Methicillin-sensitive Staphylococcus Aureus Bacteremia Research Articles

411: CEFAZOLIN VERSUS NAFCILLIN IN THE TREATMENT OF MSSA ENDOCARDITIS

Introduction: Methicillin-sensitive Staphylococcus aureus (MSSA) is associated with considerable mortality, particularly in infections such as infective endocarditis (IE). Current guidelines endorse nafcillin (NAF) as first-line therapy for MSSA IE, while cefazolin (CFZ) is an alternative for patients with penicillin allergy. Reluctance in using CFZ stems from the inoculum effect, a phenomenon of reduced CFZ susceptibility in the presence of high organism burden. CFZ is more conveniently dosed with a favorable safety profile, positioning it as an appealing option for the prolonged treatment duration required for IE. New evidence suggests similar rates of clinical failure between CFZ and NAF in MSSA bacteremia, but data in IE, where organism inoculum is higher, is limited. This study compares the effectiveness and safety of CFZ and NAF in patients with MSSA IE. Methods: This multicenter retrospective cohort study included patients with definite or possible MSSA IE from 2015-2021. Subjects were treated with CFZ or NAF within 48 hours of MSSA identification. The primary outcome examined 30-day all-cause mortality, persistent bacteremia, and changes in agent due to treatment failure. Secondary outcomes are treatment failure, and adverse events. Results: Among 140 patients, 111 received CFZ and 29 were treated with NAF. While groups had comparable durations of antibiotic therapy, CFZ patients experienced significantly shorter hospital stays at a median of 15 days compared to 24 days in the NAF group. There was no significant difference between 90-day mortality, readmission, or reinfection between treatment groups, although NAF showed a significantly increased incidence of persistent bacteremia. Beyond this, treatment NAF led to more LFT elevations, acute kidney injury and a higher rate of antimicrobial switches. Conclusions: CFZ demonstrated comparable effectiveness to NAF in the treatment of MSSA IE. Significantly fewer patients in the CFZ group had persistent bacteremia, while patients receiving NAF required more changes in therapy. This may be reflective of the significantly higher rate of acute kidney injury and LFT abnormalities. These results emphasize that CFZ continues to be better tolerated by patients, while the prospect of treatment failure from the inoculum effect was not evident in this study.

Oral step-down for Staphylococcus aureus bacteraemia: An opportunity for antimicrobial stewardship?

Long courses of intravenous antimicrobial therapy are traditionally recommended for the treatment of methicillin sensitive Staphylococcus aureus bacteraemia (MS-SAB), but are not always completed in clinical practice. Early intravenous to oral antibiotic switch is a key component of antimicrobial stewardship. This study aimed to identify whether intravenous antibiotic duration may be safely reduced in MS-SAB. We performed a single-centre retrospective study of MS-SAB management. Successful outcome was defined as 90-day recurrence-free survival. Effect of intravenous antibiotic duration on 90-day recurrence risk was examined. 281 adult cases of MS-SAB were evaluated, of which 208 (74%) had a successful outcome. 176 cases (63%) received less than 14 days of intravenous antimicrobial therapy. Very short durations of intravenous therapy were associated with increased risk of recurrence (<7 days iv, 9.8% recurrence; 7-13 days, 1.4%; ≥14 days, 2.9%; p 0.005). This effect was robust to sensitivity analysis for total antimicrobial therapy duration of 14 days. CRP reduction of at least 37% from peak value at intravenous to oral antibiotic switch was associated with decreased risk of recurrence (<37% CRP reduction, 12% recurrence; >37%, 2.0%; p 0.001). Oral antimicrobial switch may allow safe reductions in duration of intravenous therapy in MS-SAB.

262. Epidemiology, Treatment, and Clinical Outcomes of Methicillin-Sensitive Staphylococcus aureus (MSSA) Bacteremia Complicated by Central Nervous System (CNS) Disease within the Veterans Affairs (VA) Healthcare System

