Trimethoprim/sulfamethoxazole (TMP/SMX), also known as Septra, is a commonly encountered and prescribed antibiotic in emergency department patients. The side effects associated with TMP/SMX are generally mild and self-limited, but serious side effects, including Stevens-Johnson syndrome and drug-induced aseptic meningitis, have been reported. We discuss the case of a 33-year-old woman who presented to our emergency department with the signs and symptoms of meningeal inflammation after being prescribed TMP/SMX 3 days earlier for an abscess with cellulitis.

Older people are high consumers of prescription drugs and are at increasing risk of polypharmacy and adverse reactions. Pharmacokinetic and pharmacodynamic modifications due to age and co-morbidities are an important consideration, but pharmacological background evidence to guide safe and effective therapeutic approaches are often inadequate since the older population is under-represented in clinical trials. We review the pharmacokinetic and pharmacodynamic changes that are characteristic in old age and consider evidence regarding potentially safer prescription and monitoring of drugs commonly used in older patients. We also introduce the possible role of pharmacogenomics and therapeutic drug monitoring as tools to guide the individualization of drug therapy.

We screened tuberculosis (TB) contacts as an outbreak investigation with tuberculin skin test (TST) and interferon-gamma release assay (IGRA). We evaluated adverse events and TB incidence in all persons screened after rifampicin (RFP) prophylaxis, and specifically assessed the new TB cases in relation to initial TST and IGRA results. The 180 contacts were divided into four groups: TST+/IGRA+ (n=101), TST+/IGRA− (n=22), TST−/IGRA+ (n=16), and TST–/IGRA– (n=41). RFP treatment (4 months) was prescribed only to the TST+/IGRA+ group. Of 87 contacts who initiated prophylaxis, adverse events occurred in 21 contacts (24·1%) including hepatotoxicity (11·5%), flu-like syndrome (5·7%), and thrombocytopenia (3·4%). TB developed in two TST+/IGRA+ subjects after completion of prophylaxis, including one multidrug-resistant (MDR)-TB case during 21·8 months of follow-up. Adverse events were frequent, and development of TB including MDR-TB occurred after RFP prophylaxis.

We report amiodarone-induced pulmonary toxicity in an 18-year-old who had undergone corrective surgery for tetralogy of Fallot 4 years earlier, and was treated with amiodarone because of recurrent malignant postoperative ventricular tachyarrhythmias. Toxicity was recognized on the basis of clinical features, chest X-ray, high-resolution contrast enhanced computerized tomography, and resolution of the findings subsequent to withdrawal of amiodarone and treatment with steroids. pulmonary toxicity due to amiodarone, as far as we know, has not been reported in children and young adults, and its occurence even in young adults requires wider appreciation.

We report a patient who developed sudden, bilateral, sensorineural hearing loss during therapeutic use of iloprost for Raynaud's phenomenon. The sudden hearing loss was attributed to iloprost use and completely reversed in eight days with conservative therapy. Iloprost may be a potentially ototoxic drug, causing sudden hearing loss.

Summary

AstraZeneca (the manufacturer of Diprivan™) presents its review of the history of the so-called ‘propofol infusion syndrome’, highlighting the difficulties in analysing the incomplete information available. Theories as to its causality are presented and discussed; these include mitochondrial toxicity, mitochondrial defects, impaired tissue oxygenation and carbohydrate deficiency. A review of published and confidential safety data is presented and discussed; it concludes that the major risk factors for its development appear to be poor oxygen delivery, sepsis, serious cerebral injury and high propofol dosage. In some reports an increasing lipaemia was noted and was likely to be due to a failure of hepatic lipid regulation, possibly related to poor oxygenation and/or possibly a lack of glucose. In some cases an increasing lipaemia was the first indication of impending ‘propofol infusion syndrome’ onset and it should not be viewed as a benign sign. The lipaemia can lead to sequestration of propofol into the lipid phase, leading to lowered free propofol levels and apparent insensitivity to propofol. In conclusion AstraZeneca advocates good haemodynamic and oxygen delivery management, adequate glucose provision, adherence to recommended propofol dosing regimes together with active management of lipaemias to both prevent and treat ‘propofol infusion syndrome’.

Summary

Background and objective: Clonidine has cardiac and systemic effects that can modify the potentially lethal cardiovascular effects of local anaesthetics. We evaluated the effects of clonidine pre-treatment on cardiotoxicity induced by an infusion of bupivacaine or ropivacaine and the success rate of resuscitation in anaesthetized rats.

