Volume 176 Issue 11

Infectious diseases physicians, clinical microbiologists and hospital pharmacists tend to have a love–hate relationship with the antibiotic ceftriaxone and its stablemate cefotaxime. These potent third-generation cephalosporins have an important place in every Australian hospital formulary, and boast numerous entries in the current edition of Therapeutic guidelines: antibiotic (AG).1 Third-generation cephalosporins (3GCs) are the antibiotics of choice for several life-threatening infections including bacterial meningitis. They are convenient to administer and are among the safest antibiotics available. Yet, these drugs have become the bête noire of hospital epidemiologists. So, what's the problem? The problem is the increasing burden of resistant bacteria arising from the constant selective pressure exerted by our extensive use of antibiotics, especially very broad-spectrum agents such as 3GCs. Cefotaxime and ceftriaxone are now known to be associated with the emergence of vancomycin-resistant enterococci, resistant gram-negative bacteria, and Clostridium difficile-associated diarrhoea.2-6 They also likely contribute to the emergence of resistant pneumococcus and the ongoing spread of methicillin-resistant Staphylococcus aureus (MRSA).7,8 Third-generation cephalosporins are active against a wide range of gram-positive and gram-negative bacteria and have the added advantage that they penetrate into cerebrospinal fluid and other normally sterile sites, enabling a number of invasive infections to be treated. However, they have only limited activity against anaerobes and staphylococci and are inactive against MRSA. They are also inactive against Pseudomonas, Listeria, and enterococci — all causes of potentially life-threatening infections in immunocompromised patients. In Australia, we have an antibiotic guidelines handbook that is clear, concise, accurate, extensively peer-reviewed, regularly updated, and, from my own experience, extremely useful! Yet, in this issue of the Journal, Robertson and colleagues (page 524)9 have identified a widespread prescribing problem — and one that probably extends far beyond 3GCs. In a study involving most Victorian hospitals, they found extensive inappropriate use of cefotaxime and ceftriaxone. Three areas of prescribing deserve particular mention. About half of all use of these antibiotics involved empiric treatment of respiratory tract infections, and over three-quarters of these courses were not in concordance with the then current edition of AG. This is despite the fact that simpler regimens are likely to be at least as effective.10 The two other key problem areas found by the authors were inappropriate use for surgical prophylaxis and for treatment of skin and soft tissue infections. As Robertson and colleagues state, improving concordance in surgical prophylaxis should be readily amenable to intervention by withdrawing 3GCs from operating theatres. However, improving concordance in empiric therapy of respiratory and skin and soft tissue infections will require a truly concerted educational effort. A perusal of the current edition of AG1 reveals that 3GCs don't rate a mention in the first-line regimens for empiric treatment of many common infections in non-penicillin-allergic patients. They are not included in any of the first-line regimens for community-acquired or hospital-acquired pneumonia, and not included at all for the treatment of cellulitis or erysipelas or postoperative wound infections. They have virtually no role in surgical wound infection prophylaxis. Clearly, there is discordance between guidelines and practice. After 11 editions of AG in Australia, what more can be done to curb the high rate of inappropriate use of important antibiotics? The United States Centers for Disease Control and Prevention recently highlighted 12 clinicians' "action steps" for preventing antimicrobial resistance in hospitals (Box).11 Improved implementation of clinical guidelines is implicit in these steps. Although the steps highlight inter alia the role of vancomycin in the emergence of antimicrobial resistance, similar recommendations could be applied to 3GCs. Implementation of guidelines must be multifaceted and preferably supported by published evidence.12 In Australia, we must first ensure there is comprehensive and practical access to endorsed guidelines among Australian doctors. No recent surveys of access to AG have been conducted, but they appear to be widely available — almost 20 000 copies of the current edition have been sold to date (Mary Hemming, Chief Executive Officer, Therapeutic Guidelines Limited, personal communication). The Australian medicines handbook13 is also a valuable emerging resource now in its third edition. Given that many of the concordance issues highlighted by Robertson and colleagues also apply to other areas of prescribing, universal access to a range of appropriate prescribing guidelines is an essential and logical complement to the training and continuing education of all doctors in Australia. At the very least, 24-hour paper and electronic access to appropriate guidelines should be available to every public hospital doctor and medical student. Personal digital assistants are also emerging as a major practical platform that should expand access to clinical reference programs.14 Improved and adequate access to clinical guidelines is, however, only the first step to control of inappropriate use of 3GCs. Adherence to guidelines requires the support and endorsement of opinion leaders and medical educators and, in particular, obliges senior clinicians to set an example through sensible prescribing. Pharmacists should be given a greater educational role in both hospital and community practice through academic detailing, surveillance of prescribing patterns, feedback to doctors, participation in clinical decision making, and provision of relevant guidelines to specific clinical groups. Most hospital drug committees attempt to adapt generic guidelines to local conditions, which generally involves imposing restrictions on the prescribing of 3GCs and other broad-spectrum antibiotics. Their efforts are supported by the many studies that attest to reductions in the incidence of resistant bacteria and C. difficile following institution of programs to reduce use of 3GCs.8,15,16 Drug committees also have an important role in monitoring the influence of pharmaceutical industry promotions on local prescribing practice. Recent advances in medical informatics herald exciting new approaches to prescribing in Australia over the forthcoming decade. A range of opportunities is emerging for computerised integration of prescribing guidelines with clinical decision making. Although the main aims are to prevent errors, improve quality of care and reduce costs,17 there is obvious opportunity for benefit at the community level by reducing the burden of resistant bacteria through appropriate prescribing of antibiotics. Many general practitioners in Australia are already using integrated electronic prescribing programs such as Medical Director (Healthcare Portal) and pathology reports have become integrated with prescribing guidelines. The major challenge now is applying computerised prescribing decision-support programs for real-time guideline implementation in hospital wards and emergency departments.18,19 Their application to desktop computers is certainly feasible. Their application to personal digital assistants as a real-time, remote, wide-area data-access and decision-support device is an evolving challenge that will require a major change in the way we approach drug prescribing in hospitals. The report by Robertson and colleagues is not only a timely reminder of the importance of regular evaluation of drug use, but should also inspire us to seek and embrace opportunities to improve antibiotic prescribing in this country. Twelve "action steps" for preventing antimicrobial resistance in hospitals Step 1: Vaccinate — get influenza vaccine; give influenza and Streptococcus pneumoniae vaccine to at-risk patients before discharge. Step 2: Get the catheters out — use catheters only when essential; remove catheters when no longer essential. Step 3: Target the pathogen — grow cultures from the patient; target empiric therapy to likely pathogens; target definitive therapy to known pathogens. Step 4: Consult the experts — consult infectious diseases experts for patients with serious infections. Step 5: Practice antimicrobial control — engage in local antimicrobial control efforts. Step 6: Use local data — know your antibiogram. Step 7: Treat infection, not contamination. Step 8: Treat infection, not colonisation. Step 9: Know when to say "no" to vanco(mycin). Step 10: Stop antimicrobial treatment when the infection is treated or unlikely. Step 11: Isolate the pathogen — use standard infection control precautions; contain infectious body fluids (airborne/droplet/contact precautions); when in doubt, consult infection control experts. Step 12: Break the chain of contagion — stay home when you are sick; keep your hands clean; set an example!

