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Comparative effectiveness of β-lactam versus vancomycin empiric therapy in patients with methicillin-susceptible… Wong, Davie; Wong, Titus; Romney, Marc; Leung, Victor Apr 26, 2016

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Wong et al. Ann Clin Microbiol Antimicrob  (2016) 15:27 DOI 10.1186/s12941-016-0143-3RESEARCHComparative effectiveness of β-lactam versus vancomycin empiric therapy in patients with methicillin-susceptible Staphylococcus aureus (MSSA) bacteremiaDavie Wong1*, Titus Wong2,3, Marc Romney2,4 and Victor Leung2,4Abstract Background: Vancomycin may be inferior to β-lactams for the empiric treatment of methicillin-susceptible Staphy-lococcus aureus (MSSA) bacteremia. We compared empiric β-lactams to vancomycin to assess clinical outcomes in patients with MSSA bacteremia.Methods: We conducted a retrospective cohort study of adult inpatients with their first episode of MSSA bacteremia at two tertiary care hospitals in Vancouver, Canada, between 2007 and 2014. Exposure was either empiric β-lactam with or without vancomycin or vancomycin monotherapy. All patients received definitive treatment with cloxacillin or cefazolin. The primary outcome was 28-day mortality. Secondary outcomes were 90-day mortality, duration of bacte-remia, and hospital length-of-stay. Outcomes were adjusted using multivariable logistic regression.Results: Of 669 patients identified, 255 met inclusion criteria (β-lactam = 131, vancomycin = 124). Overall 28-day mortality was 7.06 % (n = 18). There were more cases of infective endocarditis in the β-lactam than in the vancomycin group [24 (18.3 %) vs 12 (9.7 %), p = 0.05]. Adjusted mortality at 28 days was similar between the two groups (OR 0.85; 95 % CI 0.27–2.67). The duration of bacteremia was longer in the vancomycin group (97.1 vs 70.7 h, p = 0.007). Transi-tion to cloxacillin or cefazolin occurred within a median of 68.3 h in the vancomycin group.Conclusions: Empiric β-lactams was associated with earlier clearance of bacteremia by a median of 1 day compared to vancomycin. Future prospective studies are needed to confirm our findings.Keywords: Staphylococcus aureus, Bacteremia, Methicillin-susceptible, Vancomycin, Beta-lactam, Empiric therapy© 2016 Wong et al. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.BackgroundStaphylococcus aureus is the leading cause of bactere-mia and carries a mortality of 20–30  % in the twenty-first century [1, 2]. Empiric vancomycin is commonly prescribed when S. aureus is isolated from a blood cul-ture but antimicrobial susceptibilities are not yet known, because up to 50–60  % of bloodstream isolates are methicillin-resistant S. aureus (MRSA) at some centres [3–8]. However, vancomycin is inferior to semi-synthetic anti-Staphylococcal penicillins (e.g., cloxacillin) and first generation cephalosporins (e.g., cefazolin) for the definitive treatment of methicillin-susceptible S. aureus (MSSA) bacteremia [9–11]. Cloxacillin and cefazolin are equally efficacious in treating MSSA bacteremia and are the optimal agents against MSSA [10]. Vancomycin is associated with higher rates of infection-related mor-tality, re-infection and bacteriologic failure compared to cloxacillin or cefazolin in the definitive treatment of MSSA bacteremia [9, 12–15]. Whether vancomycin is inferior to β-lactams for empiric therapy remains to be fully elucidated. Early studies suggested that empiric van-comycin was associated with worse outcomes compared to empiric β-lactam therapy [3, 16, 17], but more recent Open AccessAnnals of Clinical Microbiologyand Antimicrobials*Correspondence:  davie1985@hotmail.com 1 PGY-V Infectious Diseases Residency Training Program, Vancouver General Hospital, University of British Columbia, D 452 Heather Pavilion, 2733 Heather Street, Vancouver, BC V5Z 1M9, CanadaFull list of author information is available at the end of the articlePage 2 of 9Wong et al. Ann Clin Microbiol Antimicrob  (2016) 15:27 data did not demonstrate any differences [15]. Although controversial, some experts recommend the addition of a β-lactam agent to empiric therapy to provide opti-mal coverage for MSSA in patients at the highest risk of morbidity and mortality from S. aureus bacteremia (SAB) [18]. Currently, no studies have compared empiric β-lactam to vancomycin in patients with MSSA bactere-mia who are transitioned to cloxacillin or cefazolin for definitive therapy. We assessed if empiric β-lactam with or without vancomycin compared to vancomycin alone was associated with differences in clinical outcomes in patients with MSSA bacteremia who received definitive therapy with cloxacillin or cefazolin.MethodsPatientsWe