Vancomycin Use in Children and Neonates across Three Decades: A Bibliometric Analysis of the Top-Cited Articles

Vancomycin is frequently prescribed in pediatrics, especially in intensive care unit settings, to treat Gram-positive bacterial infections. This work aims to collect the top-cited articles of pediatric and infectious diseases areas to gather the current evidence and gaps of knowledge on the use of vancomycin in these populations. The most relevant journals reported in the “pediatrics” and “infectious diseases” categories of the 2019 edition of Journal Citation Reports were browsed. Articles with more than 30 citations and published over the last three decades were collected. A bibliometric analysis was performed and 115 articles were retrieved. They were published in 21 journals, with a median impact factor of 4.6 (IQR 2.9–5.4). Sixty-eight of them (59.1%) belonged to “infectious diseases” journals. The most relevant topic was “bloodstream/complicated/invasive infections”, followed by “antibiotic resistance/MRSA treatment”. As for population distribution, 27 articles were on children only and 27 on neonates, most of which were from intensive care unit (ICU) settings. The current literature mainly deals with vancomycin as a treatment for severe infections and antibiotic resistance, especially in neonatal ICU settings. Lately, attention to new dosing strategies in the neonatal and pediatric population has become a sensible topic.


Introduction
Vancomycin is one of the most frequently prescribed glycopeptides, especially in children and newborns in intensive care unit (ICU) settings for the treatment of Grampositive bacterial infections by coagulase-negative Staphylococci (CoNS), Enterococci spp, methicillin-resistant Staphylococcus aureus (MRSA), and C. difficile. It inhibits cell wall synthesis by binding to the D-Ala-D-Ala terminal of the peptide chain and has a volume of distribution of 0.4-1 L/kg [1]. There is significant variability in protein binding, which is believed to be up to 50% [2]. Its bactericidal activity is related to the area under the curve (AUC) and minimal inhibitory concentration (MIC) ratio (AUC/MIC ratio), which, as stated in the literature, has to be higher than 400 to guarantee standard efficacy [1]. Serum levels monitoring is recommended, with a target trough concentration goal of 15-20 µg/mL for severe infections. Based on these pharmacodynamics data, continuous infusion of vancomycin has been proposed for severe infections, guaranteeing higher steady-state concentrations. However, there is little consensus on choosing the optimal dosing regimen and administration schedule (intermittent vs. continuous infusion) in children and even more in neonates, especially in preterm and extremely preterm patients.
Another concern is the emergent antibiotic resistance issues, with the appearance of vancomycin-intermediate strains in methicillin-resistant S. aureus (MRSA) infections after the exposure to prolonged vancomycin therapy, due to the selection of resistant subpopulations under the pressure of antimicrobial exposure [3]. More recently, increasing MICs and decreased susceptibility have been reported for CoNS as well, for the same reason, with subsequent treatment failures [4,5].