D Ashley R Watson MB BS, MPH, FRACP

In 2000, chronic or unspecified renal failure was listed as a cause of death of 9160 Australians (7.1% of all deaths) (source: Australian Bureau of Statistics, special data request, 2002). Most would have had chronic renal impairment (CRI) for years. Each year, more than 1700 people with end-stage renal disease (ESRD) start dialysis or receive a transplant.1 These figures suggest that the impact of CRI is substantial and that in order to prevent progression to ESRD we need to develop systems for its detection and management. Prevalence and significance of proteinuria. The Australian Diabetes, Obesity and Lifestyle (AusDiab) Study,2 a cross-sectional survey of a sample of over 11 000 Australians aged 25 and over, found proteinuria in 2.5% of the study population and a serum creatinine level above 120 µmol/L (reference range, 50–110 µmol/L [adult women], 60–120 µmol/L [adult men]) in 1.1%. A recent US study estimated that 1.5% of people aged six years and over have proteinuria.3 Extrapolating from these data, it is likely that several hundred thousand Australians have proteinuria, which is associated with a 15-fold increased risk of developing ESRD within 10 years.4 Whose urine should be screened? Current evidence does not support universal screening for proteinuria. The US Multiple Risk Factor Intervention Trial,5 in which more than 300 000 men were screened and followed up for an average of 16 years, showed that older age, smoking, hypertension and diabetes were significant risk factors for ESRD. Familial aggregation of ESRD, in excess of that predicted by clustering of diabetes and hypertension, has also been demonstrated.6 Indigenous Australians, who make up less than 2% of our population, comprise more than 8% of ESRD patients;1 and, in some remote communities where screening has been conducted, almost 25% of adults have been found to have proteinuria.7 Specific groups of people known to be at increased risk of ESRD should therefore be targeted for screening (see Box 1). Dipstick testing is cheap (about $0.50 per test), with immediate results. More than a trace of protein indicates a protein excretion rate greater than 300 mg in 24 hours. In the AusDiab study,2 dipstick testing had about 85% sensitivity and specificity (S Chadban, Nephrologist, AusDiab Steering Committee, personal communication). As about 15% of people without proteinuria have a falsely positive result, people with a positive dipstick result should have their protein excretion rate quantified by further testing. Measurement of 24-hour urinary protein excretion rate has long been the gold standard, but reliable collection is often impractical. Measurement of the albumin–creatinine ratio (ACR) in a morning urine specimen is easier and sufficiently precise.9 An ACR over 34 g/mol indicates a daily protein excretion rate exceeding 300 mg. At the same time as measuring the urinary ACR, a blood sample should be sent for measurement of serum creatinine and electrolyte levels for further assessment of renal function. Most dipsticks also test the urine for substances other than protein. If leukocytes or nitrites are detected, especially with symptoms suggestive of a urinary tract infection, a midstream urine specimen should be cultured. The dipstick test for proteinuria should be repeated after treatment of any infection. Isolated haematuria rarely indicates glomerular pathology associated with progressive renal disease. However, among smokers and people screened on the basis of age, a finding of haematuria should prompt exclusion of urinary tract malignancy. Interpreting the serum creatinine level. Serum creatinine level per se is not an accurate indicator of renal function. The glomerular filtration rate (GFR), which can be estimated from the serum creatinine level, is the most meaningful single measure (see Box 2). In healthy adults, the GFR exceeds 80 mL/min; patients with a GFR between 30 and 80 mL/min have CRI; while a GFR below 30 mL/min indicates severe renal impairment with a high risk of progression to ESRD, warranting prompt referral to a nephrologist. Managing CRI in general practice. General practitioners can substantially reduce the risk of progression of renal impairment. Management guidelines developed by the Australian Kidney Foundation and the Australia and New Zealand Society of Nephrology are accessible at the "Caring for Australians with Renal Impairment" website.11 I discuss here the evidence for the interventions recommended in the guidelines. Further benefit may be obtained by reducing the high risk of cardiovascular events that accompanies renal disease.12 Intensive control of hyperglycaemia and hypertension is beneficial for people with diabetes. (Specific interventions for diabetes are beyond the scope of this article — see the guidelines of the Australian Diabetes Society.8) In all patients with CRI, management aims should be the reduction of proteinuria (to ACR < 100 g/mol) and the maintenance of renal function (ie, stable GFR). These can be achieved through intensive control of hypertension11 (Level I evidence13). Suggested blood-pressure targets are 125/75 mmHg (in people under 50 years) and 135/85 mmHg (in people ≥ 50 years). Multidrug therapy is usually required. Angiotensin-converting enzyme inhibitors and angiotensin-II-receptor antagonists have been shown to be renoprotective (Level I and Level II evidence, respectively).11 Even in the absence of hypertension, they may be effective in people with protein excretion exceeding 1 g/day (ie, an ACR above 100 g/mol). Treatment for this normotensive group should be adjusted according to the level of proteinuria and monitored with three- to six-monthly ACR estimates. Potential risks include hyperkalaemia and, in patients with renal artery stenosis, worsening of renal impairment. In randomised controlled trials of these agents, participant dropout rates due to adverse effects have been low. Because smoking is associated with increased risk of progression of renal impairment (Level III-2 evidence),11 smokers should be assisted to quit smoking. A low-protein diet is not recommended, as the benefit is minimal and malnutrition may ensue. There is little evidence regarding the impact of exercise; however, in view of its cardiorespiratory benefits, regular exercise is advised. There is currently insufficient evidence to warrant lipid-lowering therapy as a means of minimising progression. Who should be referred to a nephrologist? GPs can usually manage patients with CRI, preventing further renal damage and progression to renal failure. Indications for prompt referral to a nephrologist include estimated GFR below 30 mL/min; estimated GFR above 30 mL/min, but declining rapidly; age less than 35; ACR greater than 300 g/mol (nephrotic range for proteinuria); symptoms or signs suggestive of systemic illness (eg, systemic lupus erythematosus); or failure to reach blood pressure or ACR targets within six months of starting antihypertensive drug therapy. 1: Indications for annual dipstick testing for proteinuria Age over 50 Hypertension Smoking Diabetes* Family history of renal disease Aboriginal or Torres Strait Islander descent *People with diabetes also require annual testing for microalbuminuria. (See the Australian Diabetes Society position statement on microalbuminuria in diabetes.8) 2: Calculation of glomerular filtration rate (GFR) by the modified Cockcroft–Gault formula*10 For women Estimated GFR (in mL/min)† = 140 – age (in years)] x weight (in kg) serum creatinine level (in µmol/L) For men Calculate estimated GFR as for women, then multiply by 1.23. * The modification is an arithmetic simplification of the original formula. The GFR estimate obtained will be 4% lower for women, and unchanged for men, compared with an estimate obtained using the original formula. † A number of computerised clinical record systems include a calculator for this formula.

