Effect of Lactoferrin on Clinical Outcomes of Hospitalized Patients with COVID-19: The LAC Randomized Clinical Trial.

As lactoferrin is a nutritional supplement with proven antiviral and immunomodulatory abilities, it may be used to improve the clinical course of COVID-19. The clinical efficacy and safety of bovine lactoferrin were evaluated in the LAC randomized double-blind placebo-controlled trial. A total of 218 hospitalized adult patients with moderate-to-severe COVID-19 were randomized to receive 800 mg/die oral bovine lactoferrin (n = 113) or placebo (n = 105), both given in combination with standard COVID-19 therapy. No differences in lactoferrin vs. placebo were observed in the primary outcomes: the proportion of death or intensive care unit admission (risk ratio of 1.06 (95% CI 0.63-1.79)) or proportion of discharge or National Early Warning Score 2 (NEWS2) ≤ 2 within 14 days from enrollment (RR of 0.85 (95% CI 0.70-1.04)). Lactoferrin showed an excellent safety and tolerability profile. Even though bovine lactoferrin is safe and tolerable, our results do not support its use in hospitalized patients with moderate-to-severe COVID-19.

Prevalencia de enfermedad colorrectal en la endocarditis infecciosa por Enterococcus faecalis: resultados de un estudio multicéntrico observacional / Prevalence of colorectal disease in Enterococcus faecalis infective endocarditis: results of an observational multicenter study

INTRODUCCIÓN Y OBJETIVOS: El objetivo del estudio fue determinar la prevalencia de patología colorrectal en los pacientes con endocarditis infecciosa por Enterococcus faecalis (EIEF). MÉTODOS: Se realizó un estudio observacional, retrospectivo y multicéntrico en 4 hospitales de referencia. Se incluyeron todos los episodios consecutivos de EIEF definitivas en adultos desde el momento en que se empezó a realizar una colonoscopia por protocolo en cada centro participante hasta octubre de 2018. Se recogieron los hallazgos endoscópicos de patología colorrectal potencialmente causante de una bacteriemia. RESULTADOS: Se incluyeron 103 pacientes con EIEF; 83 (81%) eran varones, la edad mediana era 76 [rango intercuartílico, 67-82] años, y la mediana del índice de Charlson ajustado por edad fue 5 [rango intercuartílico, 4-7]. El presunto origen de la infección fue desconocido en 63 (61%), urinario en 20 (19%), digestivo en 13 (13%), bacteriemia de catéter en 5 (5%), y otros en 2 (2%). En 78 (76%) pacientes se realizó una colonoscopia, y en 47 (60%) había hallazgos endoscópicos que indicaban un potencial foco de bacteriemia. Treinta y nueve (83%) tenían una enfermedad colorrectal neoplásica, y 8 (17%) no neoplásica. De los 45 pacientes con puerta de entrada desconocida y colonoscopia, un posible origen gastrointestinal se identificó en 64%. En el subgrupo de 25 con foco de entrada conocido y colonoscopia, excluyendo aquellos con enfermedad colorrectal ya previamente diagnosticada, 44% tenían patología colorrectal. CONCLUSIONES: Realizar una colonoscopia en la EIEF, sin tener en cuenta la puerta de entrada, puede ayudar a diagnosticar la enfermedad colorrectal en estos pacientes y evitar una nueva bacteriemia (y eventualmente endocarditis infecciosa) por el mismo u otro microorganismo

INTRODUCTION AND OBJECTIVES: The aim of this study was to determine the prevalence of colorectal disease in Enterococcus faecalis infective endocarditis (EFIE) patients. METHODS: An observational, retrospective, multicenter study was performed at 4 referral centers. From the moment that a colonoscopy was systematically performed in EFIE in each participating hospital until October 2018, we included all consecutive episodes of definite EFIE in adult patients. The outcome was an endoscopic finding of colorectal disease potentially causing bacteremia. RESULTS: A total of 103 patients with EFIE were included; 83 (81%) were male, the median age was 76 [interquartile range 67-82] years, and the median age-adjusted Charlson comorbidity index was 5 [interquartile range, 4-7]. The presumed sources of infection were unknown in 63 (61%), urinary in 20 (19%), gastrointestinal in 13 (13%), catheter-related bacteremia in 5 (5%), and others in 2 (2%). Seventy-eight patients (76%) underwent a colonoscopy, and 47 (60%) had endoscopic findings indicating a potential source of bacteremia. Thirty-nine patients (83%) had a colorectal neoplastic disease, and 8 (17%) a nonneoplastic disease. Of the 45 with an unknown portal of entry who underwent a colonoscopy, gastrointestinal origin was identified in 64%. In the subgroup of 25 patients with a known source of infection and a colonoscopy, excluding those with previously diagnosed colorectal disease, 44% had colorectal disease. CONCLUSIONS: Performing a colonoscopy in all EFIE patients, irrespective of the presumed source of infection, could be helpful to diagnose colorectal disease in these patients and to avoid a new bacteremia episode (and eventually infective endocarditis) by the same or a different microorganism

