Persistent Staphylococcus aureus Bacteremia

Persistent Staphylococcus aureus bacteremia (SAB) that fails to respond to appropriate antibiotic therapy is associated with poor outcomes. Comprehensive prospective studies on risk factors and outcomes of persistent bacteremia are limited. We investigated outcomes and risk factors encompassing clinical, pharmacokinetic, microbiologic, and genotypic characteristics associated with persistent bacteremia using a case-control study nested in a prospective cohort of patients with SAB at a tertiary-care hospital from August 2008 through September 2010. We compared the clinical characteristics, management, and outcomes of patients with persistent bacteremia (Q7 d) with controls with resolving bacteremia (G3 d). To detect associations between microbiologic and genotypic characteristics of methicillin-resistant S. aureus (MRSA) isolates and persistent bacteremia, we determined the heteroresistance phenotype, SCCmec type, agr genotype and functionality, multilocus sequence typing, and presence of 41 virulence genes. Our cohort consisted of 483 patients; 76 (15.7%) had persistent bacteremia, 212 (43.5%) had resolving bacteremia. In the multivariate analysis, independent risk factors associated with persistent bacteremia were community-onset bacteremia (odds ratio EOR^, 2.91; 95% confidence interval ECI^, 1.24Y6.87), bone and joint infection (OR, 5.26; 95% CI, 1.45Y19.03), central venous catheter-related infection (OR, 3.36; 95% CI, 1.47Y7.65), metastatic infection (OR, 36.22; 95% CI, 12.71Y103.23), and methicillin resistance (OR, 16.99; 95% CI, 5.53Y52.15). For patients with eradicable foci, delay (93 d) in the removal of the infection focus was significantly associated with persistent bacteremia (OR, 2.18; 95% CI, 1.05Y4.55). There were no significant associations of persistent bacteremia with high vancomycin minimal inhibitory concentration, vancomycin heteroresistance, and microbiologic/genotypic characteristics of MRSA isolates. However, initial vancomycin trough level G15 mg/L was an independent risk factor for persistent MRSA bacteremia (OR, 4.25; 95% CI, 1.51Y11.96) in the multivariate analysis. Clinical outcomes were significantly worse for patients with persistent bacteremia. Relapse of bacteremia and attributable mortality within 12 weeks after SAB were significantly higher in patients with persistent bacteremia than in those with resolving bacteremia (9.2% E7/76^ vs. 2.4% E5/212^, p = 0.02 and 21.1% E16/76^ vs. 9.4% E20/212^, p = 0.009, respectively). In conclusion, patients with SAB should be given early aggressive treatment strategies, including early source control and maintenance of a vancomycin trough level Q15 mg/L, to reduce the risk of persistent bacteremia. (Medicine 2013;92: 98Y108) Abbreviations: AUC = area under the curve, CCs = clonal complexes, CI = confidence interval, CVC = central venous catheter, hVISA = heteroresistant vancomycin-intermediate Staphylococcus aureus, IQR = interquartile range, MIC = minimal inhibitory concentration, MLST = multilocus sequence typing, MRSA = methicillin-resistant Staphylococcus aureus, OR = odds ratio, SAB = Staphylococcus aureus bacteremia. INTRODUCTION S taphylococcus aureus bacteremia (SAB) is one of the most common serious bacterial infections, with an associated mortality of about 30%. SABmay persist in some patients despite several days of antibiotic therapy, a phenomenon called persistent bacteremia. Persistent bacteremia accounts for 6%Y38% of all episodes of SAB, is particularly common in endovascular infections, and is associated with poor clinical outcomes. The prevalence of persistent bacteremia may differ depending on the duration of bacteremia used to define ‘‘persistent bacteremia.’’ Early aggressive treatment strategies may reduce the morbidity and mortality of patients with risk factors for persistent bacteremia. A comprehensive analysis is needed to investigate various factors associated with persistent bacteremia. A 2007 retrospective study identified methicillin resistance, use of an intravascular catheter or other medical device, chronic renal failure, multiple sites of infection, and infective endocarditis as risk factors for persistent bacteremia. In other studies, vancomycin treatment, diabetes, retention of implicated devices, and methicillin-resistant S. aureus (MRSA) with vancomycin minimal inhibitory concentration (MIC) of 2 mg/L were also implicated. However, these studies are limited by their retrospective or noncomparative design and because they focused