Evaluating the heart valve tissue diffusion of amoxicillin in infective endocarditis: a pilot prospective observational non-comparative study.

OBJECTIVES: Treating patients with infective endocarditis (IE) due to streptococci and enterococci currently involves high-dosage antibiotics. Recent literature suggests a 30%-70% diffusion rate could be extrapolated to human heart valve tissue. The objective of this study was to evaluate the diffusion coefficient of amoxicillin in heart valve tissue of patients operated for IE. METHODS: Adult patients were prospectively included that underwent surgery at the European Hospital Georges Pompidou for IE due to streptococci and enterococci and had previous IV amoxicillin treatment. Plasma (taken 48 h preoperatively) and heart valve tissue amoxicillin concentrations were measured with a validated LC-MS/MS method. The MIC values of amoxicillin were measured for all available isolates. RESULTS: Seventeen patients were included. Eleven (64.7%) patients had native valve IE and six (35.3%) had prosthetic valve IE. Fourteen IE cases (82.4%) were due to streptococci, one (5.9%) was due to enterococci and two (11.8%) were Haemophilus spp, Aggregatibacter actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae group infections. Median (IQR) amoxicillin dose administered was 10.5 (8.0-12.0) g/day corresponding to 138.2 (112.5-160.0) mg/kg/day. The median amoxicillin plasma concentrations pre-surgery and intra-tissular weighted concentrations were 31.9 (25.9-51.9) mg/L and 19.0 (7.9-31.4) µg/g, respectively. Median tissue/plasma concentration ratio was 0.47 (0.24-0.67), with a median amoxicillin plasma/MIC ratio of 487 (179-745), and median amoxicillin tissue/MIC ratio of 42 (14-116). CONCLUSIONS: With a significant diffusion coefficient, amoxicillin dosage in heart valve tissues showed a concentration/MIC ratio well above current recommendations for bactericidal activity. Our study suggests that lower doses can be considered for susceptible bacteria.

Attainment of Target Antibiotic Levels by Oral Treatment of Left-Sided Infective Endocarditis: A POET Substudy.

BACKGROUND: In the POET (Partial Oral Endocarditis Treatment) trial, oral step-down therapy was noninferior to full-length intravenous antibiotic administration. The aim of the present study was to perform pharmacokinetic/pharmacodynamic analyses for oral treatments of infective endocarditis to assess the probabilities of target attainment (PTAs). METHODS: Plasma concentrations of oral antibiotics were measured at day 1 and 5. Minimal inhibitory concentrations (MICs) were determined for the bacteria causing infective endocarditis (streptococci, staphylococci, or enterococci). Pharmacokinetic/pharmacodynamic targets were predefined according to literature using time above MIC or the ratio of area under the curve to MIC. Population pharmacokinetic modeling and pharmacokinetic/pharmacodynamic analyses were done for amoxicillin, dicloxacillin, linezolid, moxifloxacin, and rifampicin, and PTAs were calculated. RESULTS: A total of 236 patients participated in this POET substudy. For amoxicillin and linezolid, the PTAs were 88%-100%. For moxifloxacin and rifampicin, the PTAs were 71%-100%. Using a clinical breakpoint for staphylococci, the PTAs for dicloxacillin were 9%-17%.Seventy-four patients at day 1 and 65 patients at day 5 had available pharmacokinetic and MIC data for 2 oral antibiotics. Of those, 13 patients at day 1 and 14 patients at day 5 did only reach the target for 1 antibiotic. One patient did not reach target for any of the 2 antibiotics. CONCLUSIONS: For the individual orally administered antibiotic, the majority reached the target level. Patients with sub-target levels were compensated by the administration of 2 different antibiotics. The findings support the efficacy of oral step-down antibiotic treatment in patients with infective endocarditis.

Emerging issues on Staphylococcus aureus endocarditis and the role in therapy of daptomycin plus fosfomycin.

