Dose Of Prophylaxis Research Articles

Standard Fixed Enoxaparin Dosing for Venous Thromboembolism Prophylaxis Leads to Low Peak Anti-Factor Xa Levels in Both Head and Neck and Breast Free Flap Patients.

Venous thromboembolism (VTE) is a serious complication, particularly in cancer patients undergoing free flap reconstruction. Subcutaneous enoxaparin is the conventional prophylaxis for VTE prevention, and serum anti-factor Xa (afXa) levels are being increasingly used to monitor enoxaparin activity. In this study, free flap patients receiving standard enoxaparin prophylaxis were prospectively followed to investigate postoperative afXa levels and 90-day VTE and bleeding-related complications. Patients undergoing free tissue transfer during an 8-month period were identified and prospectively followed. Patients received standard fixed enoxaparin dosing at 30 mg twice daily in head and neck (H&N) and 40 mg daily in breast reconstructions. Target peak prophylactic afXa range was 0.2 to 0.5 IU/mL. The primary outcome was the occurrence of 90-day postoperative VTE- and bleeding-related events. Independent predictors of afXa level and VTE incidence were analyzed for patients that met the inclusion criteria. Seventy-eight patients were prospectively followed. Four (5.1%) were diagnosed with VTE, and six (7.7%) experienced bleeding-related complications. The mean afXa levels in both VTE patients and bleeding patients were subprophylactic (0.13 ± 0.09 and 0.11 ± 0.07 IU/mL, respectively). Forty-six patients (21 breast, 25 H&N) had valid postoperative peak steady-state afXa levels. Among these, 15 (33%) patients achieved the target prophylactic range: 5 (33%) H&N and 10 (67%) breast patients. The mean afXa level for H&N patients was significantly lower than for breast patients (p = 0.0021). Patient total body weight was the sole negative predictor of afXa level (R 2 = 0.47, p < 0.0001). Standard fixed enoxaparin dosing for postoperative VTE prophylaxis does not achieve target afXa levels for the majority of our free flap patients. H&N patients appear to be a particularly high-risk group that may require a more personalized and aggressive approach. Total body weight is the sole negative predictor of afXa level, supporting a role for weight-based enoxaparin dosing.

Switching to Non-daily Pre-exposure Prophylaxis Among Gay and Bisexual Men in Australia: Implications for Improving Knowledge, Safety, and Uptake

IntroductionPreexposure prophylaxis (PrEP) dosing options such as event-driven PrEP hold promise to increase PrEP uptake among gay, bisexual, and queer men (GBQM), but their impacts have not yet been realized and uptake by GBQM suitable for PrEP remains slow in countries where it is only considered an alternative option to daily PrEP.MethodsWe conducted semi-structured interviews between June 2020 and February 2021 with 40 GBQM in Australia to understand PrEP dosing behaviors, knowledge, and preferences.ResultsAll participants commenced PrEP daily; 35% had ever switched to non-daily PrEP, mostly taking it event-driven. GBQM who preferred non-daily PrEP had infrequent or predictable sex, were concerned about cost given infrequency of sex, and/or wanted to minimize unnecessary drug exposure. Accurate knowledge of event-driven PrEP was poor. However, reflecting concepts underpinning critical pedagogy, having accurate knowledge was supported by access to consistent messaging across clinical, social, community, and public settings. Several participants who switched to event-driven PrEP had condomless sex events in which they were unable to adhere to pills due to unanticipated sex.Conclusions and Policy ImplicationsImplementation of comprehensive and consistent education about correct dosing for event-driven PrEP across multiple settings is needed to ensure increased uptake and safe use. GBQM require messaging about non-condom based HIV prevention strategies when they cannot access daily or event-driven PrEP.

Pharmacokinetic modelling of caspofungin to develop an extended dosing regimen in paediatric patients.

Echinocandins are commonly used in treatment and prophylaxis of invasive fungal diseases. Intravenous daily dosing for prophylaxis in the outpatient setting can however become a hurdle for adequate compliance in the paediatric population. Simulations were performed to assess extended twice-weekly dosing for antifungal prophylaxis using caspofungin. A population pharmacokinetic model was developed based on previously published data from children aged 3 months to 17 years. Using the final model, Monte Carlo simulations were performed to assess the dose needed for adequate exposure in a twice-weekly setting. Mean weekly AUC0-24 h/MIC together with reported AUC0-24 h from previously reported paediatric trials were used to guide adequate exposure. A two-compartment model with linear elimination and allometric scaling using fixed exponents was found most adequate to describe the given paediatric populations. Simulations showed that a 200 mg/m2 twice-weekly regimen with maximal 200 mg total dose should result in exposures matching registered daily dosing as well as commonly used pharmacokinetic/pharmacodynamic targets.

