Volume 186 Issue 2

Does drug product information need a use-by date? Do not rely on the Australian approved product information for up-to-date advice about drug therapy. This seems to be the main message of Stockigt’s review of entries for thyroid disease in prescribing references, which are based on the product information supplied for each drug. In some cases the information was so out of date, its recommendations were potentially harmful.1 While these findings will not surprise everyone,2 many health professionals will be disturbed to know that they cannot completely trust the product information approved by the Therapeutic Goods Administration (TGA). It is often the source that people turn to when seeking detailed drug information. As the product information also underpins consumer medicines information and sets the boundaries for advertising, flaws could have far-reaching consequences. The Therapeutic Goods Act 1989 (Cwlth) has little to say about product information other than it relates to “the safe and effective use of the goods, including information regarding the usefulness and limitations of the goods”. Details about what should be in the document are contained in the Australian regulatory guidelines for prescription medicines.3 These guidelines do not state that the product information should be kept up to date. When a sponsor company applies to have a new drug registered in Australia, it supplies a draft of the product information. This is scrutinised by the TGA and the Australian Drug Evaluation Committee to check that the information reflects the evidence supporting the drug’s safety and efficacy. Although the sponsor can make safety-related notifications, the product information cannot be changed after registration without the TGA’s approval. At the time of registration, the accuracy of the product information is at its zenith; however, it may soon be outdated. With the pressure to approve drugs quickly, new information is likely to emerge after the product is marketed. Some drugs seem to be approved mainly on the results of phase II trials. Their product information will therefore need updating when the results of phase III trials become available. Adverse effects may only emerge after marketing. A review in the United States of 548 new drugs found that more than 10% later acquired a “black-box” warning about serious adverse effects or were withdrawn.4 While major safety concerns are likely to trigger an update of the product information, less prominent problems may be overlooked. In Australia, the sponsor is responsible for keeping the information up to date. How seriously this responsibility is taken is unclear. Updating product information, particularly about old and possibly less profitable products, and disseminating the changes may not be a top corporate priority. The TGA also has to set priorities. It has limited resources but many areas of regulatory responsibility, including complementary medicines. While the TGA was once government-funded, it now has to recover all its costs in fees and charges. Having the regulator funded by fees from the industry it regulates may have disadvantages. Industry probably prefers to pay the TGA to register new drugs, than to dust off the product information of old drugs. To manage within its resources the TGA has adopted a “risk management approach” to regulation.5 Activities with a low risk of adverse outcomes receive less scrutiny. This is why complementary medicines are not evaluated before they are listed in the Australian Register of Therapeutic Goods. Similarly, the TGA’s risk analysis may not identify the product information of old drugs as a high risk. Many old drugs only have brief product information. This may not have been updated for years and it can be difficult to know its currency. The date of approval at the end of the document reflects the most recent change. However, this change may have been a minor variation rather than a rigorous review. Perhaps there is a need for a “use-by date”. Drugs have an expiry date, so why not extend the concept to product information? This would require a date to be set for a comprehensive check of the product information. Such reviews would be more frequent early in the product’s life to ensure emerging data were included. For older products the reviews could be less frequent, but at least there would be a mechanism for checking that the information was not obsolete. This could be an opportunity for specialist societies to assist the TGA with updating. Regularly reviewing product information would require greater resources for the TGA. As the TGA can charge for changes to the product information, the mechanism exists to recover the additional costs. (Changes to the product information involving the evaluation of data currently cost about $4000.) Although an agreement between the TGA and industry to keep product information up to date seems sensible, there are likely to be commercial objections. The TGA’s philosophy is to regulate while “freeing industry from any unnecessary regulatory burden”. Most corporations aim to cut costs, so it is possible that a company may withdraw an old drug rather than be forced to review the product information and then pay to have it approved. In 2005, the TGA circulated a discussion paper on improving access to information about prescription medicines.6 This contained several suggestions for greater use of electronic methods to make up-to-date product information easily available. The outcome of this discussion is currently unknown. Would a recommendation to update the product information regularly be accepted in a business environment focused on new products, cost containment and reduced regulation?

John S Dowden MRCGP, MICGP, FRACGP

Expert guidance is needed to balance the benefits and risks of sun exposure Vitamin D (defined in this article as serum 25-hydroxy-vitamin D) is largely obtained through the effect of sunlight on the skin. Vitamin D plays an undeniably important role in maintenance of bone health, preventing the development of rickets and osteomalacia. However, there has been increasing recent media attention given to research findings that suggest other possible benefits of vitamin D, such as prevention of certain cancers or multiple sclerosis.1,2 In the first 6 months of 2006, seven of 124 daily updates on “cancer-related news” (6%) monitored by The Cancer Council Australia featured at least one item on the importance of sun exposure for obtaining sufficient vitamin D to prevent chronic diseases. Given that the primary source of health information for most Australians is the media,3 such reports have the potential to change attitudes and behaviours to sun exposure. Some commentators have compared doctors with sherpas who need to guide their patients through an increasingly complex medical world.4 The “vitamin D story”, in which sun exposure appears to both cause cancer and prevent cancer, is one example where health consumers will need the guidance of health professionals in making an informed decision. Since the 1980s, the “Slip! Slop! Slap!” and then the “SunSmart” campaigns have sought to reduce population exposure to sunlight with the ultimate aim of reducing the burden of skin cancer in Australia.5 The challenge, given current levels of evidence, is to provide a public health message that ensures skin cancer risk is minimised while taking a precautionary approach to the possible harms of insufficient circulating levels of vitamin D. Several agencies have initiated conferences and meetings within the past 2 years, resulting in articles recommending changes to current sun-protection messages,6-8 and this year, the first issue of the journal Progress in Biophysics and Molecular Biology was wholly devoted to ultraviolet (UV) radiation exposure guidance. In Australia, a position statement on the risks and benefits of sun exposure was approved in 2005 by the Australian and New Zealand Bone and Mineral Society, Osteoporosis Australia, the Australasian College of Dermatologists and The Cancer Council Australia. The statement’s intention is to guide health professionals in giving information to the public on sun-protection behaviour. Four recommendations were made, and are summarised in the Box.9 Given the uncertainty about whether the subgroups within the population with the highest prevalence of vitamin D deficiency (the frail and elderly, people who cover themselves with clothing for cultural or religious reasons, those with dark skin pigmentation, those with mental illnesses) would benefit from a relaxation of sun-protection messages, each recommendation should be a starting point for further research. For example, considering the first recommendation (Box), the few studies available to date mostly indicate that, while most people are aware of the UV index, very few adjust their sun-protection behaviour accordingly.10-13 We need to determine ways to ensure that the UV index is routinely reported in weather forecasts in both summer and winter, and to increase public understanding of the implications of the UV index for sun-exposure behaviour. Additionally, it is likely that the association between the UV index and vitamin D production is not linear, and this needs to be explored in greater detail.14 Will the second recommendation (Box) lead to a more relaxed attitude towards sun protection in summer in southern states? Basal cell carcinomas and squamous cell carcinomas most commonly occur on the habitually sun-exposed skin sites.15 While these skin cancers are rarely fatal, their treatment can require surgical or destructive intervention and cause considerable morbidity.16 An unintended consequence of the second recommendation might be to increase incidental sun exposure of the arms and face and hence the incidence of skin cancer. Thus, the way this recommendation should be translated into a public health message needs careful consideration. For the third recommendation (Box), previous research has shown that people find it difficult to correctly assess their personal risk for skin cancer,17,18 and clinicians may need to help patients identify their risk. With regard to the fourth recommendation (Box), even though there is mandatory fortification of margarine in Australia, this is unlikely to achieve sufficient oral intake of vitamin D, especially among those most in need, and further supplementation may be necessary.19 The acceptability and effect of fortification and supplementation among at-risk groups still requires testing, and other food sources suitable for fortification need to be identified. At present, these complex recommendations are not being widely promoted to the general public, and further evidence on how to best communicate them is required, particularly in light of the media interest. Anecdotal evidence from the Queensland Cancer Fund suggests that the number of callers to their Helpline seeking advice about correct sun-protection behaviour is increasing. Further, unpublished data from a population-based survey conducted by the Queensland Cancer Fund in 2004 indicates that 837 of 5611 participants (15%) agreed with the statement, “If I regularly protect myself from the sun, I am in danger of not getting enough vitamin D”.20 These people were more likely to deliberately sunbathe than those who did not agree with this statement (odds ratio, 1.65; 95% CI, 1.30–2.09).20 Assuming that the association between various chronic diseases and vitamin D can be unequivocally established, and that the appropriate vitamin D level and the UV radiation dose required to obtain it can be quantified — which is by no means certain — it still may not be possible to provide a single message about “healthy” sun exposure appropriate for the whole of Australia, a continent that spans more than 35 degrees of latitude. It has been estimated that only 6–12 minutes of winter sun exposure three to four times a week may be sufficient to produce “healthy” levels of vitamin D in Brisbane, compared with 51 minutes in Melbourne.21 Many factors in addition to latitude (age, skin type, sun-exposure habits, other skin cancer risk factors, photoprotection, body mass index, food choices, amount of physical exercise, liver and renal health, environmental conditions such as smog, season, ozone) contribute to either people’s risk of skin cancer or their ability to synthesise vitamin D, or both. More research is needed to better understand the photobiology of vitamin D formation in the skin, and the precise effect of UV radiation on vitamin D synthesis within various subgroups of the population. We don’t yet know the minimum amount of sunlight needed to maintain healthy bones (let alone prevent internal cancers or chronic diseases, if indeed these benefits can be realised), nor whether these effects may not be better obtained through supplements. It is unlikely that the daily requirement for vitamin D could be obtained from foods fortified with vitamin D alone.22 A meta-analysis of randomised trials of vitamin D supplementation found that daily doses of 700–800 IU (17.5–20.0 μg) reduced the incidence of fractures, but lower doses did not.23 Even after the answers to these fundamental research questions are known, translating these complex messages to the Australian public effectively will remain a challenge. In the interim, the effect of current campaigns and media reports about vitamin D on sun-protective behaviours and sunburn rates should be monitored carefully, sun-safe practices should be encouraged and supplements used where necessary until we increase our basic understanding of the relationships between chronic disease, vitamin D and sunlight. Sun exposure is the primary cause of skin cancer. If sun exposure and sunburn were to increase as a result of concern about the requirement for vitamin D, several decades of effective public health promotion to reduce the incidence of the most common cancer in Australia would be jeopardised. Summary of the risks and benefit of sun exposure position statement* Sun protection is usually required if the ultraviolet (UV) index is 3 and above (and people are advised to check the forecast UV index in their local area); Most people achieve adequate vitamin D levels through incidental sun exposure, but people living in the southern Australian states in winter may need 2–3 hours of sun exposure on the hands, arms and face each week; Some people are at high risk of developing skin cancer and need more rigorous sun protection than the general population; Some subgroups of the population, such as the frail and elderly, and people who cover most of their body with clothing for cultural reasons may need to consult their doctor to have their Vitamin D status investigated and supplemented if necessary. * Modified from the full statement.9