Top-Cited Articles
The median number of citations was 94 (IQR 51-178), ranging from 30 to 2796. The complete list of the top-cited articles in the "infectious diseases" and "pediatrics" categories is displayed in Supplementary Materials (Supplementary Table S1).
As for article type, 57 top-cited articles were original articles, 38 were guidelines and/or Reviews of the literature, and only nine papers were clinical trials.
As shown in Figure 1, the most productive country of origin was the USA, with 71 manuscripts. However, 12 papers were multicenter, involving more than two countries. Topics are displayed in detail in Table 2. The most treated topic was "bloodstream/complicated/invasive infections," with 30 articles, followed by "antibiotic resistance/MRSA treatment", with 27 papers, and "state of the art" papers (13 papers). Eleven articles were about "dosing strategies/continuous vs. intermittent infusion" and Topics are displayed in detail in Table 2. The most treated topic was "bloodstream/ complicated/invasive infections", with 30 articles, followed by "antibiotic resistance/MRSA treatment", with 27 papers, and "state of the art" papers (13 papers). Eleven articles were about "dosing strategies/continuous vs. intermittent infusion" and ten about C. difficile treatment ( Table 2). Antibiotic of choice against serious Gram-positive infections, more than 50 years after its introduction. Increasing evidence suggests that it may be losing its clinical efficacy against serious MRSA infections with MICs at the higher end of the susceptibility range. Slowly bactericidal and characterized by suboptimal properties such as PK (requiring twice-daily dosing and serum level monitoring) and complex variable tissue penetration. The optimal dosing in critically ill patients remains a contentious issue.   The incidence of CDI has risen in children since 2000. Most pediatric studies have evaluated the incidence of CDI-related hospitalizations among multicenter cohorts of hospitalized children.
Highest rates of asymptomatic colonization with either toxigenic or nontoxigenic strains <12 months of age. Oral vancomycin recommended for treatment of pseudomembranous colitis due to C. difficile, for the first episode (severe/non-severe; first recurrence; second or subsequent recurrence), 10 mg/kg/dose 4 times daily for 10 days.
Local antibiograms with pathogen-specific susceptibility data should be updated at least annually, to optimize expert-based recommendations for empirical therapy.
[ As regards continuous versus intermittent infusion, most studies addressed the neonatal population. Some presented simplified schedules for continuous infusion in neonates, according to body weight and serum creatinine, that led to adequate serum vancomycin levels and a good efficacy profile, also reducing prescription error rates in this population ( Table 2) .
Other topics were "nephrotoxicity", with six articles, "healthcare epidemiology" and "antibiotic stewardship" (four papers each). Papers dealing with nephrotoxicity mostly identified high vancomycin trough levels (>15 mg/L) and concomitant furosemide use as risk factors for the development of kidney injury [69,70].
Studies on epidemiology mainly focused on hospital-acquired and MRSA infections in Neonatal Intensive Care Units (NICUs), antibiotic exposure, and inflammatory bowel disease development [9][10][11][12]. Papers reporting antibiotic stewardship experiences were from NICU and Pediatric Critical Care units, showing the widespread use of vancomycin, considered inappropriate in large proportion in critically ill children and neonates [114,115].
The least reported topics were respectively "pharmacokinetics and pharmacodynamics" (PK/PD) and "adverse reactions" (three papers each), "ototoxicity", in relation to hearing screening in newborns, and "MIC interpretative criteria", with two articles each ( Table 2). In particular, only one of the retrieved articles on PK/PD was specific for the pediatric population, while the other two dealt with PK/PD features in general and about drug penetration in biofilm [1,14]. The most useful parameters for the evaluation of vancomycin PK/PD correlation are the AUC and MIC. As reported by Rybak et al., an AUC/MIC ratio higher than 400 is related to a plasma trough level above 15 µg/mL, assuming 1 mg/L MIC or less [1]. Model studies have reported that the current empiric recommended vancomycin dose in children of 40 mg/kg/day would unlikely achieve the recommended pharmacodynamic target of AUC 24/MIC >400 in case of methicillin-resistant S. aureus (MRSA) with MIC of 1.0 µg/mL or greater, proposing an increase of the dose to 60 mg/kg/day [120,121].
Twenty-seven papers dealt with neonates, 18 of which in NICU contexts, dealing with vancomycin for the treatment of neonatal infections, especially late-onset sepsis due to Gram-positive bacteria, mainly CoNS and MRSA [11]. Major topics were antibiotic resistance and dosing strategies, which reflect the main issues in this population to date. Ototoxicity and nephrotoxicity were addressed as the most important aspects to consider in the follow-up of neonates after vancomycin treatment [66,73]. The recommended intravenous dose for treating sepsis or severe infections in neonates is 10-15 mg/kg, 15 mg/kg for central nervous system infections, with varying intervals according to gestational and postnatal age (once every 18/12/8 h accordingly). According to most studies, for infants older than one month and children up to 12 years with a normal renal function, the advised intravenous daily dose is 60 mg/kg in four divided doses. During treatment of serious infections, including those related to MRSA, trough levels should be monitored, with a target concentration goal of 15-20 µg/mL [120].
Key points on vancomycin use in pediatric patients emerging from our analysis, including what is already known and gaps of knowledge for the development of future studies, are summarized in Table 3. Table 3. Key points on vancomycin use in pediatric patients.

Discussion
To our knowledge, this is the first bibliometric analysis with a special interest in vancomycin in the pediatric and neonatal populations.
We chose evaluative bibliometrics and the method of citation analysis to evaluate research performance in this particular field and to highlight gaps of knowledge for the development of future studies. We decided to consider the last three decades as a definite search period, because especially in those years vancomycin was extensively used, with a consequent selection pressure, determining the emergence of resistance [5,26] (Figure 2).

