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Predicting high vancomycin minimum inhibitory concentration isolate infection among patients with community-onset methicillin-resistant Staphylococcus aureus bacteraemia
YJINF3309_proof ■ 9 May 2014 ■ 1/7 Journal of Infection (2014) xx, 1e7
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www.elsevierhealth.com/journals/jinf
Predicting high vancomycin minimum inhibitory concentration isolate infection among patients with community-onset methicillin-resistant Staphylococcus aureus bacteraemia Q2
Shey-Ying Chen a,b, Po-Ren Hsueh c,d, Wen-Chu Chiang a,b, Edward Pei-Chuan Huang a, Ching-Feng Lin e, Chin-Hao Chang f, Shyr-Chyr Chen a, Wen-Jone Chen a, Shan-Chwen Chang c, Mei-Shu Lai b, Wei-Chu Chie b,* a
Department of Emergency Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan b Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan c Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan d Department of Laboratory Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan e Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan f National Translational Medicine and Clinical Trial Resource Center, Taipei, Taiwan Accepted 27 April 2014 Available online - - -
KEYWORDS Methicillin-resistant Staphylococcus aureus; Minimum inhibitory concentration;
Summary Objectives: Methicillin-resistant Staphylococcus aureus (MRSA) isolates with an elevated vancomycin MIC 2 mg/L have been increasingly identified in many countries. We aimed to develop a clinical score to predict vancomycin MIC 2 mg/L in patients with community-onset MRSA bacteraemia. Methods: This retrospective cohort study enrolled 394 patients with MRSA bacteraemia. Vancomycin MICs of all MRSA isolates were determined by agar dilution method. Clinical
* Corresponding author. Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, No. 17 Xuzhou Road, Zhongzheng District, Taipei 100, Taiwan. Tel.: þ886 2 33668020. E-mail address: [email protected] (W.-C. Chie). 0163-4453/$36 ª 2014 Published by Elsevier Ltd on behalf of The British Infection Association. http://dx.doi.org/10.1016/j.jinf.2014.04.007 Please cite this article in press as: Chen S-Y, et al., Predicting high vancomycin minimum inhibitory concentration isolate infection among patients with community-onset methicillin-resistant Staphylococcus aureus bacteraemia, J Infect (2014), http://dx.doi.org/10.1016/ j.jinf.2014.04.007
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S.-Y. Chen et al.
Community-onset; Bacteraemia; Prediction rule
characteristics between patients with high (2 mg/L) and low (1 mg/L) vancomycin MIC MRSA bacteraemia were compared. Independent predictors of high vancomycin MIC isolate infection were identified and used to create a score-based predictive model. Results: Among the 394 study patients, 56 (14.2%) had MRSA isolates with a vancomycin MIC 2 mg/L. The final regression model included 6 independent predictors: chronic liver disease (adjusted odds ratio [aOR], 2.99; 95% confidence interval [CI], 1.39e6.42), prior recovery of MRSA from respiratory tract specimen (aOR, 2.54; 95% CI, 1.15e5.61), end-stage renal disease (aOR, 2.53; 95% CI, 1.33e4.78), severe sepsis or septic shock on presentation (aOR, 2.39; 95% CI, 1.28e4.44), prior vancomycin exposure (aOR, 2.21; 95% CI, 1.13e4.30), and recent hospitalization within 3 months (aOR, 2.11; 95% CI; 1.01e4.40). All independent predictors had a value of one point. Youden’s index statistics indicated a score of 3 as best cutoff value that had a sensitivity of 69.6% and specificity of 78.4%. Conclusions: Simple decision rule helps clinicians stratify the risk of high vancomycin MIC MRSA infection when deciding empirical therapy for patients with community-onset infections. ª 2014 Published by Elsevier Ltd on behalf of The British Infection Association.
Introduction Patients with methicillin-resistant Staphylococcus aureus (MRSA) infection have significant morbidity and mortality.1e3 Although various antimicrobial agents are available for the treatment of MRSA infection, vancomycin remains the most commonly used anti-MRSA agent in many countries because of its predictable pharmacological activity against MRSA.4 The successful treatment of MRSA infection with vancomycin, however, is threatened by increasing evidence showing higher mortality or risk of treatment failure among patients with bacteraemia infected with an MRSA isolate with a vancomycin minimum inhibitory concentration (MIC) at the higher end of the susceptible range.5,6 The situation is further complicated by increasing reports of vancomycin MIC creep in MRSA isolates in the susceptibility window in many institutions.7e9 Theoretically, patients in the community are less expected to be infected with high vancomycin MIC MRSA than hospitalized patients because of lower use of antibiotics and colonization pressure in non-hospital environments. However, the spread of an infection with nosocomial high vancomycin MIC MRSA isolates among patients in the community introduces a significant risk of treatment failure even though vancomycin has been frequently included in empirical antibiotic regimens in patients at risk for MRSA infection.10e14 Though the impact from delay treatment of MRSA infection remains inconclusive,15,16 earlier identification of patients in the community at risk for high vancomycin MIC MRSA infection and subsequent vancomycin treatment failure is important to augment plausible benefit from timely appropriate antimicrobial therapy.17,18 This information could be helpful for first-line clinicians to consider alternative therapy for patients with suspected or confirmed MRSA infection,19 but this is difficult in practice because microbiology and antimicrobial susceptibility results are not available when deciding on empirical antibiotic therapy. Therefore, a prediction rule that helps clinicians with early recognition and timely treatment of patients with high vancomycin MIC MRSA infection becomes crucial to improve clinical outcomes. However, there are no studies that specifically focus on the development of a clinical prediction rule for high vancomycin MIC MRSA infection among patients with community-onset infection.
The objective of the current study was to determine the independent predictors of high vancomycin MIC isolate infection among patients with community-onset MRSA bacteraemia and to develop a score-based prediction rule to help clinicians with clinical decision making on patient management.
Patients and methods Study design, setting, and participant selection This emergency department (ED)-based retrospective cohort study was conducted at National Taiwan University Hospital, a 2500-bed university-affiliated teaching hospital providing both primary and tertiary care in northern Taiwan. This hospital discharges an average of 67,000 patients each year and has an average of 100,000 ED visits annually. All ED patients aged 15 years or older diagnosed with MRSA bacteraemia from January 1, 2001, to December 31, 2011, were initially recruited. Patients referred from other hospitals who had been hospitalized for 48 h or longer or patients who had been discharged from any hospital less than 48 h earlier were considered as hospital-acquired bacteraemia. They were excluded in this study because our primary interest was to develop a high vancomycin MIC MRSA prediction score among patients with community-onset infection. For patients with repeated episodes of MRSA bacteraemia during the study period, only the first episode was included. Patients with MRSA bacteraemia were also excluded if the bloodstream isolate was not available for antimicrobial susceptibility testing or if the clinical data were missing or incomplete. Therefore, only nonduplicate adult patients with community-onset MRSA bacteraemia with available clinical data and a bloodstream isolate entered the final analysis. This study was approved by the institutional review board of the hospital, and the requirement for informed consent from each patient was waived.