Alan Cass MB BS, FRACP, GradDipClinEpid

The immediate health effects of bushfire smoke are well known to Australia's volunteer firefighters, who willingly fight bushfires each summer with no remuneration and at considerable personal risk. However, the population health impacts of pollution associated with large bushfires or "backburning" operations (prescribed burning to reduce the fuel load and the intensity of future bushfires) are less well defined, but are a matter of concern for emergency, environmental and public health agencies. A study from Darwin, published in this issue of the Journal by Johnston et al (page 535),1 is a welcome addition to this area of research. Johnston and colleagues1 analysed emergency department presentations for asthma in the Darwin region during the "dry" season, April – October (2000), when bushfire activity is high. The authors found that asthma presentations increased significantly (by nearly 2.4 times) on days when PM10 levels (ie, the concentration of respirable particulate matter with an aerodynamic diameter of 10 microns or less) were above 40 µg/m3, compared with days when PM10 levels were less than 10 µg/m3. The Australian National Environment Protection Council's target for maximum mean PM10 concentration is set at 50 µg/m3 in a 24-hour period.2 This level was exceeded on six days, with the maximum being 70 µg/m3. In fact, this value is relatively low in the international context. The Indonesian forest fires in 19973 produced maximum daily PM10 averages of over 1500 µg/m3. During Sydney's Christmas 2001 bushfires, PM10 levels above 150 µg/m3 were sustained for 10 days. In Sydney's 1994 bushfires,4 the peak PM10 was 210 µg/m3, compared with background levels of about 30 µg/m3. Previous Australian studies examined the effects of pollution in Sydney from backburning in May 19915 and bushfires in January 1994.6 Both studies analysed daily numbers of asthma presentations at several metropolitan hospitals for up to a month. The first study provided weak support for a link between particulate air pollution and asthma attendances, but the second found no difference in asthma presentations in the periods before, during and after the high-pollution event. There have been two more detailed studies of the health impacts of the 1994 Sydney bushfires. The first7 extended the period of analysis to six to seven weeks and compared asthma attendances with those in the same period the previous year. The researchers used a more complex analysis strategy, incorporating lag periods of one and two days for independent variables. They found that bushfire-generated particulate air pollution did not result in an increase in asthma presentations to emergency departments in western Sydney. The second study4 measured changes in evening peak expiratory flow rates (PEFR) during the bushfire period in children with wheeze, and used a direct measure of PM10, including pollen and alternaria counts, and meteorological factors (temperature and humidity). Thirty-two children were recruited to the study over a period of one week. Peaks in PM10 levels occurred three days before recruitment and on Days 3 and 8 (PM10 levels of about 70 µg/m3, 150 µg/m3 and 210 µg/m3, respectively, were recorded). Overall, there was no association found between mean PM10 and PEFR. Subgroup analysis of 20 of the children without bronchial hyperreactivity recorded significant falls in PEFR with rising PM10 levels. The remaining 12 children with bronchial hyperreactivity showed no significant association between PM10 and PEFR. The relative timing of exposure and recruitment may have caused changes in respiratory function before the study period, thereby biasing the results. All but one of the previous studies5-7 used indirect measures of particulate pollution, did not account adequately for confounders and did not use appropriate time-series methods. Notwithstanding these shortcomings, the potential for bias is probably low, as most important confounders do not vary on a daily basis. Johnston and colleagues' study1 has the advantage of running for a longer time period, with the episodes of pollution occurring during the study. The findings of the Darwin study should stimulate further research on the health effects of bushfire smoke. Current public health approaches to bushfire or other pollution episodes are to invoke a tiered system of warnings, moving from advice for susceptible subgroups (people with asthma, other chronic respiratory disease, or cardiovascular disease) to whole-population warnings as pollution increases. Applying "backburning" as a fire control measure, in itself an effective public health tool, may be restricted, partly because of the perceived impact of the resultant particulate pollution on urban populations. Better information about these effects will result in more appropriate risk management.

