Effectiveness and safety of daptomycin in patients with infective endocarditis undergoing heart valve replacement: a subgroup analysis from real-world data

Abstract

Background:

European Cubicin^® Outcomes Registry and Experience (EU-CORE) was a retrospective, non-interventional, multicenter registry that collected real-world clinical outcomes following daptomycin use for the treatment of Gram-positive infections. EU-CORE data from patients with infective endocarditis (IE) who underwent heart valve replacement were analysed.

Methods:

Clinical outcomes were assessed as success (cured or improved), failure, or non-evaluable. Adverse events (AEs) were recorded for up to 30 days after daptomycin treatment.

Results:

Of 610 patients with IE, 198 [32.5%; left-sided IE (LIE), 166 (83.8%); right-sided IE (RIE), 21 (10.6%); both LIE and RIE, 11 (5.6%)] underwent heart valve replacement. Other than cardiovascular disease, renal disease (18.2%), sepsis (16.2%), and diabetes mellitus (15.2%) were the most significant underlying diseases. Major pathogens in patients with positive culture results (68.0%) were Staphylococcus aureus [36.8%; methicillin-resistant S. aureus (MRSA), 12.8%] and coagulase-negative staphylococci (CoNS; 31.6%). Daptomycin treatment [median duration (range), 21 days (1–112)] resulted in high clinical success in patients with S. aureus (88.4%; MRSA, 80.0%) and CoNS (81.1%) infections, with an overall success rate of 83.3%. Clinical success rate was high (90.0%) in patients who received daptomycin dose >6 mg/kg/day. Overall clinical success rate in patients followed for up to 2 years was 90.7%. AEs and serious AEs possibly related to daptomycin were reported in 6 (3.0%) and 4 (2.0%) patients, respectively.

Conclusions:

Daptomycin treatment was effective and well tolerated with a sustained response in patients with IE who underwent heart valve surgery. A trend towards better clinical outcomes was observed with higher daptomycin doses.

Keywords

coagulase-negative staphylococci daptomycin endocarditis EU-CORE heart valve replacement high dose

Introduction

Valvular disease associated with infective endocarditis (IE) often requires both surgery and antibiotic therapy.^1,2 Despite advances in medical care, heart valve dysfunction remains one of the major causes of morbidity and mortality in patients with IE.¹ Other sequelae include neurologic, renal, musculoskeletal, and systemic infection complications. Studies suggest that heart valve surgery is potentially life saving³ and is often indicated in patients with life-threatening cardiac conditions with or without proven IE.⁴ Staphylococci, streptococci, and enterococci are among the most common causative pathogens of IE. Staphylococcus aureus [both methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA)] is a predominant pathogen of right-sided IE (RIE).² S. aureus (mainly MRSA) and Streptococcus species are the most common causative pathogens of left-sided IE (LIE).⁵ Coagulase-negative staphylococci (CoNS) are reported to be mostly associated with prosthetic valve endocarditis (PVE).⁶ S. aureus and CoNS are often found in patients with health care-associated IE, acquired during hospitalization or following invasive procedures such as surgeries.⁷ Enterococcal IE is less frequent and is generally difficult-to-treat due to higher rates of resistance to older antibiotics.^6,8 IE caused by S. aureus is associated with complications more frequently than that caused by other pathogens (stroke, 21.3% versus 14.3%; systemic emboli, 27.1% versus 18.7%; persistent bacteraemia, 17.0% versus 5.2%; and in-hospital mortality, 22.4% versus 14.6%).⁹ All patients with IE require antibiotic therapy. Although >50% of cases can be managed with antibiotic therapy alone,² heart valve replacement in combination with antibiotic treatment is recommended in high-risk patients.¹⁰

Guidelines recommend vancomycin treatment for native valve IE caused by MRSA, with daptomycin as an alternative treatment.^11–14 Daptomycin is superior to vancomycin for the treatment of MSSA and MRSA bacteraemia with vancomycin minimum inhibitory concentration (MIC) > 1 mg/l.¹⁴ In the case of PVE caused by MRSA, vancomycin in combination with rifampin and gentamicin is recommended.^13,14

Daptomycin is a therapeutic option for Gram-positive infections in patients with IE.^8,15,16 It is approved for the treatment of RIE caused by S. aureus at a dose of 6 mg/kg/day and has been reported to exhibit similar efficacy against both MSSA and MRSA.^17,18 High-dose (>6 and up to 12 mg/kg/day) daptomycin is recommended in difficult-to-treat infections by national and international guidelines owing to its concentration-dependent pharmacokinetics.^12–14,19 Reports from real-world experience have shown that daptomycin is equally effective in the treatment of LIE and RIE.^20–23 Although these reports highlighted the effectiveness and safety of daptomycin in patients with IE, data on treatment outcomes in such patients with heart valve replacement are scarce.

