Systematic review and meta-analysis of the impact of infectious diseases consultation on outcomes of Staphylococcus aureus bacteremia in children

Abstract

For adult patients with Staphylococcus aureus bacteremia (SAB), Infectious Diseases consultation (IDC) significantly lowers mortality and recurrence rate. Our systematic review and meta-analysis demonstrate that IDC is also associated with significantly lower mortality in children with SAB. Analysis of the impact of IDC on pediatric recurrence rates revealed moderate heterogeneity.

Introduction

Staphylococcus aureus is a common cause of both community-acquired and nosocomial bacteremia in children. The incidence of pediatric S. aureus bacteremia (SAB) in high-income countries is at 8–26 per 100,000 children per year; 9% of all nosocomial bloodstream infections in children in the USA are due to S. aureus. ¹ Mortality in healthy children with SAB ranges from 2%–5% but increases up to 15% in children with pre-existing risk factors such as congenital heart disease. ² Several studies evaluating the role of infectious diseases consultation (IDC) in adult patients with SAB have shown a protective effect of IDC on mortality and recurrence rates, as well as improved adherence to quality-of-care metrics. However, there is limited data available regarding the impact of IDC on outcomes of SAB in the pediatric population. The aim of this systematic review and meta-analysis is to assess the impact of IDC on the outcomes of SAB in children.

Methods

This systematic literature review and meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement and the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines. The review protocol was registered on the International Prospective Register for Systematic Reviews (PROSPERO) and is publicly available (CRD 42023473626). Institutional review board approval was not required.

A search strategy to identify publications about SAB and IDC in children was developed in collaboration with a health sciences librarian (RJS) trained in systematic searching (Supplemental Document 1). Systematic strategies were created for PubMed, Embase (Elsevier), Scopus (Elsevier), CINAHL (Ebsco), Cochrane Library (Wiley), and Web of Science (Clarivate). Search terms included controlled vocabulary (when available), synonyms, and related concepts for: Staphylococcus aureus, MRSA, bacteremia, septicemia, multi-drug resistant bacteria, pediatrics, children, infectious disease consultation, and antimicrobial stewardship. The searches were conducted in January 2024; no filters were utilized. Additional studies were identified through hand-searching.

Four independent reviewers (H.S., N.M., T.K., and A.R.M.) abstracted data from the studies using a standardized abstraction form. Details of each study were tabulated, including study design, study period, population characteristics, prevalence of methicillin-resistant Staphylococcus aureus (MRSA), source of infection, and outcome measures including mortality, SAB recurrence, and fulfillment of certain quality-of-care indicators. H.S. reviewed abstraction forms and served as a tie breaker. One author ³ was contacted for additional information, which was provided. The Downs and Black scale was used to evaluate the quality of the included studies.

The primary outcomes were all-cause mortality and SAB recurrence rates over any period. We used crude or unadjusted numbers for the pooled odds ratios (ORs) as adjusted ORs were not available in all articles. The pooled OR and 95% confidence interval were calculated using random-effect models with inverse variance weighting. Heterogeneity was assessed with I ² estimation. Funnel plots were constructed to assess publication bias. Meta-analyses were conducted using the Cochrane Review Manager (RevMan) version 5.4.

Results

Among 972 articles screened, a total of 8 studies ^2–9 met the inclusion criteria and were used in the final qualitative systematic literature review (Supplemental Figure 1). All studies evaluated pediatric patients with SAB only. Five ^2–6 of the eight publications directly evaluated the impact of IDC on outcomes in pediatric SAB; results from these studies were pooled for the meta-analysis. Of these 5 studies, 1 was a prospective cross-sectional study ³ , 1 was an observational cohort study ⁵ , 2 were retrospective cohort studies ^2,6 , and 1 was a quasi-experimental study ⁴ . One study ³ was a multicenter study across 2 countries, while the other four studies were conducted in a single center (Table 1). The multicenter study ³ was performed in Australia and New Zealand, two studies ^4,6–8 were performed in the United States, one in Australia ² , and one in the United Kingdom ⁵ .

Figure 1. Meta-analysis of outcomes of Staphylococcus aureus bacteremia in pediatric patients.