INTRODUCTION: Methicillin-resistant and -susceptible Staphylococcus aureus (MRSA/MSSA) infections are a major global health-care problem. Bacteremia with S. aureus exhibits high rates of morbidity and mortality and can cause complicated infections such as infective endocarditis (IE). The emerging resistance profile of S. aureus is worrisome, and several international agencies have appealed for new treatment approaches to be developed. AREAS COVERED: Daptomycin presents a rapid bactericidal effect against MRSA and has been considered at least as effective as vancomycin in treating MRSA bacteremia. However, therapy failure is often related to deep-seated infections, e.g. endocarditis, with high bacterial inocula and daptomycin regimens <10 mg/kg/day. Current antibiotic options for treating invasive S. aureus infections have limitations in monotherapy. Daptomycin in combination with other antibiotics, e.g. fosfomycin, may be effective in improving clinical outcomes in patients with MRSA IE. EXPERT OPINION: Exploring therapeutic combinations has shown fosfomycin to have a unique mechanism of action and to be the most effective option in preventing the onset of resistance to and optimizing the efficacy of daptomycin, suggesting the synergistic combination of fosfomycin with daptomycin is a useful alternative treatment option for MSSA or MRSA IE.

Molecular Analysis With 16S rRNA PCR/Sanger Sequencing and Molecular Antibiogram Performed on DNA Extracted From Valve Improve Diagnosis and Targeted Therapy of Infective Endocarditis: A Prospective Study.

BACKGROUND: Molecular analysis (MA) on heart valve (HV) improves the microbiologic diagnosis of infectious endocarditis (IE). The main drawback of MA is the lack of antimicrobial susceptibility information. METHODS: We conducted a prospective cohort observational study of consecutive adult patients from April 2012 to May 2021 who underwent valve surgery at our hospital. The performance of MA, blood cultures (BC) and valve cultures (VC), and the diagnostic and therapeutic impact of MA were evaluated. Molecular antibiogram results were compared to culture-based antimicrobial susceptibility testing (AST). RESULTS: A total of 137 patients with definite IE and 52 patients with no IE were enrolled in the study. Among IE cases BC, VC, and MA were positive in 75 (55%), 30 (22%), and 120 (88%) of IE cases, respectively. Among 62 cases of BC-negative IE (BCNE), 57 achieved diagnosis with MA. MA led to a change of antimicrobial therapy in 92% of BCNE. MA was negative in 100% of patients with no IE. Molecular antibiogram performed on 17 valve specimens that resulted positive for pathogens potential carrier of genes encoding for multidrug resistant mechanisms showed 100% concordance with AST. CONCLUSIONS: MA showed a high specificity and sensitivity in etiological diagnosis of IE. Molecular antibiogram could overcome the major limitation of MA that is the lack of susceptibility testing. We advocate for the inclusion of MA among diagnostic criteria for IE and for a more extensive use of molecular antibiogram when the culture result is negative, and MA is the only positive test.

Subtherapeutic Doses of Vancomycin Synergize with Bacteriophages for Treatment of Experimental Methicillin-Resistant Staphylococcus aureus Infective Endocarditis.

Background. Recurrent therapeutic failures reported for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infective endocarditis (IE) with vancomycin may be due to poor bactericidal activity. Alternative antibacterial approaches using bacteriophages may overcome this limitation. Objectives. An experimental rat model of MRSA IE (EE) was used to examine the efficacy of vancomycin combined with a 1:1 bacteriophage (phage) cocktail composed of Herelleviridae vB_SauH_2002 and Routreeviridae 66. Methods. Six hours after inoculation with ca. 5 log10 colony forming units (CFU) of MRSA strain AW7, animals were treated with either: (i) saline, (ii) an equimolar two-phage cocktail (bolus of 1 mL followed by a 0.3 mL/h continuous infusion of 10 log10 plaque forming units (PFU)/mL phage suspension), (iii) vancomycin (at a dose mimicking the kinetics in humans of 0.5 g b.i.d.), or (iv) a combination of both. Bacterial loads in vegetations, and phage loads in vegetations, liver, kidney, spleen, and blood, were measured outcomes. Results. Phage cocktail alone was unable to control the growth of strain AW7 in cardiac vegetations. However, when combined with subtherapeutic doses of vancomycin, a statistically significant decrease of ∆4.05 ± 0.94 log10 CFU/g at 24 h compared to placebo was detected (p < 0.001). The administration of vancomycin was found to significantly impact on the local concentrations of phages in the vegetations and in the organs examined. Conclusions. Lytic bacteriophages as an adjunct treatment to the standard of care antibiotics could potentially improve the management of MRSA IE. Further studies are needed to investigate the impact of antibiotics on phage replication in vivo.