performed a retrospective cohort study of adult inpatients aged 18 and older diagnosed with their first episode of MSSA bacteremia at two tertiary care hos-pitals in Vancouver, Canada, between January 2007 and December 2014, inclusive. Both hospitals are large aca-demic institutions (955 and 435 beds) affiliated with the University of British Columbia that are served by infec-tious diseases physicians who share similar treatment strategies for SAB. Consecutive patients were included if they received definitive therapy with either cloxacillin or cefazolin. Patients were excluded if there was missing data for 28-day mortality, no empiric therapy was admin-istered, death occurred within 24 h following diagnosis of bacteremia, or polymicrobial bacteremia. Patients were stratified based on empiric treatment with β-lactams or vancomycin. The β-lactam group received one or more of cloxacillin, cefazolin, β-lactam/β-lactamase inhibitor combination, a third generation cephalosporin or a car-bapenem, with or without vancomycin. The vancomycin group was not exposed to any β-lactams until the start of definitive therapy. In both groups, other antimicrobials may have been prescribed during empiric and definitive therapy.DefinitionsBacteremia was defined as the isolation of MSSA from one or more blood culture bottles. Bacteremia identified within 48 h of hospital admission was considered commu-nity-onset, while bacteremia diagnosed after more than 48  h of hospital admission was deemed hospital-onset. Immunocompromised state was present if any of the following were described: neutropenia (≤1.5  ×  109/L), congenital immune deficiencies, or use of immunosup-pressants (TNF-α inhibitors, prednisone ≥10  mg/day or its equivalent, cancer chemotherapy, methotrexate, cyclophosphamide, mycophenolate mofetil, calcineu-rin inhibitors, mTOR inhibitors, azathioprine). Definite infective endocarditis was diagnosed using the modi-fied Duke criteria [19]. The source of bacteremia was either stated explicitly or inferred as the most likely source based on available clinical data and microbiologi-cal results. Metastatic complications included infections that occurred distant from the presumed primary source such as septic emboli, mycotic aneurysms, osteoarticular infections, and distant abscesses. Surgical source con-trol included only procedures performed in the operat-ing theatre. Empiric therapy began with the first dose of empiric antibiotics and ended with the start of definitive therapy. Definitive therapy began when antimicrobial susceptibilities were released and one of the following treatments was prescribed: (1) cloxacillin or cefazolin (2) discontinuation of other empiric antibiotics for patients already on cloxacillin or cefazolin empirically, or (3) con-tinuation of empiric cloxacillin or cefazolin. Definitive therapy ended when cloxacillin or cefazolin was stopped. Time to receipt of antibiotics was measured from the time of obtaining the first positive blood culture to the time of the first dose of antibiotic. If a patient was already on antibiotics at the time of the first positive blood cul-ture, the time to receipt of antibiotics was zero.OutcomesOur primary outcome was 28-day all-cause mortal-ity. Secondary outcomes were 90-day all-cause mortal-ity, duration of bacteremia, and hospital length-of-stay (LOS). Time to mortality was measured from the date of the first positive blood culture to the date of death. Dura-tion of bacteremia was the time difference between the first positive blood culture and the first negative blood culture. Patients without follow-up blood cultures were excluded from the analysis for duration of bacteremia. Hospital LOS was measured from the date of the first positive blood culture for MSSA to the date of discharge. Patients who did not survive to hospital discharge were excluded from the hospital LOS analysis.Data extractionPatients with MSSA bacteremia were extracted from the medical microbiology laboratory information systems and medical records were reviewed. A single reviewer collected data on patient demographics and comorbidi-ties, blood culture results and antimicrobial therapy.Statistical analysisOur predicted mortality difference between the β-lactam and vancomycin group was 15  % based on a previous study [17]. We estimated a sample size of 100 for each group to capture a 15  % difference in mortality, assum-ing a mortality rate of 25 and 10  % in the vancomycin and β-lactam group respectively, with 80  % power at a Page 3 of 9Wong et al. Ann Clin Microbiol Antimicrob  (2016) 15:27 two-tailed alpha level of 0.05. Baseline categorical vari-ables were described as counts and percentages, and dif-ferences