Peter R Lewis DipObsRACOG, MPH, FAFPHM · Stephen J Corbett MPH, MRCGP, FAFPHM

"of insects . . . only the ants were troublesome . . . one green as a leaf and living upon trees where he built his nest . . . by bending the leaves together and glueing them . . . their stings were by some esteemd not much less painfull than those of a bee . . ." Joseph Banks, August 17701 Indigenous Australians co-existed with native ants for thousands of years, using them as food (honey ants) and in medicinal decoctions (green tree ants).2 It was the green tree ant (Oecophylla spp.) that first attacked the white invaders from the Endeavour, and a number of native ant species, in particular the jumper or hopper ant (Myrmecia pilosula), still cause significant morbidity. But a foreign ant has now assumed the role of invader. In this issue of the Journal, Solley et al3 (page 521) describe the first Australian patient with anaphylaxis caused by the venom of the Red Imported Fire Ant (RIFA), Solenopsis invicta, and outline the appropriate diagnostic and management strategies, including successful desensitisation. Where did the RIFAs come from? Why are they a threat to our economy as well as our health? Can they be eradicated? February 22, 2001, was a dark day for Australia with the identification of S. invicta at two sites across Brisbane. This ant has the potential to be one of Australia's biggest ecological disasters, with the ability to have an impact on the economy, the environment and society. The ant itself appears innocuous. It is a small (2–6 mm), reddish-brown ant that is hard to distinguish from many other common ants. Its behaviour sets it apart as one of the world's great invaders. The ants will literally boil out of the nest ready to attack in huge numbers. The sting is painful, which accounts for the name "fire ant". Multiple stings are the rule rather than the exception and can be excruciating. The nest is dome-shaped and the colonies consist of up to half a million ants. S. invicta originated in South America, spread to Alabama in the 1930s and now infests 12 US States. Fire ants are thought to have entered Australia via shipping containers. There are two RIFA epicentres, one on the east of Brisbane around the port area, the other in Brisbane's western suburbs and part of Ipswich. The eastern infestation has been identified by DNA testing and chemical analysis of its venom as being from the United States or northern South America. The western infestation may have originated from Argentina (Dr Robert K Vander Meer, Research Chemist, United States Department of Agriculture/University of Florida, Center for Medical, Agricultural, and Veterinary Entomology, unpublished data, personal communication). Despite this multiple encroachment, the pest seems confined to Brisbane. Ecological modelling shows that the ants are capable of surviving in most parts of Australia, while spread modelling suggests that, if uncontrolled, the ants could spread up to 2 million square kilometres (ie, about a quarter of the area of Australia) over the next 30 years.4 A study of the environmental impact of fire ants5 shows that areas infested with the ant have fewer native ant species, lower total biodiversity and an absence of scincoid lizards. The ants can decimate ground-nesting birds, turtles and frogs, and can damage farm, irrigation and electrical equipment.6 The Australian Bureau of Agriculture and Resource Economics7 estimates that the cost of fire ants over 30 years, if uncontrolled, would be $8.9 billion. Australia's response to this invader is a $123 million, five-year National Fire Ant Eradication Program funded by the Commonwealth and the State governments. What about the medical aspects? It is appropriate to compare the RIFA with our most dangerous native ant, the jumper ant: Jumper ants are distributed throughout Australia; RIFAs have only been identified in the Brisbane area. Both jumper ants and RIFAs grasp the skin with the mandibles and sting repeatedly using a retractile stinger on the end of the abdomen. Stings from jumper ants usually cause a local weal-and-flare, while RIFA stings, because of the high alkaloid content of their venom, invariably result in sterile pustules. These pustules should not be broken. Venom proteins from both ants can result in immediate sensitivity. Two proteins have been cloned and sequenced from jumper ants (Myr p 1–2) and four from RIFAs (Sol i 1–4). There is no cross-reactivity between the main proteins of the two ants. Both jumper ants and RIFAs can cause large local allergic reactions that may need to be treated with oral corticosteroids. Up to 3% of Australians describe systemic allergic reactions to jumper ant stings,8 with most allergic sting reactions reported from Tasmania, Victoria and South Australia. In comparison, 30%–60% of people living in areas infested by RIFAs in the United States are stung, with 0.6%–16% of those stung developing anaphylaxis.6 Patients with anaphylaxis should be referred to an allergist/immunologist, and must carry self-injectable adrenalin. The best device, although expensive and still not subsidised by the Pharmaceutical Benefits Scheme, is the EpiPen Autoinjector (CSL, Melbourne). There is no commercial extract for desensitising patients with anaphylaxis to jumper ant venom. A clinical trial of a jumper ant extract has just been completed in Tasmania (Dr Simon G A Brown, Director, Department of Emergency Medicine, Royal Hobart Hospital, personal communication), but commercial production will not occur without financial help from government or private sector sources. At least three commercial desensitising extracts for RIFA venom are available from the United States. Deaths from anaphylaxis to jumper ant stings9 and RIFA stings6 have been documented. Perhaps, with luck and hard work and lots of money, we might eradicate RIFAs from Australia, but no State in the United States has been successful in such a program once the ant has invaded. In some parts of the southeastern United States, stings by fire ants are the commonest cause of anaphylaxis. Let's hope that that is not the case in Australia in 2030. The cost to our health and ecology would be enormous. Interested readers may wish to refer to two excellent web sites: <http://www.dpi.qld.gov.au/fireants/> (Queensland) and <http://fireant.tamu.edu/> (Texas).

