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Risk of death from methicillin-resistant Staphylococcus aureus bacteraemia: a meta-analysis

James C Hurley
MJA 2002; 176 (4): 188-189

To the Editor: I write to offer a re-analysis of the data presented by Whitby and colleagues.1 They reported a meta-analysis of crude estimates and relative risk of death derived from nine published studies for Staphylococcus aureus bacteraemia. They concluded that bacteraemia caused by methicillin-resistant S. aureus (MRSA) is associated with a "real increase in risk of death" compared with bacteraemia caused by methicillin-sensitive S. aureus (MSSA), with a relative risk of 2.12. However, they failed to explore fully the possible confounding effect of the patients' underlying diseases and treatment in their analysis.

With this in mind, I offer a re-analysis of their data using regression analysis. Mortality rates versus median length of stay in hospital before bacteraemia (LOS) are shown in the Box (next page) for the five studies for which these data were presented by Whitby et al (in Boxes 1 and 2). The four studies without LOS data were combined, using the median LOS from the other five studies in the figure and the regression model.

The regression analysis was performed with and without the weights provided by Whitby et al (Box 2), and also with and without the four studies for which LOS data were not available.

Regression analysis revealed a significant association between mortality rate and LOS (P < 0.005). However, the addition of group status (MRSA or MSSA) failed to achieve significance in any iteration of the regression, while LOS remained a significant predictor of mortality risk.

This suggests that, with S. aureus bacteraemia, mortality rate increases with length of time in hospital before the bacteraemia. The likely explanation is that patients residing in hospital for longer periods are sicker. Moreover, they are more likely to have been exposed to antibiotics, leading to increased risk of acquiring an S. aureus strain that is methicillin-resistant. The mortality risk is no different for MRSA versus MSSA bacteraemia if LOS, a surrogate marker for severity of patient illness, is taken into account. The difference that Whitby et al observed between the groups of patients with MRSA and MSSA bacteraemia could be accounted for by the difference in LOS between these groups.

Mortality rate versus hospital length of stay before bacteraemia (LOS) in patients with MRSA or MSSA bacteraemia

  1. Whitby M, McLaws M-L, Berry G. Risk of death from methicillin-resistant Staphylococcus aureus bacteraemia: a meta-analysis. Med J Aust 2001; 175: 264-267. <PubMed>

(Received 7 Sep, accepted 22 Oct, 2001)

20 Drummond St North, Ballarat, VIC.

James C Hurley, MB BS, PhD, FRACP, General Medicine and Infectious Diseases Physician.

Correspondence: Dr James C Hurley, 20 Drummond St North, Ballarat, VIC 3350. drjameshurleyATbigpond.com

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In reply: Risk of death from methicillin-resistant Staphylococcus aureus bacteraemia: a meta-analysis

Michael Whitby, Mary-Louise McLaws and Geoffrey Berry
MJA 18 February 2002 176 (4: 189

In Reply: We thank Hurley for his comments on our meta-analysis.1 However, we strongly dispute that our analytical technique is flawed, and argue that we have been extremely cautious in drawing our conclusions. Hurley's contention is that hospital length of stay before bacteraemia (LOS) is a surrogate for severity of underlying disease and risk for colonisation with methicillin-resistant Staphylococcus aureus (MRSA), and that these factors explain the higher mortality in patients with MRSA.

We agree that LOS may be a confounder. It may be an effect modifier, whereby patients in hospital for longer may be more ill, and therefore more susceptible to infection with and death from MRSA. Both are intuitive and biologically plausible conclusions. In fact, we referred to these possibilities in our Discussion, writing that "patients who ultimately become infected with MRSA are more seriously ill than those who become infected with MSSA [methicillin-sensitive S. aureus]" and "separating the effect of the bacteraemia per se from the effects of patients' underlying disease and treatment is a major problem when comparing outcomes". We also cautioned readers that available published data on mortality made it impossible for us to adjust for numerous potential confounders, including LOS, as the information given did not link these potential confounders with the outcome in individual patients.

Hurley has not, as he suggests, undertaken an analysis that would allow him to control correctly for the potential confounder, LOS. He, like us, used "group-as-a-unit" data, but, although the groups are homogeneous for MRSA or MSSA, they are heterogeneous for LOS. Adequate examination of and control for potential confounders requires either individual patient data or data from homogeneous groups. Hurley has attempted to use analysis normally reserved for individual data.4 His analysis was analogous to treating the data as though from an ecological study, a design in which control of confounding is difficult,5 and thus does not permit him to draw his conclusions.

Our analysis (not presented in our original article) of only those studies where the authors attributed mortality to bacteraemia6-8 found that the magnitude of effect remained (fixed-effect relative risk, 2.27; 95% CI, 1.75–2.96; P < 0.001; test for heterogeneity, χ2 = 6.14, df = 4, P = 0.19).

As MRSA bacteraemia is a rare event and published studies are small, the statistical ability to control for confounding and effect modification is limited. Until sufficient suitable data for individual patients are available for analysis, we have remained restrained in our assessment. Mindful that MRSA bacteraemia is associated with increased mortality, regardless of the cause, we hold with our original conclusion that "our findings justify ongoing surveillance and proactive management of MRSA in healthcare facilities".

  1. Whitby M, McLaws M-L, Berry G. Risk of death from methicillin-resistant Staphylococcus aureus bacteraemia: a meta-analysis. Med J Aust 2001; 175: 264-267. <PubMed>
  2. Armitage P, Berry G. Statistical methods in medical research. 3rd ed. Oxford: Blackwell Science, 2001: 313.
  3. Rothman KJ. Modern epidemiology. Boston: Little, Brown and Company, 1986: 305.
  4. Selvey LA, Whitby M, Johnson B. Nosocomial methicillin-resistant Staphylococcus aureus bacteremia: Is it any worse than methicillin-sensitive Staphylococcus aureus? Infect Control Hosp Epidemiol 2000; 21: 645-648. <PubMed>
  5. Romero-Vivas J, Rubio M, Fernandez C, Picazo JJ. Mortality associated with nosocomial bacteremia due to methicillin-resistant Staphylococcus aureus. Clin Infect Dis 1995; 21: 1417-1423. <PubMed>
  6. French GL, Cheng AF, Ling JM, et al. Hong Kong strains of methicillin-resistant and methicillin-sensitive Staphylococcus aureus have similar virulence. J Hosp Infect 1990; 15: 117-125. <PubMed>
  7. Conterno LO, Wey SB, Castello A. Risk factors for mortality in Staphylococcus aureus bacteremia. Infect Control Hosp Epidemiol 1998; 19: 32-37. <PubMed>
  8. Topeli A, Unal S, Akalin HE. Risk factors influencing clinical outcome in Staphylococcus aureus bacteremia in a Turkish University hospital. Int J Antimicrob Agents 2000; 14: 57-63. <PubMed>

(Received 11 Oct 2002, accepted 22 Oct 2002)

Infection Management Services, Princess Alexandra Hospital, Brisbane, QLD.

Michael Whitby, Director.

NSW Hospital Infection, Epidemiology and Surveillance Unit, Faculty of Medicine, Sydney, NSW.

Mary-Louise McLaws, Director.

Department of Public Health and Community Medicine, University of Sydney, Sydney, NSW.

Geoffrey Berry, Professor in Epidemiology and Biostatistics.

Correspondence: Dr Michael Whitby, Infection Management Services, Princess Alexandra Hospital, Ipswich Road, Brisbane, QLD 4102. whitbymAThealth.qld.gov.au


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