Mar 09, 2026
Persistent candidemia - a systematic review and meta-analysis on risk factors and outcomes
- Dr.Alberto Enrico Maraolo1,
- Prof. Francesco Di Gennaro2,
- Dr. Roberta Astorri3,
- Dr.Giulio Viceconte4,
- Dr.Vincenzo Fotticchia1,
- Dr.Alessia D’Agostino1,
- Dr.Luisana Frallonardo2,
- Prof.Annalisa Saracino2,
- Prof.Ivan Gentile4
- 1Section of Infectious Diseases, Department of Clinical Medicine and Surgery, Naples, Italy.;
- 2Clinic of Infectious Diseases, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari "Aldo Moro", 70124 Bari, Italy.;
- 3Department of Medicine and Surgery, LUM University "Giuseppe De Gennaro" Casamassima, Italy.;
- 4Section of Infectious Diseases, Department of Clinical Medicine and Surgery, Naples, Italy
Protocol Citation: Dr.Alberto Enrico Maraolo, Prof. Francesco Di Gennaro, Dr. Roberta Astorri, Dr.Giulio Viceconte, Dr.Vincenzo Fotticchia, Dr.Alessia D’Agostino, Dr.Luisana Frallonardo, Prof.Annalisa Saracino, Prof.Ivan Gentile 2026. Persistent candidemia - a systematic review and meta-analysis on risk factors and outcomes. protocols.io https://dx.doi.org/10.17504/protocols.io.261gemx6jv47/v1
Manuscript citation:
License: This is an open access protocol distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Protocol status: Working
We use this protocol and it's working
Created: March 07, 2026
Last Modified: March 09, 2026
Protocol Integer ID: 282854
Keywords: Candidemia, Persistent Candidemia, Candida, Fungal Infections, Mortality, Outcomes, Systematic Review, Meta-analysis, clinical burden of persistent candidemia, outcomes persistent candidemia, unclear whether persistent candidemia, persistent candidemia, management strategies for candida parapsilosi, candida auris candidemia, candida parapsilosi, isolation of the same candida species, same candida species, active antifungal therapy, disease severity, utility of repeat blood culture, repeat blood culture, marker of disease severity
Disclaimer
None. The authors declare no conflicts of interest.
Abstract
Persistent candidemia represents a clinically relevant yet underexplored condition defined as the continued isolation of the same Candida species from blood cultures usually ≥5 days after initiation of active antifungal therapy. Nevertheless, there are some relevant knowledge gaps: 1. Lack of consensus definition: Heterogeneous thresholds (3, 5, or 7 days) across studies hinder accurate estimation of incidence and comparability of outcomes 2. Risk factor characterization: Limited data on modifiable vs. non-modifiable determinants of persistent candidemia across different populations 3. Outcome attribution: Unclear whether persistent candidemia is an independent predictor of mortality or a marker of disease severity and inadequate source control 4. Species-specific management: Limited evidence to guide differentiated management strategies for Candida parapsilosis and Candida auris candidemia 5. Optimal diagnostic and intervention strategies: Insufficient evidence on timing and utility of repeat blood cultures, source control procedures, and screening for occult foci This systematic review and meta-analysis aims to: 1. Quantify the clinical burden of persistent candidemia 2. Identify modifiable and non-modifiable risk factors 3. Assess the independent impact on mortality and complications 4. Evaluate the effectiveness of management strategies (particularly early source control) 5. Provide evidence-based recommendations for clinical practice and future research
Troubleshooting
Registration Protocol
Review title: Persistent candidemia: a systematic review and meta-analysis on risk factors and outcomes.
Original language title: Not applicable.
Anticipated or actual start date: 15 March 2026.
Anticipated completion date: 31 July 2026.
Stage of review at time of this submission: The review has not yet started.
Named contact: Dr. Alberto Enrico Maraolo.
Named contact email: [email protected]; [email protected].
Named contact address: Section of Infectious Diseases, Department of Clinical Medicine and Surgery, Naples, Italy.
Named contact phone number: (To be added if desired).
Organisational affiliation of the review: University of Clinical Research, Naples, Italy.
Review team members' and their organisational affiliations:
Funding sources/sponsors: None.
Conflicts of interest: None. The authors declare no conflicts of interest.
Rationale for the review
Persistent candidemia represents a clinically relevant yet underexplored condition defined as the continued isolation of the same Candida species from blood cultures usually ≥5 days after initiation of active antifungal therapy.
Nevertheless, there are some relevant knowledge gaps:
Lack of consensus definition: Heterogeneous thresholds (3, 5, or 7 days) across studies hinder accurate estimation of incidence and comparability of outcomes.
Risk factor characterization: Limited data on modifiable vs. non-modifiable determinants of persistent candidemia across different populations.
Outcome attribution: Unclear whether persistent candidemia is an independent predictor of mortality or a marker of disease severity and inadequate source control.
Species-specific management: Limited evidence to guide differentiated management strategies for Candida parapsilosis and Candida auris candidemia.
Optimal diagnostic and intervention strategies: Insufficient evidence on timing and utility of repeat blood cultures, source control procedures, and screening for occult foci.
