Risk factors for mortality of nosocomial methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infection: With investigation of the potential role of community-associated MRSA strains

Journal of Infection (2010) 61, 449e457

www.elsevierhealth.com/journals/jinf

Risk factors for mortality of nosocomial methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infection: With investigation of the potential role of community-associated MRSA strains Jann-Tay Wang a, Jiun-Ling Wang b, Chi-Tai Fang a,c, Wei-Chu Chie d, Mei-Shu Lai d, Tsai-Ling Lauderdale e, Chia-Min Weng a, Shan-Chwen Chang a,f,* a

Department of Internal Medicine, National Taiwan University Hospital, No. 7 Chung-Shan South Road, Taipei 100, Taiwan Department of Internal Medicine, E-Da Hospital / I-Shou University, Kaohsiung County 824, Taiwan c Graduate Institute of Epidemiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan d Graduate Institute of Preventive Medicine, College of Public Health, College of Medicine, National Taiwan University, Taipei 100, Taiwan e Division of Clinical Research, National Health Research Institute, Zhunan 350, Taiwan f Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, Taipei 100, Taiwan b

Accepted 17 September 2010 Available online 25 September 2010

KEYWORDS Multilocus sequence typing; Staphylococcal cassette chromosome mec; Vancomycin

Summary Objectives: The difference in the outcomes of nosocomial bloodstream infection (BSI) caused by community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) strains and healthcare-associated MRSA (HA-MRSA) strains remains unclear. Methods: From January 1, 2006 to December 31, 2008, all adult patients hospitalized at National Taiwan University Hospital with nosocomial MRSA BSI were analyzed. Available MRSA isolates were submitted for subsequent microbiologic studies to determine whether they belonged to CA-MRSA strains. Results: In total, 308 patients were enrolled and 253 MRSA isolates were available. Forty-seven isolates belonged to CA-MRSA strains. The all-cause mortality rates on Day 14 and Day 30 were 19.8% and 30.5%, respectively, and were not different between those caused by CA-MRSA and HA-MRSA strains. The independent risk factors for Day 14 mortality were septic shock, thrombocytopenia, and an inadequate serum trough level of vancomycin (p Z <0.0001, 0.0003, and 0.0381, respectively). Those for Day 30 mortality were septic shock, anemia, thrombocytopenia,

* Corresponding author. Department of Internal Medicine, National Taiwan University Hospital, No. 7 Chung-Shan South Road, Taipei 100, Taiwan. Tel.: þ886 2 23123456x65401; fax: þ886 2 23958721. E-mail address: [email protected] (S.-C. Chang). 0163-4453/$36 ª 2010 The British Infection Association. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jinf.2010.09.029

450

J.-T. Wang et al. presence of underlying malignancies, and MRSA isolates with a vancomycin minimum inhibitory concentration of 2 mg/L (p Z <0.0001, 0.0425, 0.0007, 0.0098, and 0.0012, respectively). Conclusions: The mortality rates of nosocomial MRSA BSI were not different between that caused by CA-MRSA and HA-MRSA strains. ª 2010 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Introduction Beginning in the 1990s, a version of methicillin-resistant Staphylococcus aureus (MRSA) capable of causing infection among previously healthy persons in the community setting instead of nosocomial acquisition was noted,1,2 and was termed community-associated MRSA (CA-MRSA) infection. The nosocomial version, which causes infection in hospitalized patients with specific risk factors, was accordingly designated healthcare-associated MRSA (HA-MRSA).3 Strains causing CA-MRSA infections have several phenotypic and genetic features which are different from those causing HA-MRSA infections.4,5 CA-MRSA strains carry the type IV or type V staphylococcal cassette chromosome mec (SCCmec) element, are usually Panton-Valentine leukocidin (PVL)-producing, and are not multidrug resistant; HA-MRSA strains carry the type I, II, or III SCCmec element, are usually not PVL-producing, and are multidrug resistant.3,6,7 Since their detection, CA-MRSA strains have become important pathogens both in community and hospital environments.8e11 In the community setting, CA-MRSA strains have contributed to the majority of the increase of community-acquired S. aureus infection.8,9 In the hospital setting, an increasing number of nosocomial infections caused by CA-MRSA strains have been reported during the past decades.10,11 Prior reports showed that presence of the type IV or V SCCmec element and PVL gene was useful molecular markers of CA-MRSA strains.3,7,12 In Taiwan, CA-MRSA strains were found to be of sequence type (ST) 59, which was determined by multilocus sequence typing (MLST), carrying the type IV or VT SCCmec element, and PVL gene initially.13,14 Subsequent studies, however, showed that CAMRSA strains in Taiwan, especially those carried the type IV SCCmec element, did not always harbor PVL gene.15,16 These CA-MRSA strains have been responsible for the increase of community-acquired S. aureus infection and have expanded into the hospital environment.17e20 Among the clinical syndromes caused by MRSA, bloodstream infection (BSI) is of special concern because of its association with significant morbidity and mortality.21e23 Although the mortality of nosocomial MRSA BSI has been well discussed in prior studies, those studies were conducted in the era before expansion of CA-MRSA strains into the hospital environment or did not consider the possibility that nosocomial MRSA BSI caused by CA-MRSA strains would associate with a significantly different outcome from that caused by HA-MRSA strains.21e24 CA-MRSA strains have purported superior fitness (other than resistance to antibiotics) over HA-MRSA strains and some CA-MRSA isolates carry the virulence factor PVL.19 Therefore, there is a possibility that nosocomial MRSA BSI caused by CA-MRSA strains is associated with a significantly different outcome

