External Validation of the 2023 Duke-International Society for Cardiovascular Infectious Diseases Diagnostic Criteria for Infective Endocarditis.

BACKGROUND: The 2023 Duke-International Society of Cardiovascular Infectious Diseases (ISCVID) criteria for infective endocarditis (IE) were introduced to improve classification of IE for research and clinical purposes. External validation studies are required. METHODS: We studied consecutive patients with suspected IE referred to the IE team of Amsterdam University Medical Center (from October 2016 to March 2021). An international expert panel independently reviewed case summaries and assigned a final diagnosis of "IE" or "not IE," which served as the reference standard, to which the "definite" Duke-ISCVID classifications were compared. We also evaluated accuracy when excluding cardiac surgical and pathologic data ("clinical" criteria). Finally, we compared the 2023 Duke-ISCVID with the 2000 modified Duke criteria and the 2015 and 2023 European Society of Cardiology (ESC) criteria. RESULTS: A total of 595 consecutive patients with suspected IE were included: 399 (67%) were adjudicated as having IE; 111 (19%) had prosthetic valve IE, and 48 (8%) had a cardiac implantable electronic device IE. The 2023 Duke-ISCVID criteria were more sensitive than either the modified Duke or 2015 ESC criteria (84.2% vs 74.9% and 80%, respectively; P < .001) without significant loss of specificity. The 2023 Duke-ISCVID criteria were similarly sensitive but more specific than the 2023 ESC criteria (94% vs 82%; P < .001). The same pattern was seen for the clinical criteria (excluding surgical/pathologic results). New modifications in the 2023 Duke-ISCVID criteria related to "major microbiological" and "imaging" criteria had the most impact. CONCLUSIONS: The 2023 Duke-ISCVID criteria represent a significant advance in the diagnostic classification of patients with suspected IE.

Antibiotic Exposure Leads to Reduced Phage Susceptibility in Vancomycin Intermediate Staphylococcus aureus (VISA).

In the time of antimicrobial resistance, phage therapy is frequently suggested as a possible solution for such difficult-to-treat infections. Vancomycin-intermediate Staphylococcus aureus (VISA) remains a relatively rare yet increasing occurrence in the clinic for which phage therapy may be an option. However, the data presented herein suggest a potential cross-resistance mechanism to phage following vancomycin exposure in VISA strains. When comparing genetically similar strains differing in their susceptibility to vancomycin, those with intermediate levels of vancomycin resistance displayed decreased sensitivity to phage in solid and liquid assays. Serial passaging with vancomycin induced both reduced vancomycin susceptibility and phage sensitivity. As a consequence, the process of phage infection was shown to be interrupted after DNA ejection from adsorbed phage but prior to phage DNA replication, as demonstrated through adsorption assays, lysostaphin sensitivity assays, electron microscopy, and quantitative PCR (qPCR). At a time when phage products are being used for experimental treatments and tested in clinical trials, it is important to understand possible interference between mechanisms underlying antibiotic and phage resistance in order to design effective therapeutic regimens.

The multidomain architecture of a bacteriophage endolysin enables intramolecular synergism and regulation of bacterial lysis.

Endolysins are peptidoglycan hydrolases produced at the end of the bacteriophage (phage) replication cycle to lyse the host cell. Endolysins in Gram-positive phages come in a variety of multimodular forms that combine different catalytic and cell wall binding domains. However, the reason why phages adopt endolysins with such complex multidomain architecture is not well understood. In this study, we used the Streptococcus dysgalactiae phage endolysin PlySK1249 as a model to investigate the role of multidomain architecture in phage-induced bacterial lysis and lysis regulation. PlySK1249 consists of an amidase (Ami) domain that lyses bacterial cells, a nonbacteriolytic endopeptidase (CHAP) domain that acts as a dechaining enzyme, and a central LysM cell wall binding domain. We observed that the Ami and CHAP domains synergized for peptidoglycan digestion and bacteriolysis in the native enzyme or when expressed individually and reunified. The CHAP endopeptidase resolved complex polymers of stem-peptides to dimers and helped the Ami domain to digest peptidoglycan to completion. We also found that PlySK1249 was subject to proteolytic cleavage by host cell wall proteases both in vitro and after phage induction. Cleavage disconnected the different domains by hydrolyzing their linker regions, thus hindering their bacteriolytic cooperation and possibly modulating the lytic activity of the enzyme. PlySK1249 cleavage by cell-wall-associated proteases may represent another example of phage adaptation toward the use of existing bacterial regulation mechanism for their own advantage. In addition, understanding more thoroughly the multidomain interplay of PlySK1249 broadens our knowledge on the ideal architecture of therapeutic antibacterial endolysins.

