Highlights • Staphylococcus aureus causes serious, life-threatening infections. • Increasing antibiotic resistance has driven the search for alternate therapies. • No S. aureus vaccine approach has ...been successful thus far. • Approaches to solve issues surrounding S. aureus vaccine development are presented.
Ligands for the proinflammatory C-C chemokine receptor types 2 and 5 (CCR2 and CCR5) are elevated in the eyes of patients with diabetic macular edema (DME). We evaluated the efficacy and safety of ...PF-04634817, an oral CCR2/5 dual antagonist, versus intravitreal ranibizumab, in adult subjects with DME.
In this phase II, randomized, placebo-controlled, double-masked study, eligible subjects (≥18 years of age) had type 1 or 2 diabetes and DME with best-corrected visual acuity (BCVA) of 20/32 or worse (letter score ≤ 78), and up to 20/320 or better (≥24 letter score), in the study eye. Subjects were assigned randomly 1:1 to once-daily (QD) oral PF-04634817 200 mg plus masked sham therapy as placebo or monthly intravitreal ranibizumab 0.3/0.5 mg plus QD oral placebo. The primary objective was to evaluate the efficacy of PF-04634817 compared with ranibizumab in change from baseline in BCVA after 12 weeks in a noninferiority design. Noninferiority was based on BCVA 80% confidence interval (CI): there had to be a less than three letter loss in the PF-04634817 arm compared with the ranibizumab arm.
A total of 199 subjects were randomized. Least squares mean difference in change in BCVA from baseline to week 12 in the study eye for the PF-04634817 arm was -2.41 letters (80% CI: -3.91, -0.91; P = 0.04) compared with ranibizumab. PF-04634817 was well tolerated.
Treatment with oral CCR2/5 receptor dual antagonist PF-04634817 was associated with a modest improvement in BCVA, but did not meet the predefined noninferiority criteria compared with intravitreal ranibizumab.
Staphylococcus aureus is a versatile pathogen of medical significance, using multiple virulence factors to cause disease. A prophylactic S. aureus 4-antigen (SA4Ag) vaccine comprising capsular ...polysaccharide (types 5 and 8) conjugates, clumping factor A (ClfA) and manganese transporter C (MntC) is under development. This study was designed to characterize S. aureus isolates recovered from infected patients and also to investigate approaches for examining expression of S. aureus vaccine candidates and the host response during human infection. Confirmation of antigen expression in different disease states is important to support the inclusion of these antigens in a prophylactic vaccine. Hospitalized patients with diagnosed S. aureus wound (27) or bloodstream (24) infections were enrolled. Invasive and nasal carriage S. aureus isolates were recovered and characterized for genotypic diversity. S. aureus antigen expression was evaluated directly by real-time, quantitative, reverse-transcriptase PCR (qRT-PCR) analysis and indirectly by serology using a competitive Luminex immunoassay. Study isolates were genotypically diverse and all had the genes encoding the antigens present in the SA4Ag vaccine. S. aureus nasal carriage was detected in 55% of patients, and in those subjects 64% of the carriage isolates matched the invasive strain. In swab samples with detectable S. aureus triosephosphate isomerase housekeeping gene expression, RNA transcripts encoding the S. aureus virulence factors ClfA, MntC, and capsule polysaccharide were detected by qRT-PCR. Antigen expression was indirectly confirmed by increases in antibody titer during the course of infection from acute to convalescent phase. Demonstration of bacterial transcript expression together with immunological response to the SA4Ag antigens in a clinically relevant patient population provides support for inclusion of these antigens in a prophylactic vaccine.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Obesity, metabolic syndrome (MetS), and diabetes are frequent in surgical populations and can enhance susceptibility to postoperative surgical site infections. Reduced neutrophil function has been ...linked with diabetes and risk of
infection. Therefore, neutrophil function in diabetic and obese subjects (± MetS) was assessed in this prospective serological and cellular surveillance study to determine whether vaccines administered to protect against infections after surgery could be effective in these populations.
Neutrophil function (chemotaxis, phagocytosis, and opsonophagocytic killing of
) was assessed in subjects classified according to diabetes status, body mass index, and presence/absence of MetS. Neutrophils were characterized within functional subsets by flow cytometry. A serologic assay was used to measure baseline antibody presence to each antigen in SA4Ag: capsular polysaccharide (CP) type 5, CP8, recombinant mutant Clumping factor A (rmClfA), and recombinant Manganese transport protein C (rMntC).