on clinical characteristics of the patients, but did not consider the various characteristics of S. aureus isolates. Microbiologic and genotypic characteristics of S. aureus and pharmacokinetic and pharmacodynamic properties of antimicrobial agents may also be associated with persistent bacteremia. Several previous comparative studies have examined the microbiologic and genotypic characteristics of MRSA isolates associated with persistent bacteremia. However, these studies were performed with small numbers of MRSA isolates. To the best of our knowledge, no prospective comparative studies have investigated the clinical risk factors and the 98 www.md-journal.com Medicine & Volume 92, Number 2, March 2013 From the Department of Infectious Diseases (YPC, KHP, SHK, SOL, SHC, JHW, YSK) and Department of Laboratory Medicine (MNK), Asan Medical Center, University of Ulsan College of Medicine, Center for Antimicrobial Resistance and Microbial Genetics (SJP, HSK, ESK, JYJ, YSK), Seoul, Republic of Korea. Financial support and conflicts of interest: This study was supported by Future-based Technology Development Program (grant numbers 2010-0028746 and 2010-0028747) through the National Research Foundation of Korea, which is funded by the Ministry of Education, Science and Technology. The authors have no conflicts of interest to disclose. Reprints: Prof. Yang Soo Kim, Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, Republic of Korea (e-mail: [email protected]). Copyright * 2013 by Lippincott Williams & Wilkins ISSN: 0025-7974 DOI: 10.1097/MD.0b013e318289ff1e Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. pharmacokinetic, microbiologic, and genotypic factors associated with persistent bacteremia. In the present study, we performed a large case-control study nested in a prospective cohort of patients with SAB to evaluate these factors and outcomes associated with persistent bacteremia, using a definition of persistent bacteremia as Q7 days of bacteremia. PATIENTS AND METHODS Study Population and Design This case-control study, nested in a prospective observational cohort of patients with SAB, was conducted at the Asan Medical Center, a 2700-bed tertiary referral center that admits patients from throughout Korea. From August 2008 to September 2010, all adult patients with SAB were prospectively enrolled in the cohort and observed over a 12-week period. In our hospital, more than 90% of patients with SAB receive infectious disease consultation; follow-up blood cultures with 2to 4-day intervals until negative conversion, echocardiography, and monitoring of vancomycin trough concentrations (at day 3 and then at 3to 4-day intervals) are routinely recommended. It is also recommended that vancomycin trough concentrations always be maintained at 910 mg/L in patients with suspected S. aureus infection and at 15Y20 mg/L in patients with S. aureus bacteremia. Patients were excluded if 1) they had polymicrobial bacteremia, 2) they died or were discharged before positive blood culture results, or 3) they had clinically insignificant SAB, which means that S. aureus was isolated from only 1 blood culture set and the patient did not have clinical findings consistent with bacteremia and did not received antibiotic treatment. Only the first episode of SAB in each patient was included for analysis. Case patients were those who had an episode of persistent bacteremia, defined as bacteremia for Q7 days while they were receiving appropriate antibiotic therapy. Control patients were those who had resolving bacteremia, defined as G3 days of bacteremia with all subsequent blood cultures documented to be negative after the initial positive blood culture (index blood culture). Patients with resolving bacteremia had to have at least 1 set of follow-up blood cultures 1Y3 days after the index blood culture, and had to have no further positive blood culture results during antibiotic therapy. The duration of bacteremia was defined as the number of days between the first and last positive blood culture. Patients with intermediate duration of bacteremia were excluded from analysis to enable clear distinctions between persistent bacteremia and resolving bacteremia. This study was approved by the Asan Medical Center Institutional Review Board. Data Collection and Study Definitions Demographic characteristics, laboratory results, underlying diseases or conditions, presence or absence of a central venous catheter (CVC) or prosthetic device, severity of underlying disease, severity of bacteremia, site of infection, antibiogram