The Association of Adherence to Antimicrobial Prophylactic Recommendations for Clean Neurosurgeries with Post-operative Surgical Site Infection

Objective: The use of antimicrobial prophylaxis to prevent surgical site infections (SSI) is well established. This study examined the association of adherence to antimicrobial prophylaxis for clean neurosurgeries with post-operative surgical site infection (SSI) rates. Methods: A retrospective descriptive study was conducted at the Philippine General Hospital (PGH) among pediatric patients who underwent clean neurosurgical procedures between January 1, 2018 – December 31, 2019. The outcome measured was the development of SSI. Univariate and multivariate analysis was performed to show the association of risk factors with SSI. Compliance to existing antibiotic prophylaxis recommendation was assessed. Results: One hundred eighty-nine (189) medical charts were reviewed. Overall prevalence of SSI was 9.5% and fever was the most common initial symptom of SSI. Staphylococcus species was identified from cultures of surgical sites, consistent with existing literature, however gram-negative organisms including multidrug-resistant organisms (MDRO) were noted. All cases received prophylactic antibiotics, but adherence to all parameters (antimicrobial choice, dose, timing, route, re-dosing and duration of prophylaxis) was low at 7.9%. Appropriate antibiotics were prescribed in only 15.9% and antibiotics were discontinued beyond 24 hours post-surgery in 45.5% of cases. Patients who received a regimen fully compliant with antimicrobial prophylaxis recommendations did not develop SSI. Conclusion: Adherence to existing antimicrobial prophylaxis protocol for neurosurgeries is low at 7.9%. Patients who received a regimen fully compliant with the recommendations did not develop SSI. Interventions to improve compliance to antimicrobial prophylaxis guidelines are needed.

First-line treatment (Tx) with subcutaneous (SC) epcoritamab (epco) + R-CHOP in patients (pts) with high-risk diffuse large B-cell lymphoma (DLBCL): Phase 1/2 data update.

7523 Background: Outcomes of pts with newly diagnosed DLBCL with high/poor risk according to the revised International Prognostic Index (IPI) treated with immunochemotherapy (IC) remain suboptimal, with a 4-year survival rate of 55% (Sehn et al, Blood 2007). SC epco is a well-tolerated bispecific antibody with single-agent activity in the relapsed/refractory (R/R) aggressive B-cell NHL setting. The mechanism of action and safety profile of epco are distinct from IC, and epco is well suited for use in combinations and in earlier lines of therapy. Addition of a novel agent to standard of care IC may overcome the adverse prognosis of high-risk pts. Presented here are updated results of epco + rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in previously untreated DLBCL pts with IPI 3–5 (EPCORE NHL-2 arm 1; NCT04663347). Methods: Adults with previously untreated CD20+ DLBCL and IPI ≥3 received SC epco (every week, cycle [C] 1–4; every 3 weeks, C5–6) + R-CHOP for 6 cycles (21 d) followed by single-agent epco every 4 weeks up to 1 y (in cycles of 28 d). To mitigate CRS, epco step-up dosing and corticosteroid prophylaxis were required. Response was assessed by PET-CT with contrast per Lugano 2014 criteria. Results: As of Dec 1, 2021, 33 pts (median age, 66 y; range, 19–82) received epco + R-CHOP (epco 24 mg, n = 4; 48 mg, n = 29). Median time from diagnosis to first dose was 25 d (range, 5–70). All pts had IPI ≥3 and ≥24% had double- or triple-hit DLBCL. Median follow-up was 3 mo (range, 0–9.7); median number of total cycles initiated was 5 (1–13). Overall, 94% of pts (31/33) remained on Tx. Tx-emergent adverse events (TEAEs) in ≥30% of pts were neutropenia (48%; febrile neutropenia in 9% of all pts), CRS (45%), infections (42%), anemia (39%), injection-site reactions (36%), nausea (33%), constipation (30%), and pyrexia (30%). No TEAEs led to epco discontinuation. AEs of special interest included CRS (42% grade [G] 1/2, 3% G3) and ICANS (3% G2); 1 pt had tumor lysis syndrome (3% G3). Most CRS events occurred in C1 and resolved after a median of 2 days (1–11); 4 pts with CRS received tocilizumab. No fatal TEAEs were reported. In efficacy-evaluable pts, the overall response rate (ORR) was 96% (24/25); 68% (17/25) had complete metabolic response (CMR). For the 10 pts who received 6 cycles of R-CHOP and had a subsequent response assessment, the ORR and CMR rate were 100% and 90%, respectively. As of the data cutoff, all of these 10 pts remained in response, with the longest duration of response 7.1+ mo and ongoing. Updated data will be presented. Conclusions: Epco is the first SC bispecific antibody assessed in combination with standard of care in previously untreated DLBCL. The safety profile of epco + R-CHOP is manageable. CRS events were mostly of low grade and did not lead to Tx discontinuation. ORR and CMR rate were high with no relapses as of the data cutoff date. Clinical trial information: NCT04663347.

Short-term intermittent prophylaxis post-intracranial hemorrhage in children with hemophilia

