Ceftriaxone as an Alternative Therapy for the Treatment of Methicillin-Susceptible Staphylococcus aureus Bacteremia after Initial Clearance of Bloodstream Infection

Introduction Staphylococcus spp. represent the leading cause of hospital-acquired infections and second-most frequent pathogen in bloodstream infections. Methicillin-susceptible S. aureus (MSSA) comprise approximately half of all S. aureus isolates. Standard-of-care therapies (SOCTs) display high treatment success but require frequent dosing, are problematic in penicillin allergic patients, and are nephrotoxic. Ceftriaxone may represent an alternative treatment option. Methods Adult patients hospitalized from January 2015 through June 2016 with positive MSSA blood cultures and treated with SOCT or ceftriaxone for ≥48 hours were included. Exclusion criteria were receipt of vancomycin or concomitant systemic antimicrobials with activity against MSSA, polymicrobial infections, and pregnant patients. Additional data collected included demographics, source/site of infection, and treatment. The primary endpoint was clinical cure (normalization of white blood cell count and temperature within 7 days and clearance of bloodstream within 7 days). Readmission within 60 days, length of stay, and discharge disposition were collected. Results A total of 43 patients were included: 23 receiving SOCT and 20 receiving ceftriaxone group. Sixteen patients received SOCT prior to ceftriaxone while 4 patients were initiated on ceftriaxone. Clinical cure was observed in 18/23 (78%) and 10/20 (50%), respectively (P=0.052). Clinical failure was driven by leukocytosis despite clearance of their bloodstream infection in 3/23 (13%) SOCT group compared to 8/20 (40%) in the ceftriaxone group (P=0.043). Six patients (SOCT: 2, ceftriaxone: 4; p=0.669) had infection-related readmissions, and 1 death per group was observed. Conclusion Ceftriaxone poses a reasonable alternative to consider for MSSA bacteremia when cost and feasibility are concerns for outpatient parenteral therapy after initial clearance of bloodstream infections.


Introduction
Staphylococcus aureus is a virulent pathogen and a cause of great morbidity and mortality worldwide, leading to complications in 11-53% of patients [1,2].
Currently, standard-of-care therapy (SOCT) for MSSA bacteremia includes intravenous (IV) anti-staphylococcal penicillins (ASPs) for 4 weeks or longer, depending on infection site and presence of metastatic complications [5]. ASPs, predominantly nafcillin and oxacillin, require frequent dosing (every 4 hours), are costly, and are associated with a high likelihood of adverse effects [5]. ese frequent dosing intervals place a high burden on nursing staff. In addition, for patients discharged home requiring IV antibiotic treatment for several weeks, a medication requiring administration every 4 hours is often not practical or feasible, when alternative dosing regimens are not available. Average wholesale prices (AWPs) of nafcillin (2 g, 6 times daily) and oxacillin (2 g, 6 times daily) are $224 and $174 per day, respectively [6,7]. Additionally, adverse effects associated with these agents include hepatotoxicity (22%), neutropenia (17%), rash (32%), and renal dysfunction (33%) [8][9][10]. ese adverse effects generally occur after 2 weeks of therapy, resulting in premature discontinuation in 33.8% of patients [8].
An alternative to ASP treatment for MSSA bacteremia is a cephalosporin. Cefazolin has been the most frequently studied cephalosporin in the setting of MSSA [8,[10][11][12]. Compared to ASPs, cefazolin has an improved dosing regimen with administration every 8 hours. Additionally, cefazolin (2 g, 3 times daily) is cheaper than ASPs with an AWP of $45 per day [13]. Patients treated with cefazolin for MSSA bacteremia experience fewer adverse effects than those treated with ASPs; premature discontinuation was observed in only 6.7% of patients [5,8]. Most studies have shown similar efficacy between ASPs and cephalosporins. However, cefazolin is hindered by an inoculum effect and so may be less efficacious in disease states with a high bacterial burden, including infective endocarditis. A systematic review and meta-analysis demonstrated lower 30-day mortality with ASPs in an unadjusted analysis; however, propensity-adjusted score data showed no difference in 30day mortality between ASPs and cephalosporins [14].
While cefazolin improves the dosing regimen, decreases cost, and decreases adverse effects when compared to ASPs, it still requires frequent dosing. is is a great burden for outpatient antibiotic services and on patients themselves. Ceftriaxone presents an attractive alternative to ASPs or cefazolin and can be dosed once daily. Few studies have investigated the use of ceftriaxone as an alternative to SOCT [15][16][17]. Additionally, ceftriaxone (2 g, daily) has a low AWP of $29 per day. Its adverse effect profile is favorable with no renal dosage adjustment requirements, and it is well tolerated [18]. In this retrospective study, we sought to evaluate the efficacy of ceftriaxone compared to SOCT in patients hospitalized with MSSA bacteremia.

