Pharmacology

Sex, lies and pharmaceuticals. How drug companies are bankrolling the next big condition for women . Ray Moynihan. Sydney: Allen & Unwin, 2010 (256 pp). ISBN 9781742370187. SEX SELLS, as does the implication of a good scandal, so the title alone should generate some sales of Australian investigative journalist Ray Moynihan’s latest exposé of Big Pharma’s marketing machine. Building on the success of his earlier work, Selling sickness, Moynihan here teams up with Dr Barbara Mintzes (Assistant Professor in the Department of Anesthesiology, Pharmacology and Therapeutics at the University of British Columbia in Canada) to disassemble the story behind “female sexual dysfunction” or FSD. The story of FSD is traced through an investigative journalist’s eyes, from the revolution in sexual medicine in the late 1980s, through the launch of the now infamous phosphodiesterase type 5 inhibitors, to today. Along the way, with the benefit of hindsight, the authors assemble the jigsaw pieces of pharmaceutical company influences on researchers and clinicians to paint a picture of a series of disorders being created by the very industry which then fortuitously provides the panacea. Moynihan and Mintzes are no strangers to highlighting the effects of pharmaceutical company promotion and largesse. While it could be argued that this work is part of a sustained attack on the industry, Moynihan takes great care to emphasise the usefulness of pharmaceuticals for some women who have a sexual disorder. The main theme is that these women form a small minority — not 43% or similar figures quoted by proponents of such medical treatment — and that many non-drug therapies are as effective as drugs, if not more so. Sex, lies and pharmaceuticals is very readable, and its target audience is consumers, not health professionals. Its main aim is to encourage consumers (or patients) to ask questions of their doctors to gain an understanding of the diagnosis with which they are being labelled, and for which they are subsequently treated. It is $30 well spent to see what your patients may be reading and to question “Where did those useful diagnostic tools really come from?”.

Greg Kyle

To the Editor: We report the use of nebulised frusemide for the symptomatic treatment of end-stage congestive heart failure (CHF). An 84-year-old man with New York Heart Association class IV CHF was referred to the Community Heart Failure Team at St Vincent’s Hospital, Sydney, for ongoing management after a hospital admission for acute pulmonary oedema. His medical history included aortic stenosis, pulmonary hypertension, type 2 diabetes, chronic renal failure, atrial fibrillation, hypertension, chronic obstructive pulmonary disease (COPD) and hypercholesterolaemia. The patient’s medications were home oxygen via a concentrator at 2–4 L/minute; digoxin 62.5 μg three times a week; warfarin 5 mg daily; glyceryl trinitrate 25 mg daily (delivered via a patch); simvastatin 40 mg nightly; spironolactone 12.5 mg daily; frusemide 80 mg orally twice daily (flexible regimen); insulin/isophane (Protaphane; Novo Nordisk) variable dose twice daily; fluticasone 250 μg/salmeterol 50 μg (Seretide; GlaxoSmithKline) one dose twice daily; and omeprazole 20 mg daily. Previous trials of a β-blocker and angiotensin-converting enzyme inhibitor were not tolerated. Two days after the patient was discharged, a home visit by the clinical nurse consultant (CNC) found him with grossly oedematous legs, jugular venous pressure (JVP) elevated above his ears, and crepitations from the bases to the upper mid zones of his lungs. On Day 1 and 2 of CNC care at home, the patient received intravenous bolus doses of frusemide 80 mg, resulting in good diuresis. On Day 3, the CNC was unable to gain intravenous access and, after consulting the Community Heart Failure Team cardiologist and pharmacist, administered frusemide 80 mg via a nebuliser. The patient reported immediate improvement. Oxygen saturation increased from 88% to 97% on room air and his chest was clearer on auscultation. Increased diuresis occurred, with weight loss of 1 kg. Because the patient’s JVP and leg oedema were unchanged, the dose was repeated daily for 5 days until respite admission (for social reasons and intravenous frusemide administration). Nebulised frusemide had provided symptomatic relief from dyspnoea for about 5 hours with no adverse effects for the patient, but did not provide sufficient diuresis to reduce his fluid overload symptoms. Ultimately, a central catheter (“long line”) was inserted to enable the CNC to administer frusemide intravenously at the patient’s home. CHF-associated dyspnoea causes significant morbidity and distress for patients and carers. Nebulised frusemide has been used for relief of dyspnoea associated with asthma, COPD and malignancy.1 Its precise mechanism of action is unknown, but is believed to be through local lung rather than renal effects.1 Our searches of MEDLINE, EMBASE, CINAHL and the internet found no reports of the use of nebulised frusemide for dyspnoea resulting from pulmonary oedema or CHF. Patients with CHF receiving palliative care have limited options for diuresis when oral administration is ineffective and intravenous access is unavailable. The use of nebulised frusemide could have potential in this setting, but requires further research.

Kate A Towers · Kimberley A Bardsley · Peter S Macdonald

The National Antimicrobial Utilisation Surveillance Program (NAUSP) collects aggregate data from hospitals in all Australian states and provides reports of monthly hospital inpatient antimicrobial usage to contributing hospitals. These data provide an Australian peer-group benchmark; hospitals can compare their usage with similar hospitals and identify areas of antimicrobial use that require more indepth analysis. Overall high usage has been used by hospitals and area health services as a stimulus for initiation or expansion of antimicrobial stewardship programs. High use of particular classes of antimicrobials has triggered individual drug audits and been used to tailor interventions. Longitudinal antimicrobial usage data have been used by hospitals to measure the effects of antimicrobial stewardship strategies and provide feedback to prescribers.

Vicki McNeil BPharm, GradDipPharm, GradCertPubHlth · Marilyn Cruickshank RN, PhD · Margaret Duguid BPharm, GradDipAdmin

To the Editor: Prescribing and dispensing generic medicines is an option to reduce costs in the community and is also common practice in public hospitals. In addition to the issues discussed by McLachlan,1 we have noted a concerning trend in the “branding” of many new generic medicines that has the potential to add to the confusion for patients, prescribers and pharmacists. Medicines with special release properties are branded with suffixes as a reminder of their longer duration of action, such as Sustained Release (eg, Tramal SR; CSL Limited) or eXtended Release (eg, Efexor-XR; Wyeth Australia). Different formulations may also use a suffix to indicate distinguishing properties, such as “dispersible” in Rulide D (Sanofi-Aventis) or “osmotic release oral system” in Adalat OROS (Bayer Schering). However, these suffixes, while meaningful, can be a source of misunderstanding about dosing intervals and length of action, leading to errors.2 A standard nomenclature does not exist, even for formulation descriptors. Adding to this confusion, generic medicine manufacturers are now marketing products with prefixes or suffixes, not to denote a modified formulation but to place their “brand” on the medicine. Ascent Pharmaceuticals has three different suffixes/prefixes for its generic products, reflecting the names of previous manufacturers (eg, Quinapril-GA, GN-Carvedilol), and two suffixes for simvastatin (GA and DP). Spirit Pharmaceuticals adds its name to some products (eg, Simvastatin-Spirit). Taking an oral medication history becomes challenging when patients state they use “Spirit” medication for their cholesterol, “GN” tablets for their heart and “GA” tablets for their high blood pressure. With the many generic “brands” now available (eg, 22 simvastatin products), packs with similar labelling lined up on the pharmacy or patient’s shelves increase the risk of wrong selection. Although no reports have been published to date, similarities in brand prefixes may cause medication errors in electronic prescribing and dispensing systems, when an incorrect medication is selected from a dropdown menu. Entering “Apo” in some systems selects more than 40 products manufactured by Apotex, which uses a naming pattern of the generic drug prefixed by Apo (eg, Apo-Alendronate), as well as APO-go (Hospira), which is apomorphine (and does not contain “go”). This situation could be avoided in future if the National E-Health Transition Authority’s Australian Medicines Terminology and its editorial principles are adopted in systems. These rules require that all medicines are represented by descriptions that list the generic name first, with the sponsor’s name following in parentheses (Paul Frosdick, Chief Terminologist, National E-Health Transition Authority, personal communication, 25 August 2010). The Food and Drug Administration in the United States and the Therapeutic Goods Administration in Australia have developed documents outlining approved medicines terminology,2,3 but there are no official lists of approved suffixes or prefixes. The Institute for Safe Medication Practices, a non-profit US-certified patient safety organisation internationally regarded as an expert in medication safety, has recognised this problem and maintains a list of products with drug name suffixes and their meanings.4 With more generic options available, good communication between medical and pharmacy clinicians and patients is essential to clarify the indication, along with the specific name, of medications prescribed. Pharmaceutical manufacturers need to consider the impact of meaningless prefixes and suffixes, which add to the confusion and potentially contribute to medication errors. National authorities should improve overall governance of labelling of generic medicines, to prevent errors reaching patients.