Monika Janda MPhil, PhD · Michael G Kimlin MAppSc, PhD · David C Whiteman FAFPHM, PhD · Joanne F Aitken MSc, PhD · Rachel E Neale BVSc, PhD

Results of studies on the use of antibiotics, alone or in combination with surgery, are encouraging Although Buruli or Bairnsdale ulcer (BU) was described in Uganda, Africa, in 1897, the causative organism, Mycobacterium ulcerans, was only identified in 1948, in Australia.1 Today, the disease has been reported in over 30 countries, mainly in tropical and subtropical regions of Africa, Latin America, Asia and the western Pacific.2 BU is poorly recognised within the medical community, and there is gross underreporting of cases. Australia is the only developed country that has major foci of infection, and BU is now a notifiable disease in the state of Victoria. Over the past decade, the World Health Organization has played a central role in quantifying the problem and bringing together scientists, health experts and funding organisations to increase understanding of the disease, improve management and broaden the delivery of care to patients. There are some differences in BU as it is seen in Australia compared with Africa. Small papular lesions are often seen in Australian cases, and this may not be entirely explained by patients presenting earlier — Australian strains of M. ulcerans produce a slightly different form of the toxin mycolactone.3 Outbreaks of BU in Australia have tended to affect small towns, and patients are usually adults, including the elderly. In Africa, endemic areas are poor rural farming communities, and the average age of affected patients is 5–15 years.4 Although the mode of transmission of infection is still unknown, M. ulcerans has been found in environmental water and water insects, and the epidemiology in both Africa and Australia suggests that people become infected through contact with a contaminated environment rather than with infected people. Much recent research has focused on the role of mycolactone in pathogenesis, and it is clear from animal studies that most of the tissue destruction observed in human lesions is caused by diffusion of this highly toxic macrolide molecule from clusters of M. ulcerans organisms replicating in subcutaneous fatty tissue. This raises the possibility that killing the organism with antibiotics, or even suppressing its ability to produce toxin, may be adequate management. Traditionally, BU is managed by surgical excision of the lesion followed by primary closure or skin grafting. Until recently, antibiotics were thought to have little role in management, despite the fact that M. ulcerans is sensitive to a number of drugs, including rifampicin, aminoglycosides, macrolides and quinolones, in vitro.4 Studies have shown that a combination of rifampicin and an aminoglycoside given to mice with footpad or tail lesions both healed the lesions and prevented recurrences. The combination of rifampicin and moxifloxacin is also effective,5 as is rifampicin alone. However anti-biotic-resistant mutant strains of M. ulcerans can emerge when single-drug treatment is used.6 Findings in animals provide no guarantee of success in humans, but it has now been shown that a combination of rifampicin and streptomycin for a minimum of 4 weeks kills M. ulcerans in early human lesions,7 and longitudinal studies of this combination of antibiotics in all forms of the disease for 8 weeks in Benin, in western Africa, showed that 50% of lesions, including ulcers, healed without requiring surgery.8 Although these results are very encouraging and have led to many physicians in African countries where BU is endemic using antibiotics without recourse to surgery, there have been no controlled trials to validate the treatment. Equally, there are no controlled data on the use of antibiotics together with surgery. The rate of recurrence after surgery is dependent on the surgeon’s ability to guess the extent of infection from the appearance of the lesion, and polymerase chain reaction (PCR) testing of excised tissue has shown that infection extends well beyond the visible margins of disease.9 In this issue of the Journal, O’Brien and colleagues report their experience of managing BU with surgery, antibiotics or a combination of the two.10 The main findings from this restrospective, purely observational study were that antibiotics appeared to reduce the recurrence rate when M. ulcerans was detected in the margin of the excised lesion and when the lesion was large (meaning that skin grafting was needed). The choice of antibiotics was not planned in advance, and depended on the preference of individual clinicians, but rifampicin was included in the regimen for most patients. Interestingly, the recurrence rate in this study was 10% after antibiotic treatment for up to 3 months in patients who had all had their lesions surgically excised, while the recurrence rate after therapy with rifampicin and streptomycin for 2 months in 208 patients in Benin was less than 2% with or without surgery.8 The Australians did not use intramuscular streptomycin in their older group of patients, and found amikacin poorly tolerated. We do not know if their favoured combination of ciprofloxacin with rifampicin adds any bacterial killing benefit, or whether this combination is sufficient to prevent resistance emerging. In the context of a disease that is mainly a problem for children in rural parts of humid tropical Africa, it is no surprise that the approach to management is different in south-eastern Australia where surgery is easily accessible. There is no doubt that more children in Africa are receiving treatment and at an earlier stage of disease now that physicians are offering antibiotic therapy. The opportunity to have lesions excised is available to relatively few of these patients, and they typically present late with large ulcers, both for economic reasons (treatment has a major impact on a family’s finances) and because they fear surgery. Treating large numbers of patients in Benin and Ghana has shown that most lesions become culture-negative after treatment with rifampicin and streptomycin for 8 weeks, and they go on to heal during or after that time.8 The combination of two orally administered antibiotics with powerful bactericidal activity is the therapeutic goal at present, and surgical grafting should only be necessary to speed the healing of ulcers. More work is needed to develop an ideal treatment strategy, in both developing countries and more sophisticated medical settings. The suggested guidelines for diagnosis, treatment and control of M. ulcerans infection in Victoria in this issue of the Journal11 mark a significant step in developing standardised protocols for local use. Although individual doctors in Australia see relatively few cases, if a standard management protocol is followed, considerable experience will be amassed, which may guide future research. It would be useful, for example, to establish whether after treatment with rifampicin and moxifloxacin for 2 weeks before surgery, the excised tissue is culture-negative and the recurrence rate lower. Australians have made major contributions to understanding and diagnosing this disease, and another article in the Journal highlights the role of PCR testing,12 originally developed in Melbourne,13 in tracing the source of infection by means of a PCR-based DNA fingerprinting method. Several new pockets of infection have been identified worldwide in recent years, and while the causes of outbreaks remain obscure, PCR has been a key tool in tracing environmental sources of M. ulcerans, as well as in diagnosis, where it is not only the most sensitive method available (> 90%), but also quicker than all except microscopy for acid-fast bacilli (sensitivity < 50%).14 The challenges now are to make this technology accessible to African countries, and to develop simpler diagnostic tools.

Kingsley Asiedu MD, MPH · Mark Wansbrough-Jones MB BS, MSc, FRCP

Objective: To describe the effect of antibiotics on outcomes of treatment for Buruli or Bairnsdale ulcer (BU) in patients on the Bellarine Peninsula in south-eastern Australia.Design: Observational, non-randomised study with data collected prospectively or through medical record review.Patients and setting: All 40 patients with BU managed by staff of Barwon Health’s Geelong Hospital (a public, secondary-level hospital) between 1 January 1998 and 31 December 2004.Main outcome measures: Epidemiology, clinical presentation, diagnosis, treatment and clinical outcomes.Results: There were 59 treatment episodes; 29 involved surgery alone, 26 surgery plus antibiotics, and four antibiotics alone. Of 55 episodes where surgery was performed, minor surgery was required in 22, and major surgery in 33. Failure rates were 28% for surgery alone, and 19% for surgery plus antibiotics. Adjunctive antibiotic therapy was associated with increased treatment success for lesions with positive histological margins (P < 0.01), and lesions requiring major surgery for treatment of a first episode (P < 0.01). The combination of rifampicin and ciprofloxacin resulted in treatment success in eight of eight episodes, and no patients ceased therapy because of side effects with this regimen.Conclusions: Adjunctive antibiotic therapy may increase the effectiveness of BU surgical treatment, and this should be further assessed by larger randomised controlled trials. The combination of rifampicin and ciprofloxacin appears the most promising.

