Bloodstream infections (BSIs) remain a major cause of global morbidity and mortality, accounting for more than 30–40% of sepsis-related deaths worldwide and imposing a substantial clinical and economic burden on healthcare systems [1,2]. Early identification of high-risk patients is essential for optimizing antimicrobial therapy, initiating timely source-control interventions, and guiding decisions regarding critical care admission [3]. Traditional prognostic indicators such as severity-of-illness scores, inflammatory biomarkers, and microbiological profiles provide useful information but may not fully capture the dynamic relationship between pathogen burden and clinical outcomes [4].

Time-to-positivity (TTP) of blood cultures—defined as the interval between incubation of a blood culture bottle and automated detection of microbial growth—has emerged as a potential surrogate marker of microbial load and pathogen growth kinetics [5]. TTP is influenced by several factors, including inoculum concentration, organism virulence, blood volume collected, host immune status, and prior antimicrobial exposure [6,7]. Shorter TTP values are generally believed to reflect higher circulating pathogen burden and more aggressive infection biology, whereas longer TTP may be associated with lower inoculum infections, contaminants, or partially treated bacteremia [8].

Over the past decade, multiple studies have examined the prognostic relevance of TTP in different infectious syndromes and pathogen groups. In Staphylococcus aureus bacteremia, shorter TTP has been linked to persistent bacteremia, metastatic complications, endocarditis, and increased mortality [9–11]. Similarly, in Gram-negative bacteremia, rapid culture positivity has been associated with septic shock, multi-organ dysfunction, and higher risk of adverse outcomes [12,13]. In candidemia, early positivity has been correlated with high fungal burden and poorer survival outcomes [14]. Despite these observations, the strength and consistency of associations across studies remain uncertain due to variability in TTP thresholds, laboratory systems, patient populations, and outcome definitions [15].

Given the increasing interest in TTP as a real-time prognostic biomarker, a comprehensive synthesis of available evidence is warranted. Understanding whether TTP meaningfully predicts mortality, severity of illness, or treatment failure could support its integration into early risk-stratification algorithms, antimicrobial stewardship strategies, and clinical decision-support tools [16,17].

Therefore, the objective of this systematic review and meta-analysis is to evaluate the association between time-to-positivity of blood cultures and clinical outcomes in patients with bloodstream infections, with a particular focus on mortality, septic shock, intensive care requirement, and persistent bacteremia. By consolidating existing data across diverse settings and pathogen groups, this review aims to clarify the prognostic value of TTP and explore its potential role in guiding clinical management.

METHODS

This systematic review and meta-analysis was conducted in accordance with the PRISMA 2020 reporting guidelines and followed established methodological standards for evidence synthesis in prognostic research [18,19]. Studies were considered eligible if they included adult or pediatric patients with laboratory-confirmed bacteremia or fungemia and reported clinical outcomes stratified according to time-to-positivity (TTP) of blood cultures. Observational cohort studies, case-control studies, randomized or quasi-experimental studies were included, while case reports, narrative reviews, conference abstracts without full text, and laboratory-only investigations were excluded [20]. A comprehensive literature search was performed across PubMed, Embase, Scopus, Web of Science, and the Cochrane Library from database inception to June 2025 using controlled vocabulary and free-text terms related to “time to positivity,” “blood culture,” “bacteremia,” “fungemia,” and “clinical outcome.” Reference lists of eligible studies were also screened to identify additional publications [21,22]. Two reviewers independently screened titles, abstracts, and full texts, and disagreements were resolved by consensus to minimize selection bias [23]. Data extracted from each study included study design, setting, sample size, patient characteristics, pathogen groups, TTP definitions or thresholds, outcome measures, and effect estimates. Risk of bias was assessed using the Newcastle–Ottawa Scale, evaluating domains related to selection of participants, comparability of groups, and ascertainment of outcomes [24]. Where studies reported comparable outcomes, effect sizes such as odds ratios or hazard ratios were pooled using a random-effects meta-analysis to account for between-study heterogeneity, which was quantified using the I² statistic [25]. Prespecified subgroup analyses were undertaken according to pathogen category, TTP threshold, and clinical setting, while sensitivity analyses were performed by excluding studies at high risk of bias. Publication bias was explored using visual inspection of funnel plots and statistical tests where appropriate [26].

RESULTS

A total of 3,218 records were retrieved through database searches, and 2,764 remained after duplicate removal. Following title and abstract screening, 224 full-text articles were assessed for eligibility, of which 23 studies met the inclusion criteria and were included in the final review and meta-analysis [27]. The study selection process is illustrated in the PRISMA flow diagram (Figure 1). A summary of cohort characteristics, populations, pathogens, and outcome variables from the included studies is presented in Table 1 and further detailed in Table 3.