Linda V Graudins · Michael J Dooley

To the Editor: Evidence is beginning to accumulate on the effectiveness of the low-density lipoprotein (LDL) cholesterol-lowering medicine ezetimibe. While there are no completed trials investigating ezetimibe’s effect on clinically important end points, two recent trials investigating its effect on carotid intima media thickness (CIMT) have both reported disappointing results.1,2 After each of these trials, the Journal has published editorials by Hamilton-Craig, who offers reassurance about ezetimibe and encourages ongoing prescription of this drug to patients who have elevated LDL levels despite maximum-tolerated statin therapy.3,4 Such a sanguine opinion seems at odds with the negative trial evidence, and therefore worthy of debate. Briefly, the ENHANCE (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) trial, which compared ezetimibe plus simvastatin with simvastatin treatment alone in 720 patients with familial hypercholesterolaemia, found no significant difference (and a trend in the direction of harm) with respect to the primary end point of CIMT.1 The ARBITER 6-HALTS (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6 — HDL and LDL Treatment Strategies in Atherosclerosis) trial compared ezetimibe with extended-release niacin in statin-treated patients with coronary heart disease.2 Among 315 patients with available results, the group taking niacin showed a statistically significant reduction in CIMT, but the group taking ezetimibe showed no such reduction. Of concern, increased cumulative exposure to ezetimibe was associated with progression of CIMT (P = 0.05). Although far from definitive, the results of these two trials offer no reassurance of benefit from ezetimibe and, in my view, may portend harm. It may seem counterintuitive that ezetimibe, which significantly lowers LDL cholesterol levels,1,2 could be ineffective or harmful. However, the history of medicine is replete with examples of interventions that improve numerical disease measures without benefit to patients. One recent example was torcetrapib, which, despite increasing high-density lipoprotein cholesterol and reducing LDL cholesterol levels in a promising manner, was found to cause serious adverse events, including death.5 I agree with Hamilton-Craig that we require trials measuring major cardiovascular events to really understand the effects of ezetimibe. Where we disagree is how to manage our patients during the period of uncertainty until publication of the results of these trials. While he argues for continued prescribing of ezetimibe, I suggest we should explicitly share our uncertainty about the safety and efficacy of this drug with our patients by discussing the existing research. Some patients will, like Hamilton-Craig, place their faith in the cholesterol hypothesis and be reassured by an assumption of cardiovascular protection as their LDL falls. Others will choose to wait until we have more robust evidence that ezetimibe is safe and effective. I would wait.

Brett D Montgomery

In reply: I agree with Montgomery that cardiovascular disease (CVD) outcomes are required to determine the role of ezetimibe. The Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial (in which patients with aortic stenosis were treated for 52.2 months with statin plus ezetimibe or statin plus placebo) showed a 4.7% reduction in ischaemic CVD events in the ezetimibe group (P = 0.02; number needed to treat, 23), driven by a reduced need for coronary artery bypass grafting.1 In contrast to previous trials showing regression of atherosclerosis in response to statin therapy, baseline carotid intima media thickness (CIMT) levels in the ENHANCE (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) trial were normal, due to previous statin therapy. This is likely to account for the lack of change in CIMT with ezetimibe treatment in the ENHANCE trial.2 As no placebo group was included, neither lack of benefit nor harm from ezetimibe therapy can be inferred.2 Data from animal studies have shown atherosclerosis regression after ezetimibe treatment through multiple mechanisms.3-5 Prospective randomised controlled trials with statins, resins or surgery have independently shown an approximate 1% reduction in CVD per 1% reduction in low-density lipoprotein cholesterol (LDL-C) level. Evidence for the benefits of lowering LDL-C is among the most robust in medicine. Pending the outcomes of IMPROVE-IT (the Improved Reduction of Outcomes: Vytorin Efficacy International Trial, a multicentre study of ezetimibe plus simvastatin versus simvastatin treatment of patients with acute coronary syndrome [http://clinicaltrials.gov/ct2/show/NCT00202878]), or clinical outcome data confirming those of the ARBITER 6-HALTS (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6 — HDL and LDL Treatment Strategies in Atherosclerosis) trial,6 it seems reasonable to continue to use ezetimibe to lower LDL-C levels in patients who are not achieving LDL-C targets despite statin therapy or who are intolerant to statins. Extended-release nicotinic acid (Niaspan [Abbott Laboratories, Chicago, Ill, USA]) may be an appropriate alternative to statins as second-line therapy, and should be made available under the Pharmaceutical Benefits Scheme for treating patients with dyslipidaemia. (Niaspan has approval from the Therapeutic Goods Administration for marketing in Australia, but is not being imported into Australia at this stage.)

Ian R Hamilton-Craig

Evidence concerning the safety of rosiglitazone continues to evolve In February 2010, the United States Senate Committee on Finance released a report on the safety of rosiglitazone.1 The report concluded that there were possible cardiac risks associated with rosiglitazone and that the manufacturer, GlaxoSmithKline (GSK), was aware of this well before it became public. The authors further stated that, rather than warn patients and regulatory authorities promptly, GSK executives chose to intimidate independent physicians who publicised the possible risks, minimise the impact of adverse findings, and downplay the possibly beneficial cardiovascular effects of the other available drug in the class, pioglitazone.1 A week before the Finance Committee report was released, an editorial by Steve Nissen, lead author of the meta-analysis that first raised cardiovascular concerns regarding rosiglitazone in 2007,2 was published online.3 The editorial related to an article on the increased risk of heart failure, a recognised adverse effect of glitazones, found in the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) trial.4 However, it was more a detailed account of the sequence of events surrounding rosiglitazone’s possible adverse cardiovascular effects, starting with its US approval in 1999. The editorial viewed the RECORD trial (the main results of which were published mid 20095 but not considered in the Finance Committee report) as underpowered, despite demonstrating that rosiglitazone was non-inferior to metformin or sulfonylurea for the primary endpoint of cardiovascular hospitalisation or death. Although there were no new safety concerns or efficacy data in either the Finance Committee report or Nissen’s editorial, there was a prompt media response. The New York Times, for example, highlighted a suggestion by the Finance Committee that if every diabetic patient in the US taking rosiglitazone was given pioglitazone instead, 500 heart attacks and 300 cases of heart failure would be averted every month.6 There was also a quick response from GSK, which categorically rejected the findings of the Finance Committee and the assertions of the New York Times in separate media statements, and published a point-by-point response to Nissen’s editorial.7 More recently, the results of a retrospective analysis of US Medicare data for older patients8 and an expanded meta-analysis from Nissen’s group,9 both suggesting adverse cardiovascular effects of rosiglitazone, have contrasted with a post-hoc analysis of data from the Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes study, in which rosiglitazone was found to be of significant benefit in patients with established coronary artery disease.10 At present, rosiglitazone remains approved for use in Australia as monotherapy or as part of dual oral combination therapy with metformin or a sulfonylurea,11 although only the combination therapy is subsidised by the Pharmaceutical Benefits Scheme. The product information contains a boxed warning for patients with known ischaemic heart disease, particularly those taking nitrates, and highlights the increased risk of myocardial ischaemia found in pooled short-term clinical studies.11 In the US and Europe, rosiglitazone remains available despite the recent media reports. The US product information has similar warnings to those of the Australian version, while the European version has the general recommendation that the drug not be used by patients with ischaemic heart disease and/or peripheral arterial disease. One possible reason why rosiglitazone was not withdrawn in 2007 is that the statistical methods used in the original meta-analysis2 were questionable. Alternative reasonable approaches can yield increased or decreased risks that are either statistically significant or not significant for both myocardial infarction and cardiovascular death.12 As there are no trials with cardiovascular events as the primary endpoint showing benefit of pioglitazone over other therapies, the most compelling evidence for its apparently better cardiovascular profile comes from a similar meta-analysis to that for rosiglitazone.3 A cardiovascular disease outcome study of rosiglitazone versus pioglitazone is, therefore, justifiable and in progress (Thiazolidinedione Intervention with Vitamin D Evaluation [TIDE]; ClinicalTrials.gov NCT00879970). Nevertheless, TIDE might become a casualty of the recently reactivated controversy before it reports in 2015, as the Endocrinologic and Metabolic Drugs Advisory Committee of the US Food and Drug Administration (FDA) continues to review the ethical and clinical implications of the available rosiglitazone safety data. Although the debate about the safety of rosiglitazone has centred on cardiovascular risk, a further potential concern is fracture.13 The deleterious effects of glitazones on bone emerged in animal studies dating back to 1996. Unfortunately, despite knowledge of these data, neither glitazone manufacturer included prespecified bone loss parameters and endpoints in any clinical trial. However, retrospective analyses of data from blood glucose-lowering efficacy trials involving rosiglitazone and pioglitazone, reported in 2006 and 2007, respectively, confirmed an increased fracture risk in humans.13 Given that these drugs have been available in Australia and most other countries for only 10 years, their long-term effect on fracture rates is worrying, especially in postmenopausal women. Glitazone therapy can improve glycaemic control in patients with type 2 diabetes, but patients should be selected according to drug-specific contraindications and warnings, the glycaemic effect should be reviewed after at least 3 months to confirm response, and adverse effects including weight gain, fluid retention and reduced bone density should be monitored during continued use. The recent adverse publicity regarding rosiglitazone highlights issues that can arise when drugs are approved and marketed without definitive efficacy and safety data. There is a need for pharmaceutical companies, academia and regulatory authorities to use preclinical and early phase clinical data to identify, through careful phenotyping, the patient population with the most potential for benefit and the least potential for harm when new drugs are being evaluated for registration. One important consequence of the rosiglitazone controversy is that adequately powered Phase IV cardiovascular safety studies are now required by the FDA when new therapies for diabetes are registered.3 The promise of the glitazones was that they targeted one of the central pathophysiological defects in type 2 diabetes, namely insulin resistance, and improved markers of cardiovascular risk including serum C-reactive protein and microalbuminuria. Unfortunately, based on a variety of clinical trials and observational studies, they do not appear to have a consistent cardiovascular advantage over established blood glucose-lowering agents, including metformin and sulfonylureas.

