Daptomycin for Highly Resistant Enterococcus Faecium Infection

We report a case series of 11 patients with severe E. faecium infections treated with daptomycin. All strains were resistant to ampicillin (MIC >8 mg/l), but susceptible to vancomycin. Seven out of 11 strains were also highly resistant to gentamicin (MIC >500 mg/l). All patients were treated with multiple broad-spectrum antibiotics prior to isolation of E. faecium and had severe underlying diseases. Our experience suggests that salvage therapy with daptomycin might be a safe and efficacious treatment for E. faecium infections. Mortality in invasive enterococcal (bloodstream) infections has been reported to be as high as 51% [1]. High-level resistance to gentamicin is an independent predictor of mortality in invasive enterococcal infections in addition to underlying disease and resistance to vancomycin [2, 3]. The treatment of invasive enterococcal infections is a challenge for clinicians due to the reduced susceptibility to penicillins reflected by high minimum inhibitory concentrations (MIC) compared to other streptococci [4, 5]. Treatment recommendations for invasive enterococcal infections advocate synergistic antibiotic combinations such as an aminopenicillin plus gentamicin. In recent years a shift from ampicillin-sensitive E. faecalis to ampicillin-resistant E. faecium was noted in many European centres, a development we also observed in our hospital. In the event of resistance by E. faecium to ampicillin and/or high level gentamicin, vancomycin therapy has been suggested although it is poorly bactericidal [6]. Whilst treatment options of vancomycin resistant enterococci (VRE) are addressed in the literature, studies on treatment of enterococci with resistance to penicillin and/or high-level gentamicin are scarce and no information from controlled studies is available [7, 8]. In expert opinions linezolid, quinupristin-Figure 1 Therapeutic monitoring in one patient with high-dose daptomycin of 10 mg/kg/24 h (A) and in vitro killing curves showing a bactericidal effect of daptomycin at 10 mg/l in contrast to 10 mg/l vancomycin (B).

