Efficacy Of Prophylaxis Research Articles

Letermovir Prophylaxis for High-Risk Allogenic Transplantation Recipients, Real- World Israeli Experience

Introduction: Cytomegalovirus (CMV) infection is a common complication after allogeneic hematopoietic-cell transplantation (alloHCT) causing significant morbidity and mortality. The standard approach for preventing clinically significant CMV infection (CS-CMVi) and CMV disease (CMVd), is preemptive therapy (PET) upon detection of CMV reactivation. In 2017 letermovir was approved for CMV prophylaxis in CMV-seropositive allogeneic HCT recipients from transplantation through day 100 after alloHCT. At 2020, letermovir was approved in Israel for prophylaxis in CMV-seropositive alloHCT recipients who were at higher risk for CMV reactivation (seronegative donor, HLA mismatched unrelated donor, haploidentical family donor, ex-vivo T cell depleted graft or recipient suffering from acute Graft Versus Host Disease (aGVHD) requiring >1mg/kg steroid therapy). There is paucity of real-world data regarding the efficacy and outcomes of letermovir prophylaxis in the post-transplant setting. The aim of our study was to report the real-world Israeli experience with letermovir prophylaxis in terms of incidence of CS-CMVi, CMVd and aGVHD, chronic Graft Versus Host Disease (cGVHD), survival and all-cause mortality. Methods: We retrospectively analyzed a cohort of 45 alloHCT recipients at high risk for CMV reactivation, from 4 Israeli transplant centers, who underwent alloHCT between January 2020 and -December 2021 and received letermovir prophylaxis (study group). A comparison was performed, to a matched historical cohort of 45 alloHCT recipients, who underwent alloHCT between 2014 and 2020 and were treated according to PET policy (control group). Matching was guided by the risk for CMV reactivation. Results: Demographics (recipient's age, gender, ethnicity), disease and pre-transplant characteristics (disease status at transplantation, donor match, conditioning intensity, graft source) of the two groups were comparable accept for a higher percentage of ABO minor mismatch in the control group versus the study group (37% compared to 6%, respectively; p=0.028). There was a higher rate of CS-CMVi during the first 100 days post-transplant in the control group versus the study group (53/3% compared to 35.6%, respectively; p=0.09). There was no difference in CMVd rate between the two groups as well as in relapse rate and overall survival. Acute and chronic GVHD incidence was higher in the control group compared to the study group (71.1% vs 60%; p=0.186 and 57.8% vs 33.3%; p= 0.02, respectively). Conclusions: Our real -world Israeli experience cohort of letermovir prophylaxis in high risk alloHCT recipients demonstrates a significant reduction in GVHD occurrence in patients receiving letermovir prophylaxis. GVHD is a significant cause of morbidity and mortality in alloHCT recipients. Our real-world experience is in line with the well-established contiguity and causal relation between CMV infection and GVHD, showing a reduction in CS-CMVi during the prophylaxis period with a corresponding reduction in acute and chronic GVHD. Our cohort is limited by its retrospective nature and a relatively small sample size. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy and Safety of Emicizumab Prophylaxis in Patients with Acquired Hemophilia a Who Were Deemed Ineligible for Immunosuppressive Therapy: Additional Data from the Ageha Study

INTRODUCTION: Acquired hemophilia A (AHA) is a potentially fatal hemorrhagic disease caused by the appearance of autoantibodies against factor VIII (FVIII). Immunosuppressive therapy (IST) is started immediately after diagnosis to eradicate FVIII inhibitors. This leads to remission in most patients, but infections often occur as side effects, leading to death in many cases. Emicizumab is a bispecific antibody that mimics the cofactor function of activated FVIII and prevents bleeds in patients with congenital hemophilia A regardless of inhibitor status. Emicizumab prophylaxis is expected to reduce the risk of severe bleeds in patients with AHA (PwAHA), and also allow at-risk patients to consider reducing or postponing IST, which would minimize its side effects. To investigate the safety and efficacy of emicizumab in PwAHA, we are conducting an ongoing, prospective, multicenter, open-label, non-randomized, phase III study (AGEHA; JapicCTI-205151). Primary analysis results of AGEHA suggest that emicizumab prophylaxis with a new loading regimen and completion criteria has a favorable benefit-risk profile in PwAHA. However, all enrolled patients in that primary analysis (cutoff date: April 23, 2021) had received IST before starting emicizumab, and the influence of IST, especially on efficacy data, cannot be completely ruled out. Here, we present efficacy and safety data of emicizumab in PwAHA deemed ineligible for IST at enrollment, which were collected after cutoff date of the primary analysis. METHODS: AGEHA consisted of 2 cohorts: patients already undergoing or scheduled to immediately undergo IST at enrollment (Cohort 1), and patients deemed ineligible for IST at enrollment (Cohort 2). Emicizumab was administered subcutaneously at 6 mg/kg on Day 1 and 3 mg/kg on Day 2 followed by 1.5 mg/kg once weekly from Day 8. Predefined dosing completion criteria included FVIII activity >50 IU/dL. No restriction was set on IST use during the study. AGEHA was conducted in accordance with relevant ethical standards. Data from the 12 patients enrolled in Cohort 1 (Patients 1 to 12) is beyond the scope of this presentation. RESULTS: By the cutoff date for the presentation (September 10, 2021), 2 patients had been enrolled in Cohort 2, and 1 patient (Patient 13) had completed emicizumab treatment. Durations of emicizumab treatment were 7.1 weeks in Patient 13 and 16.3 weeks in Patient 14. Clinical courses of the 2 patients are shown in Figure 1. Patient 13 was an 82-year-old female who was diagnosed with AHA 6 days before enrollment. She was judged ineligible for IST because of her poor performance status and diabetes. After starting emicizumab, the bleeding symptoms immediately disappeared and her general condition dramatically improved. Following treatment with intensive insulin therapy for diabetes, the investigator judged that IST was applicable to her. IST with prednisolone and cyclophosphamide was started on Day 5 and Day 27, respectively, and then FVIII inhibitor titer decreased and FVIII activity gradually improved. Criteria for completion of emicizumab were met on Day 64. Patient 14 was a 59-year-old female with AHA of long disease duration (1009 days) who had been receiving a prophylactic regimen of activated prothrombin complex concentrate before enrollment. She was judged ineligible for IST because IST had not been effective for a long time in the past, and because IST was nearly contraindicated due to a complication of infections associated with osteonecrosis of the jaw. During the pre-treatment period, the 2 patients experienced a total of 3 treated bleeds, 1 of which was a treated major bleed in Patient 13. During the on-treatment period, no treated bleeds and no major bleeds occurred in either patient. The requirement for coagulation factor products or transfusions decreased between the pre- and on-treatment periods. Both patients experienced adverse events (AEs), all 9 of which were grade 1 or 2. One AE (rash) in Patient 13 was considered related to emicizumab, but no modification or discontinuation of emicizumab was required. No thrombotic events, serious AEs, AEs leading to study discontinuation, or anti-drug antibodies were reported. CONCLUSIONS: These results suggest that emicizumab prophylaxis with the new dosing regimen and completion criteria is safe and efficacious for PwAHA ineligible for IST. Further, efficacy under the non-influence of IST was also suggested. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Venous Thromboembolism Prophylaxis in Inflammatory Bowel Disease Inpatients: Systematic Review and Meta-Analysis

