Risk scores' performance and their impact on operative decision-making in left-sided endocarditis: a cohort study.

The accuracy of contemporary risk scores in predicting perioperative mortality in infective endocarditis (IE) remains controversial. The aim is to evaluate the performance of existent mortality risk scores for cardiovascular surgery in IE and the impact on operability at high-risk thresholds. A single-center retrospective review of adult patients diagnosed with acute left-sided IE undergoing surgery from May 2014 to August 2019 (n = 142) was done. Individualized risk calculation was obtained according to the available mortality risk scores: EuroScore I and II, PALSUSE, Risk-E, Costa, De Feo-Cotrufo, AEPEI, STS-risk, STS-IE, APORTEI, and ICE-PCS scores. A cross-validation analysis was performed on the score with the best area under the curve (AUC). The 30-day survival was 96.5% (95%CI 91-98%). The score with worse area under the curve (AUC = 0.6) was the STS-IE score, while the higher was for the RISK-E score (AUC = 0.89). The AUC of the majority of risk scores suggested acceptable performance; however, statistically significant differences in expected versus observed mortalities were common. The cross-validation analysis showed that a large number of survivors (> 75%) would not have been operated if arbitrary high-risk threshold estimates had been used to deny surgery. The observed mortality in our cohort is significantly lower than is predicted by contemporary risk scores. Despite the reasonable numeric performance of the analyzed scores, their utility in judging the operability of a given patient remains questionable, as demonstrated in the cross-validation analysis. Future guidelines may advise that denial of surgery should only follow a highly experienced Endocarditis Team evaluation.

Impact of High-Level Daptomycin Resistance in the Streptococcus mitis Group on Virulence and Survivability during Daptomycin Treatment in Experimental Infective Endocarditis.

Among the viridans group streptococci, the Streptococcus mitis group is the most common cause of infective endocarditis. These bacteria have a propensity to be ß-lactam resistant, as well as to rapidly develop high-level and durable resistance to daptomycin (DAP). We compared a parental, daptomycin-susceptible (DAPs) S. mitis/S. oralis strain and its daptomycin-resistant (DAPr) variant in a model of experimental endocarditis in terms of (i) their relative fitness in multiple target organs in this model (vegetations, kidneys, spleen) when animals were challenged individually and in a coinfection strategy and (ii) their survivability during therapy with daptomycin-gentamicin (an in vitro combination synergistic against the parental strain). The DAPr variant was initially isolated from the cardiac vegetations of animals with experimental endocarditis caused by the parental DAPs strain following treatment with daptomycin. The parental strain and the DAPr variant were comparably virulent when animals were individually challenged. In contrast, in the coinfection model without daptomycin therapy, at both the 106- and 107-CFU/ml challenge inocula, the parental strain outcompeted the DAPr variant in all target organs, especially the kidneys and spleen. When the animals in the coinfection model of endocarditis were treated with DAP-gentamicin, the DAPs strain was completely eliminated, while the DAPr variant persisted in all target tissues. These data underscore that the acquisition of DAPr in S. mitis/S. oralis does come at an intrinsic fitness cost, although this resistance phenotype is completely protective against therapy with a potentially synergistic DAP regimen.

Early in vitro development of daptomycin non-susceptibility in high-level aminoglycoside-resistant Enterococcus faecalis predicts the efficacy of the combination of high-dose daptomycin plus ampicillin in an in vivo model of experimental endocarditis.