Abstract Background The epidemiology of methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia (BSI) complicated by central nervous system (CNS) involvement is not well defined or described. We aimed to identify patients with MSSA BSI with CNS disease using imaging reports and define the epidemiology, characteristics, management, and associated clinical outcomes. Methods We conducted a retrospective study of inpatients (1/1/2014 to 10/31/2019) with MSSA BSI and head imaging (± 7 days of BSI). Imaging reports were categorized into probable, possible, or no CNS involvement. Charts were reviewed to assess source and metastatic sites of infection, severity of illness, and clinical course. Demographics, comorbidities, antibiotic use, and morbidity and mortality were electronically extracted from the corporate data warehouse. Primary antibiotic treatment was defined as the antibiotic received for the highest proportion of treatment course. Results 1852 patients had MSSA BSI and a head imagining performed. 151 (8%) had probable and 56 (3%) had possible CNS involvement. Embolic disease (n=167 [87%]) was the most common type of CNS disease (136 [83%] with probable CNS disease). Overall, high severity of illness defined by ICU admission (52%), vasopressor (7%), or mechanical ventilation (15%) was observed overall and was more common with probable CNS disease. Cefazolin was the most common primary antibiotic (71 [40%]), followed by nafcillin or oxacillin (51 [29%]). 16 (31%) patients had an adverse reaction to nafcillin. 69 (33%) patients died by day 30 and 88 (43%) by day 90. Recurrent CNS infections and bacteremia by day 90 was observed in 11 (6%) and 6 (3%). Conclusion We propose a definition of MSSA bacteremia complicated by CNS disease. CNS disease with MSSA bacteremia is infrequent with the most common manifestation being embolic disease. A significant number of patients with MSSA bacteremia were treated with cefazolin despite evidence of CNS disease. Overall mortality was high. Given higher rates of adverse drug events with nafcillin or oxacillin, comparative effectiveness studies are needed to further define the role of cefazolin for MSSA bacteremia with CNS disease. Disclosures All Authors: No reported disclosures

Matrix metalloproteinase MMP-8, TIMP-1 and MMP-8/TIMP-1 ratio in plasma in methicillin-sensitive Staphylococcus aureus bacteremia.

BackgroundMatrix metalloproteinase-8 (MMP-8) and tissue inhibitor of metalloproteinases-1 (TIMP-1) have been shown to predict prognosis in sepsis. However, MMP-8 and TIMP-1 in Staphylococcus aureus bacteremia (SAB) lacks evaluation and their role in the pathogenesis of SAB is unclear.MethodsMMP-8 and TIMP-1 and MMP-8/TIMP-1 molar ratio were determined at days 3, 5 and 28 from positive blood cultures in patients with methicillin-sensitive SAB and the connection to disease severity and early mortality was determined.ResultsAltogether 395 SAB patients were included. Patients with severe sepsis or infection focus presented higher MMP-8 levels at day 3 and 5 (p<0.01). Higher day 3 and 5 MMP-8 levels were associated to mortality at day 14 and 28 (p<0.01) and day 90 (p<0.05). Day 3 MMP-8 cut-off value of 203 ng/ml predicted death within 14 days with an area under the curve (AUC) of 0.70 (95% CI 0.57–0.82) (p<0.01). Day 5 MMP-8 cut-off value of 239 ng/ml predicted death within 14 days with an AUC of 0.76 (95% CI 0.65–0.87) (p<0.001). The results for MMP-8/TIMP-1 resembled that of MMP-8. TIMP-1 had no prognostic impact. In Cox regression analysis day 3 or 5 MMP-8 or day 3 MMP-8/TIMP-1 had no prognostic impact whereas day 5 MMP-8/TIMP-1 predicted mortality within 14 days (HR, 4.71; CI, 95% 1.67–13.3; p<0.01).ConclusionMMP-8 and MMP-8/TIMP-1 ratio were high 3–5 days after MS-SAB diagnosis in patients with an infection focus, severe sepsis or mortality within 14 days suggesting that matrix metalloproteinase activation might play a role in severe SAB.

266. Ceftriaxone Versus Cefazolin for the Treatment of Methicillin-Susceptible Staphylococcus aureus Bacteremia

BackgroundFew studies have evaluated the use of ceftriaxone (CRO) in the treatment of Methicillin-sensitive Staphylococcus aureus (MSSA) infections. Available studies include a small number of patients with MSSA bacteremia, with conflicting results and several limitations. The purpose of this study was to compare the safety and efficacy of CRO versus cefazolin (CFZ) for patients with MSSA bacteremia.MethodsThis was a multi-center, single health-system retrospective cohort study. Patients were included if they were at least 18 years old, had a primary episode of MSSA bacteremia within Saint Luke’s Health System and received CRO or CEFZ as definitive therapy for MSSA bacteremia. Patients were excluded if they had a previous MSSA bacteremia within 6 months, a polymicrobial infection, received combination antimicrobial therapy as definitive therapy, started treatment at outside hospital, treated for less than 72 hours, or deemed palliative or comfort care. The primary endpoint was clinical cure at 7, 10, 14, and 28 days, or discharge, whichever came first. Secondary endpoints included time to clinical cure or discharge, treatment failure at 90 days, time to treatment failure, readmission due to recurrent MSSA bacteremia at 30 and 90 days, duration of bacteremia, discontinuation of definitive treatment due to adverse drug events, incidence of Clostridiodes difficile infection, and hospital length of stay.ResultsA total of 248 patients met inclusion criteria. Among these, 87 (35.1%) received CRO and 161 (64.9%) received CFZ as definitive therapy. Patient baseline and treatment characteristics are shown in Table 1. The primary outcome occurred in 75 (86.2%) patients in the CRO group vs 145 (90.1%) patients in the CFZ group (P= 0.359), even after adjusting for Charlson Comorbidity Index, Pitt bacteremia score and serum creatinine, (aOR=0.74, 95% CI 0.32 – 1.72; p=0.473). There were no differences in time to clinical cure or discharge, treatment failure at 90 days, or safety events between the two groups. Primary and secondary endpoints are included in Table 2.Table 1 Table 2 ConclusionOur study suggests that there is no clinical difference between CRO and CFZ for the treatment of MSSA bacteremia. Further studies are needed to confirm these findings.Disclosures All Authors: No reported disclosures

