or VAP. Our data support inclusion of HCAP within nosocomial pneumonia guidelines and the recommendation that empiric antibiotic regimens for HCAP should be similar to those for HAP and VAP.

Prospective observational evaluation of the particle immunofiltration anti-platelet factor 4 rapid assay in MICU patients with thrombocytopenia.

INTRODUCTION: Heparin-induced thrombocytopenia (HIT) results from antibodies to PF4/heparin complexes and clinical diagnosis is difficult. We evaluated the particle immunofiltration anti-platelet factor 4 (PIFA) rapid assay, in conjunction with a clinical risk score, in the diagnosis of HIT. METHODS: We performed a prospective observational study in all patients admitted to the medical intensive care unit (MICU) in a large academic medical center. Patients were screened daily for thrombocytopenia defined as either a platelet count that decreased by at least 33% or an absolute platelet count less than 150,000/µL. Patients with suspected HIT underwent PIFA and ELISA testing for anti-PF4/heparin antibodies. Available residual frozen sera were sent to a reference laboratory for serotonin release assay (SRA) testing. RESULTS: During the study period, 340 patients were admitted to the MICU, of which 143 patients met criteria for thrombocytopenia. Forty-three patients had no evidence of recent heparin exposure. PIFA and ELISA testing were performed on 100 patients, of which 92 had samples available for SRA analysis. PIFA results were negative in 62, positive in 28 and inconclusive in 2 patients. The 4Ts score showed low to intermediate risk in 57 of the PIFA negative patients. The ELISA results were negative in 86 and positive in 6 patients. SRA testing identified 3 patients with a positive SRA test and 89 patients with a negative result. All patients with a negative PIFA result also had a negative SRA result. In the one patient deemed to have clinical HIT, the pretest probability was high (4Ts score of 6) and the anti-PF4/heparin antibody testing revealed a positive SRA, inconclusive PIFA and a negative ELISA result. CONCLUSIONS: While thrombocytopenia in our population is common, the prevalence of HIT is low. The combination of a low to intermediate pretest probability with a negative PIFA test can rapidly exclude the presence of platelet activating anti-PF4/heparin antibodies and, therefore, HIT as the cause of the thrombocytopenia. Since a positive PIFA result has a low positive predictive value, a positive PIFA is not diagnostic of HIT and additional evaluation is warranted.

Candidemia in the critically ill: initial therapy and outcome in mechanically ventilated patients.

BACKGROUND: Mortality among critically ill patients with candidemia is very high. We sought to determine whether the choice of initial antifungal therapy is associated with survival among these patients, using need for mechanical ventilatory support as a marker of critical illness. METHODS: Cohort analysis of outcomes among mechanically ventilated patients with candidemia from the 24 North American academic medical centers contributing to the Prospective Antifungal Therapy (PATH) Alliance registry. Patients were included if they received either fluconazole or an echinocandin as initial monotherapy. RESULTS: Of 5272 patients in the PATH registry at the time of data abstraction, 1014 were ventilated and concomitantly had candidemia, with 689 eligible for analysis. 28-day survival was higher among the 374 patients treated initially with fluconazole than among the 315 treated with an echinocandin (66% versus 51%, P < .001). Initial fluconazole therapy remained associated with improved survival after adjusting for non-treatment factors in the overall population (hazard ratio .75, 95% CI .59-.96), and also among patients with albicans infection (hazard ratio .62, 95% CI .44-.88). While not statistically significant, fluconazole appeared to be associated with higher mortality among patients infected with glabrata (HR 1.13, 95% CI .70-1.84). CONCLUSIONS: Among ventilated patients with candidemia, those receiving fluconazole as initial monotherapy were significantly more likely to survive than those treated with an echinocandin. This difference persisted after adjustment for non-treatment factors.

Universal glove and gown use and acquisition of antibiotic-resistant bacteria in the ICU: a randomized trial.