Daniel P O’Brien MB BS, FRACP · Andrew J Hughes MB BS, FRACP · Allen C Cheng MB BS, FRACP, PhD · Margaret J Henry BSc, PhD · Peter Callan MB BS, FRACS · Anthony McDonald MB BS, FRACS · Ian Holten MD, FRACS, FRCS · Mike Birrell MB BS · John M Sowerby MB BS · Paul D R Johnson MB BS, FRACP, PhD · Eugene Athan MB BS, FRACP

Mycobacterium ulcerans is a slow-growing environmental bacterium that causes Buruli ulcer (also known as Bairnsdale ulcer in Victoria and Daintree ulcer in northern Queensland). We describe two patients with laboratory-confirmed Buruli ulcer who were infected either in New South Wales or overseas. A molecular epidemiological investigation demonstrated that, while one case was probably acquired in Papua New Guinea, the other was most likely to have been acquired in southern NSW. To our knowledge, this is the first case of M. ulcerans infection acquired in NSW. Clinical recordsPatient 1A 50-year-old geologist was referred in April 2005 for assessment of chronic cellulitis and ulceration of the right hand, present for 11 weeks (Box 1). An intraoperative swab showed acid-fast bacilli on Ziehl–Neelsen staining. Buruli ulcer (Mycobacterium ulcerans infection) was confirmed by polymerase chain reaction (PCR) testing. Over the next 3 months, the patient received a combination of antibiotic and surgical therapy. At follow-up 1 week after ceasing antibiotic therapy (4 months after initial presentation), the skin graft had healed, and the patient remained well. The patient lived in rural New South Wales but had travelled to the Mornington Peninsula and East Gippsland regions of Victoria 5 years previously. Two weeks before the onset of illness, he had been fishing in the Snowy Mountains. He also made frequent work trips to Papua New Guinea, with seven trips in the 15 months before illness. His most recent trip there lasted 18 days, and he returned to Australia almost 12 weeks before the onset of infection. Variable number tandem repeat (VNTR) typing (Box 2) revealed that the isolate had the same profile as a previously described M. ulcerans strain from PNG, which differed from Victorian strains at loci 8 and 19.1 Similarly, the isolate had a restriction fragment length polymorphism (RFLP) band profile identical to that of the PNG strain, but differing from that of Victorian strains.2 These results suggest that the infection was acquired in PNG, not Australia. The minimum incubation period in this case was therefore 3 months. Patient 2The second patient was a 42-year-old Australian citizen usually resident in Holland. He presented in Melbourne in January 2006 with a skin ulcer over the left ankle (Box 1) which had been present for 5 months. Buruli ulcer had been correctly diagnosed in the Netherlands, and he had been treated with appropriate antibiotics for 6 weeks with no apparent response. The lesion was excised, a skin graft applied, and further antibiotic therapy given for 6 weeks, resulting in complete resolution. PCR testing performed on resection specimens from the ulcer was positive for M. ulcerans. The patient had travelled widely in Africa between 5 and 2 months before the appearance of the skin lesion; 7 months before its appearance, he had spent 2 weeks sea kayaking near Eden on the southern NSW coast. He had not visited Victoria for at least 10 years. M. ulcerans was not able to be cultured, so typing was performed on DNA extracted from the resection specimens. The two VNTR loci that discriminate between African and Victorian strains were examined.1 The estimated PCR product sizes of 420 base pairs (locus 4) and 650 base pairs (locus 8) were consistent with the Victorian profile.1 A second typing method, multilocus sequence typing, revealed that the patient’s strain lacked the C-to-T substitution in the sodA gene characteristic of African isolates.3 These data suggest that the infection was acquired in southern NSW and not Africa. The incubation period in this case was therefore about 7 months. DiscussionMycobacterium ulcerans infection was first described in patients in the Bairnsdale district of Victoria,4 where it was known as Bairnsdale ulcer. Since then, the disease has been recognised in Far North Queensland (known as Daintree ulcer),5 central coastal Queensland6 and the Northern Territory in Australia,7 and in as many as 30 other countries, including PNG and sub-Saharan Africa.8 In the past 15 years, significant clusters of cases have occurred on Phillip Island9 and the Mornington and Bellarine Peninsulas near Melbourne (Box 3). Despite this wide distribution, no cases have been reported previously from NSW, except in patients who were exposed during interstate or overseas travel.10 M. ulcerans is an environmental pathogen, which is transmitted by an unknown mechanismn to humans who enter endemic areas. Our patients had both travelled to several regions of Australia and overseas where Buruli ulcer occurs. Using a combination of conventional epidemiology and molecular typing, we determined the most likely geographic origin of transmission for each patient: PNG for Patient 1 and southern coastal NSW for Patient 2. The latter case represents the first strong evidence for Buruli ulcer having been acquired in NSW. However, there have been cases of Buruli ulcer from Mallacoota (unpublished data), a small town in eastern Victoria adjacent to the NSW border (Box 3). It is not surprising that M. ulcerans exists in coastal environments in southern NSW, just as it does in Victoria. The rarity of cases in NSW compared with Victoria remains unexplained. It is unlikely to result from failure to recognise previous cases in NSW, as the progressive nature of the infection means that most cases are eventually diagnosed. Australian primary care clinicians need to be aware that Buruli ulcer may occur in NSW, to ensure early diagnosis and treatment to minimise disability. 1 Lesions in Patient 1 (top) and Patient 2 (bottom) 2 What is variable number tandem repeat (VNTR) typing? VNTR typing is a DNA fingerprinting method based on polymerase chain reaction (PCR). The technique detects differences in the number of tandem repeat DNA sequences in specific regions of microbial genomes (known as VNTR loci). Strains of Mycobacterium ulcerans from different geographic regions can be reliably distinguished by VNTR typing.1 VNTR typing is usually performed on cultured isolates, but can be performed using DNA extracted directly from patient specimens. 3 Victoria and southern New South Wales showing relevant regions

Caroline J Lavender BA/BSc(Hons) · Sanjaya N Senanayake MAppEpid, FRACP · Janet A M Fyfe BSc(Hons), PhD · John A Buntine FRACS · Maria Globan BSc · Timothy P Stinear BSc(Hons), PhD · John A Hayman MD, FRCPA · Paul D R Johnson MB BS, PhD, FRACP (Infectious Diseases)

Mycobacterium ulcerans causes slowly progressive, destructive skin and soft tissue infections, known as Bairnsdale or Buruli ulcer (BU). Forty-six delegates with experience in the management of BU attended a 1-day conference in Melbourne on 10 February 2006, with the aim of developing a consensus approach to the diagnosis, treatment and control of BU. An initial draft document was extended and improved during a facilitated round table discussion. BU is an environmental infection that occurs in specific locations. The main risk factor for infection is contact with an endemic area. Prompt cleaning of abrasions sustained outdoors, wearing protective clothing, and avoiding mosquito bites may reduce an individual’s risk of infection. BU can be rapidly and accurately diagnosed by polymerase chain reaction testing of ulcer swabs or biopsies. Best outcomes are obtained when the diagnosis is made early. To aid early diagnosis, health authorities should keep local populations informed of new outbreaks. BU is best treated with surgical excision, which, if possible, should include a small rim of healthy tissue. For small lesions this may be all that is required. However, there is a role for antibiotics for more extensive disease, and their use may allow more conservative surgery.

on behalf of the Mycobacterium ulcerans Study Team*

Objective: To describe changes in the iodine status of Tasmanians following voluntary fortification of bread with iodine in October 2001.Design and setting: Post-intervention, cross-sectional urinary iodine surveys of Tasmanian schoolchildren aged 8–11 years were used to assess population iodine status. Participants were selected using a one-stage cluster sampling method. The sampling frame comprised classes containing fourth-grade children from all Tasmanian government, Catholic and independent schools. Results were compared with pre-intervention survey results.Main outcome measures: Median urinary iodine concentration (UIC) and percentage of UIC < 50 μg/L ascertained from spot urine samples.Results: Median UIC was 75 μg/L in 1998, 72 μg/L in 2000, 105 μg/L in 2003, 109 μg/L in 2004 and 105 μg/L in 2005. Median UIC in post-intervention years (2003–2005) was significantly higher than in pre-intervention years. The percentage of UIC results < 50 μg/L was 16.9% in 1998, 18.7% in 2000, 10.1% in 2003, 10.0% in 2004 and 10.5% in 2005.Conclusion: Despite methodological differences between the pre- and post-intervention surveys, switching to iodised salt in bread appears to have resulted in a significant improvement in iodine status in Tasmania. Given iodine deficiency has been identified in other parts of Australia and in New Zealand, mandatory iodine fortification of the food supply in both countries is worthy of consideration. As voluntary fortification relies on industry goodwill, mandating fortification could be expected to enhance population reach and give a greater guarantee of sustainability in Tasmania.