The role of antiaggregant agents and anticoagulants in the prevention of aortic valve endocarditis: A double-cohort retrospective study.

Objective: Antiaggregants (Ag) could prevent infective endocarditis (IE) in preclinical studies. In this study we investigated whether Ag or anticoagulants (Ac) were also protective in humans. Methods: In part I we determined the incidence of IE of bioprosthetic aortic valves (PVE) in 333 consecutive patients who underwent aortic valve replacement for noninfective aortic insufficiency between 2009 and 2019. In part II we retrospectively analyzed data of 137 patients who had developed IE of the native aortic valve (NVE) between 2007 and 2015. Multivariable Fine-Gray and logistic regression models were used to investigate associations between Ag and Ac therapy and IE. Results: Sixteen of 333 (4.8%) aortic valve replacement recipients developed PVE after a median of 3.72 years. There was no association between Ag and PVE, whereas Ac was associated with a higher IE occurrence (no association for vitamin K antagonists but significant for fondaparinux or low molecular-weight heparins; hazard ratio, 4.61; 95% CI, 1.01-21.9). In contrast, among the 137 patients in part II, vitamin K antagonists (odds ratio [OR], 7.52; 95% CI, 2.51-22.6), double antiplatelet therapy (OR, 44.3; 95% CI, 4.83-407), novel oral Ac (OR, 4.17; 95% CI, 1.15-15.1), and fondaparinux or low molecular-weight heparins (OR, 9.87; 95% CI, 1.81-53.9), but not acetylsalicylic acid, were associated with NVE. Conclusions: Ac were associated with IE in both cohorts, whereas Ag were not associated with PVE. This might reflect differences in the studied populations, with Ag and Ac being prescribed for conditions associated with long-term IE risk in the NVE cohort. Therefore, determining the potential protective effect of Ag and Ac will necessitate further well-controlled studies.

Antiplatelet therapy abrogates platelet-assisted Staphylococcus aureus infectivity of biological heart valve conduits.

OBJECTIVE: Although recent advances in pulmonary valve replacement have enabled excellent hemodynamics, infective endocarditis remains a serious complication, particularly for implanted bovine jugular vein (BJV) conduits. METHODS: We investigated contributions by platelets and plasma fibrinogen to endocarditis initiation on various grafts used for valve replacement. Thus, adherence of Staphylococcus aureus and platelets to 5 graft tissues was studied quantitatively in perfusion chambers, assisted by microscopic analysis. We also evaluated standard antiplatelet therapy to prevent onset of S aureus endocarditis. RESULTS: Of all tissues, bovine pericardium (BP) showed the greatest fibrinogen binding. Perfusion of all plasma-precoated tissues identified BP and BJVwall with the greatest affinity for S aureus. Perfusions of anticoagulated human blood over all tissues also triggered more platelet adhesion to BP and BJVwall as single platelets. Several controls confirmed that both S aureus and platelets were recruited on immobilized fibrinogen. In addition, perfusions (and controls) over plasma-coated tissues with whole blood, spiked with S aureus, revealed that bacteria exclusively bound to adhered platelets. Both the platelet adhesion and platelet-mediated S aureus recruitment required platelet αIIbß3 and coated or soluble fibrinogen, respectively, interactions abrogated by the αIIbß3-antagonist eptifibatide. Also, standard antiplatelet therapy (aspirin/ticagrelor) reduced the adherence of S aureus in blood to BJV 3-fold. CONCLUSIONS: Binding of plasma fibrinogen to especially BJV grafts enables adhesion of single platelets via αIIbß3. S aureus then attaches from blood to (activated) bound platelet αIIbß3 via plasma fibrinogen. Dual antiplatelet therapy appears a realistic approach to prevent endocarditis and its associated mortality.

