Departments of 1 Internal Medicine and 2 Laboratory Medicine, Seoul National University College of Medicine; 3 Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
Received 24 February 2004; returned 28 April 2004; revised 25 May 2004; accepted 15 June 2004
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Abstract |
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Patients and methods: We used two different and complementary approaches: a retrospective cohort study and a matched casecontrol study. Of the total of all patients with S. aureus bacteraemia in a tertiary hospital over a 4 year period, 127 patients with MRSA bacteraemia were enrolled in the cohort study. The cases for the casecontrol study were defined as patients who received appropriate empirical treatment for MRSA bacteraemia; the controls, who were patients who received inappropriate empirical treatment for MRSA bacteraemia, were selected according to the matching variables of age, sex, severity of underlying illness, classification of main underlying disease and prior hospital stay. On the 14-point matching scale that was used to select the best controls, the average score (±S.D.) of the 30 controls was 11.2 (±2.0).
Results: In the cohort study, the difference in S. aureus bacteraemia-related mortality between appropriate (30%, 9/30) and inappropriate (39%, 38/97) empirical treatment was not significant (P=0.36). In addition, multivariate analysis did not indicate that inappropriate empirical treatment was associated with mortality when independent predictors for mortality were considered (adjusted OR 1.1, 95% CI 0.43.1). In the casecontrol study, S. aureus bacteraemia-related mortality in case patients was 30% (9/30) and in control patients 33% (10/30) (P>0.99, McNemar's test). In four of the nine discordant pairs, the case patients died whereas the control patients lived.
Conclusions: Our data suggest that an initial delay of 2 days in the use of appropriate antibiotics, especially of vancomycin or other glycopeptides, before the preliminary microbiological report may not adversely affect the outcome in patients with MRSA bacteraemia.
Keywords: bloodstream infections , antibiotics , matched cohort study , MRSA
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Introduction |
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Several reports have noted that appropriate empirical antibiotic treatment had a favourable effect on outcome in S. aureus bacteraemia.13 Others reported that inappropriate empirical treatment did not result in a significant difference in outcome.46 Therefore, it is uncertain whether an initial delay in the use of appropriate antibiotic treatment of MRSA bacteraemia adversely affects the outcome. We performed this study to evaluate the effect of inappropriate empirical antibiotic treatment on the outcome of patients with MRSA bacteraemia, using two different and complementary approaches: a retrospective cohort study and a matched casecontrol study.
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Patients and methods |
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Seoul National University Hospital is a university-affiliated tertiary hospital with 1500 beds. The hospital provides specialized medical and surgical care, including bone marrow and solid organ transplantation for adult (>15 years of age) patients.
All patients with blood cultures positive for S. aureus were identified from a retrospective review of the computerized records of the Clinical Microbiology Laboratory between 1 January 199831 October 2001. Only the first clinically significant episode of S. aureus bacteraemia for each patient was included in the analysis. Patients who had S. aureus bacteraemia as part of a polymicrobial bloodstream infection were excluded.
Microbiological tests
Identification of S. aureus was carried out with VITEK GPI Cards (bioMérieux, Hazelwood, MO, USA). Antibiotic susceptibilities were determined using the disc diffusion method, following the recommendations of the National Committee for Clinical Laboratory Standards.7
Study design
The first part was a retrospective cohort study of 127 cases of MRSA bacteraemia from a total with S. aureus bacteraemia. The outcome of 30 patients with appropriate empirical antibiotic treatment was compared with 97 patients with inappropriate empirical antibiotic treatment. The second part was a matched (1:1) casecontrol study. For the purpose of this study, the patients with MRSA bacteraemia treated with an appropriate empirical antibiotic regimen are designated as cases and those with MRSA bacteraemia treated with an inappropriate empirical antibiotic regimen as controls.
Definitions
Definition of terms
S. aureus bacteraemia was classified as community-acquired if the organism was isolated from blood cultures drawn within 72 h of admission, if the patient was not transferred from another hospital and had suggestive symptoms or signs of infection on admission.8 Community-acquired MRSA bacteraemia was further classified into healthcare-associated infection if the patient had been exposed recently to a healthcare setting (i.e. had attended a hospital or haemodialysis clinic, or had resided in a long-term care facility).9 Hospital-acquired MRSA bacteraemia was defined by a positive blood culture obtained from patients who had been hospitalized for 72 h or longer.
Previous antibiotic use was defined as a patient who had been treated with any antimicrobial agent for more than 7 days during the month before the S. aureus bacteraemia.3 Previous surgery was defined as a patient who had had an operation within the month before the S. aureus bacteraemia.3 A history of MRSA colonization was defined as a case in which MRSA was isolated from any specimens (i.e. sputum, wound and urine) within the preceding 6 months before the S. aureus bacteraemia. A hospital stay was defined as the length of hospital stay from the time of admission to the occurrence of S. aureus bacteraemia.
