By Dean L. Winslow, MD, FACP, FIDSA, FPIDS

Professor of Medicine, Division of General Medical Disciplines, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine

Dr. Winslow reports no financial relationships relevant to this field of study.

SYNOPSIS: In a retrospective cohort study of 350 patients, the combination of a beta-lactam antibiotic plus daptomycin was not superior to beta-lactam monotherapy in patients with bacteremia due to methicillin-susceptible Staphylococcus aureus.

SOURCE: Grillo S, Cuervo G, Carratala J, et al. Impact of β-lactam and daptomycin combination therapy on clinical outcomes in methicillin-susceptible Staphylococcus aureus bacteremia: A propensity score-matched analysis. Clin Infect Dis 2019;69:1480-1488.

Researchers at a university hospital in Spain conducted a retrospective cohort study of 514 patients with methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia. After excluding 164 patients who died in the first 48 hours in the hospital or who were treated with antibiotic combinations other than beta-lactam/daptomycin, 350 patients were evaluable. Investigators performed a 1:2 matched propensity score analysis and analyzed the data using Cox regression analysis. One hundred thirty-six patients received a beta-lactam antibiotic plus daptomycin and 214 patients received beta-lactam monotherapy. Patients who received beta-lactam plus daptomycin therapy had higher Pitt scores (a prognostic score) and persistent bacteremia more often than beta-lactam monotherapy patients. In the raw analysis, the researchers found no differences in mortality rates between the two groups. After propensity score matching, investigators identified no significant differences between the beta-lactam/daptomycin (110 patients) and beta-lactam monotherapy (168 patients) groups for all-cause mortality rates at seven days (8.18% vs. 7.74%; P = 1.000), 30 days (17.3% vs. 16.1%; P = .922), and 90 days (22.7% vs. 23.2%; P = 1.000). This was true even in a subanalysis of patients who had a high-risk infection source and in a subgroup excluding vascular catheter-related bacteremia.


While infection due to methicillin-resistant S. aureus (MRSA) gets a lot more attention, morbidity and mortality from infection due to MSSA remains very high despite treatment with various antibiotics with potent in vitro activity against MSSA. Over the years, we have tried many different antibiotic combinations to improve outcomes in MSSA bacteremia (including endocarditis). It was quite popular in the 1970s and 1980s to treat MSSA bacteremia with a beta-lactam antibiotic plus aminoglycoside. This seemed to make sense, since cell wall active antibiotics and aminoglycosides often demonstrate in vitro bactericidal synergy. Although studies showed that beta-lactam/aminoglycoside combination treatment caused more rapid clearance of bacteremia, this was at the cost of significant nephrotoxicity, and it did not reduce mortality.1

It was also popular for many years to treat S. aureus bacteremia with a beta-lactam plus rifampin based on the observation that beta-lactam/rifampin combinations often appeared synergistic in “checkerboard” studies where only minimum inhibitory concentrations (MICs) (not minimum bactericidal concentrations [MBCs]) were examined. However, rifampin not only has numerous problematic interactions with other drugs, but it actually antagonizes the bactericidal action of cell wall active antibiotics in vitro, delays clearance of bacteremia, and may even increase mortality in Staph. bacteremia.2

I remember being excited by reading a paper published in 2011 that showed that daptomycin in combination with ceftaroline (and possibly other beta-lactam antibiotics) often was effective salvage therapy in MRSA bacteremia.3 Because beta-lactams and daptomycin exert their bactericidal effects against S. aureus by different mechanisms of action, it was reasonable to examine beta-lactam plus daptomycin in MSSA bacteremia. My simplistic explanation of why MSSA remains so difficult to treat (despite antibiotics with excellent in vitro activity) is that it is an incredibly virulent pathogen, as evidenced by its tissue invasiveness and propensity to cause metastatic infection, even in healthy hosts.


  1. Cosgrove SE, Vigliani GA, Fowler VG Jr, et al. Initial low-dose gentamicin for Staphylococcus aureus bacteremia and endocarditis is nephrotoxic. Clin Infect Dis 2009;48:713-721.
  2. Riedel DJ, Weekes E, Forrest GN. Addition of rifampin to standard therapy for treatment of native valve infective endocarditis caused by Staphylococcus aureus. Antimicrob Agents Chemother 2008;52:2463-2467.
  3. Dhand A, Bayer AS, Pogliano J, et al. Use of antistaphylococcal beta-lactams to increase daptomycin activity in eradicating persistent bacteremia due to methicillin-resistant Staphylococcus aureus: Role of enhanced daptomycin binding. Clin Infect Dis 2011;53:158-163.