Pharmacology

To the Editor: A report in the Weekend Australian earlier this year described an increase in oxycodone-associated deaths, in parallel with an increase in prescriptions for the drug, sometimes known as “hillbilly heroin”.1 These increases are likely to reflect a change in doctors’ prescribing behaviour. Strong opioids were traditionally prescribed for cancer pain, often in the terminally ill, but since the 1980s they have been increasingly used for treating chronic non-cancer pain, despite an absence of new evidence of effectiveness or of whether opioids provide net benefit or harm to patients in this setting.2 Cancer patients are likely to die from their illness before the opioids have a chance to injure them, but patients with chronic non-cancer pain are not, and this is where oxycodone-associated deaths are more likely to occur. A contemporary view is that chronic non-cancer pain should be regarded as “a disease entity”,3 but equating a symptom with disease means that the patient becomes the sole arbiter of whether he or she is ill. The prescribing doctor has no means by which to objectively determine treatment outcomes. The notion of chronic non-cancer pain as a disease entity is based on neuropathological changes described as “central sensitisation”, which may result from nerve damage or from persistent peripheral nociceptive input.3 The concept is not intellectually challenging where there is objective evidence of either nerve damage or injury to somatic or visceral structures. Now, however, when medically inexplicable pain follows injury that may be so subtle as to be unassociated with any discernible abnormality, central sensitisation is invoked as the explanation du jour, without a critical assessment based on anatomical and physiological principles. Prescribing opioids in this setting may have inadvertently contributed to the reported increase in oxycodone-associated deaths. Guidelines exist for prescribing oral controlled-release opioid analgesics for chronic non-cancer pain.4-6 They advocate a signed patient–doctor agreement covering, among other things: the necessity for a single prescriber; a recommendation for all drug dispensing to be from the same pharmacy; no replacement for lost, stolen or destroyed prescriptions; and a requirement for consent for random urine and blood screens. However, these are just guidelines, not mandated, and there are no Australian data on compliance with them. Based on international data,7 the guidelines are likely to be more honoured in the breach than the observance. I advocate that a signed patient–doctor agreement should be mandatory in Australia before the prescription and dispensing of opioids for chronic non-cancer pain. This should be sighted by Pharmaceutical Benefits Scheme authorities before such dispensing is authorised, and a copy should be held by the dispensing pharmacy. A review of prescription guidelines for opioid analgesics in chronic non-cancer pain might reduce the epidemic of prescription drug misuse4 and mortality.

Mark S Awerbuch

Objective: To study patient persistence on therapy for hypertension and dyslipidaemia using a single-pill combination compared with a two-pill approach.Design and setting: Post-hoc observational assessment of Pharmaceutical Benefits Scheme claim records covering the period April 2005 to March 2010.Participants: A 10% random sample of Australian long-term concession card holders was analysed. The patients studied had commenced on either amlodipine and atorvastatin as two individual pills, or a single pill containing both amlodipine and atorvastatin (AA), with neither combined approach having been dispensed to them in the previous 6 months.Main outcome measures: The proportions of patients failing to fill their first repeat prescription after 1 month or failing to persist with treatment at 12 months, and the median persistence time (MPT) were measured.Results: Of 4146 patients prescribed the AA single pill, 11% failed to fill the first repeat prescription and 33% had ceased treatment by 12 months (MPT, 35 months). Of 6204 patients prescribed amlodipine and atorvastatin as two pills, 23% failed to fill the first repeat prescriptions and 59% had ceased treatment by 12 months (MPT, 7 months). In a multivariate model, cessation of single-pill therapy increased by 165% if there was no prior therapy, but only increased by 48%–55% if there was no prior therapy with a calcium channel blocker or statin. MPT on the single pill was 8 months in those without prior antihypertensive therapy, but was ≥ 37 months in those with any prior antihypertensive therapy.Conclusion: A single-pill combination drug is associated with superior long-term persistence compared with two-pill therapy in the management of hypertension and dyslipidaemia.

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

Building on a successful program to extend PBS copayment relief to more patients Cost is a well established influence on both access to medicines and medication adherence rates. Prescription fees can lead to patients forgoing essential medications and to a decline in health care status among needy populations,1,2 an observation that is very familiar to Aboriginal community-controlled health services (ACCHSs). While capped patient copayments and the Pharmaceutical Benefits Scheme (PBS) Safety Net minimise the medication cost burden on all Australians, these mechanisms are ineffective for many Aboriginal and Torres Strait Islander peoples. The reasons for this include high rates of unrecorded concession and Safety Net status, disproportionately higher rates of chronic disease and comorbidity, extended social and family obligations, “shame” in accessing prescriptions in culturally alienating settings, high patient mobility, and poor health literacy. PBS utilisation is further reduced in this population by factors that preclude medicines storage and adherence, such as overcrowding, and disease profiles that are inconsistent with medicines listed on the PBS. The Council of Australian Governments (COAG) National Indigenous Reform Agreement of November 2008 led to strategies designed to close the gap in Aboriginal and Torres Strait Islander people’s life expectancy.3 One of these strategies is the $88.7 million “Subsidising PBS Medicine Co-payments” measure,4 which commenced in July 2010 and is predicted to provide financial assistance to “over 70 000 Indigenous people”, to improve their access to PBS medicines.3 This measure was, in fact, built on an existing program — Quality Use of Medicines Maximised for Aboriginal and Torres Strait Islander Peoples (QUMAX)5 — the details and outcomes of which have been kept under wraps until the recent release of the findings of an independent evaluation.6 The QUMAX program, which commenced in November 2008, aimed to overcome a range of known barriers to Aboriginal and Torres Strait Islander peoples’ access to medicines, and was jointly developed and managed by the National Aboriginal Community Controlled Health Organisation and the Pharmacy Guild of Australia, and funded by the Australian Government under the Fourth Community Pharmacy Agreement (2005–2010). Aboriginal and Torres Strait Islander patients could access the QUMAX program through ACCHSs in rural, regional and urban (ie, non-remote) areas. The cost of medicines for eligible needy and disadvantaged patients (as defined in the business rules for the program6) was subsidised through an online system of coordinated, secure and accountable copayment relief arrangements between ACCHSs and participating community pharmacies. The program also supported local quality use of medicines (QUM) initiatives through support pharmacists assigned to each ACCHS, provided QUM education for ACCHS staff, provided dose-administration aids and transport for the delivery of medicines, focused attention on patients’ PBS Safety Net entitlements, and fostered collaboration with community pharmacies — all within the context of culturally appropriate primary health care. Administration of QUMAX was lean, with the majority of the funds appropriately devolved to supplying medicines. The independent evaluation showed almost universal participation by ACCHSs (69 of 70) and involvement of 541 community pharmacies. The capped nature of QUMAX funding to each ACCHS meant that only 20% of the services’ Aboriginal and Torres Strait Islander clients (nearly 34 000 of the 171 094 patients who attended the participating services annually) could receive support for medicines and medication aids. Over 271 000 medicines were dispensed to these patients with the PBS copayment waived.6 Between November 2009 and April 2010, the proportionate increase in the number of PBS medicines dispensed to patients of non-remote ACCHSs was nearly five times greater than the increase in medicines dispensed to all Australians, and exceeded the increase seen in remote areas by a factor of seven. Greater access to medicines for chronic disease (lipid-lowering, antihypertensive and asthma medications) accounted for most of the increase. This increase occurred on a background of substantial inequities in access to medicines. In the 2006–07 financial year, for every dollar per person spent on PBS medicines for non-Indigenous Australians, only 60 cents was spent on Indigenous Australians.7 Among Aboriginal and Torres Strait Islander peoples, geographical disparities in access to medicines had been the reverse of those expected — Aboriginal peoples in non-remote parts of Australia had lower PBS expenditure per person than those in remote locations ($159 in major cities versus $223 in remote and very remote areas).7 This is probably due to the enduring success of another scheme — the special PBS arrangements under section 100 of the National Health Act 1953 for the supply of medicines to remote-area Indigenous health services.8 It is unclear if QUMAX has alleviated the PBS expenditure inequities, but the evaluation report states that, for Aboriginal and Torres Strait Islander peoples, there is “strong evidence that the QUMAX program has helped to overcome the financial barrier to accessing PBS medicines in non-remote areas”.6 In addition to patients of non-remote ACCHSs, the new PBS medicine copayment measure now extends copayment relief to eligible Aboriginal and Torres Strait Islander people who have, or are at risk of, chronic disease and are patients of any private general practice. Although the QUMAX program no longer includes the copayment relief element, it has been extended until 2015 under the Fifth Community Pharmacy Agreement to continue to augment QUM within ACCHSs. PBS listings have also improved, with more medicines now available for conditions that predominate in the Aboriginal and Torres Strait Islander population.9 There is no doubt that ACCHSs have substantially improved access to medicines for their disadvantaged Aboriginal and Torres Strait Islander patients and will continue to do so — to a level likely to eliminate disparity. They are able to do this through multifaceted strategies built on their intense community knowledge and involvement. When gauging the impact of the Subsidising PBS Medicine Co-payments scheme, it will be crucial for data on PBS utilisation by Aboriginal and Torres Strait Islander peoples to be disaggregated by “service type”. While ACCHSs participating in QUMAX have transitioned readily to the new copayment measure, its effectiveness in the private general practice sector now needs to be explicitly understood.10

Sophie Couzos FRACGP, FACRRM, FAFPHM · Vicki Sheedy BA, BEd · Dea Delaney Thiele PGDipHlthMgt

The cost differential between these two drugs is no longer defensible Federal Health Minister Nicola Roxon recently met with an alliance of consumer, industry and other stakeholders to justify the government’s plan to indefinitely delay the listing of seven new medicines on the Pharmaceutical Benefits Scheme (PBS). She argued that, after considering the advice of the Pharmaceutical Benefits Advisory Committee (PBAC), it was the government’s responsibility to decide whether or not to list a new drug, taking into account other priorities across the health portfolio and current fiscal circumstances.1 Clearly, the cost of the PBS must be sustainable. However, there are other ways of reducing its cost apart from delaying the listing of drugs recommended by PBAC as cost-effective. The treatment of macular degeneration provides an illustrative example. Age-related macular degeneration (AMD) is responsible for almost half of all cases of blindness in Australia.2 In neovascular (or “wet”) macular degeneration, vision loss results from the abnormal growth and leakage of blood vessels in the macula. Ranibizumab (Lucentis), developed by Genentech and marketed by Novartis in Australia, is currently the only drug approved by the Therapeutic Goods Administration (TGA) and available on the PBS to treat wet AMD. It is administered as an intravitreal injection, usually 4–8-weekly, for 12 to 18 months or longer. The PBS-listed price of each injection is $1967. Ranibizumab is the antigen-binding fragment of a recombinant, humanised, monoclonal antibody that binds to vascular endothelial growth factor A (VEGF-A), the cytokine primarily responsible for blood vessel growth. The inhibition of VEGF-A reduces the permeability and growth of the neovascular vessels. Blindness is prevented in most patients, and the majority of treated patients go on to have some improvement in vision.3-5 Bevacizumab (Avastin) is an anti-VEGF-A humanised, monoclonal antibody (also developed by Genentech, and marketed in Australia by Roche; Genentech is a wholly owned subsidiary of Roche) that has been approved by the TGA for the systemic treatment of certain cancers. It was successfully used “off-label” for the treatment of wet AMD before ranibizumab became available, but has also been used to some degree since the availability of ranibizumab, especially in the United States, where patients bear more of the costs of drugs.5-7 It is prepared for ophthalmic use in a sterile pharmacy by taking a dose used in chemotherapy and splitting it for use in treating wet AMD for up to 25 patients. The cost of its off-label use has been significantly less than that of ranibizumab (around a 40th of the cost, at $50 per dose). Ranibizumab received PBS listing for use in treating wet AMD in 2007 and has since largely replaced bevacizumab for the treatment of AMD in Australia. Although therapy with ranibizumab has been successful, its PBS listing has come at great expense, costing taxpayers $237 million in 2010 (second only to atorvastatin and rosuvastatin). It is consistent with many of the principles of quality use of medicines (QUM), outlined in the National Medicines Policy,8,9 for ophthalmologists to select a PBS-listed therapy that has been demonstrated to be safe and effective. But advocates of QUM also emphasise the importance of choosing medicines that are cost-effective for individuals and the community. A recent study by the US National Eye Institute10 has raised the question of whether use of ranibizumab can be justified economically. The study compared bevacizumab and ranibizumab for the treatment of wet AMD, administered either monthly or as needed, in 1208 randomly assigned patients. At 1 year, bevacizumab and ranibizumab had equivalent effects on visual acuity, when administered according to the same schedule. Ranibizumab given as needed, with monthly evaluation, had effects on vision that were equivalent to those of ranibizumab administered monthly. The comparison between bevacizumab as needed and monthly bevacizumab was inconclusive. Differences in rates of serious adverse events were higher with bevacizumab but did not reach statistical significance, and require further study. Results from the second year of this study and from other comparative trials and experiential databases will provide additional information. Despite this new information having come to light, in Australia there is little motivation for clinicians, the pharmaceutical companies involved, or government bodies to pursue a broader economic agenda. There is no incentive for Australian ophthalmologists or patients to use bevacizumab off-label because the price to the patient for the PBS-listed ranibizumab is only that of the copayment, and the costs for the ophthalmologist visits are the same. There is little incentive for the sponsor of bevacizumab (Roche) to seek a new indication (wet AMD) for this drug — first from the TGA and then from PBAC — because of the substantial costs involved and the doubtful rewards. Also, the relationships between the companies involved appear to militate against moves that might change the present situation. Applications to both the TGA and PBAC are now fully cost-recovered by charges levied on the sponsor of the drug — a unique situation among equivalent developed countries. This provides a considerable disincentive for applications that are primarily in the public interest. While charges can be reduced or eliminated for so-called orphan drugs, this provision would not apply in this case because ranibizumab is currently available and patent-protected.11 And although it has been suggested that a third party, such as a Royal College, might sponsor an application to the TGA and PBAC in the public interest, this concept has foundered because the sponsor is also responsible for product liability. This leaves us with the question: what policy options might circumvent the difficulties outlined here and save taxpayers substantial amounts of money when treating neovascular AMD with anti-VEGF-A drugs? First, the drug committees and administrations of public hospitals with significant eye services could recommend off-label use of bevacizumab for AMD, in the light of the National Eye Institute study. Currently, in New South Wales public hospitals, there is no PBS access to ranibizumab. This would also accommodate public patients unable to pay for private ophthalmologist visits. Given the issues with bevacizumab of dose preparation, sterility and shelf life, combining services for efficiency and geographical coverage would make sense, as would amalgamating public clinics that already use bevacizumab off-label for other related indications (eg, diabetic retinopathy). Second, the government could consider ways in which it could withdraw the PBS listing for ranibizumab for the treatment of wet AMD, on the grounds that treatment with bevacizumab in public eye hospitals is likely to be more cost-effective. This is likely to be problematic for several reasons: the limited capacity of the public sector to provide this treatment; opposition by ophthalmologists operating privately and those who deliver public services; and opposition from the sponsor. Third, the government could negotiate with Novartis to reduce the cost of ranibizumab, or with Roche to apply to have bevacizumab approved and listed for use in treating AMD. It should be noted that the effort needed to register, list and distribute medicines internationally and in Australia should be considered in these negotiations, but the cost differential now extant in the light of the National Eye Institute study results is no longer defensible. Finally, the government could accept that it is the only body with the responsibility and capability of acting in the public interest in these matters. The Minister for Health and Ageing could ask the TGA and PBAC to consider listing bevacizumab for neovascular AMD in the public interest, perhaps with a temporary or provisional licence pending accumulation of more data, with the government accepting any liability that may accrue. Although the challenges of achieving an equitable solution to this problem are considerable, the significance to the PBS budget and subsequently for analogous situations is now a strong incentive for action.