28. Regulation of the Staphylococcal β-lactamase Plays a Major Role in the cefazolin Inoculum Effect

BackgroundCefazolin (Cz) is commonly used to treat methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia. Yet, some MSSA isolates producing the staphylococcal β-lactamase (BlaZ) exhibit the Cz inoculum effect (CzIE), defined as an increase in the minimum inhibitory concentration (MIC) to ≥ 16 µg/mL at high inoculum (107 CFU/mL, HI-MIC). Retrospective clinical data linked the CzIE to increased 30-day mortality and Cz treatment failure in patients with MSSA bacteremia, yet the mechanistic bases of this phenomenon are unknown. We aimed to explore the contribution of blaZ regulation, via BlaR (antibiotic sensor) and BlaI (transcriptional repressor) (Fig 1) to the CzIE by i) in trans expression assays and ii) analysis of their sequences in a set of isolatesFigure 1. Structure of the Staphylococcal bla OperonMethodsThe blaZ genes (with putative promoters) of strains exhibiting and lacking the CzIE (TX0117 and ATCC29213, respectively) were expressed in trans in RN4220 (blaZ neg) using the promotor-less vector pWM401 (Figure 2). We subsequently cloned the blaR and blaI genes of each TX0117 and ATCC29213 upstream of each blaZ allele (Figure 3). The presence of the CzIE was assessed in transformants using broth microdilution at standard (105 CFU/mL, SI-MIC) and high inoculum. We also performed whole-genome sequencing (WGS) in 104 MSSA isolates exhibiting and lacking the CzIE to compare the sequences of BlaZ, BlaR, and BlaI and classified them by allotypes (unique amino acid sequences) using ATCC29213 as reference. Figure 2. In trans expression of blaZ genes from a CzIE+ strain (TX0117) and a CzIE- strain (ATCC29213) in RN4220 Figure 3. In trans expression of the bla Operons from a CzIE+ strain (TX0117) and a CzIE- strain (ATCC29213) in RN4220ResultsExpression of blaZTX0117 and blaZATCC29213 with their native promoters in RN4220 resulted in the CzIE with Cz HI-MICs ≥ 64 µg/mL regardless of the origin of the allele (Table 1). Inclusion of the regulatory elements blaR and blaI from TX0117 (CzIE+) did not change the phenotype. In contrast, addition of blaR and blaI from ATCC29213 (CzIE-) led to a marked decrease in the Cz HI-MIC (Table 1). Sequence analyses of 104 MSSA isolates revealed 10, 17 and 6 BlaZ, BlaR and BlaI allotypes, respectively (Table 2). BlaZ-2 and BlaR-4 were linked to the CzIE in 90% of isolates. Table 1. MIC values of transformans after In trans expression of blaZ genes and bla Operons from a S. aureus CzIE+ strain(TX0117) and a CzIE- strain (ATCC29213) in RN4220 Table 2. BlaZ allotypes of 104 Staphylococcus aureus isolates and their association with the CzIEConclusionOur results suggest that overexpression of blaZ can lead to the CzIE in any MSSA strain. Thus, the regulation of blaZ expression via BlaR and BlaI seem to play a major role in the CzIE. Identification of specific BlaR and BlaI allotypes could predict the presence of the CzIE. Disclosures Cesar A. Arias, M.D., MSc, Ph.D., FIDSA, Entasis Therapeutics (Scientific Research Study Investigator)MeMed (Scientific Research Study Investigator)Merck (Grant/Research Support)

METHICILLIN-SENSITIVE STAPHYLOCOCCUS AUREUS (MSSA) INFECTION RESULTING IN A RARE CASE OF OSTEOMYELITIS PUBIS IN AN ELDERLY FEMALE: A CASE REPORT

A 71-year-old lady with rheumatoid arthritis developed painful peripheral vasculitic neuropathy of the lower limbs and was treated with high dose steroid and cyclophosphamide. Eight months later, she presented with left hip and back pain for a week, with minimal relief from regular analgesia. Although the initial pelvic radiograph was normal, a repeat film performed two weeks later showed a destructive lytic lesion in the left pubic bone, confirmed as osteomyelitis with intramuscular collection by MRI. Cloxacillin was started empirically, and when the blood culture isolated methicillin-sensitive Staphylococcus aureus (MSSA), it was planned to be given for six weeks via a peripherally inserted central catheter. Despite an initial response, she became febrile on the fifth week of antibiotic therapy. Subsequent blood culture isolated Trichosporon asahii. Her condition deteriorated, and she succumbed on the fourth day of antifungal therapy. In conclusion, the diagnosis of osteomyelitis pubis, a rare complication of MSSA bacteremia, could be delayed in an atypical presentation.