from that caused by HA-MRSA strains. This study was conducted to investigate this issue.

Materials and methods Patients and data collection From January 1, 2006 to December 31, 2008, all adult patients (age > 18 years) hospitalized at National Taiwan University Hospital (NTUH; a major teaching hospital located in northern Taiwan with a capacity of 2200 beds), with nosocomial MRSA BSI and without concomitant infection caused by other microorganisms were retrospectively enrolled in this study. Nosocomial MRSA BSI was defined as more than one culture from a blood specimen, taken in the presence of fever (body temperature  38  C) and 48 h after admission, yielding MRSA.25 Only patients who developed the first episode of MRSA BSI during the study period were enrolled. The blood isolates obtained from the Department of Laboratory Medicine at NTUH were preserved for subsequent microbiological examination. A standardized case report form was used to collect patients’ demographic, clinical, and routine laboratory data. These data included age, sex, the primary focus of MRSA BSI, severity of infection (shock or not within 24 h of onset),26 underlying diseases, Charlson comorbidity index,27 and immune status28 at the onset of MRSA BSI. Laboratory data from serum or blood collected 24 h before and/or after onset of MRSA BSI included the levels of albumin, C-reactive protein (CRP), creatinine, alanine aminotransferase, lactate dehydrogenase, hemoglobin, the leukocytes count, and the platelet count. The endpoints were all-cause mortality on Day 14 and Day 30. This study was approved by Institutional Review Board at NTUH (NTUH-200705068R).

Definitions Hypoalbuminemia was defined as a serum albumin level 3.5 g/L. Abnormal renal function was defined as a serum creatinine level 1.4 mg/dL. Abnormal liver function was defined as a serum alanine aminotransferase level exceeding 41 U/L. The upper limit of the normal serum lactate dehydrogenase level was 460 U/L. Anemia was defined as a hemoglobin level 11 g/dL. An abnormal leukocyte count was defined as 11,000/mL or 4000/mL. Thrombocytopenia was defined as a platelet count 150,000/mL. The effective antibiotics were defined as parenteral antibiotics to which the causative MRSA isolates were susceptible.29 An inadequate serum trough level of vancomycin was defined as a vancomycin trough level being <15 mg/L tested within one week after onset of MRSA BSI and after at least three days of treatment with vancomycin.

