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Daptomycin in the Treatment of Patients with Infective Endocarditis: Experience from a Registry
The American Journal of Medicine (2007) Vol 120 (10A), S28 –S33
Daptomycin in the Treatment of Patients with Infective Endocarditis: Experience from a Registry Donald P. Levine, MD,a and Kenneth C. Lamp, PharmDb a
Wayne State University, University Health Center, Detroit, Michigan, USA; and bCubist Pharmaceuticals, Inc., Lexington, Massachusetts, USA ABSTRACT Daptomycin (Cubicin; Cubist Pharmaceuticals, Inc., Lexington, MA) is a first-in-its-class cyclic lipopeptide approved for the treatment of patients with complicated skin and skin-structure infections due to susceptible gram-positive pathogens and recently approved for Staphylococcus aureus bloodstream infections including right-sided infective endocarditis. The clinical experience of patients registered in the Cubicin Outcomes Registry and Experience (CORE) 2004 database with daptomycin-treated infective endocarditis is described. The registry data were collected retrospectively by trained investigators to document real-world clinical experience. Study limitations included uncontrolled diagnostic criteria, noncomparative data, and lack of follow-up assessments. A total of 49 patients had a diagnosis of endocarditis: 38 with left-sided or both left-sided and right-sided endocarditis, and 11 with right-sided endocarditis alone. Renal failure was the most common comorbid condition. In all, 27 (55%) of the 49 patients had an initial creatinine clearance of ⱕ30 mL/min, and 14 (29%) were supported by dialysis. Staphylococcus aureus (59%; 83%, methicillin resistant) and enterococci (29%; 43%, vancomycin resistant) were the most commonly identified pathogens. In most instances, patients received gram-positive therapy before receiving daptomycin (43 of 49 [88%]). The median starting dose of daptomycin was 6 mg/kg (range, 4 to 7 mg/kg); 27 (55%) of the patients received a dose of ⱖ6 mg/kg. Daptomycin therapy was successful for 31 (63%) of the patients: cure was seen in 18 (37%) and improvement in 13 (27%). Therapy failed in 4 (8%) of the patients, and 14 (29%) of the cases were nonevaluable. The median duration of therapy in successful cases was 27 days. No differences in clinical response were observed based on baseline renal function, primary pathogen, or site of endocarditis. The results from the CORE 2004 database suggest that daptomycin should be considered a possible treatment for patients with right-sided infective endocarditis involving S aureus. Further studies are needed to extend daptomycin’s experience in left-sided or enterococcal endocarditis. © 2007 Elsevier Inc. All rights reserved. KEYWORDS: Bacteremia; Daptomycin; Endocarditis; Enterococci; Staphylococci
Infective endocarditis is a microbial infection of the endocardial surfaces of the heart. Infections of the left side of the heart, involving the aortic or mitral valves, have greater therapeutic failure rates compared with those of the right side, sometimes necessitate more intensive antibacterial therapy, and more often require surgical intervention.1
Please see Author Disclosure section at the end of this article. Requests for reprints should be addressed to Kenneth C. Lamp, PharmD, Cubist Pharmaceuticals, Inc., 65 Hayden Avenue, Lexington, Massachusetts 02421. E-mail address: [email protected].
0002-9343/$ -see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2007.07.011
The most prevalent pathogens are Staphylococcus aureus, coagulase-negative staphylococci (CoNS), viridans group streptococci, and enterococci.2,3 This etiology highlights the importance of antibacterial agents active against gram-positive microorganisms for treatment of this infection. The emergence and dissemination of antimicrobial resistance among gram-positive pathogens, particularly methicillin-resistant S aureus (MRSA) and vancomycin-resistant enterococci (VRE), have become troublesome.4 –9 In a recent observational cohort of 1,779 patients with infective endocarditis, S aureus was the most common pathogen, and MRSA was identified in ⬎25% of these cases.2
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Daptomycin for Infective Endocarditis
Patients with MRSA exhibited a trend toward a higher rate of mortality compared with individuals who have methicillin-susceptible S aureus (MSSA). The identification of vancomycin-intermediate and heteroresistant S aureus and, in a limited number of cases, vancomycin-resistant S aureus portends even greater difficulty in treating these infections in the future.5–7 The changing pattern of bacterial resistance emphasizes the need for antimicrobial agents with novel mechanisms of action that can eradicate multiresistant gram-positive pathogens responsible for serious infections such as endocarditis. Daptomycin (4 mg/kg) was approved by the US Food and Drug Administration (FDA) in 2003 for the treatment of patients with complicated skin and skin-structure infections and daptomycin (6 mg/kg) in 2006 for the treatment of S aureus bloodstream infections including right-sided infective endocarditis.10 –14 A large, randomized, controlled, noninferiority clinical study has shown that daptomycin is well tolerated and is as effective as standard dual-therapy comparator antibiotics (semisynthetic penicillins or vancomycin, each combined with short-course gentamicin) for the treatment of right-sided endocarditis due to S aureus.13 The outcomes were assessed by a treatment-blinded independent adjudication committee. The overall success rates at the test of cure visit (6 weeks after the last treatment dose) were 44.2% in patients treated with daptomycin and 41.7% in patients treated with the comparator. The right-sided endocarditis success rates were 42.1% in patients treated with daptomycin and 43.8% in patients treated with the comparator.13,14 Although this study was amended to allow enrollment of patients with left-sided infective endocarditis, the numbers and outcomes were insufficient to determine daptomycin’s effectiveness. The Cubicin Outcomes Registry and Experience (CORE) 2004 was a retrospective observational chart review of the cases of patients receiving daptomycin for any indication in 45 US institutions. Using the CORE 2004 database, investigators identified a cohort of 49 patients with a reported diagnosis of endocarditis. The outcomes achieved with daptomycin therapy are discussed in this article.
METHODS The methods for conducting the registry are described by Rolston and colleagues elsewhere in this supplement.15 All patients (clinically evaluable and nonevaluable) with a diagnosis of endocarditis were included in this analysis regardless of the presence of other concurrent infections. The diagnosis of endocarditis was determined by the individual investigators. Information regarding echocardiography findings or Duke criteria assessment was not collected.
Statistics Statistical analysis included both descriptive and inferential methods. Descriptive methods included the presentation of mean, median, and proportional data. Comparisons between groups were made with appropriate parametric and nonpara-
S29 Table 1
Demographics of study patients*
Characteristic Sex Female Male Weight, kg (mean ⫾ SD) Age group (yr) 31–50 51–65 ⱖ66 Comorbid conditions† Chronic renal failure Diabetes mellitus Hypertension Valvular heart disease Arrhythmias Acute coronary syndromes Other cardiovascular disease Any transplant Renal impairment CrCl ⬍30 mL/min Dialysis
LE (n ⫽ 38) RE (n ⫽ 11) All (n ⫽ 49) 20 (52.6) 4 (36.4) 24 (49.0) 18 (47.4) 7 (63.6) 25 (51.0) 80.2 ⫾ 15.3 75.3 ⫾ 17.7 79.1 ⫾ 15.8 5 (13.2) 15 (39.5) 18 (47.4)
3 (27.3) 4 (36.4) 4 (36.4)
8 (16.3) 19 (38.8) 22 (44.9)
14 8 7 8 7 5
3 4 4 1 1 1
17 12 11 9 8 6
(36.8) (21.1) (18.4) (21.1) (18.4) (13.2)
(27.3) (36.4) (36.4) (9.1) (9.1) (9.1)
(34.7) (24.5) (22.4) (18.4) (16.3) (12.2)
7 (18.4)
1 (9.1)
8 (16.3)
4 (10.5)
1 (9.1)
5 (10.2)
22 (57.9) 11 (28.9)
5 (45.5) 3 (27.3)
27 (55.1) 14 (28.6)
CrCl ⫽ creatinine clearance; LE ⫽ left-sided endocarditis or mixed left- and right-sided endocarditis; RE ⫽ right-sided endocarditis alone. *Values are given as number of patients (percentage) unless otherwise indicated. † Patients may have ⬎1 comorbid condition.
metric techniques. Statistical significance was assessed at the 5% level.