The present analysis from European Cubicin^® Outcomes Registry and Experience (EU-CORE) retrospectively assessed the real-world clinical experience with daptomycin use for the treatment of Gram-positive infections in a subgroup of patients with IE who underwent heart valve replacement.

Methods

The present subgroup analysis of EU-CORE, a non-interventional, multicenter, retrospective, patient registry,²⁴ included data from patients with IE who underwent heart valve replacement. The protocol was approved by the health authority and an institutional review board (IRB) or ethics committee (EC) in each country and a written informed consent was obtained from patients according to the requirements of the IRB or EC and/or the local data privacy regulations. Data from the registry were collected using standardized case report forms for patients who had received at least one dose of daptomycin between January 2006 and April 2012. Supplementary and 2-year follow-up (until 2014) data were collected for patients with IE.

The clinical outcomes were assessed by the investigators at the end of therapy as cured, improved, failed, or non-evaluable according to protocol-defined criteria. Clinical success was defined as outcomes of cured or improved. Time to improvement was also recorded. Furthermore, the reasons for discontinuing daptomycin therapy and other antibiotics prescribed following daptomycin were also recorded.

Assessments

IE was diagnosed according to the modified Duke criteria.²⁵ The duration of treatment was assessed based on the number of inpatient and outpatient days the patient received daptomycin therapy, even if the treatment was non-consecutive. Use of daptomycin alone or in combination with other antibiotics was recorded.

Long-term follow-up assessments were performed for up to 24 months after completion of daptomycin therapy.

All patients who received at least one dose of daptomycin were included in the safety analysis. Adverse events (AEs) and serious AEs (SAEs) were recorded during daptomycin treatment and for up to 30 days after treatment. AEs were recorded regardless of their relationship to daptomycin, and the severity was determined by the local investigators.

Statistical analyses were performed using Statistical Analysis System (SAS) version 9.3 (SAS Institute Inc., Cary, NC, USA). Inferential analyses were not conducted because of the nature of the study and no formal statistical methodology other than simple descriptive statistics was used. All analyses were considered to be explanatory. Numerical variables were summarized as arithmetic mean, standard deviation, median, minimum, first quartile, third quartile, and maximum for continuous variables and as absolute and relative frequencies for categorical variables.²³

Results

Of 610 patients with IE, 198 (32.5%) underwent heart valve replacement; 166 (83.8%) had LIE, 21 (10.6%) had RIE, and 11 (5.6%) had both left- and right-sided IE (LRIE). The median age was 58 years (range, 10–84), and 69 (34.8%) patients were aged ⩾65 years. The most significant underlying diseases other than cardiovascular disease (81.3%) were renal disease (18.2%), sepsis (16.2%), and diabetes mellitus (15.2%; Table 1). A total of 126 (64.0%) patients completed the daptomycin treatment; however, 15.2% of patients switched therapy (e.g. stepped down to oral antibiotic therapy). Discontinuation of daptomycin therapy due to AEs and treatment failure was reported in 3.6% and 2.5% of patients, respectively.

Table 1.

Baseline demographics and clinical characteristics.

Characteristics	N = 198, n (%)^a
Gender
Male	139 (70.2)
Female	59 (29.8)
Median age, years (range)	58 (10–84)
Baseline age, years
<65	129 (65.2)
⩾65 (including ⩾75)	69 (34.8)
⩾75	21 (10.6)
Race, Caucasian	170 (85.8)
Body weight (kg), median (range)	72.8 (25–120)
Significant underlying disease other than cardiovascular disease (>10%)
Renal disease	36 (18.2)
Sepsis	32 (16.2)
Diabetes mellitus	30 (15.2)
Pulmonary disease	28 (14.1)
Gastrointestinal disease	26 (13.1)

Unless otherwise indicated.