between groups were assessed with Chi square or Fisher’s exact tests. Continuous variables were pre-sented as means and standard deviations, or medians and interquartile range. Differences between groups were assessed using parametric t-tests or non-para-metric Mann–Whitney U tests, as appropriate. Logistic regression methods were used to model the odds ratio of death in the β-lactam compared to vancomycin group. In order to reduce the small sample size bias, Firth cor-rection method was applied to 28- and 90-day mortality [20]. Linear regression model was conducted for hospital LOS and duration of bacteremia. The two outcomes were log-transformed in the analysis to improve normality of the distribution of residuals. All models were adjusted for age, age-adjusted Charlson-comorbidity index (CCI) [21], infectious diseases consultation, infective endo-carditis and time to receipt of empiric antibiotics. The duration of bacteremia was further adjusted for surgical source control. All analyses were performed using the SAS 9.4 software.EthicsThe study was approved by the research ethics board at the University of British Columbia, and received insti-tutional approval from Vancouver Coastal Health and Providence Healthcare.ResultsWe identified 669 patients with MSSA bacteremia between January 2007 and December 2014, inclusive (Fig.  1). We excluded 414 patients primarily because 60.4 % did not receive cloxacillin or cefazolin for defini-tive therapy. These patients either remained on broad-spectrum antimicrobials or received vancomycin for definitive therapy due to suspected or confirmed penicil-lin allergy. Another 22.9  % were not started on empiric therapy. Our cohort consisted of 66.3 % males and 74.1 % of patients had community-onset bacteremia (Table  1). Compared to the β-lactam group, patients in the van-comycin group were older (mean age 59.4 vs 53.2 years, p  =  0.005), had more medical comorbidities (median CCI 4 vs 3, p = 0.001), and were diagnosed with a greater proportion of hospital-onset bacteremia (32.3 vs 19.8 %, p = 0.03). Infectious diseases consultation was obtained in most cases (69.8  %), but tended to be higher in the β-lactam (74.8 %) than in the vancomycin group (64.5 %).The most common sources of bacteremia in our cohort were unknown (27.1  %), skin and soft tissue infections (18.4 %), peripheral or central venous catheters (16.5 %) and injection drug use (15.7  %). Infective endocarditis was diagnosed more frequently and surgical source con-trol was achieved more often in the β-lactam (18.3 and 25.2 % respectively) compared to the vancomycin group (9.7 and 15.3 % respectively). The prevalence of infective endocarditis was 14.1 %. In the β-lactam group, the use of multiple β-lactam antibiotics reflects changes made during empiric ther-apy, but cloxacillin or cefazolin was continued until the start of definitive therapy. One patient in the vancomycin group received only a partial dose of vancomycin and was counted as not having received it. There was a greater delay in receipt of empiric antimicrobials in the vanco-mycin group (median 20.9 vs 2  h, p  <  0.001).Transition to cloxacillin or cefazolin occurred within a median of 68.3 h in the vancomycin group. Among the subgroup of patients who received combination therapy with β-lactam plus vancomycin (88/131), 3rd generation cephalospor-ins (39.8  %) and piperacillin–tazobactam (34.1  %) were the most common empiric β-lactams prescribed initially (Table 2). Initiation of cloxacillin or cefazolin during the empiric period was delayed in the combination subgroup compared to the subgroup that received β-lactam mono-therapy (median 23.1 vs 6.5 h, p = 0.001). The combina-tion subgroup had a higher Pitt bacteremia score (median 1 vs 0, p = 0.01), received more infectious diseases con-sultations (80.7 vs 62.8  %, p  =  0.03), and experienced more metastatic complications (37.5 vs 16.3 %, p = 0.02) than the β-lactam monotherapy subgroup. Hospital LOS was shorter in patients who received β-lactam monother-apy (median 14 vs 22 days, p = 0.02).The adjusted odds ratio of death at 28 and 90  days between the β-lactam and vancomycin group was 0.85 (95  % CI 0.27–2.67) and 0.88 (0.36–2.17) respectively (Table  3). The overall 28- and 90-day mortality was 18 (7.06  %) and 36 (14.1  %) respectively. Among patients with infective endocarditis, 28- and 90-day mortality was 2 (8.33 %) and 3 (12.5 %) in the β-lactam group and Fig. 1 Patient enrollment process. MSSA methicillin-susceptible S. aureus, BSI bloodstream infectionPage 4 of 9Wong et al. Ann Clin Microbiol Antimicrob  (2016) 15:27 0 and 1 (8.33 %) in the vancomycin group. No mortality differences were observed