A review of recommendations for infective endocarditis prevention in patients undergoing transcatheter aortic valve implantation.

Infective endocarditis (IE) after transcatheter aortic valve implantation (TAVI) is a new disease entity. The rate of IE after TAVI is similar to that after surgical aortic valve replacement (SAVR), but mortality and prevalence of Enterococcus spp. as causing pathogens are significantly higher. Guidelines on infection prevention measures before TAVI procedures are currently lacking. We performed a structured review of the available data to provide interim recommendations based on guidelines to prevent infections issued by the World Health Organization as well as guidelines by professional societies from Europe and the USA. Such interim recommendations based on expert opinions are probably justified until large randomised trials provide strong evidence for infection control in TAVI, because IE after TAVI is often related to the TAVI procedure itself and the associated mortality rate is high. Antibiotic prophylaxis should be adapted from an intravenous cephalosporin to, e.g., amoxicillin/clavulanic acid, to cover enterococci. In addition, infection control should follow operating room standards as far as is reasonable, even if the evidence for this recommendation is very low. These recommendations are endorsed by the International Society for Cardiovascular Infectious Diseases (ISCVID).

Marginal role of von Willebrand factor-binding protein and coagulase in the initiation of endocarditis in rats with catheter-induced aortic vegetations.

Staphylococcus aureus is the leading cause of infective endocarditis (IE). While the role of S. aureus cell-wall associated protein clumping factor A (ClfA) in promoting IE has been already demonstrated, that of the secreted plasma-clotting factors staphylocoagulase (Coa) and von Willebrand factor-binding protein (vWbp) has not yet been elucidated. We investigated the role of Coa and vWbp in IE initiation in rats with catheter-induced aortic vegetations, using Lactococcus lactis expressing coa, vWbp, clfA or vWbp/clfA, and S. aureus Newman Δcoa, ΔvWbp, ΔclfA or Δcoa/ΔvWbp/ΔclfA mutants. vWbp-expression increased L. lactis valve infection compared to parent and coa-expressing strains (incidence: 62%, versus 0% and 13%, respectively; P < 0.01). Likewise, expression of clfA increased L. lactis infectivity (incidence: 80%), which was not further affected by co-expression of vWbp. In symmetry, deletion of the coa or vWbp genes in S. aureus did not decrease infectivity (incidence: 68 and 64%, respectively) whereas deletion of clfA did decrease valve infection (incidence: 45%; P = 0.03 versus parent), which was not further affected by the triple deletion Δcoa/ΔvWbp/ΔclfA (incidence: 36%; P > 0.05 versus ΔclfA mutant). Coa does not support the initial colonization of IE (in L. lactis) without other key virulence factors and vWbp contributes to initiation of IE (in L. lactis) but is marginal in the present of ClfA.

Assessment of the Dual Role of Clumping Factor A in S. Aureus Adhesion to Endothelium in Absence and Presence of Plasma.