Nosocomial BSI by CA-MRSA strains CA-MRSA strains were defined as belonging to ST59 and carrying the type IV or VT SCCmec element in this study. Otherwise were considered as HA-MRSA strains.15,16

Determination of minimum inhibitory concentration (MIC) MICs of all available MRSA isolates to clindamycin, erythromycin, trimethoprim/sulfamethoxazole, gentamicin, minocycline, ciprofloxacin, rifampin, vancomycin, teicoplanin, and linezolid were determined using the Clinical and Laboratory Standards Institute (CLSI) agar dilution method.30 In brief, a Steers’ replicator was used to apply 104 CFUs of bacteria onto MuellereHinton agar containing serial twofold dilutions of each antimicrobial agent (0.03e256 mg/ L). The agar plates were incubated at 35  C for 18 h (24 h for vancomycin) before reading. The MIC was defined as the lowest concentration of antimicrobial agents completely inhibiting the growth of bacteria. S. aureus ATCC 29213 was used as the internal control in each test. The breakpoints used for reading as susceptible were those defined by the CLSI.31

Molecular typing and detection of the PVL gene Chromosomal DNA was prepared as described previously.32 The presence of the PVL gene lukF-lukS was determined by polymerase chain reaction (PCR) with use of a primer as described elsewhere.4 Typing of the SCCmec elements and the mecA gene was performed as previously described,6,7,12 and MLST was also performed as previously described.33

Statistical analyses Continuous variables were described as mean  standard deviation (SD) and compared using Student’s t test, or described as the median as well as range and compared with the Wilcoxon rankesum test if their distributions were not normal. Categorical variables were compared with a chi-square test or Fisher exact test if the expected values were below 10. Risk factors for all-cause Day 14 and Day 30 mortalities were identified using a logistic regression model. All parameters were initially tested by univariate analysis and those with a p value <0.05 were used for multivariate analysis. Parameters with colinearity were not simultaneously considered in the final model. Stepwise model comparison and Akaike’s information criterion were used to determine the best model of multiple variables analysis. Statistical analyses were performed using SAS 9.1.3 (SAS Institute, Cary, NC, USA). All tests were two-tailed and a p value <0.05 was considered statistically significant.

Results There were 308 patients with nosocomial MRSA BSI enrolled during the three-year study period. The male to female ratio was 200:108. The age distribution was 61.6  24.2 years. Among the 308 patients, 137 patients developed

451 nosocomial MRSA BSI in intensive care units (ICUs) and 171 in general wards. In addition, 21 patients were found to have infective endocarditis, and 12 were found to be with osteomyelitis. One hundred and twenty-nine patients had prostheses when they developed MRSA BSI, including mechanical valves (n Z 7), vascular grafts (n Z 121), and orthopedic prostheses (n Z 4). Three patients had two types of prostheses. Seventy-nine of these 129 patients were complicated with prosthesis infection. The primary foci included the urinary tract (n Z 13), respiratory tract (n Z 42), surgical wounds (n Z 8), skin (n Z 17), intra-abdomen (n Z 10), intravascular catheters or vascular grafts (n Z 127), and no obvious primary foci (n Z 134). The Charlson comorbidity index at the onset of BSI was 7.5  6.0. One hundred and twenty-nine patients developed septic shock within 24 h of the onset of BSI. Every patient had one or more underlying diseases (Table 1). The laboratory data at the onset of the BSI episodes are summarized in Table 1. Abnormal white blood cell counts, anemia, thrombocytopenia, hypoalbuminemia, abnormal liver function tests, abnormal renal function, and elevated lactate dehydrogenase levels were noted in 195, 142, 148, 25, 74, 127, and 22 patients, respectively. Effective antibiotics were started within 48 h of the onset of BSI in 255 patients (vancomycin in 209 patients, and teicoplanin in 46 patients). The first effective antibiotic used to treat MRSA BSI included vancomycin in 252 patients, teicoplanin in 55 patients, and linezolid in one patient. Only 196 patients had tests for the serum level of vancomycin within one week after the onset of MRSA BSI. Among them, 73 patients had an inadequate serum trough level of vancomycin. The all-cause mortality rate was 19.8% (61 deaths) on Day 14 and 30.5% (94 deaths) on Day 30 (Table 1). A total of 253 MRSA isolates were available for microbiological analysis. The distribution of the vancomycin MIC was 0.5 mg/L in 10 isolates, 1 mg/L in 190 isolates, and 2 mg/L in 53 isolates. MLST showed that 149 isolates were ST239, 47 isolates were ST59, 46 isolates were ST5, and 11 isolates belonged to other sequence types. All ST239 isolates carried the type III SCCmec element. Twenty-nine of the 47 ST59 isolates carried the type IV SCCmec element, and 10 of them carried the PVL gene. Eighteen of the 47 ST59 isolates carried the type VT SCCmec element, and all of them carried the PVL gene. All 46 ST5 isolates carried the type II SCCmec element. Among the 11 isolates belonging to other minor sequence types, five carried the type III SCCmec element and six carried the type II SCCmec element. Forty-seven isolates were considered CA-MRSA strains. All CA-MRSA isolates had a vancomycin MIC 1 mg/L (0.5 mg/L, eight isolates; 1 mg/L, 39 isolates). Among the 206 HA-MRSA isolates, 153 had a vancomycin MIC 1 mg/L (0.5 mg/L, two isolates; 1 mg/L, 151 isolates) and 53 had a MIC of 2 mg/L. The susceptibilities of CA-MRSA isolates to clindamycin, erythromycin, trimethoprim/sulfamethoxazole, gentamicin, minocycline, ciprofloxacin, rifampin, teicoplanin, and linezolid were 14.9%, 12.8%, 97.9%, 74.5%, 97.9%, 100%, 100%, 100%, and 100%, respectively. The corresponding susceptibilities of the HA-MRSA isolates were 10.7%, 10.2%, 19.4%, 3.9%, 0%, 0%, 100%, 100%, and 100%, respectively (Table 2).