Background: Previous studies showed development of daptomycin non-susceptibility (DNS: MIC >4 mg/L) in Enterococcus faecalis infections. However, no studies have assessed the efficacy of the combination of daptomycin/ampicillin against E. faecalis strains developing DNS in the experimental endocarditis (EE) model. Objectives: To assess the in vitro and in vivo efficacy of daptomycin at 10 mg/kg/day, daptomycin/ampicillin and ampicillin/ceftriaxone against two high-level aminoglycoside-resistant E. faecalis strains, one developing DNS after in vitro exposure to daptomycin and another that did not (DS). Methods: Subculture of 82 E. faecalis strains from patients with endocarditis with daptomycin MICs, time-kill and in vivo experiments using the EE model. Results: 33% of the strains (27 of 82) displayed DNS after subculture with daptomycin. Daptomycin MIC rose from 0.5-2 to 8-16 mg/L. In time-kill experiments, when using a high inoculum (10 8 cfu/mL), daptomycin/ampicillin was synergistic for one-third of DS strains and none of DNS strains, while ampicillin/ceftriaxone retained synergy in all cases. In the EE model, daptomycin did not significantly reduce cfu/g from vegetations compared with control against either strain, while daptomycin/ampicillin reduced significantly more cfu/g than daptomycin against the DS strain, but not against the DNS strain [2.9 (2.0-4.1) versus 6.1 (4.5-8.0); P = 0.002]. Ampicillin/ceftriaxone was synergistic and bactericidal against both strains, displaying the same activity as daptomycin/ampicillin against the DS strain. Conclusions: Performance of an Etest for daptomycin MIC after subculture with daptomycin inhibitory doses on strains of high-level aminoglycoside-resistant E. faecalis endocarditis may be an easy test to predict the in vivo efficacy of daptomycin/ampicillin.

Fosfomycin plus ß-Lactams as Synergistic Bactericidal Combinations for Experimental Endocarditis Due to Methicillin-Resistant and Glycopeptide-Intermediate Staphylococcus aureus.

The urgent need of effective therapies for methicillin-resistant Staphylococcus aureus (MRSA) infective endocarditis (IE) is a cause of concern. We aimed to ascertain the in vitro and in vivo activity of the older antibiotic fosfomycin combined with different beta-lactams against MRSA and glycopeptide-intermediate-resistant S. aureus (GISA) strains. Time-kill tests with 10 isolates showed that fosfomycin plus imipenem (FOF+IPM) was the most active evaluated combination. In an aortic valve IE model with two strains (MRSA-277H and GISA-ATCC 700788), the following intravenous regimens were compared: fosfomycin (2 g every 8 h [q8h]) plus imipenem (1 g q6h) or ceftriaxone (2 g q12h) (FOF+CRO) and vancomycin at a standard dose (VAN-SD) (1 g q12h) and a high dose (VAN-HD) (1 g q6h). Whereas a significant reduction of MRSA-227H load in the vegetations (veg) was observed with FOF+IPM compared with VAN-SD (0 [interquartile range [IQR], 0 to 1] versus 2 [IQR, 0 to 5.1] log CFU/g veg; P = 0.01), no statistical differences were found with VAN-HD. In addition, FOF+IPM sterilized more vegetations than VAN-SD (11/15 [73%] versus 5/16 [31%]; P = 0.02). The GISA-ATCC 700788 load in the vegetations was significantly lower after FOF+IPM or FOF+CRO treatment than with VAN-SD (2 [IQR, 0 to 2] and 0 [IQR, 0 to 2] versus 6.5 [IQR, 2 to 6.9] log CFU/g veg; P < 0.01). The number of sterilized vegetations after treatment with FOF+CRO was higher than after treatment with VAN-SD or VAN-HD (8/15 [53%] versus 4/20 [20%] or 4/20 [20%]; P = 0.03). To assess the effect of FOF+IPM on penicillin binding protein (PBP) synthesis, molecular studies were performed, with results showing that FOF+IPM treatment significantly decreased PBP1, PBP2 (but not PBP2a), and PBP3 synthesis. These results allow clinicians to consider the use of FOF+IPM or FOF+CRO to treat MRSA or GISA IE.

Antistaphylococcal ß-Lactams versus Vancomycin for Treatment of Infective Endocarditis Due to Methicillin-Susceptible Coagulase-Negative Staphylococci: a Prospective Cohort Study from the International Collaboration on Endocarditis.

