Fosfomycin as salvage therapy for persistent methicillin-resistant Staphylococcus aureus bacteremia: A case series and review of the literature.

Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia can be persistent and refractory; however, the optimal approach for its treatment has not been determined. Although fosfomycin (FOM) has been shown to have synergistic effects with anti-MRSA agents in vitro, clinical experience with FOM combination therapy is limited. Thus, we present cases of persistent MRSA bacteremia that improved with the addition of FOM. In case 1, a 48-year-old man with prosthetic vascular graft infection developed persistent MRSA bacteremia despite vancomycin (VCM) and daptomycin (DAP) administration. On day 46, after the first positive blood culture, we added FOM to DAP. The blood culture became negative on day 53. In case 2, an 85-year-old woman presented with pacemaker-related MRSA bacteremia. She was treated with VCM, followed by DAP and DAP plus rifampicin. However, the bacteremia persisted for 32 days because of difficulties in immediate pacemaker removal. After adding FOM to DAP, the blood culture became negative on day 38. In case 3, a 57-year-old woman developed persistent MRSA bacteremia due to pulmonary valve endocarditis and pulmonary artery thrombosis after total esophagectomy for esophageal cancer. The bacteremia continued for 50 days despite treatment with DAP, followed by VCM, VCM plus minocycline, DAP plus linezolid (LZD), and VCM plus LZD. She was managed conservatively because of surgical complications. After adding FOM to VCM on day 51, the blood culture became negative on day 58. FOM combination therapy may be effective in eliminating bacteria and can serve as salvage therapy for refractory MRSA bacteremia.

Characteristics of Gram-positive cocci infection and the therapeutic effect after liver transplantation. / è‚ç§»æ¤æœ¯åŽé©å °æ°é˜³æ€§çƒèŒçš„æ„ŸæŸ“ç‰¹ç‚¹åŠé˜²æ²»æ•ˆæžœ.

OBJECTIVES: Gram-positive cocci is the main pathogen responsible for early infection after liver transplantation (LT), posing a huge threat to the prognosis of liver transplant recipients. This study aims to analyze the distribution and drug resistance of Gram-positive cocci, the risk factors for infections and efficacy of antibiotics within 2 months after LT, and to guide the prevention and treatment of these infections. METHODS: In this study, data of pathogenic bacteria distribution, drug resistance and therapeutic efficacy were collected from 39 Gram-positive cocci infections among 256 patients who received liver transplantation from donation after citizens' death in the Third Xiangya Hospital of Central South University from January 2019 to July 2022, and risk factors for Gram-positive cocci infection were analyzed. RESULTS: Enterococcus faecium was the dominant pathogenic bacteria (33/51, 64.7%), followed by Enterococcus faecalis (11/51, 21.6%). The most common sites of infection were abdominal cavity/biliary tract (13/256, 5.1%) and urinary tract (10/256, 3.9%). Fifty (98%) of the 51 Gram-positive cocci infections occurred within 1 month after LT. The most sensitive drugs to Gram-positive cocci were teicoplanin, tigecycline, linezolid and vancomycin. Vancomycin was not used in all patients, considering its nephrotoxicity. Vancomycin was not administered to all patients in view of its nephrotoxicity.There was no significant difference between the efficacy of daptomycin and teicoplanin in the prevention of cocci infection (P>0.05). Univariate analysis indicated that preoperative Model for End-Stage Liver Disease (MELD) score >25 (P=0.005), intraoperative red blood cell infusion ≥12 U (P=0.013) and exposure to more than 2 intravenous antibiotics post-LT (P=0.003) were related to Gram-positive cocci infections. Multivariate logistic regression analysis revealed that preoperative MELD score >25 (OR=2.378, 95% CI 1.124 to 5.032, P=0.024) and intraoperative red blood cell transfusion ≥ 12 U (OR=2.757, 95% CI 1.227 to 6.195, P=0.014) were independent risk factors for Gram-positive cocci infections after LT. Postoperative Gram-positive cocci infections were reduced in LT recipients exposing to more than two intravenous antibiotics post-LT (OR=0.269, 95% CI 0.121 to 0.598, P=0.001). CONCLUSIONS: Gram-positive cocci infections occurring early after liver transplantation were dominated by Enterococcus faecalis infections at the abdominal/biliary tract and urinary tract. Teicoplanin, tigecycline and linezolid were anti-cocci sensitive drugs. Daptomycin and teicoplanin were equally effective in preventing cocci infections due to Gram-positive cocci. Patients with high preoperative MELD score and massive intraoperative red blood cell transfusion were more likely to suffer Gram-positive cocci infection after surgery. Postoperative Gram-positive cocci infections were reduced in recipients exposing to more than two intravenous antibiotics post-LT.

