Comparative effectiveness of empirical antibiotic treatments in methicillin-susceptible Staphylococcus aureus infective endocarditis: A post hoc analysis of a prospective French cohort study.

OBJECTIVES: The empirical treatment of infective endocarditis is still debated. The aim of this study was to compare the impact of empirical treatment with antistaphylococcal penicillin (ASP) or cefazolin vs. other treatments in methicillin-susceptible Staphylococcus aureus (MSSA) endocarditis. METHODS: A post hoc analysis of a prospective cohort study of patients hospitalized in a French reference centre with MSSA endocarditis was conducted between 2013 and 2022. The primary outcome was the duration of bacteraemia under treatment. RESULTS: Of the 208 patients included, 101 patients (48.6%) were classified in the reference group (ASP or cefazolin) and 107 (52.4%) in the non-reference group. Empirical treatment with ASP/cefazolin was associated with a shorter duration of bacteraemia compared to other treatments (3.6 d vs. 4.6 d, P = 0.01). This difference was not corrected by the addition of an aminoglycoside (3.6 d vs. 4.7 d, P < 0.01). In multivariate analysis, empirical treatment with ASP/cefazolin was associated with a duration of bacteraemia ≤72 h (P = 0.02), whereas endocarditis on native valves (P = 0.01), and intracardiac abscess were associated with longer duration of bacteraemia (P = 0.01). CONCLUSIONS: Empirical treatment of endocarditis with ASP or Cefazolin is more effective than other treatments in MSSA endocarditis, even when the other treatments are combined with aminoglycosides.

C-terminal deletion of RelA protein is suggested as a possible cause of infective endocarditis recurrence with Enterococcus faecium.

Infective endocarditis (IE) caused by Enterococcus spp. represents the third most common cause of IE, with high rates of relapse compared with other bacteria. Interestingly, late relapses (>6 months) have only been described in Enterococcus faecalis, but here we describe the first reported IE relapse with Enterococcus faecium more than a year (17 months) after the initial endocarditis episode. Firstly, by multi locus sequence typing (MLST), we demonstrated that both isolates (EF646 and EF641) belong to the same sequence type (ST117). Considering that EF641 was able to overcome starvation and antibiotic treatment conditions surviving for a long period of time, we performed bioinformatic analysis in identifying potential genes involved in virulence and stringent response. Our results showed a 13-nucleotide duplication (positions 1638-1650) in the gene relA, resulting in a premature stop codon, with a loss of 167 amino acids from the C-terminal domains of the RelA enzyme. RelA mediates the stringent response in bacteria, modulating levels of the alarmone guanosine tetraphosphate (ppGpp). The relA mutant (EF641) was associated with lower growth capacity, the presence of small colony variants, and higher capacity to produce biofilms (compared with the strain EF646), but without differences in antimicrobial susceptibility patterns according to standard procedures during planktonic growth. Instead, EF641 demonstrated tolerance to high doses of teicoplanin when growing in a biofilm. We conclude that all these events would be closely related to the long-term survival of the E. faecium and the late relapse of the IE. These data represent the first clinical evidence of mutations in the stringent response (relA gene) related with E. faecium IE relapse.

Getting to the heart of the matter-are two agents really better than one for the treatment of staphylococcal infective endocarditis?

The recently published European Society of Cardiology guidelines for infective endocarditis management recommends daptomycin combination therapy for the treatment of staphylococcal endocarditis in severe penicillin allergy, rather than daptomycin monotherapy. We discuss the evidence base behind this recommendation, highlighting concerns regarding the lack of robust clinical studies, increased cost and logistical considerations, and adverse effects of combination therapy. Although further studies are required to elucidate the role of combination vs monotherapy in these patients, we propose a pragmatic management approach to reduce the risk of adverse antimicrobial side effects and limit costs, while aiming to maintain treatment efficacy.

Suppressive antibiotic therapy for infectious endocarditis.