between the two hospitals. The duration of bacteremia was shorter in the β-lactam than in the vancomycin group (median 70.7 vs 97.1  h, p = 0.007) with an adjusted ratio of mean of 0.77 (95 % CI 0.62–0.95). Hospital LOS was similar between the two groups with an adjusted ratio of mean of 0.86 (95  % CI 0.66–1.10).Table 1 Comparison of  baseline characteristics and  clinical outcomes of  patients with  methicillin-susceptible S. aureus bacteremia who received empiric antimicrobial therapy with β-lactams or vancomycinPatient characteristics β-lactama (n = 131) Vancomycina (n = 124) p valueAge (mean ± standard deviation in years) 53.2 ± 16.5 59.4 ± 18.3 0.005Males 83 (63.4) 86 (69.4) 0.31Community-onset 105 (80.2) 84 (67.8) 0.03Hospital-onset 26 (19.8) 40 (32.3) 0.03HIV infection 11 (8.4) 8 (6.5) 0.55Hepatitis C infection 29 (22.1) 28 (22.6) 0.93Immunocompromised 14 (10.7) 10 (8.1) 0.47Alcohol or illicit drug abuse 41 (31.3) 38 (30.6) 0.91Intravenous drug use 29 (22.1) 29 (23.4) 0.81Charlson comorbidity index (median with IQR) 3 (1.0–6.0) 4 (1.0–7.0) 0.001Pitt bacteremia score (median with IQR) 1 (0–2) 1 (0–2) 0.17Infectious diseases consultation 98 (74.8) 80 (64.5) 0.07Source of bacteremia Central or peripheral line 20 (15.3) 22 (17.7) 0.62 Skin and soft tissue 31 (23.7) 16 (12.9) 0.04 Intravenous drug use 21 (16.0) 19 (15.3) 1.00 Bone or joint infection 18 (13.7) 10 (8.1) 0.16 Lung 4 (3.1) 3 (2.4) 1.00 Other 12 (9.2) 10 (8.1) 0.83 Unknown 25 (19.1) 44 (35.5) 0.005Infective endocarditis 24 (18.3) 12 (9.7) 0.05Metastatic complications 40 (30.5) 27 (21.8) 0.11Surgical source control 33 (25.2) 19 (15.3) 0.05Recurrent infection at 6 months 4 (3.1) 4 (3.2) 1.00Empiric antimicrobials Vancomycin 88 (67.2) 123 (99.2) <0.001 Daptomycin 2 (1.5) 0 0.50 Linezolid 2 (1.5) 0 0.50 Cloxacillin or cefazolin 131 (100) 0 <0.001 3rd generation cephalosporin 40 (30.5) 0 <0.001 Piperacillin–tazobactam 33 (25.2) 0 <0.001 Ticarcillin–clavulanic acid 3 (2.3) 0 0.25 Carbapenem 2 (1.5) 0 0.50 Otherb 47 (35.9) 66 (53.2) 0.01Blood culture time to positivity (median hours with IQR) 20 (16.5–24.9) 18.3 (15.9–23.5) 0.17Duration of empiric therapy (median hours with IQR) 54 (42.0–69.0) 48 (29.6–75.8) 0.28Duration of definitive therapy (median days with IQR) 31.5 (13.0–42.0) 28 (10.0–42.0) 0.17Time to receipt of empiric therapy (median hours with IQR) 2 (0–7) 20.9 (4.2–28.3) <0.001Time to receipt of β-lactam (median hours with IQR) 3 (0.2–16.3) 68.2 (51.5–95.4) <0.001Time to receipt of cloxacillin or cefazolin (median hours with IQR) 21.0 (4.4–31.2) 68.3 (51.6–95.4) <0.001Primary outcome 28-day mortality 7 (5.3) 11 (8.9) 0.27Page 5 of 9Wong et al. Ann Clin Microbiol Antimicrob  (2016) 15:27 DiscussionThe goal of our study was to assess if empiric β-lactams with or without vancomycin compared to vancomy-cin alone was associated with differences in outcomes in patients with MSSA bacteremia. We found no dif-ferences in all-cause mortality at 28 and 90  days, or hospital LOS between these two groups. Clearance of bacteremia was delayed by a median of 1 day in the van-comycin group. However, this outcome may have been confounded by the earlier receipt of empiric antibiotics in the β-lactam group (median 2 h). When we analyzed a subset of patients from the vancomycin group (n = 43) whose median time to receipt of empiric antibiotics was 1.97 h, the duration of bacteremia was still longer com-pared to the β-lactam group, but just shy of statistical sig-nificance (95.1 vs 70.7 h, p = 0.06), likely because of the reduced sample size. Therefore, it does not appear that time to receipt of empiric therapy had a major impact on time to clearance of bacteremia in our study. Despite the high prevalence of MRSA at both of our institutions (25 and 38 %), only 67.2 % of patients in the β-lactam group received vancomycin empirically as well. Perhaps the awareness of MRSA was low among some treating clini-cians or patients who did not receive empiric vancomycin were judged to be at low risk for MRSA infection.Interestingly, the differential time delay in receipt of empiric antimicrobials was unexpected. Patients in the β-lactam group generally received antibiotics well before the blood culture became positive, while patients in the vancomycin group tended to receive antibiotics shortly after the blood culture turned positive. The reason for this observation is likely multifactorial. First, β-lactam patients generally had more identifiable sources of bac-teremia (i.e. more skin and soft tissue infections). Second, the higher prevalence of community-onset bacteremia suggests these patients may have had their first medical contact with the emergency department where sepsis protocols