This systematic review and meta-analysis aims to:
Quantify the clinical burden of persistent candidemia.
Identify modifiable and non-modifiable risk factors.
Assess the independent impact on mortality and complications.
Evaluate the effectiveness of management strategies (particularly early source control).
Provide evidence-based recommendations for clinical practice and future research.
Review methods
Review Question(s) In patients with bloodstream infections caused by Candida species, what is the difference in clinical outcomes (including mortality, deep-seated complications, and healthcare resource utilization) between those who develop persistent candidemia compared to those with non-persistent candidemia? What are the key determinants (risk factors) of persistent candidemia?
Searches We will search the following electronic databases: MEDLINE (via PubMed), Embase, and Web of Science, from 2000 to 2025, to capture the period wherein the use of echinocandins in clinical practice started. The reference lists of included studies and relevant review articles will be hand-searched. No restrictions on language or publication date will be applied.
URL to search strategy An example search strategy for PubMed would include terms such as: (candidemia OR Candida OR fungemia) AND (persistent OR persistence OR prolonged OR unresolved OR non-resolving). The full strategy will be developed and made available.
Condition or domain being studied Candidemia (a bloodstream infection caused by Candida species) and its clinical course, specifically focusing on the distinction between infections that are rapidly cleared (non-persistent) and those that are not (persistent).
Participants/population Inclusion: Hospitalized adult (≥18 years) or pediatric with at least one blood culture positive for any Candida species (observational studies including consecutive cases of candidemia). Exclusion: Studies that do not provide separate outcome data for persistent and non-persistent candidemia and/or do not provide information about risk factors of persistent candidemia; studies about a limited number of species.
Intervention(s), exposure(s) The exposure of interest is Persistent Candidemia, defined as the continued isolation of the same Candida species from blood cultures for ≥5 days after the initiation of active antifungal therapy [10.1016/S1473-3099(25)00409-8]. Studies using alternative, clearly defined thresholds (e.g., 3 or 7 days) will be considered for pooling but also prioritized for sensitivity analysis.
Comparator(s)/control The comparator group will consist of patients with Non-Persistent Candidemia, defined as mycological clearance (negative follow-up blood cultures) within 5 days of initiating active antifungal therapy.
Types of study to be included initially Observational studies (cohort and case-control studies) will be included with at least 30 patients. Case series and case reports will be excluded.
Context Studies conducted in hospital settings, including intensive care units (ICUs), medical wards, and surgical wards.
Primary outcome(s) All-cause mortality at 28-30 days (other timings will be considered as well if available). Risk factors of persistent candidemia.
Secondary outcome(s) Incidence of deep-seated complications (e.g., endocarditis, septic thrombophlebitis, ocular candidiasis, abscesses). Length of hospital stay. Duration of antifungal therapy. Infection-related mortality. Microbiological eradication rates. Recurrence of candidemia.
Data extraction (selection and coding) Two reviewers will independently screen titles and abstracts, followed by full-text articles, against the eligibility criteria. A third reviewer will resolve any disagreements. A standardized, pre-piloted data extraction form will be used to collect information on study characteristics, patient demographics, Candida species, source of infection, definition of persistence, and outcome data.
Risk of bias (quality) assessment Two reviewers will independently assess the risk of bias. A modified version of the Joanna Briggs Institute will be used. Discrepancies will be resolved by consensus or a third reviewer.
Strategy for data synthesis A narrative synthesis of findings will be provided. If there are a sufficient number of homogenous studies (≥3) for a given outcome, a meta-analysis will be performed using a random-effects model. Dichotomous outcomes will be analyzed using odds ratios (OR) with 95% confidence intervals (CIs) and predictions intervals (PIs), the latter to gauge heterogeneity among the individual study results. If sufficient studies are available (≥10), publication bias will be assessed using funnel plots and Egger's test. Meta-analysis was performed for risk factors where at least two studies analyzed the potential association with the occurrence of persistent candidemia, and the definition of such factors was consistent across studies, by combining adjusted risk estimates and associated 95% CIs from individual studies.
Analysis of subgroups or subsets If data permit, subgroup analyses will be conducted based on: Candida species (e.g., C. albicans vs. C. parapsilosis vs. C. auris). Source of infection (e.g., catheter-related vs. primary vs. abdominal). Patient population (ICU vs. non-ICU patients, adults vs pediatric subjects). Presence of early source control. Mixed fungemia.
General information
Type of review and method of review Epidemiologic, Prognostic, Systematic review, Meta-analysis.
Language English.
Country Italy.
Other registration details None.
Reference and/or URL for published protocol Not yet available.
Dissemination plans The findings will be submitted for publication in a peer-reviewed infectious disease or internal medicine journal. Results will also be presented at relevant national and international conferences.
Keywords Candidemia; Persistent Candidemia; Candida; Fungal Infections; Mortality; Outcomes; Systematic Review; Meta-analysis.
Details of any existing review of the same topic by the same authors None.
Current review status Ongoing.
Additional information This review aims to quantify the clinical burden associated with persistent candidemia to highlight the importance of early identification and management strategies, such as source control, to prevent this complication.
Details of final report/publication(s) To be added when available.
Protocol references
10.1016/S1473-3099(25)00409-8