Culture results were available for 172 (86.9%) patients, of whom 117 (68.0%) had positive culture results. Predominant pathogens in patients with positive cultures were S. aureus (36.8%; MSSA, 18.8% and MRSA, 12.8%), CoNS (31.6%), and enterococci (13.7%).

Prescribing patterns

Overall, 108 (54.5%) patients received daptomycin at a dose of 6 mg/kg/day and 13 (6.6%) received 4 mg/kg/day, whereas 50 (25.3%) received doses >6 mg/kg/day [>8 mg/kg, 33 (16.7%)]. The median total duration of daptomycin treatment was 21 days (range, 1–112). Most of the patients (n = 166; 83.8%) received daptomycin as second-line treatment and a common reason of switching over to daptomycin treatment was failure of the prior antibiotics (n = 80; 40.4%), including glycopeptides such as vancomycin. The median duration of prior antibiotic therapy used to treat IE ranged from 6 to 10 days. Daptomycin was administered as first-line treatment in 29 (14.6%) patients. Concomitant antibiotics with daptomycin were prescribed in 76.8% of inpatients. Rifampicin was received concomitantly in 62 (31.3%) patients. In addition, other most commonly prescribed concomitant antibiotics were aminoglycosides (29.3%) and carbapenems (18.2%). Concomitant antibiotics such as carbapenems were most likely used for the treatment of other significant underlying infections.

Efficacy

The overall clinical success rate with daptomycin treatment was 83.3% (LIE, 83.1%; RIE, 81.0%; LRIE, 90.9%): 86.2% with first-line and 82.5% with second-line treatment. Daptomycin resulted in high clinical success rates in patients with S. aureus (88.4%; MRSA, 80.0%) and CoNS (81.1%) infections (Figure 1).

Figure 1.

Clinical success rates by primary pathogen.

The clinical success rate was numerically higher with high-dose (>6 mg/kg/day) daptomycin treatment (Figure 2). The overall clinical success rate in patients followed for up to 2 years was 90.7% (39/43).

Figure 2.

Clinical success rates by daptomycin dose.

Safety

Overall AEs and SAEs regardless of daptomycin treatment were reported in 47 (23.7%) and 36 (18.2%) patients, respectively. AEs possibly related to daptomycin treatment were reported in 6 (3.0%) patients; of those 4 (2.0%) were SAEs. The most commonly reported AEs possibly related to daptomycin treatment were increased blood creatine phosphokinase (CPK; 1.5%), followed by 0.5% each of eosinophilic pneumonia, rash, cholestasis, rhabdomyolysis, and agranulocytosis. Blood CPK elevation as a SAE possibly related to daptomycin was reported in 1 (0.5%) patient.

Discussion

There have been significant advances with respect to antimicrobial treatment of IE, however eradication of infection often requires surgical intervention in addition to antibiotic therapy.²⁶ This subgroup analysis from the EU-CORE study illustrated the real-world use of daptomycin in patients with IE who underwent heart valve replacement, expanding on the results from previous reports in patients with IE.^20,23 In this analysis, S. aureus (MSSA and MRSA) and CoNS were the most commonly identified primary pathogens. The results showed that the clinical effectiveness of daptomycin in patients with IE who underwent heart valve replacement was high against infections caused by various Gram-positive bacteria. Moreover, daptomycin showed a favourable safety profile in this patient population. These findings are consistent with those from published reports showing the effectiveness and tolerability of daptomycin treatment in patients with IE.^15,17,23 Moreover, Kornberger et al.¹⁶ recently reported high clinical success rates (87.0%) with daptomycin in patients with Gram-positive infections after cardiac surgery.