Judy A Seal MPH, AdvAPD · Zelda Doyle BSc(Hons), MSc(Epid) · John R Burgess MD, FRCAP · Roscoe Taylor MB BS, FAFPHM, GradDipEpid · Angus R Cameron BVSc, MVS, PhD

Objective: To determine the prevalence and content of policies, standardised order forms (SOFs) and patient information leaflets (PILs) pertaining to “not-for-resuscitation” (NFR) orders in Australian public hospitals.Design and setting: Cross-sectional postal survey conducted across Australia from August to December 2005, using a one-page questionnaire.Participants: Directors of Medical, Nursing or Clinical Services of all public hospitals in Australia with 60 or more beds, excluding psychiatric, military and private hospitals.Main outcome measures: Prevalence of documented NFR policies, by hospital characteristics, and content of these policies, SOFs and PILs.Results: 222 hospitals were surveyed, and 157 responded (71%). Of these, 85 (54%) had NFR policies, 62 (39%) had SOFs, and four (3%) had PILs. Hospitals with more than 200 beds were more likely to have NFR policies than those with 60–200 beds (P = 0.04). More metropolitan than rural hospitals had NFR policies (P = 0.01). More hospitals with 60–100 beds had SOFs than hospitals with 101–200 beds (P = 0.03). “NFR” was defined in 53% of policies, while 97% of policies explicitly stated where NFR orders were to be documented, 89% stated who was allowed to make them, 37% stated that advanced care directives (“living wills”) were to be respected, and 89% stated that competent patients should be involved in discussions regarding their NFR status. The most common items noted in SOFs were the name and signature of the issuing medical practitioner (92%) and documentation of the discussion with the patient (81%).Conclusions: There was wide variation in the content of hospital policies, SOFs and PILs pertaining to NFR orders. Aspects of current polices show room for improvement.

Navdeep S Sidhu MB ChB, PGCertHealSc(Resus) · Margaret E Dunkley MB BS · Melinda J Egan

Product information (PI) for thyroid-related medications endorsed by the Therapeutic Goods Administration, as reproduced in the commonly used compilation publications June 2006 MIMS (Monthly index of medical specialties) annual, MIMS Online and the Australian prescription products guide 2006, was evaluated to see whether it reflects contemporary therapeutic practice. Compared with current medical literature, these PI-based sources provide inadequate, inaccurate or outdated therapeutic directives. Examples include: Incorrect advice that thyroxine therapy should always begin at very low dosage. Failure to recommend increased thyroxine dosage early in pregnancy (thus placing the offspring of women being treated for hypothyroidism at risk of impaired fetal brain development). Incorrect and potentially unsafe advice to treat thyrotoxicosis with stable iodide in late pregnancy. Failure to advise serial adjustment of antithyroid drug dosage until after a patient becomes euthyroid (this can result in iatrogenic thyroid dysfunction). Outdated advice that antithyroid drugs are not compatible with breastfeeding. Recent initiatives to upgrade consumer medicine information (CMI) appear to accept PI-based sources as a reliable benchmark for CMI. That inference is not warranted for thyroid-related medications. Accountability for the updating of clinical information in PI needs to be defined, and the process for updating PI may need to be modified. Quality drug information, both PI and CMI, depends on fluent, evidence-based collaboration between suppliers, regulators, prescribers, specialist clinicians and consumers.

Jim R Stockigt MD, FRACP, FRCPA

Mishandled concerns about clinical standards resulted in whistleblowing in four Australian hospitals. Official inquiries followed with recommendations to improve patient safety. In the aftermath of the inquiries, common themes included loss of trust in management and among clinical colleagues, and loss of trust from patients and the community. Without first rebuilding trust, staff will not report mistakes or other concerns about safety. Successful implementation of patient safety procedures requires policies to stress the professional duty of staff to report concerns about colleagues when they believe there is a risk to patients.

James A Dunbar MD, FRCPEdin, FRACGP · Prasuna Reddy PhD · Bill Beresford FRACMA, FAFPHM, FRACGP · Wayne P Ramsey AM, MHA, FRACMA · Reginald S A Lord AM, MD, FRCS, FRACS

Chronic disease self-management education programs aim to empower patients through providing information and teaching skills and techniques to improve self-care and doctor–patient interaction, with the ultimate goal of improving quality of life. The recent 2006–07 federal budget allocated an unprecedented $515 million over 5 years for activation of patient self-management activities, commencing this financial year. Previous attempts in other countries to incorporate self-management education activities into the health care sector have faced setbacks because of inadequate integration into primary care. Engagement of health care professionals and their endorsement of self-management activities is critical to success.

Joanne E Jordan BSc, BA, MPH · Richard H Osborne DipApplBio, BSc, PhD

Health services research is important to ensure continued best quality of care, but often uses data obtained without explicit consent for this purpose. Obtaining consent may be difficult for many reasons, but excluding individuals may introduce biases that alter the significance of studies. Approval by ethics committees of a waiver of the need for consent allowed our study to proceed and provide evidence that has led to the implementation of a population-based screening policy for the prospective detection of hereditary non-polyposis colorectal cancer. This screening policy has resulted in more cases being detected routinely with better management for affected patients and their at-risk families. A need for consent would have prohibited this study, and the development of a more efficient screening policy could have been delayed for several more years. Ethics committees can effectively manage the need to uphold basic ethical principles without unnecessarily impeding socially useful research. Committees need to be familiar with the guidelines approved under sections 95 and 95A of the Privacy Act 1988 (Cwlth) in addition to the National Health and Medical Research Council National statement on ethical conduct in research involving humans.

Nikolajs Zeps PhD · Barry J Iacopetta PhD · Lyn Schofield MPH · Jillian M George BHealthSci, RN · Jack Goldblatt MB ChB, MD, FRACP