Data collection and information on variables Demographic data, pre-hospital living arrangement, prior health care-associated exposure history within the past
Please cite this article in press as: Chen S-Y, et al., Predicting high vancomycin minimum inhibitory concentration isolate infection among patients with community-onset methicillin-resistant Staphylococcus aureus bacteraemia, J Infect (2014), http://dx.doi.org/10.1016/ j.jinf.2014.04.007
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Predicting high vancomycin MIC MRSA bacteraemia 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62
year, pre-existing comorbidities, bedridden status, presence of a vascular or indwelling catheter, vital signs, and laboratory data at the time of ED presentation were retrieved from the medical records. For patients with prior hospitalization history within the past year, information about the admission and discharge date of each admission, intensive care unit admission, respiratory failure requiring endotracheal intubation, and discharge diagnoses were recorded. For patients with prior antibiotic exposure, antibiotic type and prescribing date were also recorded. Microbiological study results within the past year were intensively reviewed to assess the latest colonization status of MRSA. The severity of pre-existing comorbidities was assessed using the modified Charlson comorbidity score.20 Malignancy in patients indicated active haematological or solid organ malignancy diagnosed within 5 years before index blood culture. Chronic liver disease included cirrhosis and chronic hepatitis of alcoholic, viral, autoimmune, and cryptogenic aetiology. Initial vital signs on ED presentation were classified according to the International Sepsis Definitions. Bandaemia was defined as band-forming cells exceeding 10% of the white blood cells, and thrombocytopenia was defined as a platelet count <100,000/mm3 on the basis of the complete blood cell count results. Acute severity of bacteraemia as assessed by the sepsis syndrome criteria was graded as follows: no sepsis or simple sepsis, severe sepsis, and septic shock.21,22 A tunnelled central line indicated a Permcath, Hickman catheter, and Port-a-Cath, and a non-tunnelled central line included a double-lumen catheter and peripherally inserted central catheter. Prior antibiotic exposure, including vancomycin, was defined as the use of a specific antibiotic for more than 48 h before study enrolment.23,24
Microbiological procedures and determination of vancomycin MICs S. aureus was initially identified by colony morphology, Gram staining results, and a positive slide or tube coagulase test result. Initial antimicrobial susceptibility was determined by the standard disk diffusion method. A 30-mg cefoxitin disk (BBL Microbiology Systems, Cockeysville, MD) was used to detect MRSA after 2006.25 Clinical MRSA isolates were collected and stored at 70 C in trypticase soy broth (Difco Laboratories, Detroit, MI) supplemented with 15% glycerol. After thawing, the MICs of vancomycin of all available MRSA isolates were determined by microbiology laboratory technicians using the agar dilution method recommended by the Clinical and Laboratory Standards Institute.26
Statistical analysis All patients with MRSA bacteraemia finally enrolled in this study were classified into the low vancomycin MIC (1 mg/L) and high vancomycin MIC (2 mg/L) MRSA groups according to the agar dilution test results of their bloodstream isolates. Clinical characteristics between the 2 study groups were compared by chi-square test and Fisher’s exact test for binary variables and by independent
3 Student’s t test for continuous variables. Age and Charlson comorbidity score were further dichotomized at the mean value for regression modelling. Potential predictors of high vancomycin MIC isolate infection with P < 0.2 on univariate analysis were investigated by multivariate logistic regression analysis using backward stepwise variable selections. The collinearity of the covariates was evaluated and model fitting was explored based on the HosmereLemeshow goodness-of-fit test, and the discriminatory ability of the final model was assessed by the area under the receiver operating characteristic curve (AUC).27 To develop an easy-to-use clinical risk score, a regression coefficient-based scoring method was used to estimate the expected probability of high vancomycin MIC MRSA infection. Because of the similar b-coefficient values of predictor variables in the final regression model, all of these variables were assigned a single point. Sensitivity, specificity, positive predictive value, and negative predictive value with an associated 95% confidence interval (CI) for the prediction model at different cutoff values were obtained using a standard definition and methods.28 The best cutoff value for prediction of high vancomycin MIC MRSA isolates was chosen based on the Youden index statistics. Data were analysed with SPSS for Windows version 16.0 (SPSS, Chicago, IL). All P values are 2-sided, and P < 0.05 was considered statistically significant.
Results In total, 432 non-duplicate adult patients with communityonset MRSA bacteraemia were identified during the study period. Thirty patients were excluded because their bloodstream isolates were not available for antimicrobial susceptibility testing. Eight patients were further excluded because of incomplete clinical data. Finally, 394 patients with MRSA bacteraemia met the enrolment criteria and were included. The mean age was 66.2 years (standard deviation, 16.2 years), and 60.9% of the patients were men. Fifty-six patients (14.2%) had MRSA bloodstream isolates with a vancomycin MIC 2 mg/L, including 2 patients with an MRSA vancomycin MIC value of 4 mg/L. The prevalence of high vancomycin MIC (2 mg/L) isolates of MRSA bacteraemia remained stable during the study period (2001e2006, 14.4% [26/180]; 2007e2011, 14.0% [30/214]; P Z 1.00).
Clinical characteristics and univariate analysis Clinical characteristics of the patients with high (MIC 2 mg/L, n Z 56) and low (MIC 1 mg/L, n Z 338) vancomycin MIC MRSA bacteraemia are detailed in Table 1. Univariate analysis identified a number of variables that were significantly associated with high vancomycin MIC MRSA infection, including end-stage renal disease, chronic liver disease, high (>5) Charlson comorbidity score, severe sepsis or septic shock on presentation, receiving haemodialysis, recent hospitalization within 3 months, recent exposure to any antibiotics within 3 months, prior vancomycin treatment within 1 year, and prior recovery of MRSA from blood or respiratory tract specimen in the past year.
