Combination therapy with rifampicin or fosfomycin in patients with Staphylococcus aureus bloodstream infection at high risk for complications or relapse: results of a large prospective observational cohort

Abstract

Objectives To investigate whether Staphylococcus aureus bloodstream infection (SAB) patients at high risk for complications or relapse benefit from combination therapy with adjunctive rifampicin or fosfomycin. Methods In this post hoc analysis, SAB patients with native valve infective endocarditis, osteoarticular infections or implanted foreign devices were included. The co-primary endpoints were all-cause 90 day mortality and death or SAB-related late complications within 180 days. To overcome treatment selection bias and account for its time dependence, inverse probability of treatment weights were calculated and included in marginal structural Cox proportional hazard models (MSCMs). Results A total of 578 patients were included in the analysis, of which 313 (54%) received combination therapy with either rifampicin (n = 242) or fosfomycin (n = 58). In the multivariable MSCM, combination therapy was associated with a better outcome, that is, a lower rate of death or SAB-related late complications within 180 days (HR 0.65, 95% CI 0.46–0.92). This beneficial effect was primarily seen in patients with implanted foreign devices, in which combination therapy was associated with a lower rate of death or SAB-related late complications within 180 days (HR 0.53, 95% CI 0.35–0.79) and a lower 90 day mortality (HR 0.57, 95% CI 0.36–0.91). Upon agent-specific stratification, we found no significant differences in outcomes between combination therapy containing rifampicin and fosfomycin; however, the number of patients in most subgroups was not large enough to draw firm conclusions. Conclusions In patients with implanted foreign devices, combination therapy was associated with a better long-term outcome. Larger prospective studies are needed to validate these findings.

Intravenous fosfomycin for the treatment of patients with bone and joint infections: a review

“…those with failure of initial antibiotic therapy, diabetic foot infections, chronic osteomyelitis, infections with abscess formation or infected foreign bodies, particularly difficult-toreach infections (e.g. discitis), or infections with involvement of multidrug-resistant pathogens or polymicrobial infections [5,33,36,38,40,43,[47][48][49]. This observation is also in line with current treatment algorithms where fosfomycin is recommended for the combination therapy of periprosthetic joint infections or infections after fracture fixation [50][51][52].…”

The Effectiveness of Combination Therapy for Treating Methicillin-Susceptible Staphylococcus aureus Bacteremia: A Systematic Literature Review and a Meta-Analysis

“…Table 1 summarizes the characteristics of included studies. There were six RCTs [ 17 , 18 , 19 , 20 , 21 , 22 ] and six observational studies [ 23 , 24 , 25 , 26 , 27 , 28 ]. Six studies were multicentric (≥2 hospitals) [ 18 , 19 , 20 , 22 , 23 , 24 ] and five studies were published before 2000 [ 17 , 20 , 21 , 25 , 28 ].…”

“…In the monotherapy group, beta-lactams (antistaphylococcal penicillins, first-generation cephalosporins) were the main antibiotics used. Two studies including ≤11% of MRSA bacteremias also used vancomycin, teicoplanin, linezolid, or daptomycin [ 18 , 23 ]. In four studies, the monotherapy group comprised different types of antibiotics against MSSA and included a few patients receiving an antibiotic that was not the optimal standard of care (i.e., vancomycin, ceftriaxone, or clindamycin) [ 19 , 23 , 24 , 28 ].…”

“…One study described two separate analyses for patients who received combination therapy with levofloxacin and a post-hoc analysis of patients with a deep-seated focus who received additional rifampicin [ 19 ]. One study was classified in the rifampicin group despite including a small proportion of patients (19%) who received fosfomycin in combination [ 23 ]. Also, two studies including >70% of patients with a deep-seated focus used rifampicin, fluoroquinolones, or aminoglycosides along with the antibiotics in the monotherapy/combination groups [ 19 , 24 ].…”

Management of Staphylococcus aureus Bloodstream Infections

“…Theoretically, combination therapy could lead to a higher bactericidal activity compared to antibiotic monotherapy and synergistic effects could occur. Combination therapy may be superior in the eradication of intracellular staphylococci and biofilms on foreign materials and thus reduce the risk of secondary late infection and recurrence (74,75).…”