Comparative Population Pharmacokinetics of Darunavir in SARS-CoV-2 Patients vs. HIV Patients: The Role of Interleukin-6.

BACKGROUND: Darunavir is an anti-HIV protease inhibitor repurposed for SARS-CoV-2 treatment. OBJECTIVE: The aim of this study was to assess the population pharmacokinetics of darunavir in SARS-CoV-2 patients compared with HIV patients. METHODS: Two separate models were created by means of a nonlinear mixed-effect approach. The influence of clinical covariates on each basic model was tested and the association of significant covariates with darunavir parameters was assessed at multivariate regression and classification and regression tree (CART) analyses. Monte Carlo simulation assessed the influence of covariates on the darunavir concentration versus time profile. RESULTS: A one-compartment model well-described darunavir concentrations in both groups. In SARS-CoV-2 patients (n = 30), interleukin (IL)-6 and body surface area were covariates associated with darunavir oral clearance (CL/F) and volume of distribution (Vd), respectively; no covariates were identified in HIV patients (n = 25). Darunavir CL/F was significantly lower in SARS-CoV-2 patients compared with HIV patients (4.1 vs. 10.3 L/h; p < 0.001). CART analysis found that an IL-6 level of 18 pg/mL may split the SARS-CoV-2 population in patients with low versus high darunavir CL/F (mean ± standard deviation 3.47 ± 1.90 vs. 8.03 ± 3.24 L/h; proportion of reduction in error = 0.46). Median (interquartile range) darunavir CL/F was significantly lower in SARS-CoV-2 patients with IL-6 levels ≥ 18 pg/mL than in SARS-CoV-2 patients with IL-6 levels < 18 pg/mL or HIV patients (2.78 [2.16-4.47] vs. 7.24 [5.88-10.38] vs. 9.75 [8.45-13.79] L/h, respectively; p < 0.0001). Increasing IL-6 levels affected darunavir concentration versus time simulated profiles. We hypothesized that increases in IL-6 levels associated with severe SARS-CoV-2 disease may downregulate the cytochrome P450 (CYP) 3A4-mediated metabolism of darunavir. CONCLUSIONS: This is a proof-of-concept of SARS-CoV-2 disease-drug interactions, and may support the need for optimal dose selection of sensitive CYP3A4 substrates in severe SARS-CoV-2 patients.

Salvage heart transplantation for Mycoplasma hominis prosthetic valve endocarditis: A case report and review of the literature.

Heart transplantation (HT) has been rarely performed in patients with infective endocarditis (IE) and is considered a "last resort" procedure. Orthotropic HT with bicaval technique was performed in a man with culture-negative endocarditis. Mycoplasma hominis was later detected using 16S ribosomal DNA PCR from surgically removed valve tissue. Literature review and previous results are summarized. HT may be considered as salvage treatment in selected patients with intractable IE. In cases when there is no growth in culture, 16S ribosomal DNA PCR sequencing can be used to identify the pathogen in excised valvular tissue. Mycoplasma spp. is extremely uncommon and difficult to diagnose cause of infective endocarditis (IE). There are no proposed or defined criteria for heart transplantation (HT) in patients with refractory IE, and HT has been rarely performed in this setting. We report a case of M hominis prosthetic valve endocarditis diagnosed by 16S ribosomal DNA PCR in a patient who underwent a salvage HT. We reviewed in the literature other cases of IE caused by Mycoplasma spp.

Prevalence of colorectal disease in Enterococcus faecalis infective endocarditis: results of an observational multicenter study.