Targeted Killing of Staphylococcus aureus Using Specific Peptides Displayed on Yeast Vacuoles.

Staphylococcus aureus is a common pathogen that causes health care-related and community-associated infections. In this study, we provide a novel system that can recognize and kill S. aureus bacteria. The system is specifically based on a combination of the phage display library technique and yeast vacuoles. A phage clone displaying a peptide capable of specific binding to a whole S. aureus cell was selected from a 12-mer phage peptide library. The peptide sequence was SVPLNSWSIFPR. The selected phage's ability to bind specifically with S. aureus was confirmed using an enzyme-linked immunosorbent assay, and the chosen peptide was then synthesized. The results showed that the synthesized peptides displayed high affinity with S. aureus but low binding ability with other strains, including Gram-negative and Gram-positive bacteria such as Salmonella sp., Shigella spp., Escherichia coli, and Corynebacterium glutamicum. In addition, yeast vacuoles were used as a drug carrier by encapsulating daptomycin, a lipopeptide antibiotic used to treat Gram-positive bacterial infections. The expression of specific peptides at the encapsulated vacuole membrane created an efficient system that can specifically recognize and kill S. aureus bacteria. IMPORTANCE The phage display method was used to select peptides with high affinity and specificity for S. aureus, and these peptides were then induced to be expressed on the surface of yeast vacuoles. These surface-modified vacuoles can act as drug carriers, with drugs such as the lipopeptide antibiotic daptomycin loaded inside. An advantage of using yeast vacuoles as a drug carrier is that they can be easily produced through yeast culture, making the approach cost-effective and suitable for large-scale production and potential implementation in clinical settings. This novel approach offers a promising way to specifically target and eliminate S. aureus that could ultimately lead to improved treatment of bacterial infections and reduced risk of antibiotic resistance.

Population Pharmacokinetic Model for Unbound Concentrations of Daptomycin in Patients with MRSA Including Patients Undergoing Hemodialysis.

BACKGROUND AND OBJECTIVE: Unbound daptomycin concentrations are responsible for pharmacologically beneficial and adverse effects, although most previous reports have been limited to the use of total concentrations. We developed a population pharmacokinetic model to predict both total and unbound daptomycin concentrations. METHODS: Clinical data were collected from 58 patients with methicillin-resistant Staphylococcus aureus including patients undergoing hemodialysis. A total of 339 serum total and 329 unbound daptomycin concentrations were used for model construction. RESULTS: Total and unbound daptomycin concentration was explained by a model that assumed first-order distribution with two compartments, and first-order elimination. Normal fat body mass was identified as covariates. Renal function was incorporated as a linear function of renal clearance and independent non-renal clearance. The unbound fraction was estimated to be 0.066 with a standard albumin of 45 g/L and standard creatinine clearance of 100 mL/min. Simulated unbound daptomycin concentration was compared with minimum inhibitory concentration as a measure of clinical effectiveness and exposure-level-related induction of creatine phosphokinase elevation. The recommended doses were 4 mg/kg for patients with severe renal function [creatinine clearance (CLcr) ≤ 30 mL/min] and 6 mg/kg for patients with mild to moderate renal function (CLcr > 30 and ≤ 60 mL/min). A simulation indicated that dose adjusted by body weight and renal function improved target attainment. CONCLUSIONS: This population pharmacokinetics model for unbound daptomycin could help clinicians to select the appropriate dose regimen for patients undergoing daptomycin treatment and reduce associated adverse effects.

Effects of Antibacterial Agents on Cancerous Cell Proliferation.

Myelosuppression, a side effect of anticancer drugs, makes people more susceptible to infectious diseases by compromising the immune system. When a cancer patient develops a contagious disease, treatment with an anticancer drug is suspended or postponed to treat the infectious disease. If there was a drug that suppresses the growth of cancer cells among antibacterial agents, it would be possible to treat both infectious diseases and cancer. Therefore, this study investigated the effect of antibacterial agents on cancer cell development. Vancomycin (VAN) had little effect on cell proliferation against the breast cancer cell, MCF-7, prostate cancer cell, PC-3, and gallbladder cancer cell, NOZ C-1. Alternatively, Teicoplanin (TEIC) and Daptomycin (DAP) promoted the growth of some cancer cells. In contrast, Linezolid (LZD) suppressed the proliferation of MCF-7, PC-3, and NOZ C-1 cells. Therefore, we found a drug that affects the growth of cancer cells among antibacterial agents. Next, when we examined the effects of the combined use of existing anticancer and antibacterial agents, we found VAN did not affect the growth suppression by anticancer agents. However, TEIC and DAP attenuated the growth suppression of anticancer agents. In contrast, LZD additively enhanced the growth suppression by Docetaxel in PC-3 cells. Furthermore, we showed that LZD inhibits cancer cell growth by mechanisms that involve phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway suppression. Therefore, LZD might simultaneously treat cancer and infectious diseases.