Daptomycin Pharmacokinetics and Pharmacodynamics in Patients on Methadone Substitution Therapy.

BACKGROUND AND OBJECTIVE: When administered for severe infections in intravenous drug users (IDUs) at a daily dose of 6 mg/kg, daptomycin displayed abnormal pharmacokinetic parameters compared with those seen in healthy volunteers; specifically, decreased trough and maximum concentrations (Ctrough; Cmax) and increased clearance (CL). The objective of this study was to evaluate the pharmacokinetics and pharmacodynamics of daptomycin administered at a daily dosage of 12 mg/kg for Staphylococcus aureus infective endocarditis (IE) in patients concomitantly treated with methadone, and to compare the results with those published in the literature for healthy controls treated with the same daily dose. METHODS: Antibiotic treatment included daptomycin (12 mg/kg daily) in combination with an antistaphylococcal ß-lactam (cefazolin 2 g three times a day). The minimum inhibitory concentration (MIC) of Staphylococcus aureus isolated through blood cultures was used to calculate pharmacokinetic and pharmacodynamic parameters such as the ratio of the area under the concentration-time curve over 24 h to the MIC (AUC0-24/MIC) and Cmax/MIC. RESULTS: Five IDUs hospitalized for IE were enrolled. The mean measured daptomycin Cmax and Ctrough were 54.1 µg/mL (CV: 0.32) and 8.7 µg/mL (CV: 0.59), respectively; the mean calculated AUC0-24 was 742.7 µg × h/mL (CV: 0.31). The estimated average volume of distribution at the steady state (Vd,ss) and the half-life (t1/2) were 316.5 mL/kg (CV: 0.53) and 14.4 h (CV: 0.30), respectively. The mean daptomycin clearance from plasma normalized for body weight (CLwp) was 17.3 mL/(h × kg) (CV: 0.33). The calculated average Cmax and AUC0-24 (183.7 µg/mL and 1277.4 µg × h/mL, respectively) were lower than and statistically significantly different from (p < 0.001 and p = 0.001, respectively) those expected for healthy volunteers. CONCLUSIONS: Treatment of Staphylococcus aureus IE in IDUs on methadone treatment requires the use of high daptomycin daily doses in order to achieve satisfactory pharmacodynamic parameters. Close monitoring of the daptomycin plasma concentration is suggested.

Management and treatment of Aerococcus bacteremia and endocarditis.

OBJECTIVES: We describe our multicenter experience on diagnosis and management of Aerococcus bacteremia including the susceptibility profile of Aerococcus species and a suggested algorithm for clinicians. METHODS: Retrospective study of all patients with positive blood cultures for Aerococcus species from January 2005 to July 2020 in our institution with clinical data and susceptibility profile. Data were collected from both electronic health record and clinical microbiology laboratory database. RESULTS: There were 219 unique isolates with only the susceptibility profiles available, while 81 patients had clinical information available. Forty-nine of those cases were deemed as true bloodstream infection and the rest were of unclear clinical significance. Cases of endocarditis (n = 7) were high-grade, monomicrobial bacteremia caused by Aerococcus urinae. Patients with endocarditis were younger (66 vs 80 p < 0.05). The risk for endocarditis was higher if duration of symptoms was longer than 7 days (OR 105, 95% CI: 5-2271), or if there were septic emboli (OR 71, 95% CI: 3-1612). A DENOVA score cutoff of ≥ 3 was 100% sensitive and 89% specific in detecting endocarditis. The 30-day and 3-month all-cause mortality for bacteremia was 17% and 24%, respectively. Six out of seven patients with endocarditis survived. CONCLUSIONS: Antibiotic regimen for aerococcal bloodstream infections and endocarditis should be guided by species identification and antimicrobial susceptibility testing. DENOVA scoring system's performance in this study is more congruent to other studies. Hence, it can be used as an adjunctive tool in assessing the need for echocardiogram to rule out endocarditis. In our experience, two and four weeks of treatment for bloodstream infections and endocarditis, respectively, had good outcomes.