Background Intracranial hemorrhage (ICH) is one of the major bleeding events causing mortality and long-term morbidity in children with hemophilia, especially those who receive on-demand therapy.&#x0D; Objective To evaluate the outcome of children with hemophilia after ICH receiving short-term intermittent prophylactic treatment.&#x0D; Methods This retrospective study was conducted in the Department of Child Health, Dr. Cipto Mangunkusumo Hospital, Jakarta. Children £18 years of age with hemophilia presenting with ICH between 2015-2020 were included. We recorded patients’ demographics, type and severity of hemophilia, the presence of factor VIII (FVIII) inhibitor, brain CT scan, treatment, and outcomes of these patients. Patients who received short-term intermittent prophylaxis using clotting factor concentrate (CFC) post-ICH episodes were observed for ICH recurrence.&#x0D; Results There were 19 episodes of ICH experienced by 18 patients, consisting of 16 patients with hemophilia A and 2 with hemophilia B. Patients’ median age was 4 years (range 0-16 years). Hemophilia was classified as severe in 13 patients, moderate in 4 patients, and mild in 1 patient. Thirteen episodes were preceded by head trauma. The most common clinical manifestation was seizures (13.2%). The most common type of ICH was subdural hematoma. Two patients died and 2 patients had neurological sequelae during hospitalization. The median dose of short-term intermittent prophylaxis using CFC (n=16) was 20 IU/kg of FVIII twice a week and 30 IU/kg of FIX twice a week, for a median duration of 8 weeks (range 5-12 weeks). One patient who did not adhere to the prophylaxis regimen had recurrent ICH at a similar location 6 months after the first episode. &#x0D; Conclusion Our findings suggest that short-term intermittent prophylaxis is important to prevent the recurrence of ICH in children with hemophilia.

Safety and Efficacy Analysis of Apixaban Compared to Heparins in Hospitalized Non-Critically Ill COVID-19 Patients.

Purpose: Heparin-based regimens are recommended for anticoagulation in hospitalized patients with COVID-19 though a study reported similar mortality with apixaban in critically ill hospitalized COVID-19 patients. Our pilot study sought to determine the differences in all-cause mortality, venous thromboembolism (VTE), and bleeding events between apixaban and therapeutic heparin-based regimens in hospitalized non-critically ill COVID-19 patients. Methods: We conducted a retrospective analysis of non-critically ill COVID-19 patients aged ≥ 18 years admitted to 3 campuses of Montefiore Medical Center during the first (March 2020 to May 2020) and second (January 2021 to February 2021) COVID-19 surges, who received within 48 hours of admission and continued for ≥72 hours a therapeutic dose of low-molecular-weight heparin (LMWH), unfractionated heparin (UFH), or any apixaban dose for VTE prophylaxis. Outcomes data analyzed included mortality, suspected or imaging-confirmed VTE, and bleeding using a defined criteria. Results: Overall, 162 patients met eligibility for analysis. Baseline characteristics were similar between the 2 groups except liver and renal functions. Mortality occurred in 10 (13.3%) patients on apixaban and 23 (26.4%) patients on a heparin-based regimen (P = .059). Confirmed VTE events were not different between the groups (8% vs 13.8%, P = .359), but higher incidence of bleeding occurred in heparin-based group (4% vs 52.9%, P < .001). Conclusion: There were no differences in mortality or confirmed VTE between apixaban and heparin-based regimens except for more bleeding events with the heparins. This study highlights the utility of apixaban in COVID-19.

The efficacy of weight-based enoxaparin dosing for venous thromboembolism prophylaxis in trauma patients: A systematic review and meta-analysis.

Trauma patients are at high risk of developing venous thromboembolism (VTE), and standard dosing enoxaparin regimens may be inadequate for prophylaxis. This meta-analysis was performed to clarify the efficacy of alternative dosing regimens for VTE prophylaxis in this high-risk group. The objective of this systematic review was to review the evidence regarding weight-based dosing of enoxaparin for VTE prophylaxis in trauma patients. A systematic database search was undertaken for studies comparing standard versus weight-based dosing of enoxaparin for VTE prophylaxis in adult trauma patients, 18 years or older. The primary outcome was the achievement of anti-factor Xa (AFXa) levels within the prophylactic range. Secondary outcomes included subprophylactic AFXa levels, supraprophylactic AFXa levels, VTE incidence, and bleeding events. Meta-analysis was conducted using both fixed- and random-effects models, and presented as odds ratios, risk ratios (RRs), and risk differences (RDs) with 95% confidence intervals (CIs). Four cohort studies were eligible for inclusion. Compared with standard dosing, weight-based enoxaparin prophylaxis dosing was associated with increased odds of prophylactic AFXa levels (odds ratio, 5.85; 95% CI, 3.02-11.30; p < 0.00001) and reduced risk of subprophylactic AFXa levels (RR, 3.97; 95% CI, 3.02-5.22; p < 0.00001). Standard dosing was associated with a reduced risk of supratherapeutic AFXa levels (RR, 0.23; 95% CI, 0.11-0.50; p = 0.0002), but this was not associated with a difference in risk of bleeding events (RD, -0.00; 95% CI, -0.02 to 0.01; p = 0.55). There was no statistical difference in incidence VTE between the two groups (RD, 0.01; 95% CI, -0.02 to 0.03; p = 0.64). Compared with standard dosing, weight-based enoxaparin dosing regimens are associated with increased odds of prophylactic range AFXa levels. Further investigation is required to determine if this translates into improved VTE prophylaxis and reduced VTE incidence. Systematic Review and Meta-Analysis; Level III.

Comparisons of efficacy and complications between transrectal and transperineal prostate biopsy with or without antibiotic prophylaxis.