Factors associated with daptomycin consumption in French hospitals between 2019 and 2020: A nationwide surveillance study.

OBJECTIVES: This study aimed to investigate factors associated with daptomycin consumption in French healthcare facilities (HCF) between 2019 and 2020. METHODS: Antibiotic consumption expressed as number of defined daily doses (DDD) per 1,000 patient-days (PD) and antimicrobial resistance (AMR) expressed as incidence densities per 1,000PD were extracted each year from the nationwide surveillance network run by the SPARES project (Surveillance and Prevention of Antimicrobial RESistance in hospitals), collecting data at ward level among voluntary HCFs using standardized methodology and webtool. All HCF participating both in 2019 and 2020 were included. A multivariable linear regression was fitted. RESULTS: Among 622 HCFs, we analyzed daptomycin consumption and AMR data in 1,637 clinical wards. Incidence densities of methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant coagulase-negative staphylococci (MRCNS) were the highest in intensive care unit wards (0.54 and 6.83 respectively in 2020). On the most adjusted model, the year 2020 was correlated with a higher daptomycin consumption (1.53; p = 0.01). A greater number of inpatient beds (0.01; p < 0.001), the presence of orthopedic surgery activity in the HCF (1.66; p < 0.02), MRSA (4.38; p < 0.001) and MRCNS (0.61; p < 0.001) incidence densities were associated with a higher daptomycin use. The final model explained 18% of the observed variance. CONCLUSIONS: This study showed that daptomycin consumption was correlated to MRSA and MRCNS incidence densities, to the year 2020 and to non-modifiable HCF-related factors. Prevention of coagulase-negative staphylococci infections should be considered by antimicrobial stewardship teams when daptomycin use is going up in HCF.

Practical Mouse Model to Investigate Therapeutics for Staphylococcusaureus Contaminated Surgical Mesh Implants.

INTRODUCTION: The use of prosthetic mesh in hernia repair provides a powerful tool to increase repair longevity, decrease recurrence rates, and facilitate complex abdominal wall reconstruction. Overall infection rates with mesh are low, but for those affected there is high morbidity and economic cost. The availability of a practicable small animal model would be advantageous for the preclinical testing of prophylactics, therapeutics, and new biomaterials. To this end, we have developed a novel mouse model for implantation of methicillin-resistant Staphylococcus aureus-infected surgical mesh and provide results from antibiotic and immunotherapeutic testing. MATERIALS AND METHODS: Implantation of surgical mesh between fascial planes of the mouse hind limb was used to approximate hernia repair in humans. Surgical mesh was inoculated with methicillin-resistant Staphylococcus aureus to test the efficacy of antibiotic therapy with daptomycin and/or immunotherapy to induce macrophage phagocytosis using antibody blockade of the CD47 "don't eat me" molecule. Clinical outcomes were assessed by daily ambulation scores of the animals and by enumeration of mesh-associated bacteria at predetermined end points. RESULTS: A single prophylactic treatment with daptomycin at the time of surgery led to improved ambulation scores and undetectable levels of bacteria in seven of eight mice by 21 days postinfection. Anti-CD47, an activator of macrophage phagocytosis, was ineffective when administered alone or in combination with daptomycin treatment. Ten days of daily antibiotic therapy begun 3 days after infection was ineffective at clearing infection. CONCLUSIONS: This fast and simple model allows rapid in vivo testing of novel antimicrobials and immunomodulators to treat surgical implant infections.

