Clinical Progression of Methicillin-Resistant Staphylococcus aureus Vertebral Osteomyelitis Associated with Reduced Susceptibility to Daptomycin

Abstract

Daptomycin, a novel cyclic lipopeptide antibiotic, exhibits rapid bactericidal activity in vitro against most clinically relevant gram-positive organisms, including drug-resistant pathogens. Herein we describe a patient in whom methicillin-resistant Staphylococcus aureus with reduced susceptibility to daptomycin was responsible for bacteremia and progressive vertebral osteomyelitis during daptomycin therapy.

Genetic Changes That Correlate with Reduced Susceptibility to Daptomycin in Staphylococcus aureus

“…Mutations in mprF and yycG are further implicated by their identification in nonsusceptible isolates that have emerged in the clinic after weeks of daptomycin therapy (13,41). These results suggest that selective pressures found in laboratory serial-passage experiments parallel the selective pressures encountered in clinical settings, particularly in difficult infections where organisms might not be exposed to adequate levels of antibiotic (e.g., undrained abscess, dead bone).…”

“…The MIC for 90% of the S. aureus strains tested is 0.5 g/ml, and surveillance studies have not reported any strains for which the MIC is Ն4 g/ml (5, 34). Rare treatment-emergent S. aureus strains for which the MICs are 2 to 4 g/ml have been reported (13,41). This study demonstrates that an accumulation of mutations over time correlates with incremental increases in the daptomycin MIC.…”

Serial Daptomycin Selection Generates Daptomycin-Nonsusceptible Staphylococcus aureus Strains with a Heterogeneous Vancomycin-Intermediate Phenotype

“…Several studies have been performed with daptomycin-resistant strains derived in vitro (16,19,33,47,50), yet the mech- (23) described a reduced susceptibility to daptomycin-induced depolarization, permeabilization, and autolysis, as well as a significantly lowered surface binding of daptomycin and increased cross-resistance to the cationic antimicrobial host defensins hNP-1 and tPMP-1. Although the membrane has been regarded as the main target for daptomycin, our group observed a strong correlation between the presence of a thickened cell wall and daptomycin resistance.…”

“…Daptomycin exhibits rapid bactericidal activity in vitro and causes membrane depolarization, which leads to potassium release and cell death (48). Despite the effectiveness of daptomycin that has been shown during clinical trials, strains nonsusceptible both in vitro and in vivo have already been isolated (19,25,33,47,50).…”

Actividad comparativa de daptomicina frente a microorganismos grampositivos: programa SENTRY España (2002-2006)

“…Este hecho parece no afectar a su actividad bactericida 12,13 . La tasa de mutantes resistentes espontáneas in vitro a la daptomicina es baja 14 , pero se han encontrado algunos aislados clí-nicos de S. aureus y Enterococcus con sensibilidad disminuida a este compuesto [15][16][17][18] . Los ensayos clínicos realizados hasta la fecha con daptomicina demuestran su equivalencia frente a tratamientos estándares en infecciones de piel y de tejidos blandos, bacteriemia y endocarditis bacteriana [19][20][21] .…”