Table 1. Summary of the eight studies included in the systematic review

aHR, adjusted hazard ratio; aOR, adjusted odds ratio; ASP, antimicrobial stewardship program; BPA, best practice advisory; ICU, intensive care unit; ID, infectious diseases; IDC, infectious diseases consultation; MRSA, methicillin-resistant Staphylococcus aureus; MSK, musculoskeletal; NIDC, no infectious diseases consultation; QI, quality improvement; QCI, quality-of-care indicator; SAB, Staphylococcus aureus bacteremia.

Of the remaining three papers included in the qualitative systematic review (Table 1), one ⁷ evaluated the impact of a best practice advisory (BPA) recommending IDC and optimal antibiotic therapy based on rapid mecA gene detection and two ^8,9 evaluated the longitudinal impact of implementation of an antimicrobial stewardship program (ASP) on pediatric SAB outcomes. Although these studies did not directly evaluate the impact of IDC on pediatric SAB outcomes, the findings have been summarized and presented in Table 1 to demonstrate the impacts of BPAs and ASPs, which incorporate interdisciplinary infectious diseases expertise, on all-cause mortality, recurrence of SAB and quality-of-care metrics such as choice of and time to optimal antibiotic therapy. Six studies ^2–4,6–8 were considered good (>18 of 28 possible points) per the Downs and Black quality tool while two studies ^5,9 were considered fair (15 – 18 points).

When the results of the five studies ^2–6 were pooled, IDC was associated with significantly lower mortality in pediatric SAB with low heterogeneity (pooled OR = 0.44, 95% confidence interval [CI]: 0.20−0.97, I² = 0%) (Figure 1). When the results of the four studies which reported SAB recurrence rates ^2–5 were pooled, IDC was associated with lower recurrence rates, however this was not statistically significant and there was moderate heterogeneity (pooled OR = 0.24, 95% CI: 0.04−1.34, I² = 56%) (Figure 1). We conducted a publication bias analysis using funnel plots (Supplemental Figure 2). For both analyses, the studies were reasonably balanced around the pooled ORs with little evidence of publication bias.

Discussion

Our systematic review and meta-analysis revealed a noteworthy association between IDC and lower mortality among children with SAB, showing low heterogeneity. Although patients with IDC tended to have a lower recurrence rate, it did not reach statistical significance and had moderate heterogeneity.

Numerous prior studies have demonstrated the efficacy of IDC among adult patients with bacteremia caused by Staphylococcus aureus, Enterococcus species, Candida species, etcetera. ^10,11 Accordingly, for adult patients with SAB, many hospitals in the United States recommend or mandate infectious disease consultations. In contrast, our systematic review identified only five published papers evaluating the utility of IDC in pediatric patients with SAB. The observed benefits in adult studies are likely attributable to appropriateness of antibiotic choice and duration and/or identification of infectious foci ¹¹ . These practices result in optimized antibiotic treatment, definitive source control, and proper follow-up. The studies reviewed demonstrated consistent improvements in quality-of-care metrics for pediatric SAB patients when IDC (Duguid ² , Saunderson ⁵ , Whittington ⁶ ) was utilized, as well as with services that incorporate infectious diseases expertise, such as BPAs (Lloyd ⁷ ) and ASPs (Welch ⁸ ), as outlined in Table 1.

This study has limitations. Almost half of the included studies were retrospective and most were not designed to investigate the impact of IDC. The period over which outcomes were evaluated varies substantially across studies, including mortality over 30-day to 6-month periods and recurrence of SAB over 14-day to 6-month periods. Immortal time bias was not specifically evaluated in the included studies. Unmeasured confounders are likely to remain, such as the timing of IDC and/or efficacy of antibiotic selection prior to IDC. Because only 40% of the studies included adjusted odds ratios (OR), we could only use crude numbers to calculate the pooled ORs. Therefore, our calculated ORs do not adjust for confounding factors. Both the incidence and mortality of SAB in pediatric patients was much lower than that for adults. Therefore, a prospective study designed to demonstrate a benefit of IDC in pediatric SAB would necessarily be a very large, multicenter study. Thus, despite the inherent limitations, this meta-analysis of existing data provides an important indicator of the potential value of IDC in children with SAB.

In summary, our study suggests that IDC significantly improves the mortality of pediatric patients with SAB. Prospectively collected clinical information will be needed to help us establish a greater degree of accuracy and to understand the precise mechanisms by which IDC might improve outcomes in children with SAB.