RESULTS Patient Characteristics Among the 1,160 CORE 2004 patients, 49 patients (4.2%) had a diagnosis of infective endocarditis. Of these, 26 (53%) had endocarditis of the left side of the heart (LE), 11 (22%) had right-sided endocarditis (RE), and 12 (24%) had both LE and RE. Data on patients with both LE and RE were combined with those on patients with LE alone. This pooled group is referred to as the LE group. Tables 1 and 2 show the demographic characteristics of the study patients and information on concurrent infections, respectively. The LE and RE groups did not differ significantly in any demographic characteristic. In general, most (84%; n ⫽ 41) of the patients were middle-aged (i.e., aged 51 to 65 years) or elderly (ⱖ66 years), and most (73%; n ⫽ 36) were in the hospital 2 days before starting daptomycin therapy. Chronic renal failure (17 cases [35%]), diabetes mellitus (12 cases [24%]), and hypertension (11 cases [22%]) were the most common comorbid conditions. More than half (55%) of the patients had an initial creatinine clearance (CrCl) of ⬍30 mL/min, and 28.6% were undergoing dialysis. In addition, concurrent infections were reported, catheter-related bacteremia (8 cases [16%]) being the most frequent. Two patients were reported to have
S30 infected intracardiac foreign devices; however, information about the types of devices and sites was not collected.
The American Journal of Medicine, Vol 120 (10A), October 2007 Table 2
Concurrent infections* n (%)
Microbiology Table 3 shows the microbiology results for the cultures obtained at the initiation of daptomycin therapy. S aureus (29 cases [59%]) and enterococci (14 cases [29%]) were the most common pathogens isolated. MRSA accounted for 24 (83%) of the 29 S aureus isolates, whereas VRE accounted for 6 (43%) of the 14 enterococcal isolates. There were 3 patients, each of whom had 2 pathogens identified: MRSA and MSSA; Enterococcus faecalis and Staphylococcus epidermidis; and Enterococcus and MRSA. Another 3 patients had CoNS; none of these individuals had infected catheters or foreign devices. Additionally, 5 patients, all in the LE group, did not have pathogens reported. Comparisons between the LE and RE cohorts were limited by the small number of patients in the latter group. Nevertheless, MRSA was identified at a higher rate in the RE cohort than in the LE cohort (9 [82%] of 11 cases vs. 15 [39%] of 38 cases; P ⫽ 0.018). The frequency of other pathogens was generally comparable between the 2 groups.
Infection Type Bacteremia, catheter-related Urinary tract Foreign device, intravascular Foreign device, intracardiac Septic arthritis Skin and skin-structure infection† Central nervous system Diabetic foot Osteomyelitis
LE RE All (n ⫽ 38) (n ⫽ 11) (n ⫽ 49) 7 3 2 1 1 1
(18.4) (7.9) (5.3) (2.6) (2.6) (2.6)
1 (2.6) 0 0
1 (9.1) 0 0 1 (9.1) 0 0
8 3 2 2 1 1
(16.3) (6.1) (4.1) (4.1) (2.0) (2.0)
0 1 (9.1) 1 (9.1)
1 (2.0) 1 (2.0) 1 (2.0)
LE ⫽ left-sided endocarditis or mixed left- and right-sided endocarditis; RE ⫽ right-sided endocarditis alone. *Patients may have ⬎1 infection type. † Uncomplicated.
Table 3 Gram-positive pathogens isolated before daptomycin treatment* n (%)
Daptomycin Dosing The median starting dose was 6 mg/kg (range, 4 to 7 mg/kg) for the entire cohort. The median dose for LE was 6 mg/kg (range, 4 to 7 mg/kg) and for RE, 4 mg/kg (range, 4 to 6.4 mg/kg) (P ⫽ 0.644). A total of 27 (55%) of the patients received daptomycin at a dose of ⱖ6 mg/kg. The rate of use of daptomycin at doses of ⱖ6 mg/kg was significantly greater in the LE subgroup than in the RE subgroup (63% vs. 27%; P ⫽ 0.046). All patients with CrCl of ⱖ30 mL/min received daptomycin once every 24 hours. In all, 25 (93%) of 27 patients with CrCl of ⬍30 mL/min received daptomycin every 48 hours or 3 times per week. The median duration of daptomycin therapy in successfully treated patients was 27 days (range, 5 to 62 days). The daptomycin median duration for clinically evaluable patients was 26.5 days for the LE group and 27 days for the RE group (P ⫽ 0.739).
Previous and Concomitant Antibiotic Therapy Most (43 [88%]) of the patients received antimicrobial therapy before receiving daptomycin (33 [87%] patients in the LE group and 10 [91%] patients in the RE group). Specifics regarding previous therapy were not collected, with the exception of allergy, intolerance, or a contraindication for linezolid and vancomycin. In the LE group, 4 patients had allergy, intolerance, or a contraindication for linezolid, and 6 patients had contraindication for vancomycin. The pathogen was resistant to linezolid and vancomycin in 1 patient each. In the RE group, 2 patients had allergy, intolerance, or contraindication for vancomycin, although neither individual had infection involving vancomycin-resistant pathogens. Table 4 shows use of concomitant antimicrobial agents during daptomycin therapy. In all, 32 (65%) of the 49 patients received ⱖ1 dose of concomitant antimicrobial
Pathogen
LE RE All (n ⫽ 38) (n ⫽ 11) (n ⫽ 49)
Staphylococci 15 (39.5) 9 (81.8) 24 (49.0) Methicillin-resistant Staphylococcus aureus† Methicillin-susceptible 4 (10.5) 1 (9.1) 5 (10.2) S aureus Coagulase-negative 2 (5.3) 1 (9.1) 3 (6.1) staphylococci Enterococci Enterococcus faecalis 6 (15.8) 0 6 (12.2) (vancomycin susceptible) Enterococcus (vancomycin 4 (10.5) 1 (9.1) 5 (10.2) resistant, species unreported) Enterococcus (vancomycin 1 (2.6) 1 (9.1) 2 (4.1) susceptible, species unreported) E faecium (vancomycin 1 (2.6) 0 1 (2.0) resistant) Viridans group streptococci 1 (2.6) 0 1 (2.0) Culture negative‡ 5 (13.2) 0 5 (10.2) LE ⫽ left-sided endocarditis or mixed left- and right-sided endocarditis; RE ⫽ right-sided endocarditis alone. *Values total ⬎49 because some patients had ⬎1 pathogen. † LE vs. RE; P ⫽ 0.018. ‡ Defined as no pathogen reported at initiation of daptomycin.
therapy, most commonly an aminoglycoside, vancomycin, or rifampin. The overall frequency of concomitant antibiotic therapy was similar in the LE and RE groups (P ⫽ 0.725).