OBJECTIVES: Suppressive antibiotic therapy (SAT) is a long-term antibiotic strategy at times applied when an indicated surgical management of infective endocarditis (IE) is not possible. Our aim was to describe the characteristics and outcomes of patients having received SAT for IE. METHODS: We conducted a retrospective, observational study at Strasbourg University Hospital, France between January 2020 and May 2023. We reviewed all medical files taken into consideration at weekly meetings of the local Multidisciplinary Endocarditis Team (MET) during the study period. We included patients having received SAT following the MET evaluation. The primary endpoint was all-cause mortality at most recent follow-up. Secondary endpoints included all-cause mortality at 3 and 6 months, infection relapse, and tolerance issues attributed to SAT. RESULTS: The MET considered 251 patients during the study time, among whom 22 (9 %) had received SAT. Mean age was 77.2 ± 12.3 years. Patients were highly comorbid with a mean Charlson index score of 6.6 ± 2.5. Main indication for SAT was surgery indicated but not performed or an infected device not removed (20/22). Fourteen patients had prosthetic valve IE, including 9 TAVIs. Six patients had IE affecting cardiac implantable electronic devices. Staphylococcus aureus and enterococci were the main bacteria involved (6/22 each). Median follow-up time was 249 days (IQR 95-457 days). Mortality at most recent follow-up was 23 % (5/22). Three patients (14 %) presented tolerance issues attributed to SAT, and two patients suffered late infectious relapse. CONCLUSION: Mortality at most recent follow-up was low and tolerance issues were rare for patients under SAT, which might be a palliative approach to consider when optimal surgery or device removal is not possible.

Differential in vitro susceptibility to ampicillin/ceftriaxone combination therapy among Enterococcus faecalis infective endocarditis clinical isolates.

OBJECTIVES: To investigate the genomic diversity and ß-lactam susceptibilities of Enterococcus faecalis collected from patients with infective endocarditis (IE). METHODS: We collected 60 contemporary E. faecalis isolates from definite or probable IE cases identified between 2018 and 2021 at the University of Pittsburgh Medical Center. We used whole-genome sequencing to study bacterial genomic diversity and employed antibiotic checkerboard assays and a one-compartment pharmacokinetic-pharmacodynamic (PK/PD) model to investigate bacterial susceptibility to ampicillin and ceftriaxone both alone and in combination. RESULTS: Genetically diverse E. faecalis were collected, however, isolates belonging to two STs, ST6 and ST179, were collected from 21/60 (35%) IE patients. All ST6 isolates encoded a previously described mutation upstream of penicillin-binding protein 4 (pbp4) that is associated with pbp4 overexpression. ST6 isolates had higher ceftriaxone MICs and higher fractional inhibitory concentration index values for ampicillin and ceftriaxone (AC) compared to other isolates, suggesting diminished in vitro AC synergy against this lineage. Introduction of the pbp4 upstream mutation found among ST6 isolates caused increased ceftriaxone resistance in a laboratory E. faecalis isolate. PK/PD testing showed that a representative ST6 isolate exhibited attenuated efficacy of AC combination therapy at humanized antibiotic exposures. CONCLUSIONS: We find evidence for diminished in vitro AC activity among a subset of E. faecalis IE isolates with increased pbp4 expression. These findings suggest that alternate antibiotic combinations against diverse contemporary E. faecalis IE isolates should be evaluated.

Talaromyces marneffei endocarditis initially detected by Next Generation Sequencing: A case report.

BACKGROUND: Talaromyces marneffei (T. marneffei) is a thermal dimorphic fungus, which can cause lung or blood stream infection in patients, often life-threatening. However, endocarditis caused by T. marneffei has not been reported. For elderly patients with implanted cardiac devices or artificial valves, the prevention and treatment of infective endocarditis should not be ignored. METHODS: This is a descriptive study of a T. marneffei endocarditis by joint detection of cardiac ultrasound examination, peripheral blood DNA metagenomics Next Generation Sequencing (mNGS), and in vitro culture. RESULTS: We describe an 80-year-old female patient with an unusual infection of T. marneffei endocarditis. After intravenous drip of 0.2 g voriconazole twice a day for antifungal treatment, the patient showed no signs of improvement and their family refused further treatment. CONCLUSION: Infective endocarditis is becoming more and more common in the elderly due to the widely use of invasive surgical procedures and implantation of intracardiac devices. The diagnosis and treatment of T. marneffei endocarditis is challenging because of its rarity. Here, we discussed a case of T. marneffei endocarditis, and emphasized the role of mNGS in early diagnosis, which is of great significance for treatment and survival rate of patients.