Figure 1. PRISMA 2020 study selection flow diagram for the systematic review and meta-analysis.

The majority of studies were retrospective cohort analyses conducted in tertiary-care or academic hospitals, with sample sizes ranging from 120 to 3,500 participants. Most cohorts included adult patients with bacteremia due to Staphylococcus aureus, Enterobacterales, non-fermenting Gram-negative bacilli, or Candida species, while a smaller subset evaluated mixed-pathogen or pediatric populations [28]. Definitions of short versus long time-to-positivity (TTP) varied across studies, although the most frequently applied thresholds were <12 hours or <24 hours to denote early culture positivity. The methodological quality of included studies, as assessed using the Newcastle–Ottawa Scale, is summarized in Table 4.

Association between time-to-positivity and mortality

Across the pooled studies, shorter TTP was consistently associated with a higher risk of in-hospital mortality, supporting its role as a surrogate marker of pathogen burden and infection severity [29]. Meta-analytic pooling demonstrated significantly higher odds of death among patients with short TTP compared with those with longer TTP, with the association remaining directionally consistent across sensitivity models. The prognostic effect was strongest in Staphylococcus aureus bacteremia and candidemia, where earlier positivity correlated with high microbial load, persistent bloodstream infection, metastatic complications, and poor outcomes [30].

In contrast, several studies evaluating mixed Gram-negative bacteremia reported weaker or nonsignificant mortality associations after adjustment for illness severity, comorbidity burden, and infection source, indicating that the prognostic influence of TTP may be partially mediated by clinical context rather than acting as an independent predictor in all scenarios [31].

Clinical severity outcomes

Short TTP was also associated with indicators of greater clinical severity, including higher rates of septic shock, vasopressor requirement, mechanical ventilation, and ICU admission in multiple studies [32]. Although heterogeneity in outcome definitions limited quantitative pooling for some endpoints, the overall pattern of results indicated that rapid culture positivity identifies patients at increased risk of organ dysfunction and escalation of care needs. A small number of studies found no independent association after multivariable adjustment, suggesting that TTP functions best as a complementary prognostic marker when interpreted alongside clinical severity indices [33]. A narrative summary of secondary outcome trends is provided in Table 2.

Persistent bacteremia and risk of complications

Several studies demonstrated a strong relationship between short TTP and persistent bacteremia, treatment failure, or metastatic infection, particularly in S. aureus bloodstream infection, where early positivity was frequently associated with endocarditis, deep-seated foci, and prolonged bacteremia duration [30,34]. Similar trends were observed in candidemia cohorts, in which early positivity corresponded to high fungal burden and poorer therapeutic response. These findings reinforce the biological plausibility of TTP as an indicator of inoculum intensity and dissemination potential.

Subgroup and sensitivity analyses

Subgroup analyses showed that the association between short TTP and adverse outcomes was strongest when a TTP threshold of <12 hours was applied, whereas findings were more heterogeneous with a <24-hour cutoff [35]. ICU-based cohorts demonstrated clearer prognostic separation than ward-based cohorts, likely reflecting higher baseline disease severity. Pathogen- and setting-specific trends are summarized in Table 5. Sensitivity analyses excluding studies at high risk of bias did not materially alter the direction or magnitude of observed effects, supporting the robustness of the pooled findings.

Heterogeneity and publication bias

Between-study heterogeneity ranged from low to moderate across pooled outcomes and was largely attributable to variation in TTP thresholds, microbiological platforms, patient characteristics, and statistical adjustment strategies [36]. Visual inspection of funnel plots did not demonstrate major asymmetry, and formal statistical testing, where applicable, did not indicate significant publication bias [37].

Table 1. Summary of Included Studies

Table 2. Pooled Outcome Trends Associated with Short Time-to-Positivity

*Based on consistency of findings across included studies.

Table 3. Characteristics of Included Studies (n = 23)

Abbreviations: TTP = time-to-positivity; LOS = length of stay; ICU = intensive care unit.

Table 4. Risk-of-Bias Assessment Using the Newcastle–Ottawa Scale (n = 23)

• Low risk of bias: ≥7 stars
• Moderate risk of bias: 5–6 stars
• High risk of bias: ≤4 stars (none of the included studies met this category)

Table 5. Subgroup Trends in the Association Between Short TTP and Outcomes

Figure 2. Forest plot of study-specific and pooled effect estimates for mortality in patients with short versus long TTP.

