Subcutaneous Drug Administration Research Articles

Abstract PO4-12-11: Patient (pt) time burden with IV vs subcutaneous (SC) administration of trastuzumab/pertuzumab (HP): A time and motion (T+M) substudy of a single arm phase II trial of adjuvant endocrine therapy plus HP for stage I HER2+ breast cancer

Abstract Background: The time required for in-clinic drug administration may have a substantial detrimental impact on breast cancer patients’ quality of life. SC drug administration, as opposed to IV, may reduce this time commitment. The purpose of this study was to estimate the relative difference in time and logistical burden between IV and SC administration of HP. Methods: We prospectively enrolled a pre-specified sub-cohort of pts participating on the ADEPT trial (NCT04569747) to this T+M substudy. The ADEPT trial is an ongoing single arm prospective phase II trial of adjuvant SC HP (for 1 yr) plus endocrine therapy for pts with hormone receptor-positive (HR+) and HER2+ stage I (pT1N0 or pT1N1mi) breast cancer. Pts eligible for ADEPT have completed primary breast surgery and are systemic therapy-naïve. Pts who received cycle 1 of loading SC HP at Dana-Farber Cancer Institute and tolerated SC drug administration were eligible and enrolled consecutively to the T+M substudy until the T+M accrual goal; accrual to the T+M substudy was mandatory for eligible pts. The T+M substudy was a single arm crossover design in which pts received 2 cycles of IV HP, followed by 2 cycles of maintenance dose SC HP. During those 4 treatment (tx) cycles, timepoints in the drug preparation and administration process were captured from the electronic medical record or flowsheets filled out by infusion nurses. The primary endpoint of the T+M substudy was total pt chair time in the infusion area (measured from start of first drug administration to end of final post-drug observation period). Exploratory endpoints included total drug preparation time and total pt tx experience time. A sample size of 22 pts was estimated to provide 86% power with 2-sided alpha 0.05 to detect a difference of 70 mins in the primary endpoint by tx arm (IV vs SC). For all endpoints, the average time across both tx cycles was calculated for each pt, and the overall mean across pts for each of IV and SC administration was computed (with standard deviation). Average times for IV vs SC administration were compared via paired Wilcoxon signed rank tests. Adjustments for multiple comparisons were not included. Results: 22 pts participated on the T+M substudy, and each had timepoints captured during 4 tx cycles (2 IV and 2 SC cycles), for a total of 88 patient-cycles analyzed overall. Pts had median age 58 yrs (range 42-83), and were 96% female, 82% White, 9% Black, 9% Asian; and 100% non-Hispanic. Comparison of time intervals for IV vs SC drug administration is shown in the Table. Mean total pt infusion chair time was 84.3 mins with IV HP, vs 22.5 mins with SC HP, for a difference of 61.8 mins shorter pt time commitment in favor of SC administration (p< 0.0001). The mean total drug preparation time was significantly decreased in favor of SC administration (by 78.2 mins; p< 0.0001); and the total pt tx experience time was significantly decreased in favor of SC administration (by 81.8 mins; p< 0.0001). Conclusions: This prospective T+M study demonstrated that pt infusion chair time is significantly decreased with SC as compared to IV administration of HP, shortening this pt time burden by approximately one hour. SC drug administration is an approach that may help to improve and shorten the pt breast cancer therapy experience and decrease pharmacy burden. Table. SD, standard deviation Citation Format: Adrienne Waks, Noah Graham, Emily Chen, Anna Mae Frey, Victoria Attaya, Ibrahim Abbass, Anita Fung, Jesse Sussell, Patricia Cortazar, Caroline Harvey, Kenneth Almeida, Denise Leth, Wendy Chen, Jose Leone, Susan Schumer, Nabihah Tayob, Sara Tolaney. Patient (pt) time burden with IV vs subcutaneous (SC) administration of trastuzumab/pertuzumab (HP): A time and motion (T+M) substudy of a single arm phase II trial of adjuvant endocrine therapy plus HP for stage I HER2+ breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-12-11.

