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. 2022 Mar 15;149(4):e2021052165. doi: 10.1542/peds.2021-052165

Improving Vancomycin Stewardship in Critically Ill Children

Kathleen Chiotos a,b,c,d,e,✉, Julie C Fitzgerald a,c,e, Molly Hayes d, Hannah Dashefsky e, Talene A Metjian d, Charlotte Woods-Hill a,c,e, Lauren Biedron e, Hannah Stinson a,c,e, Brandon C Ku e,f, Sheila Robbins Tighe e, Scott L Weiss a,c,e, Fran Balamuth e,f, Emily Schriver d, Jeffrey S Gerber c,d
PMCID: PMC9647566  NIHMSID: NIHMS1847857  PMID: 35362066

Abstract

BACKGROUND AND OBJECTIVES

Inappropriate vancomycin use is common in children’s hospitals. We report a quality improvement (QI) intervention to reduce vancomycin use in our tertiary care PICU.

METHODS

We retrospectively quantified the prevalence of infections caused by organisms requiring vancomycin therapy, including methicillin-resistant Staphylococcus aureus (MRSA), among patients with suspected bacterial infections. Guided by these data, we performed 3 QI interventions over a 3-year period, including (1) stakeholder education, (2) generation of a consensus-based guideline for empiric vancomycin use, and (3) implementation of this guideline through clinical decision support. Vancomycin use in days of therapy (DOT) per 1000 patient days was measured by using statistical process control charts. Balancing measures included frequency of bacteremia due to an organism requiring vancomycin not covered with empiric therapy, 30-day mortality, and cardiovascular, respiratory, and renal organ dysfunction.

RESULTS

Among 1276 episodes of suspected bacterial infection, a total of 19 cases of bacteremia (1.5%) due to organisms requiring vancomycin therapy were identified, including 6 MRSA bacteremias (0.5%). During the 3-year QI project, overall vancomycin DOT per 1000 patient days in the PICU decreased from a baseline mean of 182 DOT per 1000 patient days to 109 DOT per 1000 patient days (a 40% reduction). All balancing measures were unchanged, and all cases of MRSA bacteremia were treated empirically with vancomycin.

CONCLUSION

Our interventions reduced overall vancomycin use in the PICU without evidence of harm. Provider education and consensus building surrounding indications for empiric vancomycin use were key strategies.

Vancomycin is among the most commonly used antibiotics in United States children’s hospitals.1–4 It is most often initiated for empiric or definitive treatment of methicillin-resistant Staphylococcus aureus (MRSA) and has unique activity against other Gram-positive organisms, including coagulase-negative Staphylococcus species and Enterococcus species.5 Several national guidelines, including those written for the management of sepsis and central line associated bloodstream infection, offer general recommendations for when empiric vancomycin should be prescribed. These are focused on situations in which MRSA is a likely causative pathogen, which is dependent on local MRSA prevalence, personal history of or risk factors for MRSA, comorbid medical conditions, and source of infection.6–10

Inappropriate use of vancomycin is common, estimated to occur in 20% to 65% of vancomycin courses.3,11–14 This finding is concerning, given published data demonstrating a declining prevalence of methicillin resistance among S aureus in the United States as well as a low prevalence of invasive infections due to MRSA in most series.5,12,15–18 In addition, empiric use of anti-MRSA therapy has not been associated with reductions in mortality when studied in adults with community-acquired pneumonia or as part of a general aggressive empiric antibiotic use strategy in the ICU.19,20 Finally, an association between vancomycin and risk of acute kidney injury (AKI) is well documented, with rates of AKI of up to 25% reported.21–25

Vancomycin therefore represents a key target for improved antibiotic stewardship, including at the point of empiric initiation. Interventions targeting this time point are particularly important, given that most vancomycin courses are <48 to 72 hours in duration and are therefore stopped before audit with feedback by an antimicrobial stewardship program (ASP) would typically occur.13,26 We report the results of a quality improvement (QI) project which aimed to reduce overall vancomycin days of therapy (DOT) in the PICU by at least a 10% over 3 years by reducing empiric vancomycin initiation in clinical scenarios when risk of MRSA infection is low.

