Vancomycin Area Under the Curve to Minimum Inhibitory Concentration Ratio for Treatment Effectiveness in Pediatric and Neonatal Staphylococcal Infections: A Systematic Review

Search Strategy.

The systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews checklist.¹⁰ The literature search was conducted in 5 electronic databases, including the Cochrane Library, Excerpta Medica Database (EMBASE), Open Forum Infectious Diseases (OFID), PubMed, and Web of Science (WOS) from inception through July 31, 2023, using search terms vancomycin, AUC, children or pediatric. Given that research on vancomycin therapeutic drug monitoring is often conducted with focus on serum trough concentrations, whereas studies on AUC are focused on treatment outcomes instead of therapeutic drug monitoring or a target concentration attainment, the search term AUC was used instead to retrieve as many relevant records as possible. Items identified were exported into a Microsoft Excel spreadsheet (Microsoft, Redmond, WA). The screening started with the author and title review for duplicates and relevance, followed by review of the abstract and text for eligibility based on the inclusion and exclusion criteria as described below. In addition, references of included studies, narrative reviews, guidelines, commentaries, author replies, letters, and editorials were manually checked to identify any additional sources. Three authors (R-YC, BAH, HT) independently applied the inclusion and exclusion criteria to identify eligible studies. Non-concordance was reviewed and resolved by consensus agreement.

Inclusion and Exclusion Criteria.

All publications were eligible if they met the inclusion criteria defined according to the Population, Intervention, Comparison, Outcome and Study design (PICOS) process as follows¹¹: Population: pediatric patients (age ≤18 years) who received intravenous vancomycin against culture-proven MRSA, CoNS, or S aureus; Intervention: vancomycin therapy was guided by AUC:MIC ratio; Comparison: AUC:MIC ratio above a threshold was considered the exposure, compared with those below this threshold; Outcome: treatment effectiveness, which can be any combination of measurements of clinical improvement (i.e., symptoms and/or surrogate markers), microbiologic clearance, frequency and/or time to recurrence, and incidence of mortality, as defined by each individual study; and Study designs: all published articles or abstracts, either retrospective or prospective, observational or experimental.

Exclusion criteria were studies not published in English; nonhuman or adult (>18 years old) studies; publications without original data; studies not addressing clinical or microbiologic treatment effectiveness outcomes; studies that enrolled patients with presumed infections without documented positive cultures in their assessment for treatment effectiveness target; studies without assessment of the vancomycin AUC:MIC ratio threshold for effectiveness despite data presented on AUC:MIC and treatment outcomes; and studies that enrolled patients with a variety of infection types where less than 90% were MRSA, CoNS, or S aureus on cultures.

Data Reporting.

Data collected from eligible studies included the first author, country and year of publication, study design, number of participating sites, study period, primary objective, inclusion and exclusion criteria, determination methods for vancomycin AUC, pathogen MIC, distribution of MICs, AUC:MIC ratio threshold for treatment effectiveness, characteristics of participants and of the subgroup of patients, if applicable, in the analysis of AUC:MIC threshold for effectiveness, and major findings on the AUC/MIC ratio threshold for treatment effectiveness outcomes. Data on concurrently administered antibiotics were not collected. Comparable to adult literature on MRSA bacteremia (MRSA-B), additional data were collected from eligible pediatric MRSA-B studies including common comorbidities, intensive care unit (ICU) status, and presence of high-risk infectious foci, as previously defined, with clinical manifestations indicative of a source within the endovascular system, lower respiratory tract, abdomen, or central nervous system.^12,13 Data may be missing in some enrolled studies. However, no attempt was made to obtain additional unpublished clinical data from enrolled studies owing to the requirement of approval from multiple institutional review boards.

Quality Assessment.

The Newcastle-Ottawa scale for non-randomized studies,¹⁴ as used in a recent systematic review on mortality from S aureus bacteremia,¹⁵ was used for evaluation of the methodologic quality of enrolled individual non-randomized studies (Supplemental Table S1a). Of note, some enrolled studies reported the relationship between AUC or AUC:MIC and treatment effectiveness as a secondary outcome from a subgroup of their study participants who had AUC, MIC, and treatment outcome data available. For these studies, the quality assessment was focused on their subgroup analysis, such as the representativeness of the subgroup.

Literature Search.

A combined 1020 records from Cochrane, EMBASE, OFID, PubMed, and WOS were identified. No other studies were added through individual citation reference list. Of these 1020 identified records, 312 were removed for duplicates, 362 were taken out for irrelevance, and 334 were excluded on the basis of assessment of eligibility (see Supplemental Table S1 and Supplemental Figure). The remaining 12 studies were eligible and included for data extraction. All 12 studies, including 10 articles and 2 abstracts, were cohort observational studies published between 2015 and 2022, reporting 559 patient encounters on vancomycin against MRSA, CoNS or S aureus across different geographic regions, reflecting the global prevalence of use of vancomycin in pediatrics.