How should newer therapeutic agents be incorporated into the treatment of patients with myasthenia gravis?

Generalized myasthenia gravis (gMG) is a postsynaptic neuromuscular junction disorder that results in fatigable muscle weakness. The traditional treatment approach includes the use of acetylcholinesterase inhibitors, corticosteroids, and steroid-sparing immunosuppressant therapies (ISTs) for chronic management, whereas exacerbations and crises are managed with intravenous immunoglobulin (IVIg) and plasma exchange (PLEX). Over the past 6 years, four new therapeutic agents with novel immunological mechanisms of action-complement and neonatal Fc receptor (FcRn) inhibition-were approved as a result of clinically significant improvement in gMG symptoms of those treated with these newer agents in Phase 3 clinical trials. At present, it is unclear when and in whom to initiate these therapeutic agents and how to integrate them into the current treatment paradigm. When selecting a newer therapeutic agent, we use a simple equation: Value = Clinical Improvement/(Cost + Side Effects + Treatment Burden), which guides our decision-making. We consider using these novel therapeutic agents in two specific clinical situations. Firstly, the newer agents are fast-acting, suggesting they can be used in clinically unstable patients as "bridge therapy," and secondly, they provide additional options for those patients considered treatment-refractory. There are downsides, however, including treatment cost, unique side effect profiles, and intravenous and subcutaneous drug administration (though for some, this may be an advantage). As additional drugs enter the marketplace with unique mechanisms of action, routes of administration, and dosing schedules, the placement of the novel therapeutic agents in the gMG treatment algorithm will likely evolve.

Long-Term Constant Subcutaneous Drug Administration.

In this chapter, a long-term drug delivery system for preclinical therapeutic research is introduced. By using a subcutaneously implanted ALZET® Osmotic Pumps osmotic pump, continuous zero-order delivery of drugs under investigation that need repeated oral or intravenous dosing is realizable. Compared to traditional delivery systems, implanted osmotic pumps present several advantages, such as that no external connections or researcher intervention is required during infusion and that it is possible to save time by eliminating the need for frequent animal handling and repetitive injection schedules. Most importantly, a stable peripheral concentration of a drug can be obtained using this constant drug delivery system, which would benefit researchers in verifying the efficiency of anti-rheumatoid drugs and establishing safety profiles in preclinical studies.

New directions in ocrelizumab therapy in multiple sclerosis: higher doses and subcutaneous therapy

Ocrelizumab is the first anti-CD20 monoclonal antibody approved for the treatment of relapsing and primary progressive multiple sclerosis. Ocrelizumab is administered intravenously (i.v.) at a dose of 600 mg every six months. It is a highly effective drug strongly inhibiting inflammatory changes in the central nervous system, which nearly completely prevents the development of new active magnetic resonance imaging lesions and clinical relapses. Pharmacokinetic studies and data from post hoc analyses of ocrelizumab pivotal studies suggest that a higher dose than the current dose level might have a stronger therapeutic impact. These results revealed that higher ocrelizumab exposure dependent on lower body mass correlated with increased B cell depletion and reduced risk of disability progression independent of relapse activity (PIRA). In addition, higher ocrelizumab exposure showed a correlation with decreased development of new and enlarging T2 magnetic resonance imaging lesions. Two randomised studies are currently under way to compare the efficacy and safety of the standard i.v. dose of 600 mg versus higher doses (1,200 mg or 1,800 mg) in multiple sclerosis patients. Another new direction in the development of ocrelizumab therapy in multiple sclerosis is subcutaneous (s.c.) drug administration. Recent data from the OCARINA study revealed that s.c. ocrelizumab was not inferior to the i.v. administration with respect to pharmacokinetics, magnetic resonance imaging activity, and clinical relapses. The safety of s.c. ocrelizumab was found to be comparable to the i.v. form, with a higher rate of mild local injection reactions.

Subcutaneous administration of drugs and hydration in acute palliative care units: Physician attitudes and beliefs in the United States and Canada.