Management of methicillin sensitive Staphylococcus aureus bacteraemia in an antimicrobial stewardship age

Background: Methicillin sensitive Staphylococcus aureus bacteremia (MS-SAB) is associated with significant morbidity and mortality. Long courses of intravenous antibiotics are the traditionally recommended mainstay of treatment but are often not completed in clinical practice. Shorter courses are potentially attractive from an antimicrobial stewardship and resource perspective, but require a good evidence base. Methods: A retrospective audit of MS-SAB management within Newcastle-upon-Tyne Hospitals NHS Foundation Trust (2016-17). Laboratory database was used to identify all cases of MS-SAB. Demographic details, risk factors and management were recorded from patient records. Outcomes were defined as 90d recurrence-free survival, 30d mortality, 30-90d mortality and recurrence before 90d. Results: A total of 281 adult cases were identified with adequate data available for review. Predictors of early (30d) mortality were: age, 71.4y vs 58y p&lt;0.001; HAI, 21.4% vs 8.6% p=0.003; osteo-articular infections, 2.5% vs 17.1% p=0.016; but not antibiotic choice. In cases surviving 30d (n=238), median antibiotic durations were: intravenous 10d (range, 0-115), total 18d (0-316). 83% received ≥14d total, 41% received ≥14d intravenous. Receiving &lt;9d intravenous (OR 3.33 (95%CI 1.01- 10.95) or &lt;14d total therapy (OR 4.19 (1.37-12.84) was predictive of recurrent bacteraemia, as was non-beta-lactam therapy (16% vs 4%, p=0.006), and poor CRP response at end of intravenous therapy (68% vs 35% of peak CRP, p&lt;0.001). Conclusions: These data suggest lower durations (9-14d) of intravenous therapy could be safe in MS-SAB, however very short courses (&lt;9d) are associated with worse outcomes. This new evidence helps inform guidelines, balancing optimised patient outcomes alongside improved antimicrobial stewardship.

217. Combination Salvage Therapy with Cefazolin Plus Ertapenem for Refractory Methicillin-Susceptible Staphylococcus aureus Bacteremia

BackgroundSuboptimal therapy against methicillin-sensitive Staphylococcus aureus (MSSA) may have catastrophic consequences in severe infections such as endocarditis or epidural abscess. High MSSA inocula have been associated with clinical failure in patients receiving cefazolin (CZ), particularly when used at low doses, associated with a CZ inoculum effect. We previously described that adding ertapenem (ETP) to CZ led to synergism against MSSA and sensitized the pathogen to host innate immune factors. Here we expand our experience with CZ plus ETP as salvage therapy for 11 cases of refractory MSSA bacteremia (lacking source control problems) and explore CZ+ETP combination in vitro and in vivo.MethodsSix available MSSA strains from patients treated with CZ+ETP for refractory bacteremia were tested in Mueller–Hinton Broth or RPMI media at standard (105 CFU/mL) or high (107 CFU/mL) inocula by MIC, checkerboard, and time-kill assays using ETP, CZ or nafcillin (NAF) alone vs. ETP+NAF or ETP+CZ. Disk diffusion synergy assays between CZ and ETP were also performed. CZ, ETP and CZ+ETP were tested in a rat endocarditis model using well described MSSA, TX0117 and TX0117c.Results11 consecutive patients with MSSA bacteremia (6 confirmed endocarditis) refractory to standard CZ or NAF rapidly cleared with CZ+ETP. 9 patients had daily positive blood cultures, and 8 cleared in ≤24 hr, including those with ≥2 cm vegetations. All 11 survived hospitalization. In MHB, 3/6 MSSA exhibited a CZ inoculum effect (CZ MIC >3 log2 in 107 vs. 105 CFU/mL), but only 1 showed a significant CZ inoculum effect in RPMI. CZ+ETP was significantly more efficacious than CZ in a rat model of MSSA endocarditis utilizing a strain displaying a CZ inoculum effect, despite only modest benefit observed in vitro for 6 MSSA isolates.ConclusionCZ+ETP combination therapy yielded profound clinical success in severe MSSA infections with high bacterial densities, as demonstrated by rapid bacteremia clearance. Enhanced efficacy was also observed in a rat endocarditis model. The anti-staphylococcal activity of CZ+ETP in vivo exceeded that observed in vitro, consistent with our prior observations of host innate immune cooperativity with the regimen. CZ+ETP warrants further study for the treatment of refractory MSSA bacteremia and endocarditis.Disclosures All authors: No reported disclosures.

Outcome of methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia: impact of diabetes.