The phenotypic expression of methicillin resistance among coagulase-negative staphylococci (CoNS) is heterogeneous regardless of the presence of the mecA gene. The potential discordance between phenotypic and genotypic results has led to the use of vancomycin for the treatment of CoNS infective endocarditis (IE) regardless of methicillin MIC values. In this study, we assessed the outcome of methicillin-susceptible CoNS IE among patients treated with antistaphylococcal ß-lactams (ASB) versus vancomycin (VAN) in a multicenter cohort study based on data from the International Collaboration on Endocarditis (ICE) Prospective Cohort Study (PCS) and the ICE-Plus databases. The ICE-PCS database contains prospective data on 5,568 patients with IE collected between 2000 and 2006, while the ICE-Plus database contains prospective data on 2,019 patients with IE collected between 2008 and 2012. The primary endpoint was in-hospital mortality. Secondary endpoints were 6-month mortality and survival time. Of the 7,587 patients in the two databases, there were 280 patients with methicillin-susceptible CoNS IE. Detailed treatment and outcome data were available for 180 patients. Eighty-eight patients received ASB, while 36 were treated with VAN. In-hospital mortality (19.3% versus 11.1%; P = 0.27), 6-month mortality (31.6% versus 25.9%; P = 0.58), and survival time after discharge (P = 0.26) did not significantly differ between the two cohorts. Cox regression analysis did not show any significant association between ASB use and the survival time (hazard ratio, 1.7; P = 0.22); this result was not affected by adjustment for confounders. This study provides no evidence for a difference in outcome with the use of VAN versus ASB for methicillin-susceptible CoNS IE.

Comparison of six generic vancomycin products for treatment of methicillin-resistant Staphylococcus aureus experimental endocarditis in rabbits.

Concerns have recently emerged about the potency and the quality of generic vancomycin (VAN) products approved for use in humans, based on experiments in a neutropenic mouse thigh infection model. However, other animal models may be more appropriate to decipher the bactericidal activities of VAN generics in vivo and to predict their efficacy in humans. We aimed to compare the bactericidal activities of six generic VAN products currently used in France (Mylan and Sandoz), Spain (Hospira), Switzerland (Teva), and the United States (Akorn-Strides and American Pharmaceutical Products [APP]) in a rabbit model of aortic valve endocarditis induced by 8 × 10(7) CFU of methicillin-resistant Staphylococcus aureus (MRSA) strain COL (VAN MIC, 1.5 µg/ml). In vitro, there were no significant differences in the time-kill curve studies performed with the six generic VAN products. Ten rabbits in each group were treated with intravenous (i.v.) VAN, 60 mg/kg of body weight twice a day (b.i.d.) for 4 days. Mean peak serum VAN levels, measured 45 min after the last injection, ranged from 35.5 (APP) to 45.9 µg/ml (Teva). Mean trough serum VAN levels, measured 12 h after the last injection, ranged from 2.3 (Hospira) to 9.2 (APP) µg/ml. All generic VAN products were superior to controls (no treatment) in terms of residual organisms in vegetations (P < 0.02 for each comparison) and in the spleen (P < 0.005 for each comparison). Pairwise comparisons of generic VAN products found no significant differences. In conclusion, a stringent MRSA endocarditis model found no significant differences in the bactericidal activities of six generic VAN products currently used in Europe and America.

Daptomycin is effective for treatment of experimental endocarditis due to methicillin-resistant and glycopeptide-intermediate Staphylococcus epidermidis.

This study evaluated the daptomycin activity against two methicillin-resistant Staphylococcus epidermidis (MRSE) clinical isolates with different vancomycin susceptibilities: MRSE-375, with a vancomycin MIC of 2 microg/ml, and NRS6, a glycopeptide-intermediate S. epidermidis (GISE) strain with a vancomycin MIC of 8 microg/ml. The in vivo activity of daptomycin at two different doses (standard dose [SD-daptomycin], 6 mg/kg of body weight/day intravenously [i.v.]; high dose [HD-daptomycin], 10 mg/kg/day i.v.) was evaluated in a rabbit model of infective endocarditis and compared with that of a standard dose of vancomycin (SD-vancomycin; 1 g i.v. every 12 h) for 2 days. For the MRSE-375 strain, high-dose vancomycin (HD-vancomycin; 1 g i.v. every 6 h) was also studied. For MRSE-375, SD- and HD-daptomycin therapy sterilized significantly more vegetations than SD-vancomycin therapy (9/15 [60%] and 11/15 [73%] vegetations, respectively, versus 3/16 [19%] vegetations; P = 0.02 and P = 0.002, respectively). HD-daptomycin sterilized more vegetations than HD-vancomycin (11/15 [73%] versus 5/15 [33%] vegetations; P = 0.03) and was more effective than SD- and HD-vancomycin in reducing the density of bacteria in valve vegetations (0 log(10) CFU/g vegetation [interquartile range {IQR}, 0 to 1 log(10) CFU/g vegetation] versus 2 log(10) CFU/g vegetation [IQR, 2 to 2 log(10) CFU/g vegetation] and 2 log(10) CFU/g vegetation [IQR, 0 to 2.8 log(10) CFU/g vegetation]; P = 0.002 and P = 0.01, respectively). For the NRS6 strain, SD- and HD-daptomycin were significantly more effective than vancomycin in reducing the density of bacteria in valve vegetations (3.7 log(10) CFU/g vegetation [IQR, 2 to 6 log(10) CFU/g vegetation] versus 7.1 log(10) CFU/g vegetation [IQR, 5.2 to 8.5 log(10) CFU/g vegetation]; P = 0.02). In all treatment arms, isolates recovered from vegetations remained susceptible to daptomycin and vancomycin and had the same MICs. In conclusion, daptomycin at doses of 6 mg/kg/day or 10 mg/kg/day is more effective than vancomycin for the treatment of experimental endocarditis due to MRSE and GISE.