We aimed to determine the cancer detection rate and complications of transrectal prostate biopsy (TRBx) and transperineal prostate biopsy (TPBx) in the hospital. However, given the use of antibiotic prophylaxis in TPBx remains controversial according to the current guidelines, we also investigated the safety and side effects of TPBx with and without antibiotic prophylaxis. A total of 777 patients who underwent prostate biopsy were enrolled in this study in accordance with the criteria. The primary outcome was pooled infectious complications (sepsis, fever, symptomatic urinary tract infection and urinary retention), and the secondary outcome was prostate cancer detection rate. Findings showed that TPBx and TRBx were equivalent in terms of prostate cancer detection rate (TPBx: 50.4% vs. TRBx: 47.3%; P = 0.424) and urinary retention (TPBx: 5% vs. TRBx: 6.3%; P = 0.451). However, TRBx had significantly higher incidences of sepsis (risk ratios, RR: 3.65, 95% confidence interval [CI]: 1.21-11.03; P = 0.014) and symptomatic urinary tract infection (RR: 3.04, 95% CI: 1.07-8.66; P = 0.029) than TPBx. Notably, for TPBx, patients who received a single dose of cephazolin prophylaxis were not associated with the risk of sepsis (RR: 0.78, 95% CI: 0.13-4.63; P = 0.783) and symptomatic urinary tract infection (RR: 1.17, 95% CI: 0.24-5.74; P = 0.848) in contrast to patients who did not receive any antibiotic prophylaxis. Meanwhile, no effects on prostate cancer detection rate and urinary retention were observed in the TPBx group. Our findings indicated that TPBx significantly reduced infectious complications compared with TRBx and should therefore be preferred. Importantly, we need to re-examine whether the antibiotic prophylaxis should be routinely applied before TPBx in consideration of increasing antibiotic resistance. This result complements the current national guidelines. Nevertheless, future studies on this topic with improved quality and increased sample size are still needed to minimise bacterial resistance.

Low dose prophylaxis and antifibrinolytics: Options to consider with proven benefits for persons with haemophilia.

Prophylaxis has become standard of care for persons with severe phenotype haemophilia (PWsH). However, 'standard prophylaxis' with either factor or non-factor therapies (emicizumab) is prohibitively expensive for much of the world. We sought to evaluate whether haemophilia care can be provided at a lower cost yet achieve good results using Lower dose/Lower frequency prophylaxis (LDP) and with increasing use of antifibrinolytics (Tranexamic acid and Epsilon amino caproic acid). We identified 12 studies that collectively included 335 PWsH using LDP. Additionally, we undertook a literature search regarding the benefits of antifibrinolytics in haemophilia care. Identified studies show that LDP is far superior to no prophylaxis (On demand [OD] therapy) resulting in significant patient benefits. Patients on LDP showed (in comparison to patients OD) on average: 72% less total bleeds; 75% less joint bleeds; 91% less days lost from school; 77% less hospital admission days; and improved quality of life measures. These benefits come at similar or only slightly higher (<2-fold greater) costs than OD therapy. Antifibrinolytics are effective adjunctive agents in managing bleeds (oral, nasal, intracranial, possibly other) and providing haemostasis for surgeries (particularly oral surgeries). Antifibrinolytics can substitute for more expensive factor concentrates or can reduce the use of such concentrates. There is evidence to show that antifibrinolytics may be used in conjunction with factor concentrates/emicizumab for more effective/less costly prophylaxis. The use of LDP along with appropriate and increased use of antifibrinolytics offers less resourced countries good options for managing patients with haemophilia.

First study of extended half-life rFVIIIFc in previously untreated patients with hemophilia A: PUPs A-LONG final results

AbstractPUPs A-LONG evaluated the safety and efficacy of recombinant factor VIII Fc fusion protein (rFVIIIFc) in previously untreated patients (PUPs) with hemophilia A. This open-label, phase 3 study enrolled male PUPs (<6 years) with severe hemophilia A to receive rFVIIIFc. The primary endpoint was the occurrence of inhibitor development. Secondary endpoints included annualized bleed rate (ABR). Of 103 subjects receiving ≥1 dose of rFVIIIFc, 80 (78%) were aged <1 year at the study start, 20 (19%) had a family history of inhibitors, and 82 (80%) had high-risk F8 mutations. Twenty subjects began on prophylaxis, while 81 began an on-demand regimen (69 later switched to prophylaxis). Eighty-seven (81%) subjects completed the study. Inhibitor incidence was 31.1% (95% confidence interval [CI], 21.8% to 41.7%) in subjects with ≥10 exposure days (or inhibitor); high-titer inhibitor incidence was 15.6% (95% CI, 8.8% to 24.7%). The median (range) time to high-titer inhibitor development was 9 (4-14) exposure days. Twenty-eight (27%) subjects experienced 32 rFVIIIFc treatment-related adverse events; most were inhibitor development. There was 1 nontreatment-related death due to intracranial hemorrhage (onset before the first rFVIIIFc dose). The overall median (interquartile range [IQR]) ABR was 1.49 (0.00-4.40) for subjects on variable prophylaxis dosing regimens. In this study of rFVIIIFc in pediatric PUPs with severe hemophilia A, overall inhibitor development was within the expected range, although high-titer inhibitor development was on the low end of the range reported in the literature. rFVIIIFc was well-tolerated and effective for prophylaxis and treatment of bleeds. This trial is registered at www.clinicaltrials.gov (NCT02234323).

