Recurrent Cutibacterium acnes prosthetic valve endocarditis

Abstract

A 29-year-old man with a history of congenital aortic stenosis and mechanical aortic valve replacement with previous Cutibacterium acnes prosthetic valve endocarditis (PVE) presented with a 2-week history of fevers and night sweats. Transoesophageal echocardiogram revealed a 0.6 cm×0.5 cm vegetation on the mechanical aortic valve. An anaerobic blood culture became positive for C. acnes 6 days after the blood cultures were obtained. He did not have any surgical intervention. He was successfully treated with 6 weeks of ceftriaxone, followed by chronic suppression with oral doxycycline. Despite its low virulence, a growing number of C. acnes PVE cases have been reported, owing to its biofilm production. When clinical suspicion is high, extending culture incubation duration beyond the standard 5 days might be helpful. Most cases are treated with surgical repair or replacement in conjunction with antibiotics, but medical therapy alone has been documented as being successful.

Background

Cutibacterium acnes is a facultative anaerobic Gram-positive bacillus that is part of the normal dermal and oral mucosal flora.¹ It is often considered a blood culture contaminant and is an uncommon cause of prosthetic valve endocarditis (PVE). Its fastidious nature and our tendency to dismiss it as a contaminant likely lead to the underdiagnosis of C. acnes PVE. Despite its relative rarity, C. acnes PVE should be considered on the differential for culture-negative PVE, so that it can be treated appropriately. Targeted antimicrobial therapy is of utmost importance since PVE carries a mortality rate of 15%–27%.² Here, we describe a case of recurrent C. acnes PVE treated solely with intravenous antibiotics followed by chronic oral antibiotic suppression.

Case presentation

A 29-year-old man presented with a 2-week history of fevers and night sweats. His history was significant for congenital aortic stenosis treated with aortic valve commissurotomy in 2001 and two aortic valve replacements (2001 and 2009), the latest one being a mechanical valve placed in 2009. He was on anticoagulation with warfarin since the placement of his mechanical valve. In 2018, 2 years prior to current admission, the patient presented with a 1-month history of headache, chills and fatigue. Blood cultures were obtained and grew C. acnes. A transthoracic echocardiogram (TTE) and subsequent transoesophageal echocardiogram (TEE) were unremarkable for findings suggestive of PVE although there was limited visualisation of the prosthetic aortic valve due to shadow artefact. Given his clinical presentation, predisposing condition, positive blood culture and the ambiguity of echocardiogram findings, he was treated for possible endocarditis (per modified Duke criteria) with 6 weeks of intravenous ceftriaxone. He did not undergo any immediate surgery and he was not placed on any long-term antimicrobial suppression. Later in 2018, due to worsening cardiac function that was deemed unrelated to the earlier infection, he underwent a third aortic valve replacement with revision of his aortic root reconstruction.

After 2 years of clinical stability, the patient presented once again with a 2-week history of fevers, night sweats and myalgias. He did not endorse any chest pain, dyspnoea, palpitations, joint pains or rashes. Vital signs included a temperature of 37.1°C, blood pressure of 103/69 mm Hg, heart rate of 94 beats/min and oxygen saturation of 97%. Physical examination was remarkable for a new III/VI systolic murmur and I/VI diastolic murmur in the setting of mechanical heart sounds. He did not have any evidence of volume overload or stigmata of endocarditis on examination of the skin. He denied tobacco, alcohol, illicit drug use, significant outdoor activities or recent travels. He denied any new scratches or bites from his pet dog.

Investigations

Laboratory evaluation included erythrocyte sedimentation rate (ESR) of 52 mm/hour, C reactive protein (CRP) of 5.6 mg/dL (normal 0–15 mm/hour and <0.5 mg/dL, respectively) and a white blood cell count of 6.4×10⁹/L (normal 3.7–10. 5×10⁹/L). Blood cultures were initially negative but on day 6, one anaerobic blood culture bottle grew out C. acnes, which was identified via matrix-assisted laser desorption ionisation-time of flight mass spectrometry. Antimicrobial susceptibility testing is not typically performed for this organism since it is uniformly susceptible to penicillin and vancomycin. Respiratory viral panel was negative for SARS-CoV-2. TTE did not show any vegetations; however, TEE revealed a 0.6 cm×0.5 cm vegetation on the left ventricular outflow tract (LVOT) side of the prosthetic aortic valve, with mild-to-moderate aortic regurgitation and perivalvular leak (figures 1 and 2). There was no evidence of perivalvular abscess or fistula formation.

Figure 1.

Mid-oesophageal aortic valve long-axis view showing mobile echodensity on the aortic mechanical valve leaflet (red arrow).

Figure 2.

Mid-oesophageal aortic valve long-axis view with colour Doppler of the mechanical prosthetic aortic valve showing mild regurgitation (red arrow).