452

J.-T. Wang et al. Table 1 (continued )

Table 1 Demographic, clinical, laboratory, and microbiologic data of the 308 patients with MRSA BSIs. Parameter

No. (%)

Age (years) (mean  SD)

61.6  24.2

Sex (male/female)

200 (64.9%)/108 (35.1%)

Charlson comorbidity index (mean  SD)

7.5  6.0

Parameter

No. (%)

Endocrinologic diseases Yes No

119 (38.6%) 189 (61.4%)

Malignancies Yes No

108 (35.1%) 200 (64.9%)

Autoimmune diseases Yes No

18 (5.8%) 290 (94.2%)

Immunosuppression Yes No

119 (38.6%) 189 (61.4%)

White blood cell count Leucopenia Normal count Leukocytosis

38 (12.4%) 112 (36.5%) 157 (51.1%)

Anemia Yes No

142 (46.3%) 165 (52.7%)

Thrombocytopenia Yes No

148 (48.2%) 159 (51.8%)

Hypoalbuminemia Yes No

25 (17.7%) 116 (82.3%)

Abnormal liver function test Yes No

74 (36.5%) 129 (63.5%)

CRP (mean  SD)

3.43  2.93 (mg/dL)

Primary focus of bacteremia Urinary tract Respiratory tract Surgical wound Skin Intra-abdominal Intravenous catheter No obvious focus

13 (3.7%) 42 (12.0%) 8 (2.3%) 17 (4.8%) 10 (2.9%) 127 (36.2%) 134 (38.2%)

Location ICU General ward

137 (44.5%) 171 (55.5%)

Presence of prosthesis Mechanical valve Vascular graft Orthopedic prosthesis No prosthesis

7 (2.3%) 121 (38.9%) 4 (1.3%) 179 (57.6%)

Infection of prosthesis Yes No

79 (61.2%) 50 (38.8%)

Metastatic focus of bacteremia Infective endocarditis Osteomyelitis No known

21 (6.8%) 12 (3.9%) 274 (89.3%)

Septic shock while onset Yes No

129 (41.9%) 179 (58.1%)

Cardiovascular diseases Yes No

Abnormal renal function Yes No

127 (43.0%) 168 (57.0%)

191 (62.0%) 117 (38.0%)

Respiratory diseases Yes No

Elevated lactate dehydrogenase Yes No

22 (73.3%) 8 (26.7%)

78 (25.3%) 230 (74.7%)

Neurologic diseases Yes No

Effective treatment within 48 h Yes No

255 (82.8%) 53 (17.2%)

67 (21.8%) 241 (78.3%)

Gastrointestinal tract diseases Yes No

57 (18.5%) 251 (81.5%)

Initial effective treatment Vancomycin Teicoplanin Linezolid

252 (81.8%) 55 (17.9%) 1 (0.3%)