Please cite this article in press as: Chen S-Y, et al., Predicting high vancomycin minimum inhibitory concentration isolate infection among patients with community-onset methicillin-resistant Staphylococcus aureus bacteraemia, J Infect (2014), http://dx.doi.org/10.1016/ j.jinf.2014.04.007
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S.-Y. Chen et al. Table 1 Clinical characteristics of 394 study patients with community-onset MRSA bacteraemia and univariate analysis for predictors of high vancomycin MIC MRSA isolates.
Age, mean (standard deviation) Age >65 years Male sex Comorbid medical condition Diabetes mellitus Malignancy End-stage renal disease Chronic liver disease Congestive heart failure Cerebrovascular accident Dementia Charlson score High Charlson score (>5) Tunnelled central line Non-tunnelled central line Thrombocytopenia Bandaemia >10% Severe sepsis or septic shock upon emergency department presentation Nursing home residence Haemodialysis Prior hospitalizationa Prior intensive care unit admissiona Prior intubationa Any antibiotic exposurea Prior vancomycin treatment In last week Within 1 year Prior recovery of MRSAb Blood Respiratory tract Wound or abscess Other sitesc
Vancomycin MIC 2 mg/L (n Z 56)
Vancomycin MIC 1 mg/L (n Z 338)
Univariate analysis
68.1 (14.9) 34 (60.7) 40 (71.4)
65.9 (16.4) 199 (58.9) 200 (59.2)
1.01 (0.99e1.03) 1.08 (0.61e1.93) 1.73 (0.93e3.20)
24 (42.9) 14 (25.0) 26 (46.4) 14 (25.0) 9 (16.1) 12 (21.4) 11 (19.6) 5.0 2.6 24 (42.9) 15 (26.8) 2 (3.6) 10 (17.9) 6 (10.7) 31 (55.4)
141 (41.7) 76 (22.5) 79 (23.4) 40 (11.8) 38 (11.2) 79 (23.4) 46 (13.6) 3.7 2.7 86 (25.4) 82 (24.3) 17 (5.0) 67 (19.8) 25 (7.4) 123 (36.4)
1.05 1.15 2.84 2.48 1.51 0.89 1.55 1.19 2.20 1.14 0.70 0.88 1.50 2.17
(0.59e1.86) (0.60e2.22) (1.59e5.09) (1.25e4.95) (0.69e3.33) (0.45e1.78) (0.75e3.22) (1.07e1.32) (1.23e3.94) (0.60e2.17) (0.16e3.11) (0.42e1.83) (0.59e3.85) (1.22e3.84)
0.873 0.678 <0.001 0.010 0.305 0.749 0.237 0.001 0.008 0.685 0.639 0.731 0.396 0.008
12 25 44 12 10 34
(21.4) (44.6) (78.6) (21.4) (17.9) (60.7)
52 (15.4) 81 (24.0) 201 (59.5) 49 (14.5) 31 (9.2) 143 (42.3)
1.50 2.56 2.50 1.61 2.15 2.11
(0.74e3.03) (1.43e4.58) (1.27e4.91) (0.79e3.26) (0.99e4.68) (1.18e3.76)
0.259 0.002 0.008 0.187 0.053 0.011
5 (8.9) 31 (55.4) 31 (55.4) 12 (21.4) 15 (26.8) 7 (12.5) 2 (3.6)
12 (3.6) 85 (25.1) 102 (30.2) 38 (11.2) 34 (10.1) 31 (9.2) 27 (8.0)
2.66 3.69 2.87 2.15 3.27 1.42 0.43
(0.90e7.88) (2.06e6.60) (1.61e5.10) (1.05e4.43) (1.64e6.52) (0.59e3.39) (0.10e1.85)
0.077 <0.001 <0.001 0.037 0.001 0.436 0.254
Odds ratio (95% CI)
P value 0.330 0.795 0.084
All values are expressed as n (%) unless otherwise noted. MRSA, methicillin-resistant Staphylococcus aureus; MIC, minimum inhibitory concentration. a Within 3 months before the index blood culture. b Within 1 year before the index blood culture. c Included urine (13), catheter tip (13) pleural effusion (1), ascites (1), and tissue culture (1).
Development of clinical risk score A multivariate logistic regression model that investigated all potential predictors on univariate analysis finally identified 6 independent predictors, including chronic liver disease, prior recovery of MRSA from respiratory tract specimen within 1 year, end-stage renal disease, severe sepsis or septic shock on presentation, prior vancomycin exposure within 1 year, and recent hospitalization within 3 months, for high vancomycin MIC MRSA infections (Table 2). The HosmereLemeshow goodness-of-fit statistic was 0.08, and the AUC for the model was 0.79 (95% CI, 0.72e0.85). Each independent predictor was then assigned one point to create a clinical scoring system because of the similar
b-coefficient values of these predictor variables. Overall scores for each of the patients with bacteraemia were calculated and evaluated for their performance in predicting a high vancomycin MIC isolate. The predictability of these collective scores was similar to that of individual predictor-weighted probabilities from the final multivariate logistic regression model (AUC, 0.78; 95% CI, 0.71e0.84). A summary of the diagnostic accuracy of the clinical risk score for the various score cutoff values is shown in Table 3. Youden index indicated that the clinical risk score performed best at a cutoff value of 3 points. The prevalence of high vancomycin MIC isolate infection among study patients with scores of 0, 1, 2, 3, and 4 was 2.3%, 4.4%, 9.7%, 31.1%, and 42.1%, respectively (Fig. 1).
Please cite this article in press as: Chen S-Y, et al., Predicting high vancomycin minimum inhibitory concentration isolate infection among patients with community-onset methicillin-resistant Staphylococcus aureus bacteraemia, J Infect (2014), http://dx.doi.org/10.1016/ j.jinf.2014.04.007
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Predicting high vancomycin MIC MRSA bacteraemia 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62
Table 2
5
Independent predictors of community-onset MRSA bloodstream infection with isolates of vancomycin MIC 2 mg/L.
Variable
b
P value
Adjusted odds ratio (95% CI)
Point value
Chronic liver disease Prior recovery of MRSA from respiratory tract specimen within 1 year End-stage renal disease Severe sepsis or septic shock on presentation Prior vancomycin exposure within 1 year Recent hospitalization within 3 months
1.10 0.93
0.005 0.021
2.99 (1.39e6.42) 2.54 (1.15e5.61)
1 1
0.93 0.87 0.79 0.75
0.004 0.006 0.020 0.046
2.53 2.39 2.21 2.11
1 1 1 1
(1.33e4.78) (1.28e4.44) (1.13e4.30) (1.01e4.40)
MRSA, methicillin-resistant Staphylococcus aureus; MIC, minimum inhibitory concentration.
