Staphylococcus aureus bacteraemia: a major cause of mortality in Australia and New Zealand

Staphylococcus aureus sepsis, especially that caused by methicillin-resistant S. aureus (MRSA), is widely recognised by the public and the general medical community as a problem associated with health care. Less well recognised, but equally important, is invasive S. aureus infection arising in the community. The emergence of community strains of MRSA has added significant concern about community-onset infections.1 Although there is a wide variety of manifestations of serious invasive infections caused by S. aureus, in the great majority of these cases, the organism can be detected in blood cultures. Therefore, S. aureus bacteraemia is considered a very useful marker for these serious invasive infections,2 and in some cases, is the only initial manifestation of the infection.

Published reports of experience around the world show that mortality from infections associated with S. aureus bacteraemia can range from as low as 2.5% to as high as 40%.3-5 Mortality rates are known to vary significantly with patient age, clinical manifestation and comorbidities. Until recently, there have been no national data on the incidence and outcomes of S. aureus bacteraemia in either Australia or New Zealand. Small, largely retrospective, studies have been conducted, usually in single institutions. A recent prospective study of S. aureus bacteraemia conducted in 17 sites across Australia found a crude mortality rate of 11.2% when measured at discharge or 7 days, whichever came sooner.6 An earlier study that documented outcomes in six major centres in New Zealand found an all-cause mortality of 22.4% and an attributable mortality of 18.9%.7

The Australia New Zealand Cooperative on Outcomes in Staphylococcal Sepsis (ANZCOSS) was established in 2007 to prospectively examine mortality from infections associated with S. aureus bacteraemia in a more structured way and to determine some of the risk factors for poor outcomes.8

Independent or hospital pathology laboratories in Australia and New Zealand were asked to join the cooperative on a voluntary basis. Invitations were extended to all members of the Australian Group on Antimicrobial Resistance,6 and by open invitation to selected hospital laboratories in New Zealand. The entry criterion for participating sites was a single blood culture that tested positive for S. aureus, associated with clinical manifestations in the patient consistent with staphylococcal infection. The date of study entry was the date of collection of the first positive culture in an episode of infection. A new episode in the same patient was recorded if the bacteraemia had cleared, but a further culture of blood taken more than 14 days after the initial positive culture was again positive.

Approval to conduct the prospective data collection was given by the research ethics committee associated with each participating laboratory. A web-based data entry system was constructed to enable real-time data collection into a common database. To ensure patient anonymity, but to allow follow-up of discrepant results with each participating site, a record identifier unique to the participating site was used. Data were collected on age, sex, ethnicity, date of admission (if admitted), date of discharge, relationship of the infection to a medical device and its type, the principal clinical manifestation of the infection, the principal agent used for definitive initial treatment (usually intravenous), and mortality at 7 and 30 days from date of entry. To avoid interpretive bias, no attempt was made to assign attributable mortality. Participating sites were asked to assign the susceptibility type of S. aureus to one of five types based on their locally generated antibiotic profile (Box 1). The place of onset of S. aureus infection was designated as the community (if the first positive blood culture in an episode of infection was collected before or within 48 hours of hospital admission) or hospital (if the first positive blood culture was collected more than 48 hours after admission).

Although data collection commenced in June 2007, some sites were able to include data that had been collected prospectively from January 2007. Regular audits for data discrepancies and potential duplicate entries were conducted and resolved with each of the participating sites on a regular basis during data collection. Analysis was conducted on all cases of S. aureus bacteraemia for which data entries had been completed by early May 2008.

At the time of data analysis in May 2008, 27 sites had entered patient data; 24 from Australia and three from New Zealand. Data had been entered into the database for 2297 episodes of S. aureus bacteraemia. Of these, 1994 had complete data entry for all fields; 1860 from Australia and 134 from New Zealand. Through a process of audit and data scanning, and referral of data gaps and anomalies back to participating sites for resolution, the data were considered near complete and of high quality. Seven-day mortality data were available for all 1994 completed cases, and 30-day mortality data were available for 1865 (93.5%). The all-cause mortality was 10.8% (95% CI, 9.4%–12.1%) at 7 days and 20.6% (95% CI, 18.8%–22.5%) at 30 days.

