BACKGROUND: This meta-analysis aims to evaluate the effectiveness of combination therapy for treating MSSA bacteremia.
METHODS: We searched Ovid MEDLINE, EMBASE, Cochrane CENTRAL, and clinicaltrials.gov for studies including adults with MSSA bacteremia. The monotherapy group used a first-line antibiotic active against MSSA and the combination group used a first-line antibiotic plus additional antibiotic/s. The primary outcome was all-cause mortality. Secondary outcomes included persistent bacteremia, duration of bacteremia, relapse, and adverse events. Random-effects models with inverse variance weighting were used to estimate pooled risk ratios (pRR). Heterogeneity was assessed using the I2 value and the Cochrane\'s Q statistic.
RESULTS: A total of 12 studies (6 randomized controlled trials [RCTs]) were included. Combination therapy did not significantly reduce 30-day mortality (pRR 0.92, 95% CI, 0.70-1.20), 90-day mortality (pRR 0.89, 95% CI, 0.74-1.06), or any-time mortality (pRR 0.91, 95% CI, 0.76-1.08). Among patients with deep-seated infections, adjunctive rifampicin may reduce 90-day mortality (3 studies with moderate-high risk of bias; pRR 0.62, 95% CI, 0.42-0.92). For secondary outcomes, combination therapy decreased the risk of relapse (pRR 0.38, 95% CI, 0.22-0.66), but this benefit was not maintained when pooling RCTs (pRR 0.54, 95% CI, 0.12-2.51). Combination therapy was associated with an increased risk of adverse events (pRR 1.74, 95% CI, 1.31-2.31).
CONCLUSIONS: Combination therapy not only did not decrease mortality in patients with MSSA bacteremia, but also increased the risk of adverse events. Combination therapy may reduce the risk of relapse, but additional high-quality studies are needed.

Optimal therapy for methicillin-susceptible Staphylococcus aureus (MSSA) infections is unclear. The current standard of care consists of anti-staphylococcal antibiotics (ASA), such as nafcillin, oxacillin, and cefazolin. Ceftriaxone has been evaluated due to its advantage as a once-daily outpatient regimen. However, questions remain regarding efficacy compared to ASA. We aimed to conduct a review and synthesis of available literature for outcomes of patients treated with ceftriaxone or ASA for MSSA infections. We searched Cochrane Central Register of Controlled Trials, Embase, Ovid MEDLINE, Scopus, and Web of Science from 1990 to June 2021. Risk of bias for cohort studies was assessed by the Newcastle-Ottawa quality scale. We pooled risk ratios (RR) using the DerSimonian-Laird random effects model for outcomes of those who received ceftriaxone compared to ASA. Heterogeneity was assessed by the I2-index. From 459 identified studies, 7 were included in the quantitative synthesis totalling 1640 patients. Definitive therapy with ceftriaxone was associated with a lower risk of toxicity requiring alteration of therapy [RR 0.49 (95% confidence interval [CI] 0.27-0.88, I2=0%)]. There was no difference in terms of 90-day all-cause mortality [RR 0.93 (95% CI 0.46-1.88, I2=9%)], hospital readmission [RR 0.96 (95% CI 0.57-1.64, I2=0%)], or infection recurrence [RR 1.04 (95% CI 0.63-1.72, I2=0%)]. Current evidence suggests there is no difference in efficacy between ceftriaxone and ASA for MSSA infection, with a lower risk of toxicity with ceftriaxone. Within the limitations of available retrospective studies, ceftriaxone is a consideration for definitive therapy of MSSA infection. [Trial registration: PROSPERO ID: CRD42021259086].

OBJECTIVE: We compared the effectiveness of cefazolin and cloxacillin as definitive antibiotic therapy for methicillin-susceptible Staphylococcus aureus (MSSA) spinal epidural abscess (SEA).
METHODS: This retrospective cohort study included patients with MSSA SEA from two academic hospitals in Hamilton, Ontario, Canada, between 2014 and 2020. Patients treated with cefazolin were compared to those treated with cloxacillin. Co-primary outcomes included 90-day mortality, antibiotic failure, adverse reactions and recurrence. Inverse probability of treatment weighting using propensity scores was used to balance important prognostic factors and to estimate an adjusted risk difference.
RESULTS: Of 98 patients with MSSA SEA, 50 and 48 patients were treated with cefazolin and cloxacillin, respectively. Mortality at 90 days was 8% and 13% in the cefazolin and cloxacillin groups, respectively (P = 0.52). The antibiotic failure rate was 12% and 19% in the cefazolin and cloxacillin groups, respectively (P = 0.41). The serious adverse reactions rate was 0% and 4% in the cefazolin and cloxacillin groups, respectively (P = 0.24). The recurrence rate was 2% and 8% in the cefazolin and cloxacillin groups, respectively (P = 0.20). The adjusted risk difference for mortality at 90 days was -1% [95% confidence interval (CI) -10% to 8%] favouring cefazolin. The adjusted risk differences for antibiotic failure, adverse reactions and recurrence were 1% (95% CI -12% to 14%), -5% (95% CI -11% to 2%) and -18% (-36% to -1%) respectively.
CONCLUSIONS: Cefazolin is likely as effective as an antistaphylococcal penicillin and may be considered as a first-line treatment for MSSA SEA.