Discussion
To our knowledge, this is the first bibliometric analysis with a special interest in vancomycin in the pediatric and neonatal populations.
We chose evaluative bibliometrics and the method of citation analysis to evaluate research performance in this particular field and to highlight gaps of knowledge for the development of future studies. We decided to consider the last three decades as a definite search period, because especially in those years vancomycin was extensively used, with a consequent selection pressure, determining the emergence of resistance [5,26] (Figure 2). Not surprisingly, the journal with the highest number of top-cited articles was in the infectious diseases and not the pediatric area, being ranked third among the journals of the same area. Among the top-ranked journals of the pediatric area, there were no pediatric infectious diseases sub-specialty journals. This may suggest that the search for the Not surprisingly, the journal with the highest number of top-cited articles was in the infectious diseases and not the pediatric area, being ranked third among the journals of the same area. Among the top-ranked journals of the pediatric area, there were no pediatric infectious diseases sub-specialty journals. This may suggest that the search for the most relevant articles in pediatric infectious diseases should be performed not only among pediatric journals but mainly on the most impacted journals treating topics of infectious diseases.
As for the article types, the second most cited, after original articles, were guidelines and/or reviews of the literature. According to the hierarchy provided by the Center for Evidence-Based Medicine, the latter presents the highest level of evidence [122]. They mostly were clinical practice guidelines by Infectious Diseases societies or dealt with current evidence about prescription and dosing in children and neonates. The most represented topics were antibiotic resistance, complicated infections, and C. difficile infections, correctly reflecting the main fields and emerging issues involving vancomycin and its use in pediatric patients.
The two most treated topics in the top-cited articles were complicated infections and antibiotic resistance. Again, this is not surprising, thinking of the extensive use of vancomycin to treat invasive infections in critical patients, leading to antibiotic selection pressure after prolonged exposure, with an increased risk of treatment failure [3,4,[28][29][30][31][32][33][34]. Selection pressure by indiscriminate use of vancomycin, linked to at least four genes (Van A-D), has led to the emergence of vancomycin-resistant Enterococci (VRE). As regards S. aureus, vancomycin-intermediate (VISA), and vancomycin-resistant S. aureus (VRSA) strains are described, together with the resistance of S. epidermidis, mainly linked to biofilm [3]. As highlighted by van Hal et al in a systematic review and meta-analysis, emerging data show that vancomycin may be less effective to treat serious MRSA infections with higher MICs, with treatment failure concerns. An association of high MICs and higher mortality rates in MRSA bloodstream infections has been demonstrated. [119]. Therefore, prospective studies are needed to assess if optimizing vancomycin treatment can improve outcomes without toxicity issues. This opens the chapter on second-line treatments for vancomycin treatment failures.
Among the 115 retrieved articles, 27 were about children as a selected population, dealing above all with the management of invasive infections and C. difficile infections. Two papers had the implementation of antibiotic stewardship programs as a primary focus, one of which in the context of a pediatric critical care unit [114,115]. This is indeed of Pathogens 2021, 10, 1343 9 of 15 paramount importance, considering the worldwide efforts to implement the appropriate use of antibiotics, especially in ICU settings. Vancomycin has undergone indiscriminate use for many years also in the pediatric population and the stewardship interventions aim at early therapy stop in the absence of microbiological isolates.
Despite the widespread use of vancomycin since its introduction on the market, only three top-cited papers dealt with PK/PD and one only specifically on the pediatric population. PK/PD studies and RCTs are lacking for the neonatal population, especially for preterm and extremely preterm infants, as reported by the many reviews retrieved in this study.
Dosing and safety in the pediatric and neonatal population are challenging, especially concerning continuous infusion, because of pharmacokinetics changes throughout the different ages. In general, ototoxicity and nephrotoxicity pathophysiological mechanisms are still unclear. The relation to dose exposure and treatment duration has not been proved, and focused studies are still lacking.
One central question is still open regarding the administration of vancomycin by continuous versus intermittent infusion in children and neonates. Adult evidence suggests that continuous infusion of vancomycin decreases nephrotoxicity and the incidence of infusion-related adverse events, while also diminishing time to therapeutic concentrations and drug costs [123,124]. Studies on preterm neonates and patients under three years of age on this topic are few to date, and thus evidence is limited, with data from the adult population being not completely applicable. Despite a general lack of consensus, continuous infusion regimens are already used in clinical practice in many centers, especially in the UK. Prolonged or continuous infusions strategies of time-dependent antibiotics are elsewhere still considered on a case-to-case basis in the pediatric population, and available data seem to indicate a higher probability of reaching target trough levels in children, with reported good clinical outcomes and safety profile [61,62,65,121,125].
Regarding gender description, the highest number of female first authors belonged to the Pediatrics area and were almost as represented as their male counterparts. Nevertheless, we identified a gender gap in medical research. Male authors were predominant as both first and last authors in the Infectious Diseases area and generally more represented in senior authorship in both areas. We decided to include this description as we believe it could be an interesting bibliometric parameter to be evaluated, as an added value for the readers. Any assumption related to a minor involvement of women in research teams or a less frequent presence as senior faculty members cannot be made based on our data and goes beyond the focus of our research.
Last, limitations to our study are intrinsic to the analysis type. Above all, the most recent articles may not have reached 30 citations due to a mere matter of time, and all relevant studies published in languages other than English may have been missed.

Conclusions and Future Perspectives
To conclude, top-cited articles about vancomycin use in children and neonates were almost equally distributed among journals of the "infectious diseases" and "pediatrics" areas. The most productive journal was Clinical Infectious Diseases. The most treated topics were bloodstream or complicated infections and antibiotic resistance/MRSA treatment. The pediatric area is indeed a critical one in the field of antibiotic therapy. In the last three decades, though less reported, also the role of antibiotic stewardship and attention to new dosing strategies in the neonatal and pediatric population have become sensible topics, which need to be further explored. As a widely used drug, data from studies properly conducted in the pediatric population, and not derived from adult studies, are needed. Moreover, the efficacy and safety of higher doses due to increases in MIC should be studied. Among the least represented topics, PK/PD, antibiotic stewardship, and dosing and infusion strategies, especially in neonates, represent a critical gap of knowledge, with a florid literature pointing out a lack of studies in the pediatric population since at least 30 years. This underlines the need for randomized-controlled trials to evaluate the clinical impact, safety, and acceptability of continuous infusion of vancomycin compared to intermittent infusion as a main challenge in the neonatal and pediatric population.

Data Availability Statement:
The data presented in this study are available in the Supplementary Material (S1-S3).

Conflicts of Interest:
The authors declare no conflict of interest.