Vancomycin-Resistant Enterococcus Faecium Prosthetic Valve Endocarditis Treated with Daptomycin and Ampicillin Combination

Abstract

Background:

Vancomycin resistant Enterococcus faecium (VRE) bacteremia and infective endocarditis (IE) are difficult to treat and associated with high mortality.

Methods:

We describe a case of a 78-year-old male with VRE prosthetic valve endocarditis treated with combined daptomycin/ampicillin. We review published literature on the treatment of VRE IE and summarize other published case reports of daptomycin combination therapy.

Results:

Prompt clearance of bacteremia was achieved. Cardiac valve replacement surgery was pursued but was followed by post-operative complications and ultimately the patient did not survive.

Conclusion:

There is limited published literature on the treatment of VRE IE and an optimal antibiotic regimen has not been established. This case adds to the growing body of literature demonstrating the use of daptomycin and beta-lactam combination therapy for VRE bacteremia and endocarditis. Combination therapy may be an appropriate choice for select cases; however, reports of treatment failure warrant caution.

There is limited published literature on the treatment of vancomycin-resistant enterococcus endocarditis and an optimal antibiotic regimen has not been established. In this brief summary, we review a case of vancomycin-resistant enterococcus endocarditis treated with combination daptomycin and beta-lactams. We also briefly review published literature with respect to daptomycin combination therapy.

Case presentation

A 78-year-old man with uncomplicated bio-prosthetic aortic and mitral valve replacements 6 months prior (no post-surgical complications) presented with a history of fatigue, fever, chills, and feeling unwell for a few days to weeks. He had a past medical history of atrial fibrillation, hypertension, type 2 diabetes, chronic kidney disease (estimated glomerular filtration rate 25–30 mL/min/1.73 m²), dyslipidemia, and obesity. He had no prior history of positive blood cultures or screening swabs. He was initially treated with trimethoprim/sulfamethoxazole 1 double strength tablet twice daily for an extended spectrum beta-lactamase Escherichia coli urinary tract infection and was found to have vancomycin-resistant Enterococcus faecium (VRE) (ampicillin minimum inhibitory concentration [MIC] ≥32 μg/mL, linezolid MIC 2 μg/mL, vancomycin MIC ≥32 μg/mL, daptomycin MIC ≤2 μg/mL) growing from blood cultures drawn on the day of admission. He was initially treated with vancomycin empirically and then 1 day of linezolid monotherapy. His blood cultures continued to be positive for the growth of VRE on post-admission days (PAD) 4 and 11. The infectious diseases team was consulted and the patient was switched to daptomycin (initially 8 mg/kg, increased to 10 mg/kg on PAD 18) in combination with ampicillin starting on PAD 11. Repeat blood cultures on PAD 13 were negative. Transesophageal echocardiography identified a 12 × 4 mm mobile mass, likely representing a vegetation on the sub-valvular chordal apparatus of the mitral valve and a small mobile mass measuring 6 × 4 mm attached to the aortic valve leaflet tips, likely representing vegetation. Mitral prosthetic valve stenosis, trace mitral valve regurgitation, and aortic prosthetic valve stenosis were identified, as well as concern for early aortic prosthetic valve dehiscence and associated mild paravalvular regurgitation. No brain imaging was done at the time.

Cardiovascular surgery was consulted for consideration of valve replacement; however, a medical management approach was first attempted because the patient was deemed high risk for surgery. He was set to complete a 6-week course of combination daptomycin 1 g IV every 48 hours (10 mg/kg/d) and ampicillin 2 g IV every 8–12 hours (adjusted for renal function). He was reassessed by cardiovascular surgery and was noted to have increased gradients across the mitral valve. The patient wished to pursue double-valve replacement surgery despite the high risk. On day 41 of antibiotics post–negative blood cultures, he underwent a redo sternotomy by central cannulation explant of both bio-prosthetic valves and implant of two new bio-prosthetic valves. His immediate post-operative course was complicated by profound pulmonary edema and vasogenic shock with subsequent severe right and left ventricular dysfunction. He required emergent veno-arterial extra-corporeal membrane oxygenation for 3 days post–valve replacement with no hemodynamic issues following decannulation. He developed ventilator-associated pneumonia with extended spectrum beta-lactamase E. coli and was treated with meropenem and linezolid for 7 days. Once completed, the plan was to switch back to daptomycin 10 mg/kg daily to complete 6 weeks from surgery as, unfortunately, no intra-operative valve tissue was sent for microbiological culture. Per surgical pathology report, both valves microscopically showed acute inflammation with the presence of vegetation and valve destruction. The vegetation consisted of fibrin, neutrophils, and necrosis, consistent with active endocarditis. A week after surgery, the patient did not show signs of waking up and a computed tomography scan of the patient's head was performed, which demonstrated a massive left middle cerebral artery territory infarct with midline shift. In accordance with the patient's prior expressed wishes, his goals of care were changed to comfort measures and he passed away on post-operative day 9.