Ken J Harvey MB BS, FRCPA · Richard O Day MD, FRACP · William G Campbell MB BS, FRANZCO · Wendy Lipworth MB BS, MSc, PhD

In 2010, an immigrant from Burma was the first person to be diagnosed in New Zealand with extensively drug-resistant tuberculosis (XDR-TB). The strain of Mycobacterium tuberculosis is the most resistant reported to date in Australasia. Key difficulties of managing this disease in a low-prevalence country were delays from drug-susceptibility testing and in acquiring appropriate medicines, and a lack of evidence-based guidelines. Solutions are needed for New Zealand and the wider region as more cases of XDR-TB are likely to be encountered in the future. (MJA 2011; 194: 602-604) Clinical recordA 29-year-old man presented to his general practitioner in Otago, New Zealand, in March 2010 with discharge from an enlarged left anterior cervical lymph node (Box 1). He reported two episodes of night sweats but no weight loss, fever or chills. He was not coughing or producing sputum, and had no haemoptysis or chest pain. He was born in Burma (Myanmar) but had emigrated to New Zealand in 2006. At that time, chest x-ray screening did not detect tuberculosis (TB). He had no personal history of TB and no known contacts with TB. Fine needle aspirate that was collected in late March from the affected lymph node grew Mycobacterium tuberculosis after 30 days’ incubation. The isolate was sent to a reference laboratory for drug-susceptibility testing (DST). Eight days later, the isolate was reported to be “presumptively” resistant to isoniazid, rifampicin and ethambutol based on the results of broth-based DST methods. Resistance to pyrazinamide was also reported on the basis of a negative Wayne test. Additional DST was performed against the second-line drugs capreomycin, ethionamide, ofloxacin and amikacin. A further 10 days later, the isolate was reported to be resistant to all four of these second-line drugs and a report of “presumptive” extensively drug-resistant TB (XDR-TB) was issued. Because of the isolate’s unusually resistant profile on conventional phenotypic testing, molecular tests were used to cross-check these results by identifying gene mutations associated with resistance (Box 2). Fourteen days after the preliminary report of XDR-TB was made, and a total of 66 days after the sample was initially collected, a final laboratory report confirming XDR-TB was issued. Further DST performed by an international reference laboratory revealed susceptibility to cycloserine and para-aminosalicylic acid. DST was not performed against imipenem and clofazimine owing to a lack of standardised methods. After the isolation of M. tuberculosis, the patient was initially treated in the community with standard first-line drugs. On receipt of the preliminary DST results, his urgent admission to hospital was arranged, with provision for isolation to prevent airborne disease transmission. A chest x-ray at this time showed fibrosis in the left upper zone, and a computed tomography (CT) scan showed an enlarged lymph node in the left anterior cervical chain (Box 3). The patient’s HIV serology results were negative, and an induced sputum sample set for TB was negative for acid-fast bacilli. Treatment was instituted with cycloserine 250 mg orally twice daily, para-aminosalicylic acid 4 g orally twice daily, linezolid 600 mg orally once daily, moxifloxacin 800 mg orally once daily, imipenem 1 g intravenously twice daily, clofazimine 200 mg orally once daily and isoniazid 600 mg orally once daily. The hospital pharmacy had difficulty in obtaining cycloserine, clofazimine and para-aminosalicylic acid. A 2-week supply of these agents was obtained from Auckland, New Zealand, but the remainder had to be imported from the United States. After 5 weeks of treatment, the patient’s enlarged lymph node had reduced in size and the discharge had stopped. Treatment with imipenem was stopped and treatment with amoxycillin–clavulanate 625 mg orally three times daily was begun. Three further sets of induced sputum samples were negative for TB. The patient was discharged back to the community, as the risk of him passing on the infection was now low. He attended weekly follow-up by a respiratory specialist and was monitored for treatment adherence by public health staff. A follow-up CT scan of the neck 2 months after discharge showed further significant improvement. Initially, surgical removal of the lymph node had been planned. However, with resolution of the lymph node after 5 months of medical therapy, surgery was not required. Apart from transient nausea, the patient is tolerating the treatment well and it is planned to continue treatment for a minimum of 18 months. Public health contact tracing of people who had resided with the patient showed they did not have TB. DiscussionMultidrug-resistant TB (MDR-TB) is defined as M. tuberculosis infection that is at least resistant to both isoniazid and rifampicin. XDR-TB is defined as resistance to not only isoniazid and rifampicin but also any fluoroquinolone and one of the second-line injectable drugs (such as capreomycin, amikacin or kanamycin).1 This report describes the first case of XDR-TB in New Zealand; it also describes the most resistant strain of M. tuberculosis reported to date in Australasia. By 2009, 58 countries had reported at least one case of XDR-TB. Despite this, there has been no new drug licensed to combat TB for 40 years.2 Given the increasing frequency of travel and immigration from high-risk areas, New Zealand and other countries in the region are likely to encounter more cases of XDR-TB in the future. The current cost of our patient’s medication to the government is about NZ$10 000 per month. Burma is one of 22 countries with a high health burden due to TB; in 2004, 4% of new TB cases and 15.5% of those previously treated were of MDR-TB.3 No cases of XDR-TB have been reported in Burma, but this is likely to be due to underreporting secondary to resource and laboratory constraints.1 In New Zealand, the incidence of TB is about seven per 100 000 people annually, and the rate of drug resistance for TB has been very low;4 from 2000 to 2009 there were 22 cases of MDR-TB.4 Since 2009 there have been a further nine cases reported to date (unpublished data obtained by J T F). From a regional perspective with regard to XDR-TB, Australia reported one case in the period 2002–2005 and the Pacific Islands did not report any.5 A second case was reported in Australia in 2010.6 Our patient showed primary resistance, in contrast to secondary resistance which develops from inadequate or inappropriate therapy: he arrived in New Zealand with latent infection, having been infected with XDR-TB in Burma. DST provides key information for the management of XDR-TB. This case highlights the integral role of diagnostic laboratories in rapidly and accurately reporting results to guide appropriate treatment. In this case, commercially available molecular-based methods enabled highly unusual DST results to be cross-checked and confirmed once the results of conventional, broth-based phenotypic DST had become available. However, in principle, such assays could have been used before obtaining the results of conventional DST. This could potentially have resulted in a report of MDR-TB being issued 12 days earlier, and in second-line DST results and the XDR nature of the isolate being reported about 20 days earlier. Notably, this patient came from a geographical area known to have a high prevalence of MDR-TB. It may be that, in future, risk-based laboratory DST algorithms can be devised so that molecular DST can be selectively applied as the initial method of testing for patients at high risk of MDR-TB. However, the cost-effectiveness of such risk-based testing algorithms in low-prevalence settings would need to be established. Hypothetically, if the patient had active pulmonary TB, molecular DST could have been performed directly on a respiratory specimen rather than waiting for the culture to grow.7 Use of such a test in this scenario could have potentially reduced the turnaround time by over 60 days. There are limited data available to definitively guide the management of XDR-TB, but current regimens recommend the use of four or more effective medications, based on DST.8 This includes any first-line agent that is effective, a fluoroquinolone, a second-line injectable agent and any third-line agent to make up four to six medications. Pyrazinamide and ethambutol should be included if possible, as this improves survival.8 Kanamycin can be used in streptomycin-resistant cases, and amikacin if there is resistance to both kanamycin and streptomycin. Capreomycin and viomycin can also be considered. The fluoroquinolones have variable potency — moxifloxacin and gatifloxacin are more potent then ofloxacin and levofloxacin. Ciprofloxacin is not recommended as an antituberculous agent.9 Other second-line agents like ethionamide, para-aminosalicylic acid and cycloserine can also be used. Linezolid, meropenem and amoxycillin–clavulanate are not licensed for this use but can be added if no alternatives are available. Monitoring for adverse drug reactions is important.8-10 For pulmonary XDR-TB, treatment for at least 18 months is recommended after conversion to negative sputum cultures.9 Directly observed therapy should be instituted, and treatment success may be up to 60% in patients without HIV infection.10 Surgical resection in conjunction with medical management is useful in selected patients with XDR-TB.11 However, most surgical studies are focused on pulmonary XDR-TB. There is a lack of research on surgical outcomes for head and neck XDR-TB. Early recognition of cases, with isolation in negative pressure rooms and high efficiency particulate air filtration, is necessary to prevent spread, but standard chemoprophylaxis with isoniazid, rifampicin, or rifampicin and pyrazinamide for contacts is unlikely to be effective in XDR-TB.12 Although our experience indicates that there is potential for treatment success, definitive treatment guidelines are needed and more data are required to inform treatment and help contain spread. Further, it illustrates the importance of maintaining an adequate supply of second-line drugs in New Zealand. Confirming XDR-TB in a young man from Burma who had no history of previous TB treatment suggests that XDR-TB may be more common in Burma than has been widely believed, reinforcing the need for strengthening laboratory support networks and TB surveillance systems in South-East Asia. 1 External appearance of the patient’s left anterior cervical lymph node on presentation 2 Gene mutations identified in the Mycobacterium tuberculosis isolate, and associated known antibiotic resistance Gene Mutation Associated antibiotic resistance katG S315T Isoniazid rpoB S315L Rifampicin gyrA D94A Moxifloxacin rrs A1401G Amikacin and capreomycin embB M306I Ethambutol 3 Computed tomography scan of the patient’s neck on presentation, showing an enlarged left anterior lymph node

Tze Liang Goh MBChB · Cindy R Towns PhD, MBChB, BSc(HighHons) · Katharine L Jones BMedSci, BM BS, MRCP · Joshua T Freeman MBChB, FRCPA, PGDipID · Colin S Wong DM, FRACP