Bacteriemia por Enterococcus faeciumresistente a daptomicina / Daptomycin-resistant enterococcus faecium bacteremia

La aparición de cepas de enterococos resistentes a daptomicina es un tema de preocupación clínica y epidemiológica en años recientes. Se presenta el caso de un paciente de 50 años con antecedente de artritis reumatoide e inmunosupresión crónica hospitalizado en contexto de neumonía viral por COVID-19, con sobreinfección bacteriana y choque séptico, en quien se documentó en tres oportunidades diferentes aislamientos de Enterococcus faecium vancomicino-resistente VAN A y B con falla terapéutica a daptomicina, por deterioro clínico y persistencia de hemocultivos positivos. Se inició manejo con linezolid con control de la infección, negativización de hemocultivos y evolución clínica satisfactoria. Se realiza reporte del presente caso para dar a conocer la aparición de enterococos resistentes a daptomicina, la cual es una creciente preocupación epidemiológica, con el fin de realizar identificación temprana, prevenir falla terapéutica y poder conocer la epidemiología local

n recent years, the emergence of daptomycin-resistant enterococcus strains is a growing clinical and epidemio-logical topic of concern. We report the case of a 50 year old patient with an antecedent of rheumatoid arthritis and chronic immunosuppression hospitalized in the con-text of COVID-19 pneumonia with bacterial co-infection and septic shock in which a three different moments an isolate of a "vancomycin-resistant enterococcus faecium"(VRE) Van A and B that presented therapeutic failure with daptomycin was documented after clinical deterioration and persistence of positive blood cultures. Linezolid was initiated, with clinical recovery and negativization of blood cultures following the change in antibiotic treatment. This case is reported in order to expose the ever growing con-cern of daptomycin-resistant enterococcus strains in or-der to prevent therapeutic failure, make early identifica-tion and get to know the local epidemiological status.

Ceftaroline as salvage therapy for methicillin susceptible Staphylococcus aureus complicated bacteremia.

Infections caused by methicillin-susceptible Staphylococcus aureus (MSSA) are still associated with significant morbidity and mortality. Treatment failures of cefazolin (CFZ) have been reported and probably related to the inoculum effect. New treatments for severe MSSA infections are needed and ceftaroline fosamil (CPT) could be an option. Our aim was to describe the clinical characteristics of five patients with complicated MSSA bacteremia failing CFZ and successfully treated with CPT. We performed a retrospective chart review in a Hospital in Buenos Aires, Argentina; in a 12-month period, five patients (24%) of 21 with MSSA bacteremia experienced CFZ failure and were salvaged with CPT. The median time of CFZ therapy was 10 days before changing to CPT; four patients had evidence of metastatic spread and 2 had endocarditis. All patients experienced microbiological and clinical cure with CPT, which was used as monotherapy in 4 and in combination with daptomycin in another. One patient discontinued CPT due to neutropenia on day 23 of treatment. In patients with MSSA BSI failing current therapy, CPT could be a good therapeutic option.

Las infecciones causadas por Staphylococcus aureus sensible a la meticilina (SASM) todavía se asocian con una morbilidad y mortalidad significativas. Se han informado fallas en el tratamiento de cefazolina (CFZ) probablemente relacionadas con efecto inóculo. Nuevos tratamientos son necesarios para estas infecciones y ceftarolina fosamil (CPT) podría ser una opción. Nuestro objetivo fue describir las características clínicas de cinco pacientes con bacteriemia por SASM complicada con falla a CFZ y que fueron exitosamente tratados con CPT. Realizamos una revisión retrospectiva de historias clínicas en un hospital de Buenos Aires, Argentina; en un período de 12 meses, cinco pacientes (24%) de 21 con bacteriemia por SASM experimentaron falla a CFZ y fueron tratados con CPT. La mediana de tiempo de la terapia con CFZ fue de 10 días antes de cambiar a CPT; cuatro pacientes presentaban evidencia de diseminación metastásica y 2 tenían endocarditis. Todos los pacientes experimentaron curación microbiológica y clínica con CPT, que se utilizó como monoterapia en 4 y en combinación con daptomicina en otro. Un paciente interrumpió CPT debido a neutropenia el día 23 de tratamiento. En enfermos con infecciones graves por SASM que fallan en la terapia actual, CPT podría ser una buena opción terapéutica.

Vancomycin versus daptomycin for the treatment of confirmed gram-positive catheter-related bloodstream infections in oncology patients.