Study of Single Dose of Antibiotic Prophylaxis in Clean Surgeries at a Tertiary Care Centre

Background: Pre-operative single dose antibiotic prophylaxis has shown to reduce the incidence of surgical site infections and thereby patient morbidity. Aims: To evaluate effectiveness of single dose antibiotic prophylaxis in clean surgeries at a tertiary care hospital. Material and Methods: A total of 72 patients undergoing clean surgeries were included after they satisfied the inclusion and exclusion criteria. Results: Single dose of an intravenous prophylaxis of ceftriaxone in clean surgeries excisional biopsy of lipoma, dermoid cyst, sebaceous cyst, enucleation of fibroadenoma, herniotomy, eversion of hydrocele etc. was efficacious in preventing surgical site infection. Surgical site infection was associated with patient’s age, lower haemoglobin levels and longer hospital stay in 3 out of 72 patients. Conclusion: In the present study it was observed that prophylactic single shot of antibiotic is efficacious in averting surgical site infection and is economical for patients undergoing clean surgeries. Factors associated with surgical site infection were patient’s age, haemoglobin and associated co-morbidity like diabetes.

COVID-19 related thrombosis: A mini-review.

IntroductionCOVID-19 associated VTE is a new disease entity with high morbidity and mortality. The aim of this paper is to review contemporary emerging literature on the incidence, pathophysiology, predictive prognostic indicators, and management consensus for Covid-19 related thrombotic complications, in particular DVT and PE.MethodsA literature review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. All searches were done via PubMed. References of review articles were further screened according to the exclusion criteria.ResultsIn total, 154 records were identified and 20 duplicates were removed. A final 68 articles were included in the qualitative analysis. COVID-19 related thrombosis can affect multiple organs of the body, presenting in the form of arterial or venous thrombosis such as ischemic stroke, myocardial infarction, mesenteric ischemia, limb ischemia, DVT, or PE. DVT and PE has an overall incidence of 6–26%, and severely ill COVID-19 patients have even higher incidence of thromboembolism. On the other hand, incidence of arterial thromboembolism is much lower with incidence of 0.7%–3.7%. D-dimer is found to be an independent risk factor, and IMPROVE score, Caprini score, and Padua score have all been used as predictors. International guidelines suggest the use of low molecular weight heparin (LMWH) or fondaparinux for prophylaxis of VTE, and therapeutic dosage of weight adjusted LMWH for treatment if confirmed diagnosis.ConclusionsContemporary rapidly evolving evidence shows that COVID-19 associated thrombosis was a novel clinical entity, especially in severely ill COVID-19 patients. There are multiple society-driven guidelines only, but without any level 1 evidence for management regimen. The ideal dose for prophylaxis is not established and may vary depending on balance of bleeding and thrombosis risk. The risk of bleeding may be increased in patients in intensive care unit.

Anticoagulation in coronavirus disease 2019 (COVID-19): confirmed and controversial aspects

Die Infektion mit dem „severe acute respiratory syndrome coronavirus 2“ (SARS-CoV-2) ist mit einem hohen Risiko mikrovaskulärer Immunthrombosen sowie symptomatischer und inzidenteller Thromboembolien vorrangig im venösen, aber auch im arteriellen System vergesellschaftet. Dies begründet unter anderem die hohe kardiovaskuläre Morbidität und Mortalität der Patienten. Der heutige Kenntnisstand zur Pathophysiologie der Immunthrombosen und zu derzeitigen Strategien der Antikoagulation bei an „coronavirus disease 2019“ (COVID-19) erkrankten Patienten wird in diesem Beitrag zusammenfassend beleuchtet. Gemäß den aktuellen Leitlinien sollen moderat bis schwer erkrankte Infizierte, die sich in stationärer Krankenhausbehandlung befinden, frühzeitig eine Thromboseprophylaxe mit niedermolekularem oder unfraktioniertem Heparin oder alternativ mit Fondaparinux erhalten, sofern kein deutlich erhöhtes Blutungsrisiko vorliegt. Außerhalb der etablierten Therapieindikationen sollte eine intensivierte oder therapeutisch dosierte Prophylaxe auch aufgrund vermehrter Blutungskomplikationen bei diesen kritisch erkrankten Patienten sehr zurückhaltend erwogen werden. Die routinemäßige Fortführung einer prophylaktischen Antikoagulation nach der Krankenhausentlassung wird derzeit nicht empfohlen.

Timing and duration of antibiotic prophylaxis is associated with the risk of infection after hip and knee arthroplasty.