Clinical Outcome Table 5 outlines the clinical outcomes at the end of daptomycin therapy. Overall, 31 (63%) of the patients had clin-
Levine and Lamp Table 4
Daptomycin for Infective Endocarditis
Concomitant antimicrobial agents*
S31 Table 6
Clinical outcome by primary cultured pathogen* n (%)
n (%)
Type Any concomitant antibiotics† Aminoglycoside Vancomycin Rifampin Fluoroquinolone Cephalosporin Linezolid Other penicillin Metronidazole Penicillinase-resistant penicillin Aztreonam Carbapenem Trimethoprimsulfamethoxazole Quinupristindalfopristin
LE (n ⫽ 38)
RE (n ⫽ 11)
ALL (n ⫽ 49)
24 (63.2)
8 (72.7)
32 (65.3)
11 7 7 4 1 2 3 2 1
2 3 2 3 3 2 0 0 0
13 10 9 7 4 4 3 2 1
(28.9) (18.4) (18.4) (10.5) (2.6) (5.3) (7.9) (5.3) (2.6)
(18.2) (27.3) (18.2) (27.3) (27.3) (18.2)
(26.5) (20.4) (18.4) (14.3) (8.2) (8.2) (6.1) (4.1) (2.0)
0 0 0
1 (9.1) 1 (9.1) 1 (9.1)
1 (2.0) 1 (2.0) 1 (2.0)
0
1 (9.1)
1 (2.0)
LE ⫽ left-sided endocarditis or mixed left and right-sided endocarditis; RE ⫽ right-sided endocarditis alone. *Patients may be counted in ⬎1 category. † LE vs. RE; P ⫽ 0.725.
Table 5
Clinical outcomes of daptomycin therapy n (%)
Outcome
LE (n ⫽ 38)
RE (n ⫽ 11)
All (n ⫽ 49)
Success Cure Improved Failure Nonevaluable
25 16 9 3 10
6 2 4 1 4
31 18 13 4 14
(65.8) (42.1) (23.7) (7.9) (26.3)
(54.5) (18.2) (36.4) (9.1) (36.4)
(63.3) (36.7) (26.5) (8.2) (28.6)
LE ⫽ left-sided endocarditis or mixed left- and right-sided endocarditis; RE ⫽ right-sided endocarditis alone.
ical success with daptomycin (LE: 25 of 38, 66%; RE: 6 of 11, 55%), 4 (8%) patients were classified as having failed treatment, and 14 (29%) patients had nonevaluable charts. Patients who failed did not have any significant differences compared with other patients in endocarditis site, pathogen, daptomycin dose, concomitant antibiotic use, renal function, or presence of diabetes. The LE failures all received an initial daptomycin dose of 6 mg/kg. The pathogens were MRSA in 2 patients (daptomycin duration of therapy, 6 and 28 days) and E faecalis (vancomycin susceptible) in 1 patient (daptomycin duration of therapy, 5 days). The RE patient who failed treatment received an initial daptomycin dose of 4 mg/kg; daptomycin treatment continued for 62 days, and the pathogen was VRE. If only clinically evaluable cases (n ⫽ 35) are considered, the clinical success rates were 89% for the entire cohort, 89% for the LE group (n ⫽
Staphylococcus aureus, methicillin resistant Success Failure Nonevaluable Enterococcus Success Failure Nonevaluable S aureus, methicillin susceptible Success Failure Nonevaluable Coagulase-negative staphylococci Success Failure Nonevaluable Viridans group streptococci Success Failure Nonevaluable Culture negative† Success Failure Nonevaluable
LE
RE
All
9 (60) 2 (13) 4 (27)
5 (63) 0 (0) 3 (38)
14 (71) 2 (9) 7 (30)
9 (75) 1 (8) 2 (17)
1 (50) 1 (50) 0 (0)
10 (71) 2 (14) 2 (14)
3 (75) 0 (0) 1 (25)
— — —
3 (75) 0 (0) 1 (25)
1 (100) 0 (0) 0 (0) 0 (0) 0 (0) 1 (100)
1 (50) 0 (0) 1 (50)
0 (0) — 0 (0) — 1 (100) —
0 (0) 0 (0) 1 (100)
3 (60) 0 (0) 2 (40)
3 (60) 0 (0) 2 (40)
— — —
LE ⫽ left-sided endocarditis or mixed left- and right-sided endocarditis; RE ⫽ right-sided endocarditis alone. *Outcome data by cultured primary pathogen use only a single investigator-chosen pathogen for comparison. Thus, numbers vary from microbiology isolates data. † Defined as no pathogen reported at initiation of daptomycin treatment.
28), and 86% for the RE group (n ⫽ 7). The median times to clinical response based on signs and symptoms for evaluable patients with reported data were 4 days for the LE group (n ⫽ 15) and 5 days for the RE group (n ⫽ 4); P ⫽ 0.225. Table 6 provides the clinical response data by primary cultured pathogen in the LE and RE groups. Clinical responses to all pathogens appeared to be similar in the 2 groups. In the LE group, 4 (25%) of 16 patients whose outcome was assessed as clinical cure and 2 (22%) of 9 improved patients were switched to vancomycin (n ⫽ 4), linezolid (n ⫽ 1), or a cephalosporin (n ⫽ 1) to complete therapy. The mean duration of daptomycin treatment before the switch was 21 days for vancomycin, 16 days for linezolid, and 7 days for cephalosporin. A total of 5 (13%) of the LE patients died of unknown causes; 3 of these patients had an outcome of failure, and 2 patients had a nonevaluable outcome. In the RE group, 2 (18%) of the patients received additional antibiotic therapy after daptomycin treatment was stopped; 1 patient, who had improved with 19 days of daptomycin, was subsequently given vancomycin. In all, 3
S32 of the 4 RE patients with a nonevaluable outcome died of unknown causes. If patient deaths were reclassified as failures, the corresponding failure and nonevaluable rates would be 36% and 9% for RE and 13% and 21% for LE.
DISCUSSION Data from CORE 2004 show that daptomycin was being used for treatment of patients with infective endocarditis in the real-world hospital setting, albeit somewhat infrequently. The infrequent use may be owing to the lack of FDA approval of daptomycin for endocarditis at that time and to uncertainty regarding the optimal dose. Overall, CORE 2004 included 49 patients with a diagnosis of endocarditis, representing 4.2% of the patients in the registry. On the basis of this small sample, daptomycin may be an option in treating endocarditis, as evidenced by the clinical success rate of 63% in the entire cohort and 89% among patients with clinically evaluable charts. The findings support the promise of daptomycin previously established in experimental models of endocarditis.16 –19 In these models, daptomycin was at least as effective as vancomycin in reducing bacterial cell counts. When infection was caused by methicillin-resistant staphylococci, daptomycin was often more effective than vancomycin. Moreover, daptomycin showed concentration-dependent bactericidal activity against clinical isolates of MRSA, vancomycin-intermediate S aureus, and VRE in an in vitro pharmacodynamic model with simulated endocardial vegetation, whereas vancomycin produced minimal bacterial killing and then remained bacteriostatic against the MRSA strain.19 These and other animal studies of daptomycin in endocarditis infection models suggest that daptomycin has clinical activity for these infections. Daptomycin 6 mg/kg given intravenously once daily was recently reported to be noninferior to standard dual therapy comparators (vancomycin or semisynthetic penicillinaseresistant penicillins, each combined with short-course gentamicin) in a large randomized controlled registrational trial of S aureus bacteremia and infective endocarditis.13 Patients were eligible for enrollment if they had ⱖ1 positive blood culture for S aureus within 2 days of starting the study drug. Patients were excluded if they had a CrCl of ⬍30 mL/min, polymicrobial bloodstream infections, osteomyelitis, irremovable foreign material, prosthetic heart valves, or pneumonia. For the intent-to-treat population, clinical success rates at the end of therapy were 62% with daptomycin and 61% with conventional dual therapy, and the corresponding rates at the test-of-cure visit scheduled 6 weeks after the end of therapy were 44% and 42%. The success rates for RE were 42% for daptomycin and 44% for comparators at the test-of-cure visit. Although a direct comparison would not be possible due to differences in study design and patient characteristics (45% with CrCl ⬍30 mL/min), the overall success rate for RE of 55% at the end of therapy in CORE 2004 was similar to that reported in the registrational trial.