Clinical record A 22-year-old woman of European ancestry who had a 4-year history of treatment-resistant bipolar disorder presented with symptoms of mania. On admission to hospital, a full blood examination and biochemistry results were normal. Her current doses of lithium (1500 mg daily) and risperidone (2 mg daily) were maintained while treatment with carbamazepine was commenced at 100 mg daily and then increased by 100 mg every 3 days. The patient was discharged from hospital on a regimen of 400 mg carbamazepine daily. Her plasma carbamazepine level at this time was 19 μmol/L (reference range [RR], 16–50 μmol/L). She was in good physical health, and a full blood examination and biochemistry results were normal. Three weeks after starting to take carbamazepine, the patient developed a mild, barely visible, erythematous maculopapular rash on her arms and chest that disappeared after a few days. She had no other symptoms, and full blood examination and biochemistry results remained normal. After a further 3 weeks, the patient developed marked lethargy, exercise intolerance, muscle aches, night sweats, rigors and a rash. There had been no changes to her medication and she had been complying with her treatment regimen. She lived with her family, and her parents contacted her family general practitioner as well as me (her psychiatrist). She was advised to stop taking carbamazepine, increase the dose of risperidone and seek urgent medical attention. The carbamazepine was stopped over 2 days — 45 days after it was first administered. The family consulted an emergency service on four occasions over 6 days, and the patient was variously diagnosed with contact dermatitis, non-specific allergic reaction, cytomegalovirus and rubella. She was finally admitted to hospital and was found to be febrile (temperature, 38–40º C) and tachycardic (heart rate, 108 beats per minute), with an intensely pruritic maculopapular rash that had spread over most of her body. Her face was swollen, showing periorbital oedema. There was no mucosal involvement or epidermolysis. She had occipital, supraclavicular and inguinal lymphadenopathy, and hepatosplenomegaly. Liver function test results were markedly abnormal (alanine aminotransferase [ALT], 1203 IU/L [RR, < 41 IU/L]; alkaline phosphatase, 156 IU/L [RR, 30–120 IU/L]) and her serum albumin level was low (29 g/L [RR, 35–50 g/L]. She had lymphocytosis (lymphocyte count, 5.9 × 109/L [RR, 1.0–4.0 × 109/L), but her C-reactive protein level was not raised. A diagnosis of anticonvulsant hypersensitivity syndrome was made. The patient was transferred to the intensive care unit, where she remained for 48 hours, and treatment with prednisolone 40 mg daily was commenced. Her physical state improved rapidly. After 7 days her ALT level had dropped to < 500 IU/L and she was deemed well enough to be discharged. The prednisolone was gradually tapered by 5 mg per week. Topical betamethasone helped to soothe her pruritus and inflammation, and some mild exfoliation occurred. The patient continued to improve over the next 6 weeks. Her rash disappeared, as did her hepatosplenomegaly, and liver function test results normalised. She recovered fully and has remained on lithium and risperidone. Anticonvulsants are being used increasingly for mood disorders and chronic pain. Anticonvulsant hypersensitivity syndrome (ACHS) has been reported to occur with use of phenytoin, carbamazepine, phenobarbitone and lamotrigine, but not valproate. It is a rare and potentially fatal complication. ACHS is indicated by the presence of a triad of characteristic clinical features — fever, rash and internal organ involvement. It is estimated to occur in about 1 in 1000 to 1 in 10 000 patients who are exposed to these anticonvulsants.1 A similar reaction has also been described with exposure to sulfonamides, sulfones, allopurinol and non-steroidal anti-inflammatory drugs (piroxicam in particular).2 This reaction has also been referred to as drug-related rash with eosinophilia and systemic symptoms (DRESS) syndrome, and drug-induced hypersensitivity syndrome (DIHS).3 This patient showed a pattern of symptoms quite typical of ACHS, which usually appears after a brief delay of 2–4 weeks after anticonvulsant exposure, but may appear up to 12 weeks later.1 Her symptoms began to emerge about 6 weeks after she commenced taking carbamazepine, although a mild rash appeared after 3 weeks. Transient rashes are quite common following initiation of carbamazepine therapy and are not an indication for stopping the drug. Clinicians often fail to consider a diagnosis of ACHS.4 Although the seriousness of the illness was initially not obvious, it was fortunate that administration of carbamazepine had been stopped as soon as significant symptoms began to emerge. It is noteworthy that the patient’s physical state continued to deteriorate following withdrawal of carbamazepine, and only improved 1 week later, after hospital admission and treatment with prednisolone. Her mental state did not worsen during her acute illness, and she showed great resilience. Prednisolone has potent mood-altering properties and presents a significant risk for inducing either depression or mood elevation. Close monitoring of mental state and psychiatric involvement is recommended. Carbamazepine has been linked with a variety of hypersensitivity reactions, ranging from mild and benign urticaria and erythematous maculopapular eruptions to Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). ACHS is usually not as serious as SJS or TEN but can be life-threatening, and deaths from it have been reported.5 The skin condition can be extensive in ACHS, but is not as severe as the detachment of body surface area seen with SJS or TEN, which often involves gastrointestinal or tracheobronchial epidermal surfaces. Lessons from practice Anticonvulsant hypersensitivity syndrome (ACHS) is a rare and potentially fatal complication of treatment with the anticonvulsants phenytoin, carbamazepine, phenobarbitone and lamotrigine. Diagnosis is clinical and based on a triad of features: fever, rash and internal organ involvement. Early suspicion of diagnosis is essential, as the critical component of treatment is cessation of the implicated drug. Pharmacogenetic testing for the human leukocyte antigen allele B*1502 should be considered before commencing carbamazepine in patients of Asian ancestry. Genetic factors predispose individuals towards the development of these reactions, and recent data have linked human leukocyte antigen allele B*1502 as a marker in Asian populations, except among people of Korean and Japanese ancestry. Genotyping is recommended for at-risk groups;6 the prevalence of the allele is negligible in other ethnic groups.6 ACHS is associated with complex immunological changes that include chemotoxic and T-cell-mediated inflammatory injuries to tissues containing cytochrome oxidases.2 Viral infection may increase an individual’s vulnerability.7 The most critical component of management of ACHS is discontinuation of the implicated drug.1 All clinicians who prescribe anticonvulsant drugs therefore need to be aware of ACHS and the requirement for early suspicion of the diagnosis. General supportive measures and systemic corticosteroids are usually given, which in most instances results in full recovery. There is cross-sensitivity among aromatic anticonvulsant drugs (phenytoin, carbamazepine, phenobarbitone and lamotrigine), which means that patients who have had ACHS should avoid all of these drugs.4 In addition, a familial association with ACHS exists, and family members of these patients need to be informed that they may be at increased risk of developing this syndrome. Anticonvulsant drugs that are generally considered safe are valproate and benzodiazepines.4

Isaac Schweitzer MD, DPM, FRANZCP

To the Editor: Colchicine is an alternative to anti-inflammatory agents for the treatment of acute gout.1 It is potentially toxic and can cause multiorgan dysfunction, including hepatotoxicity, neutropenia, acute kidney injury, rhabdomyolysis and hypotension. We report three cases of toxicity from supratherapeutic dosing that occurred within 2 weeks of each other. In each case, no alternative diagnoses (in particular, sepsis) were considered likely. An 87-year-old man presented with vomiting after 3 days of profuse diarrhoea, nausea and generalised myalgia without other infective symptoms. He had been prescribed 0.5 mg colchicine daily, but he was taking 1.0 mg four times daily. Clinical features included generalised abdominal tenderness, pancytopenia, rhabdomyolysis and hepatic dysfunction. These resolved over 5 days with supportive treatment. A 67-year-old woman presented with lethargy, diaphoresis, fever, nausea, vomiting and diarrhoea. She had been prescribed 1.0 mg colchicine initially, then 0.5 mg every 6 hours “until diarrhoea develops”. She was taking colchicine every hour despite diarrhoea. Initial clinical features included tachycardia, hypotension, tachypnoea and fever. Multiorgan dysfunction developed rapidly and despite aggressive resuscitation, including an intra-aortic balloon pump and broad-spectrum antibiotics, she died within 24 hours. A 77-year-old woman presented with nausea, vomiting and profuse diarrhoea. She had been prescribed 1.0 mg colchicine three times daily “until diarrhoea develops”. On presentation, she was dehydrated but haemodynamically stable, with mild renal and hepatic dysfunction and creatine kinase level elevation. These resolved over 4 days with supportive treatment. A recent randomised controlled trial demonstrated that low-dose colchicine (1.8 mg over 1 hour) was as effective as a higher dose (4.8 mg over 6 hours). Further, the adverse effects of the lower dose were similar to placebo and significantly less than those of the higher dose.2 Adapting to the Australian formulation, 1.0 mg initially and 0.5 mg 1 hour later is now recommended.3 In contrast, repeat doses of 0.5 mg until clinical improvement or side effects (in particular, diarrhoea) was previously recommended. In the cases above, the apparent dosing regimen differed significantly from current recommendations. Ineffective patient education may have also contributed to the conditions of patients 1 and 2, who up-titrated their dose. Patients 2 and 3 persisted with dosing despite gastrointestinal symptoms. Health professionals should be aware of the new dosing recommendations. These are highlighted by the National Prescribing Service4 and the Australian medicines handbook.3 Patients with renal or hepatic impairment, or concomitant use of cytochrome P450 3A4 or P-glycoprotein inhibitors (eg, clindamycin), are at increased risk.5

Myles W H Smith · Darren M Roberts · Siobhann M Ritson · Richard O Day

To the Editor: Warfarin is an orally administered vitamin K antagonist and has many well described interactions with commonly prescribed medications.1 However, only a handful of case reports worldwide have shown that flucloxacillin, a widely used antibiotic, may affect warfarin therapy by reducing its anticoagulant effect — in one instance contributing to the development of ischaemic stroke.2,3 There are several reports describing potential mech-anisms of interaction for flucloxacillin with warfarin.4,5 We describe the case of a 64-year-old man who was diagnosed with infective endocarditis on the basis of mitral valve vegetations and blood cultures that were positive for methicillin-sensitive Staphylococcus aureus. The patient underwent mitral valve replacement with a prosthetic valve and received prolonged antibiotic therapy with intravenous flucloxacillin for 8 weeks. Initially, for nearly 4 weeks, therapeutic anticoagulation with warfarin was difficult to achieve with warfarin doses ranging between 5 and 10 mg per day (target international normalised ratio [INR], 2.5–3.5). During this time, the patient was receiving intravenous flucloxacillin at a total daily dose of 8 g (2 g every 6 h). Flucloxacillin was increased to 12 g per day (2 g every 4 h) and there was a subsequent fall in the patient’s INR, which was sustained despite increasing the dose of warfarin to 25 mg per day (Box). Completion of flucloxacillin therapy was associated with a rise in the patient’s INR and a reduction in his warfarin dose requirement. No other relevant medications were commenced during this period of observation. This case highlights the potential for a dose-related effect of intravenous high-dose flucloxacillin (up to 12 g per day) on warfarin metabolism and the need for vigilance when prescribing antibiotics in conjunction with oral vitamin K antagonists. Other penicillins such as amoxicillin can, conversely, enhance the anticoagulant effects of warfarin, so the warfarin–flucloxacillin interaction may not be intuitive for many clinicians. Doses* for oral warfarin and intravenous flucloxacillin administered to a 64-year-old man with infective endocarditis, and corresponding INR INR = international normalised ratio. * Graph shows abbreviated, not daily, data. Intervals are weekly up to Week 9, then vary according to when INR was measured.

Philip Y-I Choi · Katherine L Phillips · Ian Rae

To the Editor: Frei and colleagues recently drew our attention to combination analgesic misuse-related morbidity.1 The same phenomenon has also been reported in New Zealand.2 About 50 years ago, analgesic misuse was widespread in Australia and commonly involved chronic, excessive use of combination analgesics (including the aspirin–phenacetin–caffeine [APC] products, Bex and Vincent’s Powders). After many years, some people who used APC developed “analgesic nephropathy”, which made up 12%–15% of dialysis cases.3 I recently performed a retrospective chart review of patients who were referred to the Drug and Alcohol Services at the Western Hospital (Melbourne) for excessive compound analgesic use between September 2005 and September 2010. There were 32 patients (18% of all referrals; median age, 38 years; 23 were women). All had some form of chronic pain, had initiated compound analgesic use for acute pain (eg, headache) and all described progressive use of analgesics because of psychogenic effects (eg, “gave me energy”, “helped me forget”). All 32 patients were diagnosed with opioid dependence and had medical and psychiatric problems correlating with their compound analgesic misuse. One patient, a 34-year-old man, reported taking more than 70 codeine–ibuprofen tablets daily and sustained recurrent gastric ulceration, which eventually required surgery. Despite this, he continued to misuse the analgesics until he undertook opioid replacement pharmacotherapy. A 24-year-old man misusing the same analgesic, despite completing a detoxification program, also relapsed and died after bleeding from gastric ulceration.4 Overall, the patient profiles were remarkably similar to those described by Frei and colleagues.1 Combination analgesic misuse appears largely correlated with products containing drugs of dependence (eg, codeine) and the phenomenon of “rebound pain” (ie, pain that recurs after a short-acting analgesic effect wanes, or “medication overuse headache”). Most morbidity and mortality risks associated with combination analgesic misuse are a consequence of chronic overdose of the non-steroidal anti-inflammatory drug and/or paracetamol components. Paracetamol (mostly when in combination with an opioid analgesic) is reported as the commonest cause of acute liver failure in the United States and United Kingdom.5 Another long-term complication can be hearing loss.6 Two patients in my clinic group had hearing loss, and the ear, nose and throat specialist’s opinion was that it was related to analgesic misuse. Dextropropoxyphene–paracetamol combination products are still available in Australia but are no longer available in the UK. I question the need for opioids in combination analgesic products and, if used, they should be restricted to prescription.