Over a 3-year period, seven patients who were taking HMG-CoA reductase inhibitors (statins) presented to our respiratory service with interstitial pneumonitis. Clinical course varied, with the condition responding to prednisolone treatment and cessation of statins in three patients, and progressing slowly despite this management in another three, while one patient died of associated cardiac disease. While a causative role cannot be confirmed, clinicians should be aware of the possible association. Two patients who presented with interstitial lung disease to our hospital’s respiratory service in 2000 prompted us to research a possible association between this disease and therapy with statins (hydroxymethylglutaryl-coenzyme A [HMG-CoA] reductase inhibitors). A literature review revealed several isolated cases of pneumonitis in the setting of statin therapy.1-3 Thereafter, we prospectively recorded patients referred to our unit who had interstitial lung disease and were undergoing statin therapy, where no other clear cause of the pneumonitis was evident. All cases have been reported to the Adverse Drug Reactions Advisory Committee. Clinical recordsBetween January 2000 and December 2003, our service saw 58 new presentations of interstitial lung disease, including the two patients discussed above. Data on these patients were retrieved from an ambulatory care database of newly presenting patients kept prospectively by our service. Their diagnoses are shown in Box 1. Eight cases were thought to be drug-associated: five of these were potentially linked to statin therapy, two to nitrofurantoin and one to amiodarone. Another two patients were referred to our service during hospital admissions in other specialties not included in our database. Details of these patients were retained from consultation records. Clinical details of the seven patients taking statin therapy are shown in Box 2. Most patients presented with dyspnoea and non-specific examination findings consistent with interstitial lung disease, such as bilateral crepitations on chest auscultation. None had clubbing. Some patients had a background of smoking and mild chronic obstructive airways disease, while others had no specific risk factors. Statins potentially implicated were atorva-statin (10–40 mg daily), pravastatin (40 mg daily) and simvastatin (10–40 mg daily). No patients were taking other medications known to be implicated in interstitial lung disease. Pneumonitis was diagnosed based on clinical assessment, along with demonstration of interstitial infiltrates on high-resolution computed tomography and reduced transfer factor for carbon monoxide diffusion on lung function testing (Box 3). Management comprised prednisolone or other immune-modifying treatment and/or withdrawal of the statin. In three patients treated with both prednisolone and statin withdrawal, pneumonitis decreased (Patients 3, 5 and 7). In another three, the condition progressed slowly: one of these (Patient 1) did not take prednisolone, and another (Patient 2) initially continued statin therapy and experienced respiratory failure necessitating home oxygen therapy before it was ceased. He died 18 months later of respiratory failure. The third (Patient 4) experienced slow progression despite statin withdrawal and treatment with prednisolone and azathioprine. The remaining patient (Patient 6) was treated with prednisolone but continued statin therapy, and died from coexisting cardiac disease, probably exacerbated by interstitial lung disease. DiscussionStatins are the most often prescribed class of medication for treating hypercholesterolaemia. They act primarily by inhibiting HMG-CoA reductase, thereby inhibiting cholesterol biosynthesis and improving lipid profiles. However, recent research has revealed multiple immunomodulatory, vascular endothelial, antioxidant and other effects of statins.4 These so-called “pleiotrophic” effects have led to statins being studied in a host of unrelated clinical settings, including osteoporosis, multiple sclerosis and Alzheimer’s disease. While research is ongoing, it appears that statins have profound multisystem effects that extend well beyond lipid metabolism. Statins are, on the whole, well tolerated, with the most commonly reported adverse effects being gastrointestinal upset, headache, rash and a dose-dependent elevation in serum levels of liver transaminases. The best characterised rare, but potentially serious, adverse effects are myopathy and polyneuropathy. These adverse effects are probably dose-related and may occur more often in patients taking medications known to inhibit statin metabolism.5 There are also a few reports of lupus-like syndromes, polymyositis/dermatomyositis with lung involvement, and hypersensitivity pneumonitis associated with statin therapy.1-3,6-9 The timing of onset appears unpredictable, with many patients having been taking statin therapy for many months or years before symptoms develop. Clinical features varied in severity from mild dry cough and rash through to severe and progressive respiratory failure. Low-titre antinuclear antibody (ANA) positivity and a raised erythrocyte sedimentation rate were also described in some patients. There are only four reports of open lung biopsy in these cases, two showing hypersensitivity pneumonitis with granuloma formation, one showing diffuse alveolar damage and the other showing non-specific interstitial pneumonitis. Most — but not all — patients responded to drug cessation and therapy with prednisolone or other potent immunosuppressive agents.2,8,9 Our patients shared many features with these patients. However, we did not observe rash of a dermatomyositic, lupoid or urticarial type, or lupus or polymyositis-like syndromes in our patients. Instead, all presented with respiratory symptoms — shortness of breath with or without dry cough — generally of insidious onset. Two out of six patients tested were positive for ANA with no other clinical features of connective tissue disease. The findings on transbronchial biopsy, when performed, were non-specific. Radiological appearances varied between alveolitis and fibrosis, but none showed the characteristic subpleural basal honeycombing that is common in usual interstitial pneumonia. The occurrence of alveolar eosinophilia in two out of the four patients who underwent bronchoalveolar lavage, which has previously been described in drug-hypersensitivity pneumonitis, and the response in several patients to drug cessation and/or corticosteroid therapy also point to a potential drug-induced pneumonitis. One previous case of pneumonitis has been reported in the setting of statin therapy, which was confirmed by open lung biopsy, and where the findings closely resembled those in amphiphilic drug toxicity, such as that reported with amiodarone. The authors hypothesised that a toxic mechanism, possibly mediated by statin effects on lipid metabolism, led to the observed intralysosomal lamellar inclusions in pneumocytes and interstitial cells.9 Thus, while not fully characterised, there is a putative mechanism through which statins may cause interstitial pneumonitis. Detecting rare side effects of commonly prescribed medications has always been a challenging task for the clinician. It is even more difficult when symptoms present insidiously, months or years after medication has been commenced, and the disease process has multiple potential aetiologies, which are not fully characterised. Similarly, interstitial lung disease remains a challenging diagnostic area even for experts in the field. Failure to recognise an under-lying cause of the pneumonitis often leads to the diagnosis of usual interstitial pneumonia being accepted. With continuation of the causative agent, the expected clinical pattern is progressive deterioration leading to respiratory failure and death, which also closely resembles the expected course of usual interstitial pneumonia. We hope that our description of our patients and review of the possible role of statins in interstitial lung disease will raise awareness of the potential association between statin therapy and this uncommon and often fatal condition. The effects of withdrawal of statin therapy on development of interstitial lung disease in patients taking this class of medication require further study. 1 New presentations of interstitial lung disease, 2000–2003 Diagnosis Number of patients Sarcoidosis 26 Usual interstitial pneumonitis 10 Non-specific interstitial pneumonitis 9 Drug-associated 8 Hypersensitivity pneumonitis 2 Asbestosis 2 Connective tissue disease-associated 1 2 Clinical details of seven patients with interstitial lung disease receiving statin (HMG-CoA reductase inhibitor) therapy Patient Sex, age Presentation Comorbidities Medications at presentation Investigations* Treatment Outcome 1 F, 78 Progressive dyspnoea, dry cough Hypertension, type 2 diabetes, hyperlipidaemia, non-smoker Atorvastatin (10 mg, 1 year), fosinopril, sertraline HRCT: extensive bilateral fibrosis TLCO: 46% No lavage or biopsy ANA-positive (1/40) Colchicine, atorvastatin withdrawn Slow progression: lung function deteriorated but clinical condition stable, little dyspnoea on 3-year follow-up 2 M, 78 Progressive dyspnoea (3 weeks), no cough or fever Chronic obstructive airways disease, IHD, atrial fibrillation, stroke, hyperlipidaemia, depression, ex-smoker Pravastatin (40 mg, 10 years), aspirin, frusemide, isosorbide mononitrate, perindopril, sertraline HRCT: extensive mid and upper zone emphysema, coarse bilateral basal fibrosis TLCO: 14%, mildly obstructed flow volume loop No lavage No biopsy (as poor respiratory reserve) ANA-positive (1/640) Prednisolone (50 mg), pravastatin withdrawn Progression, discharged with home oxygen, died 18 months later (respiratory failure) 3 F, 74 Cough and fever (3 days) (consistent with pneumonia) on background of worsening exertional dyspnoea Chronic obstructive airways disease, IHD, congestive cardiac failure, hyperlipidaemia, ex-smoker Simvastatin (10 mg for 2 years, then 20 mg for 1 year), aspirin, thyroxine, frusemide, diltiazem, nicorandil, long-acting nitrates HRCT: diffuse ground glass left upper lobe and bilateral lower zone No TLCO Lavage: 78% macrophages, 12% neutrophils, 9% lymphocytes Biopsy: non-specific interstitial pneumonitis No ANA test Prednisolone (50 mg), simvastatin withdrawn Gradual reduction in infiltrative change on imaging, lung function stable at 9-month follow-up 4 M, 83 Progressive dyspnoea (6 months) IHD, CABG and aortic valve replacement, atrial flutter, hyperlipidaemia, ex-smoker Pravastatin (40 mg, 1 year), aspirin, digoxin, frusemide, ramipril, ranitidine HRCT: scattered bilateral fibrosis TLCO: 33% Lavage: 68% neutrophils, 26% macrophages, 3% lymphocytes, 1% eosinophils Biopsy: non-diagnostic ANA-negative Prednisolone (40 mg), azathioprine, pravastatin withdrawn Slow progression 5 F, 67 Chronic mild dyspnoea (9 months), dry cough (6 months) Hyperlipidaemia, atypical chest pain, non-smoker Simvastatin (40 mg, 5 years), aspirin HRCT: patchy bilateral upper and lower zone ground glass TLCO: 22% No lavage or biopsy Negative for ANA, ANCA, normal ACE Prednisolone (25 mg, reduced to 10 mg after 3 months), simvastatin withdrawn Marked improvement (TLCO: 51% after 1 month, then 65% after 1 year) 6 M, 68 Progressive dyspnoea and hypoxia IHD, CABG and aortic valve replacement (10 years before), gastro-oesophageal reflux disease, hyperlipidaemia, ex-smoker Simvastatin (10 mg, 2 years), atenolol, candesartan, esomeprazole, frusemide, warfarin HRCT: bilateral fibrosis TLCO: 46%, mild restrictive defectLavage: 19% eosinophils, 19% neutrophils Biopsy: mixed inflammatory and fibrotic change ANA-negative Prednisolone (37.5 mg), azathioprine, simvastatin continued Progressive cardiac failure, died 9 months after presentation 7 M, 64 Progressive dyspnoea, dry cough IHD, CABG and aortic valve replacement (11 years before), peptic ulcer disease, hyperlipidaemia, ex-smoker Atorvastatin (20 mg for 3 years, then 40 mg for 2 years), fosinopril HRCT: bilateral ground glass infiltrates, fibrosis, some traction bronchiectasis TLCO: 44%, mildly obstructed flow volume loop Lavage: 38% eosinophils, 15% lymphocytes, 5% neutrophils Biopsy: thickened alveolar walls with interstitial fibrosis, minimal inflammation ANA-negative Prednisolone (initially 50 mg, then 10 mg maintenance), atorvastatin withdrawn Slight initial improvement (TLCO: 52% at 2-month follow-up), then stable disease HMG-CoA = hydroxymethylglutaryl-coenzyme A. IHD = ischaemic heart disease. CABG = coronary artery bypass graft surgery. HRCT = high-resolution computed tomography. TLCO = transfer factor for carbon monoxide diffusion. ANA = antinuclear antibody. ANCA = antineutrophil cytoplasmic antibody. ACE = angiotensin-converting enzyme. * All patients underwent HRCT and TLCO measurement, while most underwent bronchoscopy with broncho-alveolar lavage and transbronchial biopsy. 3 Investigations in two patients with interstitial lung disease High-resolution computed tomography in Patient 7 at presentation showed bilateral interstitial infiltrates with an area of honeycombing. Transbronchial biopsy specimen from Patient 7 showed a lymphocytic interstitial infiltrate and intra-alveolar macrophages (haematoxylin and eosin stain; original magnification, × 100). Transbronchial biopsy specimen from Patient 6 showed thickened alveolar walls with a low grade inflammatory infiltrate (haematoxylin and eosin stain; original magnification, × 400).

Tim Walker MB BS(Hons) · Joe McCaffery MB BS · Chris Steinfort FRACP

Radiograph showing diffuse dense pleural thickening encasing the left hemithorax, multiple metastatic nodules in the left lung, and a solitary deposit in the right mid zone. A 21-year-old man with a high-grade osteoblastic sarcoma of the tibia had a tumour resection and adjuvant chemotherapy. Eight months later, he became dyspnoeic and a radiograph showed a large left-sided pleural effusion and a nodule in the right mid zone. Calcified pleural metastases were confirmed on biopsy, and talc pleurodesis was performed. High-dose methotrexate was commenced, but 2 months later a chest radiograph showed marked calcification of the pleura and pulmonary metastases on the left side (Figure). The right pulmonary nodule had increased in size and the patient’s serum alkaline phosphatase level had risen to 4459 U/L (reference range, 30–130 U/L). A trial of ifosfamide transiently reduced the alkaline phosphatase level. The patient died 4 months later.