Keith I McCubbin · John M Weiner

Stings from insects of the Order Hymenoptera (bees, wasps and ants) are responsible for numerous anaphylactic events, some fatal.1,2 In Australia, allergic reactions to ant stings have, until now, been caused by native ant species (eg, the jumper ant [Myrmecia pilosula and other Myrmecia spp.],3-5 the greenhead ant [Rhytidoponera metallica], Odontomachus, Cerapachys and Brachyponera spp.). Although ants are found worldwide, the only other ant species commonly reported as inducing anaphylaxis is the Red Imported Fire Ant (Solenopsis invicta Buren),6-9 which is native to Brazil, Paraguay, Uruguay and Argentina.10 This species was accidentally introduced into Alabama in the United States in the 1930s,10,11 and since then has spread rapidly throughout the southern United States, causing economic damage to crops and primary industries, reducing biological diversity, and frequently inflicting severe stings to humans.12 In February 2001, two well established populations of S. invicta ants were discovered in Brisbane (Box 1). The mode of introduction is unknown, although it may have been through the transport of infested sea cargo. It is estimated that the incursion is more than five years old. Currently, S. invicta ants are found over 37 000 hectares of the Brisbane region, covering over 64 000 homes. Here, we describe a patient with anaphylaxis as a result of S. invicta stings, document his treatment and estimate the likely rates of anaphylaxis and mortality should these ants spread across the remainder of Australia. Clinical recordA man, aged 47 years, began work as a gardener at the Port of Brisbane in November 1999. His first Red Imported Fire Ant (RIFA) sting occurred during the summer of 1999–2000. These stings resulted in acute local pain at the sting site, leading to small pustules the following day which took two weeks to heal (a typical reaction, unique to RIFA stings, which occurs in about 85% of cases).10 These reactions were quite different from previous stings by greenhead ants, which left nothing more than local puncture marks. He was then assigned to a work party to search and destroy RIFA nests. In this task he incurred 20 to 30 separate RIFA sting events, which resulted in reactions similar to those described above. He then received two RIFA stings on his knee at the one time. Ten minutes later, he developed extreme pruritus and burning of both feet. This was quickly followed by generalised pruritus, nasal congestion, and acute tightness of his throat and chest with dyspnoea. He was transported quickly to a nearby hospital. On arrival, a rash was present on his trunk and legs, his pulse rate was 84 beats/min, his blood pressure was 131/110 mmHg and his lungs were clear. He was given intravenous saline and 200 mg of hydrocortisone, but not adrenalin. Two hours later, he was discharged well. A review by the Port of Brisbane's occupational physician highlighted this as a sentinel case and the causal agent was identified as RIFA. The patient's usual work duties were altered to avoid further, possibly life-threatening, RIFA stings. He was also provided with the semi-automatic adrenalin device, EpiPen (CSL, Melbourne). Avoidance measures were successful, although he subsequently sustained a number of stings from greenhead ants and wasps without adverse responses. Skin-prick testing with the whole-body extract of S. invicta (supplied by Stallergenes, Paris, France) showed a 10-mm weal to the 1: 1000 dilution, thus confirming the occupational physician's initial diagnosis. As a consequence, he began desensitisation with S. invicta whole-body extract in accordance with accepted treatment guidelines.13 He has now reached the "maintenance phase" of the schedule (ie, 0.5 mL of the 1: 10 dilution). Subsequent to desensitisation, he reported one RIFA sting, which caused only the expected localised pustule. DiscussionAdrenalin is the first-aid treatment of choice for a systemic allergic response with dyspnoea and/or hypotension.14 It achieves the quickest reversal of the adverse events and is very safe in a life-threatening situation. Anyone who has had stinging-insect-induced anaphylaxis should carry an EpiPen (or EpiPen Jr for children; CSL) for immediate first-aid use if hypotension or dyspnoea occurs. Specific desensitisation to prevent future anaphylaxis to RIFA stings in susceptible patients is effective,13 and anyone suspected of RIFA sting anaphylaxis should be referred to an allergist for assessment. Taxonomically, S. invicta is in a different subfamily (Myrmicinae) from that of Australian native ants responsible for anaphylactic events. Furthermore, RIFA venom is unlike that of any other Australian Hymenoptera species. As a consequence, there is a strong possibility that allergic cross-reactivity between species does not occur, as is the case in the United States. Indeed, our patient's experience would support this belief. Therefore, RIFA toxin represents a new risk to a portion of the Australian population not yet aware of this. The biology and epidemiology of S. invicta is summarised in Box 2. In the United States, over 40 million people live in areas infested by