facilitated timely administration of antibiotics.In the β-lactam group, patients who received empiric β-lactam plus vancomycin had a higher Pitt bacteremia score, experienced more metastatic complications and stayed in hospital longer than those who received empiric β-lactam monotherapy. The greater severity of illness in this combination subgroup may explain the initial use of broad-spectrum β-lactams (ceftriaxone or pipera-cillin–tazobactam), with subsequent de-escalation to cloxacillin or cefazolin during the empiric period by the infectious diseases consultant when S. aureus was identi-fied in the blood culture. De-escalation occurred within a median of 23.1 h, which follows the time to positivity of the first blood culture (median 20 h). Despite differences in baseline characteristics and antimicrobials prescribed, mortality rates and time to clearance of bacteremia were similar between these subgroups.Our study outcomes were similar to those reported in the literature. The overall 28- and 90-day mortality in our study was low at 18 (7.06 %) and 36 (14.1 %) respec-tively, but is within the range of 3.6–51.7 % described in a meta-analysis of patients with MSSA bacteremia from catheter-related infections and infective endocarditis by Cosgrove et  al. [22]. Definite infective endocarditis was diagnosed in 36 (14.1 %) of our patients, which is similar to rates reported in previous studies [10, 14, 16, 23, 24].The median duration of bacteremia was longer in the vancomycin compared to the β-lactam group (4 vs 3 days) in our study. In a similar study by Khatib et al. [3], clearance of bacteremia was delayed (duration ≥3 days) more often in patients who received empiric vancomy-cin (57.6  %) compared to those who received empiric β-lactams (37.5  %). They reported no difference in all-cause or attributable mortality between groups.We did not find any differences in mortality between treatment groups in our study. In contrast, Lodise et al. [17] demonstrated that empiric β-lactam was associated with lower infection-related mortality than with empiric vancomycin monotherapy (11.4 vs 39.3  %, p  =  0.005) IQR interquartile rangea Variables are displayed as counts and percentages in parentheses unless otherwise specifiedb Other antimicrobials used during empiric and definitive therapy included rifampin, aminoglycosides, fluoroquinolones, macrolides, trimethoprim-sulfamethoxazole, and clindamycinc 15 and 10 patients from the β-lactam and vancomycin group respectively were excluded from the analysis due to lack of follow-up blood culturesd 12 and 19 patients from the β-lactam and vancomycin group respectively were excluded from the analysis due to death during hospital admissionPatient characteristics β-lactama (n = 131) Vancomycina (n = 124) p valueSecondary outcomes 90-day mortality 14 (10.7) 22 (17.7) 0.11 Duration of bacteremia (median hours with IQR)c 70.7 (46.9–119) 97.1 (61.6–148) 0.007 ≥3 days 58 (50) 72 (63.2) 0.047 Hospital length of stay (median days with IQR)d 17 (11–36) 17 (12–36.5) 0.84Table 1 continuedPage 6 of 9Wong et al. Ann Clin Microbiol Antimicrob  (2016) 15:27 Table 2 Comparison of  baseline characteristics and  clinical outcomes of  patients with  methicillin-susceptible S. aureus bacteremia who received empiric combination therapy with β-lactam plus vancomycin or empiric β-lactam monotherapyPatient characteristics β-lactam plus vancomycina  (n = 88)β-lactam monotherapya  (n = 43)p valueAge (mean ± standard deviation in years) 50.5 ± 16.4 58.9 ± 16.6 0.006Males 53 (60.2) 30 (69.8) 0.34Community-onset 74 (84.1) 31 (72.1) 0.16Hospital-onset 14 (15.9) 12 (27.9) 0.16HIV infection 9 (10.2) 2 (4.7) 0.34Hepatitis C infection 19 (21.6) 10 (23.3) 0.83Immunocompromised 8 (9.1) 6 (14.0) 0.39Alcohol or illicit drug abuse 29 (33.0) 12 (27.9) 0.69Intravenous drug use 21 (23.9) 8 (18.6) 0.65Charlson comorbidity index (median with IQR) 2 (1–4) 3 (1–5) 0.07Pitt bacteremia score (median with IQR) 1 (0–2) 0 (0–1) 0.01Infectious diseases consultation 71 (80.7) 27 (62.8) 0.03Source of bacteremia Central or peripheral line 12 (13.6) 8 (18.6) 0.45 Skin and soft tissue 20 (22.7) 11 (25.6) 0.83 Intravenous drug use 16 (18.2) 5 (11.6) 0.45 Bone or joint infection 10 (11.4) 8 (18.6) 0.29 Lung 2 (2.3) 2 (4.7) 0.60 Other 9 (10.2) 3 (7.0) 0.75 Unknown 19 (21.6) 6 (14.0) 0.35Infective endocarditis 19 (21.6) 5 (11.6) 0.23Metastatic complications 33 (37.5) 7 (16.3) 0.02Surgical source control 22 (25) 11 (25.6) 1.00Recurrent infection at 6 months 2 (2.3) 2 (4.7) 0.60Empiric antimicrobials Daptomycin 0 2 (4.7) 0.11 Linezolid 1 (1.1) 1 (2.3) 0.55 Cloxacillin or cefazolin 88 (100) 43 (100) 1.00 3rd generation cephalosporin 35 (39.8) 5 (11.6) 0.001 