The American Journal of Medicine, Vol 120 (10A), October 2007 This study represents the largest reported group of patients with LE (n ⫽ 38) treated with daptomycin. After the S aureus bacteremia and infective endocarditis trial was initiated, an amendment allowed the enrollment of leftsided endocarditis. Therefore, the number of LE patients was small. The success rate was 11% (1 of 9) for daptomycin and 22% (2 of 9) for the dual-therapy comparator using the strict definitions required for success 6 weeks after completed therapy. Again, the differences in study design do not permit a comparison with the 66% success rate in LE patients in this analysis. To further evaluate the results in LE patients, controlled clinical trials are needed. Clinical success was independent of gram-positive isolates, including MRSA and Enterococcus. There have been few previous reports of daptomycin use for enterococcal bacteremia and endocarditis. Segreti and colleagues20 published a case series including 9 bacteremia and 2 LE patients infected with VRE. Approximately one half of patients received prior antibiotics (55%) or concomitant antibiotics (45%), similar to that seen in CORE 2004. The success rates were 56% (5 of 9) for VRE bacteremia and 0% (0 of 2) for VRE LE. This was an uncontrolled case series, as is CORE 2004, and may provide a basis for future rigorous studies of this pathogen. S aureus was the most common pathogen isolated in the CORE 2004 cohort of endocarditis patients, followed by Enterococcus. Only 3 CoNS isolates and 1 viridans group streptococcus isolate were found. S aureus was also the most common pathogen cultured in an observational cohort of 1,779 patients with infective endocarditis enrolled in the International Collaboration on Endocarditis–Prospective Cohort Study (ICE) from June 2000 to December 2003.2 In that cohort, S aureus was isolated in 31.6% of patients, viridans group streptococci in 18.0%, enterococci in 10.6%, and CoNS in 10.5%. MRSA accounted for 27.4% of the S aureus isolates. The higher prevalence of S aureus in general and MRSA in particular in the CORE 2004 cohort may be owing to differences between prevalence in the United States and internationally (as reflected in ICE) or to selection bias for daptomycin therapy. Most of the CORE 2004 patients had been previously treated with other antibiotics. This finding may indicate that patients with difficult-to-treat pathogens, notably MRSA and enterococci, were more likely to require alternative antimicrobial therapy. The present CORE 2004 data are limited in several ways. As with all registry studies, this study was retrospective and unblinded, and many variables were not controlled. It is important to note that the endocarditis diagnosis was determined by the individual investigators, and the diagnostic criteria (such as echocardiography and Duke criteria assessment) were not collected. As a result, patients included in this study should not be considered a homogeneous group. Concomitant antibiotics were administered in most of the cases, and because complete susceptibility data were not collected, it is unclear to what extent these concomitant
Levine and Lamp
Daptomycin for Infective Endocarditis
agents contributed to the observed outcomes. Surgical interventions were not captured, and their influence on the outcomes cannot be assessed. Results of previous studies involving patients with infective endocarditis suggest that relapse of infection can occur in a significant number of patients; therefore, the lack of follow-up data, including microbiologic response, also limits the conclusions. Although the median starting dose of daptomycin in the CORE 2004 cohort of endocarditis patients was 6 mg/kg, 37% of patients in the LE group and 73% of patients in the RE group were begun on less than the approved dose of 6 mg/kg. At the time these patients were treated for endocarditis, very little information on efficacy or safety was available for doses ⬎4 mg/kg, and this may have contributed to the lower doses chosen. It is unknown if lower doses may have influenced the outcomes in CORE 2004, although no differences were seen in outcomes when categorized by dose. The clinical success rate of 63% at the end of daptomycin therapy on the basis of signs and symptoms is not unexpected given the results from the recently completed clinical trial (42% at test of cure for RE). Selection bias may have led to increased numbers of patients who were difficult to treat. This selection bias is illustrated by the higher-than-expected prevalence of MRSA and the very high proportion of patients who had received previous antibiotic therapy. Finally, adverse reaction data were not specifically collected in CORE 2004, thereby precluding any analysis of the safety and tolerability of daptomycin in patients with endocarditis.
SUMMARY The results from the CORE 2004 database, combined with data from experimental endocarditis models and data from a randomized controlled study involving patients with S aureus bacteremia and endocarditis, suggest that daptomycin should be considered a possible treatment for patients with right-sided infective endocarditis involving S aureus. Further studies are needed to extend daptomycin’s experience in left-sided or enterococcal endocarditis.
AUTHOR DISCLOSURES The authors who contributed to this article have disclosed the following industry relationships: Kenneth C. Lamp, PharmD, is an employee and stockholder of Cubist Pharmaceuticals, Inc. Donald P. Levine, MD, is a member of the Speakers’ Bureau for Cubist Pharmaceuticals, Inc.; serves as a consultant to Cubist Pharmaceuticals, Inc. and Astellas Pharma Inc.; and has received research/grant support from Cubist Pharmaceuticals, Inc.