Chang of antibiotics during therapy Yes No

52 (16.9%) 256 (83.1%)

Inadequate trough vancomycin level

73 (37.2%, only 196 tested)

Day 14 all-cause death

61 (19.8%)

Day 30 all-cause death

94 (30.5%)

Hepatobiliary tract diseases Yes No

65 (21.1%) 243 (78.9%)

Genitourinary tract diseases Yes No

115 (37.3%) 193 (62.7%)

Nosocomial BSI by CA-MRSA strains

453 By multivariate analysis, septic shock, thrombocytopenia, and an inadequate serum trough level of vancomycin were independent risk factors for Day 14 mortality (odds ratio (OR): 5.34, 6.71, and 3.39, respectively; 95% confidence interval (C.I.): 1.59e17.97, 1.42e31.25, and 1.07e10.72, respectively; p value: <0.0001, 0.0003, and 0.0381, respectively); septic shock, presence of underlying malignancies, anemia, thrombocytopenia, and MRSA isolates with a vancomycin MIC of 2 mg/L were independent risk factors for Day 30 mortality (OR: 8.11, 2.49, 2.03, 3.34, and 3.69, respectively; 95% C.I.: 4.06e16.19, 1.25e4.97, 1.03e4.03, 1.66e6.76, and 1.67e8.14, respectively; p value: <0.0001, 0.0098, 0.0425, 0.0007, and 0.0012, respectively). Infection caused by CA-MRSA strains was not a significant risk factor for either Day 14 or Day 30 mortality.

Table 1 (continued ) Parameter

No. (%)

SCCmec II III IV VT

52 (20.6%) 154 (60.9%) 29 (11.5%) 18 (7.1%)

Carriage of PVL gene Yes No

28 (11.1%) 225 (88.9%)

Sequence type by MLST ST239 ST59 ST5 Others

149 (58.9%) 47 (18.6%) 46 (18.2%) 11 (4.3%)

MIC of vancomycin 0.5 mg/L 1 mg/L 2 mg/L

Discussion 10 (3.9%) 190 (75.1%) 53 (21.0%)

The characteristics of patients stratified by the causative CA-MRSA and HA-MRSA strains are summarized in Table 3. Patients infected by CA-MRSA strains were more likely to be female, have a higher Charlson comorbidity index, and have underlying malignancies; less likely to develop MRSA BSI in ICU, have metastatic foci, and have underlying cardiovascular diseases. No differences in mortality rates were noted between these two groups of patients on Day 14 and Day 30. Age, septic shock, presence of underlying hepatobiliary disease, thrombocytopenia, abnormal renal function, failure to receive effective antibiotics within 48 h, an inadequate serum trough level of vancomycin, and MRSA isolates with a vancomycin MIC of 2 mg/L were risk factors for all-cause Day 14 mortality determined by univariate analysis (Table 4). Age, septic shock, presence of underlying malignancies, thrombocytopenia, abnormal renal function, and MRSA isolates with a vancomycin MIC of 2 mg/L were risk factors for all-cause Day 30 mortality determined by univariate analysis (Table 4).

Table 2

The present study demonstrates that nosocomial MRSA BSI caused by CA-MRSA strains is not associated with a different outcome compared to that caused by HA-MRSA strains (in terms of all-cause Day 14 and Day 30 mortalities). CA-MRSA strains accounted for 18.6% of all nosocomial MRSA BSI during the study period. Septic shock and thrombocytopenia at presentation, as well as an inadequate serum trough level of vancomycin within one week after onset of MRSA BSI were independent risk factors for all-cause Day 14 mortality. Septic shock, anemia, and thrombocytopenia at presentation, presence of underlying malignancies, as well as a causative MRSA isolate with a vancomycin MIC of 2 mg/ L were independent risk factors for all-cause Day 30 mortality. The mortality rate of MRSA BSI is reported to range from 20% to 50%.24,34e36 Our study revealed a similar result. The risk factors for mortality in patients with MRSA BSI reported in previous studies include old age, delay in effective therapy, immunosuppressive status, advanced underlying diseases, and septic shock at presentation.17,23,24 Our present study showed similar findings. Recent reports recommended that trough serum vancomycin concentrations should be maintained at 15e20 mg/L during treatment of MRSA infection using vancomycin.37,38

MICs (mg/L) to the various antimicrobial agents stratified by HA- and CA-MRSA.