Piperacillin–tazobactam 30 (34.1) 3 (7.0) <0.001 Ticarcillin–clavulanic acid 2 (2.3) 1 (2.3) 1.00 Carbapenem 1 (1.1) 1 (2.3) 0.55 Otherb 27 (30.7) 20 (46.5) 0.08Blood culture time to positivity (median hours with IQR) 20 (16.0–24.0) 20.7 (18–27.3) 0.07Duration of empiric therapy (median hours with IQR) 54.1 (43.0–71.7) 51.7 (38–64.5) 0.18Duration of definitive therapy (median days with IQR) 38 (16–43) 23 (12–40) 0.08Time to receipt of empiric therapy (median hours with IQR) 1.91 (0–6.17) 3.42 (0.58–17.2) 0.19Time to receipt of β-lactam (median hours with IQR) 2.88 (0.21–15.1) 3.42 (0.58–17.2) 0.87Time to receipt of cloxacillin or cefazolin (median hours with IQR)23.1 (13.0–31.7) 6.5 (1.5–22.1) 0.001Primary outcome 28-day mortality 5 (5.7) 2 (4.7) 1.00Page 7 of 9Wong et al. Ann Clin Microbiol Antimicrob  (2016) 15:27 among injection drug users with predominantly right-sided MSSA infective endocarditis. Even when patients were switched from vancomycin to a semi-synthetic pen-icillin within a median of 3 days, infection-related mor-tality remained high at 40.9  %. The overall mortality in Lodise’s cohort was unusually high at 22.2 % compared to a rate of 0–4 % described in a systematic review by Yung et  al. [25]. The largest study to date by McDanel et  al. revealed that empiric β-lactam therapy (predominantly piperacillin–tazobactam and ceftriaxone) compared to vancomycin was not associated with differences in mor-tality in patients with MSSA bacteremia [15]. However, this study excluded patients who received empiric van-comycin plus β-lactams, did not address microbiological cure, and evaluated empiric regimens independent of the definitive antimicrobial therapy prescribed.We included a large proportion of patients who received empiric treatment with optimal anti-MSSA agents (cloxacillin or cefazolin), whereas previous obser-vational studies have either failed to specify the β-lactam agents used or enrolled patients who received mostly broad-spectrum β-lactams. This is an important point because not all β-lactams have equal efficacy against MSSA. As demonstrated in one study, empiric cefazolin or cloxacillin was associated with improved short-term survival compared to empiric regimens containing other β-lactams [26]. Therefore, the ideal study is one that com-pares a semi-synthetic anti-Staphylococcal penicillin or cefazolin to vancomycin.Our study has several limitations. The reason for the lack of difference in the primary outcome is likely mul-tifactorial. Because of the low event rate in both groups, our study was potentially underpowered to detect a sig-nificant difference in mortality. The lower than expected death rate may be partly due to the exclusion of patients who died within 24  h of the diagnosis of SAB and of patients who remained on broad-spectrum β-lactams. This group may have represented a sicker population and thus, we may have selected for less critically ill patients. The absence of matching with respect to baseline char-acteristics and the retrospective nature of the study may have also contributed to a lack of difference in the pri-mary outcome. Obtaining subsequent blood cultures was often delayed, which may have led to an overestimation Table 3 Outcome analysis comparing empiric β-lactam versus  vancomycin, adjusted for  age, age-adjusted Charlson-comorbidity index, infectious diseases consultation, infective endocarditis and time to receipt of empiric antibioticsDuration of bacteremia was further adjusted for surgical source controlOR odds ratio, CI confidence intervalOutcomes Crude OR (95 % CI) p value Adjusted OR (95 % CI) p value28-day mortality 0.60 (0.23–1.55) 0.29 0.85 (0.27–2.67) 0.7890-day mortality 0.56 (0.28–1.15) 0.11 0.88 (0.36–2.17) 0.79Ratio of mean (95 % CI) p value Adjusted ratio of mean (95 % CI) p valueDuration of bacteremia 0.77 (0.64–0.93) 0.01 0.77 (0.62–0.95) 0.01Hospital length-of-stay 0.85 (0.68–1.07) 0.16 0.86 (0.66–1.10) 0.23IQR interquartile rangea Variables are displayed as counts and percentages in parentheses unless otherwise specifiedb Other antimicrobials used during empiric and definitive therapy included rifampin, aminoglycosides, fluoroquinolones, macrolides, trimethoprim-sulfamethoxazole, and clindamycinc 6 and 9 patients from the β-lactam plus vancomycin and β-lactam monotherapy subgroup respectively were excluded from the analysis due to lack of follow-up blood culturesd 9 and 3 patients from the β-lactam plus vancomycin and β-lactam monotherapy subgroup respectively were excluded from the analysis due to death during hospital admissionPatient characteristics β-lactam plus vancomycina  (n = 88)β-lactam monotherapya  (n = 43)p valueSecondary outcomes 90-day