Data from this real-world analysis indicated that daptomycin was successfully used for the treatment of patients with RIE (approved indication) as well as the treatment of those with LIE and LRIE undergoing heart valve replacement. Daptomycin showed high clinical success rates against infections caused by S. aureus and CoNS, including resistant pathogens, in patients with IE undergoing heart valve replacement. Furthermore, daptomycin was shown to be effective against enterococcal infections in this patient cohort. These results are in line with published reports suggesting bactericidal activity of daptomycin against resistant Gram-positive pathogens causing IE.^23,27 While the total duration of daptomycin therapy was comparatively short (approximately 21 days), many patients received prior antibiotics and some were switched after daptomycin therapy to other (e.g. step-down) antibiotics. High-dose daptomycin has been shown to be associated with higher success rates. This finding is consistent with that from an earlier report in patients with IE.²⁷ Several treatment guidelines also recommend the use of daptomycin at higher doses (>6 mg/kg/day) in the treatment of patients with IE.^11,12,14 High-dose daptomycin in combination with ceftaroline for 6 weeks successfully treated patients with aortic PVE caused by MRSA.²⁸ Daptomycin was mostly used as a second-line treatment; however, the clinical success rate was higher when daptomycin was used as a first-line treatment. Seaton et al.²⁹ reported higher clinical success rates with first-line as compared with second-line daptomycin treatment in patients with MRSA infections. These results are further supported by Cervera et al.,¹⁸ suggesting the use of high-dose daptomycin as first-line treatment in patients with IE. The international treatment guidelines support the use of higher doses of daptomycin in the treatment of patients with IE.^11,19 Treatment with suboptimal doses below the approved one (6 mg/kg/day) to treat IE is associated with a lower clinical success rate and should be avoided in this patient population.

In the present analysis, the long-term, follow-up results for up to 2 years indicated high sustained clinical success rates with daptomycin in patients with IE undergoing heart valve replacement and suggested daptomycin as an effective treatment option in this patient population with IE.

AEs, such as blood CPK elevation, neuropathy, and eosinophilic pneumonia, which have been reported with daptomycin use, were uncommon in this subgroup. The safety results are consistent with those previously reported, demonstrating the safety and tolerability of daptomycin in patients with IE.^22,23 Furthermore, no new or unexpected safety findings were observed in this patient cohort with IE undergoing heart valve replacement.

This study has a few limitations, such as the relatively small number of patients in the subgroup analysis. The study was not aimed to examine the individual benefits of surgical intervention versus antibiotic therapy or the relative benefits of antibiotic combination therapy. In addition, this was a real-world, observational study, with a non-randomized and non-comparative design.

In conclusion, the results of this subgroup analysis of a real-world registry (EU-CORE) suggest that daptomycin was effective and well tolerated in the treatment of Gram-positive infections in patients with IE who underwent heart valve replacement. A trend towards better clinical outcomes was observed with high-dose daptomycin. The 2-year follow-up data indicated a high sustained response. Overall, the results suggest that daptomycin can be considered as an important treatment alternative in patients with IE who undergo heart valve replacement.

Footnotes

Acknowledgements

All authors participated in the development of this manuscript and approved the final manuscript for submission. All authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have provided final approval for the version to be published. The authors thank Anupama Tamta (Novartis Healthcare Pvt Ltd., Hyderabad, India) for medical writing support.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded by Novartis Pharma AG, Basel, Switzerland.

Conflict of interest statement

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: A.G. received fees from Novartis as a member of advisory boards and speaker panels, and consultancy fees from Astellas, AstraZeneca, MSD, and Schering-Plough. He also received support to attend scientific conferences, including accommodation and travel payments, from BD, Carefusion UK, Janssen-Cilag, and MSD. R.U. received a research grant from Novartis, fees for advisory boards and speaker panels, and support to attend meetings including accommodation and travel payments. P.D. received a research grant and fees for speaker panels from Novartis, and grants from Cepheid, Astellas, Basilea, KCI, and Smith & Nephews. K.H. is an employee of Novartis Pharmaceuticals Corporation.

References

Ashley

Niebauer

Chapter 9: valve disease. In: Ashley

Niebauer

(eds) Cardiology explained. London: Remedica, 2004, pp. 145–166, http://www.ncbi.nlm.nih.gov/books/NBK2220/?report=classic

Mcdonald

JR.

Acute infective endocarditis. Infect Dis Clin North Am 2009; 23: 643–664.

Prendergast

Tornos

Surgery for infective endocarditis: who and when?

Circulation 2010; 121: 1141–1152.

Wilson

Taubert

Gewitz

Prevention of infective endocarditis: guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. J Am Dent Assoc 2007; 138: 739–745, 747–760.

Mylonakis

Calderwood

SB.

Infective endocarditis in adults. N Engl J Med 2001; 345: 1318–1330.

Dohmen

Guleri

Capone

Daptomycin for the treatment of infective endocarditis: results from a European registry. J Antimicrob Chemother 2013; 68: 936–942.

Ferraris

Milazzo

Ricaboni

Profile of infective endocarditis observed from 2003-2010 in a single center in Italy. BMC Infect Dis 2013; 13: 545.