Discussion In this ED-based study, a significant proportion of patients with MRSA bacteraemia were infected with high vancomycin MIC isolates even though these infections were in nonhospital environments, in which there is less prior antibiotic pressure. Several independent predictors of high vancomycin MIC MRSA isolate infection were identified and used to develop an easy-to-use scoring system to help clinicians with early identification of patients with MRSA bacteraemia at higher risk for treatment failure due to increased vancomycin resistance. Patients with MRSA bacteraemia are at particular risk for contracting high vancomycin MIC isolates with a score of 3 points. The risk score developed in the current study provides clinicians a scientific basis for decisions regarding empirical antibiotic therapy when treating patients in the community at risk for MRSA infections. There are increasing reports of MRSA isolates with elevated MICs of vancomycin in many institutions.7e9 The results of these studies, however, were based on analysis of clinical isolates that were mostly identified from hospitalized patients. The prevalence of MRSA isolates with elevated vancomycin MIC among patients with community-onset infections, to our knowledge, has never been studied. Because MRSA has become an important pathogen in the community, it is imperative for clinicians to understand the prevalence and risk factors of high vancomycin MIC MRSA infection among patients with community-onset infection. Furthermore, new evidence has shown the association between higher risk of mortality or treatment failure and MRSA infections with a vancomycin MIC 2 mg/L.29 Information about high vancomycin MIC MRSA infections in the community is therefore crucial for clinicians to determine appropriate empirical antimicrobial therapy and/or a more aggressive treatment strategy when treating patients with community-onset infections.
Previous studies have identified many risk factors, including old age,24 female sex,30 higher body mass index,30 cardiovascular disease,30 chronic liver disease,24 recent surgery,30 prior vancomycin exposure,24,31,32 history of MRSA bacteraemia or occurrence in the intensive care unit,24,32 and a non-tunnelled central line,24 that were independently associated with elevated vancomycin MIC. Most of these factors have been identified to be associated with prior exposure to vancomycin or nosocomial environment of high antimicrobial selection pressure.31,32 Lubin et al. further created a simple and useful decision rule for predicting high vancomycin MIC isolate infection in patients with MRSA bacteraemia.24 These studies, however, used clinical data that were predominantly from inpatients and were therefore limited in generalizing their results in the setting of community-onset infection. Our risk score, using clinical data exclusively from patients with community-onset MRSA bacteraemia, provides a useful tool for clinicians to effectively stratify patients in the community to their risk of high vancomycin MIC MRSA infection. As new anti-MRSA agents become available for the treatment of complicated or persistent MRSA infections,19 clinicians should consider alternative anti-MRSA antibiotics as empirical antimicrobial therapy for patients in the community at high risk for MRSA infection with an elevated vancomycin MIC. This study had some limitations. First, the clinical data on this observational cohort were retrospectively collected and therefore subject to information bias. Second, the prediction risk score in the current study was constructed only from clinical data of patients with MRSA bacteraemia. The predictability of our risk score in patients with MRSA infection at other sites remains to be examined. Third, this was a single-centre study conducted in northern Taiwan. The performance of our risk score in predicting high vancomycin MIC MRSA infection in other communities
Table 3 Accuracy of the prediction rule in the identification of high (2 mg/L) vancomycin MIC isolate infection among 394 patients with community-onset MRSA bacteraemia, stratified by cutoff values of the risk score. Cutoff value
Sensitivity, % (95% CI)
Specificity, % (95% CI)
Positive predictive value, % (95% CI)
Negative predictive value, % (95% CI)
Case (%) of entire cohort
Youden index
4 3 2 1
28.6 69.6 87.5 98.2
93.5 78.4 50.9 12.4
42.1 34.8 22.8 15.7
88.8 94.0 96.1 97.7
38 112 215 351
0.221 0.480 0.384 0.139
(18.4e41.5) (56.7e80.1) (76.4e93.8) (90.6e99.7)
(90.3e95.7) (73.7e82.5) (45.6e56.2) (9.3e16.4)
(27.9e57.8) (26.6e44.0) (17.7e28.9) (12.2e19.8)
(85.1e91.6) (90.6e96.2) (92.2e98.1) (87.9e99.6)
(9.6) (28.4) (54.6) (89.1)
MIC, minimum inhibitory concentration; MRSA, methicillin-resistant Staphylococcus aureus.
Please cite this article in press as: Chen S-Y, et al., Predicting high vancomycin minimum inhibitory concentration isolate infection among patients with community-onset methicillin-resistant Staphylococcus aureus bacteraemia, J Infect (2014), http://dx.doi.org/10.1016/ j.jinf.2014.04.007
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S.-Y. Chen et al.
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Figure 1 Percentage of community-onset MRSA bacteraemia due to isolates of vancomycin MIC 2 mg/L by total score. 9.
requires further validation. Finally, in areas where the prevalence of high vancomycin MIC MRSA infection among patients in the community is lower than the prevalence in our study, the application of our prediction risk score would result in a lower positive predictive value and a higher negative predictive value. Clinicians should consider this important influential factor when adopting our risk score in their decision making on empirical antibiotic therapy. In summary, a high prevalence of isolates with an elevated vancomycin MIC 2 mg/L among patients with community-onset MRSA bacteraemia was demonstrated in the current study, suggesting that the increasing resistance of MRSA isolates to vancomycin is no longer a hospitalspecific phenomenon. Certain risk factors were independently associated with elevated vancomycin MIC isolate infection among patients in the community with MRSA bacteraemia. A prediction tool incorporating these predictors that effectively stratifies patients in the community to their risk of high vancomycin MIC MRSA infection helps clinicians with early identification of patients at risk for vancomycin treatment failure and their decision making on empirical antibiotic therapy. Q1
Funding
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No funding source. 16.