Antimicrobial agents

CA-MRSA

HA-MRSA

MIC range

MIC50

MIC90

S%

MIC range

MIC50

MIC90

S%

Clindamycin Erythromycin SXT Gentamicin Minocycline Ciprofloxacin Rifampin Vancomycin Teicoplanin Linezolid

0.125e>128 0.125e>128 0.25/4.75e4/76 0.25e>128 0.125e4 0.125e1 0.001875e1 0.5e1 0.5e4 0.25e4

>128 >128 0.5/9.5 0.5 2 0.5 0.0075 1 1 1

>128 >128 2/38 128 4 1 1 1 2 2

14.9% 12.8% 97.9% 74.5% 97.9% 100% 100% 100% 100% 100%

0.125e>128 0.25e>128 0.5/9.5e>128/2432 0.25e>128 16e128 2e>128 0.001875e1 0.5e2 0.5e4 0.25e4

>128 >128 16/304 >128 32 64 0.0075 1 1 1

>128 >128 >128/2432 >128 128 >128 1 2 2 2

10.7% 10.2% 19.4% 3.9% 0 0 100% 100% 100% 100%

Abbreviation: SXT, trimethoprim/sulfamethoxazole; S, susceptible rate.

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J.-T. Wang et al.

Table 3

Patients’ characteristics stratified by type of causative MRSA isolates.

Variables

CA-MRSA (n Z 47) (%)

HA-MRSA (n Z 206) (%)

p value

Age (years) (mean  SD) Sex (male/female) Charlson comorbidity index (mean  SD) Onset in ICU Presence of metastatic foci Septic shock Primary bacteremia Presence of prosthesis Prosthesis with infection Cardiovascular diseases Respiratory diseases Neurologic diseases Gastrointestinal tract diseases Hepatobiliary diseases Genitourinary tract diseases Endocrinologic diseases Malignancies Autoimmune diseases Immunosuppression Abnormal WBC count Anemia Thrombocytopenia Hypoalbuminemia Abnormal liver function test Abnormal renal function CRP (mean  SD) Elevation of lactate dehydrogenase Effective treatment within 48 h Inadequate trough vancomycin levela Day 14 mortality Day 30 mortality

59.8  20.8 21/26 (44.7%/55.3%) 4.5  3.5 9 (19.1%) 1 (2.1%) 14 (29.8%) 36 (76.6%) 17 (36.2%) 10 (21.3%) 20 (42.6%) 8 (17.0%) 7 (14.9%) 11 (23.4%) 14 (29.8%) 15 (31.9%) 18 (38.3%) 23 (48.9%) 4 (8.5%) 21 (44.7%) 28 (59.6%) 29 (61.7%) 25 (53.2%) 12 (25.5%) 24 (51.1%) 29 (61.7%) 7.0  5.7 1 (2.1%) 38 (80.9%) 10 (31.3%) 7 (14.9%) 12 (25.5%)

64.3  22.3 141/65 (68.4%/31.6%) 3.1  2.5 103 (50.0%) 27 (13.1%) 87 (42.2%) 156 (75.7%) 87 (42.2%) 57 (27.7%) 141 (68.4%) 57 (27.7%) 49 (23.8%) 34 (16.5%) 37 (18.0%) 79 (38.3%) 87 (42.2%) 60 (29.1%) 12 (5.8%) 79 (38.3%) 126 (61.2%) 110 (53.4%) 99 (48.1%) 88 (42.7%) 79 (38.3%) 110 (53.4%) 7.4  5.8 5 (2.4%) 174 (84.5%) 56 (42.1%) 40 (19.4%) 64 (31.1%)

0.2081 0.0022 0.0093 0.0001 0.0298 0.1159 0.9002 0.4459 0.3701 0.0009 0.1316 0.1851 0.2644 0.0682 0.4101 0.6213 0.0091 0.4949 0.4231 0.8106 0.3173 0.5446 0.0793 0.9044 0.3929 0.7084 0.4782 0.5439 0.2604 0.4718 0.4550

a

Only 32 patients with CA-MRSA BSI had serum vancomycin level and 133 patients with HA-MRSA BSI had serum vancomycin level.