The objective of this study was to compare the attitudes and beliefs of PCU physicians leaders in the United States versus Canada regarding the subcutaneous method in the administration of medications and hydration in order to gain a better understanding as to why variations in practice exist. This survey trial took place from November 2022 to May 2023. The MD Anderson Cancer Center institutional review board in Houston, Texas, approved this study. The participants were the physician leaders of the acute palliative care units (PCUs) in the United States and Canada. The survey comprised questions formulated by the study investigators regarding the perceived comfort, efficiency, and preference of using the subcutaneous versus the intravenous method. The consent form and survey links were emailed to the participants. Sixteen PCUs were identified in the United States and 15 PCUs in Canada. Nine US and 8 Canadian physicians completed the survey. Physicians in Canada were more likely to use the subcutaneous route for administering opioids, antiemetics, neuroleptics, and hydration. They preferred subcutaneous over intravenous or intramuscular routes (p = 0.017). Canadian physicians felt their nursing staff was more comfortable with subcutaneous administration (p = 0.022) and that it was easier to administer (p = 0.02). US physicians felt the intravenous route was more efficient (p = 0.013). The study results suggest that exposure to the subcutaneous route influences a physician's perception. Further research is needed to explore ways to incorporate its use to a greater degree in the US healthcare system.

Therapeutic preference for Alzheimer’s disease treatments: a discrete choice experiment with caregivers and neurologists

BackgroundAlzheimer’s disease (AD) is a major global health crisis in need of more effective therapies. However, difficult choices to optimize value-based care will need to be made. While identifying preferred therapeutic attributes of new AD therapies is necessary, few studies have explored how preferences may vary between the stakeholders. In this study, the trade-offs among key attributes of amyloid plaque-lowering therapies for AD were assessed using a discrete choice experiment (DCE) and compared between caregivers and neurologists.MethodsAn initial pilot study was conducted to identify the potentially relevant features of a new therapy. The DCE evaluated seven drug attributes: clinical effects in terms of delay in AD progression over the standard of care (SOC), variation in clinical effects, biomarker response (achieving amyloid plaque clearance on PET scan), amyloid-related imaging abnormalities-edema (ARIA-E), duration of therapy, need for treatment titration as well as route, and frequency of drug administration. Respondents were then randomly presented with 12 choice sets of treatment options and asked to select their preferred option in each choice set. Hierarchical Bayesian regression modeling was used to estimate weighted preference attributes, which were presented as mean partial utility scores (pUS), with higher scores suggesting an increased preference.ResultsBoth caregivers (n = 137) and neurologists (n = 161) considered clinical effects (mean pUS = 0.47 and 0.82) and a 5% incremental in ARIA-E (mean pUS = − 0.26 and − 0.52) to be highly impactful determinants of therapeutic choice. In contrast, variation in clinical effects (mean pUS = 0.12 and 0.14) and treatment duration (mean pUS = − 0.02 and − 0.13) were the least important characteristics of any new treatment. Neurologists’ also indicated that subcutaneous drug delivery (mean pUS = 0.42 vs. 0.07) and administration every 4 weeks (mean pUS = 1.0 vs. 0.20) are highly desirable therapeutic features. Respondents were willing to accept up to a 9% increment in ARIA-E for one additional year of delayed progression.ConclusionsCaregivers and neurologists considered incremental clinical benefit over SOC and safety to be highly desirable qualities for a new drug that could clear amyloid plaques and delay clinical progression and indicated a willingness to accept incremental ARIA-E to achieve additional clinical benefits.