Determination of Vancomycin AUC:MIC Ratio Threshold for Effectiveness.

Regarding the determination of vancomycin AUC:MIC threshold for treatment effectiveness, 4 studies had set an AUC:MIC ratio threshold of 400 mg × hr/L adopted from adult literature a priori and compared efficacy outcomes between patients with AUC:MIC ratio above and below 400 mg × hr/L.^16–19 Two studies divided their patients into treatment success and failure groups and compared the median AUC:MIC ratio between these 2 groups.^20,21 Four studies used statistical methods to identify an AUC:MIC ratio breakpoint associated with effectiveness,^22–25 and the remaining 2 did not provide the method they used to determine the AUC:MIC ratio threshold for treatment effectiveness.^26,27

The vancomycin AUC:MIC ratio value is derived from the vancomycin AUC estimate and the MIC reported from the microbiology laboratory. Various methods were used by these studies to determine MICs, including BMD,^{17,19,20,24,25} gradient diffusion,^16,18,21,26 automated systems,^{16,20–22,24,27} and 1 study did not report the methodology.²³ The MICs from different susceptibility testing methods across these studies may not be entirely consistent.

Similarly, 2 studies did not provide descriptions of AUC calculation.^17,26 The remaining 10 studies^16,18-25,27 used various methods to estimate AUC, including published validated methods by Chang et al²⁸ or Le et al,²⁹ trapezoidal rule,¹⁸ or various pharmacokinetic (PK) modeling/Bayesian estimates incorporating either one,^19,21,27 two,²⁴ or unknown number of vancomycin serum concentrations.^16,25 Notably, as stated in one study,¹⁸ the trapezoidal method requires actual vancomycin concentration from patients, whereas the methods by Chang et al²⁸ and Le et al²⁹ were developed from Monte Carlo simulation. This study found that the AUC values were not similar between the different PK methods that were used to calculate AUC.¹⁸

Risk of Bias Assessment.

All 12 eligible studies were observational in design. As demonstrated in Supplemental Table S1b, all studies enrolled patients to represent pediatric or neonatal populations admitted at their institutions except 4 studies that enrolled patients younger than 3 years,¹⁹ 2 months to 17 years of age,²⁰ both pediatric and young adults with ages of 17.2 ± 6.9 years (mean ± SD),²³ or with more extensive exclusion criteria.²⁴ Similarly, 5 studies reported their assessments of vancomycin AUC:MIC breakpoint for treatment effectiveness on a subgroup of study participants owing to microbiology and clinical outcome data availability,^{18,21,24,26,27} and did not provide descriptions of the representativeness of the selected subgroup. All 12 studies used electronic medical records to retrieve data on exposure and outcomes, although only 2 studies specified inclusion criteria of first clinical episode to ensure the outcome of interest, such as persistence of bacteremia, was not present at the start of study.^22,27 Lastly, only 1 study made statements on participants lost to follow-up, which can affect the determination of outcome of interest such as mortality.²²

Vancomycin AUC:MIC Threshold Against MRSA.

There were 5 studies involving MRSA, including 4 addressing bacteremia and 1 involving patients with cystic fibrosis, as shown in Table 1. Yoo et al²² enrolled 73 children with first-episode MRSA-B. The most frequently reported underlying diseases were congenital heart disease (28.8%), malignancy (16.4%), neurologic diseases (6.8%), and chronic lung disease (5.5%). In their multivariate analysis adjusting for age, coinfection, indwelling medical device, and presence of primary focus of MRSA-B, an initial AUC:MIC of <300 was the only statistically significant risk factor associated with persistent bacteremia at 48 to 72 hours (adjusted OR, 3.05; 95% CI, 1.07–8.68) and therefore, could be used as a predictor of persistent MRSA-B. Of note, approximately 13.7% of their patients had a MIC of 2 mg/L. Although the overall incidence of acute kidney injury was 4.1% (defined in this study as an increase in serum creatinine concentrations by 0.5 mg/dL), no data were provided on nephrotoxicity experienced in these patients who might have required an AUC of >600 mg × hr/L to achieve their goal of AUC:MIC of 300 mg × hr/L, or an alternative antibiotic was used instead.

Table 1.Description of Studies on MRSA Infections

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Hahn et al¹⁶ performed a study in 59 pediatric patients with MRSA-B. The most common underlying conditions seen in their study patients were gastrointestinal disease (22%), neurologic disease (13.6%), lung disease (13.6%), and genetic/metabolic disease (11.9%). They found no statistically significant differences between those with an AUC_{24 hr}:MIC ≥400 and <400 in treatment failure, defined as bacteremia ≥3 days, 30-day mortality, or recurrence of bacteremia within 30 days of end of treatment. Similarly, Regen et al²⁰ and Murai et al¹⁷ did not observe an impact of vancomycin AUC:MIC ratio on treatment effectiveness. However, these studies dichotomized their patients on the basis of either a predefined AUC:MIC cutoff of 400 mg × hr/L to compare outcomes,^16,17 or on treatment outcome of success vs failure to compare median AUC:MIC ratio values.²⁰ These comparisons were limited statistically to identify an AUC:MIC breakpoint for effectiveness.