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References 1. Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American
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Heart Association— endorsed by the Infectious Diseases Society of America [published corrections appear in Circulation. 2005;112:2373 and 2005;115:e408]. Circulation. 2005;111:e394 – e434. Fowler VG Jr, Miro JM, Hoen B, et al, for the ICE Investigators. Staphylococcus aureus endocarditis: a consequence of medical progress [published correction appears in JAMA. 2005;294:900]. JAMA. 2005;293:3012–3021. Baddour LM, Wilson WR. Infections of prosthetic valves and other cardiovascular devices. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. Philadelphia: Elsevier Churchill Livingstone; 2005:1022–1044. Chambers HF. The changing epidemiology of Staphylococcus aureus? Emerg Infect Dis. 2001;7:178 –182. Smith TL, Pearson ML, Wilcox KR, et al, for the GlycopeptideIntermediate. Staphylococcus aureus Working Group. Emergence of vancomycin resistance in Staphylococcus aureus. N Engl J Med. 1999; 340:493–501. Tenover FC, McDonald LC. Vancomycin-resistant staphylococci and enterococci: epidemiology and control. Curr Opin Infect Dis. 2005; 18:300 –305. Chang S, Sievert DM, Hageman JC, et al, for the VancomycinResistant Staphylococcus aureus Investigative Team. Infection with vancomycin-resistant Staphylococcus aureus containing the vanA resistance gene. N Engl J Med. 2003;348:1342–1347. Mascini EM, Bonten MJ. Vancomycin-resistant enterococci: consequences for therapy and infection control. Clin Microbiol Infect. 2005; (suppl 4):43–56. Torres-Viera C, Dembry LM. Approaches to vancomycin-resistant enterococci. Curr Opin Infect Dis. 2004;17:541–547. Carpenter CF, Chambers HF. Daptomycin: another novel agent for treating infections due to drug-resistant gram-positive pathogens. Clin Infect Dis. 2004;38:994 –1000. Eisenstein BI. Lipopeptides, focusing on daptomycin, for the treatment of Gram-positive infections. Expert Opin Investig Drugs. 2004;13: 1159 –1169. Arbeit RD, Maki D, Tally FP, Campanaro E, Eisenstein BI, for the Daptomycin 98-01 and 99-01 Investigators. The safety and efficacy of daptomycin for the treatment of complicated skin and skin-structure infections. Clin Infect Dis. 2004;38:1673–1681. Fowler VG Jr, Boucher HW, Corey R, et al, for the S. aureus Endocarditis and Bacteremia Study Group. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med. 2006;355:653– 665. Cubicin (daptomycin for injection) [prescribing information]. Lexington, MA: Cubist Pharmaceuticals, Inc.; 2006. Rolston KVI, Segreti JA, Lamp KC, Friedrich LV. Cubicin Outcomes Registry and Experience (CORE) methodology. Am J Med. 2007;120 (suppl 10A):S4 –S5. Kennedy S, Chambers HF. Daptomycin (LY146032) for prevention and treatment of experimental aortic valve endocarditis in rabbits. Antimicrob Agents Chemother. 1989;33:1522–1525. Kaatz GW, Seo SM, Reddy VN, Bailey EM, Rybak MJ. Daptomycin compared with teicoplanin and vancomycin for therapy of experimental Staphylococcus aureus endocarditis. Antimicrob Agents Chemother. 1990;34:2081–2085. Sakoulas G, Eliopoulos GM, Alder J, Eliopoulos CT. Efficacy of daptomycin in experimental endocarditis due to methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 2003;47:1714 – 1718. Akins RL, Rybak MJ. Bactericidal activities of two daptomycin regimens against clinical strains of glycopeptide intermediate-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium, and methicillin-resistant Staphylococcus aureus isolates in an in vitro pharmacodynamic model with simulated endocardial vegetations. Antimicrob Agents Chemother. 2001;45:454 – 459. Segreti JA, Crank CW, Finney MS. Daptomycin for the treatment of gram-positive bacteremia and infective endocarditis: A retrospective case series of 31 patients. Pharmacotherapy. 2006;26:347–352.
Daptomycin in the Treatment of Patients with Infective Endocarditis: Experience from a Registry Donald P. Levine, MD,a and Kenneth C. Lamp, PharmDb a
Wayne State University, University Health Center, Detroit, Michigan, USA; and bCubist Pharmaceuticals, Inc., Lexington, Massachusetts, USA ABSTRACT Daptomycin (Cubicin; Cubist Pharmaceuticals, Inc., Lexington, MA) is a first-in-its-class cyclic lipopeptide approved for the treatment of patients with complicated skin and skin-structure infections due to susceptible gram-positive pathogens and recently approved for Staphylococcus aureus bloodstream infections including right-sided infective endocarditis. The clinical experience of patients registered in the Cubicin Outcomes Registry and Experience (CORE) 2004 database with daptomycin-treated infective endocarditis is described. The registry data were collected retrospectively by trained investigators to document real-world clinical experience. Study limitations included uncontrolled diagnostic criteria, noncomparative data, and lack of follow-up assessments. A total of 49 patients had a diagnosis of endocarditis: 38 with left-sided or both left-sided and right-sided endocarditis, and 11 with right-sided endocarditis alone. Renal failure was the most common comorbid condition. In all, 27 (55%) of the 49 patients had an initial creatinine clearance of ⱕ30 mL/min, and 14 (29%) were supported by dialysis. Staphylococcus aureus (59%; 83%, methicillin resistant) and enterococci (29%; 43%, vancomycin resistant) were the most commonly identified pathogens. In most instances, patients received gram-positive therapy before receiving daptomycin (43 of 49 [88%]). The median starting dose of daptomycin was 6 mg/kg (range, 4 to 7 mg/kg); 27 (55%) of the patients received a dose of ⱖ6 mg/kg. Daptomycin therapy was successful for 31 (63%) of the patients: cure was seen in 18 (37%) and improvement in 13 (27%). Therapy failed in 4 (8%) of the patients, and 14 (29%) of the cases were nonevaluable. The median duration of therapy in successful cases was 27 days. No differences in clinical response were observed based on baseline renal function, primary pathogen, or site of endocarditis. The results from the CORE 2004 database suggest that daptomycin should be considered a possible treatment for patients with right-sided infective endocarditis involving S aureus. Further studies are needed to extend daptomycin’s experience in left-sided or enterococcal endocarditis. © 2007 Elsevier Inc. All rights reserved. KEYWORDS: Bacteremia; Daptomycin; Endocarditis; Enterococci; Staphylococci
Infective endocarditis is a microbial infection of the endocardial surfaces of the heart. Infections of the left side of the heart, involving the aortic or mitral valves, have greater therapeutic failure rates compared with those of the right side, sometimes necessitate more intensive antibacterial therapy, and more often require surgical intervention.1
Please see Author Disclosure section at the end of this article. Requests for reprints should be addressed to Kenneth C. Lamp, PharmD, Cubist Pharmaceuticals, Inc., 65 Hayden Avenue, Lexington, Massachusetts 02421. E-mail address: [email protected].
0002-9343/$ -see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2007.07.011
The most prevalent pathogens are Staphylococcus aureus, coagulase-negative staphylococci (CoNS), viridans group streptococci, and enterococci.2,3 This etiology highlights the importance of antibacterial agents active against gram-positive microorganisms for treatment of this infection. The emergence and dissemination of antimicrobial resistance among gram-positive pathogens, particularly methicillin-resistant S aureus (MRSA) and vancomycin-resistant enterococci (VRE), have become troublesome.4 –9 In a recent observational cohort of 1,779 patients with infective endocarditis, S aureus was the most common pathogen, and MRSA was identified in ⬎25% of these cases.2
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Daptomycin for Infective Endocarditis
Patients with MRSA exhibited a trend toward a higher rate of mortality compared with individuals who have methicillin-susceptible S aureus (MSSA). The identification of vancomycin-intermediate and heteroresistant S aureus and, in a limited number of cases, vancomycin-resistant S aureus portends even greater difficulty in treating these infections in the future.5–7 The changing pattern of bacterial resistance emphasizes the need for antimicrobial agents with novel mechanisms of action that can eradicate multiresistant gram-positive pathogens responsible for serious infections such as endocarditis. Daptomycin (4 mg/kg) was approved by the US Food and Drug Administration (FDA) in 2003 for the treatment of patients with complicated skin and skin-structure infections and daptomycin (6 mg/kg) in 2006 for the treatment of S aureus bloodstream infections including right-sided infective endocarditis.10 –14 A large, randomized, controlled, noninferiority clinical study has shown that daptomycin is well tolerated and is as effective as standard dual-therapy comparator antibiotics (semisynthetic penicillins or vancomycin, each combined with short-course gentamicin) for the treatment of right-sided endocarditis due to S aureus.13 The outcomes were assessed by a treatment-blinded independent adjudication committee. The overall success rates at the test of cure visit (6 weeks after the last treatment dose) were 44.2% in patients treated with daptomycin and 41.7% in patients treated with the comparator. The right-sided endocarditis success rates were 42.1% in patients treated with daptomycin and 43.8% in patients treated with the comparator.13,14 Although this study was amended to allow enrollment of patients with left-sided infective endocarditis, the numbers and outcomes were insufficient to determine daptomycin’s effectiveness. The Cubicin Outcomes Registry and Experience (CORE) 2004 was a retrospective observational chart review of the cases of patients receiving daptomycin for any indication in 45 US institutions. Using the CORE 2004 database, investigators identified a cohort of 49 patients with a reported diagnosis of endocarditis. The outcomes achieved with daptomycin therapy are discussed in this article.