Michael A McDonough

Clinical record A 33-year-old woman was admitted to our service for investigation and management of acute hepatitis. She reported symptoms of nausea, fatigue, pruritus and right upper abdominal discomfort. The symptoms had first occurred 3 weeks earlier, resolving over 5 days, then recurred 2–3 days before presentation. The symptoms were temporally related to varicose vein sclerosing procedures, of which she had had three in total. The first procedure occurred 4 weeks before admission, with no subsequent side effects. It was after the second procedure, 1 week later, that symptoms first developed. The final procedure occurred a week before admission. During each procedure, the patient was given methoxyflurane as an inhaled analgesic administered from a 3 mL disposable cartridge. Other medications administered during the procedures were the sclerosing agent sodium tetradecyl sulfate and fexofenadine. There was no history of exposure to alcohol or to other prescription or over-the-counter medications. The patient had no risk factors for viral hepatitis, and there was no history of hepatitis or liver disease in her family. Clinical examination revealed jaundice and mild tender hepatomegaly only. Initial investigations showed hepatic enzymosis, with an elevated alanine transaminase level (2710 U/L [reference range, < 34 U/L]) and hyperbilirubinaemia (bilirubin 92 μmol/L [reference range, < 20 μmol/L]). Markers of liver synthetic function (albumin and prothrombin time) were within normal limits, as were full blood counts, electrolyte levels and renal function. Abdominal ultrasound demonstrated a normal-sized spleen and mild hepatomegaly, with an increased liver echotexture. Doppler sonography of the portal vein was normal. Serological tests for hepatitis A, B and C, Epstein–Barr virus, cytomegalovirus and HIV were negative. Iron and copper studies and levels of α-1-antitrypsin, antinuclear antibodies, antimitochondrial antibodies, anti-liver/kidney microsomal antibodies, anti-smooth-muscle antibodies and antinuclear cytoplasmic antibodies were all normal. Paracetamol was undetectable. Bilirubin levels continued to rise over the following 8 days (peaking at 202 μmol/L), although liver synthetic function remained normal throughout this time. A liver biopsy revealed evidence of resolving acute hepatitis with confluent perivenular hepatocyte dropout and bridging necrosis. There was no evidence of cholestasis or underlying fibrosis. The pathological diagnosis was of an idiosyncratic drug reaction, with the implicated drug being methoxyflurane. The patient’s condition continued to improve, with resolution of symptoms over 4 weeks and associated normalisation of liver enzyme and bilirubin levels. She has since remained well, and has been advised to avoid future exposure to methoxyflurane. Methoxyflurane, a short-chain halogenated ether, is a volatile anaesthetic agent. It was used for inhalational anaesthesia in the 1960s, but was withdrawn from use for this purpose when newer anaesthetic agents with more acceptable side effects became available.1,2 Methoxyflurane also has significant analgesic properties at subanaesthetic concentrations,3 and is thought to have minimal side effects in analgesic doses.4 These properties led to its adoption for use as an analgesic in a variety of settings for over 40 years.4 It is widely used by paramedic services in Australia,5 and has recently been studied for use in procedural analgesia in children and adults.4-6 It is provided in single-dose, pre-filled delivery devices (Penthrox, Medical Developments International, Melbourne, Vic), allowing accurate dosing and convenient delivery. In 2010, Penthrox was added to the Australian Schedule of Pharmaceutical Benefits as an item available free of charge for doctors’ bags. Although subanaesthetic doses of methoxyflurane (in the form of Penthrox) are used widely in Australia by ambulance services for prehospital analgesia, there is a paucity of data on its efficacy and safety. A recent observational case series and a review article found no significant side effects associated with its use for this purpose.4,5 Over three million inhalers have been dispensed in Australia since 1970,4 with the majority of doses administered for single-episode analgesia. Lessons from practice Taking a history of all medication exposures is important in assessing acute hepatitis. Repeated exposure to methoxyflurane may increase the risk of acute hepatitis. Reporting of suspected adverse drug reactions, such as this case, are important to raise awareness of possible rare side effects of commonly used medications. Hepatotoxicity resulting from the use of methoxyflurane as an inhalation agent in general anaesthesia is well described.1-3 However, hepatotoxicity associated with low doses of methoxyflurane for analgesic purposes appears to be rare. Three cases of hepatitis complicating methoxyflurane use (at subanaesthetic doses) during labour have been reported.7,8 In another case report, repeated exposure in the form of misuse of methoxyflurane was found to be associated with hepatotoxicity.9 The mechanisms of methoxyflurane-induced hepatotoxicity are unclear and may be multiple. Adverse effects of halogenated ethers are thought to be related to immune-mediated, direct toxic effects of metabolites and/or host idiosyncrasy.1 Reactive intermediates formed during metabolism of methoxyflurane can lead to tissue acetylation, with proteins modified by acetylation forming neoantigens that may trigger an immune response.1 Drug re-exposure has also been implicated as a factor contributing to methoxyflurane-induced hepatitis.2 Although unproven, it is possible that our patient’s repeated exposure to the drug may have contributed to the development of hepatitis through dose-dependent toxicity. In the prehospital setting, where methoxyflurane is being widely used, the side effect profile is minimal.5 It seems the exposure to methoxyflurane in our patient was the likely cause of acute hepatitis, and it may be that repeated exposure was a contributing factor. This observation has implications for the way methoxyflurane is prescribed, including its use for procedural analgesia in cases in which several procedures (and hence, repeated dosing) are required.

Kacey M O’Rourke BAppSc, MB BS · Stuart McMaster MB ChB, FRACGP · Karin M C Lust MB BS, FRACP

To the Editor: A middle-aged male night-shift driver experienced dizziness, vomiting, sudden onset of limb weakness, and then collapsed and became delirious. He had no past history of renal impairment or hypertension. At presentation in an emergency department, he was hypertensive (blood pressure, 220/140 mmHg) and hyperglycaemic. An upper motor neurone pattern of persistent dysarthria and left hemiparesis was evident. An electrocardiograph and transthoracic echocardiogram confirmed sinus rhythm and left ventricular hypertrophy. Magnetic resonance angiography of the brain showed subacute basal ganglia haemorrhage (Box) and an anterior communicating artery aneurysm. Renin levels were elevated at 124.7 mU/L (reference range, 4.5–46.0 mU/L) but renal artery stenosis was absent on ultrasound. Evaluation of an elevated initial normetadrenaline level of 1610 pmol/L (reference range, < 900 pmol/L) with a diagnostic algorithm1 suggested that phaeochromocytoma was unlikely. Hypertension, proteinuria, suboptimal renal function, inactive urine sediment and normal fasting blood glucose suggested hypertensive nephropathy. Antihypertensives were initiated to mitigate the risk of further stroke, nephropathy and cardiomyopathy. Results of an electroencephalogram were normal. Further history revealed that the patient had nicotine dependence with occasional amphetamine and cannabis exposure. Before admission, he had an estimated intake of 1–2.5 bottles of cough mixture episodically (600–1500 mg of pseudoephedrine). A pattern of ingesting excessive amounts of various brands of over-the-counter combination pseudoephedrine and codeine cough mixture developed over 20 years, and he suffered cravings when abstaining. He visited various pharmacies, provided identification, was repeatedly cautioned, but rarely consulted doctors. A Naranjo score2 of 7 indicated a probable adverse drug reaction to pseudoephedrine, resulting in a disabling hypertensive haemorrhagic stroke. During 2.5 months of inpatient rehabilitation, he regained full independence in self-care and mobility. His unstable employment was interdependent with pseudoephedrine misuse. He accepted counselling regarding constructive, non-pharmacological coping strategies for social stressors. Financial, legal and housing difficulties complicated his discharge plan. He planned to return to work as a driver. Pseudoephedrine is associated with a modest elevation in blood pressure3 and hypertensive crises.4 Intracerebral haemorrhage associated with pseudoephedrine usage is anecdotally reported.5 Dependence and chronic psychoses have been reported6,7 but their prevalence is unknown. Night-shift workers, students, recreational or self-medicating users, and athletes are potentially vulnerable to misuse. Project STOP is an initiative of the Pharmacy Guild of Australia (http://www.projectstop.com.au/index.html) to curb diversion of pseudoephedrine-containing medications from retail pharmacies into illegal amphetamines. However, it is not mandatory and the National Drugs and Poisons Schedule Committee has rejected the Pharmacy Guild’s proposal to enhance Project STOP’s capabilities using an electronic messaging tool for pharmacists (NotifyRx, RelayHealth, Atlanta, Ga, USA) to regulate codeine sales (excluding cough mixtures). In contrast, New Zealand authorities now restrict the supply of pseudoephedrine to prescription only. A concerted effort from all relevant parties, including tighter regulation or legislation, is essential for harm minimisation. We urge regulatory bodies to review the effectiveness of current practice. Magnetic resonance angiogram of the patient’s brain showing likely hypertensive right basal ganglia haemorrhage