A study of teaching module on subcutaneous drug administration and communication skills in pharmacology according to competency-based medical education curriculum

Background: Theory lectures in pharmacology are covering various oral and parenteral routes of drug administration, mainly focusing on knowledge domain, but soft and psychomotor skills were less taught in undergraduate students. Demonstrating correct method of subcutaneous route of drug administration and communication skills as introduced by competency-based medical education (CBME) competency-based curriculum will help in early acquisition of the skills and minimize the errors in administration in insulin, heparin, and vaccines. Aim and Objectives: The aims of this study were to teach the subcutaneous drug administration (S/C) and communication skills to undergraduate students in pharmacology and to evaluate the perception of students and teachers toward new CBME curriculum. Materials and Methods: Correct technique of subcutaneous drug administration was demonstrated on mannequins after browsing through the videos of S/C route. Students were told to perform it independently on mannequins. Perception of students and staff members were collected with pre-validated questionnaire provided after the practical teaching hours. Results: In our study, majority of students (94%) felt that learning S/C route of drug administration correctly will help in managing various patients like administration of insulin in diabetic patients in their near future days. They were well advanced in communicating with patients regarding usage of medications and were (90%) also in favor of introduction of this experiment in UG curriculum. Conclusions: Our study concluded that subcutaneous teaching technique introduced by CBME curriculum in practical classes was well accepted by students and were more confident in soft skills and psychomotor skills at the end of the study.

Subcutaneous Drugs and Off-label Use in Hospice and Palliative Care: A Scoping Review.

Subcutaneous drug administration is an interesting approach for symptom control in hospice and palliative care. However, most drugs have no marketing authorization for subcutaneous administration and are therefore used off-label. In order to meet the requirements of a safe and effective drug therapy, especially in highly vulnerable patients, it is essential to investigate the scope of evidence of these common practices. The purpose of this scoping review was to provide an overview of available data on the tolerability and/or effectiveness of subcutaneously administered and off-label used drugs. We performed a scoping review according to the PRISMA extension to identify data available on the tolerability and/or effectiveness of 17 predefined drugs that are commonly administered subcutaneously in Swiss hospices and hospice-like institutions and that have no marketing authorization (off-label use). The scoping review identified 57 studies with most data available on their tolerability (68% local, 54% systemic), clinical effects (82%), details on dosage (96%) and routes of application (100%). Information on pharmacokinetic properties was mostly missing and only available for fentanyl, levetiracetam, midazolam, and ondansetron. For seven drugs, less than five articles were identified and no studies on codeine or clonazepam were available. This work provides an overview of current evidence on subcutaneous and off-label used drugs in hospice and palliative care. Although both are common practices, evidence on tolerability and effectiveness, particularly pharmacokinetic data, is limited and the identified information gaps need to be closed. This work establishes a basis for further research in this area.

Risk Factors, Hyaluronidase Expression, and Clinical Immunogenicity of Recombinant Human Hyaluronidase PH20, an Enzyme Enabling Subcutaneous Drug Administration

Multiple FDA-approved and clinical-development stage therapeutics include recombinant human hyaluronidase PH20 (rHuPH20) to facilitate subcutaneous administration. As rHuPH20-reactive antibodies potentially interact with endogenous PH20, we investigated rHuPH20 immunogenicity risk through hyaluronidase tissue expression, predicted B cell epitopes, CD4+ T cell stimulation indices and related these to observed clinical immunogenicity profiles from 18 clinical studies. Endogenous hyaluronidase PH20 expression in humans/mice was assessed by reverse transcriptase-polymerase chain reaction (RT-PCR), quantitative RT-PCR, and deep RNA-Seq. rHuPH20 potential T cell epitopes were evaluated in silico and confirmed in vitro. Potential B cell epitopes were predicted for rHuPH20 sequence in silico, and binding of polyclonal antibodies from various species tested on a rHuPH20 peptide microarray. Clinical immunogenicity data were collected from 2643 subjects. From 57 human adult and fetal tissues previously screened by RT-PCR, 22 tissue types were analyzed by deep RNA-Seq. Hyaluronidase PH20 messenger RNA expression was detected in adult human testes. In silico analyses of the rHuPH20 sequence revealed nine T cell epitope clusters with immunogenic potential, one cluster was homologous to human leukocyte antigen. rHuPH20 induced T cell activation in 6–10% of peripheral blood mononuclear cell donors. Fifteen epitopes in the rHuPH20 sequence had the potential to cross-react with B cells. The cumulative treatment-induced incidence of anti-rHuPH20 antibodies across clinical studies was 8.8%. Hyaluronidase PH20 expression occurs primarily in adult testes. Low CD4+ T cell activation and B cell cross-reactivity by rHuPH20 suggest weak rHuPH20 immunogenicity potential. Restricted expression patterns of endogenous PH20 indicate low immunogenicity risk of subcutaneous rHuPH20.Graphical abstract