Timothy M E Davis MB BS, DPhil, FRACP · Johannes B Prins MB BS, PhD, FRACP

To the Editor: Although Clarke and Fitzgerald’s claim that prices for generic medicines in Australia are high compared with prices in other countries1 is valid, their claim that the Pharmaceutical Benefits Scheme expenditure on statins could be reduced by up to $9.31 billion, by increasing the proportion of generic prescriptions to 100% and paying equivalent prices to those in England, is problematic. For the proportion of generic prescriptions to be increased to 100%, the available generic statins would need to be directly substitutable for currently available statins, including those whose patents have not yet expired (eg, atorvastatin and rosuvastatin). Nicholls and colleagues present the results of a meta-analysis of various doses of atorvastatin, rosuvastatin and simvastatin.2 The findings of the Pharmaceutical Benefits Advisory Committee (PBAC) on the comparative effectiveness of the various statins can be summarised as follows:3 Simvastatin is the benchmark statin; the maximum recommended dose is 80 mg/day. Pravastatin is equivalent to simvastatin on a milligram-for-milligram basis: pravastatin 10 mg is equivalent to simvastatin 10 mg. The maximum recommended dose of pravastatin is 80 mg/day. Atorvastatin 1 mg is equivalent to simvastatin 2 mg: atorvastatin 10 mg is equivalent to simvastatin 20 mg. The maximum recommended dose of atorvastatin is 80 mg/day. It is notable that a simvastatin dose equivalent to atorvastatin 80 mg (ie, simvastatin 160 mg) is beyond the maximum recommended dose of simvastatin. Rosuvastatin 1 mg is equivalent to atorvastatin 3 mg, which would be equivalent to simvastatin 6 mg (ie, rosuvastatin 10 mg is equivalent to atorvastatin 30 mg, which would be equivalent to simvastatin 60 mg). The maximum recommended dose of rosuvastatin is 40 mg/day. It is notable that a simvastatin dose equivalent to rosuvastatin 40 mg (ie, simvastatin 240 mg) is beyond the maximum recommended dose of simvastatin. By applying the therapeutic relativities accepted by the PBAC to the results reported by Nicholls and colleagues, the dose–response curves for rosuvastatin, atorvastatin and simvastatin, all expressed in simvastatin mg equivalents, can be generated as shown in the Box. As seen in the graph, simvastatin (available as a generic) may not be substitutable for atorvastatin or rosuvastatin in patients who need a reduction in low-density lipoprotein cholesterol level of > 45 mg/dL (> 1.15 mmol/L). Although having patients switch to generic prescriptions would reduce expenditure on statins, the possibility that such a switch might be associated with inferior outcomes needs to be considered. Dose–response curves for rosuvastatin, atorvastatin and simvastatin LDL-C = low-density lipoprotein cholesterol.

Liliana Bulfone

In reply: Our recent study1 estimates pharmaceutical expenditure from 2009 to 2019 for various levels of use of off-patent statins, ranging from 25% (close to the current proportion) to 100%. We also show that England has much higher use of generic statins and consequently much lower pharmaceutical expenditure. However, our study does not advocate a particular level of generic use and so it is unclear why Bulfone has chosen to focus on only one of the cases (100% use of generics) presented in our study. We agree with Bulfone’s view that it is important to consider whether the greater use of generic statins has an impact on health outcomes in addition to examining the implications for pharmaceutical expenditure. This is one of the points we have already made: “The key question is whether the health benefits resulting from using statins under patent or combination therapies justify the substantially higher subsidies from the [Pharmaceutical Benefits Scheme].”1 The appropriate framework to use to consider this question would be to examine incremental cost-effectiveness of those statins still under patent (atorvastatin and rosuvastatin) compared with off-patent alternatives (simvastatin and pravastatin). Such an evaluation would be timely, as Australia faces billions of dollars of extra pharmaceutical expenditure over the next decade if we continue to prescribe patented statin formulations at current levels.

Philip M Clarke · Edmund M FitzGerald

To the Editor: Infections caused by multiresistant gram-negative organisms are difficult to treat. Carbapenems are often used as a last resort but even these are under threat with the emergence of acquired metallo-b-lactamases worldwide, including Australia,1,2 India, China and Europe. We report the first case of a Providencia rettgeri producing the blaNDM-1 (New Delhi metallo-b-lactamase) type of metallo-b-lactamase in Australia. A man from Canberra, aged in his mid 50s, had elective plastic surgery in India in September 2009. This was complicated by a hypoxic brain injury, after which the patient spent 4 weeks in an intensive care unit. He was subsequently transferred to Canberra for ongoing hospital care. A urinary catheter specimen collected on admission in November 2009 showed a heavy growth of multidrug-resistant P. rettgeri and Pseudomonas aeruginosa. The P. rettgeri was resistant to all b-lactam antibiotics, including meropenem, as well as to all aminoglycosides, ciprofloxacin, tigecycline and colistin. The P. aeruginosa was resistant to all antipseudomonal antibiotics except for colistin (tigecycline was not tested as it has low or no antipseudomonal action). The patient was not given antibiotic therapy but the indwelling urinary catheter was changed and contact precautions were put in place. Both organisms were sent for molecular testing, which showed that the P. rettgeri had 100% homology with blaNDM-1.3 The patient cleared the organisms after 2 months, and since then has received ongoing inpatient care in the rehabilitation unit. The first NDM-1 type of metallo-β-lactamase was found in Klebsiella pneumoniae isolated from a Swedish patient who had recent medical contact in India.3 Data from the United Kingdom’s Antibiotic Resistance Monitoring and Reference Laboratory suggest that isolates with the NDM-1 enzyme have recently been repeatedly imported to the UK from the Indian subcontinent. There may now be circulation of these resistant isolates in the UK because some infected patients have no identifiable overseas links. Hospitals have been urged to be vigilant for multiresistant gram-negative bacteria in patients with recent hospital contact in the Indian subcontinent as well as the Eastern Mediterranean.4 Identification of an Enterobacteriaceae organism carrying blaNDM-1 is very concerning. No antibiotic may be available to treat patients who develop serious infection with such organisms, and there is the added concern regarding cross-infection in health care facilities. The plasmid carrying blaNDM-1 also contains genes that confer resistance to several other antibiotics.3 It appears likely that, in the near future, the NDM-1 enzyme will become a very successful metallo-b-lactamase globally. Patients infected with multiresistant gram-negative bacteria have entered the “post-antibiotic era”.