Adhesion of Staphylococcus aureus to endothelial cells (ECs) is paramount in infective endocarditis. Bacterial proteins such as clumping factor A (ClfA) and fibronectin binding protein A (FnbpA) mediate adhesion to EC surface molecules and (sub)endothelial matrix proteins including fibrinogen (Fg), fibrin, fibronectin (Fn) and von Willebrand factor (vWF). We studied the influence of shear flow and plasma on the binding of ClfA and FnbpA (including its sub-domains A, A16+, ABC, CD) to coverslip-coated vWF, Fg/fibrin, Fn or confluent ECs, making use of Lactococcus lactis, expressing these adhesins heterologously. Global adherence profiles were similar in static and flow conditions. In the absence of plasma, L. lactis-clfA binding to Fg increased with shear forces, whereas binding to fibrin did not. The degree of adhesion of L. lactis-fnbpA to EC-bound Fn and of L. lactis-clfA to EC-bound Fg, furthermore, was similar to that of L. lactis-clfA to coated vWF domain A1, in the presence of vWF-binding protein (vWbp). Yet, in plasma, L. lactis-clfA adherence to activated EC-vWF/vWbp dropped over 10 minutes by 80% due to vWF-hydrolysis by a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 and that of L. lactis-fnbpA likewise by > 70% compared to the adhesion in absence of plasma. In contrast, plasma Fg supported high L. lactis-clfA binding to resting and activated ECs. Or, in plasma S. aureus adhesion to active endothelium occurs mainly via two complementary pathways: a rapid but short-lived vWF/vWbp pathway and a stable integrin-coupled Fg-pathway. Hence, the pharmacological inhibition of ClfA-Fg interactions may constitute a valuable additive treatment in infective endocarditis.

In vitro characterization of PlyE146, a novel phage lysin that targets Gram-negative bacteria.

The recent rise of multidrug-resistant Gram-negative bacteria represents a serious threat to public health and makes the search for novel effective alternatives to antibiotics a compelling need. Bacteriophage (Phage) lysins are enzymes that hydrolyze the cell wall of bacteria and represent a promising alternative to tackle this ever-increasing problem. Despite their use is believed to be restricted to Gram-positive bacteria, recent findings have shown that they can also be used against Gram-negative bacteria. By using a phage genome-based screening approach, we identified and characterized a novel lysin, PlyE146, encoded by an Escherichia coli prophage and with a predicted molecular mass of ca. 17 kDa. PlyE146 is composed of a C-terminal cationic peptide and a N-terminal N-acetylmuramidase domain. Histidine-tagged PlyE146 was overexpressed from a plasmid in Lactococcus lactis NZ9000 and purified by NI-NTA chromatography. PlyE146 exhibited in vitro optimal bactericidal activity against E. coli K12 (3.6 log10 CFU/mL decrease) after 2 h of incubation at 37°C at a concentration of 400 µg/mL in the absence of NaCl and at pH 6.0. Under these conditions, PlyE146 displayed antimicrobial activity towards several other E. coli, Pseudomonas aeruginosa (3 to 3.8-log10 CFU/mL decrease) and Acinetobacter baumannii (4.9 to >5-log10 CFU/mL decrease) strains. Therefore, PlyE146 represents a promising therapeutic agent against E. coli, P. aeruginosa and A. baumannii infections. However, further studies are required to improve the efficacy of PlyE146 under physiological conditions.

Synergistic Interaction Between Phage Therapy and Antibiotics Clears Pseudomonas Aeruginosa Infection in Endocarditis and Reduces Virulence.

Background: Increasing antibiotic resistance warrants therapeutic alternatives. Here we investigated the efficacy of bacteriophage-therapy (phage) alone or combined with antibiotics against experimental endocarditis (EE) due to Pseudomonas aeruginosa, an archetype of difficult-to-treat infection. Methods: In vitro fibrin clots and rats with aortic EE were treated with an antipseudomonas phage cocktail alone or combined with ciprofloxacin. Phage pharmacology, therapeutic efficacy, and resistance were determined. Results: In vitro, single-dose phage therapy killed 7 log colony-forming units (CFUs)/g of fibrin clots in 6 hours. Phage-resistant mutants regrew after 24 hours but were prevented by combination with ciprofloxacin (2.5 × minimum inhibitory concentration). In vivo, single-dose phage therapy killed 2.5 log CFUs/g of vegetations in 6 hours (P < .001 vs untreated controls) and was comparable with ciprofloxacin monotherapy. Moreover, phage/ciprofloxacin combinations were highly synergistic, killing >6 log CFUs/g of vegetations in 6 hours and successfully treating 64% (n = 7/11) of rats. Phage-resistant mutants emerged in vitro but not in vivo, most likely because resistant mutations affected bacterial surface determinants important for infectivity (eg, the pilT and galU genes involved in pilus motility and LPS formation). Conclusions: Single-dose phage therapy was active against P. aeruginosa EE and highly synergistic with ciprofloxacin. Phage-resistant mutants had impaired infectivity. Phage-therapy alone or combined with antibiotics merits further clinical consideration.