Georgina Long PhD, MB BS · Martin H Tattersall MD, MSc

To the Editor: We disagree with the recent recommendation of Graham and colleagues that all medical students should be offered BCG vaccination.1 In countries with a low prevalence of tuberculosis (TB), the side effects from the vaccine and losing the use of a Mantoux test to readily diagnose recent TB infection outweigh any benefits of a vaccine with relatively poor efficacy. The incidence of pulmonary TB in Australia is low (3.3 per 100 000 per year) and only 1.5% of isolates are multidrug-resistant.2,3 Thus, the likely exposure of medical students and doctors in Australia to pulmonary TB (let alone multidrug-resistant TB) will be low. In addition, most hospitalised patients with pulmonary TB would have been suspected of having TB before being sent to hospital, so adequate respiratory precautions should have been in place for most. This makes the risk of transmission to health care workers very small. Information from the Australian immunisation handbook is also very relevant to this debate.4 BCG can be effective, but mainly in preventing disseminated TB in children (> 80% efficacy). In adults, the overall protective efficacy is only about 50%,4 and the sole Australian study showed, at best, a protective efficacy of only 30%.5 The effect of BCG may not persist for more than 10 years but repeat vaccination is not recommended.4 Adverse events occur in about 5% of those vaccinated, with 2.5% being injection site abscesses and 1% lymphadenitis. About 1% of vaccinees may need medical attention as a result of the adverse event. Anaphylactoid reactions can occur, and keloid scarring can also occur (although rarely) at the injection site. The vaccine is “live”, and therefore contraindicated in anyone who might have HIV, other forms of immunosuppression, or generalised skin diseases.4 Graham and colleagues believe the problem of BCG vaccination interfering with the interpretation of Mantoux results can be overcome by using whole blood-based interferon assays, such as QuantiFERON-TB Gold, purportedly unaffected by BCG vaccination.1 However, the data for QuantiFERON-TB Gold need to be treated with some caution because it is a new test and there is no gold standard against which to compare it for diagnosing latent TB. The specificity of interferon assays in diagnosing latent TB has been estimated at 95% or more,6 but this will still result in a poor positive predictive value if the pretest probability of latent TB infection is low — and this is the case for health care workers in Australia. In summary, Australia is far more likely to protect its health care workers from TB through effective hospital infection control measures and migrant screening than through a vaccination program with a mediocre vaccine.

Sanjaya N Senanayake · Peter J Collignon

To the Editor: Graham and colleagues correctly assert that medical students are at increased risk of infection with Mycobacterium tuberculosis in settings where they are treating patient groups with a high prevalence of active pulmonary tuberculosis (TB).1 This is well illustrated by the increasing prevalence of latent TB infection among medical students in their later clinical years in countries where community TB incidence markedly exceeds that of Australia.2 Their case for a standard approach to screening of medical students at course entry has great merit, and their arguments in favour of using an interferon gamma release assay to screen for latent TB infection would bring Australia into line with current international best practice. However, the data presented do not substantiate a policy of offering BCG vaccination to all Australian medical students whose screening test result for latent TB infection, whether by interferon gamma or tuberculin skin testing (TST), is negative. Although BCG offers definite benefits in reducing the risk of life-threatening disseminated disease in children under 2 years of age, it does not offer dependable protection against pulmonary TB in adults.4 Medical students who are vaccinated with BCG may be lulled into a false sense of security, and neglect other more effective infection control measures that would reduce their risk of TB exposure and infection. Although BCG is a relatively safe vaccine, there is a small but well defined risk of local and systemic adverse events.5 We therefore support a standardised approach to screening medical students with TST or, preferably, interferon gamma at course entry and exit. Screening for latent TB infection should be offered whenever merited during the course of study, after exposure to active TB disease in Australia or abroad. The benefits of chemoprophylaxis on conversion outweigh the risks associated with isoniazid use, and the risks associated with BCG may not be acceptable where the risk of TB exposure for many Australian medical students is currently negligible.

David N Durrheim · Michael J Hensley

In reply: The intention of our article was to highlight inconsistent approaches to tuberculosis (TB) prevention in Australian medical schools and stimulate a new informed debate. We therefore welcome the responses from Senanayake and Collignon, and Durrheim and Hensley. Interference with interpretation of tuberculin skin testing (TST) is one argument cited against the use of BCG vaccination for health care workers. While we agree that the new blood-based tests need further evaluation, unlike TST, they are not affected by BCG because they employ TB-specific antigens. The lack of a gold standard for diagnosis of latent TB affects both TST and the blood-based tests. Recent reviews of these new tests have been favourable — including one that states that, compared with TST, these new assays seem to have “better correlation with surrogate measures of exposure to M. tuberculosis” and that “because of their higher specificity they may be helpful in low-prevalence, resource-rich settings where cross-reactivity due to BCG may pose difficulty in BCG interpretation”.1 In fact, this article summarised the specificity of these new tests as between 95% and 100%. Other authors found a specificity of 98.1%.2 We agree that infection control is crucial in preventing nosocomial TB transmission, but every infection control practitioner has seen patients with unrecognised TB admitted to an open ward. One missed patient can mean contact-tracing and testing of dozens of staff. The Melbourne Mantoux study (involving 14 Melbourne hospitals) found that health care work and years of hospital employment were significantly associated with a positive Mantoux result — indicating the risk to Australian health care workers is not “negligible” as Durrheim and Hensley state. Nosocomial outbreaks of TB are well documented in low-prevalence countries.1,3 BCG is by no means a perfect vaccine. However, while BCG efficacy was once thought to only last 10 years, a recent large study suggested that it persists for 50–60 years,4 and there is new evidence that BCG vaccination may prevent some primary infections.5 While the risk of health care-associated tuberculosis in Australia is currently low, it would be unwise to assume this will remain the case, or that doctors will only work in safe environments. What will be the effects of HIV, further immigration from high-risk countries, drug resistance and the increasing use of immunosuppressant medications on the incidence of TB? We stand by the recommendations in our article, although we acknowledge they are controversial. There should, however, be no controversy about the need for a consistent policy concerning TB prevention in our medical schools.

Maryza Graham · Tanya M Howley · Robert J Pierce · Paul D R Johnson

To the Editor: In a recent observational study, Krum et al concluded that the treatment of heart failure after myocardial infarction in Australian teaching hospitals is suboptimal because angiotensin-converting enzyme (ACE) inhibitors, β-blockers and aldosterone antagonists are underutilised.1 We believe that another explanation, mentioned by the study’s authors, is worth exploring further — for valid clinical reasons, it was not appropriate for certain patients to start or continue taking some of these medications. An understanding of the enrolment criteria of relevant clinical trials is informative. The large, long-term ACE inhibitor trials quoted by Krum et al — SAVE,2 TRACE and AIRE4 — between them screened 34 037 patients with myocardial infarction and left ventricular dysfunction. Only 5986 patients (18%) met the inclusion/exclusion criteria to be enrolled in one of the trials. Unfortunately, the CAPRICORN5 (β-blocker) and EPHESUS (aldosterone antagonist) trials did not publish the number of patients screened versus the number randomised, but a glance at their exclusion criteria explains why, for some patients, it may not have been appropriate to start these medications during their hospital stay. Some of the exclusion criteria for CAPRICORN were: unstable angina, ongoing therapy with antiarrhythmics (except amiodarone), secondary or tertiary heart block or sick sinus syndrome unless paced, uncontrolled hypertension (> 160/95 mmHg), bradycardia (heart rate, < 60 beats/min), hypotension (systolic blood pressure, < 80 mmHg), requirement for intravenous diuretics or inotropes, chronic obstructive pulmonary disease with ongoing inhaled β2-agonist or steroid therapy, and unstable insulin-dependent diabetes. Is there any harm in prescribing outside the inclusion/exclusion criteria for clinical trials? A population-based, time-series analysis linking prescription-claims data and hospital admission records of 1.3 million adults in Canada6 showed that hyperkalaemia-related deaths in hospital doubled after the RALES trial (spironolactone) was published in 1999. There was no reduction in re-hospitalisation for heart failure or all-cause mortality. The authors speculated that part of the reason for this was prescription of spironolactone to patients who would have been excluded from the RALES trial. While we would not advocate prescribing strictly within the boundaries of the inclusion/exclusion criteria of clinical trials, it is important to understand these criteria, so that prescribing in “real world” patients is done with care. We are reassured that Krum et al’s study suggests there is discretion in the prescribing of drug therapy. Presumably, during ongoing medical assessment, it will be appropriate for some patients to commence some of these medications (potential benefit outweighs potential harm), while others may need to have their medications reviewed because of adverse events.

Lauren J Bailey · Vasi Naganathan

In reply: We thank Bailey and Naganathan for their thoughtful viewpoint regarding prescribing according to clinical trial criteria. We agree that prescribing in the real world often involves complex decision making, taking into account age, comorbidities, concomitant medications and other factors, whereby guidance regarding individual patients cannot readily be extracted from clinical trial literature. This may certainly contribute to underutilisation of evidence-based drug treatment.1 Nevertheless, several analyses support the contention that physicians who more closely adhere to evidence-based guidelines (which in turn are derived from randomised clinical trials) produce better outcomes for their patients.2,3 Therefore, we would still advocate prescribing as closely as possible to guideline recommendations, while acknowledging that these recommendations may not always be readily applicable to every patient.