IMPORTANCE: Antibiotic-resistant bacteria are associated with increased patient morbidity and mortality. It is unknown whether wearing gloves and gowns for all patient contact in the intensive care unit (ICU) decreases acquisition of antibiotic-resistant bacteria. OBJECTIVE: To assess whether wearing gloves and gowns for all patient contact in the ICU decreases acquisition of methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant Enterococcus (VRE) compared with usual care. DESIGN, SETTING, AND PARTICIPANTS: Cluster-randomized trial in 20 medical and surgical ICUs in 20 US hospitals from January 4, 2012, to October 4, 2012. INTERVENTIONS: In the intervention ICUs, all health care workers were required to wear gloves and gowns for all patient contact and when entering any patient room. MAIN OUTCOMES AND MEASURES: The primary outcome was acquisition of MRSA or VRE based on surveillance cultures collected on admission and discharge from the ICU. Secondary outcomes included individual VRE acquisition, MRSA acquisition, frequency of health care worker visits, hand hygiene compliance, health care­associated infections, and adverse events. RESULTS: From the 26,180 patients included, 92,241 swabs were collected for the primary outcome. Intervention ICUs had a decrease in the primary outcome of MRSA or VRE from 21.35 acquisitions per 1000 patient-days (95% CI, 17.57 to 25.94) in the baseline period to 16.91 acquisitions per 1000 patient-days (95% CI, 14.09 to 20.28) in the study period, whereas control ICUs had a decrease in MRSA or VRE from 19.02 acquisitions per 1000 patient-days (95% CI, 14.20 to 25.49) in the baseline period to 16.29 acquisitions per 1000 patient-days (95% CI, 13.48 to 19.68) in the study period, a difference in changes that was not statistically significant (difference, −1.71 acquisitions per 1000 person-days, 95% CI, −6.15 to 2.73; P = .57). For key secondary outcomes, there was no difference in VRE acquisition with the intervention (difference, 0.89 acquisitions per 1000 person-days; 95% CI, −4.27 to 6.04, P = .70), whereas for MRSA, there were fewer acquisitions with the intervention (difference, −2.98 acquisitions per 1000 person-days; 95% CI, −5.58 to −0.38; P = .046). Universal glove and gown use also decreased health care worker room entry (4.28 vs 5.24 entries per hour, difference, −0.96; 95% CI, −1.71 to −0.21, P = .02), increased room-exit hand hygiene compliance (78.3% vs 62.9%, difference, 15.4%; 95% CI, 8.99% to 21.8%; P = .02) and had no statistically significant effect on rates of adverse events (58.7 events per 1000 patient days vs 74.4 events per 1000 patient days; difference, −15.7; 95% CI, −40.7 to 9.2, P = .24). CONCLUSIONS AND RELEVANCE: The use of gloves and gowns for all patient contact compared with usual care among patients in medical and surgical ICUs did not result in a difference in the primary outcome of acquisition of MRSA or VRE. Although there was a lower risk of MRSA acquisition alone and no difference in adverse events, these secondary outcomes require replication before reaching definitive conclusions. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT0131821.

Strongyloides stercoralis hyperinfection syndrome: a known entity in an unknown provenance.

A 49-year-old man was admitted with altered mental status, high-grade fevers, tachycardia and leucocytosis. Cerebrospinal fluid (CSF) was purulent with a markedly elevated nucleated cell count with neutrophilic predominance, elevated protein and low glucose. CSF gram stain was negative. Patient received vancomycin, cefepime, ampicillin and acyclovir for presumed meningitis. He was intubated for protection of airway and underwent bronchoscopy. Microscopic examination of the bronchoalveolar lavage noted Strongyloides filariform larvae. Ivermectin was prescribed. Other laboratory tests showed a positive HIV test associated with a low CD4 count. Stool ova and parasite also revealed Strongyloides and repeat lumbar puncture identified larvae in the CSF. Albendazole was added for adjunctive therapy. However, the patient suffered a large intraparenchymal haemorrhage extending into the ventricles and he expired 36 days after admission.

Predictive Value of Sequential Organ Failure Assessment Score across Patients with and without COVID-19 Infection.