mortality 10 (11.4) 4 (9.3) 1.00 Duration of bacteremia (median hours with IQR)c 71.4 (50.3–126.9) 68.5 (36.4–115.8) 0.35 ≥3 days 41 (46.6) 17 (39.5) 0.46 Hospital length of stay (median days with IQR)d 22 (12–44) 14 (10–22.8) 0.02Table 2 continuedPage 8 of 9Wong et al. Ann Clin Microbiol Antimicrob  (2016) 15:27 of the duration of bacteremia. However, this effect was likely balanced between both groups. Data regarding adverse effects were not collected due to the difficulty of establishing drug-related events in a retrospective study. A randomized controlled trial would be ideal to address our study question because it would provide bet-ter matching of patient baseline characteristics and con-trol of antimicrobials prescribed, and permit prospective monitoring of adverse drug effects. In such a study, daily blood cultures would need to be collected to determine the exact date of clearance of bacteremia. As well, more accurate estimation of the expected mortality rates between groups would be needed when calculating the required sample size. Collaboration between the medical microbiology laboratory, infectious diseases service and antimicrobial stewardship team is essential to execute such a trial.Until we have more concrete evidence from future prospective studies, the benefit of adding a β-lactam to empiric therapy for MSSA bacteremia remains unclear. Ultimately, the choice of empiric regimen will depend on patient factors, the prevalence of MRSA in the popu-lation, and the ability of the microbiology laboratory to rapidly differentiate MSSA from MRSA.In conclusion, empiric therapy with β-lactams was associated with earlier clearance of bacteremia by a median of 1  day compared to vancomycin, but was not associated with differences in all-cause mortality or hos-pital LOS in patients with MSSA bacteremia. Our data should be interpreted with caution however, as major differences in the baseline characteristics between the groups may have overshadowed any potential treatment effect. Future prospective studies are needed to confirm our findings. For now, empiric treatment with vancomy-cin is reasonable if the prevalence of MRSA is significant. The addition of a β-lactam agent could be considered in critically ill patients. Authors’s contributionsDW conceived and designed the study, collected and analyzed the data, wrote and revised the manuscript. TW designed the study and critically reviewed the manuscript. MR critically reviewed the manuscript. VL designed the study and critically reviewed the manuscript. All authors read and approved the final manuscript.Author details1 PGY-V Infectious Diseases Residency Training Program, Vancouver General Hospital, University of British Columbia, D 452 Heather Pavilion, 2733 Heather Street, Vancouver, BC V5Z 1M9, Canada. 2 Department of Pathol-ogy and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada. 3 Medical Microbiology Laboratory, Division of Medical Microbiology and Infection Control, Vancouver General Hospital, JPPN1, 899 W 12th Ave., Vancouver, BC V5Z 1M9, Canada. 4 Medical Microbiology Laboratory, Division of Medical Microbiology, St. Paul’s Hospital, 1081 Burrard St., Vancouver, BC V6Z 1Y6, Canada. Competing interestsThe authors declare that they have no competing interests.FundingNo external funding was required.Received: 22 February 2016   Accepted: 17 April 2016References 1. Van Hal SJ, Jensen SO, Vaska VL, Espedido BJ, Paterson DL, Gosbell IB. Pre-dictors of mortality in Staphylococcus aureus bacteremia. Clin Microbiol Rev. 2012;25:362–86. 2. Thwaites GE, Edgeworth JD, Gkrania-Klotsas E, Kirby A, Tilley R, Torok ME, et al. Clinical management of Staphylococcus aureus bacteraemia. Lancet Infect Dis. 2011;11:208–22. 3. Khatib R, Saeed S, Sharma M, Riederer K, Fakih MG, Johnson LB. Impact of initial antibiotic choice and delayed appropriate treatment on the outcome of Staphylococcus aureus bacteremia. Eur J Clin Microbiol Infect Dis. 2006;25:181–5. 4. Paul M, Kariv G, Goldberg E, Raskin M, Shaked H, Hazzan R, et al. Importance of appropriate empirical antibiotic therapy for methicillin-resistant Staphy-lococcus aureus bacteraemia. J Antimicrob Chemother. 2010;65:2658–65. 5. David MZ, Daum RS. Community-associated methicillin-resistant Staphy-lococcus aureus: epidemiology and clinical consequences of an emerging epidemic. Clin Microbiol Rev. 2010;23:616–87. 6. Lodise TP, McKinnon PS, Swiderski L, Rybak M. Outcomes analysis of delayed antibiotic treatment for hospital-acquired Staphylococcus aureus bacteremia. Clin Infect Dis. 2003;36:1418–23. 7. Marchaim D, Kaye KS, Fowler VG, Anderson DJ, Chawla V, Golan Y. Case–control study to identify factors associated with mortality among patients with methicillin-resistant Staphylococcus aureus bacteraemia. Clin Microbiol Infect. 