This study provides the first reliable national estimate of percentage mortality from S. aureus bacteraemia for Australia, and provides indicative mortality for New Zealand. That so many institutions were willing to participate in the cooperative with no additional resources indicates the importance that those in the medical community attach to this problem. For Australia at least, we estimate that we have captured between a third and half of all cases over the period of data collection (about 1 year on average), based on previous estimates of the national incidence in Australia of around 6500 cases.5 The average 30-day mortality rate of around 20% is more than double that of bacterial diseases with a much higher public health profile, such as invasive meningococcal disease, and its incidence in the community is also substantially higher.10

In conducting this surveillance, we aimed to make data entry as simple and reliable as possible. To these ends, we chose web-based data entry because of its ready accessibility and consistency, and we kept the number of fields requiring data low. Further, we attempted to collect easily accessible data that required only a small additional effort above normal clinical activities, and to avoid, as far as possible, collecting data that required subjective interpretation. In particular, we did not ask participating sites to provide attributable mortality, which, in many respects, is a subjective judgement, particularly in cases with complex comorbidities. Some studies have estimated that attributable mortality is around 65% of crude mortality at 30 days.11 As an indication, the 7-day mortality rate of nearly 11% would almost all be attributable to staphylococcal sepsis.

Risk factors for mortality were readily identified in the univariate and multivariable analyses. As in most previous studies, age was the most important determinant of poor outcome, with increasing mortality with each decade. Noticeable, however, was the higher mortality in the first decade of life compared with the second and third decades. Some, but not all of these deaths, occurred in the first few months of life, presumably in hospitalised neonates. The findings of significantly increased mortality with left-sided endocarditis, device infection with a secondary focus, pneumonia/empyema and sepsis syndrome are also not unexpected.

More surprising is the fact that MRSA infection was not an independent risk factor for increased mortality in the multivariable analysis. A number of studies and meta-analyses have shown that MRSA is associated with poorer outcomes, including increased mortality.12 Our analysis suggests that this may be attributed to the antimicrobial agent used for treatment, almost always vancomycin. The likely reason that we obtained this result is that sufficient patients infected with methicillin-susceptible strains were treated with vancomycin instead of a β-lactam, and this allowed us to demonstrate a higher 30-day mortality with vancomycin than with flucloxacillin treatment. There has been increasing evidence of the inferior efficacy of vancomycin in treating staphylococcal infection,13 including recent compelling evidence of its inferiority to b-lactam treatment in treating methicillin-susceptible S. aureus infection.14 So, it may be better to consider MRSA as a major threat mostly because the drug of choice for serious invasive infection is less effective than β-lactams are against methicillin-susceptible strains. Unfortunately, new agents for treating serious MRSA infection, such as linezolid and daptomycin, have so far not shown predictable superiority over vancomycin in prospective randomised controlled trials.13 We have begun a retrospective review to determine why vancomycin does not perform as well as should be expected. Factors to consider include the pharmacokinetics and pharmacodynamics of the drug and the emergence of reduced susceptibility, especially of the heterogeneous type, in some strains of S. aureus.

A limitation of our study was that no data were collected on comorbidities. These have been shown to influence mortality significantly.11 Data such as these require more intensive efforts at collection, which we did not regard as conducive to recruitment or compliance with data collection. Moreover, the studies that have examined comorbidities have commonly used non-discriminatory measures, such as the Charlson Comorbidity Index, many components of which have no plausible link to poor outcomes for serious staphylococcal infection. Further studies are required to determine which aspects of comorbidities predict poor outcomes. It is possible that differences in comorbidities may have accounted in part for the differences in mortality rates we observed between participating sites.

Clearly, invasive S. aureus infection is a major disease in Australia and New Zealand, with substantial mortality. The substantial proportion of infections that are caused by MRSA, and the suboptimal antimicrobial agents available for MRSA treatment exacerbate the problem. There has been a perception that serious staphylococcal infection, especially that caused by MRSA, is a problem largely confined to hospitals. However, our data show that it is also a major problem in the community, where methicillin-susceptible strains are a significant cause of morbidity and mortality, and where non-multiresistant strains of MRSA are now adding to the burden of disease in a substantial way. Continuous surveillance of S. aureus bacteraemia and its outcomes should be a priority in Australia and New Zealand, so that change can be driven, interventions designed and implemented, and their effects measured.

3 Number of cases of Staphylococcus aureus bacteraemia and patient survival, by age*

* Data not shown for one patient aged 100 years, who survived.

6 Funnel plot of 30-day percentage mortality from Staphylococcus aureus bacteraemia for patients identified by the 27 participating institutions

Each data point represents the percentage mortality at a single institution, ordered on the x axis by the number of cases observed. The straight line represents the overall average 30-day mortality. The inner curves represent two SDs either side of overall average 30-day mortality, while the outer curves represent three SDs either side of the overall average. The SD (confidence) limits are wide when few cases are observed, and narrow with increasing numbers of cases. The plot allows each participating institution to compare its mortality rate against the overall average and with institutions with similar numbers of cases.