Neutrophil function was similar for comorbid and healthy cohorts, with no significant between-group differences in cell counts, migration, phagocytosis ability, neutrophil subset proportions, and
killing ability when neutrophils were isolated 3-6 months apart (Visit 1 n = 90 and Visit 2 n = 70) and assessed. Median pre-existing antibody titers to CP5, CP8, and rmClfA were comparable for all cohorts (insufficient subjects with rMntC titers for determination).
MetS, diabetes, and obesity do not impact in vitro neutrophil function with regard to
killing, suggesting that if an effective
vaccine is developed it may be effective in individuals with these comorbidities.
Background:
Spine operations may be indicated for treatment of diseases including vertebral injuries, degenerative spinal conditions, disk disease, spinal misalignments, or malformations. Surgical ...site infection (SSI) is a clinically important complication of spine surgery.
Staphylococcus aureus
, including methicillin-resistant
Staphylococcus aureus
(MRSA), is a leading cause of post-spinal SSIs.
Methods:
PubMed and applicable infectious disease conference proceedings were searched to identify relevant published studies. Overall, 343 full-text publications were screened for epidemiologic, mortality, health care resource utilization, and cost data on SSIs associated with specified spine operations.
Results:
Surgical site infection rates were identified in 161 studies from North America, Europe, and Asia. Pooled average SSI and
S. aureus
SSI rates for spine surgery were 1.9% (median, 3.3%; range, 0.1%–22.6%) and 1.0% (median, 2.0%; range, 0.02%–10.0%). Pooled average contribution of
S. aureus
infections to spinal SSIs was 49.3% (median, 50.0%; range, 16.7%–100%). Pooled average proportion of
S. aureus
SSIs attributable to MRSA was 37.9% (median, 42.5%; range, 0%–100%). Instrumented spinal fusion had the highest pooled average SSI rate (3.8%), followed by spinal decompression (1.8%) and spinal fusion (1.6%). The SSI-related mortality rate among spine surgical patients ranged from 1.1%–2.3% (three studies). All studies comparing SSI and control cohorts reported longer hospital stays for patients with SSIs. Pooled average SSI-associated re-admission rate occurring within 30 d from discharge ranged from 20% to 100% (four studies). Pooled average SSI-related re-operation rate was 67.1% (median, 100%; range, 33.5%–100%). According to two studies reporting direct costs, spine surgical patients incur approximately double the health care costs when they develop an SSI.
Conclusions:
Available published studies demonstrate a clinically important burden of SSIs related to spine operations and the substantial contribution of
S. aureus
(including MRSA). Preventive strategies aimed specifically at
S. aureus
SSIs could reduce health care costs and improve patient outcomes for spine operations.
Patients undergoing arthroplasty are at considerable risk of experiencing post-operative complications, including surgical site infections (SSIs). In addition to potential economic consequences, SSIs ...can have a negative impact on patient outcomes and may potentially be life-threatening. Staphylococcus aureus has been consistently shown as the leading cause of SSIs associated with orthopedic surgery, with an important contribution from methicillin-resistant S. aureus (MRSA). This study evaluated the global burden of SSIs among patients undergoing orthopedic surgical procedures, and specifically those undergoing knee and hip arthroplasties.
An extensive search of PubMed and recent conference proceedings was conducted. English articles published between 2003 and 2013 pertaining to SSI epidemiology, patient outcomes, and healthcare resource utilization and costs were reviewed.
Overall, 81 studies were included, mainly from North America and Europe. Median SSI and S. aureus SSI rates, calculated as percentage of all arthroplasty procedures, were 1.7% (range: 0.25%-4.4%; 15 studies) and 0.6% (range: 0.1%-23%), respectively. Median SSI rates were 1.3% (range: 0.05%-19%; 22 studies) after knee arthroplasty, and 2.1% (range: 0.05%-28%; 24 studies) after hip arthroplasty. S. aureus SSI rates ranged from 0.2%-2.4% and 0.18%-3.8% for patients undergoing knee and hip arthroplasty, respectively. The percentage of S. aureus SSIs because of MRSA varied widely within each patient category. SSI-related mortality data (14 studies) showed that in-hospital mortality rates were low (1.2%-2.5%), but increased with time after index arthroplasty procedure (up to 56% over 1 y). Studies assessing healthcare resource utilization (n = 21) revealed that developing post-orthopedic SSIs resulted in a two- to three-fold increase in length of hospital stay (LOS) compared with non-infected patients (median LOS: 18.9 d vs. 6 d for non-SSI patients). Patients with SSIs because of methicillin-resistant staphylococci incurred greater mean LOS compared with SSIs because of methicillin-sensitive organisms. Readmission rates reported in 11 studies indicate a greater likelihood in the presence of SSIs; comparison across studies was not feasible because of differences in data reporting. Consistent with increased healthcare resource utilization (LOS and readmission) associated with SSIs, cost studies (n = 23) revealed that the presence of SSIs was associated with up to three-fold cost increase compared with the absence of SSI across all orthopedic patient categories assessed.