Background: Inflammatory bowel disease (IBD) patients are three times more likely to develop venous thromboembolism (VTE) compared to the general population, especially during disease flares and while hospitalized. Current guidelines recommend prophylaxis during all hospitalizations, though data are sparse. In this systematic review and meta-analysis, we sought to pool all existing data on the efficacy and safety of VTE prophylaxis in hospitalized IBD patients. Methods: We performed a systematic review and meta-analysis. We searched MEDLINE and other databases up to 2/2022, for studies reporting on hospitalized IBD patients (both adult and pediatric, in medical or surgical wards), who were treated with non-therapeutic dose anti-coagulation during hospitalization, compared to no prophylaxis. Our primary efficacy outcome was any VTE (deep vein thrombosis, portomesenteric vein thrombosis, catheter-related thrombosis, and pulmonary emboli), and the primary safety outcome used was major bleeding. Results were pooled using a random-effects model meta-analysis. Odds ratios (OR) and 95% confidence intervals (CI) were calculated. Risk of bias was assessed with the ROBINS-I tool and the Cochrane Collaboration's tool for randomization method. Results: We were able to extract data from 18 observational studies, and 2 subgroups from randomized trials, published between 2003 and 2021. The studies were highly variable regarding the study populations, interventions, and outcome definitions, as well as methodological quality. Meta-analysis of all studies did not show a significant effect of prophylaxis on VTE events (OR 0.97 [95% CI 0.49-1.95]). A sensitivity analysis of 8 studies with moderate or lower risk of bias showed a statistically significant reduction in VTE events (OR 0.27 [95% CI 0.13-0.55), with a number needed to treat (NNT) of 35 (95% CI 26.8-49.8). Among studies with lower risk of bias, a significant protective effect of VTE prophylaxis persisted in subgroup analyses of long-term follow up VTEs (OR 0.24 [95% CI 0.08-0.69]), of adult patients only (OR 0.27 [95% CI 0.12-0.61]), and of a mixed population of surgical and medical patients (OR 0.37 [95% CI 0.19-0.74]). Major bleeding was reported in three studies classified with moderate or lower risk of bias, and meta-analysis showed a significantly increased risk in the prophylaxis group (OR 2.02 [95% CI 1.11-3.67], number needed to harm (NNH) of 114 (95% CI 40.7-very large number). Discussion: The main analysis did not show a reduction in VTE events in hospitalized IBD patients treated with prophylaxis. However, in studies with lower risk of bias, a protective benefit of prophylaxis consistent across several subgroups was shown (NNT=35), which should be carefully considered against an increased risk of major bleeding (NNH=114). Currently available data is limited, and mostly retrospective, and randomized controlled trials dedicated to hospitalized IBD patients are needed before universal VTE prophylaxis can be recommended. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy of Efanesoctocog Alfa on Physical Functioning: Results from the XTEND-1 Phase 3 Clinical Trial in Previously Treated Patients with Hemophilia A