Methods

Context

This project took place in the 65-bed PICU at our tertiary care freestanding children’s hospital. The PICU has a well-established QI infrastructure, including a multidisciplinary sepsis QI team. The ASP requires preauthorization for use of most broad-spectrum antimicrobial agents. However, use of vancomycin was permitted without ASP oversight for up to 48 hours for indications such as suspected sepsis and suspected central line associated bloodstream infection throughout the study period, after which approval from the ASP was required.8 At the start of this QI project in 2017, vancomycin was the most commonly used antibiotic in our PICU. Prevalence of MRSA among all S aureus isolates was ∼35%.

Planning the Intervention

Baseline (Retrospective) Data Collection

During the baseline period, we retrospectively defined (1) the frequency of vancomycin initiation for suspected bacterial infection in the PICU; (2) the prevalence of bacteremia caused by organisms requiring vancomycin therapy; and (3) the ability of MRSA history and source of infection to predict MRSA bacteremia (Fig 1). We included patients <21 years old admitted to the PICU between February 2014 and April 2016. Suspected bacterial infection was defined as collection of a blood culture and new administration of ≥1 broad-spectrum antibiotic within 6 hours of the blood culture. Broad-spectrum antibiotics included third and fourth generation cephalosporins, carbapenems, fluoroquinolones, piperacillin-tazobactam, aztreonam, vancomycin, and linezolid. Organisms classified as requiring vancomycin therapy included MRSA, Enterococcus species, Viridans group Streptococcus species in neutropenic patients, and coagulase-negative Staphylococcus species when identified in a patient with a central line. Common skin commensal organisms were classified as contaminants if present in a single culture and absent indwelling devices.

FIGURE 1.

FIGURE 1

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Summary of timeline and project phases.

Interventions

QI Project and Plan-Do-Study-Act Cycles

Following this retrospective data collection, we defined baseline vancomycin use over a 1-year period between July 2016 and June 2017. We then performed a series of 3 plan-do-study-act (PDSA) cycles between July 2017 and June 2020, including: (1) provider education; (2) creation of a consensus-based guideline for vancomycin initiation; and (3) implementation of the guideline through clinical decision support (CDS) tools (Fig 1).

Stakeholder Education

The first PDSA cycle occurred in July 2017 and involved education of the PICU sepsis QI team over the course of 3 ad hoc meetings, as well as clinicians in the PICU and infectious diseases divisions as one-time presentations during division-wide meetings. All faculty, fellows, and nurse practitioners are expected to attend these meetings. Sharing the data from our baseline (retrospective) data collection defining a low prevalence of MRSA infections among patients with suspected bacterial infections as well as the strong predictive value of known previous MRSA infection or colonization and suspected source of infection in identifying patients with MRSA bacteremia was a key element of this education (Fig 2). These findings were reinforced by the ASP during routine clinical activities, which generally occurred by telephone.

FIGURE 2.

FIGURE 2

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Frequency of vancomycin-requiring organisms isolated in blood culture, February 2014 to April 2016. These data were gathered retrospectively during the baseline period. CoNS, coagulase-negative Staphylococcus. a Both with deep neck space infections.

Consensus Building and Guideline Creation

On the basis of provider feedback following the first PDSA cycle and our baseline (retrospective) data, the focus of the second PDSA cycle was on developing consensus surrounding indications for empiric vancomycin use and a shared mental model across ASP and sepsis stakeholders. This occurred between July 2018 and January 2019 and involved a series of monthly and ad hoc meetings including all members of the critical care sepsis QI team and a physician and pharmacist from the ASP. Guidance around empiric initiation was selected because the majority of vancomycin courses in our PICU were <3 calendar days. Key clinical scenarios in which vancomycin was recommended (in addition to a β-lactam antibiotic) included (1) fever with central line and history of MRSA or presence of a dialysis catheter; (2) suspected MRSA infection based on source and severity (for example, severe lobar pneumonia); (3) suspected meningitis or ventriculitis; or (4) sepsis-related organ dysfunction or septic shock (Supplemental Fig 5). These recommendations were shared and agreed on by the Division of Critical Care Medicine during a consensus conference in January 2019.

CDS: Sepsis Pathway and Order Set

The third PDSA cycle occurred in August 2019 and was focused on developing CDS for implementation of the consensus-based recommendations by integrating them into the established sepsis pathway and developing a new order set. The ordering of vancomycin as an individual order was also permitted (Supplemental Fig 5).

