High Vancomycin MIC and Complicated Methicillin-Susceptible Staphylococcus aureus Bacteremia

We conducted a retrospective study of 99 patients with methicillin-suseptible Staphylococcus aureus catheter-related bacteremia in which vancomycin MIC was determined by Etest. High vancomycin MIC (>1.5 μg/mL) was the only independent risk factor for development of complicated bacteremia caused by methicillin-susceptible S. aureus (odds ratio 22.9, 95% confidence interval 6.7–78.1).

Complicated bacteremia was defi ned by one of the following events occurring after the fi rst episode of bacteremia: 1) development of endocarditis, septic thrombophlebitis (defi ned by persistent MSSA bacteremia at least 72 hours after initiation of active antimicrobial drugs + documented thrombi), arthritis, spondylitis, as well as end-organ hematogenous spread of infection to other locations; or 2) infection involving vascular or osteoarticular prostheses (excluding intravascular catheter) not removed within 4 days. We also calculated the crude death rate in the fi rst 30 days after the fi rst positive blood culture (30-day mortality) and mortality rate attributable to S. aureus bacteremia (attributable death rate).
The Student unpaired t test was used to compare continuous variables, the Mann-Whitney U test to compare continuous variables with a nonnormal distribution, and the Fisher exact test to compare proportions. All statistical tests were 2-tailed and the threshold of statistical signifi cance was p<0.05. To analyze the risk factors for development of complicated bacteremia, we performed a multivariate forward stepwise logistic regression model including all the clinically relevant variables with a p value of <0.05 and possible confounding factors with a p value of <0.1 detected in the univariate analysis (SPSS software version 15.0, SPSS, Chicago, IL, USA).
Comparative data of patients with or without a high vancomycin MIC MSSA strain are shown in Table 1. The incidence of severe sepsis/septic shock was similar in both groups (21.7% vs. 14.5%; p = 0.69), but patients with high vancomycin MIC strains had complicated bacteremia more frequently (78.3% vs. 13.2%; p<0.0001). Attributable death rate was higher in patients with high vancomycin MIC strains with a difference that nearly achieves statistical signifi cance (17.4% vs. 3.9%; p = 0.08).
Comparative data between the 28 patients in whom complicated bacteremia developed and the remaining cohort are shown in Table 2

Conclusions
The aim of our study was to evaluate whether vancomycin MIC has any infl uence on the death rates and outcomes of patients with catheter-related MSSA bacteremia. We chose a MIC >1.5 μg/mL as interpretive criteria for diminished susceptibility on the basis of the reported treatment failure for infections caused by organisms who have exhibited this level of vancomycin MIC (5,8). A fi rst relevant fi nding of our study was the relatively high incidence of high vancomycin MIC among MSSA strains producing bacteremia (23.2%), a result similar to the percentage found for MRSA strains in our hospital (9,10).
Although a previous study found that vancomycin MICs for MSSA strains recovered from hemodialysis-dependent patients with bacteremia who had been treated with vancomycin did not seem to be related to their clinical outcomes (11), recently published in vitro data suggest that isolates of S. aureus with high vancomycin MICs could be less susceptible to cloxacillin or daptomycin (6). Our data showed that patients with MSSA bacteremia caused by strains with high vancomycin MIC were not related to a higher rate of severe sepsis/septic shock development but were associated with a higher rate of complicated bacteremia. In fact, complicated bacteremia was related to a vancomycin MIC >1.5 μg/mL but not with other factors such as age, acquisition of infection, severity of underlying disease, or catheter management, which was confi rmed in the multivariate analysis.
The initial treatment most frequently associated with complicated bacteremia, in patients with and without high vancomycin MIC, was the use of glycopeptides alone or followed by antistaphylococcal β-lactams. A possible explanation for this fi nding is that the fi rst hours of antibiotic treatment are crucial to avoid complications. Nevertheless, Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 17, No. 6, June 2011 in our opinion the greatest risk for complicated bacteremia related to strains of S. aureus with high vancomycin MIC should not only be attributed to the fact that these strains are more resistant to vancomycin because patients infected with strains with high vancomycin MIC that were initially treated with β-lactams also had a clear tendency to develop more complicated bacteremia. Nevertheless, the scarce number of patients who were treated initially with β-lactams limit our results. We hypothesize that certain structural modifi cations might also occur in the cell wall of strains with high vancomycin MIC, including a thicker cell wall as it has been described in MRSA (12). Thickness of the cell wall should not only hinder the action of vancomycin, but also the arrival to the target (penicillin binding proteins of β-lactams). If this hypothesis is correct, a vancomycin MIC of 1.5-2 μg/mL in MSSA could be not only a marker of poor response to vancomycin but also a subrogate marker of suboptimal response to β-lactams and even pathogenicity, as has been recently suggested in MRSA isolates (13).
Some limitations of this study deserve specifi c consideration. For most patients a treatment schedule including glycopeptides and β-lactams was used, so it is diffi cult to analyze the role played by each antimicrobial drug. All our strains had a vancomycin MIC <2 μg/mL, so we do not know which would be the outcome of MSSA bacteremia caused by more resistant strains. We did not specifi cally test clonality of strains with high vancomycin MIC because we had previously demonstrated that MSSA strains isolated from patients with bacteremia at our institution (which coincided with most of the strains included in the present study) were polyclonal (14). Finally, some important variables such as the previous use of vancomycin or vancomycin serum levels were not included in the analysis.
A high level of resistance to vancomycin is related with the development of complicated complicated bacteremia caused by MSSA, independent of the type of initial antibiotic treatment. Failure of glycopeptides does not appear to be the unique factor for the development of complicated bacteremia in patients with high vancomycin MIC isolates, and therefore intrinsic characteristics of these strains could also explain MSSA's pathogenic role in the development of complicated bacteremia.