Background: Adults with severe hemophilia A may have reduced levels of physical functioning significantly impacting their health-related quality of life (HRQoL). Results from the Phase 3 XTEND-1 study demonstrated that once-weekly efanesoctocog alfa prophylaxis was well-tolerated and provided superior bleed protection compared with prior factor VIII (FVIII) prophylaxis. Objective: To evaluate the efficacy of once-weekly efanesoctocog alfa prophylaxis on physical functioning in adults and adolescents (≥12 years of age) with severe hemophilia A who were previously treated with standard of care FVIII prophylaxis. Methods: XTEND-1 (NCT04161495) was a phase 3, open-label, multicenter trial in previously treated patients (≥12 years of age) with severe hemophilia A. Patients received once-weekly prophylactic efanesoctocog alfa, 50 IU/kg for 52 weeks (Arm A) or on-demand efanesoctocog alfa, 50 IU/kg for 26 weeks followed by 26 weeks of once-weekly prophylaxis ([50 IU/kg]; Arm B). Physical functioning was assessed as a secondary endpoint using hemophilia-specific HRQoL questionnaire for adults (Haem-A-QoL; in patients ≥17 years of age), Patient-Reported Outcomes Measurement Information System (PROMIS)-Short Form v2.0 physical function (PF; in patients ≥18 years of age), and as exploratory endpoints using Hemophilia Activities List (HAL; in patients ≥18 years of age), and EuroQol- 5 Dimension-5 Level (EQ-5D-5L; mobility and usual activities domains). Exit interviews, ActiGraph Activity Monitors (worn for 8 consecutive days at intervals throughout the study period), and post-hoc analysis (including psychometric analyses) were also used to evaluate physical functioning. The mean change from baseline to Week 52 in Haem-A-QoL Physical Health (PH) score, PROMIS PF 6b T-score, and HAL overall score, along with 95% confidence interval (CI) were estimated by a mixed-effect model with repeated measures. Here we report results for patients in Arm A. Results of the exit interviews and Actigraphy were evaluated in the overall patients included in the trial (Arms A and B). Results: A total of 159 patients (Arm A, N=133; Arm B, N=26) were included in the XTEND-1 trial. At baseline, the Haem-A-QoL PH score (mean [standard deviation, SD]) was 37.02 (23.83), while the overall HAL score was 76.11 [20.73]. A total of 18% (22/122) and 9% (11/122) patients reported moderate to severe problems with mobility and usual activities, respectively, at baseline, as per EQ-5D-5L. Prophylactic treatment with efanesoctocog alfa resulted in significant improvement in physical health: least square (LS) mean change in the Haem-A-QoL PH score from baseline to Week 52 was -6.74 (95% CI: -10.13 to -3.36; P=0.0001). Psychometric analyses reported meaningful within-group change for Haem-A-QoL PH score of 6.8 (range: 4.8-6.8) defined in the context used in the study. Numerical improvement was observed in PROMIS PF 6b T-score (LS mean change from baseline: 0.56 [95% CI: -0.38 to 1.50] and in HAL overall score at Week 52 (LS mean change: 0.67 [95% CI: -2.03 to 3.38]). A total of 23.5% (27/115) patients reported an improvement in at least 1 category in mobility at Week 52, while usual activities improved in 19.1% (22/115) patients in the EQ-5D-5L scale. These improvements in physical functioning on various instruments were aligned with the results from the exit interviews (N=29, including 17 patients in Arm A) reporting improvement in physical functioning in most patients (26/29). In addition, trends of improved physical activity were also observed in the Actigraphy data (mean [SD]: 5376 [3796] steps/day at baseline versus 5758 [4472] steps/day at Week 52; overall patients, N=158, including 132 patients in Arm A). Conclusions: Once-weekly prophylaxis with efanesoctocog alfa resulted in improvement in physical functioning in patients with hemophilia A, positively impacting daily living activities, in patients who were on prior standard of care FVIII prophylaxis.

Dosage, Safety and Efficacy of Posaconazole As Primary Antifungal Prophylaxis in High-Risk Recipients of Allogeneic Stem Cell Transplantation

Introduction: The use of anti-mold prophylaxis with anti-aspergillus activity is recommended for patients (pts) undergoing allogeneic hematopoietic stem cell transplantation (Allo-HSCT) with high risk of fungal infection (Maertens, J Antimicrob Chemother 2018). Yet, few data are available regarding the use of posaconazole. Methods: This retrospective study included all Allo-HSCT adult recipients having benefited from posaconazole therapy in our center as a primary anti-fungal prophylaxis for high-risk of fungal infection. The latter was defined as use of i)an alternative donor, ii)sequential conditioning regimen, iii)a regimen associated with severe mucositis, iv) post-transplant cyclophosphamide (PT-Cy) or v) previous allo-HSCT. Posaconazole was programmed to be initiated at day (D) 0 or D5/6 (in case of PT-Cy) and administered up to day 100. We report here on the residual concentration of posaconazole during the neutropenic phase then on the tolerance and efficacy of such prophylaxis in this cohort. Results: Seventy high-risk pts (males 63.3%, median age 54 years old, range 20-73) received Allo-HSCT between April 2020 and December 2021 for a myeloid (n=51), lymphoid (n=17) or non-malignant hematological (n=2) disease and received posaconazole as a primary prophylaxis. The Sorror score at transplant time was ≥ 3 for 24 pts (33.8%). Twenty-two patients had already received posaconazole as a primary prophylaxis before Allo-SCT including 26 during the neutropenic phase of their induction for AML or MDS, 3 for prolonged neutropenia, 2 during treatment with alemtuzumab for T-cell leukemia/lymphoma, and 1 during a previous AlloHCST. Four patients had also received other antifungal agentsbefore Allo-SCT (caspofongine (n=1), voriconazole (n=1) or liposomal amphotericin B (n=2)) because of a suspected mold infection which has been finally excluded. All pts had at least one high-risk criterion of fungal infection. These included the use of an alternative donor in 42 pts (haplo-identical donor n= 41, umbilical cord blood n=1), sequential conditioning regimen in 9, with PT-Cy in 57, second or third allo-HSCT in 8 and conditioning regimen associated with severe mucositis in 11 (TBI 8-12gy n=3, thiotepa-based n=8). All but one pts received posaconazole using the gastroresistant tablet form at a dose of 300mg/day. One patient received the drinkable suspension form at a dose of 200mg 3 times a day. Following prophylaxis initiation, serum posaconazole concentrations were available in 51 and 16 patients at medians of 9 and 39 days, respectively. A protective residual level of posaconazole (> 0.5mg/L) was achieved in 57% of the patients (n=29) at first assessment and 87.5% (n=12) at second evaluation. Posaconazole was stopped early due to related-toxicity in 9 cases (12.6%), including liver toxicity in 7 pts, QT prolongation in 1 and skin hyperesthesia in 1. Treatment was restarted without recurrence of toxicity in 2 cases. Posaconazole was stopped early in 2 patients due to non-related toxicity, including one veno-occlusive disease and one hepatic acute GVHD. Posaconazole was temporary discontinued in 4 patients due to a suspected fungal infection before being restarted. Most patients (n=59/70, 84.2%) did not present fungal infections while being under posaconazole therapy. Only 11 cases were documented with this complication (Table 1), including 8 invasive pulmonary aspergillosis (IPA; possible n=3; probable n=5), one possible invasive fungal infection and 2 mucormycoses (1 with possible IPA). Fungal infections occurred despite documentation of a protective residual level of posaconazole (> 0.5mg/L) in 5 of 6 evaluable patients. Of note, 9/11 patients had received PTCY as GVHD prophylaxis. Posaconazole was stopped (before D7 in 3) and other antifungal drugs started (voriconazole or liposomal amphotericin B) allowing to fungal infection cure in 5 pts. However, 7 pts died including 2 of an uncontrolled fungal infection. Conclusion: Posaconazole is a well-tolerated and efficient primary prophylaxis in recipients of Allo-HSCT at high-risk of fungal infection. As some fungal infections occured very early after D0 while prophylaxis started only a D5/6 after PTCY, our results suggests to propose posaconazole as early as the beginning of the conditionning together with dose monitoring. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Probiotic prophylaxis to prevent ventilator-associated pneumonia in children on mechanical ventilation: A randomized double-blind clinical trial.