Assessment of the Effect of Organ Impairment on the Pharmacokinetics of 2'-MOE and Phosphorothioate Modified Antisense Oligonucleotides.

The pharmacokinetics (PK) of 2'-O-methoxyethyl and phosphorothioate antisense oligonucleotides (ASOs), with or without N-acetyl galactosamine conjugation, have been well characterized following subcutaneous or intravenous drug administration. However, the effect of organ impairment on ASO PK, primarily hepatic or renal impairment, has not yet been reported. ASOs distribute extensively to the liver and kidneys, where they are metabolized slowly by endo- and exonucleases, with minimal renal excretion as parent drug (<1%-3%). This short review evaluated the effect of organ impairment on ASO PK using 3 case studies: (1) a phase 1 renal impairment study evaluating a N-acetyl galactosamine-conjugated ASO in healthy study participants and study participants with moderate renal impairment, (2) a phase 2 study evaluating an unconjugated ASO in patients with end-stage renal disease; and (3) a phase 3 study evaluating an unconjugated ASO, which included patients with mild hepatic or renal impairment. Results showed that patients with end-stage renal disease had a mild increase (≈34%) in total plasma exposure, whereas mild or moderate renal impairment showed no effect on plasma PK. The effect of hepatic impairment on ASO PK could not be fully evaluated due to lack of data in moderate and severe hepatic impairment study participants. Nonetheless, available data suggest that mild hepatic impairment had no effect on ASO exposure.

Monodispersed Sirolimus-Loaded PLGA Microspheres with a Controlled Degree of Drug-Polymer Phase Separation for Drug-Coated Implantable Medical Devices and Subcutaneous Injection.

Monodispersed sirolimus (SRL)-loaded poly(lactic-co-glycolic acid) microspheres with a diameter of 1.8, 3.8, and 8.5 μm were produced by high-throughput microfluidic step emulsification—solvent evaporation using single crystal silicon chips consisted of 540–1710 terraced microchannels with a depth of 2, 4, or 5 μm arranged in 10 parallel arrays. Uniform sized droplets were generated over 25 h across all channels. Nearly 15% of the total drug was released by the initial burst release during an accelerated drug release testing performed at 37 °C using a hydrotropic solution containing 5.8 M N,N-diethylnicotinamide. After 24 h, 71% of the drug was still entrapped in the particles. The internal morphology of microspheres was investigated by fluorescence microscopy using Nile red as a selective fluorescent stain with higher binding affinity toward SRL. By increasing the drug loading from 33 to 50 wt %, the particle morphology evolved from homogeneous microspheres, in which the drug and polymer were perfectly mixed, to patchy particles, with amorphous drug patches embedded within a polymer matrix to anisotropic patchy Janus particles. Janus particles with fully segregated drug and polymer regions were achieved by pre-saturating the aqueous phase with the organic solvent, which decreased the rate of solvent evaporation and allowed enough time for complete phase separation. This approach to manufacturing drug-loaded monodisperse microparticles can enable the development of more effective implantable drug-delivery devices and improved methods for subcutaneous drug administration, which can lead to better therapeutic treatments.