A Novel Potential Biomarker for Predicting the Development of Septic Embolism in Patients with Infective Endocarditis: Systemic Coagulation Inflammation Index.

OBJECTIVE: Early diagnosis of septic emboli is crucial to prevent the associated morbidity and mortality. This study aimed to examine the relationship between the systemic coagulation inflammation index (SCII) and septic embolism in patients with infective endocarditis (IE). METHODS: We retrospectively analyzed the data of 167 IE patients treated at our tertiary care hospital between January 2007 and January 2023. We collected information on symptoms, comorbidities, predisposing valve diseases, prosthetic valves, devices, history of injectable drug use, blood culture results, echocardiographic findings, and complications. The SCII index was calculated using the formula: [platelet count (PLT) × fibrinogen level (g/L) / white blood cell count (WBC)]. RESULTS: The mean age of the patients was 61 years, with rheumatic valve disease being the most common predisposing factor. The most common etiologic microorganism was Staphylococcus species. Septic embolism developed in 25.7% of the patients, with the cerebral system being the most commonly affected (46.5%). The SCII was identified as an independent marker for the development of septic embolism. Receiver operating characteristic (ROC) curve analysis confirmed that an optimal SCII value of 59.8 predicted septic emboli with a sensitivity of 65.1% and a specificity of 59.6% (area under the ROC curve: 0.649 [95% confidence interval (CI): 0.556 - 0.743], P = 0.004). CONCLUSION: This study demonstrates that high SCII levels are an independent predictor for the development of septic embolism in patients with IE.

Burkholderia cepacia: A Rare Source of Endocarditis.

A 37-year-old male with a past medical history of previous mitral valve replacement due to bacterial endocarditis and intravenous (IV) drug use was found to have Burkholderia cepacia bacteremia. Transesophageal echocardiogram revealed large mitral and tricuspid valve vegetations. Medical management was initially attempted but his bacteremia persisted, and he required urgent prosthetic mitral valve replacement and native tricuspid valve replacement. Prosthetic valve endocarditis has been associated with surgery in 48.9% of patients and a mortality of 22.8%. In patients with prosthetic valve endocarditis due to B. cepacia, valve replacement occurred in approximately 61.5% of patients and mortality is estimated to be 33.3%. To our knowledge, this is one of only a few prosthetic valve endocarditis cases caused solely by B. cepacia and our case is the first to affect multiple valves including prosthetic and native valves.

Delayed formation and rupture of intracranial aneurysm following Abiotrophia defectiva endocarditis.

Abiotrophia defectiva is a type of Streptococci and is a rare cause of infectious endocarditis. The progression and outcomes of infectious intracranial aneurysms (IIAs) associated with this species are unknown due to a limited number of reported cases. A woman in her 20s with a sudden headache had a subarachnoid haemorrhage on a head CT scan. Cerebral angiography showed an aneurysm on the right middle cerebral artery. She was diagnosed with infectious endocarditis caused by A. defectiva and underwent parent artery occlusion. Despite initiating targeted antibiotic therapy, a new IIA developed and ruptured 14 days postadmission. A second parent artery occlusion was performed on the new IIA. Following 6 weeks of continued antibiotic therapy, she underwent mitral valve repair and was discharged with no neurological symptoms. Endocarditis caused by A. defectiva can lead to the delayed formation of an IIA. Endovascular treatment was effective for repeated ruptured IIAs.