METHODS The methods for conducting the registry are described by Rolston and colleagues elsewhere in this supplement.15 All patients (clinically evaluable and nonevaluable) with a diagnosis of endocarditis were included in this analysis regardless of the presence of other concurrent infections. The diagnosis of endocarditis was determined by the individual investigators. Information regarding echocardiography findings or Duke criteria assessment was not collected.
Statistics Statistical analysis included both descriptive and inferential methods. Descriptive methods included the presentation of mean, median, and proportional data. Comparisons between groups were made with appropriate parametric and nonpara-
S29 Table 1
Demographics of study patients*
Characteristic Sex Female Male Weight, kg (mean ⫾ SD) Age group (yr) 31–50 51–65 ⱖ66 Comorbid conditions† Chronic renal failure Diabetes mellitus Hypertension Valvular heart disease Arrhythmias Acute coronary syndromes Other cardiovascular disease Any transplant Renal impairment CrCl ⬍30 mL/min Dialysis
LE (n ⫽ 38) RE (n ⫽ 11) All (n ⫽ 49) 20 (52.6) 4 (36.4) 24 (49.0) 18 (47.4) 7 (63.6) 25 (51.0) 80.2 ⫾ 15.3 75.3 ⫾ 17.7 79.1 ⫾ 15.8 5 (13.2) 15 (39.5) 18 (47.4)
3 (27.3) 4 (36.4) 4 (36.4)
8 (16.3) 19 (38.8) 22 (44.9)
14 8 7 8 7 5
3 4 4 1 1 1
17 12 11 9 8 6
(36.8) (21.1) (18.4) (21.1) (18.4) (13.2)
(27.3) (36.4) (36.4) (9.1) (9.1) (9.1)
(34.7) (24.5) (22.4) (18.4) (16.3) (12.2)
7 (18.4)
1 (9.1)
8 (16.3)
4 (10.5)
1 (9.1)
5 (10.2)
22 (57.9) 11 (28.9)
5 (45.5) 3 (27.3)
27 (55.1) 14 (28.6)
CrCl ⫽ creatinine clearance; LE ⫽ left-sided endocarditis or mixed left- and right-sided endocarditis; RE ⫽ right-sided endocarditis alone. *Values are given as number of patients (percentage) unless otherwise indicated. † Patients may have ⬎1 comorbid condition.
metric techniques. Statistical significance was assessed at the 5% level.
RESULTS Patient Characteristics Among the 1,160 CORE 2004 patients, 49 patients (4.2%) had a diagnosis of infective endocarditis. Of these, 26 (53%) had endocarditis of the left side of the heart (LE), 11 (22%) had right-sided endocarditis (RE), and 12 (24%) had both LE and RE. Data on patients with both LE and RE were combined with those on patients with LE alone. This pooled group is referred to as the LE group. Tables 1 and 2 show the demographic characteristics of the study patients and information on concurrent infections, respectively. The LE and RE groups did not differ significantly in any demographic characteristic. In general, most (84%; n ⫽ 41) of the patients were middle-aged (i.e., aged 51 to 65 years) or elderly (ⱖ66 years), and most (73%; n ⫽ 36) were in the hospital 2 days before starting daptomycin therapy. Chronic renal failure (17 cases [35%]), diabetes mellitus (12 cases [24%]), and hypertension (11 cases [22%]) were the most common comorbid conditions. More than half (55%) of the patients had an initial creatinine clearance (CrCl) of ⬍30 mL/min, and 28.6% were undergoing dialysis. In addition, concurrent infections were reported, catheter-related bacteremia (8 cases [16%]) being the most frequent. Two patients were reported to have
S30 infected intracardiac foreign devices; however, information about the types of devices and sites was not collected.
The American Journal of Medicine, Vol 120 (10A), October 2007 Table 2
Concurrent infections* n (%)
Microbiology Table 3 shows the microbiology results for the cultures obtained at the initiation of daptomycin therapy. S aureus (29 cases [59%]) and enterococci (14 cases [29%]) were the most common pathogens isolated. MRSA accounted for 24 (83%) of the 29 S aureus isolates, whereas VRE accounted for 6 (43%) of the 14 enterococcal isolates. There were 3 patients, each of whom had 2 pathogens identified: MRSA and MSSA; Enterococcus faecalis and Staphylococcus epidermidis; and Enterococcus and MRSA. Another 3 patients had CoNS; none of these individuals had infected catheters or foreign devices. Additionally, 5 patients, all in the LE group, did not have pathogens reported. Comparisons between the LE and RE cohorts were limited by the small number of patients in the latter group. Nevertheless, MRSA was identified at a higher rate in the RE cohort than in the LE cohort (9 [82%] of 11 cases vs. 15 [39%] of 38 cases; P ⫽ 0.018). The frequency of other pathogens was generally comparable between the 2 groups.
Infection Type Bacteremia, catheter-related Urinary tract Foreign device, intravascular Foreign device, intracardiac Septic arthritis Skin and skin-structure infection† Central nervous system Diabetic foot Osteomyelitis
LE RE All (n ⫽ 38) (n ⫽ 11) (n ⫽ 49) 7 3 2 1 1 1
(18.4) (7.9) (5.3) (2.6) (2.6) (2.6)
1 (2.6) 0 0
1 (9.1) 0 0 1 (9.1) 0 0
8 3 2 2 1 1
(16.3) (6.1) (4.1) (4.1) (2.0) (2.0)
0 1 (9.1) 1 (9.1)
1 (2.0) 1 (2.0) 1 (2.0)
LE ⫽ left-sided endocarditis or mixed left- and right-sided endocarditis; RE ⫽ right-sided endocarditis alone. *Patients may have ⬎1 infection type. † Uncomplicated.
Table 3 Gram-positive pathogens isolated before daptomycin treatment* n (%)
Daptomycin Dosing The median starting dose was 6 mg/kg (range, 4 to 7 mg/kg) for the entire cohort. The median dose for LE was 6 mg/kg (range, 4 to 7 mg/kg) and for RE, 4 mg/kg (range, 4 to 6.4 mg/kg) (P ⫽ 0.644). A total of 27 (55%) of the patients received daptomycin at a dose of ⱖ6 mg/kg. The rate of use of daptomycin at doses of ⱖ6 mg/kg was significantly greater in the LE subgroup than in the RE subgroup (63% vs. 27%; P ⫽ 0.046). All patients with CrCl of ⱖ30 mL/min received daptomycin once every 24 hours. In all, 25 (93%) of 27 patients with CrCl of ⬍30 mL/min received daptomycin every 48 hours or 3 times per week. The median duration of daptomycin therapy in successfully treated patients was 27 days (range, 5 to 62 days). The daptomycin median duration for clinically evaluable patients was 26.5 days for the LE group and 27 days for the RE group (P ⫽ 0.739).
