The use of high-dose daptomycin in combination with a β-lactam antibiotic to treat enterococcal bacteremia is supported by pharmacodynamics.
Enterococcal bacteremia is a global concern as enterococcal pathogens have developed resistance to nearly all antibiotics. A new study supports the use of high-dose daptomycin in combination with another antibiotic to treat these dangerous infections.
The study, published in the International Journal of Antimicrobial Agents, looked at data from 7 published trials involving 240 adults and found that daptomycin doses of 10-12 mg/kg/day in combination with other antibiotics optimize pharmacodynamic threshold attainment for susceptible-dose dependent (S-DD) infections.
The study found that a pharmacodynamic threshold, which is predictive of 30-day survival in patients with enterococcal bacteremia, was 2-fold lower when daptomycin was given along with another antibiotic, such as a β-lactam.
Pharmacodynamic threshold attainment, in terms of free drug area under the curve to minimum inhibitory concentration (fAUC/MIC) ratio above 27.4, is associated with 30-day survival in monotherapy. Among low-acuity patients who received a β-lactam, a fAUC/MIC above 12.3 was associated with survival, and this remained significant in models that controlled for infection source and immunosuppression.
“Probabilities of threshold attainment using a 10 mg/kg/day dose were 100% for isolates with MICs ≥2mg/L and 95.2% for 12 mg/kg/day dose of MICs of 4 mg/L,” the authors noted.
The study was led by investigators at the Center for Anti-Infective Research and Development at Hartford Hospital in Hartford, Connecticut.
“Although the precise mechanisms are not fully elucidated, the finding of a lower threshold may be a consequence of increased β-lactam activity following daptomycin-induced cell envelop changes, or enhanced daptomycin surface binding in presence of β-lactams,” the study noted.
The study also noted suppression of daptomycin resistance that was seen in monotherapy.
“A lower pharmacodynamic threshold identified in combination therapy-treated patients also provides a potential mechanism responsible for improved end-of-treatment survival in enterococcal bacteremia recently observed with high-dose (≥9 mg/kg/day) daptomycin plus a β-lactam compared with daptomycin monotherapy, high-dose monotherapy, or low-dose daptomycin plus a β-lactam,” investigators wrote.
Information to identify which β-lactam antibiotics were associated with survival was unavailable along with number of doses and administration schedules.
Further studies are needed to justify specific breakpoints for antibiotics used in combination.
The emergence of drug-resistant enterococci is an ongoing concern for investigators seeking solutions, including drug combinations, to address the evolving problem.
Vancomycin-resistant enterococci (VRE) is a concerning threat, sickening 20,000 Americans each year and killing 1300, according to the US Centers for Disease Control and Prevention. In recent years, investigators have identified strains of the bacteria that are not susceptible to daptomycin, prompting drug manufacturers to evaluate drugs including telavancin, dalbavancin and oritavancin for VRE.
Investigators have debated the benefits of drug combinations to fight antimicrobial-resistant bacteria, with daptomycin being used in combination with ceftaroline to treat prolonged methicillin-resistant Staphylococcus aureus bacteremia.