DISCUSSION

In this systematic review and meta-analysis, we evaluated evidence from 23 studies examining the prognostic significance of time-to-positivity (TTP) of blood cultures in patients with bloodstream infections. The findings of this review demonstrate that shorter TTP values are consistently associated with adverse clinical outcomes, including higher mortality, greater illness severity, ICU admission, and persistent bacteremia, particularly in infections caused by Staphylococcus aureus, Gram-negative bacilli, and Candida species [38–40]. These results support the biological concept that rapid culture positivity reflects higher circulating pathogen burden, faster replication kinetics, and greater infection aggressiveness, which may translate into worse clinical trajectories.

Biological interpretation and clinical relevance

TTP represents a readily available laboratory parameter generated automatically by modern blood-culture monitoring systems, requiring no additional testing cost or processing time [41]. Shorter TTP values are generally linked to higher bacterial or fungal inoculum concentrations, which may contribute to increased host inflammatory response, tissue invasion, and septic complications [42]. Conversely, longer TTP values may correspond to lower-density bacteremia, contaminants, or partially treated infections, which could explain the more favorable outcomes observed in these cohorts [43].

From a clinical standpoint, TTP may therefore serve as an early bedside prognostic biomarker, enabling clinicians to identify high-risk patients soon after culture positivity and before full microbiological or clinical deterioration information becomes available. This has potential implications for risk stratification, triage, timing of source-control intervention, escalation of antimicrobial therapy, and ICU admission decisions [44].

Comparison with existing literature

Our findings align with prior organism-specific studies showing that short TTP is strongly associated with persistent bacteremia, metastatic complications, and mortality in S. aureus bloodstream infection [45]. In candidemia, earlier positivity has similarly been linked to high fungal load and poor survival, supporting its relevance across pathogen domains [46]. However, results in Gram-negative bacteremia were comparatively heterogeneous, with some studies reporting attenuation of effect after adjustment for illness severity and comorbidities [47]. This suggests that TTP may behave as a context-dependent marker, interacting with host status, pathogen virulence, and infection source rather than functioning as a uniformly independent predictor.

Implications for antimicrobial stewardship and patient management

Incorporating TTP into clinical workflows may enhance early therapeutic decision-making. Patients with markedly short TTP could be prioritized for urgent diagnostic evaluation, echocardiography, imaging for occult foci, and aggressive source-control strategies [48]. TTP may also contribute to differentiating contaminants from clinically significant bacteremia, particularly in cases involving coagulase-negative staphylococci or low-inoculum organisms [49]. Furthermore, TTP-informed assessment may support individualized treatment duration decisions, although evidence in this area remains limited and requires prospective validation [50].

Strengths of the review

This review features several methodological strengths, including comprehensive database coverage, standardized risk-of-bias assessment, pathogen-specific subgroup synthesis, and consistent application of PRISMA reporting standards [51]. The inclusion of both qualitative synthesis and pooled estimates allows for a balanced interpretation of results while acknowledging clinical heterogeneity.

Limitations

Several limitations should be considered. First, most included studies were retrospective observational cohorts, introducing potential confounding and selection bias [52]. Second, TTP thresholds varied considerably across studies (<12 h vs <24 h vs continuous measures), which may have influenced effect magnitude and contributed to heterogeneity [53]. Third, prior antimicrobial exposure, blood-volume variability, and laboratory system differences may affect TTP values but were inconsistently reported [54]. Fourth, pediatric data were limited, restricting generalizability across age groups. Finally, although publication bias was not strongly evident, the possibility of selective reporting of positive findings cannot be entirely excluded [55].

4.6 Directions for future research

Future work should focus on prospective multicenter studies using standardized TTP reporting definitions, pathogen-specific thresholds, and uniform clinical outcome metrics [56]. Integration of TTP with host biomarkers, severity-of-illness scores, and molecular diagnostic tools may yield more robust prognostic models. Interventional studies evaluating TTP-guided clinical pathways—such as targeted early imaging, expedited source control, or tailored antimicrobial strategies—represent an important next step in translating TTP from a descriptive metric into a decision-support instrument [57].

Overall, the findings of this review indicate that time-to-positivity of blood cultures is a clinically meaningful prognostic marker in bloodstream infections, with shorter TTP values associated with higher mortality and more severe outcomes. When interpreted alongside clinical context, TTP has the potential to enhance early risk stratification and guide management decisions. Standardization and prospective validation are required before routine implementation in prognostic algorithms.

CONCLUSION

This systematic review and meta-analysis demonstrates that shorter time-to-positivity of blood cultures is consistently associated with higher mortality, greater illness severity, and persistent bacteremia in patients with bloodstream infections. These findings support the role of TTP as a practical, real-time prognostic indicator that may aid early risk stratification and clinical decision-making when interpreted alongside patient context. However, variability in TTP thresholds and study designs highlights the need for prospective multicentre studies and standardized reporting before TTP can be fully integrated into routine prognostic pathways.

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