Ventilator-Associated Pneumonia (VAP) is one of the most common nosocomial infections in the Pediatric Intensive Care Unit (PICU). Using new strategies to prevent nosocomial infections is crucial to avoid antibiotic resistance. One of these strategies is the utilization of probiotics. This study aims to investigate the efficacy of probiotic prophylaxis in preventing VAP in mechanically ventilated children. This study was a randomized, double-blind clinical trial. The study included 72 children under 12 years of age under mechanical ventilation for more than 48 h in the Mofid Children's Hospital. Patients were randomly divided into Limosilactobacillus reuteri DSM 17938 probiotic recipients (n = 38) and placebo groups (n = 34). In addition to the standard treatment, both groups received a sachet containing probiotics or a placebo twice a day. Children were screened for VAP based on clinical and laboratory evidence. The mean age of children in the intervention and placebo groups was 4.60 ± 4.84 and 3.38 ± 3.49 years, respectively. After adjusting the other variables, it was observed that chance of VAP among probiotics compared to the placebo group was significantly decreased (OR adjusted = 0.29; 95% CI: 0.09-0.95). Also, probiotic was associated with a significantly lower chance of diarrhea than the placebo group (OR adjusted = 0.09; 95% CI: 0.01-0.96). Probiotic utilization is effective in preventing the incidence of VAP and diarrhea in children under mechanical ventilation in the PICU.

Low-Dose Antithymocyte Globulin Plus Low-Dose Post-Transplant Cyclophosphamide for Prevention of Graft-Versus-Host Disease after Haploidentical Peripheral Blood Stem Cell Transplants: A Large Sample, Long-Term Follow-up Retrospective Study

Background: The use of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) to treat hematological diseases is increasing. Two regimens for in vivo T-cell depletion are currently used in haplo-HSCT for prophylaxis of graft-versus-host disease (GVHD), including anti-thymocyte globulin (ATG)-based and posttransplant cyclophosphamide (PTCy)-based regimens. Our previous studies have demonstrated that low-dose ATG plus low-dose PTCy (low-dose ATG/PTCy) combined with cyclosporine (CSA) and mycophenolate mofetil had promising activity for the prevention of GVHD in haploidentical peripheral blood stem cell transplantation (haplo-PBSCT). Now, the efficacy of the low-dose ATG/PTCy regimen for GVHD prevention in haplo-HSCT was evaluated in a large sample with a long-term follow-up. Methods: The patients undergoing haplo-PBSCT between May 2017 and June 2021 in our center were enrolled in the retrospective study. The study included a variety of hematological diseases, such as acute myeloid leukemia (AML, n=113), acute lymphoblastic leukemia (ALL, n=49), mixed phenotype acute leukemia (MPAL, n=4), myelodysplastic syndromes (MDS, n=18), chronic myeloid leukemia (CML, n=10), non-Hodgkin's lymphoma (NHL, 30) and multiple myeloma (MM, n=1). All patients received low-dose ATG/PTCy regimen for prophylaxis of GVHD including ATG 2.5 mg/kg administered on day −2 to −1 and cyclophosphamide (Cy) 50 mg/kg on day +3, cyclosporine A (CsA) and mycophenolate mofetil (MMF) initiating on day +4. The starting infusion dose of CsA was 2 mg/kg, after which the dose was modified to obtain a nadir serum level between 200 and 300 ng/ml, eventually tapering from day +90 to day +180. MMF was administered orally at 15 mg/kg three times daily (maximum dose of 3 g per day) until day +34 and discontinued if no aGvHD. Mycophenolic acid sodium enteric tablets (MPA) correspond to MMF instead. Grafts were from mobilized peripheral blood stem cells. Family members selected as haploidentical donors were defined on the HLA-A, -B, -C, -DRB1, and -DQB1 locus at the high-resolution level of the recipient donor number of human leukocyte antigen (HLA) mismatches >2. Results: Two hundred and twenty-five patients undergoing haplo-PBSCT were enrolled in the study. There were 144 males and 81 females with a median age of 38 years (range, 6 to 69 years). At the time of transplantation, 146 (64.89%, 146/225) patients were in complete response (CR), while 79 (35.11%, 79/225) patients had active disease. One hundred and five patients received myeloablative conditioning (MAC) regimens, while 40 patients received reduced-intensity conditioning (RIC) regimens. All patients received PBSC grafts with the median CD34+ cells of 10.3 (1.64-46.55) × 108/kg, and the median mononuclear cells (MNCs) was 15.35 (3.48-39.74) × 108/kg. Ten patients failed to engraft, including 6 patients with primary graft failure and 4 with secondary graft failure. The median time for neutrophil engraftment was 12 days (range, 9-28 days), while the median time for platelet engraftment was observed in 13 days (range, 9-87 days). The cumulative incidence (CI) of grades I-IV acute GVHD (aGVHD) was 30.7% (24.6-36.9%). The CIs of grades II-IV and III-IV acute GVHD by 100 days post-transplant were 12.4% (95%CI, 8.0-16.8%) and 4.6% (95%CI, 1.8-7.4%), respectively. While chronic GVHD was 31.2% (95%CI, 24.6-37.9%) and moderate/severe chronic GVHD was 16.4% (95%CI, 11.1%-21.7%). A total of 90 patients died. Fifty-nine patients died of non-relapse causes (NRM 59/225, 26.2%). With a median follow-up of 26 months (range, 0-61 months), 50 cases relapsed. The median time of relapse was 15.5 months (range, 1−46 months). The mean OS and DFS were 38.01 months (95%CI, 34.33-41.6%) and 35.45 months (95%CI, 31.75-39.15%). The 2-year disease-free survival (DFS), overall survival (OS), and GVHD-free, relapse-free survival (GRFS) was 54.8% (95%CI, 48.94-62.26%) and 60.9% (95%CI, 54.24-67.56%) and 48.0% (95%CI, 41.14-54.86%), respectively. The 2-year CI of relapse was 26.6% and NRM was 16.6%. All patients were included in immune reconstitution studies and 81 cases were analyzed at each endpoint. On days +120, median CD3+, CD4+, CD8+, CD19+ and CD56/CD16+ counts were 954 (95-4891), 180 (8-743),754 (73-4272), 34 (1-276) and 215 (19-2539)/μl, respectively. Conclusion: The low-dose ATG/PTCy regimen presented a high efficacy for prophylaxis of GVHD in haplo-PBSCT.