S. invicta. Annually, 14 million people are stung, a quarter of whom are expected to develop some sensitivity to RIFA toxin.10 An examination of habitat preferences and estimates of the rate of uncontrolled spread suggest that, unless eradicated, S. invicta will occupy much of arable Australia within 30 years, and therefore exist in close proximity to a large portion of the Australian population. Only areas with extremes of aridity and cold would remain free of these ants. It is reasonable to expect that proportionally similar numbers of people will come into contact with fire ants in Australia and experience similar reactions to their stings. A survey of 1286 practitioners in South Carolina (USA) (population, four million), where fire ants are well established,7 estimated that annually over 33 000 people (94 per 10 000 population) seek medical consultation for RIFA stings, and, of these, 660 people (1.9 per 10 000 population) are treated for anaphylaxis. Direct extrapolation of these data to the Australian situation would suggest that about 140 000 consultations and 3000 anaphylactic reactions are to be expected each year by 2030 if RIFA eradication is not successful. 1: Map of Brisbane, showing areas infested and putatively infested with the Red Imported Fire Ant (Solenopsis invicta) shaded yellow, main roads (grey) and council boundaries (dashed) 2: Biology and epidemiology of Red Imported Fire Ants Red Imported Fire Ants are inconspicuous, reddish-brown ants with no distinguishing features visible to the naked eye. Superficially, they resemble many common native and exotic ant species present in the Brisbane region (Figure 1). They range in size from 2 mm to 6 mm, with many intermediate-sized individuals. Optimum habitats include grassed areas, gardens, sites near flowing and still water and recently disturbed soil. Fire ant nests (Figure 2) are largely subterranean and are conspicuous by an above-ground, dome-shaped mound which can be as high as 45 cm above normal ground level (usually 20–30 cm). Normally, the above-ground part of the nest resembles a mound of excavated soil, 30–60 cm in diameter, but sometimes these are absent. The nests of many native ants have obvious openings through which ants enter and exit. Two forms of Red Imported Fire Ants have been discovered in Brisbane: the monogynous (single-queen) and polygynous (multiple-queen) types. Monogyne colonies maintain territory independently from neighbouring colonies. As a result, the distance between colonies is normally greater than 10 metres, as this avoids unnecessary conflict between neighbouring colonies over territory. However, worker ants from polygyne colonies can not determine whether other fire ant workers or queens they encounter are related to them and, as a result, coalesce to form large, dense supercolonies. These polygyne infestations, which are dominant in Brisbane, present a greater hazard due to the much larger numbers of ants a site can support (thousands of polygyne colonies per hectare instead of hundreds of monogyne colonies per hectare). Both forms defend their territory aggressively and make extensive use of pheromones or chemical signals to recruit other workers, synchronise attacks and initiate stinging. For this reason, multiple stings are the rule rather than the exception (Figure 3 a–d). Their diet is unspecialised and they feed on any available sources of carbohydrates, lipids and protein. Currently, over 37 000 hectares of Brisbane's eastern and south-western suburbs are putatively infested with S. invicta (Figure 1). However, an eradication program has been initiated by the Queensland Department of Primary Industries at a cost exceeding $123 million over the next five years. This program is jointly funded by the Commonwealth Government and all Australian States and Territories. The potential for anaphylactic events in Australia due to S. invicta will be higher than for other native ants due to three key factors: The venom of S. invicta is unusual, being composed largely of alkaloids, but also including four different proteins.15,16 These proteins, as well as the non-protein components of the venom, are each individually capable of inducing anaphylaxis. The polygynous form of S. invicta often completely dominates areas where it has invaded, forming interconnected supercolonies.17 Coupled with grassy areas as its preferred habitat, the probability of contact with humans is high. Aggressive pheromone-driven group defence of territory and the colony results in a high probability of multiple stings. 1: (a) The Red Imported Fire Ant (Solenopsis invicta), and (b) Monomorium sp, a harmless native ant, demonstrating the similarity between the two species (with permission, Macquarie University, School of Biological Sciences). 2: A typical Red Imported Fire Ant mound (with permission, Queensland Department of Primary Industries). 3: Multiple stings (about 150) by S. invicta to the right arm of one of the authors (C V) as a result of accidental exposure in the field. (a) Five minutes after the event, showing raised welts at sting sites; (b) 18 hours after, showing typical pustules; (c) 48 hours after; and (d) seven days after the event.