Measures and Study of the Interventions

Process Measures

The primary process measure was the overall number of vancomycin DOT administered in the PICU per 1000 PICU patient days. Each calendar day in which ≥1 doses of vancomycin were administered was counted as 1 DOT. A measure of overall vancomycin use was selected because it reflects changes in overall consumption and the resulting risks of toxicity and emergence of resistance, and is the antibiotic use measure recommended by the Infectious Diseases Society of America.26 Secondary measures included the proportion of all vancomycin courses ≤3 calendar days, the proportion of overall vancomycin DOT accounted for by courses ≤3 days, and the number of unique vancomycin courses per 1000 patient days, measures that allow assessment of whether overall reductions in vancomycin use result from decreases in empiric initiation versus earlier discontinuation. Any duration of vancomycin administration was counted as a unique course, provided that at least 1 calendar day had elapsed between courses. Finally, we measured order set use among patients with suspected bacterial infection but were unable to assess whether providers accessed the consensus guideline-based recommendations within the Web-based clinical pathway when individual orders for vancomycin were placed.

Balancing Measures

Among patients with bacteremia, we evaluated whether the prescribed empiric antibiotic regimen was active against the causative organism. This analysis was performed for bacteremia only because vancomycin was recommended routinely for other sites of infection in which MRSA is likely to be a significant pathogen, including severe lobar pneumonia and sepsis with a suspected skin or soft tissue infection. In addition, infections of these sites are often culture-negative and diagnosed on the basis of clinical data, rather than microbiologic data, making assessment of culture-based outcomes less applicable. Finally, positive respiratory culture results may reflect colonization rather than true infection; as an illustration of this, just 12 of the 30 respiratory cultures positive for MRSA were reflective of respiratory infections in the baseline (retrospective) data collection phase (Supplemental Fig 6). However, because inadequate empiric antibiotic therapy has the potential for harm regardless of source or culture positivity, we also evaluated 30-day mortality and development of new or progressive cardiovascular, respiratory, or renal organ dysfunction among PICU patients with suspected bacterial infection (Supplemental Table 1). These were measured relative to a time 0 of blood culture collection or sepsis order set initiation, whichever occurred first.

Cost Estimation

We estimated cost savings from drug charges avoided as a result of this intervention by estimating vancomycin DOT that would have occurred if the baseline vancomycin DOT per 1000 patient days had continued unchanged throughout the PDSA cycles. We subtracted actual vancomycin DOT by month from these estimates to generate an estimate of vancomycin DOT saved. We used a cost of $2.96 per day for a 20 kg patient local pharmacy cost data.

Analysis

We generated statistical process control charts for all measures. We used X-bar S charts for continuous data and p charts for classification data. The centerline reflects the mean, and the upper and lower control limits reflect 3 SDs above or below the mean. The starting centerline and control limits were calculated by using data from a 12-month baseline period (July 2016 to June 2017). Nelson rules were applied to determine if the interventions resulted in special cause variation in vancomycin use, mortality, or organ dysfunction. Specifically, ≥8 consecutive points above or below the centerline was defined as special cause variation, and when this condition was met, a new centerline mean was calculated.27 Data were collected from the Children’s Hospital of Philadelphia Data Warehouse, and all analyses were performed by using Stata 14 (Stata Corp, College Station, TX).

Ethical Considerations

This project was undertaken as QI and met our institutional definition for nonhuman subjects research.

Results

Baseline (Retrospective) Data Collection

Of 1276 episodes of suspected bacterial infection reviewed before the start of the QI interventions, vancomycin was initiated within 6 hours of blood culture collection in 971 (76%). Excluding 15 cultures classified as contaminants, there were 19 blood cultures (1.5%) positive for organisms meeting the definition for vancomycin requiring, including 9 coagulase-negative Staphylococcus species (0.7%), 6 MRSA (0.5%), 3 Enterococcus species (0.2%), and 1 viridans group Streptococcus (0.08%). Among patients with MRSA, 4 of the 6 had a known MRSA history, and the remaining 2 patients had deep neck space infections with secondary bacteremia (Fig 2). If respiratory and urine cultures were additionally included, the overall prevalence of vancomycin-requiring organisms increased to 61 (4.8%), including 30 respiratory cultures positive for MRSA and 12 urine cultures positive for Enterococcus species (Supplemental Fig 6).