Discussion

Bloodstream infections (BSIs) with VRE and associated infective endocarditis (IE), although rare, are of significant concern due to their morbidity and mortality.¹ Canadian nosocomial VRE BSI rates rose from 2017 to 2021 and were highest in western and central Canada.² We have limited experience with VRE endocarditis in our centre but, given rising BSI rates, are concerned about future episodes. There are limited data on the treatment of VRE prosthetic valve IE and no single best regimen has been identified. The Infectious Diseases Society of America guideline discusses options for VRE IE including daptomycin, linezolid, quinupristin/dalfopristin, tigecycline, and combination therapy with daptomycin plus ampicillin or ceftaroline, but does not make a strong recommendation for a preferred regimen.³ The recently published 2023 European Society of Cardiology guidelines advise combining daptomycin with beta-lactams or fosfomycin to prevent the development of daptomycin resistance.⁴ There is limited clinical evidence to support the use of daptomycin combination therapy for enterococcal BSI and IE. The largest relevant study reported 43 cases of enterococcal IE, of which 11 were treated with daptomycin combination therapy (6 ampicillin, 1 ceftaroline, 4 gentamicin).⁵ Only one of these cases (treated with daptomycin and ampicillin) was deemed a clinical failure. Another prospective observational cohort study in patients with VRE BSI compared daptomycin monotherapy with daptomycin plus beta-lactam and found no significant difference in mortality.⁶ Subgroup analyses indicated lower mortality in those with high-dose daptomycin (≥9 mg/kg/d) with MIC ≤2 μg/mL and also in those with high-dose daptomycin plus beta-lactam regardless of MIC.⁶ Although this study included 114 patients with VRE BSI, only two had proven endocarditis. These authors also reported a larger observational study on VRE BSI that found a higher rate of clinical success for combination therapy (daptomycin plus beta-lactam) compared with monotherapy; however, no IE cases were included.¹ Additional literature on VRE IE with daptomycin combination therapy appears to be limited to case reports, summarized in Table 1.

Table 1:

Case reports of patients with vancomycin-resistant enterococcal bloodstream infections and infective endocarditis treated with daptomycin combination therapy

Reference, year	Age in years, sex; comorbidities	Infected valve(s)	Regimen(s)*	Cardiac surgery	Outcome
(14), 2005	25, F SLE, ESRD with femoral dialysis catheter, severe mitral regurgitation requiring valve replacement	PVE (mitral)	Dap + Gent + Rif	No	Cleared blood cultures after 11 weeks’ treatment, died 4 months later, cause of death unknown
(22), 2006	64, F	NR	Dap + Tobra	NR	Died
(22), 2006	51, M	NR	Dap + Amik	NR	Died
(12), 2007	60, M DM	NVE (mitral)	1. Dap 2. Gent + Vanc 3. Amp + Dap + Gent	No	Cured (6-month follow-up)
(9), 2007	62, M DM, CAD, PAD, ESRD, Hx IE, recent polymicrobial CRBSI (C. parapsilosis, E. cloacae, S. epidermidis)	NVE (mitral)	1. Dap + Tige	No	Cured (16-week follow-up)
(23), 2008	70, M	NR	1. Lin + Tige 2. Dap 3. Dap + Doxy + Gent 4. Quin	NR	Failed to clear blood cultures
(21), 2008	73, M CAD, BPH, hyperthyroidism	NVE (aortic and mitral)	1. Gent + Vanc 2. Ceftri + Lin 3. Amp-Sul + Dap 4. Amp-Sul + Lin	Yes	Cured (11-day follow-up). Dap was stopped due to toxicity.
(11), 2009	39, F Obesity, Hx IE, femoral aneurysm stenting 3 years prior, protein S deficiency, Hx PE, IVC filter (placed 4 years prior)	PVE (tricuspid), presumed†	1. Dap 2. Dap + Rif 3. Dap + Gent 4. Dap + Tige	No	Cured (26-week follow-up)
(10), 2011	86, M Cerebrovascular disease, HF due to ischemic cardiomyopathy, AF, liver abscess and duodeno-cholecystic fistula treated 1 year prior	NVE (aortic), presumed†	1. Dap 2. Dap + Tige	No	Cured (3-month follow-up)
(7), 2012	Age/sex not reported ESRD on hemodialysis	NVE (aortic)	1. Dap + Lin 2. Dap + Amp	No	Cured
(24), 2012	89, F HTN, CKD (stage 4)	NVE (mitral)	1. Dap + Amp	No	Cured (12-month follow-up)
(8), 2013	63, M HTN	NVE (aortic)	1. Amp-Sul + Gent 2. Amp + Ceftri 4. Amp + Dap 5. Ceftar + Dap	Yes	Cured (6-week follow-up)
(20), 2015	84, M	PVE	1. Ceftri + Dap	Yes	Relapse then death
(13), 2021	38, F	PVE (aortic)	1. Dap + Gent 2. Dap + Chlo	Yes	Cured (6-year follow-up)
This case, 2021	Late 70s, M HTN, AF, T2DM, CKD, DLD, obesity	PVE (bio-prosthetic aortic and mitral)	1. Lin 2. Dap + Amp	Yes	Cleared blood cultures after 48 hours, died post–cardiac surgery