Rationale: Sequential organ failure assessment (SOFA) scores are commonly used in crisis standards of care policies to assist in resource allocation. The relative predictive value of SOFA by coronavirus disease (COVID-19) infection status and among racial and ethnic subgroups within patients infected with COVID-19 is unknown. Objectives: To evaluate the accuracy and calibration of SOFA in predicting hospital mortality by COVID-19 infection status and across racial and ethnic subgroups. Methods: We performed a retrospective cohort study of adult admissions to the University of Miami Hospital and Clinics inpatient wards (July 1, 2020-April 1, 2021). We primarily considered maximum SOFA within 48 hours of hospitalization. We assessed accuracy using the area under the receiver operating characteristic curve (AUROC) and created calibration belts. Considered subgroups were defined by COVID-19 infection status (by severe acute respiratory syndrome coronavirus 2 polymerase chain reaction testing) and prevalent racial and ethnic minorities. Comparisons across subgroups were made with DeLong testing for discriminative accuracy and visualization of calibration belts. Results: Our primary cohort consisted of 20,045 hospitalizations, of which 1,894 (9.5%) were COVID-19 positive. SOFA was similarly accurate for COVID-19-positive (AUROC, 0.835) and COVID-19-negative (AUROC, 0.810; P = 0.15) admissions but was slightly better calibrated in patients who were positive for COVID-19. For those with critical illness, maximum SOFA score accuracy at critical illness onset also did not differ by COVID-19 status (AUROC, COVID-19 positive vs. negative: intensive care unit admissions, 0.751 vs. 0.775; P = 0.46; mechanically ventilated, 0.713 vs. 0.792, P = 0.13), and calibration was again better for patients positive for COVID-19. Among patients with COVID-19, SOFA accuracy was similar between the non-Hispanic White population (AUROC, 0.894) and racial and ethnic minorities (Hispanic White population: AUROC, 0.824 [P vs. non-Hispanic White = 0.05]; non-Hispanic Black population: AUROC, 0.800 [P = 0.12]; Hispanic Black population: AUROC, 0.948 [P = 0.31]). This similar accuracy was also found for those without COVID-19 (non-Hispanic White population: AUROC, 0.829; Hispanic White population: AUROC, 0.811 [P = 0.37]; Hispanic Black population: AUROC, 0.828 [P = 0.97]; non-Hispanic Black population: AUROC, 0.867 [P = 0.46]). SOFA was well calibrated for all racial and ethnic groups with COVID-19 but estimated mortality more variably and performed less well across races and ethnicities without COVID-19. Conclusions: SOFA accuracy does not differ by COVID-19 status and is similar among racial and ethnic groups both with and without COVID-19. Calibration is better for COVID-19-infected patients and, among those without COVID-19, varies by race and ethnicity.

Severity of disease and clinical outcomes in patients with hospital-acquired pneumonia due to methicillin-resistant Staphylococcus aureus strains not influenced by the presence of the Panton-Valentine leukocidin gene.

BACKGROUND: Patients with community-acquired pneumonia (CAP) infected with methicillin-resistant Staphylococcus aureus (MRSA) strains carrying the Panton-Valentine leukocidin (PVL) gene have severe clinical presentation and poor clinical outcomes. Antibiotics that suppress toxin production have been suggested for the management of these patients. The objective of this study was to compare the severity of disease and clinical outcomes of patients with hospital-acquired pneumonia/ventilator-associated pneumonia (HAP/VAP) infected with MRSA carrying the PVL gene with those patients infected with MRSA strains that do not carry the PVL gene. METHODS: This was a multicenter observational study of patients with HAP and VAP. MRSA isolates were subjected to genetic analysis to define the presence of the PVL gene, the USA type and the staphylococcal cassette chromosome mec type. Severity of disease was evaluated with the Acute Physiology and Chronic Health Evaluation II (APACHE II) score. The primary clinical outcome was mortality at hospital discharge. RESULTS: A total of 109 cases of MRSA HAP/VAP were evaluated. The incidence of PVL(+) MRSA was 27%. APACHE II score at diagnosis of HAP/VAP was 21 ± 8 for PVL(+) MRSA and 20 ± 6 for PVL(-) MRSA (P = .67). Mortality was 10% (3/29) for patients with PVL(+) MRSA versus 10% (8/80) for patients with PVL(-) MRSA (P > .99). CONCLUSIONS: In patients with HAP or VAP due to MRSA, severity of disease and clinical outcomes are not influenced by the presence of the PVL gene. Therapeutic strategies directed to block PVL exotoxin may not impact outcomes in these patients.