Addition of gentamicin or rifampin does not enhance the effectiveness of daptomycin in treatment of experimental endocarditis due to methicillin-resistant Staphylococcus aureus.

This study evaluated the activity of daptomycin combined with either gentamicin or rifampin against three methicillin-resistant Staphylococcus aureus (MRSA) clinical isolates in vitro and one isolate in vivo against a representative strain (MRSA-572). Time-kill experiments showed that daptomycin was bactericidal against these strains at concentrations over the MIC. Daptomycin at sub-MIC concentrations plus gentamicin at 1x and 2x the MIC yielded synergy, while the addition of rifampin at 2 to 4 microg/ml resulted in indifference (two strains) or antagonism (one strain). The in vivo activity of daptomycin (6 mg/kg of body weight once a day) was evaluated +/- gentamicin (1 mg/kg intravenously [i.v.] every 8 h [q8h]) or rifampin (300 mg i.v. q8h) in a rabbit model of infective endocarditis by simulating human pharmacokinetics. Daptomycin plus gentamicin (median, 0 [interquartile range, 0 to 2] log10 CFU/g vegetation) was as effective as daptomycin alone (0 [0 to 2] log10 CFU/g vegetation) in reducing the density of bacteria in valve vegetations (P = 0.83), and both were more effective than daptomycin plus rifampin (3 [2 to 3.5] log10 CFU/g vegetation; P < 0.05) for the strain studied. In addition, daptomycin sterilized a ratio of vegetations that was similar to that of daptomycin plus gentamicin (10/15 [67%] versus 9/15 [60%]; P = 0.7), and both regimens did so more than daptomycin plus rifampin (3/15 [20%]; P = 0.01 and P = 0.02, respectively). No statistical difference was noted between daptomycin plus gentamicin and daptomycin alone for MRSA treatment. In the combination arm, all isolates from vegetations remained susceptible to daptomycin, gentamicin, and rifampin. Sixty-one percent of the isolates (8/13) acquired resistance to rifampin during monotherapy. In the daptomycin arm, resistance was detected in only one case, in which the daptomycin MIC rose to 2 microg/ml among the recovered bacteria. In conclusion, the addition of gentamicin or rifampin does not enhance the effectiveness of daptomycin in the treatment of experimental endocarditis due to MRSA.

Influence of vancomycin minimum inhibitory concentration on the outcome of methicillin-susceptible Staphylococcus aureus left-sided infective endocarditis treated with antistaphylococcal ß-lactam antibiotics: a prospective cohort study by the International Collaboration on Endocarditis.