AimsAntibiotic prophylaxis involving timely administration of appropriately dosed antibiotic is considered effective to reduce the risk of surgical site infection (SSI) after total hip and total knee arthroplasty (THA/TKA). Cephalosporins provide effective prophylaxis, although evidence regarding the optimal timing and dosage of prophylactic antibiotics is inconclusive. The aim of this study is to examine the association between cephalosporin prophylaxis dose, timing, and duration, and the risk of SSI after THA/TKA.MethodsA prospective multicentre cohort study was undertaken in consenting adults with osteoarthritis undergoing elective primary TKA/THA at one of 19 high-volume Australian public/private hospitals. Data were collected prior to and for one-year post surgery. Logistic regression was undertaken to explore associations between dose, timing, and duration of cephalosporin prophylaxis and SSI. Data were analyzed for 1,838 participants. There were 264 SSI comprising 63 deep SSI (defined as requiring intravenous antibiotics, readmission, or reoperation) and 161 superficial SSI (defined as requiring oral antibiotics) experienced by 249 (13.6%) participants within 365 days of surgery.ResultsIn adjusted modelling, factors associated with a significant reduction in any SSI and deep SSI included: correct weight-adjusted dose (any SSI; adjusted odds ratio (aOR) 0.68 (95% confidence interval (CI) 0.47 to 0.99); p = 0.045); commencing preoperative cephalosporin within 60 minutes (any SSI, aOR 0.56 (95% CI 0.36 to 0.89); p = 0.012; deep SSI, aOR 0.29 (95% CI 0.15 to 0.59); p < 0.001) or 60 minutes or longer prior to skin incision (aOR 0.35 (95% CI 0.17 to 0.70); p = 0.004; deep SSI, AOR 0.27 (95% CI 0.09 to 0.83); p = 0.022), compared to at or after skin incision. Other factors significantly associated with an increased risk of any SSI, but not deep SSI alone, were receiving a non-cephalosporin antibiotic preoperatively (aOR 1.35 (95% CI 1.01 to 1.81); p = 0.044) and changing cephalosporin dose (aOR 1.76 (95% CI 1.22 to 2.57); p = 0.002). There was no difference in risk of any or deep SSI between the duration of prophylaxis less than or in excess of 24 hours.ConclusionEnsuring adequate, weight-adjusted dosing and early, preoperative delivery of prophylactic antibiotics may reduce the risk of SSI in THA/TKA, whereas the duration of prophylaxis beyond 24 hours is unnecessary.Cite this article: Bone Jt Open 2022;3(3):252–260.

Abstract P5-18-02: Final findings from the CONTROL trial of diarrheal prophylaxis or neratinib dose escalation on neratinib-associated diarrhea and tolerability in patients with HER2+ early-stage breast cancer

Abstract Background: Neratinib (NERLYNX®), an irreversible pan-HER tyrosine kinase inhibitor, is approved for the extended adjuvant treatment of early-stage HER2+ breast cancer following adjuvant trastuzumab-based therapy and in combination with capecitabine for HER2+ metastatic breast cancer. Diarrhea is the most frequently reported on-target side effect associated with neratinib; in the ExteNET adjuvant trial, where no mandatory anti-diarrheal prophylaxis was used, 39.8% of patients reported grade 3 diarrhea and 16.8% of patients discontinued neratinib due to diarrhea. The CONTROL trial (Clinicaltrials.gov: NCT02400476) was designed to investigate pre-emptive antidiarrheal prophylaxis (loperamide alone or in combination with budesonide or colestipol) or neratinib dose escalation (DE) for the prevention of neratinib-associated diarrhea. Data for the loperamide, budesonide and colestipol cohorts have been reported previously [Barcenas et al. Ann Oncol 2020]. The final findings for the two DE regimen cohorts are reported here. Methods: CONTROL is an international, multi-cohort, open-label, phase 2 study. Patients ≥18 years of age with stage I-IIIc HER2+ breast cancer received oral neratinib (240 mg/day for 1 year) after trastuzumab-based adjuvant therapy. Patients were enrolled sequentially into separate cohorts investigating: 1) mandatory loperamide prophylaxis; 2) budesonide + loperamide; 3) colestipol + loperamide; 4) colestipol + loperamide PRN; 5) neratinib DE + loperamide PRN (two cohorts). DE1 schedule: neratinib 120 mg/day for week 1, 160 mg/day for week 2, then 240 mg/day from week 3 onwards to complete 12 months of treatment. DE2 schedule: neratinib 160 mg/day for weeks 1&amp;2, 200 mg/day for weeks 3&amp;4, then 240 mg/day from week 5 onwards up to 12 months. Both DE cohorts included loperamide PRN. Adverse events were graded according to NCI-CTCAE v4.0. Primary endpoint: incidence of grade ≥3 diarrhea. Results: A total of 563 patients were enrolled in CONTROL. All preventive strategies reduced the incidence of grade 3 diarrhea compared with that seen in ExteNET (historical control: 39.8%). Median cumulative duration of grade 3 diarrhea ranged from 2-3.5 days across the CONTROL study cohorts for the entire 12-month treatment period (compared with 5.0 days for ExteNET). The proportion of patients discontinuing neratinib because of diarrhea was decreased in all cohorts compared with ExteNET (16.8%), except for loperamide alone. Adoption of neratinib DE, particularly the 2-week DE schedule (DE1), most markedly reduced the incidence, severity, and duration of neratinib-associated diarrhea in CONTROL compared with ExteNET (see Table). Conclusions: Neratinib DE + loperamide PRN during the first 2 weeks of treatment (DE1 cohort) was associated with the lowest rates of grade 3 diarrhea (13.3%) and diarrhea-related discontinuations (3.3%) compared with all other anti-diarrheal strategies investigated in CONTROL. These final findings from the study show improved tolerability of neratinib with all diarrhea prophylaxis strategies and suggest that neratinib DE1 with loperamide PRN allows patients to stay on treatment longer and receive the full benefit of neratinib therapy. Table. Patient disposition and diarrhea characteristics: ExteNET vs CONTROL DE cohortsExteNET(n=1408)CONTROL DE1 (n=60)CONTROL DE2 (n=62)Patients completing 1 year of neratinib treatment, %617874Median duration of treatment, months (range)11.6 (2.5–11.9)12.0 (0.2–12.4)11.9 (0.3–14.5)Diarrhea, %Grade 339.813.327.4Grade 4&amp;lt;100Median cumulative duration of grade 3 diarrhea,a days52.52Discontinuations due to diarrhea, %16.83.36.5Dose reductions due to diarrhea, %26311Dose holds due to diarrhea, %341213aNo grade 4 diarrhea was reported in CONTROL. Citation Format: Arlene Chan, Manuel Ruiz-Borrego, Gavin Marx, Adam Brufsky, Jo Chien, Michael Thirlwell, Maureen Trudeau, Ron Bose, José A García-Sáenz, Daniel Egle, Barbara Pistilli, Johanna Wassermann, Kerry A Cheong, Christian F Singer, Daniel Hunt, Navid Foruzan, Leanne McCulloch, Carlos H Barcenas. Final findings from the CONTROL trial of diarrheal prophylaxis or neratinib dose escalation on neratinib-associated diarrhea and tolerability in patients with HER2+ early-stage breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-18-02.