results, patient management (including infection source control and antimicrobial therapy received), and clinical outcomes were recorded. The system of McCabe and Jackson was used to classify the severity of the underlying disease. The Charlson comorbidity index was used to provide a composite score of comorbid conditions. The severity of bacteremia at the time of the first positive blood culture was assessed using the Pitt bacteremia score. The type of infection causing SAB was defined by the criteria of the Centers for Disease Control and Prevention except for catheter-related infection and infective endocarditis. Catheter-related infection was defined as SAB in a patient who has an intravascular device and at least 1 positive blood culture result obtained from the peripheral vein, clinical features of infection, and no apparent source of SAB except for the catheter. Infective endocarditis was defined according to modified Duke criteria. Bacteremia was classified as nosocomial if a positive blood culture was obtained from patients who had been hospitalized for 48 hours or longer. Communityonset bacteremia was defined by a positive blood culture obtained at the time of hospital admission or within the 48 hours after hospital admission, and was further classified as health care-associated or community-acquired bacteremia. Septic shock was defined as sepsis associated with organ dysfunction and accompanied by persistent hypotension after adequate fluid resuscitation. Suppurative thrombophlebitis was defined as the presence of positive blood culture results for S. aureus plus the demonstration of a thrombus in the great central veins by radiographic testing (computed tomography, ultrasonography). Initial appropriate antibiotic therapy was defined as the use of an antimicrobial agent with activity against the organism at the day of or 1 day after the index blood culture. Initial vancomycin trough level was defined as mean trough level during the first 7 days of vancomycin therapy. Clinical outcome measures were duration of hospitalization after bacteremia, relapse of bacteremia, death during hospitalization, and death within 30 days or 12 weeks after the day of the index blood culture. Attributable mortality was defined as death due to S. aureus infection in a previously healthy individual or as the hastening of death by S. aureus infection in the presence of an underlying condition such as cancer. Microbiologic Data and Genotypic Assays The first blood isolate from each patient was used for microbiologic and molecular assessments. All S. aureus isolates were identified by standard methods. Antimicrobial susceptibilities were determined using the MicroScan system (Dade Behring, West Sacramento, CA) and standard criteria of the Clinical and Laboratory Standards Institute. Methicillin resistance was confirmed by polymerase chain reaction (PCR) detection of the mecA gene. Vancomycin MICs of MRSA isolates were determined by the vancomycin Etest (AB Biodisk, Piscataway, NJ) on Mueller-Hinton agar according to the manufacturer’s instructions. Identification of heteroresistant vancomycinintermediate S. aureus (hVISA) was determined by modified population analysis. SCCmec type, agr genotype, and the presence of 41 putative virulence genes of MRSAwere determined using previously described methods. We determined agr dysfunction by the level of C-hemolysin production, measured by streaking the MRSA isolate adjacent to a A-hemolysin disk (Remel, Lenexa, KS). Triton-induced lysis was assessed to measure the propensity for autolysis in MRSA isolates (performed in triplicate), as described elsewhere; defective autolysis was defined as a decrease in OD630 less than 50% after 3 hours of exposure to Triton relative to the baseline reading. Multilocus sequence typing (MLST) was performed as described elsewhere. MLST allele names and sequence types were derived from the MLST database (http://www.mlst.net). Clonal complexes (CCs) were assigned to groups of isolates sharing 6 of 7 alleles by use of eBURST (http://eburst.mlst.net). Statistical Analysis We compared patients with persistent bacteremia and those with resolving bacteremia. Categorical variables were compared using the chi-square test or the Fisher exact test, as appropriate. Medicine & Volume 92, Number 2, March 2013 Persistent S. aureus Bacteremia * 2013 Lippincott Williams & Wilkins www.md-journal.com 99 Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. TABLE 1. Univariate Analysis of Demographic and Clinical Characteristics