Foci of bloodstream infection
The primary foci of infection were determined using the following definitions. Catheter-related infection was considered as the source of bacteraemia,10 if: (i) the culture of a specimen of purulent drainage from the insertion site grew S. aureus that had the same resistance pattern as the culture strain from the peripheral blood, or the clinical signs improved within 23 days after the catheter had been removed, and (ii) no other source for bacteraemia existed. We used such indirect clinical evidence of catheter-related infection in the absence of laboratory confirmation of catheter-related infection (i.e. quantitative culture of blood or semi-quantitative culture of a catheter segment, which was not conducted in our hospital during the study period). Pneumonia was considered as the source of S. aureus bacteraemia if: (i) the patient had clinical symptoms and signs of a lower respiratory tract infection, and (ii) there was radiological evidence of pulmonary infiltrates not attributable to other causes.8 Soft tissue infection was considered as the source of S. aureus bacteraemia in cases where patients: (i) had a culture of S. aureus from a tissue or a drainage specimen from the affected site and (ii) had signs of infection.8 Surgical wound infection was defined according to the definitions of the Centers for Disease Control and Prevention.11 Infective endocarditis was defined using the modified Duke criteria.12 If a primary focus of infection could not be determined, it was considered to be unknown.
Antibiotic treatment and outcome
Decisions regarding empirical antibiotic regimens were the responsibility of the primary care physicians. The empirical antibiotic treatment was considered appropriate if the empirical therapy given intravenously within the first 48 h from the onset of the bacteraemia included at least one antibiotic to which the isolate was susceptible.4,5,13 In our institution, vancomycin has been administered intermittently; none of our patientsamong either the appropriate or inappropriate empirical treatment groupsreceived vancomycin via continuous infusion.
The treatment outcomes of S. aureus bacteraemia were assessed at 12 weeks after the onset of S. aureus bacteraemia, according to the following criteria: cure (resolution of clinical signs of infection during therapy and no evidence of recurrent S. aureus bacteraemia within 12 weeks of follow-up), recurrence (clinical resolution of signs and symptoms of infection during therapy, but recurrent S. aureus bacteraemia within 12 weeks of follow-up), non-S. aureus bacteraemia-related mortality (death due to underlying diseases or another process, with no evidence of S. aureus infection at the time of death), and S. aureus bacteraemia-related mortality (death occurring before the resolution of symptoms or signs or within 7 days from the onset of S. aureus bacteraemia and if there was no other explanation).3,14
Matching process
Each patient with appropriate empirical treatment (case patient) was matched with a patient with inappropriate empirical treatment (control patient) who was selected according to age, sex, the McCabe and Jackson classification of severity of underlying illness (classified as rapidly fatal when death was expected within a period of days or weeks, ultimately fatal when death was expected within a period of months or years, and non-fatal when death was not expected),3,15,16 the same main underlying disease and length of hospital stay before S. aureus bacteraemia (stratified into four categories: <72 h, 37, 828 and >28 days).3,8 To select the best control for each case patient, we used a 14-point scoring system based on the above-listed matching variables, similar to that described elsewhere:8,17,18 matching for age (three points if age difference ±5 years, two points if age difference ±610 years, no point if age difference ±>10 years); matching for sex (two points in cases of concordance, no point if discordant matching); matching for the same McCabe and Jackson classification of severity of illnessrapidly fatal, ultimately fatal and non-fatal (three points for concordance, no point in cases of discordance); matching for the same main underlying disease, such as cardiovascular disease, haematological malignancy, solid tumour, liver cirrhosis, end-stage renal disease, rheumatological disease, other diseases and no disease (three points for concordance, no point in cases of discordance); and matching for the same length of hospital stay before S. aureus bacteraemia (three points if in the same category as mentioned above, no points if not). The best control patient was selected on a subject-to-subject basis using the above score system. If several control patients had the same point score, one of them was selected at random. Control patients were chosen without the knowledge of the case patients' survival status.
Statistical analysis
The results were analysed using the SPSS version 10.0 for Windows software package (SPSS Inc, Chicago, IL, USA). The categorical variables were compared by Fisher's exact tests or Pearson 2 tests, as appropriate, and the continuous variables were compared by MannWhitney U-test or Student t-tests. The McNemar's test with continuity correction was performed to test the comparison of mortality for the case and control patients. All tests of significance were two-tailed; P values
0.05 were considered significant. Independent predictors for S. aureus bacteraemia-related mortality in the cohort study were identified by means of backward stepwise logistic regression analysis, with a limit of removing variables with a P value >0.10 from the equation. Survival curves for patients with appropriate and inappropriate empirical treatment were prepared according to the KaplanMeier method. The log-rank test was used to determine significance between survival curves.