OBJECTIVES: Left-sided methicillin-susceptible Staphylococcus aureus (MSSA) endocarditis treated with cloxacillin has a poorer prognosis when the vancomycin minimum inhibitory concentration (MIC) is ≥1.5 mg/L. We aimed to validate this using the International Collaboration on Endocarditis cohort and to analyse whether specific genetic characteristics were associated with a high vancomycin MIC (≥1.5 mg/L) phenotype. METHODS: All patients with left-sided MSSA infective endocarditis treated with antistaphylococcal ß-lactam antibiotics between 2000 and 2006 with available isolates were included. Vancomycin MIC was determined by Etest as either high (≥1.5 mg/L) or low (<1.5 mg/L). Isolates underwent spa typing to infer clonal complexes and multiplex PCR for identifying virulence genes. Univariate analysis was performed to evaluate the association between in-hospital and 1-year mortality, and vancomycin MIC phenotype. RESULTS: Sixty-two cases met the inclusion criteria. Vancomycin MIC was low in 28 cases (45%) and high in 34 cases (55%). No significant differences in patient demographic data or characteristics of infection were observed between patients with infective endocarditis due to high and low vancomycin MIC isolates. Isolates with high and low vancomycin MIC had similar distributions of virulence genes and clonal lineages. In-hospital and 1-year mortality did not differ significantly between the two groups (32% (9/28) vs. 27% (9/34), p 0.780; and 43% (12/28) vs. 29% (10/34), p 0.298, for low and high vancomycin MIC respectively). CONCLUSIONS: In this international cohort of patients with left-sided MSSA endocarditis treated with antistaphylococcal ß-lactams, vancomycin MIC phenotype was not associated with patient demographics, clinical outcome or virulence gene repertoire.

Enterococcal endocarditis revisited.

The Enterococcus species is the third main cause of infective endocarditis (IE) worldwide, and it is gaining relevance, especially among healthcare-associated cases. Patients with enterococcal IE are older and have more comorbidities than other types of IE. Classical treatment options are limited due to the emergence of high-level aminoglycosides resistance (HLAR), vancomycin resistance and multidrug resistance in some cases. Besides, few new antimicrobial alternatives have shown real efficacy, despite some of them being recommended by major guidelines (including linezolid and daptomycin). Ampicillin plus ceftriaxone 2 g iv./12 h is a good option for Enterococcus faecalis IE caused by HLAR strains, but randomized clinical trials are essential to demonstrate its efficacy for non-HLAR EFIE and to compare it with ampicillin plus short-course gentamicin. The main mechanisms of resistance and treatment options are also reviewed for other enterococcal species.

Native valve endocarditis due to Candida glabrata treated without valvular replacement: a potential role for caspofungin in the induction and maintenance treatment.

Conventional antifungal therapy for fungal endocarditis has been associated with a poor cure rate. Therefore, combined medical and surgical therapy has been recommended. However, new potent antifungal agents, such as echinocandins, could increase the medical options and, in some cases, avoid the need for surgery. We report a case of Candida endocarditis treated successfully without valve replacement with intravenous liposomal amphotericin B (total dose, 4 g) and intravenous caspofungin (a 100-mg loading dose followed by 50 mg per day for 8 weeks) as induction therapy and intravenous caspofungin (100 mg 3 times per week for 12 weeks) as maintenance therapy.

Changes in the treatment of Enterococcus faecalis infective endocarditis in Spain in the last 15 years: from ampicillin plus gentamicin to ampicillin plus ceftriaxone.

The aim of this study was to assess changes in antibiotic resistance, epidemiology and outcome among patients with Enterococcus faecalis infective endocarditis (EFIE) and to compare the efficacy and safety of the combination of ampicillin and gentamicin (A+G) with that of ampicillin plus ceftriaxone (A+C). The study was a retrospective analysis of a prospective cohort of EFIE patients treated in our centre from 1997 to 2011. Thirty patients were initially treated with A+G (ampicillin 2 g/4 h and gentamicin 3 mg/kg/day) and 39 with A+C (ampicillin 2 g/4 h and ceftriaxone 2 g/12 h) for 4-6 weeks. Increased rates of high-level aminoglycoside resistance (HLAR; gentamicin MIC ≥512 mg/L, streptomycin MIC ≥1024 mg/L or both) were observed in recent years (24% in 1997-2006 and 49% in 2007-2011; p 0.03). The use of A+C increased over time: 1997-2001, 4/18 (22%); 2002-2006, 5/16 (31%); 2007-2011, 30/35 (86%) (p <0.001). Renal failure developed in 65% of the A+G group and in 34% of the A+C group (p 0.014). Thirteen patients (43%) in the A+G group had to discontinue treatment, whereas only one patient (3%) treated with A+C had to discontinue treatment (p <0.001). Only development of heart failure and previous chronic renal failure were independently associated with 1-year mortality, while the individual antibiotic regimen (A+C vs. A+G) did not affect outcome (OR, 0.7; 95% CI, 0.2-2.2; p 0.549). Our study shows that the prevalence of HLAR EFIE has increased significantly in recent years and that alternative treatment with A+C is safer than A+G, with similar clinical outcomes, although the sample size is too small to draw firm conclusions. Randomized controlled studies are needed to confirm these results.