OBJECTIVE: To analyse the effectiveness and safety of daptomycin versus vancomycin on the management catheter-related bloodstream  nfections in oncology patients. METHOD: A retrospective study was carried out including all patients admitted  at the Medical Oncology Unit between 2010 and 2018 with positive blood  cultures confirmed catheter-related bloodstream infections due to gram- positive microorganism, who were treated with either vancomycin or  daptomycin. The primary end point was all cause 30-days mortality, 30-days  hospital readmission and length of hospital stay (length of hospital stay). Results: A total of 70 patients with catheter-related bloodstream infections were included in the present study: vancomycin was administered to  61.4% (n = 43) and daptomycin to 38.6% (n = 27) of  patients. 78.5% (n = 55) of isolated bacteria showed a vancomycin minimum  inhibitory concentration ≤ 1 µg/ml. No differences were observed  between the two groups of patients regarding the 30-day mortality rate rate  (32.6% [n = 14] versus 29.6% [n = 8]; p = 0.797), the 30-day re-admission rate (30.2% [n = 13] versus 29.6% [n = 8]; p = 0.957) or the length of  hospital stay (18.9 versus 16.5 days; p = 0.562). Nephrotoxicity rate was  equivalent in both groups: a 7% (n = 3) of vancomycin goup versus a 7.4% (n  = 2) of daptomycin group (p = 0.946). CONCLUSIONS: Our results show that both antibiotics are equivalent in their  safety and effectiveness. Therefore, vancomycin should continue being the  treatment of chose for gram-positive catheter-related bloodstream infections,  in particular at hospital centres with a low prevalence of strains that show  diminished susceptibility to vancomycin.

OBJETIVO: Analizar la eficacia y seguridad de la daptomicina frente a la  vancomicina en el tratamiento de las infecciones del torrente sanguíneo asociadas a catéter vascular en pacientes oncológicos.Método: Se realizó un estudio retrospectivo que incluyó a los pacientes ingresados en la Unidad de Oncología-Médica entre 2010-2018 con infección del torrente sanguíneo asociada a catéter vascular causada por  grampositivos, y que fueron tratados con vancomicina o daptomicina. Como  objetivos principales se determinaron la tasa de mortalidad por todas las  causas a los 30 días, el reingreso hospitalario a los 30 días y la duración de la  estancia hospitalaria. RESULTADOS: El estudio incluyó 70 pacientes con infecciones del torrente sanguíneo asociadas a catéter vascular: el 61,4% (n = 43) recibió  vancomicina y el 38,6% (n = 27) daptomicina. El 78,5% (n = 55) de las  bacterias aisladas presentaron una concentración mínima inhibitoria de  vancomicina ≤ 1 µg/ml. No se observaron diferencias entre ambos grupos de  pacientes en cuanto a la tasa de mortalidad a 30 días (32,6% [n = 14]  frente al 29,6% [n = 8]; p = 0,797), la tasa de reingreso a 30 días (30,2% [n  = 13] frente al 29,6% [n = 8]; p = 0,957) o la duración de la hospitalización (18,9 frente a 16,5 días; p = 0,562). La tasa de nefrotoxicidad fue equivalente  en ambos grupos: 7% (n = 3) para vancomicina frente al 7,4% (n = 2) para  daptomicina (p = 0,946). CONCLUSIONES: Nuestros resultados muestran que ambos antibióticos son equivalentes en su seguridad y eficacia. Por ello, vancomicina debería seguir siendo el tratamiento de elección para la infección del torrente sanguíneo asociada a catéter vascular, especialmente en centros con  una baja prevalencia de cepas con una susceptibilidad disminuida a  ancomicina.

The systemic immune response due to cholesterol crystal embolization syndrome: a case report.

BACKGROUND: Cholesterol crystal embolization syndrome (CES) occurs when an atherosclerotic plaque causes small-vessel embolization, resulting in multi-organ damage. Although CES is pathologically characterized by an infiltration of eosinophils, the implication of the systemic inflammatory response represented by hypereosinophilia is unclear in clinical practice. Herein we present the case of a patient diagnosed with CES who developed multiple allergic organ injuries, including daptomycin-related dermatitis and later vancomycin-induced acute tubulointerstitial nephritis, which was successfully treated by the withdrawal of each medicine with or without corticosteroid therapy, one by one. CASE PRESENTATION: A 76-year-old Japanese man diagnosed with thoracic aneurysm rupture underwent total arch replacement through the open stent graft technique. Postoperatively, he developed methicillin-resistant Staphylococcus epidermidis bacteremia, which was treated with daptomycin. Subsequently, he presented with palpable purpura on both dorsal feet, erythema around his body, and hypereosinophilia. Daptomycin was replaced with vancomycin due to suspicion of drug-induced erythema. The erythema gradually faded. On nine days after vancomycin therapy, the systemic erythema rapidly reappeared followed by acute renal failure. The renal function decline prompted hemodialysis. A skin biopsy revealed cholesterol embolization, whereas a kidney biopsy revealed acute tubulointerstitial nephritis. After vancomycin discontinuation and initiation of systemic corticosteroid treatment, his kidney function was restored to the baseline level. CONCLUSIONS: The present case highlights cholesterol embolization can cause allergic complications in addition to direct organ damage.