INTRODUCTION AND OBJECTIVES: The aim of this study was to determine the prevalence of colorectal disease in Enterococcus faecalis infective endocarditis (EFIE) patients. METHODS: An observational, retrospective, multicenter study was performed at 4 referral centers. From the moment that a colonoscopy was systematically performed in EFIE in each participating hospital until October 2018, we included all consecutive episodes of definite EFIE in adult patients. The outcome was an endoscopic finding of colorectal disease potentially causing bacteremia. RESULTS: A total of 103 patients with EFIE were included; 83 (81%) were male, the median age was 76 [interquartile range 67-82] years, and the median age-adjusted Charlson comorbidity index was 5 [interquartile range 4-7]. The presumed sources of infection were unknown in 63 (61%), urinary in 20 (19%), gastrointestinal in 13 (13%), catheter-related bacteremia in 5 (5%), and others in 2 (2%). Seventy-eight patients (76%) underwent a colonoscopy, and 47 (60%) had endoscopic findings indicating a potential source of bacteremia. Thirty-nine patients (83%) had a colorectal neoplastic disease, and 8 (17%) a nonneoplastic disease. Of the 45 with an unknown portal of entry who underwent a colonoscopy, gastrointestinal origin was identified in 64%. In the subgroup of 25 patients with a known source of infection and a colonoscopy, excluding those with previously diagnosed colorectal disease, 44% had colorectal disease. CONCLUSIONS: Performing a colonoscopy in all EFIE patients, irrespective of the presumed source of infection, could be helpful to diagnose colorectal disease in these patients and to avoid a new bacteremia episode (and eventually infective endocarditis) by the same or a different microorganism.

Should High-dose Daptomycin be an Alternative Treatment Regimen for Enterococcal Endocarditis?

INTRODUCTION: Previous series on the use of daptomycin in enterococcal infective endocarditis (EIE) have shown various outcomes, including higher mortality rates. We analyzed the effectiveness of high-dose daptomycin for the treatment of EIE. METHODS: We performed a prospective study from 2010 to 2018 in a referral center in patients with native (NVE) and prosthetic valve endocarditis (PVE) due to Enterococcus spp. The standard high-dose daptomycin at our institution is 10-12 mg/kg/day (CLCr > 30 ml/min). We compared the efficacy of a daptomycin-based regimen (DBR) versus daptomycin-sparing regimen (DSR) and daptomycin monotherapy versus combination therapy. Primary endpoints of the study were evaluation of risk factors associated with 30-day mortality and failure at end of therapy. RESULTS: We collected 43 EIE cases; 29 were NVE (67.4%). Overall, 16 (37.2%) were treated with DBR, mainly with combination regimens (11, 68.7%), in the majority of cases in association with ß-lactam (7, 43.7%). The mean administered dose of daptomycin was 10.125 mg/kg/day (range 8-12 mg/kg/day). Overall, patients treated with DBR compared with patients treated with DSR had no higher mortality rates and/or failure at end of therapy (6.2% vs. 22. 2%; P 0.41 and MICs 0.25-2 mg/l, 6.2% vs. 3.7%; P 1.0). In the sub-group of patients with NVE and PVE treated with DBR and DSR, no difference was found regarding the primary endpoints on the single or combined use of daptomycin. CONCLUSION: Our findings suggest that high-dose daptomycin might be used as an alternative treatment regimen in EIE.

Daptomycin-containing regimens for treatment of Gram-positive endocarditis.

PURPOSE: Infective endocarditis (IE) is a severe infection, and a leading cause of mortality and morbidity. Due to its favourable microbiological and pharmacological characteristics, daptomycin is routinely used in clinical practice for treating IE. METHODS: A prospective study was conducted at a large tertiary-care hospital in Italy over an 8-year period (January 2010-January 2018) on all patients with native-valve endocarditis (NVE) or prosthetic-valve endocarditis (PVE) caused by Gram-positive bacteria. Patients with NVE and PVE treated with regimens that included daptomycin at different dosages (daptomycin-containing regimens, DCR) were compared with those treated with non-DCR. Primary endpoints of the study were 30-day mortality and clinical treatment failure. RESULTS: During the study period, 327 patients with Gram-positive NVE (n = 224, 68.8%) or PVE (n = 103, 31.2%) were analysed. Eighty-four (37.5%) NVE patients were treated with daptomycin, alone (59.9%) or with other antimicrobials. Most PVE patients (n = 61, 58%) were treated with a DCR, which always consisted of daptomycin plus other drugs. Among PVE patients, treatment with a DCR was associated with lower 30-day mortality than treatment with a non-DCR (6.5% vs. 38%, P < 0.001). Among NVE patients treated with DCRs, risk factors for 30-day mortality were streptococcal infections, persistent bacteraemia, and standard-dose (4-6 mg/kg) rather than high-dose daptomycin therapy. Overall, surgical treatment of IE and DCR were associated with clinical success and 30-day survival. CONCLUSIONS: Compared with non-DCRs, using single-drug or multiple-drug DCRs is associated with lower 30-day mortality in PVE, but with higher 30-day mortality in NVE at approved doses and in a subgroup of streptococcal IE.