SSIs are associated with increased morbidity, mortality rates, healthcare resource utilization, and costs. Despite the relatively low SSI incidence following orthopedic surgery and specifically arthroplasty, preventive methods, specifically those targeting S. aureus, would serve to minimize costs and improve patient outcomes.
Highlights • SA4Ag is a novel multiantigen vaccine that targets S. aureus virulence factors. • A single dose of SA4Ag was well-tolerated in healthy adults aged 18–64 years. • A robust functional ...immune response was elicited to each vaccine component. • Antibody rise was rapid and sustained after one dose of SA4Ag vaccine. • SA4Ag is a promising candidate vaccine to prevent invasive S. aureus infections.
Background: MGTA-145, a CXCR2 agonist, has shown promising activity for hematopoietic stem cell (HSC) mobilization with plerixafor in pre-clinical models and healthy volunteers. It has the potential ...to become the first GCSF free regimen for HSC mobilization/apheresis in preparation for transplant, with fewer side effects, better patient experience and optimal resource utilization.
Methods: We conducted a single center phase 2 trial of MGTA-145 + plerixafor for HSC mobilization in patients with multiple myeloma (MM), NCT04552743. Primary endpoint was collection of ≥2 x 10 6 CD34+ cells/kg in up to 2 days of mobilization/apheresis. Secondary endpoints were collection of 4 and 6 x 10 6 CD34+ cells/kg, safety and engraftment. Patients with MM, 18-70 years of age, within 1 year of starting treatment & CrCl > 30 ml/min were eligible.
Patients received plerixafor 0.24 mg/kg (0.16 mg/kg if renal dysfunction) SQ, followed 2 hours later by MGTA-145 (0.03 mg/kg) IV over 3-10 minutes and apheresis within 30 minutes. Mobilization and collection were repeated for a second consecutive day if day 1 yield was < 6 x 10 6 CD34+ cells/kg.
The study was open-label single arm trial of 15 patients. If 13 or more patients met primary endpoint, an expansion cohort of 10 patients was planned. The trial has 85% power at a 5% one-sided type I error rate. Our analysis is based on aggregated results from total cohort of 25 patients.
Results: Median age was 62 years, 52% were female, 24% had ISS stage 3, 57% had high-risk FISH (primarily gain1q). Induction therapy was VRD in 68% (17), daratumumab VRD in 24% (6), CyBorD in 8% (2) patients. Median duration of induction was 4 months (3-6) and median lenalidomide exposure was 5 cycles (1-8), with > VGPR in 88% of patients. (Table 1)
Plerixafor 0.24 mg/kg was given in 24 (96%) patients. Median pre-apheresis CD34 count was day 1, 24/uL (3-99) & day 2, 15/uL (5-46). Median total HSC cell yield (CD34+ cells/kg x 10 6) was 5.0 (1.1-16.2), day 1 yield was 3.4 (0.3-16.2) and day 2 yield was 1.9 (0.5-4.6) (Fig1). 88% (n=22) of patients met the primary endpoint of collecting sufficient HSCs in < 2 days of mobilization + apheresis to proceed to transplant, 68% (17) in 1 day (2 x 10 6 CD34+ cells/kg). 3 patients who did not meet primary endpoint successfully collected HSCs with standard GCSF + plerixafor dosing & 2-3 apheresis sessions. Secondary endpoints of 4 and 6 x 10 6 CD34+ cells/kg in < 2 days were met in 68% (17) and 40% (10) patients.