Graham O Solley MB BS, FACP · Cas Vanderwoude ADipAppSc(For), BAppSc(Hons), PhD · Gregory K Knight MB BS, MPH, FAFOM

Objective: To determine patterns of use of ceftriaxone and cefotaxime (CEFX) in Victorian hospitals and to identify areas for improvement.Design, patients and setting: A concurrent, observational evaluation of CEFX use in patients commencing a course of these drugs between 8 and 14 September, 1999, in 51 Victorian hospitals.Main outcome measures: Proportion of patients treated with CEFX; indications; duration of use; concordance with recommendations of national antibiotic guidelines (Therapeutic guidelines: antibiotic, 10th edition [AG10]).Results: 671 patients were treated with CEFX. The overall rate of use was 43 patients per 1000 inpatient separations. Treatment of respiratory tract infection accounted for 352 patients (52%) and surgical prophylaxis for 99 patients (15%). Treatment of skin/soft tissue, urinary tract and gastrointestinal tract infections accounted for about 7% of patients each. The median duration of CEFX courses was 3.0 days. The overall rate of concordance with indications recommended in AG10 was 27%. The rate of concordance for empirical treatment of respiratory tract infection was 24%. Of the 195 patients treated empirically with CEFX for community-acquired respiratory tract infection and assessed as non-concordant, 64% did not have radiological evidence of pneumonia, and a further 30% did not fulfill the criteria for severe pneumonia. All courses given for surgical prophylaxis were non-concordant.Conclusions: CEFX is widely used in Victorian hospitals, mostly to treat lower respiratory tract infection and in surgical prophylaxis of infection. The rate of concordance with AG10 is low. Potential areas for intervention include empirical treatment of respiratory tract infection and use in surgical prophylaxis.

Marion B Robertson BPharm, MSc · Jonathan G A Dartnell BPharm, PhD · Tony M Korman FRACP · Lisa L Ioannides-Demos BPharm, PhD · Sue W Kirsa BPharm, GradDipHospPharm · Julie A V Lord BPharm · Liliana Munafo BPharm · Graham B Byrnes BSc, PhD

Objectives: To determine whether naltrexone is beneficial in the treatment of alcohol dependence in the absence of obligatory pyschosocial intervention.Design: Multicentre, randomised, double-blind, placebo-controlled trial.Setting: Hospital-based drug and alcohol clinics, 18 March 1998 – 22 October 1999.Patients: 107 patients (mean age, 45 years) fulfilling Diagnostic and statistical manual of mental disorders (4th edition) criteria for alcohol dependence.Interventions: Patients with alcohol dependence were randomly allocated to naltrexone (50 mg/day) or placebo for 12 weeks. They were medically assessed, reviewed and advised by one physician, and encouraged to strive for abstinence and attend counselling and/or Alcoholics Anonymous, but this was not obligatory.Main outcome measures: Relapse rate; time to first relapse; side effects.Results: On an intention-to-treat basis, the Kaplan–Meier survival curve showed a clear advantage in relapse rates for naltrexone over placebo (log-rank test, χ21 = 4.15; P = 0.042). This treatment effect was most marked in the first 6 weeks of the trial. The median time to relapse was 90 days for naltrexone, compared with 42 days for placebo. In absolute numbers, 19 of 56 patients (33.9%) taking naltrexone relapsed, compared with 27 of 51 patients (52.9%) taking placebo (P = 0.047). Naltrexone was well tolerated.Conclusions: Unlike previous studies, we have shown that naltrexone with adjunctive medical advice is effective in the treatment of alcohol dependence irrespective of whether it is accompanied by psychosocial interventions.

Noeline C Latt MB BS, MRCP, MPhil · Stephen Jurd MB BS, FRANZP · Jennie Houseman BPharm, MA(ClinDrugDepStud) · Sonia E Wutzke BSc(Psych)(Hons), MPH, PhD

Objective: To examine the relationship between the mean daily concentration of respirable particles arising from bushfire smoke and hospital presentations for asthma. Design and setting: An ecological study conducted in Darwin (Northern Territory, Australia) from 1 April – 31 October 2000, a period characterised by minimal rainfall and almost continuous bushfire activity in the proximate bushland. The exposure variable was the mean atmospheric concentration of particles of 10 microns or less in aerodynamic diameter (PM10) per cubic metre per 24-hour period. Outcome measure: The daily number of presentations for asthma to the Emergency Department of Royal Darwin Hospital. Results: There was a significant increase in asthma presentations with each 10-µg/m3 increase in PM10 concentration, even after adjusting for weekly rates of influenza and for weekend or weekday (adjusted rate ratio, 1.20; 95% CI, 1.09–1.34; P < 0.001). The strongest effect was seen on days when the PM10 was above 40 µg/m3 (adjusted rate ratio, 2.39; 95% CI, 1.46–3.90), compared with days when PM10 levels were less than 10 µg/m3. Conclusion: Airborne particulates from bushfires should be considered as injurious to human health as those from other sources. Thus, the control of smoke pollution from bushfires in urban areas presents an additional challenge for managers of fireprone landscapes.

Fay H Johnston MAppEpi, FAFPHM · Anne M Kavanagh PhD, FAFPHM · David M J S Bowman PhD, DSc · Randall K Scott BAppSci (Biol)