Candida bloodstream infections in intensive care units: analysis of the extended prevalence of infection in intensive care unit study.

OBJECTIVES: To provide a global, up-to-date picture of the prevalence, treatment, and outcomes of Candida bloodstream infections in intensive care unit patients and compare Candida with bacterial bloodstream infection. DESIGN: A retrospective analysis of the Extended Prevalence of Infection in the ICU Study (EPIC II). Demographic, physiological, infection-related and therapeutic data were collected. Patients were grouped as having Candida, Gram-positive, Gram-negative, and combined Candida/bacterial bloodstream infection. Outcome data were assessed at intensive care unit and hospital discharge. SETTING: EPIC II included 1265 intensive care units in 76 countries. PATIENTS: Patients in participating intensive care units on study day. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: Of the 14,414 patients in EPIC II, 99 patients had Candida bloodstream infections for a prevalence of 6.9 per 1000 patients. Sixty-one patients had candidemia alone and 38 patients had combined bloodstream infections. Candida albicans (n = 70) was the predominant species. Primary therapy included monotherapy with fluconazole (n = 39), caspofungin (n = 16), and a polyene-based product (n = 12). Combination therapy was infrequently used (n = 10). Compared with patients with Gram-positive (n = 420) and Gram-negative (n = 264) bloodstream infections, patients with candidemia were more likely to have solid tumors (p < .05) and appeared to have been in an intensive care unit longer (14 days [range, 5-25 days], 8 days [range, 3-20 days], and 10 days [range, 2-23 days], respectively), but this difference was not statistically significant. Severity of illness and organ dysfunction scores were similar between groups. Patients with Candida bloodstream infections, compared with patients with Gram-positive and Gram-negative bloodstream infections, had the greatest crude intensive care unit mortality rates (42.6%, 25.3%, and 29.1%, respectively) and longer intensive care unit lengths of stay (median [interquartile range]) (33 days [18-44], 20 days [9-43], and 21 days [8-46], respectively); however, these differences were not statistically significant. CONCLUSION: Candidemia remains a significant problem in intensive care units patients. In the EPIC II population, Candida albicans was the most common organism and fluconazole remained the predominant antifungal agent used. Candida bloodstream infections are associated with high intensive care unit and hospital mortality rates and resource use.

Anidulafungin compared with fluconazole for treatment of candidemia and other forms of invasive candidiasis caused by Candida albicans: a multivariate analysis of factors associated with improved outcome.

BACKGROUND: Candida albicans is the most common cause of candidemia and other forms of invasive candidiasis. Systemic infections due to C. albicans exhibit good susceptibility to fluconazole and echinocandins. However, the echinocandin anidulafungin was recently demonstrated to be more effective than fluconazole for systemic Candida infections in a randomized, double-blind trial among 245 patients. In that trial, most infections were caused by C. albicans, and all respective isolates were susceptible to randomized study drug. We sought to better understand the factors associated with the enhanced efficacy of anidulafungin and hypothesized that intrinsic properties of the antifungal agents contributed to the treatment differences. METHODS: Global responses at end of intravenous study treatment in patients with C. albicans infection were compared post-hoc. Multivariate logistic regression analyses were performed to predict response and to adjust for differences in independent baseline characteristics. Analyses focused on time to negative blood cultures, persistent infection at end of intravenous study treatment, and 6-week survival. RESULTS: In total, 135 patients with C. albicans infections were identified. Among these, baseline APACHE II scores were similar between treatment arms. In these patients, global response was significantly better for anidulafungin than fluconazole (81.1% vs 62.3%; 95% confidence interval [CI] for difference, 3.7-33.9). After adjusting for baseline characteristics, the odds ratio for global response was 2.36 (95% CI, 1.06-5.25). Study treatment and APACHE II score were significant predictors of outcome. The most predictive logistic regression model found that the odds ratio for study treatment was 2.60 (95% CI, 1.14-5.91) in favor of anidulafungin, and the odds ratio for APACHE II score was 0.935 (95% CI, 0.885-0.987), with poorer responses associated with higher baseline APACHE II scores. Anidulafungin was associated with significantly faster clearance of blood cultures (log-rank p < 0.05) and significantly fewer persistent infections (2.7% vs 13.1%; p < 0.05). Survival through 6 weeks did not differ between treatment groups. CONCLUSIONS: In patients with C. albicans infection, anidulafungin was more effective than fluconazole, with more rapid clearance of positive blood cultures. This suggests that the fungicidal activity of echinocandins may have important clinical implications. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00058682.