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7 25. Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing. Sixteenth informational supplement M100eS17. Wayne, PA, USA: CLSI; 2007. 26. Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing. Seventeen informational supplement M100eS22. Wayne, PA, USA: CLSI; 2012. 27. McNeil BJ, Hanley JA. Statistical approaches to the analysis of receiver operating characteristic (ROC) curves. Med Decis Making 1984;4:137e50. 28. Diagnosis. In: Fletcher RH, Fletcher SW, Wagner EG, editors. Clinical epidemiology: the essentials. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 1996. pp. 48e50. 29. van Hal SJ, Lodise TP, Paterson DL. The clinical significance of vancomycin minimum inhibitory concentration in Staphylococcus aureus infections: a systematic review and meta-analysis. Clin Infect Dis 2012;54:755e71. 30. Maclayton DO, Suda KJ, Coval KA, York CB, Garey KW. Casecontrol study of the relationship between MRSA bacteremia with a vancomycin MIC of 2 mg/mL and risk factors, costs, and outcomes in inpatients undergoing hemodialysis. Clin Ther 2006;28:1208e16. 31. Moise PA, Smyth DS, El-Fawal N, Robinson DA, Holden PN, Forrest A, et al. Microbiological effects of prior vancomycin use in patients with methicillin-resistant Staphylococcus aureus bacteraemia. J Antimicrob Chemother 2008;61:85e90. 32. Lodise TP, Miller CD, Graves J, Evans A, Graffunder E, Helmecke M, et al. Predictors of high vancomycin MIC values among patients with methicillin-resistant Staphylococcus aureus bacteraemia. J Antimicrob Chemother 2008;62: 1138e41.
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www.elsevierhealth.com/journals/jinf
Predicting high vancomycin minimum inhibitory concentration isolate infection among patients with community-onset methicillin-resistant Staphylococcus aureus bacteraemia Q2
Shey-Ying Chen a,b, Po-Ren Hsueh c,d, Wen-Chu Chiang a,b, Edward Pei-Chuan Huang a, Ching-Feng Lin e, Chin-Hao Chang f, Shyr-Chyr Chen a, Wen-Jone Chen a, Shan-Chwen Chang c, Mei-Shu Lai b, Wei-Chu Chie b,* a
Department of Emergency Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan b Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan c Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan d Department of Laboratory Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan e Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan f National Translational Medicine and Clinical Trial Resource Center, Taipei, Taiwan Accepted 27 April 2014 Available online - - -
KEYWORDS Methicillin-resistant Staphylococcus aureus; Minimum inhibitory concentration;
Summary Objectives: Methicillin-resistant Staphylococcus aureus (MRSA) isolates with an elevated vancomycin MIC 2 mg/L have been increasingly identified in many countries. We aimed to develop a clinical score to predict vancomycin MIC 2 mg/L in patients with community-onset MRSA bacteraemia. Methods: This retrospective cohort study enrolled 394 patients with MRSA bacteraemia. Vancomycin MICs of all MRSA isolates were determined by agar dilution method. Clinical
* Corresponding author. Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, No. 17 Xuzhou Road, Zhongzheng District, Taipei 100, Taiwan. Tel.: þ886 2 33668020. E-mail address: [email protected] (W.-C. Chie). 0163-4453/$36 ª 2014 Published by Elsevier Ltd on behalf of The British Infection Association. http://dx.doi.org/10.1016/j.jinf.2014.04.007 Please cite this article in press as: Chen S-Y, et al., Predicting high vancomycin minimum inhibitory concentration isolate infection among patients with community-onset methicillin-resistant Staphylococcus aureus bacteraemia, J Infect (2014), http://dx.doi.org/10.1016/ j.jinf.2014.04.007
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S.-Y. Chen et al.
Community-onset; Bacteraemia; Prediction rule
characteristics between patients with high (2 mg/L) and low (1 mg/L) vancomycin MIC MRSA bacteraemia were compared. Independent predictors of high vancomycin MIC isolate infection were identified and used to create a score-based predictive model. Results: Among the 394 study patients, 56 (14.2%) had MRSA isolates with a vancomycin MIC 2 mg/L. The final regression model included 6 independent predictors: chronic liver disease (adjusted odds ratio [aOR], 2.99; 95% confidence interval [CI], 1.39e6.42), prior recovery of MRSA from respiratory tract specimen (aOR, 2.54; 95% CI, 1.15e5.61), end-stage renal disease (aOR, 2.53; 95% CI, 1.33e4.78), severe sepsis or septic shock on presentation (aOR, 2.39; 95% CI, 1.28e4.44), prior vancomycin exposure (aOR, 2.21; 95% CI, 1.13e4.30), and recent hospitalization within 3 months (aOR, 2.11; 95% CI; 1.01e4.40). All independent predictors had a value of one point. Youden’s index statistics indicated a score of 3 as best cutoff value that had a sensitivity of 69.6% and specificity of 78.4%. Conclusions: Simple decision rule helps clinicians stratify the risk of high vancomycin MIC MRSA infection when deciding empirical therapy for patients with community-onset infections. ª 2014 Published by Elsevier Ltd on behalf of The British Infection Association.
Introduction Patients with methicillin-resistant Staphylococcus aureus (MRSA) infection have significant morbidity and mortality.1e3 Although various antimicrobial agents are available for the treatment of MRSA infection, vancomycin remains the most commonly used anti-MRSA agent in many countries because of its predictable pharmacological activity against MRSA.4 The successful treatment of MRSA infection with vancomycin, however, is threatened by increasing evidence showing higher mortality or risk of treatment failure among patients with bacteraemia infected with an MRSA isolate with a vancomycin minimum inhibitory concentration (MIC) at the higher end of the susceptible range.5,6 The situation is further complicated by increasing reports of vancomycin MIC creep in MRSA isolates in the susceptibility window in many institutions.7e9 Theoretically, patients in the community are less expected to be infected with high vancomycin MIC MRSA than hospitalized patients because of lower use of antibiotics and colonization pressure in non-hospital environments. However, the spread of an infection with nosocomial high vancomycin MIC MRSA isolates among patients in the community introduces a significant risk of treatment failure even though vancomycin has been frequently included in empirical antibiotic regimens in patients at risk for MRSA infection.10e14 Though the impact from delay treatment of MRSA infection remains inconclusive,15,16 earlier identification of patients in the community at risk for high vancomycin MIC MRSA infection and subsequent vancomycin treatment failure is important to augment plausible benefit from timely appropriate antimicrobial therapy.17,18 This information could be helpful for first-line clinicians to consider alternative therapy for patients with suspected or confirmed MRSA infection,19 but this is difficult in practice because microbiology and antimicrobial susceptibility results are not available when deciding on empirical antibiotic therapy. Therefore, a prediction rule that helps clinicians with early recognition and timely treatment of patients with high vancomycin MIC MRSA infection becomes crucial to improve clinical outcomes. However, there are no studies that specifically focus on the development of a clinical prediction rule for high vancomycin MIC MRSA infection among patients with community-onset infection.
The objective of the current study was to determine the independent predictors of high vancomycin MIC isolate infection among patients with community-onset MRSA bacteraemia and to develop a score-based prediction rule to help clinicians with clinical decision making on patient management.