Clinical and microbiological characteristics of bacterial meningitis in umbilical cord blood transplantation recipients.

Bacterial meningitis is a rare but severe infectious complication after hematopoietic stem cell transplantation. However, its clinical features were previously not clear. We reviewed the cases of 7 patients diagnosed with bacterial meningitis with a positive cerebrospinal fluid culture among 1147 patients who underwent cord blood transplantation (CBT) at our institution between September 2007 and September 2020. The diagnosis was made on day + 5- + 45, and 5 patients developed bacterial meningitis before neutrophil engraftment. The causative organisms were all Gram-positive cocci: Enterococcus faecium and Enterococcus gallinarum (2 patients each), and Staphylococcus haemolyticus, Streptococcus mitis/oralis, and Rothia mucilaginosa (1 patient each). Six patients developed bacterial meningitis secondary to prior or concomitant bacteremia caused by the same bacterium. Five patients had received anti-MRSA agents at onset: vancomycin in 3, teicoplanin in 1, and daptomycin in 1. After diagnosis of bacterial meningitis, linezolid was eventually used for 6 patients. Two patients with E. gallinarum were alive at day + 1380 and + 157 after CBT, respectively, whereas 5 patients died 17-53 (median 43) days after the onset of bacterial meningitis. Breakthrough meningitis in CBT can occur even during the use of anti-MRSA drugs, and intensive antibiotic treatment is necessary.

Daptomycin exerts differential immunomodulatory effects on host responses against methicillin-resistant Staphylococcus aureus biofilms.

Daptomycin (DAP) is indicated for difficult-to-treat Gram-positive infections, especially those caused by methicillin-resistant Staphylococcus aureus (MRSA). Exposure of S. aureus to subinhibitory antimicrobial concentrations (sub-MICs) has been shown to alter cell morphology and biofilm formation. This study aimed to investigate the influence of DAP biofilm sub-MICs on the damage caused by human polymorphonuclear neutrophils (PMNs) against MRSA biofilms and the potential immunomodulatory activity of DAP on human monocytes (MNCs) exposed to MRSA biofilms. DAP activity against biofilms and the impact of DAP on PMN-induced biofilm damage were evaluated by the XTT reduction assay, whereas pathogen recognition, signal transduction and cytokine modulation of DAP on MNCs in response to MRSA biofilms were assessed by RT-PCR and ELISA methodology. The MIC50 of DAP to MRSA biofilms was 16-32 mg/L. Pre-treatment of MRSA with 1, 2 or 4 mg/L DAP caused a synergistic effect on PMN-mediated biofilm damage, being dependent on the effector-to-target ratio. MNCs responded to MRSA biofilms and DAP through Toll like receptor 2 (TLR2) upregulation and increased NLRP3 inflammasome production. DAP caused 2.5-fold greater TLR2 mRNA levels than those caused by MRSA biofilms. A predominantly inflammatory response was induced by either component, causing the release of significantly increased IFN-γ, TNF-α, IL-8 and IL-6 levels by MNCs exposed to the combination treatment. MRSA biofilms alone or combined with DAP caused low amounts of IL-10 production, but increased IL-1ß levels. DAP may condition MNCs towards an inflammatory response through TLR2 engagement and NLRP3 inflammasome activation, possibly controlling biofilm-associated pathogenicity.

A retrospective multicentre study on dalbavancin effectiveness and cost-evaluation in sternotomic wound infection treatment: DALBA SWIT Study.

OBJECTIVE: To evaluate the cost-effectiveness of dalbavancin compared with standard of care (SoC) treatment as daptomycin or teicoplanin in patients with sternal wound infections (SWI). METHODS: Multicentre retrospective study of patients diagnosed with SWI from January 2016 to December 2019 at two cardiac surgery facilities treated with dalbavancin, teicoplanin or daptomycin. Patients with SWI treated with dalbavancin were compared with SoC to evaluate resolution of infection at 90 and 180 days from infection diagnosis, length of stay (LoS) and management costs. RESULTS: 48 patients with SWI were enrolled, 25 (50%) male, median age 67 (60-73) years, Charlson index score 5 (4-7). Fifteen patients were treated with dalbavancin (31%) and 33 with SoC (69%): teicoplanin in 21 (63%), and daptomycin in 12 (37%). Staphylococcus species were the most frequent isolates (44, 92%), mostly (84%) resistant to methicillin. All patients were treated with surgical debridement followed by negative pressure wound therapy. Wound healing at day 90 and 180 was achieved in 46 (95.8%) and 34 (82.9%) of patients, respectively. A shorter length of hospitalization in patients treated with dalbavancin compared with SoC [12 (7-18) days vs 22 (12-36) days, p:0.009] was found. Treatment with dalbavancin resulted in total cost savings of €16 026 (95% CI 5976-26 076, P < 0.001). Savings were mainly related to the LoS that was significantly shorter in the dalbavancin group, generating significantly lower cost compared to SoC group. CONCLUSION: Dalbavancin treatment of sternal wound infections is effective and seems to reduce hospitalization length, leading to significantly lower costs.