The aim of this study was to describe the epidemiology of methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia in a diabetic and a non-diabetic population of the University Hospital of Charleroi and to analyze medical outcomes, including risk of metastatic infection and mortality. Descriptive and multivariable analyses were performed using MedCalc 18.9 (MedCalc Software bvba, Ostend, Belgium). A total of 248 patients with MSSA bacteremia were identified between 1st January 2012 and 28th June 2017 out of which 32.7% were diabetic. Within the diabetic patients, we observed more prolonged hospital duration of stay (p = 0.034), more secondary bacteremia of cutaneous sources (including cellulitis, diabetic foot and ulcer) (p = 0.037), and more metastatic infection (p = 0.002). The overall 30-day mortality was 24.2% with no difference between the two groups. With a logistic regression analysis, it was demonstrated that age ≥ 60years (odds ratio (OR), 2.20 (95% CI, 1.03-4.67)) and Charlson Comorbidity Index (CCI) ≥ 3 (OR, 2.95 (95% CI, 1.51-5.79)) were the only independent risk factors of mortality, while removal of the primary site of infection was a protective factor (OR, 0.27 (95% CI, 0.12-0.62)). Risk of developing metastatic infection was increased with diabetes (OR, 2.08 (95% CI, 1.12-3.90)), while early empirical antibiotic therapy (OR, 0.38 (95% CI, 0.20-0.71)) decreased this risk. Diabetes was not associated with increased 30-day mortality after MSSA bacteremia. However, diabetes increased significantly the risk of metastatic infection. An aggressive treatment of MSSA bacteremia seems crucial to improve the outcome of diabetic patients.

STAPHYLOCOCCUS AUREUS BAKTERİYEMİLERİNDE MORTALİTE RİSK FAKTÖRLERİNİN ANALİZİ: SEFAZOLİN DAHA İYİ SONUÇLA İLİŞKİLİ

<div><!--block-->Objective: Methicillin-sensitive Staphylococcus aureus (MSSA) is frequent cause of bacteraemias and associated with substantial mortality. We defined risk factors for mortality among patients with either community-acquired (CA) or healthcare-associated (HCA) MSSA bacteraemia with special emphasis on treatment options including cefazolin and other antimicrobials (mainly ampicillin-sulbactam).&nbsp;<br><br>Material and Method: All adult patients who were hospitalized and whose blood cultures were positive for MSSA between 2009 and 2014 were included. Patients with CA and HCA MSSA bacteraemia were compared.&nbsp;<br><br>Results: 83% of the 127 patients with MSSA bacteraemia had HCA. The mortality rate of patients was 20.5% and this did not differ between patients with either CA or HCA MSSA bacteraemia. In the multivariate analysis, higher comorbidity index (HR 1.557), presence of metastatic foci (HR 2.883), and requirement for ICU support (HR 16.239) were found as independent risk factors for mortality, and cefazolin use was found to be protective against mortality (HR 0.178).&nbsp;<br><br>Conclusion: Patients with MSSA bacteraemia should be treated with cefazolin instead of other antimicrobial options, especially in countries where anti-staphylococcal penicillins are not available or in patients who cannot tolerate anti-staphylococcal penicillins, as cefazolin was found to be protective against mortality.&nbsp;</div>

Changes in hemostasis parameters in nonfatal methicillin‐sensitive Staphylococcus aureus bacteremia complicated by endocarditis or thromboembolic events: a prospective gender‐age adjusted cohort study

The aim of this study was to examine the changes in hemostasis parameters in endocarditis and thromboembolic events in nonfatal methicillin-sensitive Staphylococcus aureus bacteremia (MS-SAB) - a topic not evaluated previously. In total, 155 patients were recruited and were categorized according to the presence of endocarditis or thromboembolic events with gender-age adjusted controls. Patients who deceased within 90days or patients not chosen as controls were excluded. SAB management was supervised by an infectious disease specialist. Patients with endocarditis (N=21), compared to controls (N=21), presented lower antithrombin III at day 4 (p<0.05), elevated antithrombin III at day 90 (p<0.01), prolonged activated partial thromboplastin time at days 4 and 10 (p<0.05), and enhanced thrombin-antithrombin complex at day 4 (p<0.01). Thromboembolic events (N=8), compared to controls (N=34), significantly increased thrombin-antithrombin complex at day 4 (p<0.05). In receiver operating characteristic analysis, the changes in these hemostasis parameters at day 4 predicted endocarditis and thromboembolic events (p<0.05). No differences in hemoglobin, thrombocyte, prothrombin fragment, thrombin time, factor VIII, D-dimer or fibrinogen levels were observed between cases and controls. The results suggest that nonfatal MS-SAB patients present marginal hemostasis parameter changes that, however, may have predictability for endocarditis or thromboembolic events. Larger studies are needed to further assess the connection of hemostasis to complications in SAB.