Henry Krum

To the Editor: The guidelines for managing acute coronary syndromes, published in a supplement to the Journal in 2006, provide a readily accessible tool for clinicians to enhance patient care.1 However, unfortunately the recommendations concerning adjunctive anticoagulation in patients with acute coronary syndromes (ACS) are suboptimal. The 2006 guidelines recommend that high-risk patients with non-ST-segment-elevation ACS should be treated with aggressive medical management, including unfractionated heparin or the low molecular weight heparin (LMWH) enoxaparin, based on evidence from randomised trials showing that these agents reduce the risk of non-fatal myocardial infarction (MI).1 However, neither unfractionated heparin nor enoxaparin have been shown to reduce mortality in patients with non-ST-segment-elevation ACS, even when compared against placebo, and enoxaparin increases the risk of bleeding when compared with unfractionated heparin.2-4 By contrast, the OASIS-5 study, presented at the European Society of Cardiology Meeting in September 2005 and published in early 2006, showed that fondaparinux (a pentasaccharide inhibitor of factor Xa) compared with enoxaparin reduced death and stroke rates, and reduced the risk of bleeding by one half.5 Updating the recommendation so that enoxaparin was replaced with fondaparinux for patients with non-ST-segment-elevation ACS would save six Australian lives at 30 days for every 1000 patients treated, and would cause 19 fewer bleeds. The recommendations of the 2006 ACS guidelines concerning the management of patients with ST-segment-elevation MI are similarly suboptimal. There are now convincing data from randomised trials that enoxaparin is more effective than unfractionated heparin for preventing recurrent MI in patients with ST-segment-elevation MI who have been treated with fibrinolytic therapy.4,6 However, as in the case with non-ST-segment-elevation ACS, enoxaparin has never been shown to reduce mortality in ST-segment-elevation MI. By contrast, both the LMWH reviparin, and fondaparinux, reduce mortality,7,8 and fondaparinux does so without increasing the risk of bleeding.8 We appreciate that rapid advances in the management of ACS make it increasingly difficult for evidence-based guidelines to reflect the best evidence from clinical trials. However, when new evidence becomes available that is clinically relevant at the individual and population level, we believe the guidelines working group and the Journal have a responsibility to update the readers.

John W Eikelboom · Graeme J Hankey · Paul E Langton

In reply: We thank Eikelboom et al for presenting new data on acute coronary syndrome (ACS) management. In this field of rapid advances, another recent study, ACUITY, has also been published, which examined bivalirudin in ACS.1 The Australian guidelines2 are based on peer reviewed published reports, and neither OASIS-53 nor ACUITY1 were released at the conclusion of the formulation of the guidelines. Also, fondaparinux is only available on the Pharmaceutical Benefits Scheme (PBS) in Australia for thromboembolic prophylaxis, and bivalirudin is currently only approved by the PBS for therapy during percutaneous coronary interventions. The Australian guidelines are consistent with international guidelines for both unfractionated heparin and low molecular weight heparin considered as Grade A recommendations for treating non-ST-segment-elevation ACS, based on Level 1 evidence (American College of Cardiology/American Heart Association guidelines). For example, the FRISC trial showed a significant reduction in mortality and myocardial infarction with dalteparin (compared with placebo; 1.8% v 4.8%; P = 0.001) at 6 days, which persisted at 40 days.4 The Australian ACS guidelines are a living document, and new evidence, such as the OASIS-5 (fondaparinux)3 and ACUITY (bivalirudin)1 findings, will be considered on their relative merits in future updates of the guidelines (available on the National Heart Foundation Australia website at http://www.heartfoundation.com.au).

Constantine N Aroney · Philip Aylward

To the Editor: A seminal 1997 article by Fine et al described the pneumonia severity score from the Pneumonia Patient Outcomes Research Team study and raised the role for Hospital in the Home (HIH): For the remaining patients in [risk] classes II and III for whom treatment at home with oral antimicrobial therapy is judged to be unsuitable, there are alternatives to traditional inpatient care. These include parenteral antimicrobial therapy at home or a short stay . . . in a hospital observation unit.1 A recent article in the Journal by Charles et al2 omitted a role for HIH in managing community-acquired pneumonia (CAP). Where their protocol mentions outpatient care, readers are led to interpret this as oral therapy only, managed by a general practitioner. Similarly, it is implied that inpatient therapy relates to traditional treatment in a hospital ward. No further clarification is given. This is a surprising omission, given that one of the authors has written extensively in support of HIH in the past.3 HIH administers hospital-level therapy (intravenous antibiotics, oximetry, rehydration, medical and nursing attendance, with 24-hour cover) to a clinical subgroup of CAP patients who can be defined and included within any protocol. Evidence suggests that HIH can offer effective and safe treatment of patients with acute CAP referred directly from hospital emergency departments after diagnosis.4-6 Many patients with pneumonia appreciate the option of well organised, acute, home-based care. An important and growing subgroup of patients living in residential nursing care facilities can also receive acute CAP treatment in facilities with HIH involvement.7 A significant proportion of patients receiving HIH care have failed oral therapy.4-7 Why the omission of HIH? Protocols are tools of influence to be tussled over. This sometimes conflicts with their general aim of organising science into process and progress. Fine and colleagues’ intent in investigating the use of pneumonia severity scores was to help address the question of where and how to treat acute pneumonia. One of the aims of developing scores was to broaden the treatment options, not to narrow them.

Michael Montalto

To the Editor: The recent editorial on community-acquired pneumonia (CAP) stated that “even in an era in which penicillin resistance appears to be increasing among some Streptococcus pneumoniae isolates, there have been no documented failures of high-dose penicillin in treating pneumococcal pneumonia or bacteraemia”.1 The medical literature suggests otherwise. Firstly, North American guidelines do not mention penicillin at all, and, in one analysis of 25 996 hospitalised patients who received monotherapy, mortality was about 50% higher with penicillin monotherapy than with monotherapy with ceftriaxone, another cephalosporin, a macrolide or a quinolone.2 More importantly, however, the same study found that the mortality rate in patients (even low-risk patients) treated with two antibiotics, one of which was a macrolide, was half the mortality rate of patients treated with one antibiotic. Dual therapies used were a macrolide agent in combination with ceftriaxone, another cephalosporin, a penicillin or a quinolone. Best outcomes were achieved with a ceftriaxone–macrolide combination. In a review of seven studies, Waterer3 found that patients with severe pneumococcal pneumonia or bacteraemic pneumococcal disease who were treated with two antibiotics had a significantly lower mortality rate than patients treated with a single antibiotic. This was despite the fact that the patients treated with a single antibiotic were not as ill initially as those treated with two antibiotics. Research by Waterer and colleagues4 showed that the benefit of taking two antibiotics was most apparent in the highest risk hospitalised patients, in whom mortality was five times higher in those receiving one antibiotic than in those receiving two. Thus, it is imperative that all patients with severe pneumococcal CAP be treated with two antibiotics, one of which should be a macrolide.

Patrick J Bradley

In reply: Whether Hospital in the Home (HIH) care is suitable for managing patients with community-acquired pneumonia (CAP) depends on what is considered an appropriate use of resources. Overall, we see relatively few indications for treating CAP patients with parenteral antibiotics via HIH, as, in our experience, most patients who do not need supplemental oxygen and are well enough to be treated at home are usually also well enough to be treated with oral antibiotics. If they are not well enough to take oral antibiotics, then admission to hospital as an inpatient is generally appropriate. The occasional exceptions to this are selected patients in nursing homes (where around-the-clock supervision is available if required) and some patients with CAP caused by pathogens like Pseudomonas or Acinetobacter who benefit from longer treatment courses and may not have the option of oral antibiotics. Furthermore, a report submitted to the Victorian Department of Human Services regarding HIH care of CAP patients at a number of Melbourne HIH units identified significantly worse outcomes at some centres, mainly related to inappropriate patient selection. Notable, but fortunately rare, cases included some patients with pulmonary embolism incorrectly diagnosed as CAP. Given that between 20% and 50% of patients given a diagnosis of CAP in the emergency department do not have pneumonia confirmed by a radiologist,1-3 the ability of busy emergency department doctors to select patients appropriately is definitely a concern. Thus, HIH treatment of CAP patients may be appropriate occasionally, but very careful patient selection is vital. In response to Bradley, the statement that there have not been any failures in treating pneumococcal CAP with penicillins refers to microbiological failures due to antibiotic resistance. Although several studies have suggested that combination therapy may reduce mortality from bacteraemic pneumoccocal infections, all of these have been retrospective observational studies. Thus, they lack the ability to control accurately for potential confounding variables such as disease severity, patient or family wishes, pre-morbid quality of life, or “not for resuscitation” status. Data are also lacking on co-infection with “atypical” pathogens such as Legionella. The immunomodulatory effects of macrolides, quinolones and tetracyclines on treatment response are also still being elucidated.4 We agree with the CAP treatment recommendations in the Australian antibiotic guidelines,5 which recommend dual therapy with a β-lactam antiobiotic plus either a macrolide or doxycycline for all patients who are not allergic to these drugs.

Patrick G P Charles · Paul D R Johnson · M Lindsay Grayson

To the Editor: The article by Jordan and Osborne1 highlights some of the key issues to be addressed if chronic disease self-management programs are going to be effectively incorporated into the Australian health care system, particularly in primary care. Although the National Chronic Disease Strategy2 recommends that self-management programs be integrated and supported at all entry points into the health care system, many of the self-management strategies and programs have been developed with little engagement of general practitioners and have not been integral components of primary health care. Jordan and Osborne highlight that, without the support of GPs, programs such as the Expert Patients Programme3 may have limited success. We recently completed a systematic review for the Australian Primary Health Care Research Institute to explore the evidence for managing chronic disease in primary care, with specific reference to the Australian health care system.4 The self-management programs found to be most effective were those that developed self-efficacy in relation to specific behaviours, such as diet and exercise for diabetes, rather than those that were more general. The combination of self-management support with delivery system design changes (such as multidisciplinary team care and follow-up) was effective in improving patient health outcomes for a number of chronic diseases. This highlights an important and developing role for practice nurses in chronic disease management. Given the burden of chronic disease in Indigenous populations, it is important to conduct more research on the role of self-management education and support in Indigenous communities, as there were few relevant studies identified in our systematic review. The funding available through the Australian Better Health Initiative5 will enable primary health care professionals, such as GPs and practice nurses, to receive self-management education training. Furthermore, to ensure that self-management support is embedded in primary care, we suggest that self-management support be included in care plans or annual cycles of care for conditions such as diabetes. Self-management support could also be incorporated into allied health services that are provided as part of a care plan.

