The management of COVID-19 has become more complex due to the expansion of available therapies. The presence of SARS-CoV-2 variants and mutations further complicate treatment due to their differing susceptibilities to therapies. Here we outline the use of real-time whole genome sequencing to characterise infections and guide treatment decisions.

Susceptibility to adverse drug reactions (ADRs), multimorbidity, and frailty are associated with human aging, yet there is wide variation in the severity and age at which individuals are afflicted. Identifying genetic markers of increased risk of this phenotype would help stratify individuals to specialist interventions. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) regulates a cell’s response to stressors, including the expression of enzymes involved in drug metabolism. Its expression has been shown to decline in animal aging models. In this study, we tested the hypothesis that Nrf2 gene (NFE2L2) transcription/translation decline in human aging and that single-nucleotide polymorphisms (SNPs) in the NFE2L2 gene are associated with increased ADR risk, multimorbidity, and frailty in older people. Gene expression and protein levels were measured in peripheral blood mononuclear cells donated from healthy patients aged 18–80 years old. NFE2L2 genotypes were determined at three loci in a subpopulation of patients recruited to the PRIME study (a multicenter prospective cohort study that followed older adults for 8 weeks post-discharge to determine ADR). Both NFE2L2 gene and Nrf2 protein expression declined significantly with age in human peripheral blood mononuclear cells. In the PRIME substudy population, the rs35652124 NFE2L2 SNP was associated with increased ADR risk and decreased frailty and multimorbidity scores.

We report the successful use of combination therapy with two direct acting antivirals for treatment of chronic COVID-19. An immunocompromised 60 year old male with persistent SARS-CoV-2 infection over 4 months had chronic, progressive COVID-19 requiring mechanical ventilation. After failing monotherapy with two antivirals and neutralising monoclonal antibodies, he was treated with a 10 day course of intravenous remdesivir and crushed nirmatrelvir/ritonavir (Paxlovid) administered through a nasogastric tube. Following treatment, SARS-CoV-2 RNA became undetectable, with resolution of supplemental oxygen requirement and acute inflammatory changes on computed tomography. This case demonstrates potential synergy between remdesivir and nirmatrelvir/ritonavir in treating persistent, symptomatic SARS-CoV-2 infection.

Background Appropriate vancomycin dosing and therapeutic monitoring is important to optimize treatment for serious Gram-positive infections. In St George's Hospital ICUs, the treatment protocol is a loading dose (<65 kg, 1000 mg; ≥65 kg, 1500 mg), followed by a continuous infusion based on creatinine clearance (CLCR). Vancomycin serum concentrations are taken daily at 0600 hours (target therapeutic range 20–25 mg/L). Non-therapeutic concentrations may negatively affect clinical outcomes and prolong length of stay.1 Methods Electronic prescribing and medicine administration data (vancomycin dose, dose timings, indication, patient biochemistry and demographics) within a 66-bed ICU service were reviewed retrospectively (July 2020–July 2021). Cockcroft-Gault CLCR was calculated using total body weight (TBW), or adjusted body weight in obese1 patients. Standards (i) Proportion of patients with a therapeutic concentration within two serum samples; and (ii) time taken to achieve therapeutic concentration. Results Ninety-four percent (51/54) of patients received a correct protocol instructed loading dose, 31% (17/54) received a correct loading and maintenance dose, and 70% (38/54) had a vancomycin serum concentration taken. Forty-one percent (7/17) of correctly protocol dosed and monitored patients were therapeutic at their first day serum concentration, which decreased to 20% (3/15) by their second day serum concentration. Consistently therapeutically dosed patient groups included obese and normal weight patients with CLCR 10–20  mL/min and 21–50  mL/min. Whereas underweight and obese patients with CLCR >50  mL/min and 21–50  mL/min became supratherapeutic by their second day serum concentration. Obese and normal weight patients with CLCR >50  mL/min were consistently subtherapeutic. The mean time taken for non-therapeutic patients who continued treatment (n = 7) to become therapeutic after dose adjustments was 4 days. Patients (n = 17) were 82% male and of a mean age of 62 ± 17 years. Mean TBW was 79 ± 23 kg and mean CLCR 65 ± 48  mL/min. Sepsis was the most common vancomycin indication (65%). Conclusions Multiple drug recording formats, plus adherence to and dosing of different aspects of the vancomycin protocol, requires review. This is to ensure accurate vancomycin administration documentation and that therapeutic concentrations are achieved more rapidly and consistently, whilst minimizing toxicity. A quality improvement project has been instigated to focus on protocol education, accessibility and improving IT infrastructure. Increased patient volume of distribution and renal function variability within the ICU population adds complexity to vancomycin pharmacokinetics. Research into pharmacokinetic models better representing the local ICU population and AUC24 drug monitoring is being explored based on recent international guidance.1