Study Design.
All adult inpatients with positive blood cultures for MSSA were evaluated for inclusion in this single-center cohort study. e primary objective was to determine clinical cure rates for MSSA bacteremia with ceftriaxone versus SOCT. Clinical cure was a composite endpoint defined as resolution of fever, normalization of white blood cell (WBC) count, and negative blood cultures within 7 days of starting therapy similar to prior studies of S. aureus infections [19][20][21]. Secondary outcomes included microbiological cure rates, length of stay, and disease recurrence. Microbiological cure rate was defined as negative blood cultures within 7 days of starting therapy. Disease recurrence was defined as the incidence of a positive blood culture with MSSA after an initial clearance within 6 months of completion of therapy. e ceftriaxone group was defined as patients that definitively received ceftriaxone therapy.

Patient Selection.
Patients admitted and diagnosed with MSSA bacteremia between February 1, 2015, and January 31, 2016, were eligible for inclusion. Patients were identified through eraDoc ® clinical decisions support software and were stratified into two treatment groups: SOCT or ceftriaxone/SOCT followed by ceftriaxone therapy. SOCT was defined as treatment with nafcillin, oxacillin, or cefazolin. Patients were included if they received ≥48 hours of therapy and treated with the appropriate duration for the source of their bloodstream infection. Excluded patients were those treated definitively with vancomycin for their MSSA infection, received alternative antimicrobials with in vitro MSSA activity, patients with polymicrobial infections, or pregnant women. Patients could only be included for their first MSSA bloodstream infection during the study period. No written consent was obtained from the patients as there are no patient identifiable data included in this case series.

Data Collection.
Patient demographics, source of infection, infection acquisition, and treatment regimen were collected. Infection acquisition was defined as follows: community if the patient came in with the infection; nosocomial if the infection developed ≥48 hours of admission; healthcare defined as hospitalization in an acute care hospital for two or more days within 90 days of the infection, resided in a nursing home or long-term care facility, received recent intravenous antibiotic therapy, chemotherapy, or wound care within the past 30 days of the current infection, or attended a hospital or hemodialysis clinic. Additional data collected included clinical cure, microbiological cure, readmission for another MSSA infection within 60 days of clearance of the initial bacteremia, length of stay, retreatment within 3 months of discharge, mortality, and discharge disposition.

Statistical Analysis.
All consecutive patients meeting inclusion criteria were analyzed. Descriptive statistics were calculated; continuous, normally distributed data were analyzed using the Student's t-test, and non-normal data were analyzed using the Mann-Whitney U test. Chi square or Fisher's exact test was used to compare nominal data. A 2sided P value of <0.05 was considered statistically significant. Statistical analysis was performed using SPSS software version 24.0 (IBM).