SOP—subcutaneous drug administration and infusions in adult palliative medicine

SOP—subcutaneous drug administration and infusions in adult palliative medicine

Pharmacokinetic Study and Toxicity of Leukovir: A New Combined Drug for the Treatment of Multiple Sclerosis

Leukovir, an enteric-coated tablet, is the original drug product for internal use. The well-known nucleosides cladribine and ribavirin are the active ingredients of the drug product leukovir. Pharmacokinetic parameters of the drug product for the internal use of leukovir active ingredients have been established. The cladribine half-absorption period was t1/2a = 49.5 h, C0 = 276.4 μg/ml, Cmax = 6.0 μg/ml. Distribution and accumulation parameters (Vd, Vss and AUC) have indicated that the drug distribution between the blood cells and blood plasma takes place in the same way, irrespective of the dosage form. Cladribine half-life period is t1/2e = 0.62 hours. The molecule total clearance and average lifetime in the body in the case of subcutaneous drug administration are approximately the same. Ribavirin is characterized by a half-absorption period of t1/2a = 0.71 h, C0 = 115.6 μg/ml and Cmax = 75.5 μg/ml. Ribavirin total volume of distribution (Vd = 1.3 l/kg) and stationary volume of distribution (Vss = 1.64 l/kg) were practically similar to leukovir when administered subcutaneously. The AUC value = 504.2 μg h/ml, which is 2.5 times less than that in the case of drug form administration. Leukovir was regarded as slightly toxic in an acute toxicity study. The risk of cumulation for this drug product is low.

Payer Perspectives on Intravenous versus Subcutaneous Administration of Drugs.

The coronavirus disease 2019 (COVID-19) pandemic has brought increased attention to vulnerable populations such as older or immunocompromised patients and heightened the focus on alternatives to intravenous (IV) formulations, particularly those that may be administered in a non-clinical setting. Among these alternative formulations are subcutaneous (SC) injections, which comprise an increasing share of commercialized and pipeline therapies. While much has been published about the benefits and limitations of IV versus SC administration to patients and health systems, less attention has been given to payer considerations regarding these routes of administration. Accordingly, this article provides payer perspectives on some of the key differences between IV and SC administration as they relate to management and billing, cost, treatment adherence and safety, and patient preference and quality of life. The benefits and limitations of these drug administration routes to key healthcare stakeholders—namely patients, physicians, and payers—are also discussed. Considerations of relevance are highlighted, including the potential for misalignment of stakeholder interests and countervailing factors that may impact decision-making about IV and SC formulations.

Intramuscular and subcutaneous administration of antiretroviral drugs, compared with oral, enhances delivery to lymphoid tissues in BALB/c mice.

Multiple tissue reservoirs are established soon after HIV infection, and some tissues may also be pharmacological sanctuaries. Parenteral administration of antiretroviral (ARV) drugs for treatment and prevention of HIV infection is an active area of drug development. The influence of route of administration on ARV tissue pharmacokinetics is not known. To investigate ARV pharmacokinetics in lymphatic and select non-lymphatic tissues (e.g. brain and testes) after intramuscular and subcutaneous administration compared with oral in BALB/c mice. Tissue concentrations of cobicistat, efavirenz, elvitegravir, maraviroc, rilpivirine, tenofovir alafenamide and tenofovir disoproxil fumarate were determined. The tissue penetration ratio (TPR) was the primary measure for comparison; a change in TPR arises from factors affecting tissue distribution controlling for changes in systemic bioavailability. Intramuscular and subcutaneous delivery increased TPRs in the lymph node and spleen for 27 of 28 (96%) drug administration events. Decreased TPRs, however, were found in some tissues such as the brain and testes. These results demonstrate a change in route of drug administration from oral to intramuscular or subcutaneous can change tissue uptake. This has implications for HIV pharmacotherapy. For example, HIV persists in lymphoid tissues despite long-term oral ARV therapy, and low ARV concentrations have been found in lymphoid tissues. The improved ARV lymphatic tissue bioavailability with intramuscular and subcutaneous administration allows future studies to investigate these routes of drug administration as a therapeutic manoeuvre to limit viral persistence and eliminate viral sanctuaries in the lymphatic tissues, which is a prerequisite for eradication of HIV.