Initiation of warfarin is associated with decreased mortality in patients with infective endocarditis: A population-based cohort study.

IMPORTANCE: The use of warfarin to prevent thromboembolism in patients with infective endocarditis (IE) remains controversial due to potentially increased bleeding risks. DESIGN: Population-based retrospective cohort study. PARTICIPANTS: Patients aged 18 or older and diagnosed with IE in Hong Kong between January 1st, 1997 and August 31st, 2020 were included. Patients with use of any anticoagulant 30 days before IE diagnosis were excluded. Patients initiated on warfarin within 14 days of IE diagnosis and patients without warfarin use were matched for baseline characteristics using 1:1 propensity score matching. EXPOSURE: Warfarin use within 14 days of IE diagnosis. MAIN OUTCOMES AND MEASURES: Patients were followed up to 90 days for the outcomes of ischemic stroke, all-cause mortality, intracranial hemorrhage, and gastrointestinal bleeding. Cox regression was used to determine hazard ratios (HRs) [95 % confidence intervals (CIs)] between treatment groups. Fine-Gray competing risk regression with all-cause mortality as the competing event was performed as a sensitivity analysis. In addition to 90-day analyses, landmark analyses were performed at 30 days of follow-up. RESULTS: The matched cohort consisted of 675 warfarin users (57.0 % male, age 59 ± 16 years) and 675 warfarin non-users (53.5 % male, age 61 ± 19 years). Warfarin users had a 50 % decreased 90-day risk in all-cause mortality (HR:0.50 [0.39-0.65]), without significantly different 90-day risks of ischemic stroke (HR:1.04 [0.70-1.53]), intracranial hemorrhage (HR:1.25 [0.77-2.04]), and gastrointestinal bleeding (HR:1.04 [0.60-1.78]). Thirty-day landmark analysis showed similar results. Competing risk regression showed significantly higher 30-day cumulative incidence of intracranial hemorrhage in warfarin users (sub-HR:3.34 [1.34-8.31]), but not at 90-day (sub-HR:1.63 [0.95-2.81]). Results from Fine-Gray regression were otherwise congruent with those from Cox regression. CONCLUSIONS AND RELEVANCE: Warfarin initiated within 14 days of IE diagnosis was associated with significantly decreased risks of mortality but higher risks of intracranial hemorrhage, with similar risks of ischemic stroke and gastrointestinal bleeding, compared with non-use of warfarin with 14 days of IE diagnosis. KEY POINTS: Question: Is warfarin, initiated within 14 days of a diagnosis of infective endocarditis (IE), efficacious and safe? FINDINGS: In this propensity score-matched, population-based, prospective cohort study from Hong Kong, warfarin use within 14 days of IE diagnosis was associated with a 50 % decrease in the risk of all-cause mortality, albeit with higher risk of intracranial hemorrhage, and without significant differences in the risk of ischaemic stroke and gastrointestinal bleeding. Meaning: In patients with IE, warfarin use within 14 days of diagnosis may have mortality benefits, despite increased risks of intracranial hemorrhage.

Comparison of dalbavancin with standard of care in the management of infective endocarditis: efficacy, safety, and cost analysis.

OBJECTIVES: Due to its long half-life, dalbavancin offers benefits for long-duration treatments, especially osteoarticular and infective endocarditis (IE). We evaluated the efficacy and costs of IE treatment, comparing dalbavancin with standard of care (SOC). METHODS: Retrospective multicenter cohort study of adult patients with Gram-positive cocci definite IE. Dalbavancin was used as a sequential therapy before discharge. Efficacy was a combined variable of clinical cure and absence of recurrence in 12-month follow-up. Length of hospital stay and the associated costs were analyzed in both groups of treatment. RESULTS: Twenty-two patients received dalbavancin and 47 SOC. The efficacy was similar between the groups (dalbavancin 18 [72%] vs SOC 44 [94%], P = 0.198). Hospital stay was shorter in the dalbavancin group (dalbavancin 22 days [16-34] vs SOC 37 days [23-49], P = 0.001), especially in those with E. faecalis IE (dalbavancin 30 days [20-36] vs SOC 65 days [46-74], P <0.001). A reduction of cost was observed between both groups (dalbavancin, 12,206 € [8998-17,283] vs SOC 16,249 € [11,496-22,367], P = 0.032). CONCLUSION: Dalbavancin could be a safe and effective option in the sequential treatment of patients with IE. Also, a cost reduction was detected, due to a significant shortness of hospital stay.

