Ceftaroline Restores Daptomycin Activity against Daptomycin-Nonsusceptible Vancomycin-Resistant Enterococcus faecium

Abstract

c Daptomycin-nonsusceptible vancomycin-resistant Enterococcus faecium (VRE) strains are a formidable emerging threat to patients with comorbidities, leaving few therapeutic options in cases of severe invasive infections. Using a previously characterized isogenic pair of VRE strains from the same patient differing in their daptomycin susceptibilities (Etest MICs of 0.38 mg/liter and 10 mg/liter), we examined the effect of ceftaroline, ceftriaxone, and ampicillin on membrane fluidity and susceptibility of VRE to surface binding and killing by daptomycin and human cathelicidin antimicrobial peptide LL37. Synergy was noted in vitro between daptomycin, ampicillin, and ceftaroline for the daptomycin-susceptible VRE strain, but only ceftaroline showed synergy against the daptomycin-nonsusceptible VRE strain (ϳ2 log 10 CFU reduction at 24 h). Ceftaroline cotreatment increased daptomycin surface binding with an associated increase in membrane fluidity and an increase in the net negative surface charge of the bacteria as evidenced by increased poly-L-lysine binding. Consistent with the observed biophysical changes, ceftaroline resulted in increased binding and killing of daptomycin-nonsusceptible VRE by human cathelicidin LL37. Using a pair of daptomycinsusceptible/nonsusceptible VRE strains, we noted that VRE is ceftaroline resistant, yet ceftaroline confers significant effects on growth rate as well as biophysical changes on the cell surface of VRE that can potentiate the activity of daptomycin and innate cationic host defense peptides, such as cathelicidin. Although limited to just 2 strains, these finding suggest that additional in vivo and in vitro studies need to be done to explore the possibility of using ceftaroline as adjunctive anti-VRE therapy. Loss of susceptibility to daptomycin is an increasing concern among vancomycin-resistant Enterococcus faecium (VRE) (1). When faced with invasive infections by daptomycin-nonsusceptible VRE, clinicians have limited therapeutic options. Of great concern are the lack of a bactericidal agent, antibiotic-associated side effects such as linezolid-induced thrombocytopenia and quinupristin-dalfopristin (QD)-associated myalgias, and drug-drug interactions such as microsomal P450 effects of QD and serotonin syndrome concerns with linezolid and concomitant serotonin reuptake inhibitors. Therefore, a great need exists for infectiousdisease physicians practicing in tertiary medical centers with patients at high risk for VRE infections, e.g., bone marrow and liver transplant recipients, to develop innovative pharmacotherapies to treat such patients (2, 3). The clinical dilemma faced by physicians treating these patients is further compounded by the facts that novel therapeutics targeting VRE are lacking and that single or combination antibiotics with in vitro activity against VRE have not been clinically validated by appropriate trials (4).Our group has previously shown a perhaps counterintuitive effect of ampicillin in converting daptomycin from a bacteriostatic to a bactericidal an...

β-Lactams Enhance Daptomycin Activity against Vancomycin-Resistant Enterococcus faecalis and Enterococcus faecium in In Vitro Pharmacokinetic/Pharmacodynamic Models

“…LL37 is not only a marker of immune response but also an endogenous analogue to DAP (49). Our data echo previous findings demonstrating the synergistic effects of ␤-lactam agents on LL37 activity in E. faecalis, E. faecium, and Staphylococcus aureus (24,25,50,51). From the available data, it appears that ␤-lactams have the ability to amplify both portions of the innate immune response (LL37) and DAP activity against enterococci and that this augmentation of DAP activity may explain the enhancement we have demonstrated.…”

“…Mechanistically, it appears that these ␤-lactams decrease the surface charge of enterococcal cells and increase DAP binding to confer their synergistic effects (23)(24)(25). Two of these studies also demonstrated that AMP and CPT restore not only DAP activity but also endogenous, cationic antimicrobial peptide activity, demonstrating that the effect ␤-lactams have on membrane charge may be imperative for the synergistic effect (24,25).…”

“…Two of these studies also demonstrated that AMP and CPT restore not only DAP activity but also endogenous, cationic antimicrobial peptide activity, demonstrating that the effect ␤-lactams have on membrane charge may be imperative for the synergistic effect (24,25). Case reports have also demonstrated the clinical efficacy of the DAP-AMP and DAP-CPT combinations against E. faecalis and E. faecium (24,26,27).…”

“…Ampicillin (AMP), ceftriaxone (CRO), and ceftaroline (CPT) specifically have demonstrated synergy, and CPT has demonstrated the ability to restore DAP susceptibility to DAP-nonsusceptible strains (23)(24)(25).…”

Fosfomycin Enhances the Activity of Daptomycin against Vancomycin-Resistant Enterococci in an In Vitro Pharmacokinetic-Pharmacodynamic Model

“…Synergy between daptomycin and beta-lactams is believed to be mediated through beta-lactam-induced alterations in surface charge that facilitate an increase in daptomycin binding, leading to enhanced membrane depolarization (23)(24)(25)(26)(27)(28). Since fosfomycin also disrupts cell wall synthesis, it could be theorized that there is a similar mechanism that drives the synergy that has been observed with daptomycin and fosfomycin.…”