High rate of decreasing daptomycin susceptibility during the treatment of persistent Staphylococcus aureus bacteremia

Abstract

Daptomycin is bactericidal against Staphylococcus aureus, with susceptibility defined as a minimal inhibitory concentration (MIC) < or =1 microg/ml. Higher MIC developed in a few cases during therapy. The frequency of MIC rise in persistent bacteremia is unknown. We evaluated all patients with S. aureus bacteremia (SAB) treated with daptomycin (> or =2 days) from 1 April 2004 to 30 October 2006. All patients with post-daptomycin-exposure saved isolates were studied. Daptomycin susceptibility was determined (in duplicate) on all pre- and post-daptomycin-exposure isolates by the broth (Mueller-Hinton) microdilution method. Among 74 treatment courses in 67 patients, 18 were for SAB. Ten had persistent bacteremia (median = 11 days; range = 1-21) and post-daptomycin-exposure saved isolates. The patient age was 29-84 years (median = 57.5 years). Intravascular catheter was the most common source (50%). Most patients (90%) failed therapy prior to starting daptomycin. The initial daptomycin dose was 4 mg/kg in four (40%) cases. The pre-exposure MIC was 0.125-0.5 microg/ml. The post-exposure MIC increased in four cases and was elevated in two cases (60%), to 2 microg/ml in five and 4 microg/ml in one. MIC rise was noted within 5-15 days of exposure and persisted up to 247 days after stopping daptomycin. Pulse-field gel electrophoresis (PFGE) band pattern of isolates with increased MIC revealed 1-3-band differences, implying genetic relatedness. All patients with non-susceptible isolates relapsed or failed therapy. These findings illustrate that daptomycin susceptibility often decreases during the treatment of persistent SAB. Therefore, susceptibility should be closely monitored during therapy.

A Current Perspective on Daptomycin for the Clinical Microbiologist

“…In a large, multinational randomized clinical trial of S. aureus bacteremia and endocarditis, among 120 patients who received daptomycin therapy, 6 experienced microbiological failure that coincided with the emergence of daptomycin-NS isolates (74); in this study, treatment failure was most frequently associated with deep-seated infection that did not receive surgical intervention (74). Sharma and colleagues reported NS daptomycin MICs for 6 of 10 patients at a single center with persistent bacteremia, ranging from 1 to 21 days, who were treated with daptomycin as vancomycin salvage therapy (85). In this study, an intravenous catheter was the most common source of bacteremia, and the initial daptomycin dose was suboptimal, at 4 mg/kg, for 40% of the patients (85).…”

“…A number of case reports have documented the emergence of daptomycin-NS S. aureus isolates during unsuccessful therapy with this agent (see Table S1 in the supplemental material) (76,(85)(86)(87)(88)(89)(90). In most instances, NS isolates emerged in the setting of recalcitrant, deep-seated infections and those associated with a high burden of the infecting organism, such as endocarditis, catheter-related bacteremia, or an undrained abscess (Table 2) (91).…”

“…Sharma and colleagues reported NS daptomycin MICs for 6 of 10 patients at a single center with persistent bacteremia, ranging from 1 to 21 days, who were treated with daptomycin as vancomycin salvage therapy (85). In this study, an intravenous catheter was the most common source of bacteremia, and the initial daptomycin dose was suboptimal, at 4 mg/kg, for 40% of the patients (85). We have also noted a stepwise increase in daptomycin MIC in a patient who was bacteremic over multiple days (92).…”

Frequency of Susceptibility Testing for Patients with Persistent Methicillin-Resistant Staphylococcus aureus Bacteremia

“…In these cases, persistent bacteremia does not reflect antimicrobial failure but rather a residual source of infection. Regardless, the most common element associated with decreased susceptibility to daptomycin, vancomycin, and linezolid is previous or current therapy with the respective antimicrobial agent (11)(12)(13), and this was documented in all three cases herein.…”

In Vivo Pharmacodynamic Evaluation of an FtsZ Inhibitor, TXA-709, and Its Active Metabolite, TXA-707, in a Murine Neutropenic Thigh Infection Model

“…The study period was 24 h. The y axis data represent the changes in organism burden from that measured at the start of therapy. q6 h, every 6 h; q8 h, every 8 h; q12 h, every 12 h; q24 h, every 24 h. has been repeatedly exhibited very soon after clinical introduction (23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39).…”