QI Project and PDSA Cycles

Process Measures

Baseline use of vancomycin was 182 DOT per 1000 patient days between July 2016 and August 2017. Starting immediately after PDSA cycle 1 (stakeholder education) in July 2017, we observed a downward shift in the vancomycin DOT per 1000 patient days centerline to 155 DOT per 1000 patient days, a 15% reduction in vancomycin DOT per 1000 patient days. Additional centerline shifts occurred in March 2018 to 128 vancomycin DOT per 1000 patient days (a 31% reduction from baseline) and during PDSA cycle 2 in December 2018 to 109 vancomycin DOT per 1000 patient days (a 40% reduction from baseline). No change in the centerline was observed following PDSA 3 (Fig 3). However, use of the sepsis order sets occurred in only 13% of the cohort. The proportion of vancomycin courses lasting ≤3 days increased from a baseline mean of 79% to 83%, whereas the proportion of total DOT accounted for by courses ≤3 days increased from 53% to 61%. The total number of vancomycin courses per 1000 patient days decreased from 66 to 45 (Supplemental Fig 7).

FIGURE 3.

FIGURE 3

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Vancomycin DOT per 1000 patient days, July 2016 to June 2020. COVID-19, coronavirus disease 2019; LCL, lower control limit; UCL, upper control limit.

Balancing Measures

Between July 2017 and June 2020, there were 72 episodes of bacteremia. In 2 cases, vancomycin was not started empirically and both patients grew an Enterococcus species. In all other cases, the empiric antibiotic regimen selected covered all vancomycin-requiring organisms (Fig 4). Of the 2 patients who did not receive vancomycin empirically and grew Enterococcus, neither died or experienced organ dysfunction associated with their bacteremia. Thirty-day mortality and new or worsening day 3 respiratory, renal, and cardiovascular organ dysfunction were unchanged after our interventions (Supplemental Fig 4).

FIGURE 4.

FIGURE 4

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Episodes of bacteremia and need for vancomycin therapy, July 2017 to June 2020. These data were gathered during the QI project.

Cost Savings

We estimate that $12 988 in drug costs were avoided over the 3 PDSA cycles.

Discussion

Summary

We describe a multiyear initiative focused on reducing vancomycin use in a tertiary care PICU through a combination of provider education, consensus building, and CDS. Total vancomycin use decreased 40% over the study period. Importantly, no MRSA bacteremias were missed with empiric therapy, and there was no increase in 30-day mortality or new or progressive respiratory, renal, or cardiovascular organ dysfunction.

Interpretation

Provider education and consensus building among key stakeholders were impactful interventions associated with decreasing vancomycin use. This appeared to be driven both by decisions not to start vancomycin empirically (based on the decline in vancomycin courses per 1000 patient days) and to a lesser extent earlier discontinuation (based on a greater proportion of vancomycin courses lasting ≤3 days). We attribute the unexpectedly large impact of these interventions to 2 factors. First, education was focused on local data demonstrating a low absolute of MRSA bacteremia and strong predictive performance of source of infection and MRSA history, data that likely resonated with clinicians making prescribing decisions. Second, changes in individual prescribing behavior reflecting the consensus discussions likely occurred before these recommendations were finalized, given that many PICU and ASP stakeholders were engaged in the consensus discussions. No further decrease in overall vancomycin use was observed after implementation of the clinical pathway and order set, perhaps because of low use of the order set. It is also possible that integration of the vancomycin recommendations into these tools supported the sustainability when provider education and active consensus discussions were no longer occurring. These findings are significant because they support the idea that focused education and stakeholder-engaged consensus guidelines can be effective strategies for improving antibiotic use in the PICU setting. Finally, this work reveals that significant reductions in vancomycin use are feasible, even in a setting with complex and critically ill patients.

This work expands on the published literature, which has largely been focused on interventions targeting discontinuation of vancomycin.13,28–34 Turner et al29 demonstrated a 38% reduction in overall vancomycin use after implementation of an ASP using audit with feedback performed at 72 hours, with no change in length of stay or mortality. A more modest 15% reduction was demonstrated in the work of Choe et al,13 likely because of the fact that just 19% of vancomycin courses met criteria for review, as audit with feedback occurred only after 96 hours of vancomycin therapy. These studies support the importance of interventions targeting earlier points of prescribing. For example, based on our estimated prevalence of MRSA and presuming patients with suspected bacterial infections receive 48 hours of vancomycin therapy administered every 6 hours, nearly 1600 doses of vancomycin would be administered per 1 patient with MRSA bacteremia (and all before the time point ASPs would generally perform an audit with feedback).