Geethanie A T P Fernando · Peter J Collignon · Jan M Bell

To the Editor: In her editorial, Christiansen states that the 2010 edition of Therapeutic guidelines: antibiotic (version 14) is very likely to recommend 24 hours of antibiotic prophylaxis for cardiac surgery,1 rather than the present regimen, which recommends that patients having routine cardiac surgery be given a large dose of cephazolin at induction, with a second dose if the operation is prolonged for more than 3 hours, and no doses after surgery.2 The only evidence presented in support of this proposed change is a single randomised controlled trial that purported to show a higher rate of surgical site infections after a single dose of cephazolin, than after a prolonged, multidose regimen.3 The study was flawed, for two reasons. First, cephazolin was not given until 20–30 minutes after induction of anaesthesia, which is likely to have been too late, because, as Christiansen points out, β-lactams should be given 30–60 minutes before incision.1 Second, the trial was analysed on a per-protocol, rather than an intention-to-treat basis, and 189 of the 1027 participants (18%) were excluded, so the findings may be seriously biased.4 Three other trials have compared one or two doses of a cephalosporin with multiple doses of the same antibiotic in patients having cardiac surgery; none found that multiple doses were superior, although all three were small studies with faults in their design.5-7 In 1998, McDonald and colleagues published a detailed review of single versus multiple doses of antimicrobial prophylaxis for major surgery. The analysis was in response to a suggestion by Christiansen and others that single-dose antibiotic prophylaxis may be inadequate for patients undergoing vascular surgery.8 McDonald and colleagues pointed out that the recommendation for single-dose surgical prophylaxis in Therapeutic guidelines: antibiotic (version 13),2 is based on microbiological first principles, published studies reporting efficacy, convenience of administration, reduced antibiotic resistance and toxicity, and relatively low cost. Their careful analysis of 28 randomised trials, in which the same antimicrobial was used in each arm, showed no advantage from the administration of multiple doses; the odds ratio for infection was 1.06 (95% CI, 0.89–1.25). There is no microbiological reason to suppose that the crucial interaction between contaminating bacteria and the prophylactic antibiotic in the heart is any different from that in the lung, biliary tree, uterus, bowel, prostate or bone.8 In the absence of such evidence, there is no sound reason to change the current, long-standing Therapeutic guidelines: antibiotic2 recommendation.

Frank Shann

In reply: Professor Shann raises three issues regarding the recommendation for 24 hours’ prophylaxis for cardiac surgery. First, he states that the trial1 on which this recommendation was made was flawed, because “cephazolin was not given until 20–30 minutes after induction of anaesthesia, which is likely to have been too late”. The trial included patients having coronary artery surgery and/or cardiac valve replacement, and, for these procedures, the time between induction of anaesthesia and surgical incision is about 60–75 minutes, as patients require the placement of intravenous lines and preparation for coronary artery bypass surgery. Antibiotic administration is recommended 30–60 minutes before incision, thus, administration 30 minutes after induction provides optimal serum concentrations at incision, in patients undergoing cardiac surgery. Second, the per-protocol analysis is perhaps less than ideal, but the demographics, clinical characteristics and operative data were comparable for the patients included in the analysis. Third, as stated by Professor Shann, the three earlier studies2-4 were either very small or flawed in design. The McDonald systematic review5 included 28 studies, only two of which were on cardiac surgery, both being the earlier flawed studies2,3 quoted above. The Therapeutic guidelines: antibiotic review process involves a rigorous, evidence-based assessment with input from experts in the field. The medical community of Australia can have every confidence that the recommendations made are current and evidence-based.

Keryn J Christiansen

A 66-year-old woman on peritoneal dialysis for end-stage renal disease secondary to diabetic nephropathy was admitted on Christmas Day with suspected osteomyelitis of her left third toe. During admission, she complained of constipation and mild abdominal pain. There were no focal abdominal findings on examination. Of note, she was prescribed 750 mg three times daily of the rare metal lanthanum carbonate hydrate for hyperphosphataemia of renal failure. An abdominal x-ray was taken after the second dose of the day (Figure). Lanthanum has been shown to be radio-opaque on x-ray1,2 and computed tomography,3 and this is briefly mentioned in the full product information. The radiology report in this case suggested alternative diagnoses of residual contrast from a barium study, sclerosing peritonitis, tuberculosis or lead ingestion, none of which were consistent with the clinical history. The use of lanthanum as a phosphate binder is likely to increase since it was listed on the Pharmaceutical Benefits Schedule in 2009. Awareness of its radio-opaque features will prevent unnecessary investigations.

Yohan Chacko · Carolyn J Clark

Cross-border importation of traditional and prescription medications is common, and many of these drugs are not approved by the Australian Therapeutic Goods Administration. Furthermore, counterfeit versions of prescription medications are also available (eg, weight-loss medications, anabolic steroids, and medications to enhance sexual performance). We describe a 54-year-old man with the first Australian case of severe hypoglycaemia induced by imported, laboratory-confirmed counterfeit Cialis. This serves to remind medical practitioners that counterfeit medication may be the cause of severe hypoglycaemia (or other unexplained illness). Clinical recordA 54-year-old male truck driver was admitted to a regional hospital with profuse sweating, slurred speech, ataxia and confusion. He had a history of heavy smoking and moderate alcohol consumption, but denied taking any medications or using recreational drugs. On the evening before his illness, he had four standard alcoholic drinks. On examination, his blood pressure was 150/97 mmHg, body mass index was 33.3 kg/m2, and his score on the Glasgow Coma Scale was 12/15 (eye response, 3; motor response, 6; and verbal response, 3). The rest of the general and systemic examination was unremarkable. In the emergency department, his blood glucose level indicated severe hypoglycaemia (1.1 mmol/L; reference range [RR], 3.0–6.0 mmol/L). After administering 50 mL of an intravenous infusion of 50% dextrose and giving an intramuscular injection of 1 mg glucagon, his Glasgow Coma Scale score improved to 15/15. Subsequently, apart from a high-carbohydrate diet, he required an intravenous infusion of 5% dextrose at a variable rate for 4 days to maintain euglycaemia. His glucose requirement decreased slowly over the following 4 days. He was extensively investigated for hypoglycaemia while in hospital. All other haematological and biochemical parameters, except β-hydroxybutyrate, insulin and C-peptide, were normal. His serum insulin and C-peptide levels, measured on Day 1 and Day 2, were abnormally elevated relative to his low blood glucose level (ie, for the low blood glucose level in this case, the serum insulin level would be expected to be lower). The serum insulin and C-peptide levels had normalised by Day 9 (Box). The serum β-hydroxybutyrate level, measured on Day 2, was particularly low at 0.05 mmol/L (RR, < 0.20 mmol/L), consistent with insulin excess. Magnetic resonance imaging of the pancreas gave negative results for insulinoma. A plasma sulfonylurea screening test, first done on Day 9, gave a negative result. No conclusive diagnosis about this self-limiting hypoglycaemic episode was made during admission. The patient was discharged after making a full recovery. He was advised to self-monitor his capillary blood glucose level and was referred to the endocrinology clinic at our hospital for further evaluation. He attended the endocrinology clinic 2 weeks after discharge. In view of his self-limiting hypoglycaemic episode, specific enquiry was made about the use of oral medication that may have caused the hypoglycaemia. He admitted that, an hour before developing the symptoms, he took a sexual performance-enhancing medication. This was the first time he had taken any medication of this type. The medication had been bought in Vietnam by a friend. This raised the suspicion of contaminated or counterfeit medicine as the cause of the hypoglycaemia. The medication from Vietnam was in a bottle labelled “Cialis 50”. When compared with Cialis manufactured by Eli Lilly, gross differences in packaging, labelling and dose strength were noticed. High-performance liquid chromatography performed by the Australian Therapeutic Goods Administration (TGA) confirmed that one tablet of counterfeit Cialis 50 contained 152.8 mg of glibenclamide and 0.5 mg of sildenafil. The TGA and Eli Lilly Australia were subsequently officially notified. DiscussionThis is the first report of a laboratory-confirmed counterfeit Cialis tablet in Australia. There have been recent warnings about this counterfeit drug and other similar sexual performance-enhancing medications on several health websites.1-4 Cialis (tadalafil), a phosphodiesterase-5 (PDE-5) inhibitor, is a pharmaceutical drug manufactured and marketed by Eli Lilly. It can be obtained only with a prescription, and is dispensed in 5 mg, 10 mg and 20 mg, but not 50 mg, doses. Our case reveals the poor quality-control measures used during the manufacturing process of counterfeit Cialis, which not only contained a lethal dose of a sulfonylurea, but also a subtherapeutic amount of a different agent from the PDE-5 inhibitor class. Glibenclamide is not known to have any sexual performance-enhancing effect, and hypoglycaemia is not a known adverse reaction of tadalafil. Consumption of counterfeit medicines may be harmful. As many countries have not yet enacted deterrent legislation, counterfeiters often do not need to fear prosecution.5 Medicines for erectile dysfunction or sexual enhancement have a huge global market, and this is not the first report of this adverse reaction. An outbreak of hypoglycaemia, secondary to ingestion of sexual performance-enhancing drugs, including counterfeit Cialis and other unlicensed drugs, was reported recently from South-East Asia.6 These drugs also contained high doses of glibenclamide and low doses of sildenafil. The World Health Organization estimates that up to 1% of medicines available in the industrialised countries, and 10% globally, may be counterfeit.7 In Australia, the TGA is an effective regulatory authority; however, despite the regulations, overseas travel and internet purchasing may allow counterfeit medicines to be imported. Under the “Personal import scheme”, many complementary medicines can be legally imported without import permits.8 Additionally, drugs from the PDE-5 inhibitor class, such as tadalafil, which are prescription-only medicines, are not listed under “Prohibited imports and exports (drugs and precursor chemicals)” and so can be purchased on the internet with a prescription from Australia.9 A universal cyberlaw or some other form of international convention is needed to regulate promotion and sales of these types of products on the internet. The WHO acknowledges that increasing international trade in pharmaceuticals, as well as sales via the internet, has further facilitated the entry of counterfeit products into the supply chain. To combat this, in 2006 the WHO helped to create the International Medical Products Anti-Counterfeiting Taskforce (IMPACT).5 Consumers are encouraged to use web sources like the TGA, Health on the Net Foundation, and the WHO to get useful and reliable online health information on medicinal products.10-12 Based on this case, we suggest that health warnings about counterfeit sexual performance-enhancing medications should be published on the TGA website. Glucose, insulin and C-peptide levels during admission Day 1 Day 2 Day 9 Glucose (RR, 3.0–6.0), mmol/L 2.4 2.8 4.7 Insulin (RR, 2–23), mU/L 17 11 0.3 C-peptide (RR, 0.3–1.4), nmol/L 2.6 Not done 0.7 RR = reference range.