Patients and methods Study design, setting, and participant selection This emergency department (ED)-based retrospective cohort study was conducted at National Taiwan University Hospital, a 2500-bed university-affiliated teaching hospital providing both primary and tertiary care in northern Taiwan. This hospital discharges an average of 67,000 patients each year and has an average of 100,000 ED visits annually. All ED patients aged 15 years or older diagnosed with MRSA bacteraemia from January 1, 2001, to December 31, 2011, were initially recruited. Patients referred from other hospitals who had been hospitalized for 48 h or longer or patients who had been discharged from any hospital less than 48 h earlier were considered as hospital-acquired bacteraemia. They were excluded in this study because our primary interest was to develop a high vancomycin MIC MRSA prediction score among patients with community-onset infection. For patients with repeated episodes of MRSA bacteraemia during the study period, only the first episode was included. Patients with MRSA bacteraemia were also excluded if the bloodstream isolate was not available for antimicrobial susceptibility testing or if the clinical data were missing or incomplete. Therefore, only nonduplicate adult patients with community-onset MRSA bacteraemia with available clinical data and a bloodstream isolate entered the final analysis. This study was approved by the institutional review board of the hospital, and the requirement for informed consent from each patient was waived.
Data collection and information on variables Demographic data, pre-hospital living arrangement, prior health care-associated exposure history within the past
Please cite this article in press as: Chen S-Y, et al., Predicting high vancomycin minimum inhibitory concentration isolate infection among patients with community-onset methicillin-resistant Staphylococcus aureus bacteraemia, J Infect (2014), http://dx.doi.org/10.1016/ j.jinf.2014.04.007
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Predicting high vancomycin MIC MRSA bacteraemia 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62
year, pre-existing comorbidities, bedridden status, presence of a vascular or indwelling catheter, vital signs, and laboratory data at the time of ED presentation were retrieved from the medical records. For patients with prior hospitalization history within the past year, information about the admission and discharge date of each admission, intensive care unit admission, respiratory failure requiring endotracheal intubation, and discharge diagnoses were recorded. For patients with prior antibiotic exposure, antibiotic type and prescribing date were also recorded. Microbiological study results within the past year were intensively reviewed to assess the latest colonization status of MRSA. The severity of pre-existing comorbidities was assessed using the modified Charlson comorbidity score.20 Malignancy in patients indicated active haematological or solid organ malignancy diagnosed within 5 years before index blood culture. Chronic liver disease included cirrhosis and chronic hepatitis of alcoholic, viral, autoimmune, and cryptogenic aetiology. Initial vital signs on ED presentation were classified according to the International Sepsis Definitions. Bandaemia was defined as band-forming cells exceeding 10% of the white blood cells, and thrombocytopenia was defined as a platelet count <100,000/mm3 on the basis of the complete blood cell count results. Acute severity of bacteraemia as assessed by the sepsis syndrome criteria was graded as follows: no sepsis or simple sepsis, severe sepsis, and septic shock.21,22 A tunnelled central line indicated a Permcath, Hickman catheter, and Port-a-Cath, and a non-tunnelled central line included a double-lumen catheter and peripherally inserted central catheter. Prior antibiotic exposure, including vancomycin, was defined as the use of a specific antibiotic for more than 48 h before study enrolment.23,24
Microbiological procedures and determination of vancomycin MICs S. aureus was initially identified by colony morphology, Gram staining results, and a positive slide or tube coagulase test result. Initial antimicrobial susceptibility was determined by the standard disk diffusion method. A 30-mg cefoxitin disk (BBL Microbiology Systems, Cockeysville, MD) was used to detect MRSA after 2006.25 Clinical MRSA isolates were collected and stored at 70 C in trypticase soy broth (Difco Laboratories, Detroit, MI) supplemented with 15% glycerol. After thawing, the MICs of vancomycin of all available MRSA isolates were determined by microbiology laboratory technicians using the agar dilution method recommended by the Clinical and Laboratory Standards Institute.26
Statistical analysis All patients with MRSA bacteraemia finally enrolled in this study were classified into the low vancomycin MIC (1 mg/L) and high vancomycin MIC (2 mg/L) MRSA groups according to the agar dilution test results of their bloodstream isolates. Clinical characteristics between the 2 study groups were compared by chi-square test and Fisher’s exact test for binary variables and by independent
3 Student’s t test for continuous variables. Age and Charlson comorbidity score were further dichotomized at the mean value for regression modelling. Potential predictors of high vancomycin MIC isolate infection with P < 0.2 on univariate analysis were investigated by multivariate logistic regression analysis using backward stepwise variable selections. The collinearity of the covariates was evaluated and model fitting was explored based on the HosmereLemeshow goodness-of-fit test, and the discriminatory ability of the final model was assessed by the area under the receiver operating characteristic curve (AUC).27 To develop an easy-to-use clinical risk score, a regression coefficient-based scoring method was used to estimate the expected probability of high vancomycin MIC MRSA infection. Because of the similar b-coefficient values of predictor variables in the final regression model, all of these variables were assigned a single point. Sensitivity, specificity, positive predictive value, and negative predictive value with an associated 95% confidence interval (CI) for the prediction model at different cutoff values were obtained using a standard definition and methods.28 The best cutoff value for prediction of high vancomycin MIC MRSA isolates was chosen based on the Youden index statistics. Data were analysed with SPSS for Windows version 16.0 (SPSS, Chicago, IL). All P values are 2-sided, and P < 0.05 was considered statistically significant.
Results In total, 432 non-duplicate adult patients with communityonset MRSA bacteraemia were identified during the study period. Thirty patients were excluded because their bloodstream isolates were not available for antimicrobial susceptibility testing. Eight patients were further excluded because of incomplete clinical data. Finally, 394 patients with MRSA bacteraemia met the enrolment criteria and were included. The mean age was 66.2 years (standard deviation, 16.2 years), and 60.9% of the patients were men. Fifty-six patients (14.2%) had MRSA bloodstream isolates with a vancomycin MIC 2 mg/L, including 2 patients with an MRSA vancomycin MIC value of 4 mg/L. The prevalence of high vancomycin MIC (2 mg/L) isolates of MRSA bacteraemia remained stable during the study period (2001e2006, 14.4% [26/180]; 2007e2011, 14.0% [30/214]; P Z 1.00).
Clinical characteristics and univariate analysis Clinical characteristics of the patients with high (MIC 2 mg/L, n Z 56) and low (MIC 1 mg/L, n Z 338) vancomycin MIC MRSA bacteraemia are detailed in Table 1. Univariate analysis identified a number of variables that were significantly associated with high vancomycin MIC MRSA infection, including end-stage renal disease, chronic liver disease, high (>5) Charlson comorbidity score, severe sepsis or septic shock on presentation, receiving haemodialysis, recent hospitalization within 3 months, recent exposure to any antibiotics within 3 months, prior vancomycin treatment within 1 year, and prior recovery of MRSA from blood or respiratory tract specimen in the past year.