Despite its novelty and these strengths, our work has several limitations. First, culture-based techniques are limited in their ability to identify all infections with vancomycin-requiring organisms, and there is potential for nonbloodstream and culture-negative infections to cause significant morbidity if untreated. Although our analysis of the microbiologic data was focused on only bloodstream infections, we observed no change in the prevalence of organ dysfunction or mortality in our cohort, suggesting that reductions in vancomycin use did not result in quantifiable changes in clinical outcomes among patients with culture-positive or culture-negative infections, regardless of source. However, because of the small numbers of vancomycin-requiring organisms, we cannot rule out the potential for benefit of empiric vancomycin for individual patients not detected on a population level. Second, whereas empiric vancomycin was recommended by the guideline in all cases of MRSA bacteremia (the organism primarily targeted by the guideline), vancomycin was not recommended for 6 patients who ultimately had Enterococcus bacteremia. Because vancomycin was prescribed to 4 of the 6 patients despite the guideline recommendations, it is difficult to known if any deleterious consequences of a lack of empiric vancomycin would have been experienced had the guideline been specifically followed, although no adverse events were experienced by the 2 patients not prescribed vancomycin empirically. Third, our findings may not be generalizable to other settings because our baseline vancomycin use was high and we have a well-established QI infrastructure for process improvement. Nevertheless, published data suggest that vancomycin is among the most commonly used antibiotics at many pediatric centers, so we would expect that reductions could be achievable elsewhere with the available QI resources to invest in this work. Fourth, our intervention may be less feasible at centers with higher MRSA prevalence. However, with declining MRSA prevalence nationally and several studies revealing that infections caused by MRSA are infrequent, our approach is likely generalizable to many other centers.5,12,15–18 Finally, the coronavirus disease 2019 pandemic may have influenced measures of vancomycin use during the final 4 months of our intervention through changes in case mix, confounding the interpretation of the impact of our CDS intervention and sustainability of this work.

In conclusion, we used local data to demonstrate low MRSA prevalence and strong predictive ability of previous MRSA history and source of infection to develop a consensus-based approach to empiric vancomycin use in our tertiary PICU. Vancomycin use was reduced by 40%, without an adverse impact on clinical outcomes or inadequate empiric coverage of organisms causing bacteremia in this population. In future work, researchers should refine formal clinical prediction rules and electronic health record supports using suspected source of infection, history of MRSA, and previous antibiotic exposures to identify patients in whom empiric vancomycin therapy is appropriate. In addition, future studies should rigorously evaluate the implementation of these interventions, including measurements of adherence, as well as patient centered outcomes, including rates of AKI, intravenous catheter infiltrates, and length of stay.

Supplementary Material

Supplemental Information
Click here for additional data file. (1.9MB, pdf)

Acknowledgments

We thank Christian Minich for his assistance with data collection.

Glossary

AKI

acute kidney injury

ASP

antimicrobial stewardship program

CDS

clinical decision support

DOT

day of therapy

MRSA

methicillin-resistantStaphylococcus aureus

PDSA

plan-do-study-act

QI

quality improvement

Footnotes

Drs Chiotos, Gerber, and Hayes conceptualized and designed the study, led the quality improvement interventions, collected and reviewed the data, performed all analyses, drafted the initial manuscript and figures, and reviewed and revised the manuscript; Drs Fitzgerald, Woods-Hill, Stinson, Weiss, Balamuth, Metjian, and Ku, Ms Biedron, Ms Dashefsky, and Ms Robbins-Tighe contributed to design of the study, reviewed data, and critically reviewed and revised the manuscript; Ms Schriver was responsible for data management and analysis; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of work.

FUNDING: Supported by the Centers for Disease Control and Prevention Cooperative Agreement FOA#CK16-004-Epicenters for the Prevention of Healthcare Associated Infections. Dr Chiotos receives support through the Agency for Healthcare Research and Quality (K12-HS026393). Dr Fitzgerald receives support through the National Institute of Diabetes and Digestive, and Kidney Diseases (K23 DK119463. Funded by the National Institutes of Health (NIH).

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplemental Information
Click here for additional data file. (1.9MB, pdf)

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