Santosh K Chaubey MB BS, MD · Kunwarjit S Sangla MB BS, FRACP · Emershia N Suthaharan MB BS, MD · Yong M Tan MB BS, FRACP, FRCP(Edin)

To the Editor: Hydroxychloroquine is used infrequently (in less than 0.1% of Australians) for the long-term management of chronic conditions (eg, rheumatoid arthritis).1 Hydroxychloroquine retinopathy is a rare but sight-threatening side effect that is usually not reversible.2-5 Various eye screening recommendations for hydroxychloroquine toxicity have been proposed overseas,3-5 but there is no recommended consensus for eye screening in Australia. As a result, screening is currently not uniform or universal, and this sometimes leads to significant consequences. A 36-year-old woman with a longer than 10-year history of hydroxychloroquine therapy (400 mg/day; body weight, 62–67 kg) for rheumatoid arthritis presented to her general practitioner after a year of central visual disturbance and photopsias (a sensation of flashes of light). She was referred to the Medical Retinal Clinic at the Royal Victorian Eye and Ear Hospital in August 2009 with suspected hydroxychloroquine toxicity. She had undergone screening by her optometrist for an initial period, but had not been screened within the past 4 years because she failed to attend; she appeared unaware of the potential serious side effect of the medication on her vision. On examination, her visual acuity was 6/9 in the right eye and 6/12 + 2 letters in the left. Her colour vision (assessed by Ishihara plates for colour blindness) was normal. She had left vortex keratopathy (a whorl-like corneal epithelial deposit) and examination of her fundus revealed subtle macular pigment change and retinal arteriolar attenuation (Box, A). Fundus autofluorescence showed significant changes at the level of the retinal pigment epithelium (Box, B). Dense bilateral paracentral field defects were detected on visual field testing. The rheumatologist was notified of the hydroxychloroquine retinal toxicity, and therapy with the drug was ceased. At 6-month eye review, the patient’s vision was stable. Recommendations on the timing of eye screening vary.3 The manufacturer’s product information recommends quarterly ophthalmological examinations, but this is impractical and not cost-effective.3,5 The Royal College of Ophthalmologists (RCO) in the United Kingdom found no evidence-based justification for a systematic screening program.4 They recommend ophthalmological referral only when there are visual symptoms (eg, distorted or patchy central vision, reading difficulties), or eye disease is detected at baseline and confirmed by an optometrist. In contrast, the American Academy of Ophthalmology (AAO) suggests a systematic approach, determined by risk status, that is based on factors such as hydroxychloroquine dose and duration of intake.5 Despite their differences, these protocols both aim to detect toxicity early and minimise the degree of visual loss, rather than to prevent visual loss. This is because there are currently no established criteria to identify toxicity at a reversible stage.4 We recommend adoption of the AAO or RCO protocols and alerting patients to the symptoms of toxicity. Careful counselling of patients at commencement of hydroxychloroquine treatment and on an ongoing basis is essential to promote early presentation and minimise toxicity. Hydroxychloroquine toxicity, although rare, can lead to severe loss of vision if therapy is not stopped. By stopping treatment, the condition may stabilise, and further irreversible vision loss can potentially be avoided. Hydroxychloroquine retinopathy in a 36-year-old woman A: Subtle macular pigment change (black arrows) and some arteriolar narrowing (white arrows). B: Autofluorescence imaging showing symmetrical changes at the level of the retinal pigment epithelium. Mottled loss of autofluorescence (black arrows) indicates loss of retinal pigment epithelium cells, and the adjacent increased autoflourescence (white arrows) indicates cell abnormality.

Elvis Ojaimi · Robyn H Guymer · Tien Y Wong · C Alex Harper

To the Editor: In their letter in the 1 February 2010 issue of the Journal, Rashid and Grant reported the first Australian case of hepatotoxicity associated with the weight-loss product Hydroxycut.1 They noted that, in May 2009, the United States Food and Drug Administration (FDA) advised consumers to stop using Hydroxycut products on the basis of 23 reports linking them to serious injury, including one fatal case of liver failure. In response, the Australian sponsor, Export Corporation (Australia) Pty Ltd told the Therapeutic Goods Administration (TGA) that there were differences between the US and Australian formulations of Hydroxycut products. As the TGA had received no reports of adverse reactions similar to those reported in the US, they allowed local marketing to continue. The TGA website advised consumers to exercise caution when using Australian Hydroxycut products;2 however, no such warnings appeared in local promotional material. In contrast, despite also being told that products marketed in the United Kingdom had different formulations, the UK Food Standards Agency (FSA) said: The specific ingredient or dosage which might be causing health problems has not yet been identified. However, as a precautionary measure, the FSA is warning people not to take them. There are no reported illnesses in the UK related to these products. . . . Hydroxycut products have been withdrawn from sale in the USA, Finland and Canada. Ireland has also advised retailers to withdraw the product and consumers to discontinue use of the products.3 Meanwhile, there have been three complaints upheld about the promotion of Australian Hydroxycut products, with another in progress.4 In 2008, the Complaints Resolution Panel (CRP) requested that the sponsor, retailers and website publishers withdraw any representations that the advertised product(s) has benefits in relation to fat-burning, weight loss, or weight management. Regardless, these claims continue to be made by numerous Australian internet pharmacies, and supplement and health food sites. This highlights the impotence of the CRP (which lacks the power to impose sanctions), the ineffectiveness of the TGA (which can impose sanctions, but apparently declines to do so) and the need for regulatory reform.5 A reformulated Hydroxycut is back on the shelves in the US. An FDA spokesperson said: “The only ingredient left in from the original formulation is caffeine. We do not have any evidence that caffeine causes liver toxicity.”6 However, on 14 February 2010, I had no difficulty in purchasing Hydroxycut (AUST L 154243) from a local pharmacy. This product has a similar formulation to products withdrawn overseas. Rashid and Grant called on the TGA to re-examine the continued availability of these products in Australia.1 I reiterate their call. Why is the TGA out of step with other regulators? Why are these products still on the Australian market if their benefits are negligible or absent, if unethical promotion continues despite CRP determinations, and when the risks are clear?