^*Cases involving multiple antibiotic regimens are numbered in chronological order of use

^†Diagnosed via Duke criteria without conclusive findings on echocardiography

Disease/comorbidity abbreviations: AF = Atrial fibrillation; BPH = Benign prostatic hyperplasia; CAD = Coronary artery disease; CKD = Chronic kidney disease; CRBSI = Catheter related bloodstream infection; DLD = dyslipidemia; (T2)DM = (Type 2) diabetes mellitus; ESRD = End stage renal disease; HF = Heart failure; HTN = Hypertension; Hx = history; IE = Infective endocarditis; IVC = Inferior vena cava; NVE = Native valve endocarditis; NR = Not reported; PAD = Peripheral artery disease; PE = Pulmonary embolism; PVE = Prosthetic valve endocarditis; SLE = Systemic lupus erythematosus

Antibiotic abbreviations: Amik = Amikacin; Amp = Ampicillin; Sul = Sulbactam; Cefep = Cefepime; Ceftar = Ceftaroline; Ceftri = Ceftriaxone; Cipro = Ciprofloxacin; Chlo = Chloramphenicol; Dap = Daptomycin; Doxy = Doxycycline; Gent = Gentamicin; Lin = Linezolid; Quin = Quinupristin/dalfoprostin; Rif = Rifampin; Tige = Tigecycline; Tobra = Tobramycin; Vanc = Vancomycin

Case reports of daptomycin combined with beta-lactams have demonstrated variable success. One case report of a hemodialysis patient with VRE aortic valve IE demonstrated rapid clearance of persistently positive blood cultures with daptomycin/ampicillin combination therapy after failing daptomycin/linezolid.⁷ Of note, the daptomycin dose was increased from 6 mg/kg every 48 hours to 12 mg/kg in the regimen containing ampicillin. Another report documented the failure of multiple regimens including daptomycin (8 mg/kg/day) plus ampicillin, but eventually succeeded with daptomycin (8 mg/kg/d) plus ceftaroline.⁸

Case reports supporting the use of daptomycin combination therapy for VRE BSI and IE are not limited to beta-lactams; success has been reported with daptomycin/tigecycline,^9–11 daptomycin/ampicillin/gentamicin,¹² and daptomycin/chloramphenicol.¹³ One of the earliest case reports describing daptomycin combination therapy was of a VRE prosthetic valve IE treated with daptomycin/gentamicin/rifampin triple therapy, a regimen that was chosen based on the results of time-kill curves for bactericidal activity of different combinations of these antibiotics.¹⁴ The patient appeared to clear their infection but re-presented 4 months following completion of treatment with abdominal pain and hypotension and passed away shortly thereafter. It was not known if the cause of death was related to recurrent infection.

