Infection and Prophylaxis During Normothermic Liver Perfusion: Audit of Incidence and Pharmacokinetics of Antimicrobial Therapy.

BACKGROUND: Ex situ normothermic liver perfusion (NMP) in a blood-based perfusate is associated with a risk of microbe growth, resulting in life-threatening posttransplant sepsis. Antibiotics are widely used, but the pharmacokinetics of these agents are unknown as is their efficacy. We wished to assess the perfusate concentrations of the meropenem and fluconazole that we use and to audit the incidence of infection with this antimicrobial therapy. METHODS: Fluconazole and meropenem (100 mg each) were added to the perfusate before NMP began, and serial samples were taken and assayed for drug concentrations. Perfusate cultures were available from 210 of the 242 perfusions performed between February 1, 2018, and April 6, 2023; these were reviewed. RESULTS: Following administration of 100 mg fluconazole, levels fell slightly from a median of 24.9 mg/L at 1 h to 22.6 mg/L at 10 h. In contrast, meropenem concentrations fell over time, from a median of 21.8 mg/L at 1 h to 9.4 mg/L at 10 h. There were 4 significant microorganisms grown in the perfusions, including 3 Candida species and an Enterococcus faecium . All the Candida -infected livers were transplanted with no adverse consequences, the recipients being treated with anidulafungin upon identification of the infecting organism; the Enterococcus -infected liver was not transplanted. CONCLUSIONS: Serious infection is a risk with NMP but appears to be mitigated with a protocol combining fluconazole and meropenem. This combination may not be appropriate in areas where resistance is prevalent. Routine culture of NMP perfusate is essential to identify breakthrough organisms early and enable recipient treatment.

Phase II/III trial of hyperimmune anti-COVID-19 intravenous immunoglobulin (C-IVIG) therapy in severe COVID-19 patients: study protocol for a randomized controlled trial.

BACKGROUND: COVID-19 poses a global health challenge with more than 325 million cumulative cases and above 5 million cumulative deaths reported till January 17, 2022, by the World Health Organization. Several potential treatments to treat COVID-19 are under clinical trials including antivirals, steroids, immunomodulators, non-specific IVIG, monoclonal antibodies, and passive immunization through convalescent plasma. The need to produce anti-COVID-19 IVIG therapy must be continued, alongside the current treatment modalities, considering the virus is still mutating into variants of concern. In this context, as the present study will exploit pooled diversified convalescent plasma collected from recovered COVID-19 patients, the proposed hyperimmune Anti-COVID-19 intravenous immunoglobulin (C-IVIG) therapy would be able to counter new infectious COVID-19 variants by neutralizing the virus particles. After the successful outcome of the phase I/II clinical trial of C-IVIG, the current study aims to further evaluate the safety and efficacy of single low dose C-IVIG in severe COVID-19 patients for its phase II/III clinical trial. METHODS: This is a phase II/III, adaptive, multi-center, single-blinded, randomized controlled superiority trial of SARS-CoV-2 specific polyclonal IVIG (C-IVIG). Patients fulfilling the eligibility criteria will be block-randomized using a sealed envelope system to receive either 0.15 g/Kg C-IVIG with standard of care (SOC) or standard of care alone in 2:1 ratio. The patients will be followed-up for 28 days to assess the primary and secondary outcomes. DISCUSSION: This is a phase II/III clinical trial evaluating safety and efficacy of hyperimmune anti-COVID-19 intravenous immunoglobulin (C-IVIG) in severe COVID-19 patients. This study will provide clinical evidence to use C-IVIG as one of the first-line therapeutic options for severe COVID-19 patients. TRIAL REGISTRATION: Registered at clinicaltrial.gov with NCT number NCT04891172 on May 18, 2021.

Terrorist bombings: medical response in a developing country.

OBJECTIVE: To evaluate the process of transport and immediate Emergency Department (ER) management of mass casualties following the recent bomb blasts in Karachi and review in detail the medical response and management of victims undertaken in these two incidents. METHODS: Eyewitness accounts of the victims, medical personnel and newspaper clippings were used to understand and identify difficulties faced during the rescue process. Data regarding presenting injuries and their outcomes was also collected from all victims presenting to the emergency department at Aga Khan University Hospital. RESULTS: Seventy nine individuals died and over 250 victims were injured in the two incidents. All victims and dead bodies were shifted to the nearest public sector hospital overwhelming the health care facility. Subsequently all victims were evacuated to private sector hospitals creating similar difficulties. Over half of the victims presenting at the emergency department had minor injuries and did not require admission. Most patients requiring admission needed orthopaedic intervention. CONCLUSION: A comprehensive disaster plan with a centralized command and control system is required for the city of Karachi, involving all stake holders including charity ambulance services, security agencies, and trauma management facilities. Training courses and exercises for health care personnel should also be made mandatory to achieve professional excellence.

Choice of rotation speed (rpm) for bio-relevant drug dissolution testing using a crescent-shaped spindle.