Anidulafungin compared with fluconazole in severely ill patients with candidemia and other forms of invasive candidiasis: support for the 2009 IDSA treatment guidelines for candidiasis.

INTRODUCTION: During the past decade, the incidence of Candida infections in hospitalized patients has increased, with fluconazole being the most commonly prescribed systemic antifungal agent for these infections. However, the 2009 Infectious Diseases Society of America (IDSA) candidiasis guidelines recommend an echinocandin for the treatment of candidemia/invasive candidiasis in patients who are considered to be "moderately severe or severely" ill. To validate these guidelines, clinical trial data were reviewed. METHODS: A secondary analysis of data from a previously published prospective, randomized, double-blind clinical trial was performed; it compared anidulafungin with fluconazole for the treatment of invasive candidiasis and candidemia. Patients with critical illness were identified at study entry by using the following criteria: Acute Physiology and Chronic Health Evaluation (APACHE) II score of ≥ 15, evidence of severe sepsis (sepsis and one or more end-organ dysfunctions) present, and/or patient was in intensive care. Global response rates were compared at the end of intravenous study treatment (the primary end point of the original study) and all-cause mortality at 14 and 28 days from study entry in this group. RESULTS: The patients (163 (66.5%) of 245) fulfilled at least one criterion for critical illness (anidulafungin, n = 89; fluconazole, n = 74). No significant differences were found in baseline characteristics between the two treatment groups. The global response rate was 70.8% for anidulafungin and 54.1% for fluconazole (P = 0.03; 95% confidence interval (CI): 2.0 to 31.5); all-cause mortality was 10.1% versus 20.3% at 14 days (P = 0.08; 95% CI, -0.9 to 21.3) and was 20.2% versus 24.3% at 28 days (P = 0.57; 95% CI, -8.8 to 17.0) for anidulafungin and fluconazole, respectively. CONCLUSIONS: In this post hoc analysis, anidulafungin was more effective than fluconazole for treatment of severely ill patients with candidemia, thus supporting the 2009 IDSA guidelines. TRIAL REGISTRATION: Clinicaltrials.gov NCT00058682.

Development and implementation of a performance improvement project in adult intensive care units: overview of the Improving Medicine Through Pathway Assessment of Critical Therapy in Hospital-Acquired Pneumonia (IMPACT-HAP) study.

INTRODUCTION: In 2005 the American Thoracic Society and Infectious Diseases Society of America (ATS/IDSA) published guidelines for managing hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), and healthcare-associated pneumonia (HCAP). Although recommendations were evidence based, collective guidelines had not been validated in clinical practice and did not provide specific tools for local implementation. We initiated a performance improvement project designated Improving Medicine Through Pathway Assessment of Critical Therapy in Hospital-Acquired Pneumonia (IMPACT-HAP) at four academic centers in the United States. Our objectives were to develop and implement the project, and to assess compliance with quality indicators in adults admitted to intensive care units (ICUs) with HAP, VAP, or HCAP. METHODS: The project was conducted in three phases over 18 consecutive months beginning 1 February 2006: 1) a three-month planning period for literature review to create the consensus pathway for managing nosocomial pneumonia in these ICUs, a data collection form, quality performance indicators, and internet-based repository; 2) a six-month implementation period for customizing ATS/IDSA guidelines into center-specific guidelines via educational forums; and 3) a nine-month post-implementation period for continuing education and data collection. Data from the first two phases were combined (pre-implementation period) and compared with data from the post-implementation period. RESULTS: We developed a consensus pathway based on ATS/IDSA guidelines and customized it at the local level to accommodate formulary and microbiologic considerations. We implemented multimodal educational activities to teach ICU staff about the guidelines and continued education throughout post-implementation. We registered 432 patients (pre- vs post-implementation, 274 vs 158). Diagnostic criteria for nosocomial pneumonia were more likely to be met during post-implementation (247/257 (96.1%) vs 150/151 (99.3%); P = 0.06). Similarly, empiric antibiotics were more likely to be compliant with ATS/IDSA guidelines during post-implementation (79/257 (30.7%) vs 66/151 (43.7%); P = 0.01), an effect that was sustained over quarterly intervals (P = 0.0008). Between-period differences in compliance with obtaining cultures and use of de-escalation were not statistically significant. CONCLUSIONS: Developing a multi-center performance improvement project to operationalize ATS/IDSA guidelines for HAP, VAP, and HCAP is feasible with local consensus pathway directives for implementation and with quality indicators for monitoring compliance with guidelines.