Epidemiology of skin event rates among users of pumps for the subcutaneous administration of drugs for chronic conditions

Objective To provide the epidemiology of skin events occurring during long-term administration of medications delivered by continuous subcutaneous infusion pump (CSIP) systems as background rates for the development of novel CSIP treatments to use in community-based settings. Methods Using a United Kingdom general practice database, we conducted a study to assess the rates of skin events among new users of apomorphine and insulin delivered by CSIP in patients with Parkinson’s disease or diabetes, respectively. Skin events included skin infections, skin nodules/localized swelling, dermatitis/eczema, urticaria/erythema, and rash/other non-specific skin eruptions. Results Five hundred and fifty-seven adults (age 30+) were included in this descriptive cohort. The median duration of CSIP use was 17 months among 255 apomorphine users and 41 months among 302 insulin users. By 60 months, ∼40% of both cohorts experienced skin events. Repeated skin events occurred in 11% of the apomorphine cohort and 14% of the insulin cohort at any time during follow-up. The overall skin event rate in the apomorphine cohort was 17 per 1000 person-months (PM) and 13 per 1000 PM in the insulin cohort. The most common skin events in both cohorts were infection and rash/unspecified skin eruptions. The highest rates of skin events occurred soon after apomorphine CSIP initiation (36 per 1000 PM in weeks 1–2 and 50 per 1000 PM in weeks 3–4), with lower rates after 4 weeks. Insulin CSIP users’ skin event rates were consistent over the treatment duration. Conclusions Clinically important skin events are common during long-term administration of medications by CSIP.

Pharmacokinetic/Pharmacodynamic Dosage Individualization of Suppressive Beta-Lactam Therapy Administered by Subcutaneous Route in Patients With Prosthetic Joint Infection.

Suppressive parenteral antibiotic therapy with beta-lactams may be necessary in patients with Gram-negative bone and joint infection (BJI). Subcutaneous drug administration can facilitate this therapy in outpatient setting, but there is limited information about this practice. We have developed an original approach for drug dosing in this context, based on therapeutic drug monitoring (TDM) and pharmacokinetic/pharmacodynamic (PK/PD) principles. The objective of this study was to describe our approach and its first results in a case series. We analyzed data from patients who received suppressive antibiotic therapy by subcutaneous (SC) route with beta-lactams as salvage therapy for prosthetic joint infection (PJI) and had TDM with PK/PD-based dose adjustment. Ten patients (six women and four men with a mean age of 77 years) were included from January 2017 to May 2020. The drugs administered by SC route were ceftazidime (n = 4), ertapenem (n = 4), and ceftriaxone (n = 2). In each patient, PK/PD-guided dosage individualization was performed based on TDM and minimum inhibitory concentration (MIC) measurements. The dose interval could be prolonged from twice daily to thrice weekly in some patients, while preserving the achievement of PK/PD targets. The infection was totally controlled by the strategy in nine out the 10 patients during a median follow-up of 1,035 days (~3 years). No patient acquired carbapenem-resistant Gram-negative bacteria during the follow-up. One patient presented treatment failure with acquired drug resistance under therapy, which could be explained by late MIC determination and insufficient exposure, retrospectively. To conclude, our innovative approach, based on model-based TDM, MIC determination, and individualized PK/PD goals, facilitates, and optimizes suppressive outpatient beta-lactam therapy administered by SC route for PJI. These encouraging results advocate for larger clinical evaluation.

Antithrombotic drugs and patients’ outcomes at Cairo University Hospitals: critical care nurses’ knowledge and practices