Our present study also demonstrated that an inadequate serum trough level of vancomycin (<15 mg/L) within one week after onset of MRSA BSI was an independent risk factor for Day 14, but not Day 30, all-cause mortality. Other factors may have played more important roles in Day 30 mortality. Some prior studies demonstrated that a delay in effective treatment (no effective antibiotics against MRSA within 48 h after onset of MRSA BSI) was not a significant risk factor for mortality.23,29,39 If the factor of an inadequate serum trough level of vancomycin had not been in the final model for multivariate analysis in the present study, then a delay in effective treatment would have been an independent risk factor for Day 14 all-cause mortality (OR: 4.79; 95% C.I.: 1.66e13.82). However, with the inadequate serum trough level of vancomycin in the final model, a delay in treatment was no longer an independent risk factor for Day 14 mortality. This seems to imply that an early achievement of adequate serum trough level of vancomycin is more important than just early introduction of vancomycin. A routine method for determination of serum teicoplanin level was not available in Taiwan during the study period. Septic shock and thrombocytopenia immediately after development of MRSA BSI were indicators of the severity of

MRSA BSI. Therefore, it was reasonable that these two factors were associated with a poor outcome in both Day 14 and Day 30 mortalities. Similar findings have been reported previously.18,23,24 Presence of underlying malignancies represented the unfavorable underlying conditions and was therefore a risk factor for mortality due to MRSA BSI as described in previous reports.18,23,24 However, in the present study, it was not a risk factor for Day 14 mortality. This might imply that presence of underlying malignancies contribute more to long-term outcomes, but not to outcomes evaluated at the more acute phase. Causative MRSA isolates with a vancomycin MIC of 2 mg/ L were revealed to be a significant risk factor for Day 30 allcause mortality in our study, in which most (252/308) patients received vancomycin as their initial treatment. Previous studies showed that patients with MRSA infection, of which the causative MRSA isolate had a vancomycin MIC 2 mg/L, might have prolonged bacteremia and poor outcomes even when treated with vancomycin (vancomycin treatment failure).21,22 A consensus on the therapeutic monitoring of vancomycin suggested that vancomycin should not be used in patients with an infection caused by MRSA with a vancomycin MIC 2 mg/L, and alternatives,

Nosocomial BSI by CA-MRSA strains Table 4

455

Univariate analysis for risk factors for Day 14 and Day 30 mortalities of nosocomial MRSA BSI.

Variables

Age Sex Charlson comorbidity index Onset in ICU Presence of metastatic foci Septic shock Primary bacteremia Presence of prosthesis Prosthesis with infection Cardiovascular diseases Respiratory diseases Neurologic diseases Gastrointestinal tract diseases Hepatobiliary diseases Genitourinary tract diseases Endocrinologic diseases Malignancies Autoimmune diseases Immunosuppression Abnormal white blood cell count Anemia Thrombocytopenia Hypoalbuminemia Abnormal liver function Abnormal renal function C-reactive protein Elevation of lactate dehydrogenase Without effective treatment within 48 h Initial treatment: vancomycin vs. others Inadequate trough vancomycin level SCCmec element Type II vs. type IV or VT Type III vs. type IV or VT Causative MRSA carrying PVL CA-MRSA vs. HA-MRSA MRSA vancomycin MIC Z 2 mg/L

Day 14 mortality

Day 30 mortality

OR

p value

OR

p value

1.02 1.37 1.05 1.38 1.10 14.91 0.53 0.96 2.02 0.93 0.95 0.97 1.59 1.98 1.44 0.67 1.37 0.80 1.72 1.34 1.55 5.71 1.92 1.19 1.92 1.04 3.27 2.70 0.69 5.11

0.0157 0.3111 0.2611 0.2669 0.8380 <0.0001 0.0868 0.8740 0.0604 0.8073 0.8829 0.9260 0.1744 0.0339 0.2131 0.1817 0.2804 0.7311 0.0605 0.3347 0.1364 <0.0001 0.2664 0.6063 0.0268 0.1143 0.3087 0.0441 0.2479 0.0030