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Differential diagnosis

In the setting of a newly appreciated murmur, TEE findings of a vegetation on the prosthetic aortic valve (one major criterion), presence of a prosthetic valve (predisposing condition), fevers and a single positive blood culture (three minor criteria), the diagnosis of definite endocarditis was made per the modified Duke criteria. We were unable to get any tissue culture or pathology since the patient did not have any surgical intervention. Differential diagnosis for culture-negative endocarditis include the Hemophilus spp, Aggregatibacter spp, Cardiobacterium hominis, Eikenella corrodens and Kingella spp organisms, Bartonella, Coxiella, Brucella, Histoplasma, Blastomyces and mycobacteria (including Mycobacterium chimaera). Serologic tests and blood cultures for all these organisms were negative.

Differential diagnosis of culture-negative endocarditis includes non-infectious aetiologies as well, which can lead to valvular or cardiac vegetations and present with systemic embolisation.³ Rheumatological aetiologies to be considered include antiphospholipid syndrome, systemic lupus erythematosus and systemic vasculitides. Other differentials to be considered for non-bacterial thrombotic endocarditis include malignancy, hypercoagulable states and mural thrombi from atrial fibrillation or heart failure. These conditions can be investigated with antinuclear antibodies (ANAs), rheumatoid factor, coagulation studies, appropriate imaging and histopathological analysis of valvular biopsies if obtained.^{4 5} Our patient had a negative ANA screen and normal coagulation studies.

Treatment

While awaiting blood cultures, the patient was started empirically on therapy for PVE with vancomycin, cefepime and gentamicin. Cardiology and cardiothoracic surgery teams were consulted for assessment for prosthetic aortic valve replacement. In the setting of multiple previous sternotomies, surgical intervention was deemed high risk and was not indicated given the lack of heart failure, embolic manifestations, immunologic manifestations, cardiac conduction abnormalities and the absence of a fistula or perivalvular abscess. Once his blood cultures revealed C. acnes, antibiotics were narrowed to intravenous ceftriaxone monotherapy with a plan to treat for at least 6 weeks. Owing to interactions with warfarin, rifampin was not added as an adjunct for biofilm penetration in PVE.

Outcome and follow-up

At a 6-week follow-up, the patient’s constitutional symptoms had resolved. Repeat ESR and CRP were normal at 15 mm/hour and <0.5 mg/dL, respectively. Follow-up TEE demonstrated a decrease in the size of the original mobile echodensity on the aortic mechanical valve leaflet. Given his subjective and objective improvement, ceftriaxone was discontinued. Owing to recurrent PVE with C. acnes in the absence of surgical intervention (needed for definitive cure), the patient was started on chronic antibiotic suppressive therapy with oral doxycycline 100 mg given two times per day. The patient continues to do well without any clinical signs of infection at a 3-month follow-up visit.

Discussion

C. acnes is a facultative anaerobic non-spore-forming Gram-positive bacillus that is part of the normal dermal, oral mucosal and intestinal flora.⁶ It is a common cause of acne vulgaris.¹ Despite its low virulence, it has been known to cause infections of prosthetic joints, cerebrovascular shunts, spinal implants and cardiovascular devices typically postsurgically and associated with the presence of prosthetic material.^{7 8} It remains a rare cause of infective endocarditis, implicated in 0.3% of cases.^{9 10} C. acnes can cause infection either through direct seeding of the prosthetic material during the time of surgery from the patient’s skin or an exogenous source, or through haematogenous seeding from a mucocutaneous source.^{1 11} Its pathogenicity is associated with the production of biofilms.⁸ Compared with skin isolates of C. acnes which are poor biofilm producers, invasive isolates are superior biofilm-producers.¹² The presentation of C. acnes PVE can vary significantly and often with minimal clinical signs. Thirty-one per cent of cases can be asymptomatic despite valvular dysfunction. Other manifestations include fevers, malaise, acute heart failure exacerbation in the setting of valvular insufficiency, myocardial abscess, and cerebral and peripheral emboli.^13–15

The diagnosis of C. acnes PVE remains difficult to make due to unique clinical, microbiologic and pathologic features. The pathogen’s fastidious nature makes it difficult to isolate on culture.¹⁶ The previous literature illustrated the need for an extended incubation period of 14 days to isolate C. acnes, though this has improved with modern culture techniques.^{8 9} In a case series of 24 patients with C. acnes PVE, 2 patients had positive blood cultures with a standard incubation period of 5 days and 6 patients had positive blood cultures with an extended incubation period beyond 5 days with a median time to positivity of 7 days.¹⁷ In our patient, the blood culture became positive on day 6. Blood cultures have also been reported to be negative in a third of cases with C. acnes PVE.¹⁸ Often a single positive blood culture with C. acnes in the setting of endocarditis is misinterpreted as a contaminant.^{19 20} The fastidious nature of this organism along with it being a common contaminant leads to difficulty in diagnosing C. acnes PVE when conventional culture methods are applied.²¹ In the modified Duke’s criteria, a positive culture with C. acnes constitutes a minor criterion as it is not a typical pathogen. As such, patients with C. acnes PVE may not meet the modified Duke’s criteria, leading to its under-recognition.¹