Risk factors for persistent enterococcal bacteraemia: a multicentre retrospective study.

OBJECTIVES: Conditions favouring persistent enterococcal bacteraemia (p-EB) have not been fully investigated yet. The aim of our study is to analyse risk factors for p-EB and its impact on mortality. METHODS: International two-centre retrospective study of all hospitalised adults with enterococcal bacteraemia managed with follow-up blood cultures (BCs) during the period 2011-2019. Exclusion criteria were: (1) death within 72 hours from index BCs and (2) polymicrobial bacteraemia. Primary endpoint was p-EB, defined as further isolation of the same species of Enterococcus spp. from BCs after at least 72 hours of appropriate antibiotic therapy. Multivariable logistic regression model was performed to assess risk factors for p-EB. The impact of p-EB on 30-day mortality was assessed by Kaplan-Meier survival curve and Cox regression multivariable model. RESULTS: During the study period, 244 enterococcal bacteraemia were diagnosed. P-EB were 13.5% (33/244). At multivariable analysis, factors independently associated with p-EB were hematologic malignancy (OR 4.60 [95% CI 1.32-16.00], P = 0.01), infective endocarditis (OR 7.99 [95% CI 2.20-28.9], P = 0.002), and use of daptomycin as initial treatment (OR 4.50 [95% CI 1.29-15.61], P = 0.018). Mortality rate was higher in the p-EB group (32% vs. 18%). Kaplan-Meier survival curve showed that patients with p-EB were less likely to survive at 30 days from index BCs (log-rank P = 0.002). Using a Cox regression model, independent predictors of 30-day mortality were hematologic malignancy (HR 2.30 [95% CI 1.02-4.11], P = 0.043), p-EB (HR 1.93 [95% CI 0.92-4.04], P = 0.08), and septic shock (HR 5.92 [95% CI 2.17-16.30], P = 0.001). CONCLUSION: P-EB was diagnosed mainly in very fragile patients and in those receiving daptomycin as frontline therapy. P-EB may have an impact on mortality.

Simplified daptomycin dosing regimen for adult patients with methicillin-resistant Staphylococcus aureus infections based on population pharmacokinetic analysis.

Daptomycin is used to treat methicillin-resistant Staphylococcus aureus (MRSA) infections. Current guidelines recommend higher daptomycin doses (8-10 mg/kg) for severe infections; however, pharmacokinetic (PK) and pharmacodynamic-based dosing strategies are still limited. Therefore, we designed a new optimal daptomycin dosing regimen for patients with MRSA infections using a population PK modeling approach. A total of 110 plasma concentrations from 47 adult patients who received daptomycin in general wards were enrolled for population PK modeling. The target area under the concentration-time curve/minimum inhibitory concentration (MIC) ratio, target peak/MIC ratio, and threshold of the trough concentration for safety were set to >666, >60, and 24.3 mg/L, respectively. Renal function was indicated as a significant covariate for daptomycin clearance. The simulated probability of target attainment was more than 90% at MIC values of 0.25 and 0.5 mg/L in all patients at the standard dose (6 mg/kg). In contrast, comprehensive simulation assessments recommended 10 mg/kg every 24 h in patients with creatinine clearance >60 mL/min for MIC values of 1.0 mg/L. We propose a new simplified daptomycin dosing regimen stratified by renal function and MIC values based on PK model-based simulation analyses. The proposed regimen is expected to maximize clinical efficacy and minimize adverse events.

Proteomics and Transcriptomics Uncover Key Processes for Elasnin Tolerance in Methicillin-Resistant Staphylococcus aureus.