Muropeptide signature of inhibitors of protein synthesis correlates with ß-lactam synergism against methicillin-resistant Staphylococcus aureus.

Quinupristin/dalfopristin (Q/D) and ß-lactams interact positively against methicillin-resistant Staphylococcus aureus (MRSA). The effect extends to other inhibitors of protein synthesis, but not to inhibitors of polynucleotide synthesis or assembly, or to Q/D plus non-ß-lactam cell wall inhibitors. Moreover, electron microscopy studies have correlated this effect with a thickened cell wall. In this study, we sought to determine whether inhibitors of protein synthesis might produce a specific peptidoglycan muropeptide signature that would correlate with their positive ß-lactam interaction. The muropeptides of six S. aureus isolates (three methicillin-susceptible and three MRSA) were analysed using high-performance liquid chromatography and mass spectrometry. Exposure to 0.25× the minimum inhibitory concentration of inhibitors of protein synthesis consistently produced three main alterations irrespective of methicillin resistance: (i) an increase in peak 12 (a cyclic dimer of glycine-containing disaccharide-tetrapeptide); (ii) an increase in poorly resolved late-eluting materials; and (iii) a decrease in peak 1 (a disaccharide-pentapeptide). Eventually, the rate of autolysis was also decreased, supporting the structural alteration of the peptidoglycan. Other drug classes did not produce these anomalies. An increase in peak 12 was also observed in staphylococci treated with fosfomycin, which decreases expression of the native penicillin-binding protein (PBP) 2 and 4. Parallel blockage of normal PBPs with ß-lactams abolished the anomalies, indicating that they resulted from altered function of native PBPs. This underlines the potential of inhibiting both protein synthesis and transpeptidation simultaneously and suggests that such a drug combination strategy might be efficaciously exploited.

Antibodies Targeting Hsa and PadA Prevent Platelet Aggregation and Protect Rats against Experimental Endocarditis Induced by Streptococcus gordonii.

Streptococcus gordonii and related species of oral viridans group streptococci (VGS) are common etiological agents of infective endocarditis (IE). We explored vaccination as a strategy to prevent VGS-IE, using a novel antigen-presenting system based on non-genetically modified Lactococcus lactis displaying vaccinogens on its surface. Hsa and PadA are surface-located S. gordonii proteins implicated in platelet adhesion and aggregation, which are key steps in the pathogenesis of IE. This function makes them ideal targets for vaccination against VGS-IE. In the present study, we report the use of nonliving L. lactis displaying at its surface the N-terminal region of Hsa or PadA by means of the cell wall binding domain of Lactobacillus casei A2 phage lysine LysA2 (Hsa-LysA2 and PadA-LysA2, respectively) and investigation of their ability to elicit antibodies in rats and to protect them from S. gordonii experimental IE. Immunized and control animals with catheter-induced sterile aortic valve vegetations were inoculated with 106 CFU of S. gordonii The presence of IE was evaluated 24 h later. Immunization of rats with L. lactis Hsa-LysA2, L. lactis PadA-LysA2, or both protected 6/11 (55%), 6/11 (55%), and 11/12 (91%) animals, respectively, from S. gordonii IE (P < 0.05 versus controls). Protection correlated with the induction of high levels of functional antibodies against both Hsa and PadA that delayed or totally inhibited platelet aggregation by S. gordonii These results support the value of L. lactis as a system for antigen delivery and of Hsa and PadA as promising candidates for a vaccine against VGS-IE.