Recently a new crescent-shaped spindle has been proposed to address the issues related to poor hydrodynamics of the USP paddle apparatus and its associated artifacts of high variability and lack of bio-relevant results. For improved comparison of drug dissolution characterization, it is highly desirable to conduct testing using common experimental conditions such as spindle rotation speed. A study was conducted in which different products were tested using the crescent-shaped spindle to propose a common rpm speed for improved comparative drug dissolution testing. Conventional- (200 mg) and extended-release (200 and 400 mg) carbamazepine tablets of multiple brands and amoxicillin capsules (250 and 500 mg) were analysed using the crescent- shaped spindle at 25, 50 and/or 75 rpm. Drug release was evaluated for 1.5h for amoxicillin and for 3.0 and 24h for conventional- and extended-release carbamazepine tablets products respectively. The dissolution media used were 0.05 M phosphate buffer for amoxicillin capsules and water containing 0.5% sodium lauryl sulphate for carbamazepine tablet products. All products showed characteristic drug release profiles, reflecting the fast and slow drug release natures of the products tested with complete drug release within expected time durations. Based on an expected maximum drug release criterion of 85% in a reasonable time, at a relatively slow drug release rate and within a dosing interval, a spindle speed of 25 rpm was found to be the most appropriate. Thus, it is concluded that drug products can be analysed using a single spindle type (crescent) with a single rpm (25) which would, not only result in simpler dissolution procedures, but also provide enhanced efficiencies from economical and regulatory aspects.

Improved drug dissolution and product characterization using a crescent-shaped spindle.

Drug release characteristics of two amoxicillin capsule products, 250 and 500 mg strength each, have been described using USP Paddle and crescent-shaped spindles. Using the same spindles, dissolution experiments were conducted with USP disintegrating (prednisone) and non-disintegrating (salicylic acid) calibrator tablets. Dissolution tests were conducted at 50 and 25 rev min(-1) using USP Paddle and crescent-shaped spindles, respectively. In all cases, even with the higher 50 rev min(-1), lower percent drug release results were observed with the Paddle spindle than with the crescent-shaped spindle, which was operated at 25 rev min(-1). The observed lower dissolution for amoxicillin capsule products (< 36 vs > 87% at 30 min) and USP prednisone calibrator tablets (45.5 vs 99.8% at 30 min) with Paddle spindles appeared to occur because of the accumulation of the disintegrated material (cone formation) at the bottom, thus restricting product-medium interaction. Crescent-shaped spindles did not allow any accumulation of the product and provided improved interaction by mixing and stirring, and thus appeared to provide true drug dissolution characteristics of the products. On the other hand, in the case of non-disintegrating USP salicylic acid tablets (18.5 vs 24.4% at 30 min), lower results with Paddle spindles appeared to be because of stagnation of the tablets, which provided poor product-medium interaction for the surface touching the vessel surface. In this case, the crescent-shaped spindles moved the tablets at the base of the vessel, providing improved and efficient product-medium interaction, thus appearing to reflect truer dissolution characteristics of the tablets. The results highlight the possible artifacts of the USP Paddle spindle, which could lead to inaccurate characterization of drug release properties of test products. As reported previously, the artifacts of high variability in results and lack of relevance to product properties appeared to be related to poor mixing and variable hydrodynamics within a dissolution vessel. Results from this study provide further evidence that these artifacts might be addressed adequately using the crescent-shaped spindle, thus resulting in improved drug release as well as better product characterization.

Applications of a new device (spindle) for improved characterization of drug release (dissolution) of pharmaceutical products.

A crescent spindle (patent pending) is described which may be used in place of the USP paddle component in USP dissolution apparatus 2. The new spindle is curve shaped, corresponding to the bottom of a dissolution vessel, with attached bristles to fill in the gap between the spindle and the surface of the vessel. The geometry of the new spindle provides more efficient mixing than the USP paddle and prevents accumulation of disintegrated material (no cone formation). Using the new spindle, in comparison with the USP paddle, dissolution characteristics of three drug products: 250 mg amoxicillin capsules, 15.6 g acetylsalicylic acid (ASA) boluses and 200 mg carbamzepine tablets were evaluated. The experimental conditions for dissolution testing with the two stirring devices included; 900 ml of 0.05 M phosphate buffer, pH 6.8 with 50 rpm, 900 ml of 0.05 M acetate buffer, pH 4.5-ethanol (7:3) with 50 rpm, and water containing 1% sodium lauryl sulphate with 75 rpm for amoxicillin capsules, ASA boluses and carbamazepine tablets, respectively. Uncharacteristic of the test products, which are fast release, the USP paddle provides significantly slower drug release. For example, 90 min for <80% drug release vs. 10 min for >90% for amoxicillin capsules and 6 h for 80% vs. 30 min for >90% for ASA boluses with USP paddle vs. the new spindle. In case of the carbamazepine tablets, three products which are bioequivalent and prescribed interchangeably, the USP paddle method shows significantly different dissolution characteristics. However, with the new device, all these products show similar drug release characteristics, a better reflection of product release characteristics and in vivo drug release behaviour. Compared with the USP paddle, the suggested device (spindle) provides improved stirring and mixing which appears to provide more appropriate (biorelevant) characterization of pharmaceutical products.