MGTA-145+plerixafor was well tolerated. At least 1 treatment emergent AE (TEAE) with MGTA-145 was seen in 60% of patients (grade 1, n= 14, grade 2, n=1). Pain (all grade 1) was most common, seen in 44% (11), with 38% (9) patients experiencing acute onset transient bone pain with MGTA-145 (duration: 7 minutes, range: 3-28). Using the validated Brief Pain Inventory, 56% (14) patients self-reported pain with mobilization vs 40% (10) at baseline. 7/15 patients without baseline pain reported pain with mobilization. An increase for worst pain was seen on mobilization day 1, that returned to the baseline, but no difference for aggregate score of pain severity/interference (linear mixed effects model).
At last follow-up, 18 patients have completed transplant with MGTA-145 mobilized graft, with melphalan 200 mg/m 2 in 15 (83%) patients. Median of 3.5 (2.2-8.1) x 10 6 CD34+ cells/kg were infused. All patients have engrafted. Median time to neutrophil engraftment of 12 days (range: 11-15) & platelet engraftment (platelets > 20,000, no transfusion in 7 days) of 17.5 days (15-33) are comparable to historical data (DiPersio et al. 2009). RBC transfusion was needed in 3 (17%) patients. 14 patients have day 100 follow-up, all with durable engraftment.
MGTA-145 + plerixafor mobilized grafts had a favorable graft composition. We observed high enrichment for CD90+CD45RA- among CD34+ cells, a CD34 subset of long term engrafting HSCs (median: 36% of CD34+ cells, range 10-66%, N=25). 74% (17 of 23) grafts were minimal residual disease negative with next generation flow cytometry.
Conclusions: This is the first study to evaluate the novel G-CSF-free regimen of MGTA-145 + plerixafor for HSC cell mobilization & collection for hematologic malignancies. The study cohort was representative of transplant eligible patients with MM, with 88% patients meeting the primary endpoint. The regimen was well tolerated. Patients achieved timely & durable engraftment. Our data support further development of this regimen for rapid HSC mobilization.
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Sidana: Janssen: Consultancy, Research Funding; Allogene: Research Funding; Magenta Therapeutics: Consultancy, Research Funding; BMS: Consultancy. Kumar: Bluebird Bio: Consultancy; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Carsgen: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Oncopeptides: Consultancy; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tenebio: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy; Antengene: Consultancy, Honoraria; Amgen: Consultancy, Research Funding; Roche-Genentech: Consultancy, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Muffly: Pfizer, Amgen, Jazz, Medexus, Pfizer: Consultancy; Astellas, Jasper, Adaptive, Baxalta: Research Funding; Adaptive: Honoraria, Other: fees for non-CME/CE services: , Research Funding. Arai: Magenta Therapeutics: Research Funding. Meyer: Indee, Jura: Consultancy; Orca Biosystems: Research Funding; GigaImmune: Current holder of stock options in a privately-held company; Triursus Therapeutics: Current holder of stock options in a privately-held company. Rezvani: US Department of Justice: Consultancy; Kaleido: Other: One-time scientific advisory board; Nohla Therapeutics: Other: One-time scientific advisory board; Pharmacyclics-Abbvie: Research Funding. Weng: Kite Pharma: Research Funding. Frank: Kite-Gilead: Membership on an entity's Board of Directors or advisory committees; Allogene Therapeutics: Research Funding; Adaptive Biotechnologies: Research Funding. Shiraz: Kite Pharma-Gilead: Research Funding. Girgenti: Magenta Therapeutics: Current Employment. Goncalves: Magenta Therapeutics: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Schmelmer: Magenta Therapeutics: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Davis: Magenta Therapeutics: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Shizuru: Jasper Therapeutics, Inc.: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Chair of scientific advisory board; Forty seven Inc: Other: Inventor on a patent licenses by Forty Seven. Forty seven was acquired by Gilead in 2020. Miklos: Pharmacyclics: Patents & Royalties; Kite, a Gilead Company, Amgen, Atara, Wugen, Celgene, Novartis, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Bioscience, Adicet, Pharmacyclics, Janssen, Takeda, Adaptive Biotechnologies and Miltenyi Biotechnologies: Consultancy; Pharmacyclics, Amgen, Kite, a Gilead Company, Novartis, Roche, Genentech, Becton Dickinson, Isoplexis, Miltenyi, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Biosciences, Adicet, Adaptive Biotechnologies: Research Funding; Adaptive Biotechnologies, Novartis, Juno/Celgene-BMS, Kite, a Gilead Company, Pharmacyclics-AbbVie, Janssen, Pharmacyclics, AlloGene, Precision Bioscience, Miltenyi Biotech, Adicet, Takeda: Membership on an entity's Board of Directors or advisory committees.
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