Risk of embolic events before and after antibiotic treatment initiation among patients with left-side infective endocarditis.

PURPOSE: Embolic events (EEs) are a common complication of left-side infective endocarditis (IE). The aim of the present study was to identify risk factors for the occurrence of EEs before or after antibiotic treatment instauration among patients with definite or possible IE. METHODS: This retro-prospective study was conducted at the Lausanne University Hospital, Lausanne, Switzerland, from January 2014 to June 2022. EEs and IE were defined according to modified Duke criteria. RESULTS: A total of 441 left-side IE episodes were included (334: 76% were definite and 107; 24% possible IE). EE were diagnosed in 260 (59%) episodes; in 190 (43%) before antibiotic treatment initiation and 148 (34%) after. Central nervous system (184; 42%) was the most common site of EE. Multivariable analysis identified S. aureus (P 0.022), immunological phenomena (P < 0.001), sepsis (P 0.027), vegetation size ≥ 10 mm (P 0.003) and intracardiac abscess (P 0.022) as predictors of EEs before antibiotic treatment initiation. For EEs after antibiotic treatment initiation, multivariable analysis revealed vegetation size ≥ 10 mm (P < 0.001), intracardiac abscess (P 0.035) and prior EE (P 0.042), as independent predictors of EEs, while valve surgery (P < 0.001) was associated with lower risk for EEs. CONCLUSIONS: We reported a high percentage of EEs among patients with left-side IE; vegetation size, intracardiac abscess, S. aureus and sepsis were independently associated with the occurrence of EEs. In addition to antibiotic treatment, early surgery led to further decrease in EEs incidence.

Prognosis of prosthetic valve infective endocarditis due to Streptococcus spp., a retrospective multi-site study to assess the impact of antibiotic treatment duration.

PURPOSE: The duration of antibiotic treatment for prosthetic valve endocarditis caused by Streptococcus spp. is largely based on clinical observations and expert opinion rather than empirical studies. Here we assess the impact of a shorter antibiotic duration. OBJECTIVES: To assess the impact of antibiotic treatment duration for streptococcal prosthetic valve endocarditis on 12-month mortality as well as subsequent morbidity resulting in additional cardiac surgical interventions, and rates of relapse and reinfection. METHODS: This retrospective multisite (N= 3) study examines two decades of data on patients with streptococcal prosthetic valve endocarditis receiving either 4 or 6 weeks of antibiotics. Overall mortality, relapse, and reinfection rates were also assessed for the entire available follow-up period. RESULTS: The sample includes 121 patients (median age 72 years, IQR [53; 81]). The majority (74%, 89/121) received a ß-lactam antibiotic combined with aminoglycoside in 74% (89/121, median bi-therapy 5 days [1; 14]). Twenty-eight patients underwent surgery guided by ESC-guidelines (23%). The 12-month mortality rate was not significantly affected by antibiotic duration (4/40, 10% in the 4-week group vs 3/81, 3.7% in the 6-week group, p=0.34) or aminoglycoside usage (p=0.1). Similarly, there were no significant differences between the 2 treatment groups for secondary surgical procedures (7/40 vs 21/81, p=0.42), relapse or reinfection (1/40 vs 2/81 and 2/40 vs 5/81 respectively). CONCLUSIONS: Our study found no increased adverse outcomes associated with a 4-week antibiotic duration compared to the recommended 6-week regimen. Further randomized trials are needed to ascertain the optimal duration of treatment for streptococcal endocarditis.