Although pvl-positive MRSA is now a leading cause of cSSSI in many parts of the world, the impact of pvl in determining the severity of these infections is controversial. Using a large international collection of well-characterized MRSA cSSSI isolates from two phase 3 clinical trials, the current investigation has provided additional insights into the contribution of pvl to the outcome of patients with cSSSI.
The present study demonstrates that cSSSI due to pvl
-positive MRSA is significantly more likely to be cured than cSSSI due to MRSA not containing this gene. This finding persisted when the analysis was adjusted for patient comorbidity as well as for infection type, severity, and surgical intervention. The results of this study validate previous observations for patients with cSSSI (2
) and bacteremia (15
) and are also consistent with a recent study showing that the presence of pvl
did not adversely influence the outcome of uncomplicated SSSI (10
). Taken together, these results clearly indicate that factors other than the simple presence of pvl
determine the clinical outcome of cSSSI caused by MRSA.
The presence of pvl
was associated with important clinical characteristics in patients with MRSA cSSSI. Patients with pvl
-positive MRSA cSSSI were younger, more likely to have major abscess, and less likely to have health care contact. In contrast, pvl
-negative strains were more likely to have originated from older patients with nonabscess infections and health care-associated strains. These findings are consistent with previous reports (19
). It is likely that these patient characteristics may contribute, in part, to the better outcome seen in patients infected with pvl
The role of pvl
in the pathogenesis of S. aureus
infection remains incompletely understood. A large body of epidemiologic evidence links the presence of pvl
with the presence of skin and soft tissue infections (19
). Several clinical observations also support the potential role of pvl
in the initiation of skin and soft tissue infections, although this role is still undefined. For example, Ellis et al. (7
) showed that persons asymptomatically colonized with pvl
-positive S. aureus
were significantly more likely to develop soft tissue infections with these same strains than persons who were colonized with S. aureus
isolates that did not contain pvl
. In addition, outbreak transmission (11
), including interfamilial transmission (3
) of skin infections, is a prominent feature of pvl
-positive MRSA. While the role of pvl
in the initiation of skin infections is an area of active research, the current investigation demonstrates that its presence is not the primary determinant of clinical outcome in patients with MRSA cSSSI. Thus, factors other than pvl
should be considered when potential therapeutic or diagnostic laboratory-based prognostic strategies for cSSSI are targeted.
Our investigation showed that the presence of some toxin genes (sed
, and sej
) was associated with poor clinical outcome and that the presence of some adhesin genes (fnbA
, and map-eap
) was associated with good clinical outcome. Our previous study showed that the toxin gene seh
was associated with persistent S. aureus
). Peacock et al. (22
) reported that several virulence genes were significantly more common in S. aureus
isolates from invasive disease than in those from nasal carriage. These findings may indicate that several toxin genes are independently or jointly associated with the clinical outcome of cSSSI due to MRSA. On the other hand, the genes found in this study to be associated with clinical outcome may simply be markers of particular bacterial clones and are not themselves directly involved in the pathogenesis of more-severe infection. This explanation is supported by our finding of significant differences in outcome among different PFGE types. Because these genotyping strategies were unadjusted for confounding effects, it is likely that these associations between PFGE and outcome are also due in part to epidemiologic and infection-related characteristics.
The strengths of this study include the size, scope, and detail of the clinical material. The MRSA isolate collection used in this study is large, contemporary, international, cSSSI specific, and characterized using clinical data generated to the level of rigor of a U.S. Food and Drug Administration (FDA) registrational trial. Limitations include the fact that we did not evaluate quantitative expression or the presence of polymorphisms within pvl
, as these properties may influence the function of gene products (12
). This evaluation focused, by design, only upon infections in which the causative pathogen was available for culture and was a subgroup analysis; therefore, it provided data that can lead only to a limited conclusion. We were also unable to consider potential relationships between vancomycin trough levels and outcome. Patients with pvl
-negative MRSA isolates were relatively infrequent and differed significantly from patients with pvl
-positive MRSA. Because of the small number of patients in the pvl
-negative group, we were unable to employ multivariable analysis to simultaneously adjust for these differences. However, when we examined the relationship between pvl
status and clinical outcome by adjusting for a single covariate at a time, our findings of a worse cure rate in patients with pvl
-negative MRSA CSSI remained consistent and robust.
In summary, this study has demonstrated that pvl-positive MRSA strains appear to be associated with better outcome in patients with cSSSI. These findings indicate that factors other than the presence of pvl are the primary determinants of clinical outcome in cSSSI. Future efforts are required for a better understanding of the role of pvl in the pathogenesis of serious infections due to MRSA.