Please cite this article in press as: Chen S-Y, et al., Predicting high vancomycin minimum inhibitory concentration isolate infection among patients with community-onset methicillin-resistant Staphylococcus aureus bacteraemia, J Infect (2014), http://dx.doi.org/10.1016/ j.jinf.2014.04.007
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S.-Y. Chen et al. Table 1 Clinical characteristics of 394 study patients with community-onset MRSA bacteraemia and univariate analysis for predictors of high vancomycin MIC MRSA isolates.
Age, mean (standard deviation) Age >65 years Male sex Comorbid medical condition Diabetes mellitus Malignancy End-stage renal disease Chronic liver disease Congestive heart failure Cerebrovascular accident Dementia Charlson score High Charlson score (>5) Tunnelled central line Non-tunnelled central line Thrombocytopenia Bandaemia >10% Severe sepsis or septic shock upon emergency department presentation Nursing home residence Haemodialysis Prior hospitalizationa Prior intensive care unit admissiona Prior intubationa Any antibiotic exposurea Prior vancomycin treatment In last week Within 1 year Prior recovery of MRSAb Blood Respiratory tract Wound or abscess Other sitesc
Vancomycin MIC 2 mg/L (n Z 56)
Vancomycin MIC 1 mg/L (n Z 338)
Univariate analysis
68.1 (14.9) 34 (60.7) 40 (71.4)
65.9 (16.4) 199 (58.9) 200 (59.2)
1.01 (0.99e1.03) 1.08 (0.61e1.93) 1.73 (0.93e3.20)
24 (42.9) 14 (25.0) 26 (46.4) 14 (25.0) 9 (16.1) 12 (21.4) 11 (19.6) 5.0 2.6 24 (42.9) 15 (26.8) 2 (3.6) 10 (17.9) 6 (10.7) 31 (55.4)
141 (41.7) 76 (22.5) 79 (23.4) 40 (11.8) 38 (11.2) 79 (23.4) 46 (13.6) 3.7 2.7 86 (25.4) 82 (24.3) 17 (5.0) 67 (19.8) 25 (7.4) 123 (36.4)
1.05 1.15 2.84 2.48 1.51 0.89 1.55 1.19 2.20 1.14 0.70 0.88 1.50 2.17
(0.59e1.86) (0.60e2.22) (1.59e5.09) (1.25e4.95) (0.69e3.33) (0.45e1.78) (0.75e3.22) (1.07e1.32) (1.23e3.94) (0.60e2.17) (0.16e3.11) (0.42e1.83) (0.59e3.85) (1.22e3.84)
0.873 0.678 <0.001 0.010 0.305 0.749 0.237 0.001 0.008 0.685 0.639 0.731 0.396 0.008
12 25 44 12 10 34
(21.4) (44.6) (78.6) (21.4) (17.9) (60.7)
52 (15.4) 81 (24.0) 201 (59.5) 49 (14.5) 31 (9.2) 143 (42.3)
1.50 2.56 2.50 1.61 2.15 2.11
(0.74e3.03) (1.43e4.58) (1.27e4.91) (0.79e3.26) (0.99e4.68) (1.18e3.76)
0.259 0.002 0.008 0.187 0.053 0.011
5 (8.9) 31 (55.4) 31 (55.4) 12 (21.4) 15 (26.8) 7 (12.5) 2 (3.6)
12 (3.6) 85 (25.1) 102 (30.2) 38 (11.2) 34 (10.1) 31 (9.2) 27 (8.0)
2.66 3.69 2.87 2.15 3.27 1.42 0.43
(0.90e7.88) (2.06e6.60) (1.61e5.10) (1.05e4.43) (1.64e6.52) (0.59e3.39) (0.10e1.85)
0.077 <0.001 <0.001 0.037 0.001 0.436 0.254
Odds ratio (95% CI)
P value 0.330 0.795 0.084
All values are expressed as n (%) unless otherwise noted. MRSA, methicillin-resistant Staphylococcus aureus; MIC, minimum inhibitory concentration. a Within 3 months before the index blood culture. b Within 1 year before the index blood culture. c Included urine (13), catheter tip (13) pleural effusion (1), ascites (1), and tissue culture (1).
Development of clinical risk score A multivariate logistic regression model that investigated all potential predictors on univariate analysis finally identified 6 independent predictors, including chronic liver disease, prior recovery of MRSA from respiratory tract specimen within 1 year, end-stage renal disease, severe sepsis or septic shock on presentation, prior vancomycin exposure within 1 year, and recent hospitalization within 3 months, for high vancomycin MIC MRSA infections (Table 2). The HosmereLemeshow goodness-of-fit statistic was 0.08, and the AUC for the model was 0.79 (95% CI, 0.72e0.85). Each independent predictor was then assigned one point to create a clinical scoring system because of the similar
b-coefficient values of these predictor variables. Overall scores for each of the patients with bacteraemia were calculated and evaluated for their performance in predicting a high vancomycin MIC isolate. The predictability of these collective scores was similar to that of individual predictor-weighted probabilities from the final multivariate logistic regression model (AUC, 0.78; 95% CI, 0.71e0.84). A summary of the diagnostic accuracy of the clinical risk score for the various score cutoff values is shown in Table 3. Youden index indicated that the clinical risk score performed best at a cutoff value of 3 points. The prevalence of high vancomycin MIC isolate infection among study patients with scores of 0, 1, 2, 3, and 4 was 2.3%, 4.4%, 9.7%, 31.1%, and 42.1%, respectively (Fig. 1).
Please cite this article in press as: Chen S-Y, et al., Predicting high vancomycin minimum inhibitory concentration isolate infection among patients with community-onset methicillin-resistant Staphylococcus aureus bacteraemia, J Infect (2014), http://dx.doi.org/10.1016/ j.jinf.2014.04.007
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Predicting high vancomycin MIC MRSA bacteraemia 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62
Table 2
5
Independent predictors of community-onset MRSA bloodstream infection with isolates of vancomycin MIC 2 mg/L.