Mortality in invasive enterococcal (bloodstream) infections has been reported to be as high as 51% [1].High-level resistance to gentamicin is an independent predictor of mortality in invasive enterococcal infections in addition to underlying disease and resistance to vancomycin [2,3].The treatment of invasive enterococcal infections is a challenge for clinicians due to the reduced susceptibility to penicillins reflected by high minimum inhibitory concentrations (MIC) compared to other streptococci [4,5].Treatment recommendations for invasive enterococcal infections advocate synergistic antibiotic combinations such as an aminopenicillin plus gentamicin.In recent years a shift from ampicillin-sensitive E. faecalis to ampicillin-resistant E. faecium was noted in many European centres, a development we also observed in our hospital.In the event of resistance by E. faecium to ampicillin and/or high level gentamicin, vancomycin therapy has been suggested although it is poorly bactericidal [6].Whilst treatment options of vancomycin resistant enterococci (VRE) are addressed in the literature, studies on treatment of enterococci with resistance to penicillin and/or high-level gentamicin are scarce and no information from controlled studies is available [7,8].In expert opinions linezolid, quinupristin- Therapeutic monitoring in one patient with high-dose daptomycin of 10 mg/kg/24 h (A) and in vitro killing curves showing a bactericidal effect of daptomycin at 10 mg/l in contrast to 10 mg/l vancomycin (B).
dalfopristin, tigecyclin, daptomycin, or the new antibiotics dalbavancin, telavancin, ceftobiprole and ceftaroline are under discussion as alternative treatments [6,[9][10][11].Linezolid, a bacteriostatic agent which can be given orally due to its high oral bioavailability, is not approved for the treatment of endocarditis.Quinupristin-dalfopristin, a bactericidal combination of two synergistic working streptogramins, is not available in Switzerland.Furthermore, neither quinupristin-dalfopristin nor tigecyclin are approved for the treatment of endocarditis.For the new glycopeptides dalbavancin and telavancin, and the novel betalactams ceftobiprole and ceftaroline, only limited clinical data are available.Ceftobiprole showed high affinity to PBP5fm in vitro [12], but was withdrawn from the market by the company for further development.Daptomycin, a cyclic lipopeptide with bactericidal activity against Gram-positive bacteria [13], is approved for complicated skin and soft tissue infections with Gram positive bacteria, as well as for Staphylococcus aureus bloodstream infections.Daptomycin has been shown to be efficient in rat models of experimental endocarditis with E. faecium [14], but clinical data are scarce [15].Here we report a case series of 11 retrospectively collected cases of severely ill patients with invasive E. faecium infections treated with daptomycin between 2007 and 2009.The study was approved by the local ethics committee.All strains were resistant to ampicillin (MIC >8 mg/l) but susceptible to vancomycin, and 7/11 strains were highly resistant to gentamicin (MIC >500 mg/l).Table 1 summarises the underlying disease, the infectious focus, the dosage of daptomycin and the patients' outcome.All patients had severe underlying diseases: five had haematological malignancies, two had repeated episodes of cholangiosepsis, two had severe atherosclerosis after multiple vascular surgical procedures, and one had undergone liver transplantation.The majority of patients (10/11) were treated either on an intensive care unit or bone marrow transplant unit prior to isolation of the E. faecium.In the majority of patients daptomycin was started in a dosage of 6 mg/kg/day.Two patients with endocarditis were treated with a higher dosage of 10 mg/kg/d according to therapeutic drug monitoring (TDM).In one patient with persistent bacteraemia, hypoproteinaemia and severe immunosuppression the dosage was increased to 10 mg/kg/d after in vitro kill-curves had shown a bactericidal effect defined by loss of ≥3 log/CFU/24h with a concentration of 10 mg/l daptomycin (fig.1B).It was noteworthy that vancomycin at a dose of 10 mg/l was bacteriostatic.In this patient TDM was performed (fig.1A).In a second patient right-sided endocarditis developed whilst the patient was under treatment with vancomycin.Therapy was therefore switched to daptomycin 10 mg/kg/d and therapeutic drug monitoring was performed (data not shown).Elevation of creatine kinase was noted in one patient with severe sepsis in multi-organ failure.Eosinophilic pneumonia did not occur.Treatment outcomes are shown in table 1.Seven patients recovered and 4 died.Only in one case was death attributed to E. faecium infection.The patient died in severe sepsis after 2 doses of antibiotics.Death in the other three cases was attributed to the underlying condition.
Our case series illustrates that patients affected by bacteraemia with resistant enterococci suffer from severe underlying diseases.Monotherapy with vancomycin can result in treatment failure and bactericidal treatment is urgently needed.Failures of daptomycin monotherapy for enterococcal infections have been described in case reports mainly for E. faecalis [16,17].The mechanisms of resistance are not yet elucidated and may potentially limit the use of daptomycin in the treatment of E. faecium [18].Although we observed favourable effects with daptomycin at 6 mg/kg/d for the treatment of infections with E. faecium, the appropriate dosage remains to be elucidated in controlled studies.Our case series indicates that salvage therapy with daptomycin was likely to be effective in 7/11 patients with refractory invasive infections due to multi-resistant E. faecium.Thus, daptomycin may be a reasonable alternative for E. faecium infections.However, it has not been proven superior in a comparative clinical study and retrospective cohort studies in patients with vancomycin-resistant enterococci show overlapping results [19][20][21].Consequently, randomised controlled trials on the optimal dosage, efficacy and safety are urgently needed for these multiresistant bacteria which are difficult to treat [22] .

Figures (large format)
Therapeutic monitoring in one patient with high-dose daptomycin of 10 mg/kg/24 h (A) and in vitro killing curves showing a bactericidal effect of daptomycin at 10 mg/l in contrast to 10 mg/l vancomycin (B).

Table 1 :
Patient characteristics, antibiotic treatment and outcome.
Recovered f = female; m = male; HSCT = haematopoietic stem cell transplantation; GvHD = Graft-versus-host disease; strains susceptible to high level gentamicin are marked as follows: #.Swiss Medical Weekly • PDF of the online version • www.smw.ch