Ajay Bharatula · Peter W New

We report the first recognised case of infection with Clostridium difficile PCR ribotype 027 acquired in Australia. This pathogen has caused significant morbidity and mortality in widespread hospital-based outbreaks in the northern hemisphere. Clinicians need to be aware of the clinical picture, limitations of diagnostic tests, availability of further testing for epidemic strains, new therapeutic approaches, and in-hospital control strategies for this infection. (MJA 2011; 194: 369-371) Clinical recordAn 83-year-old Latvian man underwent an aortic valve replacement for aortic stenosis in late January 2010 at a hospital in Melbourne, Australia. He had a history of hypertension and chronic renal failure. He lived alone in his own home, and had not travelled outside Australia since September 2009 when he returned from a 3-month trip to Latvia. Between his return to Australia and the surgery, he had not received any antibiotics except for a single preoperative dose of cephalothin. His regular medications included various supplements, but no proton-pump inhibitor. He was admitted to the hospital the day before surgery. Two days after the surgery, he developed severe sepsis from a urinary tract infection, for which he received ticarcillin–clavulanate and a noradrenaline infusion. A coagulase-negative Staphylococcus was isolated from blood cultures, and he was given vancomycin. He later developed an infiltrate at the left lung base, but no change was made to his therapy. Five days after the surgery, he developed watery diarrhoea. Clostridium difficile was isolated from stool samples, although the results of enzyme-linked fluorescent assays (VIDAS, bioMérieux, Sydney, NSW) for C. difficile toxins were negative at this time. His leukocyte count was 9.5 × 109/L (reference range, 4.0–11.0 × 109/L) and his serum albumin concentration was 42 g/L (reference range, 35–50 g/L). Therapy with metronidazole (400 mg orally, 8-hourly) was commenced for presumed C. difficile infection (CDI), and the patient was placed under contact precautions. Alcohol-based hand rub was replaced with traditional soap and water hand washing (see below). Therapy with ticarcillin–clavulanate was subsequently ceased. After 9 days of metronidazole therapy, the diarrhoea became more frequent and vancomycin (250 mg orally, 6-hourly) was substituted. Repeat stool specimens were tested. This time, C. difficile toxins were identified by enzyme-linked fluorescent assay, and C. difficile was isolated again. Because of the patient’s deteriorating condition, the laboratory was alerted to the possibility of a hypervirulent strain. The isolate was tested for susceptibility to moxifloxacin (Etest, bioMérieux, Sydney, NSW) and found to be resistant, with a minimum inhibitory concentration of > 32 μg/L. The stool sample was positive by real-time polymerase chain reaction (PCR; GeneXpert, Cepheid, Sunnyvale, Calif, USA) when tested for the presence of C. difficile organisms carrying genes for toxin B (tcdB), binary toxin (cdtB) and an 18-base-pair deletion within the tcdC gene that is characteristic of the PCR ribotype 027 strain. These findings were confirmed by sequencing the tcdC gene, and this also identified a point mutation at nucleotide position 117, which is also characteristic of this strain. PCR ribotyping was undertaken using a previously published method1 that confirmed the isolate as PCR ribotype 027 (Box). Nineteen days after surgery, the patient’s condition deteriorated further. His temperature was 39.2°C, his leukocyte count was 31.2 × 109/L and his serum albumin concentration was 25 g/L. The diarrhoeal frequency fell to a single bowel action per day, and an abdominal x-ray showed a distended right colon. The oral vancomycin dose was increased to 500 mg, 6-hourly, and therapy with intravenous metronidazole was commenced along with vancomycin enemas (500 mg in 500 mL normal saline, 6-hourly). Ticarcillin–clavulanate therapy was recommenced. A surgical opinion was sought and subtotal colectomy discussed. As there was felt to be a high risk of mortality with surgery, medical management was preferred. After 5 days, the fever and diarrhoea improved. The enemas were ceased after 8 days and metronidazole therapy after 14 days. The patient subsequently recovered, and the diarrhoea had not recurred at 3-month follow-up. DiscussionAn epidemic strain of C. difficile (PCR ribotype 027) was first identified in Quebec Province in Canada in 2005, as a cause of hospital outbreaks of severe infection with high mortality rates.2 Retrospective analyses suggested that this strain had caused outbreaks across North America since 2000.3 The organism later spread to Europe, and cases have now been described in Asia and Central America.4 Increased toxin production by C. difficile PCR ribotype 027 may be responsible for its increased virulence,5 and fluoroquinolone resistance is likely to be contributing to its spread.6 Infection with this strain more often leads to severe disease, and is associated with more recurrences and a greater risk of death.2 Until now, only one case has been described in Australia in a patient who was thought to have acquired the infection in North America.7 This is the first case of hypervirulent CDI diagnosed in Australia with apparent local acquisition. Several factors support the conclusion that the infection was not acquired overseas. First, although the patient had travelled to Latvia 4 months before being admitted, the possibility that he acquired C. difficile PCR ribotype 027 then and remained colonised is remote. C. difficile does not colonise the normal adult gastrointestinal tract, and the patient received no antibiotics that may have disrupted his gut flora in the time between returning from Latvia and admission to hospital. Second, a recent publication from Latvia indicates that C. difficile ribotype 027 was not present in the country when our patient was there.8 Finally, there were at least two other subsequently confirmed cases of infection with C. difficile PCR ribotype 027 in the hospital at the time the patient developed symptoms of infection (it is not known where these cases were acquired). The case illustrates important features of hypervirulent CDI. The identification of severe disease is critical in guiding management. For surveillance purposes, severe disease may be simply identified as infections requiring ICU admission or surgery, or infections resulting in death, or a diagnosis of toxic megacolon.9 More sensitive diagnostic criteria for severe disease in addition to those above are required to guide patient care. While no such criteria have yet been prospectively validated, proposed markers of severe disease include age greater than 65 years, leukocytosis greater than 20 × 109 cells/L, deterioration of renal function, temperature greater than 38.3°C, serum albumin concentration less than 25 g/L and an elevated serum lactate concentration.10 Our patient met all these criteria except for the serum lactate concentration, which was not recorded. Although metronidazole remains the recommended first-line agent for mild to moderate CDI, oral vancomycin is now recommended for severe disease.9,10 Although there is no evidence that high-dose oral vancomycin (500 mg, 6-hourly) is any better than standard doses of 125 mg 6-hourly, higher doses are favoured by many clinicians. Evidence of benefit for vancomycin enemas is limited to case series; eight of nine patients with refractory severe disease had complete resolution with this therapy.11 In the setting of ileus with toxic megacolon, oral vancomycin will not reach the colon and intravenous delivery of metronidazole is preferable.12 Surgery should be considered if severe disease is unresponsive to medical therapy after 48 hours, or if there is bowel perforation or multiorgan failure.13 Elevation of plasma lactate to between 2.2 and 4.9 mmol/L has been identified in a retrospective review of a selected group of severely ill patients as a guide to when colectomy is most beneficial.14 Other strategies requiring further investigation for use in severe disease include intravenous immunoglobulin, alternative antibiotics such as tigecycline, and monoclonal antibodies. C. difficile spores are highly resistant to killing by alcohol and most other disinfectants. In outbreaks of CDI, health care workers should be instructed to wash their hands with soap and water in addition to using alcohol-based hand disinfection when caring for infected patients. Patients should be isolated and contact precautions with gowns and gloves are recommended. Environmental cleaning with hypochlorite-based solutions is necessary to eliminate the spores.9 Antibiotic stewardship is also an important element in control strategies, with studies of antibiotic restriction showing benefit.15 In Australia, laboratory diagnosis of CDI is most commonly made through detection of C. difficile toxins A and B using enzyme immunoassay (EIA) kits. EIA kits have reported sensitivities of 75%–95%, but most of the evaluations reporting these sensitivities use faecal cytotoxin detection (a flawed test) as the gold standard.16 In addition, the positive predictive value of these tests declines markedly in situations where the prevalence of disease is low.16 Poor sensitivity of the assay is the likely explanation for the initial negative result of the enzyme-linked fluorescent assay in our case. Despite this limitation, EIA kits remain widely used because of their simplicity and relatively low cost. Commercial real-time PCR testing for toxin genes (usually tcdB), has better sensitivity (93%) and specificity (97%),16 and is now available in several Australian laboratories. Toxigenic culture — isolation of the organism followed by toxin testing of the isolate — is extremely sensitive, but it is labour intensive and takes at least 3 days.16 There is currently great debate about the value of an algorithmic approach to diagnosing CDI, whereby a sensitive screening test is used to screen out negatives, thus improving the positive predictive value of a secondary test, particularly when the prevalence of infection is low.17 Distinguishing C. difficile PCR ribotype 027 from other strains of C. difficile does not affect individual patient management, but is important for surveillance purposes. Some commercially available PCR methods can presumptively identify PCR ribotype 027 based on detection of binary toxin genes and the characteristic 18-base-pair deletion in the tcdC gene. An alternative, less expensive, approach is to screen for moxifloxacin resistance by using a 5 μg moxifloxacin disc on a lawn culture of C. difficile on Mueller-Hinton agar. Worldwide, most PCR ribotype 027 isolates are resistant to moxifloxacin,2 while, in Australia, the prevalence of resistance in all strains of C. difficile is 1%. (T V Riley, B Elliot and colleagues, unpublished data). Zones of inhibition for resistant strains (potentially PCR ribotype 027) are > 16 mm while for susceptible strains, they are ≥ 16 mm (T V Riley and colleagues, unpublished data). Isolates of moxifloxacin-resistant C. difficile identified in this way can then be sent for further typing. Given the arrival of C.difficile PCR ribotype 027 in this country, periodic PCR ribotyping of a representative sample of isolates now needs to be performed at designated reference laboratories Australia-wide, and recurrent funding is required for this task. This will be an important adjunct to local screening measures, and will also detect the emergence of virulent PCR ribotypes other than 027. An Australian Commission on Safety and Quality in Healthcare recommendation for hospital surveillance programs in all states and territories to monitor C. difficile was approved by Australian Health Ministers in November 2008. As yet, the states and territories have not implemented this recommendation, and there has been no collation or analysis of national surveillance data. With the identification of the first case of PCR ribotype 027 C. difficile infection acquired locally, it is important that clinicians in Australia are aware of the clinical picture, limitations of diagnostic tests, availability of further testing for PCR ribotype 027, new therapeutic approaches,18 and in-hospital control strategies for this infection.19 The solution to the bigger problem of the emergence of virulent strains of C. difficile continues to lie in the basics of surveillance, antimicrobial stewardship, infection control and environmental cleanliness. Ribotyping pattern of the Clostridium difficile strain isolated from the patient compared with a reference and an unrelated strain Patient isolate Unrelated strain PCR ribotype 027 reference strain 100-base-pair DNA ladder PCR = polymerase chain reaction.

Michael Richards MB BS, MD, FRACP · James Knox BSc(Med), MB BS, DTM · Briony Elliott BSc(Hons) · Kate Mackin BA/BSc(Hons) · Dena Lyras BSc(Hons), PhD · Lynette J Waring MB BS, FRCPA · Thomas V Riley PhD, FASM, FRCPath

A national interdisciplinary body is urgently needed to manage the looming antimicrobial resistance crisis The introduction of antibiotics was one of the most important developments in modern medicine. Their availability has facilitated increasingly complex care and, not surprisingly, microbial resistance to antibiotics has been identified as one of the greatest threats to human health. A return to the “pre-antibiotic era” would render many routine infections untreatable and would seriously affect current practice in surgery, intensive care, organ transplantation, neonatology and cancer services through major increases in morbidity and mortality. The time to act is now — before we lose these “miracle” drugs for good. Preserving the “miracle” of antibioticsIn response to a looming crisis in antimicrobial resistance, the Australasian Society for Infectious Diseases and the Australian Society for Antimicrobials convened the Antimicrobial Resistance Summit in Sydney on 7–8 February 2011. The meeting brought together an interdisciplinary group of experts from the medical, veterinary, agricultural, infection control and public health sectors to establish priorities and a joint plan for action, focusing on the key elements shown in Box 1. The threat of antibiotic overuseThe keynote address at the Summit was given by Professor Otto Cars (Professor of Infectious Diseases, Uppsala University, Sweden, and Chair of STRAMA, the Swedish strategic program against antibiotic resistance). STRAMA, a government-funded body, has supervised a multidisciplinary effort to improve surveillance and infection prevention and promote rational antimicrobial usage. This has been very successful in reducing usage in Sweden. Professor Cars highlighted that the key factor contributing to the alarming resistance trend in bacteria is the indiscriminate use of antibiotics. This is occurring in a number of settings including hospitals, general practice and veterinary medicine. Agricultural practices involving the use of antibiotics for prophylaxis and growth promotion rather than treatment also contribute to this problem. Repeated studies have demonstrated that a significant proportion of antibiotic use is unnecessary and that antibiotic use varies markedly between countries despite similar clinical outcomes.1 For many bacterial pathogens, resistance to last-line antibiotics, such as carbapenems, fluoroquinolones, glycopeptides and third-generation cephalosporins, is now commonly found in Australian hospitals and, to an increasing extent, in the community. Examples include methicillin-resistant Staphylococcus aureus, multiresistant Streptococcus pneumoniae, vancomycin-resistant enterococci and multiresistant Escherichia coli.2 This growing ineffectiveness of once-reliable drugs has seen health care professionals increasingly turning to alternatives that are more toxic, more expensive and less likely to be orally available, putting increased pressure on a strained hospital system. In addition, compared with susceptible bacteria, antibiotic-resistant strains are associated with increased patient morbidity and mortality and increased costs of health care.1 A dwindling pipelineWhile the issue of antimicrobial resistance is not new, it has long been assumed that this problem would be overcome by the ongoing development of new compounds. However, there has been an alarming decline in antibiotic development over time, highlighting that this strategy cannot be relied upon.1 The Antimicrobial Resistance Summit plan for actionSurveillanceMeasuring the extent of antimicrobial resistance in community- and health care-associated infections is crucial to defining the issue and measuring outcomes of any interventions designed to address it. While passive surveillance by electronic collation of routine susceptibility results can provide the broadest view of phenotypic changes, targeted surveillance by prospective studies of specific pathogens of interest provides details of newly emerging resistance mechanisms and strains. At present, the extent of antimicrobial resistance in Australia remains poorly defined. The current systems of data collection and collation vary between states and territories and there is limited coordination at a national level. In addition to measuring antimicrobial resistance, it is important to understand antibiotic usage. Currently, the National Antimicrobial Utilisation Surveillance Program represents the only nationwide systematic surveillance of antibiotic usage, but it is based on voluntary data submitted from major hospitals, representing about 50% of Australian tertiary referral beds3 (Box 2). Education and stewardshipEducation of the public as well as medical, veterinary and public health sectors is a crucial component in achieving judicious prescribing and dispensing of antibiotics. However, research has demonstrated that education campaigns and guidelines are ineffective unless they are combined with sustained interventions such as audit and feedback methods and/or a system where proactive steps are taken to assist prescribing and interventions are made to address poor performance.4 Antimicrobial stewardship acts at an organisational level and defines collective strategies to optimise antimicrobial prescribing through sustainable changes in practice. Further initiatives are required in the community, where the majority of human antibiotics are prescribed (Box 3). Infection prevention and control strategiesGeneric measures such as hand hygiene, avoidance of patient contamination during invasive procedures, environmental cleaning and disinfection, vaccination, and antibiotic stewardship are crucial in infection prevention and control. Surveillance is critical for determining the health care infection burden, identifying the people who are most at risk, and demonstrating the effectiveness of infection prevention or control interventions. To be effective, nationally coordinated surveillance is essential. Screening and effective isolation of patients carrying multiresistant organisms also has an important role1 (Box 4). Future research agendaWhile basic science research on microbiology is currently adequately funded by the National Health and Medical Research Council (NHMRC) and the Australian Research Council, a number of essential aspects required to combat antibiotic resistance do not find a ready place in existing project grant structures (Box 5). RegulationImplementing effective regulatory controls represents an important aspect of reducing indiscriminate use of antibiotics and keeping levels of antimicrobial resistance low in both human and animal settings (Box 6). An urgent call to actionThe threat of multiresistant bacteria is a critical public health issue that requires a coordinated, multifaceted response. To achieve this level of cooperation, we propose the creation of a national antimicrobial resistance management body comprising a wide range of stakeholders, including health care professionals, veterinarians, agriculturalists, pharmaceutical manufacturers, government, media representatives, consumers and other interested parties. The role of this body would include: implementing a comprehensive national resistance monitoring and audit system coordinating education and stewardship programs implementing infection prevention and control guidelines expanding funding to support research into all aspects of antibiotic resistance reviewing and upgrading the current regulatory system applying to antibiotics. This strategy is recommended by the World Health Organization1 and has been adopted by many other countries. The scourge of antimicrobial resistance has increased inexorably over the years. We believe that the window for overcoming antimicrobial resistance is still open, but we must act decisively now — Australia cannot bury its head in the sand any longer and hope that the problem will just go away. 1 An agenda for addressing antimicrobial resistance 2 Surveillance: key recommendations Antimicrobial resistance surveillance A comprehensive national surveillance system encompassing both passive and targeted components should be developed to monitor how much resistance is present, in which bacteria and where. This should include medical (hospital and community) and veterinary areas, as well as agriculture (including imported food). Priority should be given to staphylococci and Escherichia coli, which have the greatest impact on human health (emerging resistance in E. coli and other Gram-negative bacteria poses a major new threat). Methods used in resistance testing should be standardised wherever possible to enable comparison and pooling of data. In particular, minimum inhibitory concentration breakpoints need to be standardised. Antibiotic usage surveillance A comprehensive national monitoring and audit system covering all areas of antibiotic usage should be established. This should include comprehensive surveillance of hospital usage (eg, by expanding the National Antimicrobial Utilisation Surveillance Program), representative sampling of community prescribing, and collating distribution data from agricultural antibiotic suppliers. Data on the appropriateness of usage should also be evaluated (using point-prevalence surveys comparing diagnosis with prescription). Voluntary identification of hospitals in surveillance programs is recommended to encourage benchmarking and transparency. 3 Education and stewardship: key recommendations Educational initiatives need to define antimicrobial resistance as an urgent public health issue. The skills of social marketers and behavioural change experts should be used to drive a national campaign targeting both the public and prescribers. The National Prescribing Service (NPS) antibiotic educational campaign should also be reinstituted. A uniform national medical curriculum should be implemented that acknowledges overuse of antibiotics and embraces better stewardship, building on the NPS National Prescribing Curriculum. Stewardship, based on national antibiotic guidelines and local epidemiology, must be mandated in all hospitals within a quality framework based on audit and feedback. Effective stewardship requires a team-based approach including infection prevention units, microbiologists, pharmacists and clinicians. It must be strongly supported by senior hospital management and underpinned by effective use of information technology. Stewardship should also be extended beyond health care institutions to community care, long-term care facilities and non-medical antibiotic use. A well resourced national body should be created to provide effective national coordination of educational activities and antibiotic stewardship. Recognising that antibiotic resistance does not respect international borders, Australia has an obligation to contribute to international programs to control antibiotic use and resistance. 4 Infection prevention and control strategies: key recommendations Improved training on strategies for infection prevention and control should be provided to health care workers. All major hospitals should have the epidemiological capacity to identify and investigate outbreaks of multiresistant organisms, and to monitor and respond to changing patterns of pathogens causing health care-associated infections. National evidence-based standards for multiresistant organism control in aged care facilities should be developed, implemented and robustly enforced and monitored. A national coordinating centre for the control of antimicrobial resistance is needed, with the authority and capacity to collect and analyse data on multiresistant organisms from all jurisdictions. This will facilitate timely, consistent and effective control of multiresistant organisms. 5 Future research agenda: key recommendation A new National Health and Medical Research Council funding call (similar to that for pandemic [H1N1] 2009 influenza) is needed for research on antimicrobial resistance and usage in Australia and its near neighbours. The key areas of focus should be: epidemiology (in both human and animal settings) effective interventions for the public sectors, focusing on education and behavioural change effective interventions for the health care sector. 6 Regulation: key recommendations Resistance risk assessments should be part of the regulatory process for bringing new antibiotics to market for both humans and animals. The Pharmaceutical Benefits Advisory Committee should consider resistance in the criteria for inclusion or restriction of antibiotics in the Pharmaceutical Benefits Scheme. Strategies should be implemented to fast-track important new antimicrobials through the regulatory approval system. Strategies should be implemented to enable the registration of non-commercial “orphan” drugs that have the potential to improve patient outcomes and reduce disease burden. Adopting an antibiotic importance rating system as regulatory policy should be considered.