Previous and Concomitant Antibiotic Therapy Most (43 [88%]) of the patients received antimicrobial therapy before receiving daptomycin (33 [87%] patients in the LE group and 10 [91%] patients in the RE group). Specifics regarding previous therapy were not collected, with the exception of allergy, intolerance, or a contraindication for linezolid and vancomycin. In the LE group, 4 patients had allergy, intolerance, or a contraindication for linezolid, and 6 patients had contraindication for vancomycin. The pathogen was resistant to linezolid and vancomycin in 1 patient each. In the RE group, 2 patients had allergy, intolerance, or contraindication for vancomycin, although neither individual had infection involving vancomycin-resistant pathogens. Table 4 shows use of concomitant antimicrobial agents during daptomycin therapy. In all, 32 (65%) of the 49 patients received ⱖ1 dose of concomitant antimicrobial
Pathogen
LE RE All (n ⫽ 38) (n ⫽ 11) (n ⫽ 49)
Staphylococci 15 (39.5) 9 (81.8) 24 (49.0) Methicillin-resistant Staphylococcus aureus† Methicillin-susceptible 4 (10.5) 1 (9.1) 5 (10.2) S aureus Coagulase-negative 2 (5.3) 1 (9.1) 3 (6.1) staphylococci Enterococci Enterococcus faecalis 6 (15.8) 0 6 (12.2) (vancomycin susceptible) Enterococcus (vancomycin 4 (10.5) 1 (9.1) 5 (10.2) resistant, species unreported) Enterococcus (vancomycin 1 (2.6) 1 (9.1) 2 (4.1) susceptible, species unreported) E faecium (vancomycin 1 (2.6) 0 1 (2.0) resistant) Viridans group streptococci 1 (2.6) 0 1 (2.0) Culture negative‡ 5 (13.2) 0 5 (10.2) LE ⫽ left-sided endocarditis or mixed left- and right-sided endocarditis; RE ⫽ right-sided endocarditis alone. *Values total ⬎49 because some patients had ⬎1 pathogen. † LE vs. RE; P ⫽ 0.018. ‡ Defined as no pathogen reported at initiation of daptomycin.
therapy, most commonly an aminoglycoside, vancomycin, or rifampin. The overall frequency of concomitant antibiotic therapy was similar in the LE and RE groups (P ⫽ 0.725).
Clinical Outcome Table 5 outlines the clinical outcomes at the end of daptomycin therapy. Overall, 31 (63%) of the patients had clin-
Levine and Lamp Table 4
Daptomycin for Infective Endocarditis
Concomitant antimicrobial agents*
S31 Table 6
Clinical outcome by primary cultured pathogen* n (%)
n (%)
Type Any concomitant antibiotics† Aminoglycoside Vancomycin Rifampin Fluoroquinolone Cephalosporin Linezolid Other penicillin Metronidazole Penicillinase-resistant penicillin Aztreonam Carbapenem Trimethoprimsulfamethoxazole Quinupristindalfopristin
LE (n ⫽ 38)
RE (n ⫽ 11)
ALL (n ⫽ 49)
24 (63.2)
8 (72.7)
32 (65.3)
11 7 7 4 1 2 3 2 1
2 3 2 3 3 2 0 0 0
13 10 9 7 4 4 3 2 1
(28.9) (18.4) (18.4) (10.5) (2.6) (5.3) (7.9) (5.3) (2.6)
(18.2) (27.3) (18.2) (27.3) (27.3) (18.2)
(26.5) (20.4) (18.4) (14.3) (8.2) (8.2) (6.1) (4.1) (2.0)
0 0 0
1 (9.1) 1 (9.1) 1 (9.1)
1 (2.0) 1 (2.0) 1 (2.0)
0
1 (9.1)
1 (2.0)
LE ⫽ left-sided endocarditis or mixed left and right-sided endocarditis; RE ⫽ right-sided endocarditis alone. *Patients may be counted in ⬎1 category. † LE vs. RE; P ⫽ 0.725.
Table 5
Clinical outcomes of daptomycin therapy n (%)
Outcome
LE (n ⫽ 38)
RE (n ⫽ 11)
All (n ⫽ 49)
Success Cure Improved Failure Nonevaluable
25 16 9 3 10
6 2 4 1 4
31 18 13 4 14
(65.8) (42.1) (23.7) (7.9) (26.3)
(54.5) (18.2) (36.4) (9.1) (36.4)
(63.3) (36.7) (26.5) (8.2) (28.6)
LE ⫽ left-sided endocarditis or mixed left- and right-sided endocarditis; RE ⫽ right-sided endocarditis alone.
ical success with daptomycin (LE: 25 of 38, 66%; RE: 6 of 11, 55%), 4 (8%) patients were classified as having failed treatment, and 14 (29%) patients had nonevaluable charts. Patients who failed did not have any significant differences compared with other patients in endocarditis site, pathogen, daptomycin dose, concomitant antibiotic use, renal function, or presence of diabetes. The LE failures all received an initial daptomycin dose of 6 mg/kg. The pathogens were MRSA in 2 patients (daptomycin duration of therapy, 6 and 28 days) and E faecalis (vancomycin susceptible) in 1 patient (daptomycin duration of therapy, 5 days). The RE patient who failed treatment received an initial daptomycin dose of 4 mg/kg; daptomycin treatment continued for 62 days, and the pathogen was VRE. If only clinically evaluable cases (n ⫽ 35) are considered, the clinical success rates were 89% for the entire cohort, 89% for the LE group (n ⫽
Staphylococcus aureus, methicillin resistant Success Failure Nonevaluable Enterococcus Success Failure Nonevaluable S aureus, methicillin susceptible Success Failure Nonevaluable Coagulase-negative staphylococci Success Failure Nonevaluable Viridans group streptococci Success Failure Nonevaluable Culture negative† Success Failure Nonevaluable
LE
RE
All
9 (60) 2 (13) 4 (27)
5 (63) 0 (0) 3 (38)
14 (71) 2 (9) 7 (30)
9 (75) 1 (8) 2 (17)
1 (50) 1 (50) 0 (0)
10 (71) 2 (14) 2 (14)
3 (75) 0 (0) 1 (25)
— — —
3 (75) 0 (0) 1 (25)
1 (100) 0 (0) 0 (0) 0 (0) 0 (0) 1 (100)
1 (50) 0 (0) 1 (50)
0 (0) — 0 (0) — 1 (100) —
0 (0) 0 (0) 1 (100)
3 (60) 0 (0) 2 (40)
3 (60) 0 (0) 2 (40)
— — —
LE ⫽ left-sided endocarditis or mixed left- and right-sided endocarditis; RE ⫽ right-sided endocarditis alone. *Outcome data by cultured primary pathogen use only a single investigator-chosen pathogen for comparison. Thus, numbers vary from microbiology isolates data. † Defined as no pathogen reported at initiation of daptomycin treatment.
28), and 86% for the RE group (n ⫽ 7). The median times to clinical response based on signs and symptoms for evaluable patients with reported data were 4 days for the LE group (n ⫽ 15) and 5 days for the RE group (n ⫽ 4); P ⫽ 0.225. Table 6 provides the clinical response data by primary cultured pathogen in the LE and RE groups. Clinical responses to all pathogens appeared to be similar in the 2 groups. In the LE group, 4 (25%) of 16 patients whose outcome was assessed as clinical cure and 2 (22%) of 9 improved patients were switched to vancomycin (n ⫽ 4), linezolid (n ⫽ 1), or a cephalosporin (n ⫽ 1) to complete therapy. The mean duration of daptomycin treatment before the switch was 21 days for vancomycin, 16 days for linezolid, and 7 days for cephalosporin. A total of 5 (13%) of the LE patients died of unknown causes; 3 of these patients had an outcome of failure, and 2 patients had a nonevaluable outcome. In the RE group, 2 (18%) of the patients received additional antibiotic therapy after daptomycin treatment was stopped; 1 patient, who had improved with 19 days of daptomycin, was subsequently given vancomycin. In all, 3
S32 of the 4 RE patients with a nonevaluable outcome died of unknown causes. If patient deaths were reclassified as failures, the corresponding failure and nonevaluable rates would be 36% and 9% for RE and 13% and 21% for LE.