In Vitro and In Vivo Effectiveness of an Innovative Silver-Copper Nanoparticle Coating of Catheters To Prevent Methicillin-Resistant Staphylococcus aureus Infection.

In this study, silver/copper (Ag/Cu)-coated catheters were investigated for their efficacy in preventing methicillin-resistant Staphylococcus aureus (MRSA) infection in vitro and in vivo Ag and Cu were sputtered (67/33% atomic ratio) on polyurethane catheters by direct-current magnetron sputtering. In vitro, Ag/Cu-coated and uncoated catheters were immersed in phosphate-buffered saline (PBS) or rat plasma and exposed to MRSA ATCC 43300 at 10(4) to 10(8) CFU/ml. In vivo, Ag/Cu-coated and uncoated catheters were placed in the jugular vein of rats. Directly after, MRSA (10(7) CFU/ml) was inoculated in the tail vein. Catheters were removed 48 h later and cultured. In vitro, Ag/Cu-coated catheters preincubated in PBS and exposed to 10(4) to 10(7) CFU/ml prevented the adherence of MRSA (0 to 12% colonization) compared to uncoated catheters (50 to 100% colonization; P < 0.005) and Ag/Cu-coated catheters retained their activity (0 to 20% colonization) when preincubated in rat plasma, whereas colonization of uncoated catheters increased (83 to 100%; P < 0.005). Ag/Cu-coating protection diminished with 10(8) CFU/ml in both PBS and plasma (50 to 100% colonization). In vivo, Ag/Cu-coated catheters reduced the incidence of catheter infection compared to uncoated catheters (57% versus 79%, respectively; P = 0.16) and bacteremia (31% versus 68%, respectively; P < 0.05). Scanning electron microscopy of explanted catheters suggests that the suboptimal activity of Ag/Cu catheters in vivo was due to the formation of a dense fibrin sheath over their surface. Ag/Cu-coated catheters thus may be able to prevent MRSA infections. Their activity might be improved by limiting plasma protein adsorption on their surfaces.

Development of Potent and Selective S. aureus Sortase A Inhibitors Based on Peptide Macrocycles.

Sortases are transpeptidase enzymes that anchor surface proteins, including virulence factors, to the cell wall of Gram-positive bacteria, and they are potential targets for the development of anti-infective agents. While several large compound libraries were searched by high-throughput screening, no high-affinity inhibitors of sortases could be developed to date. Here, we applied phage display to screen billions of peptide macrocycles against sortase A (SrtA) of Staphylococcus aureus (S. aureus). We were able to identify potent and selective inhibitors of SrtA that blocked SrtA-mediated anchoring of synthetic substrates to the surface of live S. aureus cells. A region present in all inhibitory peptides (Leu-Pro-Pro) resembled the natural substrates of SrtA (Leu-Pro-Xaa-Thr-Gly), suggesting that the macrocycles bind to the enzyme's active site and that they form similar molecular contacts as natural substrates. The evolved peptide macrocycles may be used as lead structures for the development of potent peptidomimetic SrtA inhibitors.

Aspirin plus ticlopidine prevented experimental endocarditis due to Enterococcus faecalis and Streptococcus gallolyticus.

Enterococcus faecalis and Streptococcus gallolyticus cause infective endocarditis (IE), which can originate from the continuous release or translocation of low bacterial numbers into the bloodstream. In this context, IE cannot be prevented with antibiotics. We previously demonstrated that aspirin plus ticlopidine protected rats from IE due to S. gordonii and Staphylococcus aureus. Here we showed that aspirin plus ticlopidine significantly reduced vegetation weight and protected 73 and 64% rats (P < 0.005) from IE due to E. faecalis and S. gallolyticus, respectively. These results further support the potential use of aspirin plus ticlopidine for a global prevention of IE in high-risk patients.

