Acknowledging the need for accurate and precise estimates of the clinical impact of methicillin resistance in S. aureus, we set out to determine the patient mortality at day 30 and the instantaneous risk of dying during the hospital stay, as well as the extra length of stay attributable to MRSA BSI, by conducting the largest prospective cohort study designed for this purpose. An effect attributable to methicillin resistance could be discerned only for mortality within 30 days, which was increased by 80% (OR, 1.8; CI, 1.04 to 3.2), but not for hospital mortality (HR, 1.1; CI, 0.7 to 1.8) or length of hospital stay (excess days, 0.6; CI, −3.7 to 5.3). Irrespective of the methicillin resistance trait, S. aureus BSI alone increased mortality, as well as LOS, and infected patients died 2 to 4 times more often within 30 days, the instantaneous probability for dying during the entire hospital admission was 3 to 4 times higher, and the patients stayed on average 9 days longer in the hospital than their controls. These findings were consistent among all participating hospitals.
Although mortality as a study endpoint seems straightforward, different measures can lead to different conclusions. It is important to realize that mortality within a predefined interval is a static measure indicating excess mortality within that interval (proportion), while hospital mortality is a dynamic measure that provides insight into the temporal dynamics of dying during the entire hospital stay (rate). Since mortality during hospital admission is easier to determine than mortality within a certain period of follow-up, hospital mortality is regularly used as a measure for the impact of resistance. For reasons of comparability, we included the same measure, despite the complexities related to time-to-event analyses and difficulties when interpreting the resulting hazard ratios. Although not statistically significant, we found that the mortality rate (deaths/hospital day) was higher for MRSA than for MSSA patients; at the same time, statistical tests confirmed that in absolute numbers, more MRSA than MSSA patients died within 30 days.
In comparison with previously published research, three important characteristics of this study stand out. The parallel matched-cohort design made it possible to match infected patients to controls with similar hospital exposure, thereby increasing he comparability of the risk profiles of infected and control patients and, as a consequence, diminishing time-dependent bias (40
), as well as severity-of-illness bias (20
). Furthermore, two explicitly defined mortality measures were included, of which hospital mortality was analyzed by appropriate analytical methods, taking into account the duration of hospital admission, as well as competing events, i.e., the fact that patients who are discharged alive will not die in the hospital and vice versa (31
). Finally, the generalizability and precision of the estimates were improved by sampling from 777,030 patients treated in 13 tertiary care centers from as many different European countries for a total of 4.8 million bed days.
The possible limitations of this study include the potential distortion of results due to discrepancies between hospitals, such as variation in blood culture frequencies or local differences in clinical management. However, multilevel analyses, which were used to test for heterogeneity, indicated that differences between participating centers did not modify the results. Nevertheless, as with any observational study, residual bias or confounding can never be completely ruled out. Second, the nature of the matched-cohort design and our stringent matching criteria meant that we had to exclude exposed patients with excessive length of hospitalization before infection, because we were unable to find appropriate controls. These patients differed in a systematic manner from those enrolled, as they had a higher mortality (MRSA patients) or extra length of stay (MSSA patients). To impute the direction of impact of counterfactual controls is difficult, but due to the low number of excluded patients, the magnitude of the impact is expected to be small.
The differences in study design make this study unique and less amenable to a direct comparison with previously published results. Nonetheless, several studies lend support to our findings. A recent study focusing specifically on 30-day mortality but directly comparing MRSA and MSSA patients found a similarly increased ratio (OR, 2.2; CI, 1.0 to 5.0) (3
). Three other studies (17
) analyzing the impact of methicillin resistance on hospital mortality using time-to-event methods, but ignoring competing events, also found no impact on the instantaneous risk of dying. Finally, another study (6
) supported our finding that patients with MRSA and MSSA infections have equal durations of hospitalization after enrollment. Others who made claims to the contrary ignored the influence of the duration of hospital exposure before infection (1
There are four intuitive explanations for the 80% excess mortality of MRSA patients over MSSA patients in our study: (i) increased vulnerability of the host, (ii) inappropriate empirical antibiotic treatment, (iii) delayed appropriate therapy, and (iv) inferior effectiveness of reserve antibiotics. In this prospective study, great efforts were undertaken to control for important host factors through matching for length of hospital admission prior to the onset of infection and adjusting for important confounders, like the severity of disease, making increased vulnerability an improbable explanation. Although it seems likely that administration of inappropriate therapy could lead to higher mortality in MRSA patients (18
), a recent systematic review (26
) argues that this has never been adequately assessed, since detailed analyses that take into account timeliness and drug levels of empirical therapy are still lacking. Moreover, poor interrater agreement on the multiple factors that influence judgments about appropriateness make it difficult to measure (34
). A priori
, one would also assume that inappropriate empirical therapy should have had a different impact in each participating center due to distinct local prescribing practices. However, we found no evidence of heterogeneity between hospitals. The most likely reason for the increased mortality among MRSA patients is the delay in administration of appropriate therapy and the fact that conventional MRSA treatment, consisting of vancomycin, is not as effective as beta-lactams against MSSA (24
In conclusion, data from 13 tertiary care centers from different European countries showed that mortality and LOS attributable to S. aureus BSIs are significant. MSSA infections increased mortality more than 2-fold, and methicillin resistance contributed an additional 80% excess mortality at day 30 after infection. These results emphasize the clinical importance of invasive S. aureus infections but unequivocally underline the additional burden imposed by resistance, which not only aggravates the clinical outcome, but adds to the overall caseload of patients with S. aureus BSI. Ideally, interventions should be targeted at prevention or improved management of both resistant and susceptible S. aureus BSI.