Dalbavancin and telavancin in the treatment of infective endocarditis: a literature review.

Glycopeptides have an established role in the management of infective endocarditis, and feature in current treatment guidelines. Newer lipoglycopeptide agents (dalbavancin, telavancin and oritavancin), which are analogues of glycopeptides with structural modifications giving rise to added novel mechanisms of antimicrobial activity, are approved for the treatment of Gram-positive skin and skin structure infections, and also for nosocomial pneumonia (only telavancin has approval for the latter indication). Recent evidence has also emerged to support their use in the treatment of bone and joint infections. This article reviews the current literature on dalbavancin and telavancin in the treatment of infective endocarditis, a condition for which the role of these agents is yet to be established.

Tedizolid as Step-Down Therapy following Daptomycin versus Continuation of Daptomycin against Enterococci and Methicillin- and Vancomycin-Resistant Staphylococcus aureus in a Rat Endocarditis Model.

Tedizolid (TZD) and daptomycin (DAP) were assessed in a rat endocarditis model against Enterococcus faecalis, Enterococcus faecium (resistant to vancomycin and ampicillin), and Staphylococcus aureus As a monotherapy, TZD for 5 days was not effective in a comparison with no-treatment controls, while DAP for 5 days was significantly effective against these bacteria. Step-down therapy (DAP for 3 days followed by TZD for 2 days) was as effective as DAP for 5 days and was comparable to 3 days of DAP plus ceftriaxone against all bacteria and to 3 days of DAP plus gentamicin against E. faecalis OG1RF.

[PRACTICE OF MANAGEMENT OF PATIENTS WITH INFECTIOUS ENDOCARDITIS IN CONDITIONS OF LOW FREQUENCY OF ETIOLOGICALLY SIGNIFICANT PATHOGENS IN THE RUSSIAN FEDERATION].

The article presents the results of a multicenter study of the etiology, antibiotic sensitivity and pharmacoepidemiology of infective endocarditis in the Russian Federation. The purpose of this study is to analyze the current practice of management of patients with infective endocarditis in conditions of low frequency of etiologically significant pathogens in the Russian Federation. The study included patients of both sexes of all age groups with definite and probable infective endocarditis. 406 cases of infectious endocarditis (240 in retrospect and 166 in the prospective part) were analyzed. Etiologically significant pathogen was isolated in 144 cases (35.5%). The structure of pathogens was dominated by gram (+) cocci (90.3%), most often - Staphylococcus aureus (46.5% of all isolated pathogens). Aminoglycosides (22.8%), parenteral cephalosporins of the III generation (22.1%) and glycopeptides (14.5%) were most frequently used in the course of starting antimicrobial therapy. When changing the mode of antimicrobial therapy, glycopeptides (18.6%), aminoglycosides (15.3%), fluoroquinolones (11.2%) and parenteral cephalosporins of generation III (9.5%) were most often prescribed.

Molecular Mechanisms of Leonurus Cardiaca L. Extract Activity in Prevention of Staphylococcal Endocarditis-Study on in Vitro and ex Vivo Models.

Better understanding the mechanisms of Leonurus cardiaca L. extract (LCE) activity is necessary to prepare recommendations for the use of LCE-based herbal products for preventive/supportive purposes in case of infective endocarditis (IE) and other staphylococcal invasive infections. The aim of the study was to analyze molecular mechanisms of LCE effect on Staphylococcus aureus and blood platelets in the context of their interactions playing a pivotal role in such disorders. Using atomic force microscopy, we demonstrated that adhesion forces of S. aureus were markedly reduced after exposure to LCE at subinhibitory concentrations. The effect resulted from the impact of LCE on S. aureus cell morphology and the composition of phospholipids and fatty acids in bacterial membranes (assessed by HPLC), which modulated their stabilization, hydrophobicity, and charge. Moreover, using FACS we showed also that LCE significantly reduced GP IIb/IIIa expression on blood platelets, thus the disruption of platelet-fibrinogen interactions seems to explain antiplatelet effect of LCE. The obtained results prove the usefulness of LCE in the prevention of S. aureus adhesion, platelet activation, and vegetations development, however, also pointed out the necessity of excluding the cationic antibiotics from the treatment of S. aureus-associated IE and other invasive diseases, when motherwort herb is used simultaneously as an addition to the daily diet.