The mechanism underlying the apparent synergy in daptomycin/beta-lactam combination therapy has been studied. Ampicillin has been shown to reduce the net positive bacterial surface charge of VRE, which leads to increased bactericidal activity of daptomycin.⁷ One analysis of in vitro time-kill studies on daptomycin non-susceptible enterococci looked at daptomycin in combination with different antibiotics, including ampicillin, cefazolin, ceftriaxone, ceftaroline, ertapenem, gentamicin, tigecycline, and rifampin. Combination with ampicillin yielded the most consistent synergy, but only for isolates with mutations to the liaFSR system and not for isolates with mutations to the yycFGHIJ system.¹⁵ Ampicillin was also found to enhance the killing activity of the host defense peptide human cathelicidin LL-37. One study of time-kill experiments reported greater synergistic killing at 24 hours with ceftaroline, cefepime, ceftriaxone, ampicillin, and ertapenem compared with other agents.¹⁶ Another study reported synergy with daptomycin in combination with either ampicillin or ceftaroline for a daptomycin-susceptible VRE isolate, but not with a daptomycin non-susceptible isolate.¹⁷ Synergy between daptomycin and ceftriaxone was also demonstrated in an in vitro-simulated endocardial vegetation model with VRE and vancomycin-resistant Enterococcus faecalis strains.¹⁸

Clinical failure with daptomycin combination therapy in VRE BSI/IE has been documented. One example was a liver transplant patient with polymicrobial BSI consisting of E. faecium, Pseudomonas, and Enterobacter species arising from a biliary source. The patient failed combination therapy with daptomycin (10 mg/kg/d) and cefepime, and ultimately cleared the infection on a combination of pristinamycin and ciprofloxacin.¹⁹ Another failure was reported for a case of E. faecalis prosthetic valve endocarditis that relapsed after treatment with daptomycin/ceftaroline and died post–cardiac surgery.²⁰ Another report described multiple unsuccessful trials of combination regimens including ampicillin-sulbactam plus daptomycin, with eventual cure on ampicillin-sulbactam plus linezolid.²¹ Thus far, there is inadequate data to suggest VRE prosthetic valve endocarditis is a risk factor for treatment failure (see Table 1—PVE: four cures, one failure; NVE: six cures, one failure; valve type not reported: three failures).

The case we report demonstrated clearance of blood cultures on daptomycin/ampicillin combination therapy prior to cardiac surgery. The decision to use this regimen was based on a review of the cases available in the literature and an assessment that this would be the least toxic regimen for the patient. We felt that the data for combining daptomycin with fosfomycin was minimal and only documented in bacteremia cases, not in endocarditis cases. Additionally, our lab does not perform fosfomycin susceptibilities for blood cultures as there are no CLSI breakpoints available. Factors that may have contributed to successful eradication of VRE from blood cultures include susceptibility of the isolate to daptomycin with MIC ≤2 and daptomycin dose ≥9 mg/kg/d, both of which have been implicated in success of combination therapy.⁶ Of the beta-lactams to select for combination therapy, ampicillin appears to consistently demonstrate success, albeit from case report data. Successful use of daptomycin/ampicillin has been demonstrated in VRE even with in vitro resistance to ampicillin,⁷ which applies to our case. The patient's death was thought to be reflective of complications following a high-risk surgery rather than failure of antibiotic therapy, given that the surgery was known to be high risk and the patient had cleared blood cultures beforehand.

This case adds to the growing body of literature demonstrating effectiveness with daptomycin and beta-lactam combination therapy for VRE BSI/IE. Combination therapy may be an appropriate choice for select cases; however, reports of treatment failure warrant caution. There are currently no randomized controlled trial data to help answer this question and there is limited understanding of the mechanisms of action with combination therapy. More research is required to understand how combination therapy overcomes mechanisms of resistance and higher quality evidence is required to make stronger claims about the efficacy of daptomycin/beta-lactam combination therapy.

Funding Statement

No funding was received for this work.

Contributors:

Conceptualization, J Salmon, I Rajakumar; Data Curation, I Rajakumar; Supervision, J Salmon; Investigation, J Salmon, I Rajakumar, A Krishnan; Writing – Review & Editing, I Rajakumar, A Krishnan, J Salmon.

Ethics Approval:

Ethics approval was not required for this article.

Informed Consent:

The authors confirm that informed patient consent has been secured from all patients.

Registry and the Registration No. of the Study/Trial:

N/A

Data Accessibility:

No datasets were used in the current study.

Funding:

No funding was received for this work.

Disclosures:

The authors have nothing to disclose.

Peer Review:

This manuscript has been peer reviewed.

Animal Studies:

N/A