PVE occurs in 1%–6% of patients with prosthetic heart valves and has a mortality rate of 15%–27%.^{2 22} There have been a limited number of case series and retrospective studies that have described C. acnes PVE. Osteoarticular prosthetic infections and PVE secondary to C. acnes have a higher male preponderance thought to be due to men having a higher concentration of pilosebaceous glands.^23–25 Studies have also found that men have a higher rate of C. acnes growth on their skin.^{26 27}

According to the 2015 American Heart Association guidelines, indications for cardiac surgery in patients with PVE include heart failure resulting from valve dehiscence/dysfunction, intracardiac fistula, heart block, annular or aortic abscess, or destructive penetrating lesions. Other indications for surgery include PVE caused by fungi, highly resistant organisms or persistent bacteraemia despite appropriate antibiotic therapy and exclusion of metastatic sites of infection.²⁸ Similar recommendations are included in the 2015 European Society of Cardiology Infective Endocarditis guidelines and the 2016 American Association for Thoracic Surgery guidelines.^{29 30}

Despite a lack of specific guidelines for C. acnes PVE treatment, it has traditionally involved surgical repair or replacement, along with an extended course of antibiotics.^{1 16} Banzon et al¹⁷ describe a case series in which 23 of 24 patients underwent valve surgery. The one patient who was treated medically developed relapse a few months after antibiotic completion. However, Kurz et al³¹ describe a case of a 29-year-old patient with C. acnes PVE complicated by LVOT abscess successfully treated with antibiotics for 7.5 months who remained symptom-free at 2 years with no evidence of relapse of infection. In a Swedish registry-based study, 19 of 51 patients were treated with antibiotics alone, with 16 of those 19 considered cured at follow-up.¹⁶ Medical therapy alone was elected in our patient due to multiple previous sternotomies, high risk of complications with surgery, and a lack of heart failure, conduction abnormalities or embolic complications.

Owing to the limited number of cases, no definitive antibiotic treatment guidelines exist for C. acnes PVE.¹⁵ Antibiotic regimens that have been previously reported include beta-lactams or glycopeptides in combination with a short course of adjunctive aminoglycosides or rifamycins.^{1 16 17} Beta-lactams that were used include benzylpenicillins, third-generation cephalosporins or carbapenems.¹¹ Crane et al³² tested antimicrobial susceptibility against 33 strains of C. acnes with 28 strains from surgeries on the shoulder and 5 strains isolated from bloodstream or deep infections. This study illustrated the strong efficacy of penicillins and cephalosporins against C. acnes, indicating a MIC₅₀ of 0.006 and 0.016 for penicillin G and ceftriaxone, respectively. Rifamycins allow for biofilm disruption and foreign body sterilisation.^{18 33} A treatment duration of 6 weeks has been commonly noted in the literature.^{1 9 18} Our patient’s antimicrobial treatment regimen consisted of intravenous ceftriaxone for a 6-week course. Ceftriaxone was chosen due to ease of single daily administration, patient preference and his favourable clinical response to ceftriaxone during his previous PVE infection in 2018. Owing to its interaction with warfarin, rifamycins were not incorporated in our patient’s treatment regimen. With infections, the term ‘relapse’ suggests an incompletely treated primary infection whereas ‘reinfection’ refers to a new infection and the typical time period used to indicate one versus the other is 6 months.¹⁶ As our patient’s previous episode preceded the current infection by 2 years, this was considered a reinfection. We attempted to explain the cause of an invasive reinfection with such a rare pathogen. Our patient had recurrent outbreaks of acne vulgaris which could have led to an invasive infection. Our patient also underwent dental cleaning 1 month prior to presenting to the hospital which may have led to invasive infection since C. acnes bacteraemia is reported as a complication of odontogenic procedures in the literature.^{34 35} Given the rarity of this condition, there are no antimicrobial guidelines on managing recurrent C. acnes PVE, thus, we relied on expert opinion in making this clinically difficult decision. We elected to treat the patient with chronic oral antibiotic suppression with oral doxycycline 100 mg, two times per day, given the lack of surgical treatment and recurrent C. acnes PVE to reduce the risk of breakthrough infections.^{36 37} In addition, there was suspicion that his untreated acne vulgaris, which is commonly treated with doxycycline, may have contributed to his illness and treatment may reduce the risk of reinfection.^{38 39}

Learning points.

• Though rare, Cutibacterium acnes has the potential to infect prosthetic devices including valves due to its ability to form biofilms.

• Patients affected by C. acnes prosthetic valve endocarditis (PVE) have an indolent clinical course with heart failure progression and constitutional symptoms.

• C. acnes PVE should be considered on the differential for culture-negative endocarditis.

• When C. acnes PVE is suspected, blood culture incubation time should be extended to increase diagnostic yield.

• The mainstay of treatment for C. acnes PVE is surgical intervention with a minimum of 6 weeks of parenteral antibiotics. However, antibiotic treatment alone has been shown to be successful in some cases.

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