Variable
b
P value
Adjusted odds ratio (95% CI)
Point value
Chronic liver disease Prior recovery of MRSA from respiratory tract specimen within 1 year End-stage renal disease Severe sepsis or septic shock on presentation Prior vancomycin exposure within 1 year Recent hospitalization within 3 months
1.10 0.93
0.005 0.021
2.99 (1.39e6.42) 2.54 (1.15e5.61)
1 1
0.93 0.87 0.79 0.75
0.004 0.006 0.020 0.046
2.53 2.39 2.21 2.11
1 1 1 1
(1.33e4.78) (1.28e4.44) (1.13e4.30) (1.01e4.40)
MRSA, methicillin-resistant Staphylococcus aureus; MIC, minimum inhibitory concentration.
Discussion In this ED-based study, a significant proportion of patients with MRSA bacteraemia were infected with high vancomycin MIC isolates even though these infections were in nonhospital environments, in which there is less prior antibiotic pressure. Several independent predictors of high vancomycin MIC MRSA isolate infection were identified and used to develop an easy-to-use scoring system to help clinicians with early identification of patients with MRSA bacteraemia at higher risk for treatment failure due to increased vancomycin resistance. Patients with MRSA bacteraemia are at particular risk for contracting high vancomycin MIC isolates with a score of 3 points. The risk score developed in the current study provides clinicians a scientific basis for decisions regarding empirical antibiotic therapy when treating patients in the community at risk for MRSA infections. There are increasing reports of MRSA isolates with elevated MICs of vancomycin in many institutions.7e9 The results of these studies, however, were based on analysis of clinical isolates that were mostly identified from hospitalized patients. The prevalence of MRSA isolates with elevated vancomycin MIC among patients with community-onset infections, to our knowledge, has never been studied. Because MRSA has become an important pathogen in the community, it is imperative for clinicians to understand the prevalence and risk factors of high vancomycin MIC MRSA infection among patients with community-onset infection. Furthermore, new evidence has shown the association between higher risk of mortality or treatment failure and MRSA infections with a vancomycin MIC 2 mg/L.29 Information about high vancomycin MIC MRSA infections in the community is therefore crucial for clinicians to determine appropriate empirical antimicrobial therapy and/or a more aggressive treatment strategy when treating patients with community-onset infections.
Previous studies have identified many risk factors, including old age,24 female sex,30 higher body mass index,30 cardiovascular disease,30 chronic liver disease,24 recent surgery,30 prior vancomycin exposure,24,31,32 history of MRSA bacteraemia or occurrence in the intensive care unit,24,32 and a non-tunnelled central line,24 that were independently associated with elevated vancomycin MIC. Most of these factors have been identified to be associated with prior exposure to vancomycin or nosocomial environment of high antimicrobial selection pressure.31,32 Lubin et al. further created a simple and useful decision rule for predicting high vancomycin MIC isolate infection in patients with MRSA bacteraemia.24 These studies, however, used clinical data that were predominantly from inpatients and were therefore limited in generalizing their results in the setting of community-onset infection. Our risk score, using clinical data exclusively from patients with community-onset MRSA bacteraemia, provides a useful tool for clinicians to effectively stratify patients in the community to their risk of high vancomycin MIC MRSA infection. As new anti-MRSA agents become available for the treatment of complicated or persistent MRSA infections,19 clinicians should consider alternative anti-MRSA antibiotics as empirical antimicrobial therapy for patients in the community at high risk for MRSA infection with an elevated vancomycin MIC. This study had some limitations. First, the clinical data on this observational cohort were retrospectively collected and therefore subject to information bias. Second, the prediction risk score in the current study was constructed only from clinical data of patients with MRSA bacteraemia. The predictability of our risk score in patients with MRSA infection at other sites remains to be examined. Third, this was a single-centre study conducted in northern Taiwan. The performance of our risk score in predicting high vancomycin MIC MRSA infection in other communities
Table 3 Accuracy of the prediction rule in the identification of high (2 mg/L) vancomycin MIC isolate infection among 394 patients with community-onset MRSA bacteraemia, stratified by cutoff values of the risk score. Cutoff value
Sensitivity, % (95% CI)
Specificity, % (95% CI)
Positive predictive value, % (95% CI)
Negative predictive value, % (95% CI)
Case (%) of entire cohort
Youden index
4 3 2 1
28.6 69.6 87.5 98.2
93.5 78.4 50.9 12.4
42.1 34.8 22.8 15.7
88.8 94.0 96.1 97.7
38 112 215 351
0.221 0.480 0.384 0.139
(18.4e41.5) (56.7e80.1) (76.4e93.8) (90.6e99.7)
(90.3e95.7) (73.7e82.5) (45.6e56.2) (9.3e16.4)
(27.9e57.8) (26.6e44.0) (17.7e28.9) (12.2e19.8)
(85.1e91.6) (90.6e96.2) (92.2e98.1) (87.9e99.6)
(9.6) (28.4) (54.6) (89.1)
MIC, minimum inhibitory concentration; MRSA, methicillin-resistant Staphylococcus aureus.
Please cite this article in press as: Chen S-Y, et al., Predicting high vancomycin minimum inhibitory concentration isolate infection among patients with community-onset methicillin-resistant Staphylococcus aureus bacteraemia, J Infect (2014), http://dx.doi.org/10.1016/ j.jinf.2014.04.007
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Figure 1 Percentage of community-onset MRSA bacteraemia due to isolates of vancomycin MIC 2 mg/L by total score. 9.
requires further validation. Finally, in areas where the prevalence of high vancomycin MIC MRSA infection among patients in the community is lower than the prevalence in our study, the application of our prediction risk score would result in a lower positive predictive value and a higher negative predictive value. Clinicians should consider this important influential factor when adopting our risk score in their decision making on empirical antibiotic therapy. In summary, a high prevalence of isolates with an elevated vancomycin MIC 2 mg/L among patients with community-onset MRSA bacteraemia was demonstrated in the current study, suggesting that the increasing resistance of MRSA isolates to vancomycin is no longer a hospitalspecific phenomenon. Certain risk factors were independently associated with elevated vancomycin MIC isolate infection among patients in the community with MRSA bacteraemia. A prediction tool incorporating these predictors that effectively stratifies patients in the community to their risk of high vancomycin MIC MRSA infection helps clinicians with early identification of patients at risk for vancomycin treatment failure and their decision making on empirical antibiotic therapy. Q1
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No funding source. 16.
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Please cite this article in press as: Chen S-Y, et al., Predicting high vancomycin minimum inhibitory concentration isolate infection among patients with community-onset methicillin-resistant Staphylococcus aureus bacteraemia, J Infect (2014), http://dx.doi.org/10.1016/ j.jinf.2014.04.007
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