Time to positivity of blood culture is a risk factor for clinical outcomes in Staphylococcus aureus bacteremia children: a retrospective study

Staphylococcus aureus bacteremia (SAB) was defined as at least 1 positive S. aureus blood culture with systemic inflammation reaction syndrome status (SIRS), SIRS was defined according to the criteria previous published on Pediatr Crit Care Med [18]. Time to positivity (TTP) was defined as the time period between blood incubation and the positive signal, whereby all individuals were included only once. When multiple cultures were positive, the shortest TTP was enrolled. Prior antibiotic exposure was considered when the antibiotic was used before hospital-admission, regardless of administration time and dosage, appropriateness was judged by latter susceptibility results. Immunosuppressants consisted of corticosteroid and other cytotoxic agents, it was considered when duration of use ≥1 month. Neutropenia in this manuscript was associated with chemotherapy, defined by ANC (absolute neutrophil count) < 6.0 × 10⁹/L (infants), < 1.0 × 10⁹/L (< 1 year old), and < 1.5 × 10⁹/L (≥1 year old). The source of infection consisted of pneumonia, bone and joint, skin or soft tissue, endocarditis, CNS (central nervous system) infection, incisions, catheter related infection (urethral catheters and thoracic drain tube), and multiple sites. Nosocomial infection was defined as S. aureus infection that occurred > 48 h after hospital (not include the emergency department) admission or < 48 h after discharge. The length of hospitalization was defined as the time period between admission and discharge. The classification of septic shock was defined according to the criteria previously published in JAMA [19].

Approximately 3 mL of blood was inoculated into BACTEC plus aerobic bottles, which were then transported to the laboratory and immediately incubated in an automated continuous monitoring system. The BD diagnostic system was used for blood culture, which monitors CO₂ production every 5 min by means of a fluorescent signal. Bottles with positive results were examined by Gram staining, and their contents were subcultured. Species identification and susceptibility tests were performed using Vitek identification and susceptibility cards (bioMe’rieux Vitek).

The collected data included TTP of blood culture, demographic characteristics (age, gender, weight), underlying conditions (hematologic malignancy, congenital heart disease, neutropenia, primary immunodeficiency, chronic kidney disease), hypoalbuminemia, APACHE (acute physiology and chronic health evaluation) II scores, sources of infection as mentioned earlier, prior antibiotic exposure, appropriate antibiotic exposure, immunosuppressants use, nosocomial infection, methicillin-resistance, need for invasive mechanic ventilation, need for vasoactive agent, length of hospitalization, the incidence of septic shock and in-hospital mortality.

The primary outcome was in-hospital mortality. Since previous studies suggested that septic shock meant worse outcomes in adult SAB patients [20], it was chosen as the second outcome.

The continuous variables were presented as medians, and the first and third quartiles; the Student’s t test, Chi-square test, or the Mann-Whitney U test were used for analysis. The categorical variables were presented as rates and incidences, and assessed by means of the Χ² test or Fisher’s exact test. The log-rank test for Kaplan-Meier time-to-positivity analysis was constructed. Receiver operating characteristic (ROC) curves were plotted for the rate of sensitivity and 1-specificity. Youden’s Index was used for optimal cut-off selection, and the area under the curve (AUC) was calculated. The non-parametric test was constructed for the comparison of two groups. Univariate and multivariate logistic regression tests were constructed, for exploring the independent risk factors of septic shock and in-hospital mortality. Univariate logistic regression test was constructed for all independent risk factor exploration of in-hospital mortality, septic shock. Multivariate logistic regression test was constructed for the variates that showed differences in Univariate logistic regression test. The odds ratio (OR) and their 95% confidence interval (CI) were calculated for the statistically significant variables. All the tests were performed using SPSS (Version 19.0.0 for Windows), and p-value < 0.05 was considered to be statistically significant.

During the study period, 95 inpatient children with ≥1 S. aureus blood culture positive and systemic inflammation reaction syndrome status were enrolled retrospectively. Of them, 4 cases were lost to follow-up, 3 cases had incomplete clinical information and 4 cases missed their TTPs in medical records. Therefore, 84 cases were finally included in the study (Fig. 1).

The median (IQR) age of the enrolled SAB children was 56.00 (10.95, 126.25) months, median (IQR) weight was 15.00 (8.00, 35.00) kilogram, and 65.5% (55/84) of them were male. Less than half of the patients (45.2%, 38/84) had underlying conditions. Among the 35 patients (41.7%) with prior antibiotic exposure, only 13 cases (15.5%) reported appropriate. Immunosuppressants were used in 20 cases (23.8%). The most frequent infection source was multiple sites (28.57%, 24/84), followed by pneumonia (27.38%), and bone or joint infection (15.48%). Methicillin-resistance was detected in 29 cases (34.5%), and nosocomial infection in 14 cases (16.7%).

The median time to positivity (TTP) of blood culture of the 84 SAB children was 21.80 h (IQR 17.90, 27.42). The bar chart of TTP is shown in Fig. 2. The Kaplan-Meier tests of TTP analysis were constructed respectively with the categorical variables of outcomes. We observed a significant association of TTP with in-hospital mortality (P = 0.001) and septic shock incidence (P = 0.001) (Fig. 3). Receiver operating characteristic (ROC) curves of the TTP were plotted according to the primary outcome (in-hospital mortality) (See “Clinical outcomes” under Methods). Following Youden’s index methodology, we found 16.955 h to be the optimal cut-off point (61.5% sensitivity, 91.5% specificity, the area under the curves - AUC - were 0.776, with 95% CI 0.625–0.927) (Fig. 4). Therefore, we selected 17 h as the standard cut-off. Based on this, patients were divided into two groups: early detection group (TTP ≤17 h) and late detection group (TTP > 17 h).

A comparison between these two TTP groups was shown in Table 1. Demographic characteristics, the proportion of underlying conditions, APACHE II scores, hypoalbuminemia, prior antibiotic exposure, immunosuppressant use, nosocomial infection, methicillin-resistance and length of hospitalization – all were similar between the two groups. However, the other parameters showed important differences. In the early TTP group, 42.9% cases (6/14) needed invasive mechanical ventilation, but only 17.1% cases (12/70) in the late TTP group needed it (P = 0.033). Vasoactive agent was needed in 50.0% cases (7/14) in early TTP group but only in 18.6% cases (13/70) in the late TTP group (P = 0.012). In-hospital mortality was 57.1% (8/14) in early TTP group but 7.1% (5/70) in late TTP patients (P = 0.000). Septic shock occurred in 8 patients (8/14, 57.1%) in early TTP group and in 13 patients (13/70, 18.6%) in late TTP patients (P = 0.002). Taken together, these results indicated critical clinical differences between the early and late TTP groups.

Univariate logistic regression test demonstrated that in-hospital mortality was correlated with hematologic malignancy, immunosuppressants use, need for invasive mechanical ventilation and vasoactive agent, neutropenia, APACHE II score ≥ 15 and early TTP. Multivariable logistic regression test showed that early TTP, need for vasoactive agent were independent risk factors of in-hospital mortality (Table 2).

The univariate logistic regression test demonstrated that the incidence of septic shock was correlated with hematologic malignancy, immunosuppressants use, need for invasive mechanical ventilation and vasoactive agents, neutropenia, APACHE II score ≥ 15, and early TTP. As before, multivariable logistic regression showed that early TTP, need for vasoactive agent and APACHE II score ≥ 15 were independent risk factors of incidence of septic shock (Table 3).