of Patients With Persistent Bacteremia and Resolving Bacteremia Characteristic Persistent Bacteremia (n = 76) No. (%) Resolving Bacteremia (n = 212) No. (%) P OR (95% CI) Age (yr), median (IQR) 65 (54Y71.5) 63 (50.5Y72) 0.24 NA Male 50 (65.8) 138 (65.1) 0.99 1.03 (0.59Y1.80) Site of acquisition Community-onset 32 (42.1) 65 (30.7) 0.07 1.65 (0.96Y2.83) Community-acquired 10 (13.2) 15 (7.1) 0.11 1.99 (0.85Y4.64) Health care-associated 22 (28.9) 50 (23.6) 0.35 1.32 (0.73Y2.38) Nosocomial 44 (57.9) 147 (69.3) 0.07 0.61 (0.35Y1.04) Underlying disease/condition Solid tumor 26 (34.2) 91 (42.9) 0.18 0.69 (0.40Y1.19) Hematologic malignancy 8 (10.5) 22 (10.4) 0.97 1.02 (0.43Y2.39) Diabetes mellitus 26 (34.2) 69 (32.5) 0.79 1.08 (0.62Y1.88) Chronic renal failure 12 (15.8) 33 (15.6) 0.96 1.02 (0.50Y2.09) Liver cirrhosis 7 (9.2) 43 (20.3) 0.03 0.40 (0.17Y0.93) Neutropenia 5 (6.6) 13 (6.1) 0.99 1.08 (0.37Y3.13) McCabe and Jackson criteria Ultimately or rapidly fatal disease 30 (39.5) 97 (45.8) 0.34 0.77 (0.45Y1.32) Prior antibiotic use within 3 mo 51 (67.1) 121 (57.6) 0.15 1.50 (0.87Y2.60) Immunosuppressant use 14 (18.4) 40 (18.9) 0.93 0.97 (0.50Y1.91) Recent surgery 17 (22.4) 47 (22.2) 0.97 1.01 (0.54Y1.90) Recent chemotherapy 10 (13.2) 40 (18.9) 0.26 0.65 (0.31Y1.38) Charlson comorbidity index, median (IQR) 2.5 (1Y4) 3 (2Y5) 0.11 NA APACHE II, median (IQR) 16 (12Y21.5) 16 (11Y21) 0.65 NA Pitt bacteremia score, median (IQR) 1 (0Y2) 1 (0Y2) 0.39 NA Septic shock 16 (21.1) 30 (14.2) 0.20 1.62 (0.83Y3.17) CVC* 43 (56.6) 90 (42.5) 0.03 1.76 (1.04Y2.99) Prosthetic device† 12 (15.8) 14 (6.6) 0.02 2.65 (1.17Y6.03) Characteristics of infection‡ Metastatic infection 42 (55.3) 12 (5.7) G0.001 20.58 (9.85Y43.04) Lung (septic pneumonia) 17 (22.4) 3 (1.4) G0.001 20.07 (5.69Y70.83) Skin and soft tissue 13 (17.1) 4 (1.9) G0.001 10.73 (3.38Y34.08) Bone and joint 11 (14.5) 2 (0.9) G0.001 17.77 (3.84Y82.23) Central nervous system 5 (6.6) 2 (0.9) 0.02 7.39 (1.40Y38.96) Cardiac valve (endocarditis)§ 8 (10.5) 0 G0.001 NA Eye (endophthalmitis) 4 (5.3) 1 (0.5) 0.02 11.7 (1.29Y106.59) CVC-related infection 39 (51.3) 56 (26.4) G0.001 2.94 (1.71Y5.06) Removal of CVC 39/39 (100) 51/56 (91.1) 0.08 NA Retention of CVC at day 1¶ 22/39 (56.4) 32/56 (57.1) 0.94 1.03 (0.45Y2.35) Retention of CVC at day 8¶ 2/39 (5.1) 5/56 (8.9) 0.70 1.81 (0.33Y9.87) Infective endocarditis** 10 (13.2) 3 (1.4) G0.001 10.56 (2.82Y39.50) Bone and joint infection 10 (13.7) 11 (5.2) 0.02 2.77 (1.13Y6.81) Peripheral catheter-related infection 1 (1.3) 28 (13.2) 0.003 0.09 (0.01Y0.66) *Central venous catheters were removed after bacteremia from 100% of patients with persistent bacteremia (median, 1 d [IQR, 0Y2.5 d]) and from 84.4% (76/90) of patients with resolving bacteremia (median, 1 d [IQR, 0Y3 d]) (p = 0.005). †Prosthetic devices were orthopedic device (3 patients), prosthetic valve (2 patients), and vascular graft (7 patients) in the persistent bacteremia group and cardiac pacemaker (1 patient), orthopedic device (4 patients), prosthetic valve (4 patients), and vascular graft (5 patients) in the resolving bacteremia group. ‡Complication or principal focus of infection at presentation. §All were native valves. ¶Day 1 represents the day of the index blood culture. Retention of CVC at day 1 means that the infected CVC was not removed at the onset of bacteremia. **Echocardiography was performed in 96.1% (73/76) of patients with persistent bacteremia and in 68.9% (146/212) of patients with resolving bacteremia. One patient with persistent bacteremia had prosthetic valve endocarditis (he underwent valve replacement surgery at day 3), and the remaining 12 patients had native valve endocarditis. Chong et al Medicine & Volume 92, Number 2, March 2013 100 www.md-journal.com * 2013 Lippincott Williams & Wilkins Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Normally and non-normally distributed continuous variables were compared using the Student t test and the Mann-Whitney U test, respectively. Logistic regression was used to assess risk factors associated with persistent bacteremia and attributable mortality. All variables with p values less than 0.1 in the univariate analysis and other variables of clinical importance were included in the multiple logistic regression model to identify independent risk factors. The final model was constructed using the stepwise selection procedure. A 2-tailed p value less than 0.05 was considered statistically significant. All statistical analyses were performed using SPSS software, v. 18.0 (SPSS Inc., Chicago, IL).