Thomas Gottlieb MB BS, FRACP, FRCPA · Graeme R Nimmo MD, FRCPA, FASM

Renal tubular acidosis is an underreported complication of ibuprofen misuse, and can result in life-threatening hypokalaemia. We describe four patients who presented with profound hypokalaemia and muscle weakness associated with excessive ibuprofen ingestion. Ibuprofen cessation and supportive management resulted in complete biochemical resolution within a few days. These cases remind practitioners about potential complications of unmonitored use of over-the-counter analgesics, including those with potential for misuse due to their codeine content. (MJA 2011; 194: 313-316) Clinical recordsPatient 1A 32-year-old woman presented to the emergency department with a 2-day history of evolving paralysis associated with profound hypokalaemia (potassium, 1 mmol/L; reference range [RR], 3–5 mmol/L). She also had epigastric pain without diarrhoea or vomiting and a past medical history of depression, iron deficiency anaemia, chronic constipation, migraines, cigarette smoking and previous intravenous drug use. Family history was unremarkable. Her only medications were citalopram 20 mg daily and a combination of ibuprofen (200 mg) and codeine phosphate (12.8 mg) for migraines. She denied taking laxatives, diuretics, alcohol or illicit drugs. On examination, the patient weighed 38 kg (body mass index, 14 kg/m2), her blood pressure was 90/55 mmHg, and other vital signs were normal. There was generalised flaccid weakness (graded 3/5) with normal sensation. She also had epigastric tenderness. Results of initial laboratory investigations (Box 1) were consistent with distal renal tubular acidosis (dRTA). An electrocardiogram (ECG) demonstrated features of hypokalaemia, including widespread ST-segment depression and U waves. Endoscopy revealed oesophageal erosions and a benign gastric ulcer. An abdominal computed tomography scan demonstrated enlarged, oedematous kidneys without nephrocalcinosis. The patient’s husband revealed she had been consuming the combination ibuprofen–codeine over a prolonged period — at least 25 tablets (5.0 g of ibuprofen) per week and up to 20 tablets in 1 day. Ibuprofen toxicity explained both the gastrointestinal symptoms and the biochemical manifestations of dRTA. No alternate explanation for dRTA was found. The ibuprofen–codeine combination was ceased, and intravenous potassium chloride (KCl) was administered (610 mmol at 5–10 mmol/h over 5 days), with concurrent oral replacement of 64 mmol potassium/day. No signs of opioid withdrawal were detected. Within 5 days, her serum potassium level stabilised at 4 mmol/L and bicarbonate levels normalised without bicarbonate supplementation. She was discharged 3 weeks later on a regimen of 16 mmol of potassium daily; her serum potassium level at discharge was 5 mmol/L. Patient 2A 37-year-old man presented with 3 days of progressive muscle weakness. He had been taking ibuprofen–codeine for several years, with a daily dose of 24 tablets (4.8 g ibuprofen). He was a smoker and denied taking any other medications. There was no history of diarrhoea or vomiting, and family history was unremarkable. He had proximal muscle weakness (graded 3/5) with hyporeflexia and muscle tenderness, but sensation was preserved. Initial investigation revealed a very low serum potassium level (2 mmol/L) and biochemical features consistent with dRTA (Box 1). The ibuprofen–codeine was ceased, and intravenous KCl was administered for 4 days (10–30 mmol/h) with 112 mmol of oral potassium/day. The weakness resolved after 2 days. Oral sodium bicarbonate supplementation (2520 mg/day for 9 days) contributed to normalisation of serum bicarbonate levels. Symptoms of overt opioid withdrawal developed on Day 3 and buprenorphine treatment was commenced. He was discharged on Day 9 after cessation of potassium and bicarbonate supplements, with a serum potassium level of 4 mmol/L. Patient 3A 45-year-old woman, with a remote history of intravenous drug use, presented after 7 days of lethargy and anorexia. She had multiple dental caries, and for several months had ingested 9.6–14.4 g/day of ibuprofen (about 50 tablets per day). She took no other medications and had an unremarkable family history and physical examination. Initial investigations revealed hypokalaemia (potassium, 2 mmol/L) with acute kidney injury, renal potassium wasting and biochemistry consistent with dRTA (Box 1). Gastroscopic investigation of microcytic anaemia found gastric antral ulceration with a peptic oesophageal stricture. No cause for RTA other than ibuprofen overdose was found. Ibuprofen was ceased, and intravenous sodium bicarbonate and KCl (220 mmol over 3 days at a maximum rate of 10 mmol/h) were administered. Concurrent oral potassium replacement occurred at 60 mmol/day. On discharge, 5 days later, renal function was normal and the serum potassium level was 3 mmol/L. Patient 4A 40-year-old man presented with a 2-day history of profound generalised weakness associated with hypokalaemia (potassium, 1 mmol/L). He had consumed 1.4–2.0 g/day of ibuprofen for 3 months for degenerative back pain. There was no history of diarrhoea or vomiting, he took no other medications and had no significant family history, and he was a smoker. The patient had normal vital signs apart from bradycardia (50 beats/min), with generalised flaccid weakness (graded 1–2/5) with preserved reflexes and sensation. An ECG demonstrated sinus bradycardia with prolonged QTc interval and U waves. Initial biochemistry results (Box 1) were consistent with RTA. Although the urine pH of 6.5 was higher than expected for the low serum bicarbonate level (11 mmol/L), proximal RTA (pRTA) was diagnosed in view of the negative urine anion gap and findings suggesting proximal tubular dysfunction. These included hypouricaemia (0.18 mmol/L; RR, 0.20–0.42 mmol/L), hypophosphataemia (0.40 mmol/L; RR, 0.8–1.5 mmol/L) and mild proteinuria. As there were no features suggesting alternative causes for pRTA, ibuprofen was considered the most likely causative factor, and was discontinued. Intravenous potassium (1010 mmol over 3 days at a maximum rate of 20 mmol/h), bicarbonate (total dose, 500 mmol) and phosphate (total dose, 50 mmol) were administered under electrocardiographic monitoring. The patient’s muscle strength improved within 24 hours and he was discharged 4 days later with a serum potassium level of 3 mmol/L. Potassium supplementation was ceased on discharge. DiscussionIbuprofen, a non-steroidal anti-inflammatory drug (NSAID), is widely used and readily available over the counter (OTC). Excessive ingestion of ibuprofen, in combination with codeine or alone, can result in ibuprofen toxicity, including RTA. In Australia, the maximum quantity of ibuprofen–codeine available OTC has recently been reduced from 72 to 28 tablets due to problems related to codeine misuse. We have described four patients with profound hypokalaemia due to ibuprofen-induced RTA. This is an underreported complication, which may present with hypokalaemic paralysis. Three of the patients were admitted to the same tertiary care hospital within 3 months of each other. The remaining patient was admitted to a peripheral hospital the previous year. In each case, the differential diagnosis of hypokalaemia initially included transcellular potassium shift, renal potassium wasting and gastrointestinal losses. Medication histories were uniformly negative for drugs known to cause intracellular potassium movement. Thyroid function was normal and there was no family history of hypokalaemic periodic paralysis. Urinary potassium wasting was documented in all cases by excessive urine potassium excretion (> 20 mmol/day or spot urine potassium > 20 mmol/L) in the presence of hypokalaemia.1 This was not explained by diuretic use or magnesium deficiency. The hyperchloraemic metabolic acidosis and non-acidified urine pH were in keeping with RTA. Gastrointestinal potassium and bicarbonate loss was unlikely in the absence of diarrhoea or laxative use. In two cases, gastric ulceration provided corroborative evidence for ibuprofen toxicity. Investigations found no alternative aetiology for RTA (Box 2). Ibuprofen cessation and supportive therapy allowed complete biochemical resolution within days. Unfortunately, no follow-up information could be obtained to ascertain whether the RTA was recurrent, or whether a previously unrecognised aetiology for RTA had become apparent. Characteristics of RTA are summarised in Box 3. Renal acidification is impaired, resulting in a hyperchloraemic metabolic acidosis.2 Hypokalaemia due to kaluresis is a feature of both proximal and distal RTA. Multiple factors contribute to hypokalaemia. Metabolic acidosis impairs proximal sodium reabsorption, leading to increased distal sodium delivery, secondary hyperaldosteronism and increased potassium secretion.3 In distal RTA, impaired hydrogen ion excretion promotes potassium loss in exchange for sodium to maintain electroneutrality. Reduced H–K-ATPase pump activity results in reduced distal potassium reabsorption.4 Four previously published case reports5-8 have described similar clinical presentations occurring with ibuprofen use of 4.8 to 28 g per day. However, one of our patients (Patient 4) developed RTA at a dose below the maximum recommended. No other NSAID has yet been implicated with this complication. The mechanism by which ibuprofen induces RTA is unknown. Other nephrotoxic effects of NSAIDs, including acute and chronic kidney injury, interstitial nephritis and nephrotic syndrome, result from impaired synthesis of cytoprotective prostaglandins, a consequence of cyclo-oxygenase-1 (COX-1) inhibition. It is hypothesised that the pathogenesis of ibuprofen-induced RTA may involve carbonic anhydrase (CA) inhibition. CA catalyses the interconversion between carbon dioxide and bicarbonate and is crucial to renal acid–base regulation. It is present in renal proximal tubules and collecting ducts as well as a variety of other tissues, including bone, brain and gut.9 Congenital CA deficiency is characterised by proximal and distal RTA, osteopetrosis and cerebral calcification.10 High titres of an auto-antibody directed against CA II have been noted in some patients with dRTA associated with Sjögren syndrome.11 Induction of these auto-antibodies has resulted in the development of RTA in a mouse model of Sjögren syndrome.12 Other NSAIDs including aspirin13 and flurbiprofen14 have been shown to have CA-inhibitory activity in vitro. More recently, celecoxib and valdecoxib, which are COX-2 selective NSAIDs, have been demonstrated to be potent inhibitors of CA due to binding of their sulfonamide moiety to its zinc (Zn2+) ion.15 Although ibuprofen lacks a sulfonamide moiety, it can inhibit human and bovine erythrocyte CA II.14 CA inhibition would be consistent with our observations of both proximal and distal RTA. In conclusion, profound hypokalaemia due to RTA is a potentially fatal complication of ibuprofen use. Although it usually occurs with excessive doses, it can occur at doses below the maximum recommended. The pathogenesis is unknown but may involve CA inhibition. Opioid addiction with deliberate misuse of ibuprofen–codeine analgesics is common.16 Therefore, ibuprofen toxicity should be considered in the differential diagnosis of patients presenting with severe hypokalaemia or hypokalaemic paralysis. 1 Baseline laboratory investigations and other characteristics of four patients with ibuprofen-induced renal tubular acidosis Reference range Patient 1 Patient 2 Patient 3 Patient 4 Sex, age in years Female, 32 Male, 37 Female, 45 Male, 40 Ibuprofen dose* 0.6–4.0 g/day 4.8 g/day 9.6–14.4 g/day 1.4–2.0 g/day Other medications Citalopram 20 mg/day; no complementary medicines, laxatives, diuretics or illicit drugs No prescription medicines, laxatives, diuretics or illicit drugs No other prescribed or over-the-counter medicines No other prescribed, over-the-counter or complementary medicines, diuretics or laxatives Serum pH 7.32–7.43 7.26 7.28 7.16 (venous) 7.27 Pco2, mmHg 37–50 21 32 22 27 HCO3-, mmol/L 22–32 10 14 8 11 Anion gap 7–17 10 8 16 15 Na+, mmol/L 134–146 141 140 134 141 Cl-, mmol/L 98–108 122 120 112 116 Urea, mmol/L 3.8 3.9 5.4 18.0 6.0 Creatinine, μmol/L 60–110 106 83 222 83 K+, mmol/L at presentation 3–5 1 2 2 1 K+, mmol/L on discharge 3–5 5 4 3 3 Urine pH 6.5 6.9 6.5 6.5 Na+, mmol/L 63 49 35 42 K+, mmol/L 25 25 22 25 Cl-, mmol/L 85 69 32 78 Anion gap 3 5 25 − 11 Pco2 = partial pressure of carbon dioxide. HCO3- = bicarbonate ion. Na+ = sodium ion. Cl- = chloride ion. K+ = potassium ion. * Maximum recommended: 3.2 g/day. 2 Causes of renal tubular acidosis (RTA)1 Causes of proximal RTA Primary Secondary With Fanconi syndrome (eg, multiple myeloma, light chain disease) Drugs and toxins (acetazolamide, outdated tetracycline, aminoglycosides, sodium valproate, 6-mercaptopurine, streptozotocin, iphosphamide, lead, cadmium, mercury) Associated with other clinical entities (vitamin D deficiency, hyperparathyroidism, chronic hypocapnia, cyanotic congenital heart disease, medullary cystic kidney disease, Alport syndrome, corticoresistant nephrotic syndrome, renal transplantation, amyloidosis, recurrent nephrolithiasis) Causes of distal RTA Primary Secondary Autoimmune diseases (eg, systemic lupus erythematosus, Sjögren syndrome, chronic active hepatitis, primary biliary cirrhosis, thyroiditis, fibrosing alveolitis, rheumatoid arthritis) Drugs and toxins (amphotericin B, lithium, toluene, amiloride, trimethoprim, pentamidine, vanadium) Calcium disorders (eg, primary hyperparathyroidism, vitamin D intoxication, idiopathic hypercalciuria with nephrocalcinosis) Dysproteinemic syndromes (hypergammaglobulinemia, amyloidosis, cryoglobulinemia) Renal diseases (eg, renal transplant rejection, medullary sponge kidney, obstructive and reflux nephropathy) Liver disease (hepatic cirrhosis) Genetic diseases (eg, osteopetrosis, sickle cell disease, Ehlers–Danlos syndrome) 3 Characteristics of renal tubular acidosis (RTA)1 Distal RTA (type 1) Proximal RTA (type 2) RTA type 4 Primary defect Impaired distal H+ excretion Impaired proximal HCO3 2 reabsorption Decreased aldosterone secretion or effect Plasma potassium Usually reduced (hyperkalaemic forms exist) Reduced Increased Urine pH > 5.5 Variable: usually > 5.5 if plasma HCO3- > 16mmol/L; < 5.5 if plasma HCO3- < 16 mmol/L < 5.5 Urine anion gap Positive Negative Positive Nephrocalcinosis Common Rare Rare Other tubular defects Rare Common (generalised proximal tubular dysfunction) Rare H+ = hydrogen ion. HCO3 - = bicarbonate ion.