Background Antithrombotic agents are widely used for thrombotic disorder management among critically ill patients. Subcutaneous administration of heparin is a repeated clinical practice done by nurses, which may cause adverse outcomes.Aim To investigate critical care nurses’ knowledge and practices regarding subcutaneous antithrombotic drugs and associated patients’ outcomes at Cairo University Hospitals.Research questions What do critical care nurses know regarding subcutaneous antithrombotic administration? What are critical care nurses’ practices regarding subcutaneous antithrombotic administration? What are the outcomes associated with subcutaneous antithrombotic drug administration among critically ill patients?Research design A descriptive exploratory research design.Setting Selected ICU affiliated to Cairo University Hospitals.Sample A convenience sample of 30 nurses and purposive sample of 60 adult male and female critically ill patients.Tools of data collection Four tools were utilized. Tool 1: critically ill patients’ personal characteristics and medical data sheet, tool 2: nurses’ knowledge-assessment questionnaire regarding subcutaneous antithrombotic drugs, tool 3: nurses’ practice observational checklist regarding subcutaneous antithrombotic drug administration, and tool 4: subcutaneous antithrombotic drug administration observational sheet of critically ill patients’ outcomes.Results About 60% of the studied nurses were females, 53.3% of the sample’s age ranged from 20 to less than 30 years. As well, 51.7% of critically ill patients were females, 38.3% of the sample’s age ranged from 60 to less than 70 years. The studied nurses were having unsatisfactory general knowledge level about subcutaneous anticoagulants, subcutaneous anticoagulants’ adverse effects, and nurses’ responsibilities concerning subcutaneous anticoagulants in percentages of 96.7, 96.7, and 90%, respectively. Also, unsatisfactory practice level as regards preinjection, during, and postinjection of subcutaneous anticoagulants in percentage of 100%. The most frequent adverse outcomes were localized pain, bruising, itching, and hematoma in percentages of 93, 85, 70, and 58%, respectively, where less frequent adverse outcomes were systemic thrombocytopenia, hematuria, and epistaxis in percentages of 6, 4, and 3.3%, respectively.Conclusion All critical care nurses had unsatisfactory knowledge and practice regarding antithrombotic therapy, inspite of their vital role in assessment, drug administration, care of critically ill patients, and monitoring drug-adverse effects. Also, the most frequent adverse outcomes among critically ill patients were pain, bruising, itching, and hematoma.Recommendations Updating ICU nurses’ knowledge and practice about antithrombotic drugs and maintaining close observation and record for both local and general patient’s response to antithrombotics by staff nurses during and after drug administration are highly recommended to safeguard critically ill patients against such complications.

Anakinra in COVID-19: important considerations for clinical trials

Anakinra in COVID-19: important considerations for clinical trials

Adherence to subcutaneous anti-TNFα agents in patients with rheumatoid arthritis is largely influenced by pain and skin sensations at the injection site.

The aims of this prospective study were to determine the dimension of adherence in rheumatoid arthritis (RA) patients receiving subcutaneously administered anti-tumor necrosis factor-α (anti-TNFα) agents and to evaluate the influence of injection site pain and skin perceptions following subcutaneous administration of anti-TNFα drugs on patients' adherence. An inception cohort of patients starting subcutaneously administered anti-TNFα treatment was enrolled. Injection site pain perception was assessed through the Self-Injection Assessment Pain Questionnaire (SIAPQ), and adherence to treatment was ascertained by the Compliance Questionnaire for Rheumatology (CQR5). Associations between beliefs and non-adherence, and the influence of demographic (age, disease duration, educational level), clinical (body mass index, patient global assessment, physician global assessment, Numerical Rating Scale of pain, Health Assessment Questionnaire-Disability Index, Simplified Disease Activity Index, and comorbidities measured by the modified Rheumatic Disease Comorbidty Index), and radiographic (Simple Erosion Narrowing Score) variables were assessed using logistic regression models. Adherence data over a 12-month interval were available for 193 patients. Of these, 21.7% reported non-adherence to anti-TNFα therapy. No difference (P=.383) was found for anti-TNFα drugs (adalimumab, etanercept, certolizumab pegol and golimumab). In the logistic model, age (P=.0029), higherdisease activity (P=.020), low numbers of comorbidity conditions (P=.0004), injection site pain and skin perception (P=.0008), were significantly associated with increased likelihood of medication adherence. Adherence is influenced by both demographic characteristics (age) and clinical factors (disease activity, comorbidity burden and injection site pain and skin perception) in RA patients.