Ken J Harvey

To the Editor: Newby and Robertson’s study of the effect of computerised prescribing on the frequency of repeat prescriptions for antibiotics is important in highlighting unnecessary repeat prescribing.1 However, their work has highlighted another issue — researchers’ growing habit of using the prescription of selected antibiotics to infer indication, and then to measure appropriateness of care. When using the term “upper respiratory tract infections” (URTIs), do the authors mean viral infections or all URTIs, including bacterial infections? They state: While we did not include data on the indication for treatment in our study, the antibiotics we chose are those commonly used for respiratory tract infections. Therefore, the continued high rate of repeat ordering for these antibiotics remains a concern.1 We support the latter statement wholeheartedly, but the inference that the antibiotics examined in the study were used to manage URTIs (because these antibiotics are “commonly used to treat URTIs”) is inappropriate and incorrect. A media report misguidedly described Newby and Robertson’s study as examining “how GPs’ use of computerised prescribing systems affects antibiotic prescribing for upper respiratory tract infection.”2 The study was not about prescribing of antibiotics for URTIs, but this implication is apparent in their article. From the national Bettering the Evaluation and Care of Health (BEACH) program 2006–2009,3 we examined 20 011 general practitioner prescriptions for Newby and Robertson’s selected antibiotics: amoxycillin, amoxycillin/clavulanate, roxithromycin, and cefaclor. We would usually include cephalexin, because it is prescribed as often as cefaclor for URTIs at BEACH encounters, but we have limited our comparison to the above four antibiotics. In the BEACH program, GPs link the prescription to the problem being managed so we can determine the indication for which these antibiotics have been prescribed. Over the 3-year period of the 2006–2009 BEACH program, only 21.1% of these antibiotics were prescribed for URTIs (adults [≥ 15 years], 20.6%; children [0–14 years], 22.7%). In four out of five cases, the prescriptions were for acute bronchitis, sinusitis, acute otitis media or myringitis, tonsillitis, urinary tract infections, skin infections, pneumonia, and a variety of systemic infections. It cannot be assumed that a URTI is the indication simply because these antibiotics are most commonly used for its management, and by inference, that GPs are prescribing inappropriately. Newby and Robertson are not alone — the 2010 Productivity Commission report used the number of prescriptions for “antibiotics most commonly used to treat URTI” as one indicator of the appropriateness of GP services.4 These antibiotics are, in most cases, prescribed for indications other than URTI. The appropriateness of this prescribing cannot be assessed without knowledge of the indication, and without clear guidelines as to what level of antibiotic prescribing for each indication is “best” quality.

Joan V Henderson · Christopher M Harrison · Helena C Britt

In reply: We accept the evidence presented by Henderson and colleagues that the antibiotics examined in our study are not used exclusively for upper respiratory tract infections (URTIs), and we acknowledge in our article the lack of information on indication for treatment. However, data from the Bettering the Evaluation and Care of Health (BEACH) program have been used by others to suggest that the four antibiotics represent over 60% of the prescribed antibiotics for URTIs.1 Our study does not assess the appropriateness of the antibiotic choices, focusing instead on duration of therapy as implied by the issuing of repeat prescriptions. Irrespective of indications for use of these antibiotics, our data still support our primary conclusion that computerised prescribing is associated with increased repeat ordering for these, and probably other, antibiotics. The increase in repeat ordering could possibly be explained if doctors who use computers to prescribe see “sicker” patients or a significantly different case-mix from those who write prescriptions by hand. However, the size of the difference (70% v 40% of prescriptions with repeats, respectively), the consistency across the antibiotics examined, and the identical rate of repeat ordering on handwritten prescriptions in both surveys, makes this conclusion unlikely.

David A Newby · Jane Robertson

For generic substitution to be safe, consumers and clinicians need to fully understand what is the same or different about various brands of the same medicine A main aim of the National Medicines Policy is to provide Australians with access to safe, high-quality medicines at prices consumers and government can afford.1 As such, generic medicines have an important place in health care. Consumers see generic medicines as an opportunity to access cheaper medicines, while governments see the opportunity to achieve the same health outcomes for patients at a lower cost. Clinicians, on the other hand, have mixed views regarding the role of generic medicines. Many pharmacists see generic medicines as an opportunity to reduce patient costs while maintaining effectiveness, whereas some prescribers express concern that generic medicines are not appropriate or equivalent alternatives in some therapeutic areas (eg, anticonvulsants) and that brand substitution is a challenge to their clinical decision making, with a significant risk of patient confusion. Brand substitution is investigated by Ortiz and colleagues in this issue of the Journal (Ortiz et al).2 This is an important study in many ways, and it provides quantitative information on the extent of brand substitution and switching, a question which is often shrouded in anecdote. As it turns out, these data suggest that the extent of switching between brands of three major classes of medicines on the Pharmaceutical Benefits Scheme is probably less than many clinicians suspect. The study found that about 20% of patients switched brands of selected medicines two or more times during the course of a year. Not surprisingly, medicines that had more brands on the market were generally more likely to be switched. An interesting observation was that brand switching was less likely to be undertaken by older people than younger people. This may be related to a range of factors, including greater caution on the part of the prescriber and pharmacist when dealing with medications for older people. The results of this study, derived from community-dispensing information, need to be considered in the broader context of the health system. Generic (or brand) substitution occurs regularly when patients are admitted to or discharged from a public hospital. Hospitals typically stock only a limited number of brands of a medicine, and these are often generic products. Ortiz et al conclude that generic substitution is occurring and is likely to increase in the future.2 Indeed, their data may underestimate the current brand-switching situation, as the study was conducted before August 2008, when incentives for pharmacists to supply a generic medicine (where one exists) were introduced. The impact of medicine brand switching on health outcomes in the Australian community is unknown. However, a meta-analysis of cardiovascular studies found that different brands of (bioequivalent) medicines were clinically equivalent.3 Ortiz et al speculate on the “potential for patient confusion”.2 Patient confusion about medicines and the risk of double dosing of medicines that contain the same active ingredient are a real concern. There are a number of strategies that can be used in combination to reduce the risk of confusion about medicines, especially in the context of generic substitution. These include: Knowing the drug name. Prescribers and pharmacists should explain the name of each medicine, with the aim of helping consumers know the active ingredient in the medicine they are taking rather than the product’s brand name. Medicines information. Information such as consumer medicine information should be provided (and explained). Knowing what the medicine is for. Consumers should be encouraged to know what each medicine is for. Up-to-date medicines list. Consumers should be supported in keeping a list of their current medicines that includes the name of the active ingredient (sometimes called the generic name), the brand name and the dosage regimen. Clear medicine labels. Labelling of prescription (branded and generic) medicines should be improved so that the active ingredient in the product is displayed with equal or greater prominence to the brand name on the packaging, as recommended by the Therapeutic Goods Administration in the Best practice guideline on prescription medicine labelling.4 Each of these strategies relates to health literacy5 and points to the need for greater “medicines literacy” for consumers and carers. There have been recent attempts to improve “generic medicines literacy” among clinicians in Australia, many of whom still challenge the foundation principle of bioequivalence6 and the quality of generic medicines.7-9 Generic medicines provide an opportunity for consumers and government to offset the rising cost of health care. However, the quality use of generic medicines10 requires careful attention by prescribers and pharmacists to the strategies outlined here to minimise the potential for confusion on the part of the patient. If there is a risk of dose duplication, generic substitution may need to be avoided (independent of the drug involved) unless the patient or carer fully understands both the similarities and the differences between various brands of the same medicine.

Andrew J McLachlan BPharm, PhD

Objective: To study the extent of brand substitution and switching in three commonly used classes of drugs available on the Pharmaceutical Benefits Scheme (PBS).Design, setting and participants: Assessment of PBS claim records for a 1-year period from 1 August 2007 to 31 July 2008 for long-term concession cardholders drawn from a 10% random sample of the Australian population. The target drug classes were: statins (pravastatin, simvastatin), calcium channel blockers (CCBs) (amlodipine, felodipine, nifedipine), and selective serotonin reuptake inhibitor (SSRI) antidepressants (fluoxetine, fluvoxamine, paroxetine, sertraline).Main outcome measures: Proportion of patients who were non-switchers (single brand only) and multiple switchers (two or more brand switches).Results: We retrieved information relating to 935 334 prescriptions for 122 000 patients. Of those patients filling at least four prescriptions for a product, 41 174 patients received statins, 27 230 received CCBs and 21 342 received SSRIs. More than half the patients received only one brand during the study period: 57% for statins, 60% for CCBs, and 63% for SSRIs. Multiple switching was recorded for 24% of patients with statins, 19% with CCBs, and 21% with SSRIs, with smaller proportions receiving three or more brands: 14% for statins, 10% for CCBs, and 12% for SSRIs. Multiple switching was more common among younger patients for all drug classes (28% for those aged < 50 years v 18% for those aged ≥ 80 years).Conclusion: Generic substitution with multiple switches is occurring in a small proportion of patients being treated with statins, CCBs or SSRIs. The potential for patient confusion appears to be relatively small, but this may change with recent incentives included in pharmacy reimbursement arrangements.

