The clinical use of vancomycin in both adults and children has increased with the emergence of methicillin-resistant Staphylococcus aureus (MRSA)1, ²⁾. A recent report regarding increase of vancomycin minimal inhibitory concentration (MIC) documented treatment failures associated with heterogeneous-vancomycin intermediate S. aureus (hVISA)3, ⁴⁾. Despite limitations including poor tissue penetration (particularly in the lung), relatively slow bacterial killing, and the potential for toxicity⁵⁾, vancomycin is regarded as the gold-standard for antibiotic treatment of MRSA infections due to its low cost and established clinical response⁶⁾.

Major pediatric dosing references for vancomycin recommend a daily dose of 40 mg/kg/day for empiric therapy, while a dose of 60 mg/kg/day is recommended for central nervous system infections7, ⁸⁾. In adults, the recommended daily dose is 1 g every 12 hours and the recommended trough level is 5 to 10 mg/L9, ¹⁰⁾ or 5 to 15 mg/L¹¹⁾.

However, a review recently published by the American Society of Health System Pharmacists (ASHP), the Infectious Diseases Society of America (IDSA), and the Society of Infectious Disease Pharmacists (SIDP) recommended a daily vancomycin dosage of 15 to 20 mg/kg every 8 to 12 hours (based on actual body weight, including obese patients) and maintaining a vancomycin trough concentration between 15 and 20 mg/L for treatment of bacteremia, endocarditis, osteomyelitis, meningitis, and pneumonia¹²⁾. The purpose of the present study is to evaluate the adequacy of the recommended initial dosage of vancomycin in pediatric patients by analyzing serum trough levels after the initial dosage.

In this study, we investigated the relationships between vancomycin trough concentrations and initial vancomycin dose in 309 pediatric patients with normal renal function. Patients who received dosages of 40 mg/kg/day exhibited mean trough levels that were lower (6.58±3.52 mg/L) than those of patients who received 60 mg/kg/day (12.7±6.34 mg/L), and the proportion of patients maintaining trough levels >10 mg/L was also lower among patients receiving 40 mg/kg/day (14% of group A vs. 49% of group B).

Vancomycin has been used as the primary therapeutic agent to treat MRSA infections for the past 40 years in both adults and children¹³⁾. Although several recent reports have highlighted the limitations of vancomycin, which include relatively slow bactericidal activity, the development of resistance and associated therapeutic failure, poor tissue penetration, and the potential for serious toxicity5, ¹⁴⁾, and newer anti MRSA medications show great promise, vancomycin is well-tolerated and is still the drug of choice to empirically treat all types of MRSA infection1, ¹⁵⁾. Until recently, vancomycin was usually administered intravenously to adults at a dosage of 1 g every 12 hours, with the targeted serum trough level set between 5 and 10 mg/L9, 10, 16, ¹⁷⁾.

Although the American Thoracic Society advises that vancomycin should be given in doses sufficient to achieve a trough level between 15 to 20 mg/L for the treatment of MRSA pneumonia because of the emergence of MRSA strains with reduced susceptibility to vancomycin, the optimal doses and trough levels in adults remain controversial due to pharmacokinetic and pharmacodynamic properties of vancomycin¹⁸⁾, lack of well designed randomized clinical evaluations, and lack of data to support a clear relationship between specific serum concentrations and patient outcome. However, a recent consensus review on therapeutic monitoring of vancomycin recommended maintaining vancomycin trough concentration between 15 and 20 mg/L for bacteremia, endocarditis, osteomyelitis, meningitis, and pneumonia¹²⁾.

The area-under-the-concentration-time-curve (AUC) divided by the MIC (AUC/MIC) best predicts treatment outcomes when treating invasive MRSA infections with vancomycin in adults, and an AUC/MIC values >400 for vancomycin are associated with optimal outcomes in the treatment of adults19, ²⁰⁾. For pathogens with MICs of 1 mg/L, the minimum trough serum vancomycin concentration would have to be at least 15 mg/L to obtain this target AUC/MIC¹²⁾. Vancomycin dosages of 15-20 mg/kg given every 8-12 hours are required for most adult patients with normal renal function to achieve the suggested serum concentrations when the MIC is ≤1 mg/L¹²⁾.

Some data suggest that low serum levels of vancomycin early in the treatment course of MRSA infections may also be associated with the emergence of VISA and hVISA20, ²¹⁾. Howden et al.²²⁾ suggested that not only previous MRSA infection and glycopeptide exposure, but trough serum vancomycin concentrations of <10 mg/L may predict therapeutic failure and the potential for the emergence of VISA or vancomycin-resistant Staphylococcus aureus (VRSA). For this reason, it is recommended that trough serum vancomycin concentrations always be maintained above 10 mg/L to avoid development of resistance by consensus review¹²⁾.