Methods: Thirty-two Sprague–Dawley rats (250–300 g) were anaesthetized with thiopental and ketamine. Lung ventilation was maintained mechanically, and the electrocardiograph and invasive blood pressure were recorded continuously. Two separate groups of rats were treated with intravenous clonidine 5 μg kg−1 (n = 16) or saline (n = 16) in a randomized fashion. Fifteen minutes later, each group was randomly subdivided into two equal groups and an infusion of bupivacaine or ropivacaine, 3 mg kg−1 min−1, was given until cardiac arrest (asystole) occurred. The times when the cardiotoxic events (25%, 50% and 75% reduction of arterial pressure and heart rate, first dysrhythmia and asystole, respectively), induced by the local anaesthetic, occurred and the resuscitation outcome scores were recorded.

Results: Clonidine reduced heart rate and arterial pressure (P < 0.01). Clonidine did not alter cardiotoxicity or the success rate of resuscitation in bupivacaine-treated rats. In the ropivacaine group, clonidine increased the 25%, 50% and 75% reduction times of arterial pressure and the 50% and 75% reduction times of heart rate, times to first dysrhythmia and asystole (P < 0.05). Clonidine also increased the success rate of resuscitation in ropivacaine-treated rats (P < 0.05).

Conclusions: Although pre-treatment with clonidine protects the effects of ropivacaine cardiotoxicity and increases the success rate of resuscitation, it does not affect bupivacaine toxicity.

Testing of otoacoustic emissions (OAE) has been successfully applied to study outer hair cell function. We used this methodology to evaluate and compare the effect of topically applied normal saline, and gentamicin- and ciprofloxacin-containing drops into the middle ear of guinea pigs. All three solutions similarly decreased the distortion product OAE (DPOAE) and all three caused an inflammatory reaction in the guinea pig’s middle-ear. OAE failed to detect adequately the ototoxicity of topically administered drops in this animal model because the opening of the bulla affected DPOAE, and both inflamed middle-ear mucosa and osteoneogenesis caused a decrease in DPOAE amplitude.

This is the first report examining the influence of topically used otic drops on inner ear function as demonstrated by OAE.

Laudanosine is a metabolite of the neuromuscular-blocking drugs atracurium and cisatracurium with potentially toxic systemic effects. It crosses the blood-brain barrier and may cause excitement and seizure activity. Its interest in recent years has increased because of the recognized interaction with γ-aminobutyric acid, opioid and nicotinic acetylcholine receptors. It has been shown to produce analgesia in animals. In the cardiovascular system, high plasma concentrations produce hypotension and bradycardia. In hepatic failure, its elimination halflife is prolonged but only moderate accumulation occurs in adults, whereas in infants and children plasma concentration are greater. In patients undergoing liver transplantation, laudanosine concentrations are increased during preanhepatic, anhepatic and postanhepatic stages. Patients with renal failure have higher plasma concentrations and a longer mean elimination half-life. In pregnancy, laudanosine crosses the placental barrier. The mean transplacental transfer is 14% of maternal blood concentrations. Except for prolonged administration of atracurium in intensive care units, laudanosine accumulation and related toxicity seem unlikely to be achieved in clinical practice. When cisatracurium is used, plasma concentrations of laudanosine are lower. Further studies are needed, especially around the interactions with γ-aminobutyric acid, opioid and nicotinic acetylcholine receptors.

Background and objective: Some halogenated agents, especially methoxyflurane, because of a higher level of fluoride production, induce a renal concentrating defect that could be related to an ascending limb impairment. We investigated the mechanisms of fluoride toxicity on an immortalized cell line.

Methods: Cells were cultured for 2, 6 or 24 h in the presence of fluoride. Toxicity evaluation was based on: cell numbers, protein content, leucine-incorporation, lactate dehydrogenase (LDH) and N-acetyl-βglucosaminidase (NAG) releases, Na-K-ATPase and Na-K-2Cl activities, electron microscope studies. Infrared analysis and fluoride microdetermination allowed crystal components.

Results: At 5 mmol after 24 h, fluoride decreased cell numbers (−14%, *P < 0.05), protein content (−16%*), leucine incorporation (−54%*), Na-K-2Cl activity (−84%*), increased LDH (+145%*) and NAG release (+190%*). Na-K-ATPase was more sensitive and impaired from 1 mmol for 24 h and after 2 h at 5 mmol. Crystal formation in mitochondria occurred after 6 h at 5 mmol. Infra-red analysis and fluoride microdetermination established that crystals contained sodium, phosphate and fluoride.

Conclusions: The results suggest that the Na-K-ATPase pump is a major target for fluoride toxicity in Henle's loop.

Ecstasy is a substance of abuse commonly associated with the dance scene and taken by many young people. A brief history of Ecstasy and its side-effects is given. A case of ototoxicity is presented, as an additional side-effect to the long list of complications caused by Ecstasy.

Two cases of bilateral moderate to severe sensorineural hearing loss due to oral administration of metronidazole are reported. There has been only one case report of deafness following metronidazole therapy in the world literature. The hearing loss recovered gradually in a period of four to six weeks following withdrawal of drug and oral steroid therapy. The possible mechanism of ototoxicity is discussed. Awareness by the treating physician of ototoxicity due to any drug is stressed.