Treatment of tricuspid valve endocarditis with daptomycin and linezolid therapy.

PURPOSE: A case report of the use of linezolid and daptomycin for the treatment of multidrug-resistant right-sided infective endocarditis is presented. SUMMARY: A 36-year-old patient with a history of intravenous drug use was hospitalized for treatment of native tricuspid valve endocarditis resulting in persistent methicillin-resistant Staphylococcus aureus bacteremia. During the admission the patient was unsuccessfully treated with vancomycin monotherapy (final E-test minimum inhibitory concentration, 4 µg/mL). The patient's treatment was switched to daptomycin and gentamicin, with no improvement in blood culture results over 4 days. Gentamicin was discontinued, and linezolid was administered in combination with daptomycin; bacteremia was cleared after 13 days of linezolid and daptomycin combination therapy. Due to daptomycin resistance (minimum inhibitory concentration, 4 µg/mL), gentamicin was substituted for daptomycin due to the former agent's synergistic effects with linezolid. After 23 days of therapy the patient was transferred to another facility for a tricuspid valve replacement procedure, which was completed without complications. The patient was transferred in stable condition to a skilled nursing facility to continue antibiotic therapy lasting 6 weeks from the date of surgery. The patient's blood cultures remained negative. CONCLUSION: A 36-year-old woman with resistant tricuspid valve endocarditis was successfully treated with linezolid in combination with daptomycin.

Endocarditis infecciosa por bacilos gram negativos no HACEK. Experiencia en un centro de alta complejidad de la República Argentina (1998-2016) / Infective endocarditis due to non-HACEK gram-negative bacilli in a Level III cardiovascular center in Argentina (1998-2016)

Los bacilos gram negativos (BGN) que no pertenecen al grupo HACEK son una causa infrecuente de endocarditis infecciosa. Los aspectos epidemiológicos, diagnósticos y pronósticos de esta entidad son poco conocidos y la experiencia aún es limitada. Nuestros objetivos fueron analizar las características clínicas y microbiológicas de las endocarditis infecciosas (EI) por BGN no HACEK diagnosticadas en un centro de alta complejidad de Argentina en el período 1998-2016 y conocer su evolución hospitalaria, a fin de compararlas con las EI debidas a otros microorganismos.

Non-HACEK Gram-negative bacilli are a rare cause of infective endocarditis. Epidemiological, diagnostic and prognostic aspects of this entity are little known, and there is limited experience. The aim of this study was to analyze the clinical, microbiological and in-hospital outcomes of non-HACEK Gram negative bacilli endocarditis and to compare them with those due to other microorganisms.

Occult bacteraemia in cardiac implantable electronic device patients: a review of diagnostic workflow and mandatory therapy.

: Cardiac implantable electronic device (CIED) implantation has greatly increased, with an associated exponential increase in CIED infections (CDIs). Cardiac device related infective endocarditis (CDRIE) has high morbidity and mortality: approximately 10-21%. Therefore, a prompt diagnosis and radical treatment of CDRIE are needed; transvenous lead extraction (TLE) is the mainstay for the complete healing, even if associated with wide logistic problems, high therapeutic costs and high mortality risk for patients. Some criticisms about the value of Duke criteria and their limitations for the diagnosis of CDRIE are known. The significance of classic laboratory data, transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE), considered in the Duke score, are reviewed and critically discussed in this article, with regard to the specific field of the diagnosis of CDI. The need for new techniques for achieving the diagnostic reliability has been well perceived by physicians, and additional techniques have been introduced in the new European Society of Cardiology (ESC) and British Heart Rhythm Society (BHRS) guidelines on infective endocarditis. These suggested techniques, such as 18-Fluorodeoxyglucose PET/computed tomography (FDG-PET/CT), white blood cell PET (WBC PET) and lung multislice CT (MSCT), are also discussed in the study. This short review is intended as an extensive summary of the diagnostic workflow in cases of CDI and will be useful for readers who want to know more about this issue.