Other than these 4 studies addressing MRSA-B, Fusco et al²³ performed a study in 49 patients with cystic fibrosis with acute pulmonary exacerbation and MRSA on sputum culture. The authors concluded that only younger age and lower admission lung function, but not AUC:MIC ratio values, were significant predictors for a positive vancomycin response in pulmonary function tests by multivariate analysis. As stated by the authors, both younger patients who have not had time to develop advanced lung disease yet and those patients with lower admission pulmonary function might experience a greater change in pulmonary function test values between admission and discharge. Therefore, a more defined patient population or a wider distribution of serum vancomycin trough concentrations (and therefore, AUC values derived from serum troughs) might be necessary to further define the optimal target.

Vancomycin AUC:MIC Threshold Against CoNS.

All 4 studies against infections caused by CoNS were performed in neonates and young infants, as presented in Table 2. Gwee et al²⁵ enrolled 30 young infants with postnatal age ≤90 days who developed staphylococcal bacteremia (93% with CoNS, defined as CoNS from at least 2 blood cultures, and 7% MRSA-B). The authors reported that 33% of MICs of CoNS were >1 mg/L (range, 0.5–4.0) by BMD and a target AUC_{0–24 hr} and AUC_{24–48 hr} of 300 and 424 mg × hr/L, respectively, increased the chance of microbiologic cure by 7.8- and 7.3-fold, respectively, regardless of MIC. Of note, the authors found that the presence or absence of central venous catheters did not have a predictive value in their pharmacodynamic (PD) model linking vancomycin exposure metrics to time to bacteremia clearance, despite the general recommendation of removal of contaminated device if feasible (data not available). The authors concluded the importance of early target attainment on microbiologic cure with a proposed rationale of being able to prevent CoNS to form biofilms in indwelling venous catheters, which would make eradication more challenging.

Chen et al²⁴ explored the vancomycin effectiveness threshold from 54 neonates with CoNS infection, defined as CoNS from at least 2 blood cultures or with a positive tracheal culture and imaging evidence in ventilated patients (65% and 35% of the subgroup, respectively). The authors reported that an AUC:MIC ratio >280 mg × hr/L was a predictor of culture sterilization within 72 hours and/or clinical improvement. It is worth noting that this study had extensive exclusion criteria (Table 2). Therefore, the findings might not be generalizable to other patients who would have been excluded from their study. Furthermore, the current guideline targeting AUC:MIC ratio of 400 to 600 mg × hr/L is for severe MRSA infections assuming a vancomycin MIC of 1 mg/L. In contrast, this study was focused on CoNS infection and 54% of their isolates had a MIC of >1 mg/L by BMD. Aiming at their proposed goal AUC:MIC ratio of 280 mg × hr/L in these patients would require an AUC of 560 mg × hr/L or higher, which likely exceeded the average AUC of 500 mg × hr/L observed by them for nephrotoxicity, defined by the authors as an increase in serum creatinine by 26.5 μmol/L within 48 hours, or an increase by 1.5 times or higher within 7 days.

The other 2 studies from Padari et al²¹ and Viel-Thériault et al²⁷ in patients with CoNS infections did not observe a correlation between AUC-based strategy and clinical outcomes, although both studies required only 1 positive blood culture for inclusion and no description was given to distinguish between true pathogens and contaminants. It is possible that the efforts to identify a potential AUC or AUC:MIC ratio goal for vancomycin efficacy against CoNS may have been negated because of less strict inclusion criteria for CoNS infections, given some patients with only 1 positive blood culture, treated by vancomycin for 3 to 5 days, may represent contamination instead of true infection. Moreover, none provided data of whether the CoNS were methicillin resistant or susceptible, which makes identification of an AUC or AUC:MIC breakpoint for efficacy difficult.

Vancomycin AUC:MIC Threshold Against S aureus.

Literature findings addressing S aureus infections are presented in Table 3, including 2 for bacteremia and 1 for pneumonia. For S aureus bacteremia, Ruiz et al¹⁹ found that the predefined efficacy goal of a vancomycin AUC:MIC ratio of 400 mg × hr/L was associated with early clinical but not microbiologic response or mortality in 51 children younger than 3 years (25.5% MRSA-B), whereas Kishk et al¹⁸ concluded no difference in time to first negative blood culture or clinical outcomes between those who achieved the predefined vancomycin AUC:MIC target of 400 mg × hr/L and those who did not in 29 children (percentage of MRSA not reported). McNeil et al²⁶ performed a study in 23 children with S aureus pneumonia and found no correlation between values of AUC:MIC and duration of bacteremia, clinical improvement, or mortality.