Que

Moreillon

Infective endocarditis. Nat Rev Cardiol 2011; 8: 322–336.

Fowler

Jr Miro

Hoen

Staphylococcus aureus endocarditis: a consequence of medical progress. JAMA 2005; 293: 3012–3021.

10.

Jiang

Zhang

Surgical treatment of isolated right-sided infective endocarditis. Tex Heart Inst J 2011; 38: 639–642.

11.

Liu

Bayer

Cosgrove

Clinical practice guidelines by the infectious diseases Society of America for the treatment of Methicillin-Resistant Staphylococcus aureus infections in adults and children: executive summary. Clin Infect Dis 2011; 52: 285–292.

12.

Gould

Denning

Elliott

Guidelines for the diagnosis and antibiotic treatment of endocarditis in adults: a report of the working party of the British Society for Antimicrobial Chemotherapy. J Antimicrob Chemother 2012; 67: 269–289.

13.

Baddour

Wilson

Bayer

Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association. Circulation 2015; 132: 1435–1486.

14.

Habib

Lancellotti

Antunes

2015 Esc guidelines for the management of infective endocarditis: the task Force for the management of infective endocarditis of the European Society of Cardiology (ESC). Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM). Eur Heart J 2015; 36: 3075–3128.

15.

Kullar

Mckinnell

Sakoulas

Avoiding the perfect storm: the biologic and clinical case for reevaluating the 7-day expectation for methicillin-resistant Staphylococcus aureus bacteremia before switching therapy. Clin Infect Dis 2014; 59: 1455–1461.

16.

Kornberger

Luchting

Kur

Daptomycin for the treatment of major Gram-positive infections after cardiac surgery. J Cardiothorac Surg 2016; 11: 120.

17.

Fowler

Jr Boucher

Corey

Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med 2006; 355: 653–665.

18.

Cervera

Castaneda

Pericas

Clinical utility of daptomycin in infective endocarditis caused by Gram-positive cocci. Int J Antimicrob Agents 2011; 38: 365–370.

19.

Smith

Claeys

Barber

High-dose daptomycin therapy for Staphylococcal endocarditis and when to apply it. Curr Infect Dis Rep 2014; 16: 429.

20.

Levine

Lamp

KC.

Daptomycin in the treatment of patients with infective endocarditis: experience from a registry. Am J Med 2007; 120: S28–S33.

21.

Das

Saluja

Steeds

Use of daptomycin in complicated cases of infective endocarditis. Eur J Clin Microbiol Infect Dis 2011; 30: 807–812.

22.

Kaya

Yilmaz

Kalkan

Treatment of Gram-positive left-sided infective endocarditis with daptomycin. J Infect Chemother 2013; 19: 698–702.

23.

Guleri

Utili

Dohmen

Daptomycin for the treatment of infective endocarditis: results from European Cubicin^® Outcomes Registry and Experience (EU-CORE). Infect Dis Ther 2015; 4: 283–296.

24.

Gonzalez-Ruiz

Beiras-Fernandez

Lehmkuhl

Clinical experience with daptomycin in Europe: the first 2.5 years. J Antimicrob Chemother 2011; 66: 912–919.

25.

Durack

Lukes

Bright

DK.

New criteria for diagnosis of infective endocarditis: utilization of specific echocardiographic findings. Duke Endocarditis Service. Am J Med 1994; 96: 200–209.

26.

Luk

Kim

Ross

Native and prosthetic valve infective endocarditis: clinicopathologic correlation and review of the literature. Malays J Pathol 2014; 36: 71–81.

27.

Carugati

Bayer

Miro

High-dose daptomycin therapy for left-sided infective endocarditis: a prospective study from the international collaboration on endocarditis. Antimicrob Agents Chemother 2013; 57: 6213–6222.

28.

Cunha

Gran

Successful treatment of meticillin-resistant Staphylococcus aureus (MRSA) aortic prosthetic valve endocarditis with prolonged high-dose daptomycin plus ceftaroline therapy. Int J Antimicrob Agents 2015; 46: 225–226.

29.

Seaton

Gonzalez-Ruiz

Cleveland

Real-world daptomycin use across wide geographical regions: results from a pooled analysis of CORE and EU-CORE. Ann Clin Microbiol Antimicrob 2016; 15: 18.