Antibacterial and Anti-Inflammatory Properties of Peptide KN-17.

Peri-implantitis, an infectious disease originating from dental biofilm that forms around dental implants, which causes the loss of both osseointegration and bone tissue. KN-17, a truncated cecropin B peptide, demonstrated efficacy against certain bacterial strains associated with peri-implantitis. This study aimed to assess the antibacterial and anti-inflammatory properties and mechanisms of KN-17. The effects of KN-17 on oral pathogenic bacteria were assessed by measuring its minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). Moreover, the cytotoxicity and anti-inflammatory effects of KN-17 were evaluated. KN-17 inhibited the growth of Streptococcus gordonii and Fusobacterium nucleatum during in vitro biofilm formation and possessed low toxicity to hBMSCs cells. KN-17 also caused RAW264.7 macrophages to transform from M1 to M2 by downregulating pro-inflammatory and upregulating anti-inflammatory factors. It inhibited the NF-κB signaling pathway by reducing IκBα and P65 protein phosphorylation while promoting IκBα degradation and nuclear P65 translocation. KN-17 might be an efficacious prophylaxis against peri-implant inflammation.

Infective endocarditis in adult patients with congenital heart disease

BackgroundCongenital Heart Disease (CHD) predisposes to Infective Endocarditis (IE), but data about characterization and prognosis of IE in CHD patients is scarce. MethodsThe ESC-EORP-EURO-ENDO study is a prospective international study in IE patients (n = 3111). In this pre-specified analysis, adult CHD patients (n = 365, 11.7%) are described and compared with patients without CHD (n = 2746) in terms of baseline characteristics and mortality. ResultsCHD patients (73% men, age 44.8 ± 16.6 years) were younger and had fewer comorbidities. Of the CHD patients, 14% had a dental procedure before hospitalization versus 7% in non-CHD patients (p < 0.001) and more often had positive blood cultures for Streptococcus viridans (16.4% vs 8.8%, p < 0.001). As in non-CHD patients, IE most often affected the left-sided valves. For CHD patients, in-hospital mortality was 9.0% vs 18.1% in non-CHD patients (p < 0.001), and also, during the entire follow-up of 700 days, survival was more favorable (log-rank p < 0.0001), even after adjustment for age, gender and major comorbidities (Hazard Ratio (HR) 0.68; 95%CI 0.50–0.92). Within the CHD population, multivariable Cox regression revealed the following effects (HR and [95% CI]) on mortality: fistula (HR 6.97 [3.36–14.47]), cerebral embolus (HR 4.64 [2.08–10.35]), renal insufficiency (HR 3.44 [1.48–8.02]), Staphylococcus aureus as causative agent (HR 2.06 [1.11–3.81]) and failure to undertake surgery when indicated (HR 5.93 [3.15–11.18]). ConclusionsCHD patients with IE have a better outcome in terms of all-cause mortality. The observed high incidence of dental procedures prior to IE warrants further studies about the current use, need and efficacy of antibiotic prophylaxis in CHD patients.

Determination of the Postexposure Prophylactic Benefit of Oral Azithromycin and Clarithromycin Against Inhalation Anthrax in Cynomolgus Macaques.

Sufficient and diverse medical countermeasures against severe pathogenic infections, such as inhalation anthrax, are a critical need. Azithromycin and clarithromycin are antimicrobials commonly used for both upper and lower respiratory infections. They inhibit protein synthesis by blocking the formation of the 50S ribosomal subunit. To expand the armamentarium, these 2 antibiotics were evaluated in a postexposure prophylactic model of inhalation anthrax in cynomolgus macaques. This prophylaxis study had 4 test arms: azithromycin, clarithromycin, a levofloxacin control, and a placebo. Beginning 24 hours after exposure to a target challenge dose of 200 lethal dose 50 (LD50) of Bacillus anthracis Ames spores, animals were treated orally until 30 days postchallenge and then observed until 75 days postchallenge. The test group that received clarithromycin had a survival rate of 67%. The test group that received azithromycin had a survival rate of 50%, but the peak azithromycin plasma levels achieved were <30 ng/mL-much lower than the expected 410 ng/mL. The levofloxacin positive control had a survival rate of 50%; all of the negative controls succumbed to infection. The efficacy of clarithromycin prophylaxis was statistically significant compared with placebo, while azithromycin prophylaxis was indistinguishable from placebo. Given the low plasma concentrations of azithromycin achieved in the study, it is not surprising that half the animals succumbed to anthrax during the dosing period; the animals that survived beyond the time during which placebo control animals succumbed survived to the end of the observation period.

Outcomes of high‑dose methotrexate for CNS prophylaxis in diffuse large B‑cell lymphoma with an intermediate or high CNS‑International Prognostic Index: A single‑center retrospective cohort study.