Comparative Effectiveness of Exclusive Exposure to Nafcillin or Oxacillin, Cefazolin, Piperacillin/Tazobactam, and Fluoroquinolones Among a National Cohort of Veterans With Methicillin-Susceptible Staphylococcus aureus Bloodstream Infection

Beta-lactam antibiotics are recommended as first-line for treatment of methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia. The objective of this study was to compare effectiveness of anti-MSSA therapies among bacteremia patients exclusively exposed to 1 antimicrobial. This was a national retrospective cohort study of patients hospitalized in Veterans Affairs medical centers with MSSA bacteremia from January 1, 2002, to October 1, 2015. Patients were included if they were treated exclusively with nafcillin, oxacillin, cefazolin, piperacillin/tazobactam, or fluoroquinolones (moxifloxacin and levofloxacin). We assessed 30-day mortality, time to discharge, inpatient mortality, 30-day readmission, and 30-day S. aureus reinfection. Hazard ratios (HRs) and 95% confidence intervals (CI) were calculated using propensity-score (PS) matched Cox proportional hazards regression model. When comparing nafcillin/oxacillin (n = 105) with cefazolin (n = 107), 30-day mortality was similar between groups (PS matched n = 44; HR, 0.67; 95% CI, 0.11-4.00), as were rates of the other outcomes assessed. As clinical outcomes did not vary between nafcillin/oxacillin and cefazolin, they were combined for comparison with piperacillin/tazobactam (n = 113) and fluoroquinolones (n = 103). Mortality in the 30 days after culture was significantly lower in the nafcillin/oxacillin/cefazolin group compared with piperacillin/tazobactam (PS matched n = 48; HR, 0.10; 95% CI, 0.01-0.78), and similar when compared with fluoroquinolones (PS matched n = 32; HR, 1.33; 95% CI, 0.30-5.96). In hospitalized patients with MSSA bacteremia, no difference in mortality was observed between nafcillin/oxacillin and cefazolin or fluoroquinolones. However, higher mortality was observed with piperacillin/tazobactam as compared with nafcillin/oxacillin/cefazolin, suggesting it may not be as effective as a monotherapy in MSSA bacteremia.

1067. Comparative Effectiveness of Nafcillin or Oxacillin, Cefazolin, and Piperacillin/Tazobactam in Methicillin-Sensitive Staphylococcus aureus Bacteremia

Backgroundβ-Lactam antibiotics are recommended as first line for treatment of methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia. The objective of this study was to compare effectiveness among β-lactam therapies in MSSA bacteremia patients that were exclusively treated with one antibiotic.MethodsThis was a retrospective cohort study of patients hospitalized at Veterans Affairs (VA) medical centers with MSSA bacteremia from January 1, 2002 to October 1, 2015. Patients were included if they were treated exclusively with nafcillin, oxacillin, cefazolin, or piperacillin/tazobactam (i.e., monotherapy with no changes in therapy). The primary outcome was 30-day mortality, and secondary outcomes were time to discharge, inpatient mortality, 30-day readmission, and 30-day S. aureus reinfection. Hazard ratios (HRs) and 95% confidence intervals (CI) were calculated using unadjusted, quintile adjusted, and propensity-score (PS) matched (nearest neighbor, 0.05 caliper) Cox proportional hazards regression.ResultsA total of 326 patients were included in the final analysis. When comparing nafcillin (n = 75)/oxacillin (n = 30) with cefazolin (n = 108), 30-day mortality was similar between groups (PS matched n = 40, HR 4.0, 95% CI 0.45–35.79), as were rates of the other outcomes assessed. When combining nafcillin/oxacillin with cefazolin, and comparing to piperacillin/tazobactam (n = 113), 30-day mortality was significantly lower in the nafcillin/oxacillin/cefazolin group (PS matched n = 66, HR 0.29, 95% CI 0.09–0.87). Inpatient mortality and 30-day mortality were significantly lower with nafcillin/oxacillin/cefazolin in PS-adjusted analyses (HR 0.29, 95% CI 0.11–0.73 and HR 0.23, 95% CI 0.10–0.50, respectively).ConclusionIn hospitalized patients with MSSA bacteremia, no difference in mortality was observed between nafcillin/oxacillin and cefazolin in patients that were exclusively treated with these monotherapies. However, higher mortality was observed with piperacillin/tazobactam as compared with nafcillin/oxacillin/cefazolin, suggesting that it may not be as effective as other monotherapies for MSSA bacteremia.Disclosures K. LaPlante, Merck: Grant Investigator, Research grant. Pfizer Pharmaceuticals: Grant Investigator, Research grant. Allergan: Scientific Advisor, Honorarium. Ocean Spray Cranberries, Inc.: Grant Investigator and Scientific Advisor, Honorarium and Research grant. Achaogen, Inc.: Scientific Advisor, Honorarium. Zavante Therapeutics, Inc.: Scientific Advisor, Honorarium. A. Caffrey, Merck: Grant Investigator, Research grant. The Medicine’s Company: Grant Investigator, Research grant. Pfizer: Grant Investigator, Research grant.