2010;16:747–52. 8. Schweizer ML, Furuno JP, Harris AD, Johnson JK, Shardell MD, McGregor JC. Empiric antibiotic therapy for Staphylococcus aureus bacteremia may not reduce in-hospital mortality: a retrospective cohort study. PLoS One. 2010;5:e11432. 9. Kim SH, Kim KH, Kim HB, Kim NJ, Kim EC, Oh MD, et al. Outcome of vanco-mycin treatment in patients with methicillin-susceptible Staphylococcus aureus bacteremia. Antimicrob Agents Chemother. 2008;52:192–7. 10. Lee S, Choe PG, Song KH, Park SW, Kim HB, Kim NJ, et al. Is cefazolin inferior to nafcillin for treatment of methicillin-susceptible Staphylococcus aureus bacteremia? Antimicrob Agents Chemother. 2011;55:5122–6. 11. Liu C, Bayer A, Cosgrove SE, Daum RS, Fridkin SK, Gorwitz RJ, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52:1–38. 12. Chang FY, Peacock JE, Musher DM Jr, Triplett P, MacDonald BB, Mylotte JM, et al. Staphylococcus aureus bacteremia recurrence and the impact of antibiotic treatment in a prospective multicenter study. Medicine. 2003;82:333–9. 13. Chan KE, Warren HS, Thadhani RI, Steele DJR, Hymes JL, Maddux FW, et al. Prevalence and outcomes of antimicrobial treatment for Staphylo-coccus aureus bacteremia in outpatients with ESRD. J Am Soc Nephrol. 2012;23:1551–9. 14. Stryjewski ME, Szczech LA, Benjamin DK Jr, Inrig JK, Kanafani ZA, Enge-mann JJ, et al. Use of vancomycin or first-generation cephalosporins for the treatment of hemodialysis-dependent patients with MSSA bactere-mia. Clin Infect Dis. 2007;44:190–6. 15. McDanel JS, Perencevich EN, Diekema DJ, Herwaldt LA, Smith TC, Chrischilles EA, et al. Comparative effectiveness of beta-lactams versus vancomycin for treatment of methicillin-susceptible Staphylococcus aureus bloodstream infections among 122 hospitals. Clin Infect Dis. 2015;61:361–7. 16. Schweizer ML, Furuno JP, Harris AD, Johnson JK, Shardell MD, McGregor JC, et al. Comparative effectiveness of nafcillin or cefazolin versus vanco-mycin in methicillin-susceptible Staphylococcus aureus bacteremia. BMC Infect Dis. 2011;11:279. 17. Lodise TP Jr, McKinnon PS, Levine DP, Rybak MJ. Impact of empirical-therapy selection on outcomes of intravenous drug users with Page 9 of 9Wong et al. Ann Clin Microbiol Antimicrob  (2016) 15:27 •  We accept pre-submission inquiries •  Our selector tool helps you to find the most relevant journal•  We provide round the clock customer support •  Convenient online submission•  Thorough peer review•  Inclusion in PubMed and all major indexing services •  Maximum visibility for your researchSubmit your manuscript atwww.biomedcentral.com/submitSubmit your next manuscript to BioMed Central and we will help you at every step:infective endocarditis caused by MSSA. Antimicrob Agents Chemother. 2007;51:3731–3. 18. McConeghy KW, Bleasdale SC, Rodvold KA. The empirical combination of vancomycin and a β-lactam for staphylococcal bacteremia. Clin Infect Dis. 2013;57:1760–5. 19. Li JS, Sexton DJ, Mick N, Nettles R, Fowler VG Jr, Ryan T, et al. Proposed modifications to the duke criteria for the diagnosis of infective endocardi-tis. Clin Infect Dis. 2000;30:633–8. 20. Firth D. Bias reduction of maximum likelihood estimates. Biometrika. 1993;80:27–8. 21. Schneeweiss S, Wang PS, Avorn J, Glynn RJ. Improved comorbidity adjust-ment for predicting mortality in Medicare populations. Health Serv Res. 2003;38:1103–20. 22. Cosgrove SE, Sakoulas G, Perencevich EN, Schwaber MJ, Karchmer AW, Carmeli Y. Comparison of mortality associated with methicillin-resistant and methicillin-susceptible Staphylococcus aureus bacteremia: a meta-analysis. Clin Infect Dis. 2003;36:53–9. 23. Bai AD, Showler A, Burry L, Steinberg M, Ricciuto DR, Fernandes T, et al. Comparative effectiveness of cefazolin versus cloxacillin as definitive antibiotic therapy for MSSA bacteraemia: results from a large multicentre cohort study. J Antimicrob Chemother. 2015;70:1539–46. 24. Yilmaz M, Elaldi N, Balkan İİ, Arslan F, Batırel AA, Bakıcı MZ, et al. Mortality predictors of Staphylococcus aureus bacteremia: a prospective multi-center study. Ann Clin Microbiol Antimicrob. 2016;15:7. doi:10.1186/s12941-016-0122-8. 25. Yung D, Kottachchi D, Neupane B, Haider S, Loeb M. Antimicrobials for right-sided endocarditis in intravenous drug users: a systematic review. J Antimicrob Chemother. 2007;60:921–8. 26. Paul M, Zemer-Wassercug N, Talker O, Lishtzinsky Y, Lev B, Samra Z, et al. Are all beta-lactams similarly effective in the treatment of methicillin-sensitive Staphylococcus aureus bacteraemia? Clin Microbiol Infect. 2011;17:1581–6.

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