ABSTRACT
BACKGROUND: Around 10-15% of the in-patient population carry unsubstantiated 'penicillin allergy' labels, the majority incorrect when tested. These labels are associated with harm from use of broad-spectrum non-penicillin antibiotics. Current testing guidelines incorporate both skin and challenge tests; this is prohibitively expensive and time-consuming to deliver on a large scale. We aimed to establish the feasibility of a rapid access de-labelling pathway for surgical patients, using direct oral challenge. METHODS: 'Penicillin allergic' patients, recruited from a surgical pre-assessment clinic, were risk-stratified using a screening questionnaire. Patients at low risk of true, immunoglobulin E (IgE)-mediated allergy were offered direct oral challenge using incremental amoxicillin to a total dose of 500 mg. A 3-day course was completed at home. De-labelled patients were followed up to determine antibiotic use in surgery, and attitudes towards de-labelling were explored. RESULTS: Of 219 patients screened, 74 were eligible for inclusion and offered testing. We subsequently tested 56 patients; 55 were de-labelled. None had a serious reaction to the supervised challenge, or thereafter. On follow-up, 17 of 19 patients received appropriate antimicrobial prophylaxis during surgery. Only three of 33 de-labelled patients would have been happy for the label to be removed without prior specialist testing. CONCLUSION: Rapid access de-labelling, using direct oral challenge in appropriately risk-stratified patients, can be incorporated into the existing surgical care pathway. This provides immediate and potential long-term benefit for patients. Interest in testing is high among patients, and clinicians appear to follow clinic recommendations. Patients are unlikely to accept removal of their allergy label on the basis of history alone. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: AN17/92982.
Subject(s)
Amoxicillin/administration & dosage , Anti-Bacterial Agents/administration & dosage , Drug Hypersensitivity/diagnosis , Elective Surgical Procedures , Penicillins/administration & dosage , Preoperative Care/methods , Feasibility Studies , Humans , United KingdomABSTRACT
BACKGROUND: The human p.G2434R variant of the RYR1 gene is most frequently associated with malignant hyperthermia (MH) in the UK. We report the phenotype of a knock-in mouse that expresses the RYR1 variant p.G2435R, which is isogenetic with the human variant. METHODS: We observed the general phenotype; determined the sensitivity of myotubes to caffeine-, KCl, and halothane-induced Ca2+ release; determined the in vivo response to halothane or increased ambient temperature; and determined the in vivo myoplasmic intracellular Ca2+ concentration in skeletal muscle before and during exposure to volatile anaesthetics. RESULTS: RYR1 pG2435R/MH normal (MHS-Heterozygous[Het]) or RYR1 pG2435R/pG2435R (MHS-Homozygous[Hom]) mice were fully viable under typical rearing conditions, although some male MHS-Hom mice died spontaneously. The normalised half-maximal effective concentration (95% confidence interval) for intracellular Ca2+ release in myotubes in response to KCl [MH normal, MHN, 21.4 (19.8-23.1) mM; MHS-Het 16.2 (15.2-17.2) mM; MHS-Hom 11.2 (10.2-12.2) mM] and caffeine (MHN, 5.7 (5-6.3) mM; MHS-Het 4.5 (3.9-5.0) mM; MHS-Hom 1.77 (1.5-2.1) mM] exhibited a gene dose-dependent decrease, and there was a gene dose-dependent increase in halothane sensitivity. Intact animals show a gene dose-dependent susceptibility to MH with volatile anaesthetics or to heat stroke. RYR1 p.G2435R mice had elevated skeletal muscle intracellular resting [Ca2+]i, (values are expressed as mean (SD)) (MHN 123 (3) nM; MHS-Het 156 (16) nM; MHS-Hom 265 (32) nM; P<0.001) and [Na+]i (MHN 8 (0.1) mM; MHS-Het 10 (1) mM; MHS-Hom 14 (0.7) mM; P<0.001) that was further increased by exposure to volatile anaesthetics. CONCLUSIONS: RYR1 pG2435R mice demonstrated gene dose-dependent in vitro and in vivo responses to pharmacological and environmental stressors that parallel those seen in patients with the human RYR1 variant p.G2434R.
Subject(s)
Calcium/metabolism , Heat Stress Disorders/genetics , Malignant Hyperthermia/genetics , Ryanodine Receptor Calcium Release Channel/genetics , Anesthetics, Inhalation/pharmacology , Animals , Caffeine/pharmacology , Calcium Signaling/drug effects , Calcium Signaling/genetics , Dose-Response Relationship, Drug , Gene Knock-In Techniques , Halothane/pharmacology , Male , Mice , Mice, Inbred C57BL , Muscle Fibers, Skeletal/drug effects , Muscle, Skeletal/drug effects , Muscle, Skeletal/metabolism , Mutation/genetics , Phenotype , Potassium Chloride/pharmacologyABSTRACT
Dehydroepiandrosterone (DHEA) and its metabolites, DHEA-sulphate (DHEA-S) and androsterone, have neurosteroid activity. In this study, we examined whether DHEA, DHEA-S and androsterone, can influence serotonin (5-HT) neuronal firing activity via modulation of γ-aminobutryic acid (GABA(A)) receptors. The firing of presumed 5-HT neurones in a slice preparation containing rat dorsal raphe nucleus was inhibited by the GABA(A) receptor agonists 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridinyl-3-ol (THIP) (25 µM) and GABA (100 µM). DHEA (100 and 300 µM) and DHEA-S (1, 10 and 100 µM) caused a rapid and reversible attenuation of the response to THIP. DHEA (100 µM) and DHEA-S (100 µM) also attenuated the effect of GABA. Androsterone (10 and 30 µM) markedly enhanced the inhibitory response to THIP (25 µM). The effect was apparent during androsterone administration but persisted and even increased in magnitude after drug wash-out. The data indicate that GABA(A) receptor-mediated regulation of 5-HT neuronal firing is sensitive to negative modulation by DHEA and its metabolite DHEA-S is sensitive to positive modulation by the metabolite androsterone. The effects of these neurosteroids on GABA(A) receptor-mediated regulation of 5-HT firing may underlie some of the reported behavioural and psychological effects of endogenous and exogenous DHEA.