Jennifer L Ng MB BS(Hons) · David J R Morgan MB BS, DCH, DRANZCOG · Nelson K M Loh MB BS, BMedSci, FRACP · Seng K Gan MB BS(Hons), FRACP, PhD · Patrick L Coleman MB, MRCPI, FRACP · Gregory S Y Ong MB BS · David Prentice MB BS, FRACP

To the Editor: The supplement of the Journal published on 16 August 2010 — “Bipolar disorder: new understandings, emerging treatments”1 — illustrates a number of features of the current implementation of the Journal’s supplement policy that are problematic. While it is clearly stated that the supplement “was supported by an unconditional grant from AstraZeneca Neuroscience”, the amount of sponsorship, to whom it was paid, and how it was used were not disclosed. Such information is particularly pertinent as evidence suggests that the pharmaceutical industry has financial motivation to see a widening of the diagnostic boundaries of bipolar disorder and a rebadging of atypical antipsychotics as “mood stabilisers”.2 The provenance of the articles is not revealed — it is not clear whether the articles were solicited, part of a symposium, or from some other source. Bipolar disorder is a controversial area in psychiatry,3 yet despite much useful information in the articles in the supplement, discussion of this controversy is a minor feature and no significant critical appraisal is offered. To give a more balanced view to readers, it would have been desirable to have included articles that highlight the controversy regarding bipolar II and bipolar spectrum diagnoses and discuss the ways in which personality disorders arising from developmental trauma and attachment problems can present with mood and behavioural disturbances that can be confused with bipolar disorder.

Jon N Jureidini · Peter I Parry · Catherine M Houen · Malcolm W Battersby

In reply: Jureidini and colleagues raise legitimate issues pertinent to our Medical Journal of Australia supplement on bipolar disorders, and we are pleased to respond. First, the extent of sponsorship from AstraZeneca was for publication only. One of us (D J C) discussed the idea of the supplement with the Editor of the Journal, and AstraZeneca expressed interest in supporting the project. Neither the Journal editors nor any of the supplement authors were involved in the sponsorship negotiations between AstraZeneca and the publisher of the Journal, and neither received any financial or other assistance or reimbursement from AstraZeneca. Second, as Coordinating Editors of the supplement, we determined the content of the supplement without any input from AstraZeneca, and we directly solicited articles from leading experts of our choice in appropriate fields. All articles were subject to the usual review process accorded all publications in the Journal. Regarding the general issue of the boundaries of the bipolar concept, we are very much aware of the ongoing debate. This is a pervasive issue for a discipline devoid of biological markers that can be used to define a plane of cleavage. Indeed, we highlighted this in the second paragraph of our editorial1 as an “immediate area of controversy”. We also solicited the article by Tiller and Schweitzer specifically to address the diagnostic problems in the area of mood instability; in that article, there is specific mention of both the bipolar spectrum and mood instability in the so-called personality disorders.2 With respect, Jureidini and colleagues fall into a common trap by considering that the use of some atypical antipsychotics in bipolar disorder is a rebadging exercise. This is silliness. One could equally argue that sodium valproate, carbamazepine and lamotrigine are not legitimate mood stabilisers but, rather, rebadged anticonvulsants. Tricyclic antidepressants started life as antihistamines. What matters to us as clinicians and researchers is that people with bipolar disorder are offered the best possible care, irrespective of labels. We are also very much aware of the undeniable burden associated with mood instability and hope that the supplement we helped produce will assist general practitioners, in particular, to deliver better care to patients so afflicted.

David J Castle · Michael Berk · Barbara M Hocking

To the Editor: Two studies in nursing homes in Sydney, New South Wales, in the 1990s1,2 showed inappropriately high use of psychotropic medications. A similar study was conducted in 2003.3 Over time, revision of management guidelines, warnings about potentially lethal side effects, and introduction of new drugs have contributed to changes in the pattern of use of psychotropic medications in aged care facilities. Following the same procedure as the earlier studies, in 2009, we examined medication use in nursing homes in half the catchment area of Sydney South West Area Health Service (SSWAHS). We obtained details of drugs prescribed for residents from medication record cards in 44 of the area’s 48 nursing homes and checked whether medications had been given as prescribed. If given regularly on at least 25 of the previous 28 days, use was recorded as regular. We noted whether medication prescribed “as required” had been taken. The SSWAHS ethics review committee approved the study. Medication cards of all 2465 residents (895 men, 1570 women; mean age, 78.7 and 84.2 years, respectively) were reviewed. The mean number of all medications charted per resident was 8.7. Data obtained from all four surveys on patients taking psychotropic medication regularly are shown in the Box. The catchment area expanded between the 1998 and 2003 surveys. However, half the nursing homes open in 1993 closed before 2009. Use of antipsychotic agents fell between 1993 and 1998. By 2003 there had been a change from conventional antipsychotics to a two-to-one preference for atypical antipsychotic medication. Since 2003, regular use of antipsychotic medication has increased by about 19%, although at a lower mean dosage than previously. The rise is mainly attributable to increased prescription of risperidone and needs continuing review to monitor for morbidity. The proportion of residents taking antipsychotic medication only as required has remained almost the same in each survey (range, 1.2%–1.4%). Regular use of anxiolytic and hypnotic medication has decreased, and of antidepressants has increased, since the 1990s. Only 3.5% of residents were regularly taking a tricyclic antidepressant in 2009. The proportions of residents prescribed anxiolytic or hypnotic medication only as required have also fallen (to 3.8% and 2.3%, respectively, in the 28 days preceding our audit). Our findings cannot be generalised. Recent evidence from Tasmania4 showed that 42% of residents were taking benzodiazepines regularly. Nevertheless, changes in medication use should provoke discussion. Number (%*) of Sydney nursing home residents taking psychotropic medication regularly Medication 19931 (n = 2414) 19982 (n = 1975) 20033 (n = 3093) 2009 (n = 2465) Any psychotropic† 1422 (58.9%) 957 (48.5%) 1461 (47.2%) 1170 (47.5%) Antipsychotics‡ 662 (27.4%) 447 (22.6%) 730 (23.6%) 690 (28.0%) Conventional‡ 662 (27.4%) 401 (20.3%) 251 (8.1%) 182 (7.4%) Haloperidol 190 (7.9%) 159 (8.1%) 167 (5.4%) 121 (4.9%) Thioridazine 354 (14.7%) 193 (9.8%) 17 (0.5%) — Chlorpromazine 53 (2.2%) 24 (1.2%) 25 (0.8%) 20 (0.8%) Trifluoperazine 57 (2.4%) 30 (1.5%) 16 (0.5%) 8 (0.3%) Pericyazine 15 (0.6%) 3 (0.2%) 10 (0.3%) 13 (0.5%) Fluphenazine 44 (1.8%) 23 (1.2%) 10 (0.3%) 11 (0.4%) Flupenthixol — 2 (0.1%) 9 (0.3%) 7 (0.3%) Zuclopenthixol — — — 9 (0.4%) Atypical‡ 48 (2.4%) 506 (16.4%) 537 (21.8%) Olanzapine — 8 (0.4%) 225 (7.3%) 180 (7.3%) Risperidone — 40 (2.0%) 219 (7.1%) 286 (11.6%) Quetiapine — — 18 (0.6%) 63 (2.6%) Amisulpride — — 4 (0.1%) 7 (0.3%) Clozapine — — 3 (0.1%) 7 (0.3%) Aripiprazole — — — 4 (0.2%) Hypnotics‡ 641 (26.6%) 335 (17.0%) 350 (11.3%) 274 (11.1%) Temazepam 530 (22.0%) 313 (15.8%) 307 (9.9%) 255 (10.3%) Nitrazepam 105 (4.3%) 17 (0.9%) 35 (1.1%) 17 (0.7%) Anxiolytics‡ 207 (8.6%) 123 (6.2%) 127 (4.1%) 117 (4.7%) Diazepam 113 (4.7%) 77 (3.9%) 92 (3.0%) 71 (2.9%) Oxazepam 72 (3.0%) 40 (2.0%) 32 (1.0%) 26 (1.1%) Antidepressants‡ 377 (15.6%) 316 (16.0%) 635 (20.5%) 630 (25.6%) Tricyclics 249 (10.3%) 120 (6.1%) 110 (3.6%) 86 (3.5%) Mianserin 87 (3.6%) 37 (1.9%) 22 (0.7%) 8 (0.3%) Moclobemide 21 (0.9%) 40 (2.0%) 20 (0.6%) 9 (0.4%) SSRIs 18 (0.7%) 103 (5.2%) 354 (11.4%) 338 (13.7%) Venlafaxine — — 81 (2.6%) 61 (2.5%) Mirtazapine — — 51 (1.6%) 126 (5.1%) Lithium 11 (0.5%) 8 (0.4%) 24 (0.8%) 17 (0.7%) — = Drug not approved for use or not prescribed in year of survey. SSRI = selective serotonin reuptake inhibitor. * All percentages are proportion of total number of residents. † Clonazepam and other anticonvulsants (apart from diazepam) were not included as psychotropic drugs. ‡ Numbers do not add to totals as some patients were prescribed more than one drug and some little-used psychotropic drugs are not listed.