Risk scores and surgery for infective endocarditis: in search of a good predictive score.

Objectives: To evaluate scoring systems that have been created to predict the risk of death post-surgery in infective endocarditis (IE). Design: Eight scores - (1) The Society of Thoracic Surgery (STS) risk score for IE, (2) De Feo score, (3) PALSUSE score (prosthetic valve, age ≥70, large intracardiac destruction, Staphylococcus spp, urgent surgery, sex [female], EuroSCORE ≥10), (4) ANCLA score (anemia, New York Heart Association class IV, critical state, large intracardiac destruction, surgery of thoracic aorta), (5) Risk-Endocarditis Score (RISK-E), (6) score for heart valve or prosthesis IE (EndoSCORE), and (7,8) Association pour l'Étude et la Prévention de l'Endocadite Infectieuse (AEPEI) score I and II - were evaluated in 324 (mean age, 61.8 ± 14.6 years) consecutive patients having IE and undergoing cardiac operation (1999-2018, Regione Autonoma Friuli-Venezia Giulia, Italy). Results: There were 45 (13.9%) in-hospital deaths. Despite many differences on the number and the type of variables, all the investigated scores showed good goodness-of-fit (Hosmer-Lemeshow test, p ≥.28). For five scores, accuracy of prediction (receiver-operating characteristic curve analysis) was good (ANCLA score) or fair (STS risk score for IE, PALSUSE score, AEPEI score I and II). When compared one-to-one (Hanley-McNeil method), accuracy of prediction of ANCLA score was higher than all of other risk scores except for AEPEI score I (p = .077). Conclusions: Five of eight scores that were evaluated in this study showed satisfactory performance in predicting in-hospital mortality following surgery for IE. The ANCLA score should be preferred.

Ceftolozane/tazobactam for the treatment of MDR Pseudomonas aeruginosa left ventricular assist device infection as a bridge to heart transplant.

BACKGROUND: Ceftolozane/tazobactam (C/T) is a novel antibiotic with enhanced microbiological activity against multidrug-resistant (MDR) gram-negative bacteria, including MDR Pseudomonas aeruginosa. CASE REPORT: Five months after left ventricular assist device (LVAD) implantation, a 49-year old man developed fever and blood culture was positive for MDR P. aeruginosa, susceptible only to aminoglycosides, ciprofloxacin and colistin. A diagnosis of LVAD-related infection was made based on persistent bacteremia associated with moderate 18 F-fluorodeoxyglucose positron emission tomography/CT uptake in the left ventricular apex. Disk diffusion testing for C/T was performed (MIC 2 µg/mL) and intravenous antibiotic therapy with C/T and amikacin was started, with clinical and microbiological response. Initial conservative management with 6 weeks of systemic antibiotic therapy was attempted, but the patient relapsed one month after antibiotic discontinuation. Priority for transplantation was given and after 4 weeks of antibiotic therapy (C/T + amikacin), LVAD removal and heart transplant were performed, with no infection relapse. CONCLUSIONS: We reported the first off-label use of C/T in the management of MDR P. aeruginosa LVAD infection as a bridge to heart transplant. C/T has shown potent anti-pseudomonal activity and good safety profile making this drug as a good candidate for suppressive strategy in intravascular device-associated bloodstream infections caused by MDR P. aeruginosa.

Multidrug-resistant Pseudomonas aeruginosa skin and soft-tissue infection successfully treated with ceftolozane/tazobactam.

Ceftolozane/tazobactam (C/T) is a novel ß-lactam/ß-lactamase inhibitor combination antibiotic approved by the US Food and Drug Administration for the treatment of complicated intra-abdominal and urinary tract infections due to Gram-negative bacteria, particularly extended-spectrum ß-lactamase-producing Enterobacteriaceae and multidrug-resistant (MDR) Pseudomonas aeruginosa strains. Here we report a case of MDR P. aeruginosa skin and soft-tissue infection successfully treated with C/T.