In vitro activity of several antimicrobial peptides against colistin-susceptible and colistin-resistant Acinetobacter baumannii.

At present, colistin is among the few antibiotics effective against Acinetobacter baumannii clinical isolates. However, in the last few years, colistin-resistant A. baumannii strains have been isolated. Therefore, antibiotics effective against these usually pan-resistant colistin-resistant A. baumannii strains are required. The main objective of this study was to analyse the activity of 15 peptides against colistin-susceptible and colistin-resistant A. baumannii. The MICs were determined by microdilution. Among these 15 antimicrobial peptides (AMPs), melittin, indolicidin and mastoparan showed good activity against both colistin-susceptible and colistin-resistant A. baumannii. Further studies of mastoparan with time-killing curves showed bactericidal activity at MIC ×8 for both colistin-susceptible and colistin-resistant A. baumannii. In conclusion, mastoparan may be a potential alternative for the treatment of colistin-resistant A. baumannii infections.

Staphylococcus lugdunensis infective endocarditis: description of 10 cases and analysis of native valve, prosthetic valve, and pacemaker lead endocarditis clinical profiles.

OBJECTIVE: To evaluate the incidence and the clinical and echocardiographic features of infective endocarditis (IE) caused by Staphylococcus lugdunensis and to identify the prognostic factors of surgery and mortality in this disease. DESIGN: Prospective cohort study. SETTING: Study at two centres (a tertiary care centre and a community hospital). PATIENTS: 10 patients with IE caused by S lugdunensis in 912 consecutive patients with IE between 1990 and 2003. METHODS: Prospective study of consecutive patients carried out by the multidisciplinary team for diagnosis and treatment of IE from the study institutions. English, French, and Spanish literature was searched by computer under the terms "endocarditis" and "Staphylococcus lugdunensis" published between 1989 and December 2003. MAIN OUTCOME MEASURES: Patient characteristics, echocardiographic findings, required surgery, and prognostic factors of mortality in left sided cases of IE. RESULTS: 10 cases of IE caused by S lugdunensis were identified at our institutions, representing 0.8% (four of 467), 1.5% (two of 135), and 7.8% (four of 51) of cases of native valve, prosthetic valve, and pacemaker lead endocarditis in the non-drug misusers. Native valve IE was present in four patients (two aortic, one mitral, and one pulmonary), prosthetic valve aortic IE in two patients, and pacemaker lead IE in the other four patients. All patients with left sided IE had serious complications (heart failure, periannular abscess formation, or shock) requiring surgery in 60% (three of five patients) of cases with an overall mortality rate of 80% (four of five patients). All patients with pacemaker IE underwent combined medical treatment and surgery, and mortality was 25% (one patient). In total 59 cases of IE caused by S lugdunensis were identified in a review of the literature. The combined analysis of these 69 cases showed that native valve IE (53 patients, 77%) is characterised by mitral valve involvement and frequent complications such as heart failure, abscess formation, and embolism. Surgery was needed in 51% of cases and mortality was 42%. Prosthetic valve endocarditis (nine of 60, 13%) predominated in the aortic position and was associated with abscess formation, required surgery, and high mortality (78%). Pacemaker lead IE (seven of 69, 10%) is associated with a better prognosis when antibiotic treatment is combined with surgery. CONCLUSIONS: S lugdunensis IE is an uncommon cause of IE, involving mainly native left sided valves, and it is characterised by an aggressive clinical course. Mortality in left sided native valve IE is high but the prognosis has improved in recent years. Surgery has improved survival in left sided IE and, therefore, early surgery should always be considered. Prosthetic valve S lugdunensis IE carries an ominous prognosis.