Use of Systemic Anticoagulation in COVID-19: Delving Beyond Theoretical Hypothesis.

BackgroundStudies suggest that COVID-19 infection may induce increased hypercoagulability, leading to thrombotic complications. The high rates of thrombotic complications among patients receiving standard-dose deep venous thrombosis (DVT) prophylaxis have prompted some clinicians to support the empiric increase of anticoagulation (AC) doses used for prophylaxis in patients with COVID-19. At present, the optimal anticoagulant agents, dosages, and duration have not been designated. We conducted a retrospective study to assess for outcomes in patients who received treatment for COVID-19 based on various dosings of AC.MethodsThis was a single-institution, retrospective cross-sectional study including patients with a positive COVID-19 test who were admitted within the St. Joseph’s Health Network from September to November of 2020. The inclusion criteria were men and women aged 18 years or older who had confirmed COVID-19 by polymerase chain reaction (PCR). Medical charts of patients who met the inclusion criteria were audited to obtain information. The patients were separated into three cohorts: those who received DVT prophylactic dose of AC, those who received an intermediate dose of AC, and those who received therapeutic AC.ResultsA total of 440 patients were included in the study, of whom 236 were Hispanic (50.3%), 131 were Caucasian (27.1%), 47 were African American (10.7%), and 26 were Asian (5.9%). The most common comorbidities were hypertension (273/440 [62.2%]), diabetes 189/440 [43.1%]), and coronary artery disease (60/440 [13.7%]). In the DVT prophylactic dose of AC cohort, there were 215 patients, and the average length of stay was 10.3 days. Eleven patients experienced bleeding events, five patients experienced thrombotic events, 16 patients required mechanical ventilation, and 20 patients died. In the intermediate dose of AC cohort, there were 63 patients, and the average length of stay was 10.3 days. Three patients experienced bleeding events, two patients experienced thrombotic events, seven patients required mechanical invasive ventilation, and 11 patients died. In the therapeutic dose of AC cohort, there were 162 patients, and the average length of stay was 14 days. In this cohort, 19 patients experienced bleeding events, 12 patients experienced thrombotic events, 26 patients required invasive mechanical ventilation, and 29 patients died. Patients who received intermediate dosing of AC also had the lowest risk of thrombotic events (0.05). Patients who received intermediate dosing of AC had the lowest rates of requiring both high-flow nasal cannula (p = 0.0001) and invasive mechanical ventilation (p = 0.031). Patients who received intermediate dosing of AC had a lower rate of bleeding compared to those who received the DVT prophylaxis dose and systemic AC dose (p = 0.037). The DVT prophylactic and intermediate dosing of AC groups had a shorter length of stay in comparison to the systemic AC group (p = 0.0002).ConclusionIn comparison to the venous thromboembolism prophylaxis dose and systemic AC dose groups, intermediate dosing of AC had the lowest rates of hemorrhage, mortality, length of stay, and requirement of high-flow nasal cannula or mechanical invasive ventilation. In the systemic dose AC group, there were worse clinical outcomes in terms of length of stay, incidence of bleeding events, requirement of mechanical ventilator use, and rate of mortality.

Evaluation of anti-factor Xa concentrations using a body mass index-based enoxaparin dosing protocol for venous thromboembolism prophylaxis in trauma patients.

The aim of this study was to evaluate the effectiveness of a body mass index (BMI)-based enoxaparin prophylaxis dosing protocol at achieving target anti-factor Xa (anti-Xa) concentrations in the trauma population. This retrospective chart review evaluated anti-Xa concentrations in adult trauma patients who received prophylactic enoxaparin over a three-month period. The primary outcome was the percentage of patients that achieved target anti-Xa concentrations after ≥3 doses of enoxaparin. Secondary outcomes included correlations of anti-Xa concentrations with enoxaparin dose per BMI, total body weight (TBW), and estimated blood volume (EBV). The prevalence of clinically relevant bleeding and venous thromboembolism was also recorded. Multivariable logistic regression was used to identify associated variables for target anti-Xa concentration attainment. Ninety-nine consecutive patients were included in the study. Included patients were predominately male (69.7%) and Black (50.5%) with a mean age of 44.1years. Target anti-Xa concentrations were achieved in 62.6% of patients. Anti-Xa concentrations were moderately correlated with enoxaparin dose per EBV (ρ=0.57), followed by dose per TBW (ρ=0.46), and dose per BMI (ρ=0.20). Multivariable logistic regression demonstrated that categorization of enoxaparin dose per EBV and per TBW were the only statistically significant predictors of reaching target anti-Xa concentrations (p=<0.001). In adult trauma patients, the rate of achieving target anti-Xa concentrations remains suboptimal and provides room for further improvement. Enoxaparin dose per EBV was more closely correlated with anti-Xa concentrations when compared to TBW and BMI. Dosing per EBV and TBW was the only variables associated with reaching target anti-Xa concentrations within the study. Further investigation is warranted to elucidate optimal EBV- and TBW-based dosing regimens.