Vaccination against Staphylococcus aureus experimental endocarditis using recombinant Lactococcus lactis expressing ClfA or FnbpA.

Staphylococcus aureus is a major cause of serious infections in humans and animals and a vaccine is becoming a necessity. Lactococcus lactis is a non-pathogenic bacterium that can be used as a vector for the delivery of antigens. We investigated the ability of non-living L. lactis heterologously expressing S. aureus clumping factor A (ClfA) and fibronectin-binding protein A (FnbpA), alone or together, to elicit an immune response in rats and protect them from S. aureus experimental infective endocarditis (IE). L. lactis ClfA was used for immunization against S. aureus Newman (expressing ClfA but not FnbpA), while L. lactis ClfA, L. lactis FnbpA, as well as L. lactis ClfA/FnbpA, were used against S. aureus P8 (expressing ClfA and FnbpA). Vaccination of rats with L. lactis ClfA elicited antibodies that inhibited binding of S. aureus Newman to fibrinogen, triggered the production of IL-17A and conferred protection to 13/19 (68%) of the animals from IE (P<0.05). Immunization with L. lactis ClfA, L. lactis FnbpA or L. lactis ClfA/FnbpA also produced antibodies against the target proteins, but these did not prevent binding of S. aureus P8 to fibrinogen or fibronectin and did not protect animals against S. aureus P8 IE. Moreover, immunization with constructs containing FnbpA did not increase IL-17A production. These results indicate that L. lactis is a valuable antigen delivery system able to elicit efficient humoral and cellular responses. However, the most appropriate antigens affording protection against S. aureus IE are yet to be elucidated.

In vivo effect of flucloxacillin in experimental endocarditis caused by mecC-positive staphylococcus aureus showing temperature-dependent susceptibility in vitro.

Methicillin-resistant Staphylococcus aureus (MRSA) carrying the mecC gene (mecC-MRSA) exhibited at 37°C MICs of oxacillin close to those of methicillin-susceptible S. aureus (MSSA). We investigated whether at this temperature, mecC-MRSA strains respond to flucloxacillin treatment like MSSA strains, using a rat model of endocarditis. Flucloxacillin (human-like kinetics of 2 g intravenously every 6 h) cured 80 to 100% of aortic vegetations infected with five different mecC-MRSA strains. These results suggest that mecC-MRSA infections may successfully respond to treatment with ß-lactams.

Prophylaxis of experimental endocarditis with antiplatelet and antithrombin agents: a role for long-term prevention of infective endocarditis in humans?

BACKGROUND: Infective endocarditis (IE) mostly occurs after spontaneous low-grade bacteremia. Thus, IE cannot be prevented by circumstantial antibiotic prophylaxis. Platelet activation following bacterial-fibrinogen interaction or thrombin-mediated fibrinogen-fibrin polymerization is a critical step in vegetation formation. We tested the efficacy of antiplatelet and antithrombin to prevent experimental IE. METHODS: A rat model of experimental IE following prolonged low-grade bacteremia mimicking smoldering bacteremia in humans was used. Prophylaxis with antiplatelets (aspirin, ticlopidine [alone or in combination], eptifibatide, or abciximab) or anticoagulants (antithrombin dabigatran etexilate or anti-vitamin K acenocoumarol) was started 2 days before inoculation with Streptococcus gordonii or Staphylococcus aureus. Valve infection was assessed 24 hours later. RESULTS: Aspirin plus ticlopidine, as well as abciximab, protected 45%-88% of animals against S. gordonii and S. aureus IE (P < .05). Dabigatran etexilate protected 75% of rats against IE due to S. aureus (P < .005) but failed to protect against S. gordonii (<30% protection). Acenocoumarol was ineffective. CONCLUSIONS: Antiplatelet and direct antithrombin agents may be useful in the prophylaxis of IE in humans. In particular, the potential dual benefit of dabigatran etexilate might be reconsidered for patients with prosthetic valves, who require life-long anticoagulation and in whom S. aureus IE is associated with high mortality.