Candida prophylaxis and therapy in the ICU.

The incidence of invasive candidiasis in critically ill patients has increased over the past decade and is associated with considerable morbidity and mortality. CANDIDA is identified in up to 17% of ICU patients, with candidemia occurring in ∼1%. CANDIDA ALBICANS continues to account for approximately half of the invasive candidiasis cases, with non- ALBICANS CANDIDA species, such CANDIDA GLABRATA, increasing in frequency. Diagnosis of invasive candidiasis is commonly based on blood culture results; however, the sensitivity of blood culture to identify CANDIDA is low. Because early, appropriate therapy has been associated with improved outcomes, antifungal therapy is being implemented in critically ill patients with risk factors for candidemia (prophylaxis). Systemic antifungal therapy is also being utilized in patients at increased risk for invasive candidiasis based on surrogate markers of infection such as colonization (preemptive therapy), or in patients with unresolving sepsis despite appropriate management (empirical therapy). Recent guidelines on the use of antifungal therapy have better identified patients who can be treated with azole derivatives and those who may benefit from echinocandins or polyenes. However, prospective trials are still needed to better identify appropriate therapy for patients at risk for, or with, confirmed invasive CANDIDA infections.

Assessment of Disparities Associated With a Crisis Standards of Care Resource Allocation Algorithm for Patients in 2 US Hospitals During the COVID-19 Pandemic.

Importance: Significant concern has been raised that crisis standards of care policies aimed at guiding resource allocation may be biased against people based on race/ethnicity. Objective: To evaluate whether unanticipated disparities by race or ethnicity arise from a single institution's resource allocation policy. Design, Setting, and Participants: This cohort study included adults (aged ≥18 years) who were cared for on a coronavirus disease 2019 (COVID-19) ward or in a monitored unit requiring invasive or noninvasive ventilation or high-flow nasal cannula between May 26 and July 14, 2020, at 2 academic hospitals in Miami, Florida. Exposures: Race (ie, White, Black, Asian, multiracial) and ethnicity (ie, non-Hispanic, Hispanic). Main Outcomes and Measures: The primary outcome was based on a resource allocation priority score (range, 1-8, with 1 indicating highest and 8 indicating lowest priority) that was assigned daily based on both estimated short-term (using Sequential Organ Failure Assessment score) and longer-term (using comorbidities) mortality. There were 2 coprimary outcomes: maximum and minimum score for each patient over all eligible patient-days. Standard summary statistics were used to describe the cohort, and multivariable Poisson regression was used to identify associations of race and ethnicity with each outcome. Results: The cohort consisted of 5613 patient-days of data from 1127 patients (median [interquartile range {IQR}] age, 62.7 [51.7-73.7]; 607 [53.9%] men). Of these, 711 (63.1%) were White patients, 323 (28.7%) were Black patients, 8 (0.7%) were Asian patients, and 31 (2.8%) were multiracial patients; 480 (42.6%) were non-Hispanic patients, and 611 (54.2%) were Hispanic patients. The median (IQR) maximum priority score for the cohort was 3 (1-4); the median (IQR) minimum score was 2 (1-3). After adjustment, there was no association of race with maximum priority score using White patients as the reference group (Black patients: incidence rate ratio [IRR], 1.00; 95% CI, 0.89-1.12; Asian patients: IRR, 0.95; 95% CI. 0.62-1.45; multiracial patients: IRR, 0.93; 95% CI, 0.72-1.19) or of ethnicity using non-Hispanic patients as the reference group (Hispanic patients: IRR, 0.98; 95% CI, 0.88-1.10); similarly, no association was found with minimum score for race, again with White patients as the reference group (Black patients: IRR, 1.01; 95% CI, 0.90-1.14; Asian patients: IRR, 0.96; 95% CI, 0.62-1.49; multiracial patients: IRR, 0.81; 95% CI, 0.61-1.07) or ethnicity, again with non-Hispanic patients as the reference group (Hispanic patients: IRR, 1.00; 95% CI, 0.89-1.13). Conclusions and Relevance: In this cohort study of adult patients admitted to a COVID-19 unit at 2 US hospitals, there was no association of race or ethnicity with the priority score underpinning the resource allocation policy. Despite this finding, any policy to guide altered standards of care during a crisis should be monitored to ensure equitable distribution of resources.