1.02 1.22 1.08 1.56 0.98 11.70 0.62 0.92 1.57 1.05 1.02 0.88 1.72 1.58 0.99 0.86 1.81 0.64 1.44 1.25 1.60 4.74 2.49 1.01 2.08 1.05 2.50 1.43 0.88 1.42

0.0029 0.4429 0.0644 0.0743 0.9668 <0.0001 0.1181 0.7312 0.1284 0.8571 0.9557 0.6642 0.0761 0.1191 0.9801 0.5559 0.0198 0.4347 0.1496 0.3979 0.0642 <0.0001 0.0711 0.9711 0.0041 0.0505 0.3203 0.2997 0.6949 0.3227

1.21 0.89 0.71 0.73 2.36

0.6515 0.7213 0.6630 0.4734 0.0164

1.30 1.13 1.30 0.76 2.89

0.4847 0.6660 0.6495 0.4560 0.0009

such as daptomycin and linezolid, should be considered.38 Our study provides additional evidence for this suggestion. An MRSA isolate with a vancomycin MIC of 2 mg/L was not a significant factor for Day 14 mortality of nosocomial MRSA BSI in our study. No prior study has discussed this issue directly. It is possible that these isolates are associated with prolonged bacteremia when treated with vancomycin,21,22 and would not be associated with early mortality (Day 14 mortality) as vancomycin treatment still might have a partial effect. Nosocomial MRSA BSI caused by CA-MRSA strains was not associated with a different outcome from that caused by HA-MRSA strains in our present study. However, 53 HA-MRSA isolates had a vancomycin MIC of 2 mg/L. No CA-MRSA isolates had a vancomycin MIC >1 mg/L. Therefore, a subgroup analysis stratified by vancomycin MIC was conducted to avoid a possible confounding effect between these two factors. One hundred and fifty-three episodes caused by HA-MRSA strains with vancomycin MICs 1 mg/L were

compared to the 47 episodes caused by CA-MRSA strains. Infection caused by CA-MRSA strains was still not a significant factor associated with Day 14 or Day 30 mortality in this subgroup analysis (OR: 0.94 and 1.04, respectively; 95% C.I.: 0.38e2.35 and 0.49e2.20; p value: 0.8955 and 0.9229, respectively). Although we stratified the CA-MRSA strains further into those carrying and not carrying the PVL gene, the CA-MRSA strains were still not a significant factor associated with mortality (Day 14 mortality: OR Z 0.70 and 0.66, respectively; 95% C.I. Z 0.15e3.26 and 0.24e1.79, respectively; Day 30 mortality: OR Z 1.36 and 0.57, respectively; 95% C.I. Z 0.43e4.30 and 0.24e1.35, respectively). The major limitation in our study was the retrospective design. This might have led to loss or misclassification of information and also the exclusion of 55 causative MRSA isolates for subsequent microbiological studies. The relatively small number of cases of MRSA BSI caused by CA-MRSA strains might also have compromised the statistic power. However, our study was the first to directly consider the

456 potential role of CA-MRSA strains in the outcome of nosocomial MRSA BSI and point out the possibility that nosocomial MRSA BSI caused by CA-MRSA stains might not be associated with a different outcome from that caused by HA-MRSA strains. Our study could be the basis of subsequent large-scale investigation. In conclusion, infection caused by CA-MRSA strains was not a significant factor associated with the mortality of nosocomial MRSA BSI when compared to HA-MRSA strains in the present study. This might imply that differentiating CA-MRSA from HA-MRSA strains in nosocomial MRSA BSI is not necessary in current situations. In this study, septic shock and thrombocytopenia at presentation, as well as an inadequate serum trough level of vancomycin within one week after onset of MRSA BSI were independent risk factors for all-cause Day 14 mortality. Septic shock, anemia, and thrombocytopenia at presentation, presence of underlying malignancies, and a causative MRSA isolate with a vancomycin MIC of 2 mg/L were independent risk factors for allcause Day 30 mortality.

J.-T. Wang et al.

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Acknowledgements

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This study was supported by the National Science Council, Taiwan (NSC 95-2314-B-002-250-MY2). The authors have no conflicts of interest.

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