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Results |
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During the study period, 127 patients with MRSA bacteraemia were identified. Eight patients were classified as having community-acquired infection, but all had been recently exposed to a healthcare setting. Thirty (24%) of 127 patients with MRSA bacteraemia were treated with an appropriate empirical antibiotic regimen. Of 127 MRSA bacteraemic patients, 57 (45%) were cured and four (3%) recurred. The overall death ratenon-S. aureus bacteraemia-related death and S. aureus bacteraemia-related death at 12 weeks after the onset of S. aureus bacteraemiawas 52% (66/127), 15% (19/127) and 37% (47/127), respectively. Of 47 patients with S. aureus bacteraemia-related deaths, 15 (32%) deaths occurred within 4 days of obtaining a blood sample for culture and 39 (83%) within 14 days (Figure 1). The mean time (±S.D.) from the onset of bacteraemia to S. aureus bacteraemia-related death was 9.1±7.6 days (range 130 days).
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Matched casecontrol study
There were 30 pairs of case and control patients who were matched for age, sex, the McCabe and Jackson classification of severity of underlying illness, main underlying disease and the length of hospital stay. The average age was 55 years in case and 56 years in control, respectively. Of 30 casecontrol pairs, 23 (77%) were successfully matched for sex, 28 (93%) for the same McCabe and Jackson classification of severity of illness, 22 (73%) for the same main underlying disease and 19 (63%) for the length of hospital stay before S. aureus bacteraemia (concordance in the same categories mentioned above). The details of the results of matching are shown in Table 3. Overall, on the 14-point matching scale, the 30 controls had an average score of 11.2 points (S.D. 2.0, range 814).
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Discussion |
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Previous studies showing an association of inappropriate empirical treatment with mortality may have overestimated the efficacy of the empirical antibiotic treatment due to inadequate adjustment for underlying disease or severity of clinical condition. A good example may be found in a previous report,13 where we demonstrated that the difference in S. aureus bacteraemia-related mortality between inappropriate and appropriate empirical treatment was not significant in patients with eradicable foci of S. aureus bacteraemia (OR 1.2, 95% CI 0.44.3, P=0.78). However, inappropriate empirical treatment affected the outcome adversely in patients with non-eradicable foci of S. aureus bacteraemia (OR 2.1, 95% CI 1.14.2, P=0.03). Since methicillin resistance was closely correlated with inappropriate empirical treatment, the logistic regression model did not reveal that inappropriate empirical therapy was associated with mortality in this subgroup after adjustment for methicillin resistance.
A recent meta-analysis showed that MRSA bacteraemia was associated with significantly higher mortality than MSSA bacteraemia.24 This was true both if all-cause mortality and S. aureus bacteraemia-related mortality were evaluated. Hence, methicillin resistance itself may confound the association of inappropriate empirical treatment with mortality. Therefore, we included only patients with MRSA bacteraemia in the cohort study in order to evaluate the impact of empirical antibiotic treatment on mortality without the influence of methicillin resistance. Univariate and multivariate analysis in our cohort study did not show any association of initial delay in appropriate antibiotic treatment with mortality of patients with MRSA bacteraemia (OR 1.5, 95% CI 0.63.6; adjusted OR 1.1, 95% CI 0.43.1). In addition, after patients with inappropriate and appropriate empirical antibiotic treatment were carefully matched, the impact of an initial delay of appropriate antibiotic treatment on outcome remained marginal (attributable S. aureus bacteraemia-related mortality 3.3%, 95% CI 20.2%-26.9%). A possible explanation for these results is that most Gram-positive pathogens are usually not rapidly lethal.25 That is, the infection progresses rapidly to fatal sepsis in only a minority of patients with MRSA bacteraemia, and an initial delay in appropriate treatment might not necessarily lead to a worse outcome.4 This hypothesis is supported by many clinical studies with neutropenic cancer patients.2628 We believe that the initial antibiotic choice seldom, if ever, influences the fate of rapidly fatal outcomes of S. aureus bacteraemia. The hypothesis that there is a physiological point of no return prior to antibiotic therapy has been confirmed in pneumococcal bacteraemia29,30 and sepsis of critically ill patients.31
There is a growing concern about community-acquired MRSA.32 No case of true community-acquired MRSA bacteraemia was included in this study, but it is an interesting issue whether inappropriate empirical treatment in recently emerged virulent community-acquired MRSA infection may adversely affect the outcome. Non-glycopeptide anti-staphylococcal antibiotics, such as co-trimoxazole, quinupristin/dalfopristin and linezolid, were not used as empirical therapy in this study but may have a favourable effect if used empirically. In addition, vancomycin-intermediate resistant S. aureus or heterogeneous vancomycin-intermediate resistant S. aureus strains might be a confounding factor, although none of our MRSA isolates showed reduced susceptibility to vancomycin.33
Some may consider that a simple measurement of mortality is too crude a way to measure the differences between two groups. Although we did not detect any significant differences in endocarditis or metastatic infection, we could not rule out occult endocarditis or metastatic infection because it was, in the retrospective nature of this study, difficult to assess these complications. However, observational prospective studies on an effect of the adequacy of initial empirical antimicrobial treatment on outcome are not easy to conduct because awareness of the ongoing study might influence medical prescription.34 One may argue that a certain proportion of patients who were classified into the inappropriate empirical treatment group might receive adequate partial treatment (i.e. an aminoglycoside). Almost all MRSA strains isolated in our hospital were resistant to aminoglycosides.35 All patients who were classified as inappropriate empirical therapy received other antibiotics to which the isolates were resistant in vitro.