Central nervous system (CNS) relapse in patients with diffuse large B-cell lymphoma (DLBCL) is rare (2-5% of cases), but is a devastating complication with a poor survival rate. The administration of high-dose methotrexate (HDMTX) for CNS prophylaxis in patients with DLBCL is controversial and variable in the literature. The present study aimed to evaluate the clinical outcomes of HDMTX CNS prophylaxis in patients with intermediate and high CNS-International Prognostic Index (IPI) DLBCL using real-world data. An observational retrospective cohort study was conducted of all patients with intermediate and high CNS-IPI DLBCL treated at Princess Noorah Oncology Center (King Abdulaziz Medical City, Jeddah, Saudi Arabia) between January 2010 and December 2020. Patients were treated with HDMTX either intravenously or intrathecally, according to the physician's evaluation of the patient. Data on patient clinical characteristics, CNS relapses, risk factors and survival rates were obtained from hospital records. Data were analyzed using Student's unpaired t-test and the χ2 test to compare the two subgroups, the Kaplan-Meier survival method with log-rank test to calculate and compare the survival rates, and regression analysis to determine the risk factors for CNS relapse and death. The study included 358 patients (n=32 with HDMTX CNS prophylaxis and n=326 without CNS prophylaxis). Patients in the CNS prophylaxis group had a significantly higher CNS relapse rate than those in the non-CNS prophylaxis group (12.5% vs. 1.8%; P=0.008). Patients who received CNS prophylaxis were younger and had an advanced stage of disease, with extranodal involvement and a high serum lactate dehydrogenase level at presentation. CNS prophylaxis was significantly associated with CNS relapse, while relapsed disease was associated with the risk of death (all P<0.05). In conclusion, the present study found that patients with intermediate and high CNS-IPI who received HDMTX CNS prophylaxis did not have fewer CNS relapses; however, those without CNS relapse had higher survival rates. In addition to CNS prophylaxis, Stage of DLBCL and IPI were significantly associated with CNS relapse. Future randomized control trials are needed to evaluate the efficacy of HDMTX CNS prophylaxis in patients with DLBCL.

Factors associated with suboptimal retention in HIV pre-exposure prophylaxis care among men who have sex with men

ABSTRACT Despite the efficacy of HIV pre-exposure prophylaxis (PrEP), retention in care in the United States remains suboptimal. The goal of this study was to explore factors that lead to suboptimal retention in PrEP care for men who have sex with men (MSM) in real-world clinical settings in the United States. Trained interviewers conducted semi-structured interviews with MSM (N = 49) from three clinics who had been engaged in PrEP care in the Midwest (n = 15), South (n = 15), and Northeast (n = 19) geographic regions and had experienced a lapse in PrEP use. Factors that emerged as related to suboptimal retention in PrEP care included structural factors such as transportation and out-of-pocket costs; social factors such as misinformation on media and in personal networks; clinical factors such as frequency and timing of appointments; and behavioral factors such as changes in sexual behavior and low perceived risk for HIV. Participants suggested reducing the out-of-pocket costs of medications and lab visits, having flexible appointment times, culturally responsive services, and comprehensive patient navigation to help retention in care. These findings leveraged real-world experiences and opinions of patients to inform gaps in current services and how to make changes to optimize PrEP care.

Prophylaxis for the Prevention of PJI after TAA: Is It Economically Justifiable?

Category: Ankle Arthritis; Ankle; Other Introduction/Purpose: Prosthetic joint infection (PJI) is a costly and potentially fatal complication in total ankle arthroplasty (TAA). Some surgeons will use intraoperative vancomycin powder or copiously irrigate the surgical site with Povidone-iodine to prevent this outcome. Additionally, many surgeons will prescribe a short course of postoperative antibiotics. However, the efficacy of such prophylaxis continues to be debated, and little is known about the cost-effectiveness of these agents. Therefore, the purpose of this study was to perform a 'break-even' analysis to determine the number of cases that could be performed while only preventing a single PJI and still breaking even on cost. Methods: The literature was searched to determine the rate of PJI and the mean cost of total ankle replacement. The prices of topical vancomycin powder and Povidone-iodine were obtained from our institution's purchasing records. An online drug database was then used to determine the cost of a 14 day twice daily course of Sulfamethoxazole/Trimethoprim (800/160 mg), Cephalexin (500 mg), and Amoxicillin/Potassium Clavulanate (875/125 mg). A break-even analysis was then performed to determine the absolute risk reduction (ARR) necessary to make a drug cost-effective. Using the ARR, we calculated the number of patients that would need to be treated with these agents to prevent a single PJI (NNT). Results: The price of intraoperative vancomycin powder was found to be $3.06 while povidone-iodine was found to cost $3.64. Sulfamethoxazole/Trimethoprim (800/160 mg), Cephalexin (500 mg), and Amoxicillin/Potassium Clavulanate (875/125 mg) were determined to cost $3.00, $3.64, and $14.51, respectively. At the prices obtained Vancomycin Powder, Povidone-iodine, Sulfamethoxazole/Trimethoprim, and Cephalexin were all cost-effective if the initial rate decreased by ARRs of 0.01%. Likewise, Amoxicillin/Potassium Clavulanate was cost-effective if the initial rate decreased by an ARR of 0.03%. Additional analyses run found that all drugs-maintained cost-effectiveness even if the initial rate of PJI was as low as 0.1%. Conclusion: PJI following TAA is devastating and costly. Despite the ongoing debate regarding the efficacy of prophylactic measures to reduce the risk of PJI in TAA, limited is known about their cost-effectiveness. Our study demonstrates that intraoperative vancomycin powder, povidone-iodine lavage, and multiple commonly prescribed antibiotics are all highly cost- effective to prevent PJI following TAA. We feel that a tailored approach to taking measures to reduce PJI with cost-effectiveness in mind is crucial to providing value-based care.