1216. Cost-Effectiveness of Penicillin Skin Allergy Testing in Methicillin-Sensitive Staphylococcus aureus (MSSA) Bacteremia

Backgroundβ-Lactams remain the gold standard for treatment of MSSA bacteremia due to superior outcomes compared with vancomycin. Approximately nine in 10 patients receiving penicillin skin testing (PST) will be de-labeled of a penicillin allergy and able to receive a β-lactam antibiotic. The study aims to evaluate the cost-effectiveness of penicillin allergy confirmation during acute care admission for methicillin-sensitive staphylococcus aureus (MSSA) bacteremia through a PST service.MethodsA decision tree analysis was used to compare a PST intervention in patients with a registeredpenicillin allergy during an inpatient admission for MSSA bacteremia vs. usual care (No PST). The model was created from the health sector perspective with a 1-year time horizon. Patients with a penicillin allergy label were expected to receive vancomycin while patients with no penicillin allergy were expected to receive cefazolin. Potential inpatient, outpatient, and adverse reaction costs were considered in all arms of the model. The effects were measured in quality adjusted life years (QALY) and were calculated for patients who were cured, hospitalized, experienced severe adverse events, or died from MSSA infection.ResultsPatients who received PST services had a mean yearly cost of $12,802, mean quality adjusted life years (QALY) of 0.70, and mean cost/QALY of $18,311. The comparator group not receiving PST services had a mean yearly cost of $12,264, mean quality adjusted life years (QALY) of 0.64, and mean cost/QALY of $19,192. The model produced a final base case ICERof $8,966/QALY for receiving a PST during a hospital admission for the treatment of methicillin-sensitive staphylococcus aureus (MSSA) bacteremia.ConclusionPenicillin allergy confirmation through PST services was cost-effective for patients with a reported penicillin allergy admitted for MSSA bacteremia. Additional research to determine potential benefits of PST services beyond one year could further improve the cost-effectiveness of this intervention.Disclosures S. Meninger, ALK-Abelló: Grant Investigator, Research grant. E. Heil, ALK-Abelló: Grant Investigator, Research grant. T. J. Mattingly II, ALK-Abelló: Grant Investigator, Research grant.

Meta-analysis of trials comparing cefazolin to antistaphylococcal penicillins in the treatment of methicillin-sensitive Staphylococcus aureus bacteraemia.

The objective of this study was to determine the effectiveness and safety of cefazolin vs. antistaphylococcal penicillin (ASP) in the treatment of methicillin-sensitive Staphylococcus aureus (MSSA) bacteraemia. The databases of PubMed, Embase and Cochrane Central were used to identify comparative trials of cefazolin vs. ASP in MSSA bacteraemia. Meta-analysis of included trials was performed to assess any differences regarding mortality, clinical cure, recurrence and withdrawal from adverse effects between groups. Data were analysed using fixed effect model. Studies were weighted using Mantel-Haenszel methodology. Heterogeneity was calculated using the I2 statistic. Nine retrospective and one prospective trials were identified involving 4728 patients, 2954 with ASP and 1774 with cefazolin. Meta-analysis showed a lower mortality rate with cefazolin vs. ASP using fixed effect model [risk ratio (RR) 0.78, 95% confidence interval (CI) 0.69-0.88, P<0.0001] with borderline high heterogeneity (I2 =51%). Clinical cure was noted more often with cefazolin (RR 1.09, 95% CI 1.02-1.17, P=0.02), although no difference was noted with relapse (RR 1.29, 95% CI 0.96-1.74 P=0.09). Analysis also showed more withdrawals from adverse events with ASP vs. cefazolin (RR 0.27, 95% CI 0.16-0.47, P<0.00001). A minority of patients enrolled in these trials were admitted to the intensive care unit or had endocarditis (11.4% with ASP and 9% with cefazolin). Our meta-analysis of retrospective data demonstrate that cefazolin is more effective and safer ASP in patients with MSSA bacteraemia from various causes. Low quality of trials, borderline high heterogeneity, and possible publication bias may limit the validity of our findings. Randomized trials are needed to confirm these findings.

Are we missing the Staphylococcus aureus bacteraemia forest for the MRSA trees?

In this edition of the journal, Jokinen et al. report on a population based study of Staphylococcus aureus bacteraemia (SAB) in Finland. They observe increasing incidence of cases over time that are associated with an increase in blood culture sampling. As compared to methicillin-sensitive SAB that increases during the study period, the incidence of methicillin-resistant SAB increases and then decreases. The proportion of cases with penicillin-sensitive SAB markedly increases in the study representing 43% of isolates in the most recent year of surveillance. While much attention and focus is typically placed on methicillin-resistant SAB, the major part of the burden of illness associated with SAB is from methicillin-sensitive and penicillin-sensitive strains. A narrow focus on prevention of methicillin-resistant Staphylococcus aureus will only have a limited impact on the overall burden of disease due to SAB.

