Delaying the Empiric Treatment of Candida Bloodstream Infection until Positive Blood Culture Results Are Obtained: a Potential Risk Factor for Hospital Mortality

Morrell, Matthew; Fraser, Victoria J.; Kollef, Marin H.

doi:10.1128/aac.49.9.3640-3645.2005

Cited by 1,286Antifungal resistance and susceptibilityInfective Endocarditis Diagnosis and ManagementSepsis Diagnosis and Treatment

Delaying the Empiric Treatment of Candida Bloodstream Infection until Positive Blood Culture Results Are Obtained: a Potential Risk Factor for Hospital Mortality

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Morrell, Matthew, Fraser, Victoria J., Kollef, Marin H.·2005·Antimicrobial Agents and Chemotherapy

DOI 10.1128/aac.49.9.3640-3645.2005PMC PMC1195428

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Abstract

Fungal bloodstream infections are associated with significant patient mortality and health care costs. Nevertheless, the relationship between a delay of the initial empiric antifungal treatment until blood culture results are known and the clinical outcome is not well established. A retrospective cohort analysis with automated patient medical records and the pharmacy database at Barnes-Jewish Hospital was conducted. One hundred fifty-seven patients with a Candida bloodstream infection were identified over a 4-year period (January 2001 through December 2004). Fifty (31.8%) patients died during hospitalization. One hundred thirty-four patients had empiric antifungal treatment begun after the results of fungal cultures were known. From the time that the first blood sample for culture that was positive was drawn, 9 (5.7%) patients received antifungal treatment within 12 h, 10 (6.4%) patients received antifungal treatment between 12 and 24 h, 86 (54.8%) patients received antifungal treatment between 24 and 48 h, and 52 (33.1%) patients received antifungal treatment after 48 h. Multiple logistic regression analysis identified Acute Physiology and Chronic Health Evaluation II scores (one-point increments) (adjusted odds ratio [AOR], 1.24; 95% confidence interval [CI], 1.18 to 1.31; P < 0.001), prior antibiotic treatment (AOR, 4.05; 95% CI, 2.14 to 7.65; P = 0.028), and administration of antifungal treatment 12 h after having the first positive blood sample for culture (AOR, 2.09; 95% CI, 1.53 to 2.84; P = 0.018) as independent determinants of hospital mortality. Administration of empiric antifungal treatment 12 h after a positive blood sample for culture is drawn is common among patients with Candida bloodstream infections and is associated with greater hospital mortality. Delayed treatment of Candida bloodstream infections could be minimized by the development of more rapid diagnostic techniques for the identification of Candida bloodstream infections. Alternatively, increased use of empiric antifungal treatment in selected patients at high risk for fungal bloodstream infection could also reduce delays in treatment.

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In a study of 10,811 patients treated in four Utah hospitals, each hour delay in time from ED arrival to administration of antimicrobials was associated with 1.16 increased odds of in-hospital and 1.10 increased odds of 1-year mortality (1.13 in patients with hypotension vs 1.09 in patients without hypotension).
“Finally, in a study of 10,811 patients treated in four Utah hospitals, each hour delay in time from ED arrival to administration of antimicrobials was associated with 1.16 increased odds of in-hospital and 1.10 increased odds of 1-year mortality (1.13 in patients with hypotension vs 1.09 in patients without hypotension) (111).”
From Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. (2021) · cites this paper as [111]
The Materials and Methods and Patients sections describe a single-hospital study at Barnes-Jewish Hospital of 157 patients with Candida bloodstream infections, not 10,811 patients at four Utah hospitals. The Study design and data collection section measures delay from the first positive blood-culture sample to antifungal treatment, rather than from ED arrival, and identifies hospital mortality—not one-year mortality—as the main outcome. Page numbers were not available in our copy. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured
Observational studies suggest that mortality may increase after intervals exceeding 3-5 hours from hospital arrival and/or sepsis recognition.
“Observational studies do, however, suggest that mortality may increase after intervals exceeding 3-5 hours from hospital arrival and/or sepsis recognition (98,111,119,120).”
From Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. (2021) · cites this paper as [111]
The Discussion reports an association between delayed antifungal treatment and hospital mortality in patients with Candida bloodstream infection. But the delay studied was more than 12 hours after the first positive blood sample was drawn—not 3–5 hours after hospital arrival or sepsis recognition. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Attributable mortality from IC remains high and increases with delays in treatment.
“Attributable mortality from IC remains high and increases with delays in treatment.”
From Epidemiology of Invasive Candidiasis (2024) · cites this paper as [136]
The Abstract reports that 50 of 157 patients with Candida bloodstream infection died during hospitalization, and the Discussion links treatment after 12 hours to greater hospital mortality. The study measures hospital mortality, not mortality attributable to invasive candidiasis, and its findings concern bloodstream infection rather than all forms of invasive candidiasis. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Blood cultures take an average of 2-3 days to grow Candida, or longer depending on the species.
“Blood cultures take an average of 2–3 days to grow Candida, or longer depending on the species.”
From Epidemiology of Invasive Candidiasis (2024) · cites this paper as [136]
The Blood culture technique section describes how samples were processed, and Study design and data collection measures time from sample collection to antifungal treatment—not time for cultures to grow Candida. Searches for a 2–3-day growth time and species-dependent differences found no passage in our copy addressing either point. (LLM, conf=0.74)
Experimental — accuracy not yet measured
Some observational studies suggested prompt appropriate empiric antifungal therapy may be associated with reduced mortality, but these do not prove causality or clarify timing, and other studies failed to show the association.
“Some observational studies suggested that prompt initiation of appropriate empiric antifungal therapy may be associated with a reduction in mortality, however these studies do not prove a causal relationship between antifungal therapy and outcome, nor do they clarify the role of timing of treatment, and some other studies have failed to show this association [167, 171–173].”
From Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021 (2021) · cites this paper as [173]