The inclusion of patients who died in the first 4 days, when antibiotics are unlikely to have an effect on outcome, and any patient who never received appropriate antibiotics would seem to dilute our results. Thus, we compared the outcome of two subgroups, excluding patients with rapidly fatal outcomes or those treated without susceptible antibiotics in the cohort study and matched case-control study. These analyses revealed similar results.
The results of the cohort study showed a 9% difference in mortality between inappropriate and appropriate empirical antibiotic treatment, although this did not reach statistical significance. However, it is possible that our sample size was too small to achieve statistical significance. The relatively wide confidence interval also suggested this possibility. Indeed, the statistical power was 15% in the cohort study. The study should include more than 870 patients (435 in each group) to detect this statistically significant difference with a 5% bilateral alpha and a power of 80%. Because of this limitation, we used the complementary approach in a matched casecontrol study. We believed that consistency (similar marginal elevation of risk) in two different analytic approaches would support our results. Furthermore, the subgroup analyses to exclude the cases that could dilute our results revealed similar results. However, this matching analysis and subgroup analyses could not control for a detection bias due to a limited power of our study.
In addition, some might criticize an atypical method of performing a casecontrol study.36 However, we believe that if there had been any intrinsic association of the appropriateness of empirical treatment with S. aureus bacteraemia-related mortality, the measure of association (OR) could have been presented in this study design, regardless of their sequence in real time.36 In fact, this study design should be considered a matched cohort study. The efficacy and appropriateness of matching in cohort studies remains to be evaluated.37 Several studies demonstrated the usefulness of a matched cohort study with a design similar to ours.3,8,17,18,38,39 The use of a tertiary hospital cohort and the high mortality rate because of the inclusion of patients with rapid fatality and severe underlying diseases does, nevertheless, limit the extent to which our findings can be generalized. Another limitation was that we did not attempt to determine the factors influencing the delay in the attending physicians' use of appropriate antibiotic treatment. Hence we cannot rule out the possibility that any unmeasured confounding factor might affect our results. Finally, this was an observational study, not one designed to prove causality between appropriate empirical regimen and outcome; a randomized, controlled trial would provide more valid data. However, as prospective clinical trials are neither feasible nor ethical, alternative study designs, such as the one used in our study, are often needed to answer important policy questions.
The alternative strategy to glycopeptide restriction before the culture results are available is to include vancomycin in all empirical antibiotic regimens. This strategy inevitably results in unnecessary use of vancomycin and the possible emergence of vancomycin-resistant organisms. A good option for prudent glycopeptide use is to give glycopeptides to patients with risk factors for MRSA infection, and to optimize the therapy when microbiological data are provided. However, one major problem of this approach is that most patients with hospital infection receive empirical glycopeptides if MRSA is endemic in the institution. Indeed, MRSA is becoming endemic in more institutions. Rapid bacterial identification and antimicrobial susceptibility testing may reduce unnecessary glycopeptide use.
In conclusion, our data suggest that an initial delay of 2 days in the use of appropriate antibiotics, especially of vancomycin, prior to a preliminary microbiological report does not adversely affect outcome in patients with MRSA bacteraemia. Therefore, our study supports the view that restriction of glycopeptide application could be warranted when empirical antibiotics are used if a patient is stable, not deteriorating rapidly, and has no known risk factors for MRSA infection. A large prospective study will be required to confirm our findings.
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Acknowledgements |
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Footnotes |
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References |
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