Michael Ortiz BPharm, PhD · Leon A Simons MD, FRACP · Gordon Calcino BA, GradMedStats

Objective: To examine the prevalence of perianal Crohn’s disease (PCD) and the eligibility of PCD patients to access anti-tumour necrosis factor-alpha (anti-TNFα) treatment under current Australian Pharmaceutical Benefits Scheme (PBS) guidelines.Design, setting and participants: A retrospective study of patients with Crohn’s disease (CD) and PCD attending four large adult inflammatory bowel disease (IBD) centres in Australia between January 2004 and May 2008. Patients for whom anti-TNFα therapy was clinically indicated were assessed to determine whether they satisfied PBS criteria for subsidised medication.Main outcome measures: Prevalence of CD and PCD in patients attending different IBD centres; eligibility of PCD patients for PBS-subsidised anti-TNFα medication.Results: Data were available on 3589 patients, representing about 6% of all patients with IBD in Australia. Of the 1815 patients with CD, 310 (17%) had PCD. Anti-TNFα therapy was deemed clinically indicated for 166 patients with PCD (54%), of whom 49 (30%) did not qualify for PBS-funded therapy.Conclusion: Thirty per cent of patients with clinically significant PCD currently do not have access to PBS-subsidised optimal medical treatment. We believe that PBS criteria should be extended to include this subgroup of IBD patients.

Daniel C Burger BSc, MB BS(Hons) · Ian C Lawrance MB BS(Hons), FRACP, PhD · Peter A Bampton MB BS, MD, FRACP · Ruth Prosser RN, BNurs · Anthony Croft BSc(Hons) · Kristen Gilshenan BMaths(Hons), BInfoTech · Graham L Radford-Smith MRCP, FRACP, DPhil · Timothy H Florin BSc(Hons), MSc, FRACP

Quality Use of Medicines indicators can be used to drive system improvements in health care Use of clinical indicators with collection and monitoring of meaningful data has been recognised as important for driving improvements in the safety and quality of health care.1 Quality Use of Medicines (QUM) is one aspect of health care in which continual improvement is vitally important. QUM forms part of Australia’s National Medicines Policy and involves judicious selection of treatment options (including choice between drug or non-drug treatment and no treatment), appropriate choice of medicines when they are required, and safe and efficacious use of medicines.2 Problems with medicines use are costly and occur commonly at all stages of the medicines management pathway3 and in all health care settings. Elderly, paediatric and chronically ill patients are at particular risk of experiencing adverse drug events. In Australia, some 190 000 admissions per year are associated with medicine-related problems, costing the health care system about $660 million, and adverse events involving medicines are consistently among the most frequently reported incidents in voluntary incident-reporting systems.4 Thus, to stimulate quality improvement in this area of health care, it is critical to systematically collect meaningful data about medicines use. Organisations such as the Australian Commission on Safety and Quality in Health Care, the Australian Council on Healthcare Standards (ACHS), the Australian Institute of Health and Welfare, the Council of Australian Governments and the National Prescribing Service are developing clinical indicators for measuring and improving the safety and quality of health care. However, QUM issues are addressed inconsistently in indicators relating to hospitalised patients — probably because medicines management is complex and multidisciplinary3 and not wholly “owned” by any one profession, specialty or discipline. Accordingly, the New South Wales Therapeutic Advisory Group, in collaboration with the Clinical Excellence Commission, has developed Indicators for quality use of medicines in Australian hospitals (QUM indicators).5 The QUM indicators address 30 aspects of care in six areas of practice (Box), including high-risk or high-use medicines (eg, anticoagulants and antibiotics); high-risk populations (eg, paediatric patients); and high-risk clinical settings (eg, transfer from hospital to home or to another health care setting). Many indicators are released for routine use without prior testing or validation in clinical environments, despite the recognised importance of this step.6 We undertook a rigorous development process that included systematic and structured decision making for selecting indicators; consultation with a broad range of clinicians and stakeholders; and pilot-testing in a wide variety of hospitals across Australia. Consequently, each QUM indicator meets the properties of an ideal indicator, such as content validity, face validity, clarity, comparability, measurability, remediability and usefulness.6-8 As we excluded indicators not meeting these criteria, not every area of QUM is addressed. However, our development process has ensured that all the indicators are accepted by clinicians as valid, measurable, important and useful for informing local improvements in QUM. This is likely to enhance their uptake in routine practice. The QUM indicators are primarily designed as tools to inform quality improvement initiatives at the unit, department, or organisation level. They are process measures and provide information about the way medicines management is delivered. Improved performance in the aspects of care measured by process indicators is expected to result in improved health outcomes, as has been demonstrated by Peterson and colleagues.9 The QUM indicator manual (available at http://www.ciap.health. nsw.gov.au/nswtag/indicators.html) describes how to use the indicators to drive improvements in practice and contains detailed instructions for data collection. Using an effective improvement method (eg, drug use evaluation or clinical practice improvement)10,11 and supporting clinicians with appropriate resources and expertise can promote the use of indicators and lead to improvements over time.11 To date, implementing the QUM indicators has included incorporation of selected indicators into programs such as the Electronic Medical Record State Base Build developed by NSW Health; the ACHS Clinical Indicators program, the evaluation of the paediatric National Inpatient Medication Chart, and the National Prescribing Service national drug use evaluation program. The indicators will evolve as their use continues. Adjustments may be needed for a number of reasons, such as clinician feedback and experience; changes in evidence and clinical practice; and alignment with other programs. For example, minor adjustments have been made to the indicators incorporated by the National Prescribing Service and the ACHS in their programs. However, changes should not be introduced without sound reasons and supporting evidence. These indicators are not designed for making comparisons between institutions (benchmarking) or for accountability purposes. If they are to be used for such purposes, further testing of their validity and reliability and appropriate modification is warranted to ensure that comparisons are fair.12 The QUM indicators will be of most use in supporting improvements in health care when data collection and feedback are incorporated into routine clinical practice in all health care settings. To facilitate uptake of the indicators and improvements in care, results must be presented in a time frame and format that is meaningful to clinicians and encourages reflection and discussion.12-15 Clinical teams must be motivated to change their practice and systems in response to results. Using indicators routinely will become easier as electronic medical records and electronic medicines management become more widespread. Appropriate allocation of resources and expertise to support data collection and design and delivery of evidence-based interventions will help.11 We encourage clinicians from all disciplines and specialties to regularly use the QUM indicators relevant to their practice, interpret results in the light of clinical expertise, and drive appropriate system improvements. The effectiveness of these indicators will ultimately be determined by demonstrated improvements in QUM over time at the local and population level. Aspects of care assessed by Quality Use of Medicines indicators5 Antithrombotic therapy Venous thromboembolism risk assessment Venous thromboembolism prophylaxis Enoxaparin dosing Warfarin initiation doses Management of raised international normalised ratio Management of patients with atrial fibrillation Antibiotic therapy Surgical antibiotic prophylaxis Prescribing restricted antibiotics Management of aminoglycoside levels Assessment of community-acquired pneumonia Management of community-acquired pneumonia Medication ordering Medication reconciliation at admission Documentation of adverse drug reactions Use of error-prone abbreviations Prescribing for paediatric patients Prescribing intermittent therapy Prescribing cytotoxic chemotherapy Pain management Assessment of pain intensity Written postoperative pain management plan Continuity of care Discharge management of patients with acute coronary syndrome Discharge management of patients with chronic heart failure Inclusion of medication changes in discharge summary Written information regarding ongoing warfarin management Written information regarding new adverse drug reaction Written asthma action plan New prescriptions for sedatives Hospital-wide medication management policies Potassium storage Clinical pharmacist review Use of pethidine Formulary submissions

Jocelyn S Lowinger BSc(Med), MB BS(Hons), GradCertPublHlth · Helen E Stark BPharm, MBA · Maria Kelly BPharm, DipEd, GradCertBioethics · Clifford F Hughes AO, FRACS, FACC, FACS · Madlen Gazarian MB BS(Hons), MSc(ClinEpi), FRACP · Karen I Kaye BPharm, DipHospPharm, GradCertPharmacoecon