Extended antibiotic prophylaxis after pancreatoduodenectomy reduces postoperative abdominal infection in high-risk patients: Results from a retrospective cohort study

BackgroundPreoperative biliary stenting before pancreatoduodenectomy is associated with a greater risk of bacteribilia and thus could lead to more frequent and severe surgical site infections. We hypothesized that an extended antibiotic prophylaxis could reduce the risk of surgical site infections for these high-risk patients compared with standard antibiotic prophylaxis. MethodsAll consecutive patients who underwent pancreatoduodenectomy between January 1, 2010 and December 31, 2016 were included in a tricentric retrospective cohort and classified according to the risk of surgical site infections (high or low) and the type of antibiotic prophylaxis (standard or extended). Extended antibiotic prophylaxis was defined by the use of high-rank β-lactams >2 days after surgery. Standard antibiotic prophylaxis concerned all single dose of low-rank β-lactams antibiotic prophylaxis. The primary outcome was postoperative surgical site infections. ResultsThree hundred and eight patients were included; 146 (47%) were high-risk patients, and 81 (55%) received extended antibiotic prophylaxis, mostly composed of piperacilline-tazobactam and gentamicin. There were significantly fewer surgical site infections in high-risk patients receiving extended antibiotic prophylaxis versus standard antibiotic prophylaxis (odds ratio = 0.4; 95% confidence interval, 0.2–0.8; P = .011), even after adjusting on age, sex, and duration of the surgical procedure (adjusted odds ratio = 0.3; 95% confidence interval, 0.1–0.7; P = .0071). There was no statistical difference in 28-day mortality (P = .32) or 90-day mortality (P = .13). Microorganisms identified in bile culture were more often sensitive to antibiotic prophylaxis in high-risk extended antibiotic prophylaxis group than in high-risk standard antibiotic prophylaxis group (64% versus 38%; P = .01). ConclusionExtended antibiotic prophylaxis is associated with a reduced risk of surgical site infections for high-risk patients with no significant reduction on 28-day mortality. Additional studies are required to determine the optimal duration of extended antibiotic prophylaxis for these patients.

Anticoagulation practices and venous thromboembolism in COVID-19 patients in a Philippine tertiary hospital

Funding AcknowledgementsType of funding sources: None.INTRODUCTIONCOVID-19 poses an increased risk for thrombosis and initiation of prophylactic anticoagulation has been shown to have mortality benefit in earlier studies. However, the use of full dose anticoagulation as prophylaxis and evidence of the efficacy and safety of anticoagulation on COVID-19 patients remains to be a topic of interest. This study aimed to explore the aspects of anticoagulation applied in a tertiary hospital in the Philippines and to further elucidate on its outcomes and development of complications among COVID-19 patients.METHODSIn this retrospective, observational study, we collected data from the case record forms of 945 patients with COVID-19 from two tertiary centers. Patients given anticoagulant therapy were classified as treated with standard, intermediate and therapeutic dose anticoagulation. The incidence of mortality and venous thromboembolism (VTE) among the three groups were compared as well as the risk for bleeding complications. Categorical variables were analyzed using the Chi-squared test and logistic regression analysis was done to quantify odds for mortality and complications among the treatment groups.RESULTSAmong available agents, Enoxaparin was the anticoagulant of choice in 96.1% of cases. The percentage of patients given anticoagulation was noted to increase with increasing severity. Overall, there were 168 (17.8%) inpatient deaths wherein 128 received anticoagulation. 51.3% of those who received therapeutic anticoagulation were intubated at any time during their hospital stay (p value 0.00). In-hospital survival for patients given prophylactic anticoagulation was 78.3% with the highest mortality among patients given therapeutic anticoagulation at 53.8%. Using binary logistic regression, there was increasing odds of mortality as anticoagulant dosage increased with an odds ratio of 2.818 for therapeutic anticoagulation (p = 0.00, b = 1.036). There was significantly lower incidence of pulmonary embolism and among patients given standard prophylactic therapy. The odds of incurring VTE (OR = 3.38, p = 0.001) and PE (OR = 4.315, p = 0.000) were found to increase as dosage increased. Major bleeding after given anticoagulant therapy was recorded in 4.7% of patients. Although half of the patients who presented with bleeding were given standard dose prophylaxis, the incidence of bleeding was highest within the intermediate dose category at 9.2%.CONCLUSIONTherapeutic dose anticoagulation was associated with higher odds of mortality. The incidence of recorded venous thromboembolism was low but still showed increasing odds as dosage of anticoagulation increased. In lieu of these findings, we recommend that therapeutic dose anticoagulation be given with caution to patients diagnosed with COVID-19, especially among those with severe to critical disease. Patients with the highest risks for VTE and requiring higher anticoagulant dosages should be monitored closely due to higher odds of bleeding. Figure. Figure.