Once-Daily Treatments for Methicillin-Susceptible Staphylococcus aureus Bacteremia: Are They Good Enough?

Methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia is a common cause of morbidity and mortality. First-line treatment requires frequent daily doses of an anti-staphylococcal beta-lactam. However, some physicians prescribe simpler once-daily regimens to improve compliance and improve healthcare utilization. We reviewed the literature regarding advantages, pitfalls, and efficacy of once-daily treatment options for MSSA bacteremia. Several once-daily antibiotics are effective in vitro against MSSA (ceftriaxone, daptomycin, telavancin, dalbavancin, oritavancin, tedizolid, ertapenem, fluoroquinolones, and others), but there is insufficient evidence to support these agents for MSSA bacteremia. Ceftriaxone may be considered for therapy completion with MSSA bacteremia from osteomyelitis, and daptomycin may be considered in patients who cannot tolerate first-line therapy. However, they have not been compared to traditional second-line agents, and their role remains uncertain. Current evidence does not support the use of once-daily treatment options for MSSA bacteremia.

Prognostic impact of hyperglycemia at onset of methicillin-sensitive Staphylococcus aureus bacteraemia.

Previous reports have associated hyperglycemia to poor outcome among aged and comorbid Staphylococcus aureus bacteraemia (SAB) patients. However, the prognostic impact of hyperglycemia in SAB irrespective of age and underlying conditions including a diagnosis of diabetes has received little attention. The objective here was to evaluate the prognostic relevance of hyperglycemia at onset of methicillin-sensitive SAB (MS-SAB). It was a retrospective study of MS-SAB patients. Blood glucose was measured within 24h of positive blood cultures. The patient cohort was analyzed en bloc and by categorization according to age, underlying conditions and a diagnosis of diabetes. Altogether 161 patients were identified. High initial blood glucose levels were observed among diabetics (p < 0.001), patients with deep infections (p < 0.05) and poor outcome at 28- or 90-days (p < 0.05). Receiver operating characteristics presented the glucose cut-off level of 7.2mmol/L as a significant predictor of mortality with an area under the curve of 0.63 (95% CI 0.52-0.75, p < 0.05). Blood glucose ≥7.2mmol/L connected to higher 28- (9 vs. 20%, p < 0.05) and 90-day (14 vs. 29%, p < 0.01) mortality. In Cox proportional hazard regression the blood glucose cut-off value of 7.2mmol/L significantly predicted 90-day mortality (HR, 2.12; 95% CI, 1.01-4.46; p < 0.05). Among young and healthy non-diabetics the negative prognostic impact of high glucose was further accentuated (HR 7.46, p < 0.05). High glucose levels had no prognostic impact among diabetics. Hyperglycemia at SAB onset may associate to poor outcome. The negative prognostic impact is accentuated among young and healthy non-diabetics.

Thrombocytopaenia during methicillin-sensitive Staphylococcus aureus bacteraemia.

The prognostic impact of thrombocytopaenia in Staphylococcus aureus bacteraemia (SAB) has previously been determined at bacteraemia onset only and relevant pre-bacteraemic thrombocytopaenia predisposing parameters have not been accounted for. We evaluated the prognostic impact of low thrombocyte count in SAB excluding pre-bacteraemic factors potentially causing thrombocytopaenia. This was a multicentre retrospective analysis of methicillin-sensitive SAB (MS-SAB) patients. Thrombocyte count was determined at blood culture collection and at days 3 and 7. Thrombocytopaenia was defined as a thrombocyte count less than 150 ×109/L. Patients with chronic alcoholism, liver diseases and haematologic malignancies were excluded. Altogether, 495 patients were identified. Thrombocytopaenia at blood culture and at day 3 associated to endocarditis (p < 0.05 and p < 0.01) and defervescence (p < 0.001 and p < 0.01). Mortality at 90days was higher for patients with thrombocytopaenia at blood culture collection (26 vs. 16%, p < 0.05), at day 3 (32 vs. 13%, p < 0.01) and at day 7 (50 vs. 14%, p < 0.001). In receiver operating characteristic analyses, thrombocytopaenia predicted a poor outcome at blood culture collection (p < 0.05), at day 3 (p < 0.001) and at day 7 (p < 0.001). When accounting for all prognostic parameters, thrombocytopaenia at day 3 [hazard ratio (HR), 1.83; p = 0.05] demonstrated a trend towards poor outcome, whereas thrombocytopaenia at day 7 (HR, 3.64; p < 0.001) associated to poor outcome. Thrombocytopaenia at blood culture collection was not a prognostic parameter when all prognostic factors were taken into account. However, thrombocytopaenia at day 3 indicated a poor outcome and thrombocytopaenia at day 7 was a significant independent negative prognostic marker that has not been previously reported in SAB.