Diagnosis of invasive candidiasis and candidemia remains a great challenge because symptoms and signs are usually non-specific, microbiological cultures are difficult to analyze, and histological specimens require invasive procedures.
“As mentioned previously, diagnosis of invasive candidiasis and candidemia remains a great challenge, since symptoms and signs are usually non-specific, microbiological cultures are difficult to analyze, and histological specimens require invasive procedures [29,30,46].”
From Management of invasive candidiasis and candidemia in adult non-neutropenic intensive care unit patients: part I. Epidemiology and diagnosis (2009) · cites this paper as [30]
In a single-center retrospective cohort of 157 consecutive patients with Candida bloodstream infection, there was a trend toward improved survival when appropriate antifungal therapy was administered within 12 hours of blood culture collection (mortality 11.1% vs 33.1%; P = .169).
“Another single-center retrospective cohort of 157 consecutive patients with a Candida BSI showed a trend toward improved survival when appropriate antifungal therapy was administered within 12 hours of blood culture collection (mortality 11.1% vs 33.1%; P 5 .169).45”
From Fungal Sepsis: Optimizing Antifungal Therapy in the Critical Care Setting (2011) · cites this paper as [45]
In multivariate analysis, the odds of death were twofold higher if adequate therapy was delayed more than 12 hours (P = .018).
“In multivariate analysis the odds of death was 2-fold higher if adequate therapy was delayed more than 12 hours (P 5 .018).”
From Fungal Sepsis: Optimizing Antifungal Therapy in the Critical Care Setting (2011) · cites this paper as [45]
Invasive candidiasis is associated with high mortality rates due to delays in recognition and initiation of appropriate antifungals.
“Invasive candidiasis occurs frequently in hospitalized patients, and is associated with high mortality rates due to delays in recognition and initiation of appropriate antifungals.”
From Treatment of Invasive Candidiasis: A Narrative Review (2018) · cites this paper as [70]
Delayed initiation of appropriate antifungal treatment is associated with increased mortality in patients with invasive candidiasis.
“There is extensive clinical evidence that delayed initiation of appropriate antifungal treatment is associated with increased mortality in patients with invasive candidiasis [70,71,72].”
From Treatment of Invasive Candidiasis: A Narrative Review (2018) · cites this paper as [70]
Mortality rates for Candida infections are estimated to be as high as 45%, probably due to inefficient diagnostic methods and inappropriate initial antifungal therapies.
“Mortality rates are estimated to be as high as 45% [16], probably due to inefficient diagnostic methods and inappropriate initial antifungal therapies [17].”
From CandidaInfections, Causes, Targets, and Resistance Mechanisms: Traditional and Alternative Antifungal Agents (2013) · cites this paper as [17]
The Clinical and Laboratory Standards Institute (CLSI) Subcommittee for Antifungal Testing has developed standardized broth microdilution (BMD) and disk diffusion methods for in vitro susceptibility testing of Candida spp.
“The Clinical and Laboratory Standards Institute (CLSI) Subcommittee for Antifungal Testing has developed standardized broth microdilution (BMD) (169) and disk diffusion (170) methods for in vitro susceptibility testing of Candida spp.”
From Epidemiology of Invasive Candidiasis: a Persistent Public Health Problem (2007) · cites this paper as [170]

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Self-citation
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These include: REFERENCES
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Authors: Morrell, M., Fraser, V. J., & Kollef, M. H.
Affiliations: Washington University in St. Louis (US)
Pulmonary and Critical Care Division
Corresponding author: Kollef, Marin H.
ORCID: Morrell, Matthew
Fraser, Victoria J.
Kollef, Marin H.
Venue: Antimicrobial Agents and Chemotherapy
Publisher: American Society for Microbiology
Published: 2005-09
Volume: 49
Issue: 9
Pages: 3640-3645
ISSN: 0066-4804 (ISSN-L)
1098-6596
DOI: 10.1128/aac.49.9.3640-3645.2005
PMC: PMC1195428
OpenAlex: W2137575148
Cited by: 1,286
References: 47
Citations by year: 2026: 33 · 2025: 33 · 2024: 41 · 2023: 33 · 2022: 53 · 2021: 51 · 2020: 58 · 2019: 63 · 2018: 65 · 2017: 67 · 2016: 71 · 2015: 77 · 2014: 97 · 2013: 75 · 2012: 78
FWCI: 27.08
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Antimicrobial Agents and Chemotherapy (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
Topics: Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
Health Sciences › Medicine › Epidemiology › Infective Endocarditis Diagnosis and Management
Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
Keywords: candidemia, fungemia, empirical antifungal therapy, treatment delay, blood culture, in-hospital mortality, APACHE II score, prior antibiotic use, rapid diagnostic tests
MeSH terms: Adult, Aged, Aged, 80 and over, Candidiasis, Cross Infection, Female, Humans, Male, Middle Aged, Retrospective Studies, Risk Factors, Cohort Studies, Logistic Models, Fungemia, Treatment Outcome

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Delaying the Empiric Treatment of Candida Bloodstream Infection until Positive Blood Culture Results Are Obtained: a Potential Risk Factor for Hospital Mortality

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