Our study raises a number of important issues. First, few studies of MRSA infections in children have focused specifically on bacteremia treated with vancomycin. Second, 50% of the patients failed treatment with vancomycin in our pediatric population. The high number of failures is not likely due to differences in care between the two groups. There was a trend for earlier administration of vancomycin in the treatment failure patients, the times until a vancomycin trough of >15 μg/ml were not different between the two groups, and equal numbers of patients from each group received treatment in an ICU setting. Only one isolate had the hVISA phenotype; the remainder of the isolates were considered susceptible to vancomycin. Addition of rifampin to patients who were failing vancomycin appeared to be beneficial, as has been reported previously for pediatric patients (33
Premature infants were significantly more likely to fail vancomycin therapy in our study. Such infants are likely at an increased risk of invasive MRSA infections because of the frequent use of glucocorticoids and invasive procedures and devices, prolonged hospital stays, and the immaturity of the immune system. Morbidity due to invasive staphylococcal infections in infants is significant, often leading to the development of septic shock and deep-seated infections, frequently despite the use of appropriate antimicrobial chemotherapy (13
). Though mortality was significant in previous reports (13
), the overall mortality in our cohort was relatively low (13.6%) and all deaths occurred in premature infants.
A strong association between treatment failure and PVL-positive isolates was found (P
= 0.008). Isolates harboring PVL have been associated with skin infections such as cutaneous abscesses, furunculosis, and necrotic skin infections (22
), although more-serious infections such as necrotizing pneumonia have also been documented (9
). Interestingly, one study of adult bacteremic patients found that PVL-positive MRSA isolates were less likely to cause persistent bacteremia than PVL-negative isolates (20
). Another study of an adult population showed that infections with PVL-positive isolates were more likely to be cured than infections with PVL-negative isolates in patients with skin and soft-tissue infections (4
). While the outcome of PVL-positive MRSA infections in adults appears to be favorable, our study results suggest that PVL-positive isolates have the potential to cause significant morbidity in the pediatric patient population, especially in premature infants. The precise mechanism by which PVL may serve as a virulence factor remains unclear. PVL is a toxin that consists of two components, LukS-PV and LukF-PV, that are secreted and assemble on polymorphonuclear leukocyte membranes, where they can cause cell lysis or apoptosis (2
). It has also been demonstrated that PVL expression may result in upregulated expression of protein A, which provides evasion of the immune system by binding to the Fc portion of IgG, and that this plays a proinflammatory role in the immune response by binding to tumor necrosis factor receptor 1 (7
). Th1 responses, the production of certain cytokines, and immunoglobulin synthesis are all considerably reduced in premature infants (8
). This makes the innate immune system especially important for control of infection in infants while the adaptive immune system is developing, and, consequently, pediatric patients may be more dependent on neutrophils for clearance of MRSA bacteremia than adults. Alternatively, other investigations have suggested that α-hemolysin, but not PVL, is essential for the virulence of certain S. aureus
). Whether PVL is a direct cause of pathogenesis or is a marker for other virulence factors remains to be determined.
PVL is generally epidemiologically linked to CA MRSA (35
). This does not appear to be the case in the pediatric population at our institution. In our cohort, 37.5% of HA isolates were PVL positive and 43.8% harbored SCCmec
IV. Five isolates that caused HA infections resembled the USA300 clone by DL typing. Recent reports have indicated that MRSA isolates with CA genotypes including PVL, SCCmec
IV, and sequence type (ST) 8 have been found in infections that are considered HA (6
). These reports along with our results suggest that CA MRSA strains are becoming endemic in an increasing number of hospitals. A dominant clone was not responsible for the high number of vancomycin treatment failures in this population.
Numerous studies of adult populations have found that isolates with higher vancomycin MICs, even those in the “susceptible” range, are associated with a worse clinical outcome (23
). We did not observe this in our study. This may reflect geographic differences in our isolates or differences between the pediatric and adult patient populations.
Limitations of this study include its small sample size and the retrospective design. It is entirely possible that additional factors, not identifiable because of the small number of patients in our study, may predict treatment failure. It must be noted that MRSA bacteremia in children is a rare disease. Only 14 cases of pediatric MRSA bacteremia were reported in a 4-year period in Buffalo, NY (12
), and over a 3-year period in North Carolina (34
). Similar case numbers are also reported elsewhere (10
). In contrast, our institution had 145 cases of MRSA bacteremia in the adult patient population over this same time period. Multi-institutional studies are likely needed to identify all of the characteristics predictive of vancomycin treatment failure in pediatric patients.
Further limiting our study is the lack of a standard definition of treatment failure of MRSA bacteremia in children. The definitions of treatment failure used in this study have been applied to adult patients (23
) and were used to avoid bias by classifying outcomes based on a retrospective chart review. We cannot exclude the possibility that different definitions of failure may be needed in children. Only the first bloodstream isolate from each patient is stored by our clinical microbiology laboratory; therefore, isolates from patients with a recurrence of bacteremia could not be definitively determined to be caused by the same strain, and thus the definition of recurrence used by Lodise et al. (23
) was applied. Nonetheless, we found a high rate of failure of vancomycin in children with MRSA bacteremia, especially in premature infants, that were treated at a large pediatric hospital in the fourth largest city in the United States. This may reflect a more generalized problem with the use of vancomycin for treatment of MRSA bacteremia in this population. Larger studies are needed to clarify the role of PVL in MRSA bacteremia. If PVL is confirmed to be a marker of vancomycin treatment failure, switching to an alternate agent or addition of a second antimicrobial such as rifampin once the presence of PVL is determined should be considered in pediatric patients, especially in premature infants. Additionally, further studies can be performed in areas where PVL is highly prevalent to evaluate the use of alternate agents as empirical therapy for presumed MRSA bacteremia.