Sarah M Dennis · Nicholas A Zwar · Iqbal Hasan · Mark F Harris

Sleep disorders: a clinical textbook. Antonio Ambrogetti, Michael J Hensley, Leslie G Olson, editors. London: Quay Books, 2006 (xiii + 561 pp). ISBN 1 85642 237 2 The Australian sleep disorders community has contributed disproportionately to the world body of knowledge about the science and measurement of sleep, and the treatment of sleep disordered breathing, including non-respiratory aspects. Ambrogetti, Hensley, and Olson have produced a comprehensive yet very readable clinical textbook with significant contributions from many Australian authors, who also carry international reputations. At over 500 pages, in contrast to its daunting look, this book is eminently readable, aimed at anyone interested in sleep medicine. The first main component looks at the scientific knowledge of sleep, including neuroana-tomy and chronobiology, followed by the clinical application of sleep medicine, with a grounding in the basics of polysomnography. The second component is a tour through the clinical treatments of sleep disordered breathing, with interesting chapters on sleep disorders in children, medications, and ventilation. The book is very well set out, with numerous break-out boxes highlighting important messages, illustrations and case discussions. The chapters and topics are well marked and easily accessed, and there are appendices with explanations and resource materials. Interesting areas explored include sleep and other conditions such as pregnancy, and various common medications used for depression and anxiety. The development of sleep in children, and abnormalities, are well represented. Useful as a reference book or as an introduction for those interested in sleep medicine, this is a comprehensive, basic clinical textbook without the daunting content of commonly quoted reference books. It could easily be picked up by medical students and trainees in sleep medicine, and would sit well in a sleep clinic or laboratory, as a good example of the depth of Australian expertise in this area.

Peter Solin

Introduction to telemedicine. 2nd ed. Richard Wootton, John Craig, Victor Patterson, editors. London: Royal Society of Medicine Press, 2006 (xii + 206 pp). ISBN 1 85315 677 9. Telemedicine is a health service intervention involving the remote communication of information for clinical care. Now in its second edition, this revised text meets a growing need for a straightforward overview of telemedicine. Rather than presenting telemedicine as the application of a specific technology, the authors are explicit about the health service dimension, the types of services, and the building blocks required — indeed most useful for an audience of health care workers considering telemedicine. The structure of the first edition has been maintained. Each chapter comes from well known practitioners of the discipline, and the editors have done an excellent job of linking all the material within the text. Telemedicine set-ups for a range of clinical settings are well illustrated. The need for a practical problem-driven approach to implementing telemedicine is a common thread. In this respect, the book is balanced in its assessment of telemedicine. In keeping with the initial chapters (with detailed steps for designing a service and the barriers to implementation), readers would have been greatly assisted by a list of evaluation questions for each stage of implementation and the key questions for developing a mature, sustainable service. As the book itself acknowledges, the patchy diffusion of telemedicine is not well understood. Perhaps one area that could have been explored further is the sociotechnical dimension of information and communications interventions pertaining to the social and organisational issues which determine success. This is no criticism of the book but rather the discipline itself, which is still not mature enough to provide evidence about which particular models of telemedicine work in specific settings and why. Introduction to telemedicine does, however, do what it sets out to do. It is pragmatic and even-handed, and the reader comes away with an appreciation of the realities of integrating telemedicine with routine care.

Farah Magrabi

After abuse. Gita Mammen. Melbourne: ACER Press, 2006 (ix + 139 pp). ISBN 0 86431 405 1. I wish this book had been available when I went to work in a women’s health centre over 20 years ago. Then, I was taken aback to discover how often the experience of childhood sexual abuse underlay many patient presentations. Gita Mammen, a psychiatrist and psychotherapist with a wealth of experience, shares with us her calm, compassionate and elegant approach to working with adult survivors of abuse. Written mainly for primary care counsellors, it is also relevant for general practitioners and specialists. The book is clearly structured, providing an understanding of the social context of abuse and abuse-specific work. Mammen provides insight into the way survivors may present — very useful for the new practitioner and the practitioner who does not yet recognise those survivors among their patients. Her framework emphasises the need to develop a respectful partnership with the client or patient, and she gives careful advice on how to enable a therapeutic relationship. This includes the importance of understanding the dynamics of childhood trauma and how this shapes a person’s current life-coping skills. She outlines a holistic assessment process, best suited to those with long appointments, but still useful within a general practice context. Mammen provides enlightening vignettes to illustrate key points, demonstrating a skilful form of questioning both respectful and supportive of the patient. The book is well laid out and each chapter provides summary boxes of key points, which I found very handy. I would have liked a little more on dealing with patients with somatising disorders and the controversial borderline personality disorder, but I appreciate that this was beyond the parameters of the book. The discussion on memory was similarly tantalising and had me wishing for more. I liked the way Mammen included the focus on balance in regard to therapy and for workers. Her awareness of interpersonal dynamics and her sage advice on avoiding some resultant problems could have saved me from making some beginner’s mistakes 20 years ago. I will read this book again and again.

Lesley R Shorne

Babies after breast cancer After a diagnosis of breast cancer, women are often advised to wait 2 years before attempting to fall pregnant. Now, Australian researchers say that women with localised disease (and who have completed their treatment) need not wait the full 2 years. Ives and colleagues studied pregnancy and survival outcomes in 2539 younger women in Western Australia diagnosed with breast cancer between 1982 and 2000. About 5% of the women had at least one pregnancy after breast cancer, with half conceiving within 2 years of their cancer diagnosis. The researchers reported that the women who conceived had improved survival compared with those who had not conceived, with a definite protective effect for women who waited at least 6 months. BMJ Online, 8 Dec 2006 Botch-up A case of potentially fatal paralytic botulism can hardly be what patients are expecting after receiving intramuscular injections of botulinum toxin for crow’s feet and other facial lines; however, that is exactly what happened to four people. They were administered much more than the estimated human lethal dose of the toxin, due to a dilution error of a preparation of the toxin intended for laboratory research only and never intended or approved for human use. All survived after receiving antitoxin, but not without prolonged mechanical ventilation. One of the four was a doctor (with an already suspended medical licence) who had injected himself as well as the other three people. He was sentenced to 3 years in prison after pleading guilty to a US federal criminal charge of misbranding a drug. JAMA 2006; 296: 2476-2479 Unexpected aneurysms Coronary aneurysms can occur after the use of drug-eluting stents, warn US authors. They reported four cases in which a coronary aneurysm was discovered 6 to 21 months after implantation of either a sirolimus-eluting or paclitaxel-eluting stent. The authors suggest localised hypersensitivity to these stents may be responsible for aneurysm formation. Management of the cases varied from observation to percutaneous coiling to surgical excision with a bypass graft to the distal artery. In one case, nearly complete resolution of the aneurysm had been observed. Ann Intern Med Online, 5 Dec 2006 Sports deafness Attending sporting events can be hazardous to your hearing, caution Canadian authors. One of the authors had worn a noise dosimeter to a series of ice hockey games. While goal-scoring led to spikes in the noise level (roughly equivalent to that of a jet plane taking off), even during intermissions the noise level was such that hearing protection would be required by law if the sporting arena had been an 8-hour day work environment. Hearing tests before and after a game confirmed a temporary deterioration in hearing consistent with noise damage and with an attendant risk of permanent damage if there had been further noise exposure before full recovery. The authors suggested that spectators wear earplugs to protect their hearing — also pointing out that, contrary to popular belief, communication in noisy environments is easier with, rather than without, earplugs. CMAJ 2006; 175: 1541-1542 Diagnosis by Google In difficult diagnostic cases, it may be useful to “google for a diagnosis”, suggest Australian authors. Tang and Ng used Google searches to reveal the correct diagnosis in 15 of 26 diagnostic cases published in the New England Journal of Medicine in 2005. For each case they chose three to five search terms (while blind to the diagnosis) and then, from search results, selected the three most prominent diagnoses that seemed to fit the signs and symptoms described. Tang and Ng suspect that using Google to search for a diagnosis will be more effective for conditions with unique symptoms and signs, and less effective for complex diseases with non-specific symptoms and for rare presentations of common diseases. BMJ 2006; 333: 1143-1145 Much more than a load of Hogwarts? Good Samaritan laws protect doctors who give assistance in medical emergencies — but what about the doctor who spots a less threatening yet nevertheless important diagnosis in someone on the street? Here, the situation is murkier. Should we speak — and risk being charged with invasion of privacy or being an ambulance-chaser-of-sorts — or should we walk away? Lim and colleagues used magical examples from the fictional world of You-Know-Who (think Harry Potter) to demonstrate how “uninvited” medical interventions, if beneficent in intent, can, they say, only result in good outcomes. Such acts would seem to be in keeping with the spirit of Good Samaritan clauses. Thus, “To all of you, we say: go forth and do good!” they enjoin us. CMAJ 2006; 175: 1557-1559

Ann Gregory