BACKGROUND: Methicillin-susceptible Staphylococcus aureus (MSSA) is a frequent cause of bloodstream infections (BSI). Treatment with nafcillin (NAF) has been preferred to cefazolin (CFZ). However, comparable outcomes have been found with CFZ with possibly lower risk for side-effects. This study compared safety and effectiveness of NAF versus CFZ for MSSA BSI.
METHODS: This single center retrospective study evaluated adults admitted with MSSA BSI who received NAF or CFZ. Patients receiving ≥24 h of antibiotics were included for safety analyses. Patients receiving NAF or CFZ for ≥75% of a 14 day minimum treatment course were assessed for clinical effectiveness. The primary safety outcome was incidence of renal toxicity with multiple secondary safety endpoints. Clinical success was defined as symptom resolution, repeat negative cultures, lack of additional therapy for presumed failure, and lack of recurrence within 30 days.
RESULTS: A total of 130 patients receiving NAF (n = 79) or CFZ (n = 51) were included for safety analysis. Of those, 90 met criteria for effectiveness assessment (NAF n = 40, CFZ n = 50). Baseline characteristics were well matched. NAF was associated with a higher incidence of nephrotoxicity compared to CFZ (25% vs. 2%, RR 1.31, 95% CI 1.15-1.5, p < 0.001), allergic reactions (p = 0.01) and a trend for hepatotoxicity (p = 0.08). Clinical success was achieved in 82% NAF and 94% CFZ treated patients (p = 0.1).
CONCLUSIONS: CFZ was associated with less nephrotoxicity and no difference in clinical success compared to NAF for MSSA BSI. A prospective study comparing NAF to CFZ for MSSA BSI should be conducted to elucidate differences in therapies.

BACKGROUND: Vancomycin may be inferior to β-lactams for the empiric treatment of methicillin-susceptible Staphylococcus 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 bacteremia, 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). Transition 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.

We report characterization of a methicillin-susceptible, vancomycin-resistant bloodstream isolate of Staphylococcus aureus recovered from a patient in Brazil. Emergence of vancomycin resistance in methicillin-susceptible S. aureus would indicate that this resistance trait might be poised to disseminate more rapidly among S. aureus and represents a major public health threat.

Both bacteremia and infective endocarditis caused by Staphylococcus aureus are common and severe diseases. The prognosis may darken not infrequently, especially in the presence of intracardiac devices or methicillin-resistance. Indeed, the optimization of the antimicrobial therapy is a key step in the outcome of these infections. The high rates of treatment failure and the increasing interest in the influence of vancomycin susceptibility in the outcome of infections caused by both methicillin-susceptible and -resistant isolates has led to the research of novel therapeutic schemes. Specifically, the interest raised in recent years on the new antimicrobials with activity against methicillin-resistant staphylococci has been also extended to infections caused by susceptible strains, which still carry the most important burden of infection. Recent clinical and experimental research has focused in the activity of new combinations of antimicrobials, their indication and role still being debatable. Also, the impact of an appropriate empirical antimicrobial treatment has acquired relevance in recent years. Finally, it is noteworthy the impact of the implementation of a systematic bundle of measures for improving the outcome. The aim of this clinical guideline is to provide an ensemble of recommendations in order to improve the treatment and prognosis of bacteremia and infective endocarditis caused by S. aureus, in accordance to the latest evidence published.

Bacteremia and infective endocarditis caused by Staphylococcus aureus are common and severe diseases. Optimization of treatment is fundamental in the prognosis of these infections. The high rates of treatment failure and the increasing interest in the influence of vancomycin susceptibility in the outcome of infections caused by both methicillin-susceptible and -resistant isolates have led to research on novel therapeutic schemes. The interest in the new antimicrobials with activity against methicillin-resistant staphylococci has been extended to susceptible strains, which still carry the most important burden of infection. New combinations of antimicrobials have been investigated in experimental and clinical studies, but their role is still being debated. Also, the appropriateness of the initial empirical therapy has acquired relevance in recent years. The aim of this guideline is to update the 2009 guidelines and to provide an ensemble of recommendations in order to improve the treatment of staphylococcal bacteremia and infective endocarditis, in accordance with the latest published evidence.