Development of High-Level Daptomycin Resistance in Abiotrophia and Granulicatella Species Isolates from Patients with Infective Endocarditis

Abstract

Abiotrophia and Granulicatella species are fastidious organisms, representing around 1%–3% of infective endocarditis (IE). Little is known about the optimal antibiotic treatment of these species, and daptomycin has been suggested as a therapeutic option. We describe the antimicrobial profile in Abiotrophia and Granulicatella IE isolates, investigate high-level daptomycin resistance (HLDR) development and evaluate daptomycin activity in combination therapy. In vitro studies with 16 IE strains (6 A. defectiva , 9 G. adiacens and 1 G. elegans ) were performed using microdilution to determine minimal inhibitory concentration (MIC) and time-kill methodology to evaluate combination therapy. Daptomycin non-susceptibility (DNS; MIC≥ 2 mg/L) and HLDR (MIC≥256 mg/L) were based on existing Clinical and Laboratory Standards (CLSI) breakpoints for viridans streptococci. All isolates were susceptible to vancomycin: G. adiacens was more susceptible to penicillin and ampicillin than A. defectiva (22% vs. 0%, and 67% vs. 33%) but less susceptible to ceftriaxone and daptomycin (56% vs. 83%, and 11% vs. 50%). HLDR developed in both A. defectiva (33%) and G. adiacens (78%) after 24h exposure to daptomycin. Combination therapy did not prevent the development of daptomycin resistance with ampicillin (2/3 strains), gentamicin (2/3 strains), ceftriaxone (2/3 strains) or ceftaroline (2/3 strains). Once developed, HLDR was stable for a prolonged time (>3 weeks) in G. adiacens , whereas in A. defectiva the HLDR it reversed to baseline MIC at day 10. This study is first to demonstrate rapid HLDR development in Abiotrophia and Granulicatella species in vitro . Resistance was stable, and most combination therapies did not prevent it.

An Aminoglycoside-Sparing Regimen with Double Beta-Lactam to Successfully Treat Granulicatella adiacens Prosthetic Aortic Valve Endocarditis—Time to Change Paradigm?

“…After being incubated with inhibitory concentrations of DAP, all strains rapidly increased the baseline MIC of daptomycin and showed resistance with either a DNS or HLDR profile. Even combination therapy did not prevent the development of DAP resistance with AMP (2/3 strains), CN (2/3 strains), CRO (2/3 strains), or ceftaroline (2/3 strains), thus rising further doubts about the optimal antibiotic treatment for these species [ 34 ].…”

Right-sided Infective Endocarditis with Ventricular Free Wall Vegetation Caused by <i>Abiotrophia defectiva</i> in a Patient with Unrepaired Ventricular Septal Defect

“…Among the few reported cases of infective endocarditis due to A. defectiva, the majority underwent valvular replacement despite adequate antibiotic therapy (15)(16)(17). A. defectiva strains that are highly resistant to Penicillin G or multidrug-resistant have also been reported (18), and patients with penicillin-resistant A. defectiva IE may experience worse outcomes with a higher rate of recurrence in comparison to patients with IE caused by other viridans group streptococci. Blood cultures do not always predict the appropriate antibiotic treatment for this pathogen as it is difficult to culture on standard blood agar media without supplementation, which may lead to false-negative results.…”