Anidulafungin versus fluconazole for invasive candidiasis.

BACKGROUND: Anidulafungin, a new echinocandin, has potent activity against candida species. We compared anidulafungin with fluconazole in a randomized, double-blind, noninferiority trial of treatment for invasive candidiasis. METHODS: Adults with invasive candidiasis were randomly assigned to receive either intravenous anidulafungin or intravenous fluconazole. All patients could receive oral fluconazole after 10 days of intravenous therapy. The primary efficacy analysis assessed the global response (clinical and microbiologic) at the end of intravenous therapy in patients who had a positive baseline culture. Efficacy was also assessed at other time points. RESULTS: Eighty-nine percent of the 245 patients in the primary analysis had candidemia only. Candida albicans was isolated in 62% of the 245 patients. In vitro fluconazole resistance was infrequent. Most of the patients (97%) did not have neutropenia. At the end of intravenous therapy, treatment was successful in 75.6% of patients treated with anidulafungin, as compared with 60.2% of those treated with fluconazole (difference, 15.4 percentage points; 95% confidence interval [CI], 3.9 to 27.0). The results were similar for other efficacy end points. The statistical analyses failed to show a "center effect"; when data from the site enrolling the largest number of patients were removed, success rates at the end of intravenous therapy were 73.2% in the anidulafungin group and 61.1% in the fluconazole group (difference, 12.1 percentage points; 95% CI, -1.1 to 25.3). The frequency and types of adverse events were similar in the two groups. The rate of death from all causes was 31% in the fluconazole group and 23% in the anidulafungin group (P=0.13). CONCLUSIONS: Anidulafungin was shown to be noninferior to fluconazole in the treatment of invasive candidiasis. (ClinicalTrials.gov number, NCT00056368 [ClinicalTrials.gov]).

Anidulafungin in the treatment of patients with invasive candidiasis.

Echinocandins have emerged as important agents for the treatment of invasive candidiasis. Forthcoming guidelines are expected to recommend an echinocandin agent as initial primary therapy in patients who are severely ill and/or have risk factors for azole resistance. Amphotericin B deoxycholate and fluconazole should be considered for initial therapy in specific populations. The echinocandin, anidulafungin, has been shown to have higher response rates compared with fluconazole in patients with invasive candidiasis. Additionally, patients treated with anidulafungin compared with patients receiving fluconazole have exhibited a trend toward improved survival. The three echinocandins (anidulafungin, caspofungin and micafungin) offer proven efficacy along with excellent side-effect profiles. While these three drugs have important differences, the empirical selection of an echinocandin should be based on the specific patient population, including clinical status, the suspected pathogen, and the susceptibility pattern at the institution. Once the Candida species is identified and its susceptibility is determined, clinicians should consider step-down therapy to either fluconazole or voriconazole, with possible conversion from intravenous to oral therapy.