Results
One hundred ninety-four patients were screened for inclusion with 43 (22.1%) patients meeting inclusion criteria ( Figure 1). Twenty-three (53.5%) patients received SOCT only; 16 (37.2%) patients received SOCT before transitioning to ceftriaxone; 4 (9.3%) patients received only ceftriaxone. Due to the limited number of patients in the ceftriaxone arm, those patients were analyzed with patients who were transitioned to ceftriaxone after initial treatment with SOCT.

Discussion
In this study, we evaluated SOCT as compared to ceftriaxone or SOCT followed by ceftriaxone. Clinical cure, a composite endpoint, was not statistically different between groups. Although there was an almost 30% difference numerically, this was largely driven by white blood count resolution in 7 days, which was significantly different between groups. e 10 patients who did not meet the day 7 endpoint had a mean white blood count normalization within 14 days. e other two components of the composite endpoint (cultures cleared in 7 days and temperature normalization in 7 days) were not different between groups. It is important to note that, while cultures cleared in both groups, patients in both groups received a median of 5 days of SOCT, which is likely responsible for clearing the blood cultures. Mortality and readmissions were not different between groups. Interestingly, both hospital length of stay and MSSA bacteremiarelated length of stay were numerically longer in the ceftriaxone group, but this was not statistically significant.
ese results suggest that, after cultures are clear, ceftriaxone may be appropriate follow-up or continuation therapy for patients initially hospitalized with MSSA bacteremia.
Few studies have evaluated ceftriaxone versus SOCT for MSSA bloodstream infections, and all have small sample  sizes [17,22]. Despite this, we found comparable microbiological cure rates for both treatment arms (SOCT [91.3% vs 94.1%] and ceftriaxone [80% vs 95.2%]) and no differences between the groups in clinical cure rates [22]. However, Patel and colleagues' study (n � 93) was performed at a VA Hospital and included a predominately older all-male population (median age � 68 years SOCT, 63 years ceftriaxone), whereas our study had an evenly distributed gender as well as a much younger population (median age � 45 years). Additionally, the majority of their patients received ceftriaxone in an ambulatory setting, whereas all of our patients were treated initially as inpatients, regardless of treatment group. Another evaluation of ceftriaxone for MSSA bloodstream infections (n � 71) performed by Carr and colleagues also took place at a VA Medical Center and found similar failure rates [17]. However, in this study, failure was associated with ceftriaxone usage despite similar durations of bacteremia and days of empiric therapy to our study. Lastly, a study by Paul and colleagues evaluated outcomes for betalactams against MSSA bacteremia which determined that odds of death were lower for oxacillin or cefazolin versus other betalactams [23]. However, data were not provided on patient characteristics or specific outcomes with ceftriaxone treated patients. If we were to remove WBC from the definition of clinical cure, our clinical cure rates are more comparable at 80% for ceftriaxone treated patients and 78% for SOCT patients. is study is not without limitations. First, there were a limited number of patients who qualified for inclusion. is is because patients who received vancomycin or other agents with MSSA coverage (piperacillin-tazobactam, cefepime, etc.), which are routinely used at our hospital, were excluded. Second, only four patients received ceftriaxone as initial therapy. As a result, conclusions cannot be derived from this information regarding ceftriaxone as initial therapy. In addition, both groups received SOCT initially, further limiting the ability to determine the clinical utility of ceftriaxone before cultures have cleared. Next, a composite endpoint was used to define "clinical cure," which may have impacted significance and may not correlate with markers used to determine cure or resolution in clinical practice. Finally, readmission rates, reoccurrences, and mortality were determined from our hospital system. Patients who presented to outside hospitals or were treated as outpatients may not be appropriately represented in these data.
In summary, there was no difference in clinical cure rates between SOCT and ceftriaxone for MSSA bacteremia. Ceftriaxone poses a reasonable alternative to consider for MSSA bacteremia when cost and feasibility are concerns for outpatient parenteral therapy after initial clearance of bloodstream infections.

Data Availability
No data were used to support this study.

Disclosure
is work was presented, in part, at ID Week 2016 in New Orleans, LA (poster 1077).