Compassionate Use of Cefiderocol as Adjunctive Treatment of Native Aortic Valve Endocarditis Due to Extremely Drug-resistant Pseudomonas aeruginosa.

Serious infections such as endocarditis due to extremely drug-resistance gram-negative bacteria are an increasing challenge. Here, we present successful adjunctive use of cefiderocol for a patient with persistently bacteremic healthcare-associated native aortic valve endocarditis due to an extended-spectrum beta-lactamase-positive Pseudomonas aeruginosa susceptible in vitro only to colistin, following failure of conventional therapeutic options.

Teicoplanin for treating enterococcal infective endocarditis: A retrospective observational study from a referral centre in Spain.

This study aimed to evaluate the effectiveness and safety of teicoplanin for treating enterococcal infective endocarditis (EIE). A retrospective analysis of a prospective cohort of definite EIE patients treated with teicoplanin in a Spanish referral centre (2000-2017) was performed. The primary outcome was mortality during treatment. Secondary outcomes were mortality during 3-month follow-up, adverse effects and relapse. A total of 22 patients received teicoplanin, 9 (40.9%) as first-line (8 Enterococcus faecium and 1 Enterococcus faecalis) and 13 (59.1%) as salvage therapy (13 E. faecalis). Median (IQR) age was 71.5 (58.3-78) years and Charlson comorbidity index was 4.5 (3-7). Five (22.7%) affected prosthetic valves. Median duration of treatment in survivors was 53 (42.5-61) days for antibiotics and 27 (17-41.5) days for teicoplanin [median dose 10 (10-10.8) mg/kg/day]. Reasons for teicoplanin use were resistance to ß-lactams (40.9%), adverse events with previous regimens (31.8%) and outpatient parenteral antimicrobial therapy (OPAT) (27.3%). Teicoplanin was withdrawn due to adverse events in 2 patients (9.1%). Five patients (22.7%) died during treatment: four in the first-line (three with surgery indicated but not performed) and one in the salvage therapy group (surgery indicated but not performed). Two deaths (11.8%) occurred over the 3-month follow-up. There were no relapses during a median of 43.2 (22.1-69.1) months. Teicoplanin can be used as an alternative treatment for susceptible E. faecium IE and as a salvage therapy in selected patients with E. faecalis IE when adverse events develop with standard regimens or to allow OPAT.

Probiotics and infective endocarditis in patients with hereditary hemorrhagic telangiectasia: a clinical case and a review of the literature.

BACKGROUND: In the last decades, probiotics have been widely used as food supplements because of their putative beneficial health effects. They are generally considered safe but rare reports of serious infections caused by bacteria included in the definition of probiotics raise concerns on their potential pathogenic role in patients with particular predisposing factors. Patients with hereditary hemorrhagic telangiectasia (HHT) are exposed to infections because of telangiectasias and arteriovenous malformations (AVMs). We describe what is, to our knowledge, the first case of infective endocarditis (IE) caused by Lactobacillus rhamnosus in a patient with HHT. A systematic review of the relevant medical literature is presented. CASE PRESENTATION: A patient with HHT and an aortic bioprosthesis was admitted because of prolonged fever not responding to antibiotics. The patient had a history of repeated serious infections with hospitalizations and prolonged use of antibiotics, and used to assume large amounts of different commercial products containing probiotics. Weeks before the onset of symptoms the patient had been treated with nasal packings and with surgical closure of a nasal bleeding site because of recurrent epistaxis. A diagnosis of IE of the aortic bioprosthesis was made. All blood coltures were positive for L. rhamnosus. The patients responded to a cycle of 6 weeks of amoxicillin/clavulanate plus gentamicin. A systematic review of IE linked to consumption of probiotics, and of infective endocarditis in patients with HHT was conducted. 10 cases of IE linked to probiotics consumption and 6 cases of IE in patients with HHT were found. CONCLUSIONS: Consumption of probiotics can pose a risk of serious infections in patients with particular predisposing factors. Patients with HHT can be considered at risk because of their predisposition to infections. Prophylaxis with antibiotics before nasal packings in patients with HHT can be considered.