John Snowdon · Daniel Galanos · Divya Vaswani

To the Editor: At budget estimates hearings of the Senate Community Affairs Committee in June 2010, answers were provided to questions on notice asked by Senator Guy Barnett to the Therapeutic Goods Administration (TGA) about the use of mifepristone for medical abortion in Australia since 2006.1 The answers are of interest as they include the number of practitioners who have become authorised prescribers of mifepristone in Australia since the “Harradine Amendment” was overturned in federal parliament in February 2006, as well as details of their practice. Nationally, 81 medical practitioners now have TGA authorised prescriber approval for mifepristone: 33 in New South Wales and 18 in Victoria (several large private clinics have gained approval in these states); 15 in South Australia, six in the Australian Capital Territory, five in Western Australia, and four in Queensland. There are none in Tasmania or the Northern Territory, so women in these two regions have no access to mifepristone abortion. There is very accurate documentation of all adverse effects of mifepristone–misoprostol medical abortion, which must be reported 6-monthly to the TGA. This information is then available to the general public through Senate estimates questioning. To 31 December 2009, 2926 medical abortions using mifepristone and misoprostol were performed in Australia by authorised prescribers. These include early and late procedures. The following adverse events were reported in that period: significant haemorrhage (7; 0.24%); retained products of conception requiring dilatation and curettage (D&C) or dilatation and extraction (84; 2.9%); ongoing pregnancy requiring surgical evacuation (14; 0.48%); and nausea and vomiting (10; 0.34%). These results are all well within the parameters expected from Australian and overseas studies of mifepristone–misoprostol use,2-5especially as a high proportion of the 2926 abortions would have been performed in the second trimester, as reported in a recent WA study.2 Large overseas studies on the use of mifepristone–misoprostol for early medical abortion (to 63 days of pregnancy) show a continuing pregnancy rate of around 1%, the need for D&C in 2%–3% of cases, and heavy vaginal bleeding requiring transfusion among 1 : 500 to 1 : 1000 women.3-5 These complications are more common in second-trimester procedures than in early medical abortions.2-5 Use of mifepristone in Australia is still restricted to authorised prescribers, and it is therefore not accessible to many women who might wish to use it. However, the number of cases performed in Australia is now large enough to conclude that mifepristone is safe and effective for the Australian women able to access it.

Caroline M de Costa

To the Editor: The article by Philip Sambrook et al on the impact of adverse news media on prescriptions for osteoporosis1 contains a number of serious errors and ignores more recent data. Their article quotes the estimated incidence of osteonecrosis of the jaw (ONJ) after oral bisphosphonate treatment for osteoporosis to be between 1 in 10 000 and 1 in 100 000 patient treatment-years. This is in fact a gross underestimate.2 The results of an independent study funded and conducted by the United States Food and Drug Administration (FDA) found an incidence of between 1 in 537 and 1 in 1537.3 This result is similar to that of an independent Australian study, which found an incidence of 1 in 296 to 1 in 1130.4 Thus, there is evidence that bisphosphonate-associated ONJ is much more common in patients treated with oral bisphosphonates for osteoporosis than the authors claim. Bisphosphonate-associated ONJ is also much more serious than presented. Patients with ONJ can be affected for years. The condition causes considerable morbidity, with greater interference in a patient’s life than the condition of osteoporosis and vertebral fractures. It should be noted that the FDA study3 and the Australian study4 were based on documented cases of ONJ, whereas the study by Sambrook et al1 was not based on actual fractures. It is unfortunate that, despite the wording of the Pharmaceutical Benefits Scheme (PBS) regulations, the Pharmaceutical Benefits Advisory Committee has let it be known that osteoporosis diagnosed by bone mineral density is not a requirement for PBS-supported bisphosphonate therapy — all that is required is a minimal trauma fracture, although it is well known that most patients with minimal trauma fracture do not have osteoporosis (however that is defined).5 The issue of adverse effects of bisphosphonate treatment for osteoporosis is currently being tested by a US class action. In the bellwether case of Boles v Merck & Co,6 the issue being tested is whether it was appropriate to prescribe alendronate for a patient with osteopenia but no fractures, and how much this treatment contributed to the patient’s end-stage ONJ. The plaintiff had exposed bone, constant pain, a pathological fracture, and pus dripping from her chin. The New York Supreme Court found in her favour. Despite the claim by Sambrook and colleagues that unbalanced media coverage “has the potential to do more harm than good”,1 the media do have an important role to play in exposing to the public the risks of pharmaceutical products and the actions of some pharmaceutical companies. It should be noted that Professor Sambrook was not only involved in The 7:30 Report current affairs program, but was also subsequently granted the unusual right of reply on that program. Following these two programs, the public made its decision based on facts about the incidence and morbidity of ONJ that have been confirmed by recent independent studies.3,4,6

Paul J Sambrook · B E Christopher Nordin · Alastair N Goss

In reply: Readers will probably deduce that Paul J Sambrook is no relation of Philip N Sambrook. The Australian Broadcasting Corporation, which aired The 7:30 Report that Paul Sambrook and colleagues refer to, subsequently acknowledged in writing that there were a number of factual errors in the original program. Under these circumstances, a right of reply was entirely appropriate. There is ongoing debate about the incidence of osteonecrosis of the jaw (ONJ), but as the modelling used in our study1 did not involve any assumptions about this, it is irrelevant to our findings. The studies by Lo et al2 and Mavrokkoki et al3 did not report incidence of ONJ — they reported prevalence. Moreover, one of the coauthors of the letter by Paul Sambrook et al (above) has published that the estimates by Mavrokkoki et al, being from a retrospective postal survey, must be viewed with caution.4 The Lo et al study was approved by an institutional review board of the United States Food and Drug Administration (FDA), not “funded and conducted” by the FDA, as Sambrook and colleagues state in their letter. There have been numerous studies of the effects of vertebral fractures and osteoporosis on quality of life. The authors claim that ONJ causes greater interference to a patient’s life than osteoporosis or vertebral fractures, but cite no references to justify this bald assertion. The US court case of Boles v Merck & Co5 was not an “independent study” (as implied in the last paragraph of the letter by Sambrook et al), but a legal proceeding that is being appealed. One of the coauthors of the letter was a paid expert for the plaintiff. ONJ is a serious complication of bisphosphonate therapy in the small proportion of affected individuals. We agree that patients need to be informed of the risks of therapy, but they also need to be informed of the consequences of not taking therapy (ie, the benefits forgone) to make a really informed decision. Our article was intended to let patients understand what those consequences might be. The courts are certainly not the place for informed debate. And the media should appreciate that unbalanced reporting can have significant consequences.

Philip N Sambrook · Jiang S Chen · Judy M Simpson · Lyn M March

To the Editor: Clarke and Fitzgerald showed that substantial savings could arise from the implementation of alternative pricing arrangements for off-patent statins that provide incentives to reduce prices and increase generic substitution.1 This is exemplified by comparing statin prices between Australia and England. Europe offers some more lessons with respect to savings based on generic medicine usage and how they can be attained. The size of savings reported by Clarke and Fitzgerald needs to be interpreted with caution. A scenario of 100% generic substitution is proposed. Such a scenario has not been observed in any European country and, for therapeutic reasons, is probably not desirable.2 Furthermore, the comparator country matters: for instance, generic medicine prices in England are lower than in France, the Netherlands and Germany, but are higher than those in Scandinavian countries.3 Finally, the implementation of a tendering system for statins may create unintended effects, such as a switch in prescribing behaviour. For example, the Belgian tendering system for simvastatin reduced expenditure on off-patent medicines containing simvastatin by 30%, but increased expenditure for patented medicines containing atorvastatin or rosuvastatin by 16% and 40%, respectively.4 Clarke and Fitzgerald’s article does not go into detail on how savings can be attained through use of generic medicines. The majority of European countries regulate generic medicine prices by pricing rules or reference pricing. For instance, the implementation of a minimum price difference between originator and generic medicines is the driver of savings arising from generic substitution in some countries, including France, Portugal and Spain. The reference pricing system in Norway stimulated generic competition to a greater extent and led to lower prices than regulation that imposed maximum prices.4 However, price regulation may constitute a barrier for further price competition: no additional price reductions may occur beyond those imposed by regulation.4 The European experience also indicates that the ability of the generic medicine industry to deliver competitive prices can be achieved if it is assured a high volume of the pharmaceutical market. High volume is dependent on demand-side measures that create incentives for physicians, pharmacists and patients to use generic medicines. For example, a European study showed that savings as a result of price competition are higher in countries that have a higher market share of generic medicines.5 Therefore, demand-side measures are critical to increase the generic substitution rate and to maximise the effect of competition based on generic medicine prices.

Steven R A Simoens

In reply: The main purpose of our recent article1 was to quantify estimates of pharmaceutical expenditure over the next decade using various assumptions regarding the price and use of generic statins. We report estimates of billions of dollars in potential savings associated with various scenarios that increase the current off-patent statin use in Australia from around 25% of prescriptions to between 50% and 100%. Simoens misinterprets our conclusions as recommending only using generic statins in Australia. We do not advocate any particular level of generic substitution, but argue that the optimal mix of patented and generic statins should be determined by using cost-effectiveness analysis. Simoens questions whether our results would change if we had compared statin prices with a country other than England. To address this issue we have compiled a comparison of current or recent wholesale price of 40 mg simvastatin across 13 countries in the Organisation for Economic Co-operation and Development (Box). Although there is some variation between countries, the main difference is with Australia, which has the highest wholesale price — about five times greater than the average price across all comparator countries. This price ratio is similar to the one used in our original study. Also, Simoens highlights several issues relating to alternative pricing arrangements for statins and other generic drugs in European countries. We agree that Australia may be able to learn from overseas experience when reforming its system of pricing generic pharmaceuticals. The impact on expenditure of the tendering system for supply of generic pharmaceuticals may have been counteracted by changes in prescribing behaviour in Belgium, but it has been successfully used in the Netherlands to cut the price of simvastatin and other major generics by over 80%. This has been estimated to save around 310 million euros annually.2 However, tenders are not the only way to reduce the price of generic pharmaceuticals. In Canada, the Ontario Ministry of Health and Long-Term Care has recently introduced a policy which sets the subsidy for generics at 25% of the original price under patent. Generic 40 mg atorvastatin, whose patent in Canada recently expired, now costs just A$17 per month.3 In contrast, under the recent Memorandum of Understanding4 between the Australian Government and Medicines Australia, the current wholesale price of A$61 for 40 mg atorvastatin will decline by only 16% after the patent expires in Australia in 2012, and there will be no further downward adjustment until at least 2014. Wholesale price of simvastatin 40 mg in 13 countries in the OECD* OECD = Organisation for Economic Co-operation and Development. * Comparator prices were converted to Australian dollars using the average exchange rate over the past 3 years, and 1 month supply was assumed to be equivalent to 30 tablets.

Philip M Clarke · Edmund M Fitzgerald

To the Editor: I am writing about important errors contained in a letter of reply by Hamilton-Craig.1 In his response to a letter by Montgomery,2 he states: 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 [cardiovascular disease] events in the ezetimibe group (P = 0.02; number needed to treat, 23), driven by a reduced need for coronary artery bypass grafting. However, in the SEAS trial, patients were treated with statin plus ezetimibe or with placebo, not with statin plus placebo. Therefore, the reduction in ischaemic events in the statin/ezetimibe group cannot be attributed to ezetimibe, as it could have been caused by the effect of simvastatin alone (or by the combined effect of the two drugs). I note also that the absolute reduction in ischaemic events over the course of the trial was 4.4% (15.7% v 20.1%), not 4.7%.3 With respect to the ENHANCE (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) trial, Hamilton-Craig states: As no placebo group was included, neither lack of benefit nor harm from ezetimibe therapy can be inferred.1 In the ENHANCE trial, patients with familial hypercholesterolaemia were treated with simvastatin plus ezetimibe or simvastatin plus placebo. There was no significant difference in progression of mean carotid intima media thickness (CIMT) between the two groups (0.0058 mm in the simvastatin/placebo group v 0.0111 mm in the simvastatin/ezetimibe group [P = 0.29]).4 Therefore, contrary to Hamilton-Craig’s statement, there was a placebo group, and a lack of benefit from ezetimibe was shown in the trial. Thus, the SEAS trial was unable to confirm a benefit of ezetimibe, as the active treatment arm included both a statin and ezetimibe, while the ENHANCE trial showed no additional benefit of ezetimibe on the surrogate endpoint of CIMT progression in patients taking a statin. Author’s note: The United States Securities and Exchange Commission disclaims responsibility for any private publication or statement of any Commission employee or Commissioner. This letter expresses my views and does not necessarily reflect those of the Commission, the Commissioners, or other members of the Commission staff.

Marilyn K Mann

To the Editor: I would like to endorse the letter by Montgomery1 questioning the efficacy of ezetimibe. As yet there are no data to support its use in clinical trials using carotid intima media thickness (CIMT) as a measure of treatment effectiveness, and there is also some evidence to suggest it could be harmful. A randomised trial conducted by Berneis et al2 suggested that ezetimibe may induce an unfavourable pro-atherogenic low-density lipoprotein (LDL) subfraction profile by increasing small, dense LDLs. The Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial3 compared simvastatin/ezetimibe 40/10 mg daily with placebo, so any benefit from that treatment may have been from either the ezetimibe or the simvastatin. It tells us nothing about the effectiveness of ezetimibe alone. Until the results of clinical trials are available, I believe ezetimibe should be used with much reluctance and only considered as a last resort. I agree with Hamilton-Craig4 that it is a matter of concern that slow-release niacin, which is effective and safe, is not available under the Pharmaceutical Benefits Scheme in Australia. Searching for supplies of this drug in Australia or overseas seems the best option for treating patients whose levels of LDL cholesterol are inadequately controlled with statin therapy.

Brett H Forge

In reply: In the interests of scientific exactitude, I am indebted to Marilyn Mann for corrections regarding the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial. However, as the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial did not include the control group ezetimibe versus placebo, the effects of ezetimibe on carotid intima media thickness remain somewhat speculative.1

Ian R Hamilton-Craig