Objectives: To assess the impact of two interventions on computer-generated prescriptions for antibiotics — (i) an educational intervention to reduce automatic computerised ordering of repeat antibiotic prescriptions, and (ii) a legislative change prohibiting the “no brand substitution” box being checked as a default setting in prescribing software — and to compare these findings with those of a similar survey we conducted in 2000.Design and setting: Prospective audit of consecutive prescriptions for four antibiotics (amoxycillin, amoxycillin/clavulanate, roxithromycin, and cefaclor) commonly prescribed for upper respiratory tract infections in community pharmacies in New South Wales and Queensland between 1 November 2008 and 31 January 2009.Main outcome measures: Primary outcome: rate of repeat prescription ordering on computer-generated versus handwritten prescriptions. Secondary outcome: rate of checking of the “no brand substitution” box on computer-generated versus handwritten prescriptions.Results: Data were collected on 2807 prescriptions presented to 51 pharmacies (50 in NSW, one in Queensland), of which 2354 were computer-generated. Repeats were ordered on 1633 computer-generated prescriptions (69%) compared with 183 handwritten prescriptions (40%). These proportions were identical to those found in 2000, although the rates of computer prescribing were much higher in this study (84% v 54%). This difference in repeat prescribing was statistically significant (odds ratio adjusted for clustering at pharmacy level, 2.87; 95% CI, 2.32–3.55). Twenty-three (1%) of the computer-generated prescriptions had the “no brand substitution” box checked compared with 3 (0.7%) of the handwritten prescriptions (27% and 1%, respectively, in our previous survey).Conclusions: The legislative change which disallowed having the “no brand substitution” box checked as a default setting in prescribing software had a dramatic impact on the checking of the “no brand substitution” box. In contrast, there was no sustained effect of educating prescribers about software default settings relating to repeat prescribing of antibiotics. Other actions are required if unnecessary repeat prescriptions for some medicines, such as antibiotics, are to be reduced.

David A Newby BPharm, PhD · Jane Robertson BPharm, MMedSci, PhD

The latest evidence for the essential elements of surgical prophylaxis protocols There is no question that antibiotic prophylaxis for cardiac surgery reduces surgical site infections.1 The successful implementation of prophylactic regimens, however, is often inconsistent or inadequate. The use of prophylaxis protocols or decision-support systems as either a single measure2 or as part of a patient care pathway3 has been demonstrated to improve adherence to prophylaxis, with a reduction in surgical site infections. In this issue of the Journal (page 141), a study by Haydon and colleagues4 shows that antibiotic prophylaxis protocol use in 45 Australian cardiac surgery units increased significantly between 2004 and 2008 (from 58% to 80%), but concordance with version 13 of the Australian Therapeutic guidelines: antibiotic5 was poor when both choice of agent and duration of administration were considered. In particular, there was an increased use of multidrug regimens, an increased use of vancomycin for routine prophylaxis, and a prolonged duration. The study did not examine surgical site infection rates. As prophylaxis protocols improve patient outcomes, and adherence to protocols in Australian cardiac surgery units seems to be high, it is timely to consider the optimum elements of such protocols in terms of timing of prophylaxis, duration of prophylaxis, and choice of agent. There have been a number of studies that show the relationship between timing of antibiotic administration and surgical site infections. An observational cohort study in a consecutive series of 3836 surgical procedures (vascular, trauma and abdominal) showed the optimal time for administration of β lactams was 30–60 minutes before incision.6 The risk-adjusted odds ratio of surgical site infections was 3.16 (95% CI, 1.4–7.0) if given 75–120 minutes before, 2.82 (95% CI, 1.5–5.3) for administration 15–29 minutes before, and 1.75 (95% CI, 0.9–3.4) if given in the last 14 minutes before incision. In a prospective study of 2048 patients given vancomycin prophylaxis for cardiac surgery (coronary artery bypass graft [CABG] or valve replacement), the optimum time for the start of a vancomycin infusion was shown to be 16–60 minutes before incision.7 The relative risk of infection was 7.8 (95% CI, 2.5–24.7) if started 0–15 minutes before incision and 2.2 (95% CI, 0.99–5.09) if started 61–120 minutes before. Duration of prophylaxis has been a controversial issue. The Society of Thoracic Surgeons practice guidelines8 recommend that prophylactic antibiotics be given for 48 hours or less, citing some evidence for effectiveness of single-dose or 24-hour regimens, but comment that additional studies are required to confirm the effectiveness of shorter courses. This has been addressed in a study on 838 patients undergoing CABG or valve replacement.9 Patients received cephazolin as either a single dose before incision or a prolonged regimen, with a dose before incision, then 8-hourly for 24 hours. There was a statistically significant difference in surgical site infections between the two groups (8.3% v 3.6%; P = 0.004). The choice of agent is mainly between a β lactam and vancomycin, although alternative choices are possible (eg, flucloxacillin plus gentamicin). The Society of Thoracic Surgeons practice guidelines10 recommend cephazolin for standard practice in populations that do not have a high incidence of methicillin-resistant Staphylococcus aureus (MRSA). Haydon et al’s study showed that routine vancomycin use for CABG surgical prophylaxis increased from 13% in 2004 to 44% in 2008, with similar increases seen for valve surgery — from 31% to 62% over the same period.4 Vancomycin prophylaxis for cardiac surgery is recommended in the current Therapeutic guidelines: antibiotic for institutions with a high prevalence of MRSA, for β lactam-allergic patients, or for procedures where there is a higher risk of infection with a coagulase-negative staphylococcus (eg, valve surgery, reoperations).5 Excessive vancomycin use is to be discouraged, as its activity is inferior to β lactam antibiotics for susceptible organisms and it will add selective pressure for hVISA (heteroresistant vancomycin-intermediate S. aureus), particularly if the duration of administration is prolonged. With the advent of rapid MRSA molecular detection tests, it is now possible to screen patients before surgery and use vancomycin selectively in those found to carry MRSA. An alternative is to use intranasal mupirocin routinely in the absence of a documented negative test for MRSA (and methicillin-sensitive S. aureus [MSSA]), as this agent has been shown to reduce both MSSA and MRSA surgical site infections.11 How do these recommendations relate to the Therapeutic guidelines: antibiotic? The current guidelines, version 13 (published in 2006),5 are concordant, except for the duration of therapy. It is very likely that this is the major issue that has resulted in the lack of adoption of the guidelines’ cardiac surgery prophylaxis regimens found by Haydon and colleagues. Version 14 of Therapeutic guidelines: antibiotic is currently in preparation and due to be published in 2010, and the recent studies described here have been noted by the writing committee. It is very likely that version 14 will recommend a 24-hour prophylaxis regimen and that the recommended antibiotic agents will remain unchanged. The purpose of any surgical prophylaxis protocol is to ensure adherence to the optimum choice of agent, timing of administration and duration of prophylaxis. With such adherence, surgical site infections will be minimised, thereby reducing morbidity and mortality for patients undergoing cardiac surgery.

Keryn J Christiansen MB BS, FRCPA

Objective: To evaluate national practice for antibiotic prophylaxis in cardiac surgery with respect to the use of protocols, agent selection and duration of administration.Design, setting and participants: Two point-prevalence surveys of intensive care units in 24 public and 27 private hospitals performing cardiac surgery in Australia, conducted in 2004 and 2008, using a structured telephone questionnaire of the attending senior intensive care clinician in each unit.Main outcome measures: Existence of a protocol in the unit for antibiotic prophylaxis, specific antibiotic agents used and their duration of administration.Results: Between 2004 and 2008, reported protocol use increased from 58% to 80% (P = 0.02), while concordance with version 13 of the Australian Therapeutic guidelines: antibiotic for both choice of agent and timing (duration of administration) remained around 10%. Use of multiple agents was common, as was continued antibiotic administration after completion of surgery. Over 4 years, the proportion of cardiac surgical units reporting vancomycin administration for routine valve surgery prophylaxis doubled to 62% (P < 0.001).Conclusion: Despite an increase in reported protocol use for antibiotic prophylaxis in cardiac surgery, concordance with national antibiotic guidelines remained low, with duration of antibiotic administration deviating most from recommendations. Prophylactic vancomycin use appears to have increased substantially in recent years. Clinical implementation of recommended perioperative cardiac surgical antibiotic prophylaxis may not occur until supported by evidence from either a large prospective randomised study or standardised national surveillance of cardiac surgical site infection rates.

Timothy P Haydon FRACP, FJFICM, FANZCA · Jeffrey J Presneill MB BS, MBiostat, PhD · Megan S Robertson FRACP, FJFICM, FANZCA