Elasnin is a new antibiofilm compound that was recently reported to have excellent activity against methicillin-resistant Staphylococcus aureus (MRSA) biofilms. In this study, we established that elasnin also has antibacterial activity against growing S. aureus planktonic cells. To explore elasnin's potential as an antibiotic, we applied adaptive laboratory evolution (ALE) and produced evolved strains with elevated elasnin tolerance. Interestingly, they were more sensitive toward daptomycin and lysostaphin. Whole-genome sequencing revealed that all of the evolved strains possessed a single point mutation in a putative phosphate transport regulator. Subsequently, they exhibited increased intracellular phosphate (Pi) and polyphosphate levels. Inhibition of the phosphate transport regulator gene changed the phenotype of the wild type to one resembling those observed in the evolved strains. Proteomics and transcriptomics analyses showed that elasnin treatment resulted in the downregulation of many proteins related to cell division and cell wall synthesis, which is important for the survival of growing exponential-phase cells. Other downregulated processes and factors were fatty acid metabolism, glycolysis, the two-component system, RNA degradation, and ribosomal proteins. Most importantly, transport proteins and proteins involved in oxidative phosphorylation and the phosphotransferase system were more upregulated in the evolved strain than in the ancestral strain, indicating that they are important for elasnin tolerance. Overall, this study showed that elasnin has antibacterial activity against growing S. aureus cells and revealed the altered processes due to elasnin treatment and those associated with its tolerance. IMPORTANCE Besides the excellent antibiofilm properties of elasnin, we discovered that it can also kill growing methicillin-resistant Staphylococcus aureus (MRSA) planktonic cells. We subjected MRSA cells to an in vitro evolution experiment, and the resulting evolved strains exhibited increased elasnin tolerance, reduced growth rate, loss of pigmentation, and an increased proportion of small-colony formation, and they became more sensitive toward daptomycin and lysostaphin. Through multiomics analysis, we uncovered the affected processes in growing S. aureus planktonic cells following elasnin treatment, including the downregulation of cell wall synthesis, cell division, and some genes/proteins for the two-component system. These findings suggest that elasnin suppressed processes important for the cells' survival and adaptation to environmental stresses, making it an ideal drug adjuvant candidate. Overall, our study provides new insights into the mechanism of elasnin in S. aureus planktonic cells and pointed out the potential application of elasnin in clinics.

REACTIVE AMYLOID A PROTEIN AMYLOIDOSIS IN THE SETTING OF INFECTIVE ENDOCARDITIS MANIFESTING AS BILATERAL ORBITOPATHY AND CHOROIDOPATHY.

PURPOSE: To describe a case of amyloid A protein amyloidosis that produced an orbital inflammatory response with a novel presentation. METHODS: Case report. RESULTS: A 24-year-old Caucasian women with a history of intravenous heroin use was hospitalized for tricuspid valve endocarditis and methicillin-resistant Staphylococcus aureus bacteremia, as well as acute renal failure. She received hemodialysis and intravenous daptomycin and had negative blood cultures for 3 weeks, when she developed sudden bilateral orbital swelling and blurred vision. Visual acuity was 20/200 in the right eye and 20/400 in the left eye. Examination revealed proptosis, conjunctival chemosis and desiccation, optic disk swelling, creamy choroidal infiltrates, and inferiorly located exudative retinal detachments in both eyes. Multimodal imaging demonstrated thickening of the sclera, choroid, and choriocapillaris as well as outer retinal disruption, subretinal fluid, and deposits of hyperfluorescent debris within the choriocapillaris, outer retina, and vitreous. Oral prednisone at 60 mg per day resolved the choroidal infiltrates and exudative detachments. Persistent nephrotic syndrome called for a renal biopsy, which demonstrated amyloid A protein amyloidosis. CONCLUSION: Orbital and choroidal Amyloid A protein amyloidosis can induce a local inflammatory response manifesting as orbital swelling, papillitis, posterior scleritis, choroiditis, and exudative retinal detachment, which responds to steroid therapy. The underlying pathology is likely a reactive inflammatory, vasoocclusive process involving the choriocapillaris and orbital vasculature to the presence of amyloid fibrils.

Detection of in-frame mutation by IS30-family insertion sequence in the phospholipid phosphatidylglycerol synthase gene (pgsA2) of high-level daptomycin-resistant Corynebacterium striatum.

The emergence of high-level daptomycin (DAP)-resistant (HLDR) Corynebacterium striatum has been reported as a result of loss-of-function point mutations or premature stop codon mutations in a responsible gene, pgsA2. We herein describe the novel detection of an HLDR C. striatum clinical isolate, in which IS30-insertion was corroborated to cause destruction of pgsA2 gene. We isolated an HLDR C. striatum from a critically ill patient with underlying mycosis fungoides who had been treated with DAP for 10 days. With a sequence investigation, IS30-insertion was discovered to split pgsA2 in the HLDR C. striatum strain, which may cause disrupted phospholipid phosphatidylglycerol (PG) production. Future studies should survey the prevalence of IS-mediated gene inactivation among HLDR C. striatum clinical isolates.