DISCUSSION Data from CORE 2004 show that daptomycin was being used for treatment of patients with infective endocarditis in the real-world hospital setting, albeit somewhat infrequently. The infrequent use may be owing to the lack of FDA approval of daptomycin for endocarditis at that time and to uncertainty regarding the optimal dose. Overall, CORE 2004 included 49 patients with a diagnosis of endocarditis, representing 4.2% of the patients in the registry. On the basis of this small sample, daptomycin may be an option in treating endocarditis, as evidenced by the clinical success rate of 63% in the entire cohort and 89% among patients with clinically evaluable charts. The findings support the promise of daptomycin previously established in experimental models of endocarditis.16 –19 In these models, daptomycin was at least as effective as vancomycin in reducing bacterial cell counts. When infection was caused by methicillin-resistant staphylococci, daptomycin was often more effective than vancomycin. Moreover, daptomycin showed concentration-dependent bactericidal activity against clinical isolates of MRSA, vancomycin-intermediate S aureus, and VRE in an in vitro pharmacodynamic model with simulated endocardial vegetation, whereas vancomycin produced minimal bacterial killing and then remained bacteriostatic against the MRSA strain.19 These and other animal studies of daptomycin in endocarditis infection models suggest that daptomycin has clinical activity for these infections. Daptomycin 6 mg/kg given intravenously once daily was recently reported to be noninferior to standard dual therapy comparators (vancomycin or semisynthetic penicillinaseresistant penicillins, each combined with short-course gentamicin) in a large randomized controlled registrational trial of S aureus bacteremia and infective endocarditis.13 Patients were eligible for enrollment if they had ⱖ1 positive blood culture for S aureus within 2 days of starting the study drug. Patients were excluded if they had a CrCl of ⬍30 mL/min, polymicrobial bloodstream infections, osteomyelitis, irremovable foreign material, prosthetic heart valves, or pneumonia. For the intent-to-treat population, clinical success rates at the end of therapy were 62% with daptomycin and 61% with conventional dual therapy, and the corresponding rates at the test-of-cure visit scheduled 6 weeks after the end of therapy were 44% and 42%. The success rates for RE were 42% for daptomycin and 44% for comparators at the test-of-cure visit. Although a direct comparison would not be possible due to differences in study design and patient characteristics (45% with CrCl ⬍30 mL/min), the overall success rate for RE of 55% at the end of therapy in CORE 2004 was similar to that reported in the registrational trial.
The American Journal of Medicine, Vol 120 (10A), October 2007 This study represents the largest reported group of patients with LE (n ⫽ 38) treated with daptomycin. After the S aureus bacteremia and infective endocarditis trial was initiated, an amendment allowed the enrollment of leftsided endocarditis. Therefore, the number of LE patients was small. The success rate was 11% (1 of 9) for daptomycin and 22% (2 of 9) for the dual-therapy comparator using the strict definitions required for success 6 weeks after completed therapy. Again, the differences in study design do not permit a comparison with the 66% success rate in LE patients in this analysis. To further evaluate the results in LE patients, controlled clinical trials are needed. Clinical success was independent of gram-positive isolates, including MRSA and Enterococcus. There have been few previous reports of daptomycin use for enterococcal bacteremia and endocarditis. Segreti and colleagues20 published a case series including 9 bacteremia and 2 LE patients infected with VRE. Approximately one half of patients received prior antibiotics (55%) or concomitant antibiotics (45%), similar to that seen in CORE 2004. The success rates were 56% (5 of 9) for VRE bacteremia and 0% (0 of 2) for VRE LE. This was an uncontrolled case series, as is CORE 2004, and may provide a basis for future rigorous studies of this pathogen. S aureus was the most common pathogen isolated in the CORE 2004 cohort of endocarditis patients, followed by Enterococcus. Only 3 CoNS isolates and 1 viridans group streptococcus isolate were found. S aureus was also the most common pathogen cultured in an observational cohort of 1,779 patients with infective endocarditis enrolled in the International Collaboration on Endocarditis–Prospective Cohort Study (ICE) from June 2000 to December 2003.2 In that cohort, S aureus was isolated in 31.6% of patients, viridans group streptococci in 18.0%, enterococci in 10.6%, and CoNS in 10.5%. MRSA accounted for 27.4% of the S aureus isolates. The higher prevalence of S aureus in general and MRSA in particular in the CORE 2004 cohort may be owing to differences between prevalence in the United States and internationally (as reflected in ICE) or to selection bias for daptomycin therapy. Most of the CORE 2004 patients had been previously treated with other antibiotics. This finding may indicate that patients with difficult-to-treat pathogens, notably MRSA and enterococci, were more likely to require alternative antimicrobial therapy. The present CORE 2004 data are limited in several ways. As with all registry studies, this study was retrospective and unblinded, and many variables were not controlled. It is important to note that the endocarditis diagnosis was determined by the individual investigators, and the diagnostic criteria (such as echocardiography and Duke criteria assessment) were not collected. As a result, patients included in this study should not be considered a homogeneous group. Concomitant antibiotics were administered in most of the cases, and because complete susceptibility data were not collected, it is unclear to what extent these concomitant
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Daptomycin for Infective Endocarditis
agents contributed to the observed outcomes. Surgical interventions were not captured, and their influence on the outcomes cannot be assessed. Results of previous studies involving patients with infective endocarditis suggest that relapse of infection can occur in a significant number of patients; therefore, the lack of follow-up data, including microbiologic response, also limits the conclusions. Although the median starting dose of daptomycin in the CORE 2004 cohort of endocarditis patients was 6 mg/kg, 37% of patients in the LE group and 73% of patients in the RE group were begun on less than the approved dose of 6 mg/kg. At the time these patients were treated for endocarditis, very little information on efficacy or safety was available for doses ⬎4 mg/kg, and this may have contributed to the lower doses chosen. It is unknown if lower doses may have influenced the outcomes in CORE 2004, although no differences were seen in outcomes when categorized by dose. The clinical success rate of 63% at the end of daptomycin therapy on the basis of signs and symptoms is not unexpected given the results from the recently completed clinical trial (42% at test of cure for RE). Selection bias may have led to increased numbers of patients who were difficult to treat. This selection bias is illustrated by the higher-than-expected prevalence of MRSA and the very high proportion of patients who had received previous antibiotic therapy. Finally, adverse reaction data were not specifically collected in CORE 2004, thereby precluding any analysis of the safety and tolerability of daptomycin in patients with endocarditis.
SUMMARY The results from the CORE 2004 database, combined with data from experimental endocarditis models and data from a randomized controlled study involving patients with S aureus bacteremia and endocarditis, suggest that daptomycin should be considered a possible treatment for patients with right-sided infective endocarditis involving S aureus. Further studies are needed to extend daptomycin’s experience in left-sided or enterococcal endocarditis.
AUTHOR DISCLOSURES The authors who contributed to this article have disclosed the following industry relationships: Kenneth C. Lamp, PharmD, is an employee and stockholder of Cubist Pharmaceuticals, Inc. Donald P. Levine, MD, is a member of the Speakers’ Bureau for Cubist Pharmaceuticals, Inc.; serves as a consultant to Cubist Pharmaceuticals, Inc. and Astellas Pharma Inc.; and has received research/grant support from Cubist Pharmaceuticals, Inc.
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