SAFO: No advantage to using two antibiotics to treat MSSA bacteraemia

The use of cloxacillin alone is just as good as the combination of cloxacillin plus fosfomycin in terms of achieving treatment success among hospitalized patients with methicillin-susceptible Staphylococcus aureus (MSSA) bacteraemia, according to the results of the open-label, phase IV-III SAFO trial presented at the ECCMID 2023.

In an intention-to-treat analysis, the primary endpoint of treatment success at day 7 was achieved in 79.8 percent of patients who received cloxacillin plus fosfomycin vs 74.5 percent in those who received cloxacillin alone. Treatment success was defined as a composite of the following outcomes: patient survival, stable or improved quick-Sequential Organ Failure Assessment score, absence of fever, and negative blood cultures for MSSA. [ECCMID 2023, abstract O0037]

The difference of 5.3 percent (95 percent confidence interval [CI], –5.95 to 16.48) in treatment success rates was not statistically significant, reported lead study investigator Dr Sara Grillo, of Bellvitge University Hospital in L'Hospitalet de Llobregat, Barcelona, Spain.

“The findings of the SAFO trial are in line with those of other randomized clinical trials evaluating different antibiotic combinations that also failed to improve treatment success and outcomes in patients with MSSA bacteraemia,” she said.

SAFO was conducted at 19 Spanish hospitals, with the intent-to-treat population comprising 214 adult inpatients with MSSA bacteraemia. Intravascular catheter infection was the most common cause of bacteremia (31.8 percent), followed by bone and joint (14.9 percent) and skin and soft tissue infections (12.6 percent). None of the patients had liver cirrhosis, NYHA Class III-IV heart failure, allergy to beta-lactams or fosfomycin, prosthetic endocarditis, and SARS-CoV-2 infection.

Of the patients, 110 received intravenous cloxacillin at 2 g every 4 hours (median age 68 years, 74 percent men), while 104 received cloxacillin in combination with intravenous fosfomycin at 3 g every 6 hours (median age 69 years, 66 percent men). Add-on fosfomycin was given in the initial 7 days of treatment, and sequential antibiotic therapy was left to the discretion of attending physicians.

Grillo noted that the trial was terminated before reaching a planned enrolment of 366 patients for showing no benefit of combination antibiotic therapy on treatment success.

However, despite the failure to meet the primary endpoint, the antibiotic combination resulted in significantly lower rate of persistent bacteraemia at day 3 compared with cloxacillin alone (3.85 percent vs 16.4 percent; p=0.003), she pointed out.

Other secondary endpoints, including all-cause mortality (at day 7, end of treatment [EOT], and test of cure [TOC]), persistent bacteraemia at day 7, relapsing bacteraemia at TOC, complicated bacteraemia at TOC, and emergence of fosfomycin-resistant strains at TOC, were similar in the two treatment groups.

In terms of safety, cloxacillin plus fosfomycin was associated with a slightly higher rate of adverse events that led to discontinuation of therapy as compared with cloxacillin alone (10.6 percent vs 8.2 percent; risk difference, 2.4 percent, 95 percent CI, –5.43 to 10.22).

To date, antistaphylococcal beta-lactam monotherapy is the current standard of treatment for MSSA bacteraemia. Since mortality is still high, there has been an increasing interest in finding new treatment combinations that could improve outcomes in S aureus bacteraemia, Grillo shared. [Antimicrob Agents Chemother 2016;60:478-486]

In light of the findings of the SAFO study, Grillo called for additional trials to evaluate other strategies of treatment for MSSA bacteraemia.