Efficacy of Ciprofloxacin in Prevention of Sepsis Among the Patients with Chemotherapy-Induced Neutropenia: A Randomized Double-Blind Clinical Trial in a University Hospital in Tehran, Iran

Background: Neutropenia is a common side effect of chemotherapy and one of the most common causes of severe infection and mortality in patients with hematological malignancies. Some studies showed that antimicrobial prophylaxis resulted in lower febrile neutropenia (FN) episodes and mortality rates. Objectives: We aimed to determine the efficacy of prophylaxis with ciprofloxacin in patients with hematological malignancies. Methods: In a randomized double-blinded clinical trial from 1 March to 1 September 2016, we assigned patients with chemotherapy-induced neutropenia into two groups. We used the random permuted blocks method for randomization. The first group received oral ciprofloxacin at a dose of 500 milligrams daily until the neutrophil count reached 1000 cells per microliter or fever occurrence, defined as the primary outcome. The second group received a placebo in the same shape and size. We compared FN episodes and the mortality rate in these two groups by SPSS-22 software, using chi-square, Fischer's exact tests, and student t-test at P-value &lt; 0.05. Results: Seventy-three males (60.8%) and 47 females (39.2%) entered our study. The mean age of the patients was 47 ± 14.6 years. Acute leukemia was the most common underlying malignancy in 81 out of 120 subjects (67.5%). Fever (P = 0.005) was significantly lower in the ciprofloxacin group, but the mortality rate (P = 0.783) did not differ between the two groups. Conclusions: We found that the prophylaxis with ciprofloxacin decreased FN in our patients but did not influence the mortality rate. We believe that antimicrobial prophylaxis may be helpful in neutropenic patients, especially in decreasing FN and its related comorbidity.

Preoperative antibiotic prophylaxis in mastectomy: A retrospective comparative analysis of 1413 patients with breast cancer.

The reported rate of surgical site infections (SSIs) in breast cancer surgery varies widely in previous literature. The use of antibiotic prophylaxis is controversial but recommended by several guidelines. The aim of this study was to evaluate the efficacy of routine antibiotic prophylaxis in patients with breast cancer undergoing mastectomy. In this retrospective single-institution study, we reviewed 1413 consecutive female breast cancer patients who underwent mastectomy and/or axillary lymph node surgery between years 2012 and 2019. Prophylactic antibiotics for all patients undergoing mastectomy was introduced in our hospital in 2016 and before that the prophylaxis was prescribed individually on surgeons' preference. All patient records for 30 postoperative days were evaluated in detail and all SSIs were recorded. The rate of SSIs was compared between patients who received antibiotic prophylaxis and those who did not. A multivariate logistic regression model was used to define the odds ratio (OR) for the efficacy of antibiotic prophylaxis. A total of 335 patients underwent mastectomy without antibiotic prophylaxis and 1078 with prophylaxis. The rate of SSIs was 6.9% in patients who received prophylaxis and 6.3% in patients without prophylaxis (p = 0.70). The rate of SSIs was similar before and after the introduction of regular antibiotic prophylaxis and there was no difference in any of the patient subgroups investigated. In multivariable logistic regression analysis, the OR for antibiotic prophylaxis was 1.04 (95% CI: 0.62-1.73, p = 0.88). Routine use of antibiotic prophylaxis did not reduce the rate of SSIs in mastectomy. Unselective antibiotic prophylaxis for all patients does not seem mandatory in mastectomy.

Effect of a Reminder System on Pre-exposure Prophylaxis Adherence in Men Who Have Sex With Men: Prospective Cohort Study Based on WeChat Intervention.

BackgroundThe efficacy of pre-exposure prophylaxis (PrEP) is highly dependent on adherence, and one of the main reasons for poor adherence is forgetfulness. Therefore, it is important to explore how to remind users to take their medicine on time.ObjectiveThis study aims to explore the effect of a reminder system on PrEP adherence in men who have sex with men (MSM) to improve adherence. The main function of the reminder system based on the WeChat social media app is to send daily messages to PrEP users reminding them to take their medicine.MethodsAn open-label, multicenter, prospective cohort study of PrEP in HIV-negative MSM was conducted from November 2019 to June 2021. Study participants who met the criteria were randomly divided into 2 groups: no-reminder group and reminder group. Both groups received daily oral PrEP with follow-up every 3 months. Adherence was measured on the basis of self-report and was defined as the percentage of medications taken on time. Participants in the reminder group scanned a WeChat QR code and received a reminder message every day. Participants in the no-reminder group took daily oral medicines without reminders. The longitudinal trajectories of adherence for both groups were displayed to compare the variability in adherence at each time point. The association between the changes in adherence (no change, improvement, decline) at each time point and the use of the reminder system was analyzed by multinomial logistic regression models to further explore the effectiveness of the system.ResultsA total of 716 MSM were included in the analysis, that is, 372 MSM in the no-reminder group and 344 MSM in the reminder group. Adherence in the no-reminder group fluctuated between 0.75 and 0.80 and that in the reminder group gradually increased over time from 0.76 to 0.88. Adherence at each time point was not statistically different between the 2 groups. Further analysis showed that an improvement in adherence in the early stage was associated with the use of the reminder system (odds ratio [OR] 1.65, 95% CI 1.01-2.70; P=.04). An improvement in average adherence compared to initial adherence was positively associated with the use of the reminder system (OR 1.82, 95% CI 1.10-3.01; P=.02).ConclusionsThe effect of the reminder system on PrEP adherence in MSM was more significant in the early stage, which is related to the increased motivation of users and the development of medicine-taking habits. The reminder system is potentially effective for early-stage medicine management, encouraging users to develop healthy medicine-taking habits and to increase their adherence.Trial RegistrationChinese Clinical Trial ChiCTR190026414; http://www.chictr.org.cn/showproj.aspx?proj=35077

Antimicrobial prophylaxis and the rate of blood stream infections and Clostridioides difficile in pediatric stem cell transplantation: A single-center retrospective study.