In pediatric patients, until recently the recommended daily dose of vancomycin was 40 mg/kg/day for common infections, while a dose of 60 mg/kg/day was recommended for serious infections such as central nervous system infections. The recommended trough level was 5-15 mg/L, as in adult patients7, ⁸⁾.

In a previous study²³⁾ of infants and children treated for suspected staphylococcal infections, vancomycin was administered in total dose of 40 mg/kg/day divided into four doses of 10 mg/kg/day every 6 hours. This regimen achieved goal trough levels (5-15 mg/L) in only 45% of 31 control patients. In 33 patients with malignancies, 88% required doses of 60 mg/kg/day to achieve goal trough levels. In another study²⁴⁾, 76 pediatric intensive care unit patients with normal renal function required a mean dose of 60 mg/kg/day to achieve a mean trough level of 7.8 mg/L. These data support the contention that a starting vancomycin dose of 40 mg/kg/day may not be optimal to achieve recommended trough levels in children.

Recently, in a study¹⁵⁾ in which pediatric patients received vancomycin doses of 40 mg/kg/day, the AUC/MIC target of 400 was achieved only when the MIC of MRSA isolates was 0.5 g/mL. For MRSA isolates with MIC 1.0 g/mL, the AUC/MIC was always <400 at this dose, suggesting that empiric treatment of invasive MRSA infections in children should implement vancomycin doses of 60 mg/kg/day.

We observed that the mean vancomycin trough level in group A was far short of the recommended trough levels (>10 mg/L) for adults that are required to avoid development of resistance. The results of the present study imply that an initial vancomycin dose 40 mg/kg/day, which is the current standard recommended dose for pediatric patients, may not yield optimal therapeutic effects or prevent the development of antibiotic resistance. However, given only this result, it is too early to confirm that the recommended initial dose of vancomycin for pediatric patients should be higher. A prospective study is warranted exploring the influences of the initial dose of vancomycin and trough levels on the therapeutic results when treating MRSA infections.

This study had several limitations. First, this was a retrospective, observational single center study. Second, we did not evaluate AUC or the MIC because these data were not available for all patients. However, increased serum trough levels are associated with greater AUCs and serum trough levels are considered adequate surrogate markers for AUC, although serum trough levels do not directly reflect AUC. Third, most patients treated with vancomycin had underlying diseases (88.3%), and there were relatively few cases for which the pathogen was microbiologically confirmed (79 cases, 25.6%) of the confirmed cases, only 66.7% were cases of MRSA or MRSE. Therefore we were unable to evaluate microbiological and clinical therapeutic effects of initial vancomycin doses and trough levels. Concomitant use of diuretics such as furosemide were more frequently observed in patients receiving usual dosages (40 mg/kg/day) of vancomycin, and furosemide may influence vancomyin trough levels25-²⁷⁾.

On the other hand, some data indicate that there are no benefits of high dose strategies. Jeffres et al.²⁸⁾ retrospectively evaluated 102 patients with health-care-associated MRSA pneumonia and observed no significant differences in mean vancomycin trough levels or AUC between survivors and nonsurvivors. Similarly, Hermsen et al.⁶⁾ retrospectively evaluated 55 patients with pneumonia, osteomyelitis, and endocarditis and also observed no significant differences in clinical outcomes between patients who achieved high trough levels (≥15 mg/L) and those with low trough levels (<15 mg/L).

Some published studies report significant associations between increased vancomycin trough concentrations and nephrotoxicity6, ²⁹⁾. However, current consensus is that the nephrotoxic risk of vancomycin is minimal in patients without risk factors for nephrotoxicity, and the relationship of between vancomycin trough concentrations and nephrotoxicity remains controversial because patients receiving aggressive dosing are more likely to receive concomitant nephrotoxins and have other risk factors for nephrotoxicity¹⁾. In our study, we did not observe significant association between high initial vancomycin dose and nephrotoxicity.

In conclusion, we observed that traditional recommended doses of vancomycin in pediatric patient (40 mg/kg/day) was insufficient to achieve recommended trough levels for therapeutic effect (5-10 mg/L). However, before recommending increases in the initial vancomycin doses for pediatric patients, further studies are necessary to clarify the relationship between vancomycin trough levels and clinical efficacy, as well as the possibilities of nephrotoxicity in children.