The use of prophylactic antibiotics in the pre-engraftment period to minimize the risk of bacteremia is debatable given concerns of Clostridioides difficile (C.diff), antibiotics resistance, and disruption of gut microbiota. We retrospectively reviewed the rate and characteristics of bacteremia and C.diff infections within the first 100 days post-HSCT in all pediatric patients who received routine antibacterial prophylaxis during HSCT from 2015 to 2018. C.diff infection was defined by the presence of three or more unformed stools in 24h and positive stool test for C.diff or its toxins. One hundred and thirty-five (100 allogeneic and 35 autologous) transplants in 123 patients were eligible for analysis. Median age at transplant was 7.1 (range 0.2-13.7), 67 (55%) were women, and diagnosis was malignant condition in 68 patients. Median time to neutrophil engraftment was 18 days (13-23). Cefepime or piperacillin-tazobactam prophylaxis was used in 105 (78%) and 28 (21%) of patients, respectively. Only five (3%) patients had bacteremia during the pre-engraftment period, and 13 (11%) patients developed bacteremia postengraftment. Septic shock was present in only one patient pre-engraftment and was due to gram-negative bacteria. All patients who developed bacteremia received MAC. Thirteen patients (10%) of patients fulfilled C.diff infection definition. There was no mortality related to bacterial infections among our patients. The use of antibiotic prophylaxis was associated with low rate of bacteremia in the pre-engraftment period and a 10% risk of C.diff infections. More studies are needed to better evaluate the efficacy of antibiotic prophylaxis in HSCT patients.

Female Genital Fibroblasts Diminish the In Vitro Efficacy of PrEP against HIV.

The efficacy of HIV pre-exposure prophylaxis (PrEP) is high in men who have sex with men, but much more variable in women, in a manner largely attributed to low adherence. This reduced efficacy, however, could also reflect biological factors. Transmission to women is typically via the female reproductive tract (FRT), and vaginal dysbiosis, genital inflammation, and other factors specific to the FRT mucosa can all increase transmission risk. We have demonstrated that mucosal fibroblasts from the lower and upper FRT can markedly enhance HIV infection of CD4+ T cells. Given the current testing of tenofovir disoproxil fumarate, cabotegravir, and dapivirine regimens as candidate PrEP agents for women, we set out to determine using in vitro assays whether endometrial stromal fibroblasts (eSF) isolated from the FRT can affect the anti-HIV activity of these PrEP drugs. We found that PrEP drugs exhibit significantly reduced antiviral efficacy in the presence of eSFs, not because of decreased PrEP drug availability, but rather of eSF-mediated enhancement of HIV infection. These findings suggest that drug combinations that target both the virus and infection-promoting factors in the FRT—such as mucosal fibroblasts—may be more effective than PrEP alone at preventing sexual transmission of HIV to women.

Analysis of fibrinogen concentrate pharmacokinetics and dosing for bleeds and surgery in adults, adolescents, and children with congenital afibrinogenaemia and hypofibrinogenaemia.

Congenital afibrinogenaemia and hypofibrinogenaemia are rare coagulation disorders where clotting is impaired due to a lack of fibrinogen. Consequent bleeding episodes (BEs) are treated using human fibrinogen concentrate (HFC). This post-hoc analysis compared HFC pharmacokinetics (PK) and dosing between patient age groups and defined the in vivo recovery (IVR) for children with a- and hypofibrinogenaemia. The analysis used data from the FORMA-01 (Phase 2), FORMA-02 and FORMA-04 (Phase 3) multinational, prospective, open-label studies in patients with a- and hypofibrinogenaemia. HFC PK in adults/adolescents (≥12 years; FORMA-01) and children (<12 years; FORMA-04) was examined. Haemostatic efficacy in BE treatment and perioperative prophylaxis was examined in FORMA-02 and FORMA-04 using an objective 4-point scale, with success defined as excellent/good. Median (range) age was 23 years for FORMA-01 (12-53; n=22), 26.5 years for FORMA-02 (12-54; n=25), and 6 years for FORMA-04 (1-10; n=13). Mean PK parameters were lower for children (AUC, Cmax , IVR; p=.02), while clearance was higher. Median (range) total dose of HFC for all BEs was 59.41mg/kg (32.12-273.80) in adults/adolescents and was 24% higher (ns) in children at 73.91mg/kg (47.45-262.50). Treatment was successful in 98.9% of the 89 BEs in adults/adolescents and in 100% of the 10 BEs in children, with comparable results for perioperative prophylaxis. As expected, HFC PK differed between adults/adolescents and children. However, with the higher doses given to children, HFC showed similar efficacy across age groups. Dose adaptation based on age groups appears recommendable.

Substance Use and Healthcare Utilization Across the Pre-Exposure Prophylaxis (PrEP) Care Cascade among Black and Latino Men Who Have Sex with Men

Background: Despite the documented efficacy of pre-exposure prophylaxis (PrEP) for HIV prevention, large disparities in uptake and adherence exist among Black and Latino/Hispanic men who have sex with men (BLMSM). Limited data exists among BLMSM on the impact of substance use at different stages of the PrEP Care Cascade. We examined the ways substance (alcohol, cannabis, other drug) use is related to PrEP experiences across the PrEP Care Cascade (PrEP aware/no use; PrEP use/discontinuation; PrEP use/adherent). Methods: We utilized data from a national sample of 908 BLMSM (Mage = 25.17, range: 18–29), collected between February and October 2020. Results: We found that heavier alcohol use, more other drug (e.g., cocaine) use, more participant healthcare utilization, and higher number of partners across all measures of substance use were separately associated with a lower likelihood of being aware of PrEP. These same factors were also associated with a higher likelihood of PrEP adherence. Conversely, only cannabis use was associated with discontinuation of PrEP use. Conclusions: While we confirm some earlier findings (i.e., alcohol use is associated with both PrEP discontinuation and PrEP use), we newly identify cannabis as a barrier to the adherence of PrEP. Our findings highlight the need for improved PrEP interventions to increase awareness among BLMSM with substance use who are among the most at-risk for HIV infection.