Clinical Record A 30-year-old woman in the 30th week of pregnancy was admitted with a two-day history of fever, malaise, dysuria, frequent micturition and mild lower abdominal pain. Slight lower abdominal tenderness was the only clinical abnormality. Results of urine microscopy were white blood cell (WBC) count, 33 × 106/L (normal range, 0–10); red blood cell count, 15 × 106/L (normal range, 0–12); epithelial cell count, 21 × 106/L (normal range, 0–5); and culture was sterile. Full blood count revealed haemoglobin, 113 g/L (normal range, 100–180); WBC count, 11.6 × 109/L (normal range, 5–18); platelet count, 215 × 109/L (normal range, 150–450); and lymphocyte count, 0.23 × 109/L (normal range, 2–8). Liver function tests were mildly abnormal at presentation (Table). The patient was treated with empirical ampicillin and gentamicin, with resolution of her symptoms. However, her liver function tests worsened. Leptospiral serology was negative and blood cultures were sterile. Hepatitis A, B and C, flavivirus, Ross River virus, cytomegalovirus, Epstein–Barr virus, HIV, parvovirus and toxoplasmosis were all excluded. Negative antinuclear, mitochondrial and smooth muscle antibodies and normal immunoglobulin levels indicated that autoimmune hepatitis was unlikely. From the fifth day after admission, her condition deteriorated, with marked upper abdominal pain and worsening liver function tests (Table). On admission to the intensive care unit she was confused, febrile (37.5°C) and tachycardic (112/min). Blood pressure was 105/70 mmHg and results of cardiorespiratory examination were normal. Right hypochondrial tenderness was present. There were no clinical stigmata of hepatic decompensation. Results of laboratory tests (Day 7) were international normalised ratio of prothrombin time, 1.7 (normal, < 1.2); lymphocyte count, 0.57 × 109/L; leukocyte count, 3.1 × 109/L; and liver function tests as shown in the Table. Renal function and platelet counts were normal. Delivery was deemed necessary to preserve the baby's life. A live baby was delivered by caesarean section (Day 10). There were no orogenital lesions on the mother. The baby was well, with no clinical abnormalities. After the caesarean section, the patient remained stable for 24 hours and then suffered progressive circulatory insufficiency. Despite escalating doses of vasopressors, she developed renal failure. Bilateral pneumonia and pleural effusions led to respiratory failure, and the patient was intubated for assisted mechanical ventilation. Results of liver function tests (Table) confirmed worsening of disordered hepatic synthesis, progressive hepatocellular injury and coagulopathy. An abdominal computed tomography scan revealed gross hepatomegaly, with diffuse low attenuation of the left lobe of the liver and mottling of the right lobe of the liver. Liver biopsy, precluded by coagulopathy during the caesarean section, was accomplished on Day 13. Histology revealed hepatic necrosis, with 40%–50% of the hepatic parenchyma showing haemorrhagic necrosis with a neutrophilic infiltrate (Box 1A). At the interface between necrotic areas and surviving parenchyma, many liver cells showed glazed amphophilic chromatin consistent with herpesvirus inclusions. Polyclonal herpes simplex virus immunoperoxidase stain showed strong nuclear staining in these cells (Box 1B). Polymerase chain reaction testing of her serum subsequently revealed herpes simplex virus (HSV) DNA and HSV 2 was cultured from a vaginal swab. The patient was treated with intravenous aciclovir (750 mg every 8 h), but remained critically ill, with persistent circulatory shock, anuric renal failure and fulminant hepatic failure. Enterococcus faecalis bacteraemia compounded her shock. On Day 25, she died of fulminant hepatitis and multiorgan failure. Autopsy revealed severe hepatic architectural distortion, with almost complete absence of portal tracts and central veins. The necrotic foci were more extensive than those seen at biopsy. HSV immunohistochemical stain showed cytoplasmic staining. Interstitial pneumonitis and autolysis of the kidneys were seen, with no evidence of glomerulonephritis. Viral inclusions were seen only in the liver. Her infant was treated empirically with aciclovir and is growing and developing normally. Days after admission Normal range 1 4 7 10 13 16 19 25 Serum aspartate transaminase (U/L) 7–56 66 919 1738 3814 2499 1592 144 103 Serum alanine transaminase (U/L) 7–56 62 558 522 700 443 335 77 25 Bilirubin (µmol/L) < 17 8 10 11 24 47 68 400 600 Albumin (g/L) 35–45 20 15 12 17 14 15 18 16 Serum alkaline phosphatase (U/L) 30–120 123 333 378 471 345 294 155 125 Serum γ-glutamyltransferase (U/L) 10–75 16 76 105 126 100 71 28 25 Many pregnancy-specific liver disorders occur in the third trimester; thus, an aetiological diagnosis of liver diseases can be difficult. Common liver disorders in pregnancy are intrahepatic cholestasis of pregnancy, HELLP syndrome (haemolysis, elevated liver enzymes and low platelets), and acute fatty liver of pregnancy. The commonest cause of jaundice in pregnancy is acute viral hepatitis, which can result from primary infections with hepatitis viruses A to E or as part of a systemic infection with viruses such as cytomegalovirus, Epstein–Barr virus, varicella zoster virus and herpes simplex virus (HSV).1 Except when caused by hepatitis E virus or HSV, viral hepatitis does not usually increase maternal or fetal mortality.2 Hepatitis due to HSV infection is a rare but frequently fulminant disease. Most reports have been in immunocompromised patients3 or newborns.4 Fulminant HSV hepatitis has been reported in immunocompetent adults,5-7 mostly pregnant women.8-10 Two per cent of susceptible women acquire HSV infection during pregnancy, and seroconversion can be asymptomatic.6 Most reported cases of HSV hepatitis followed a primary orogenital infection with HSV type 1 or 2.5,8-10 As in our patient, the reported cases included initially normal serum bilirubin levels, markedly elevated serum transaminase levels, and very high AST/ALT ratios. In our patient, liver histology and immunohistochemistry established the diagnosis. Serology, PCR and vaginal swab cultures were complementary. Early administration of aciclovir has been successful in treating HSV hepatitis.5,7 Liver transplantation is another treatment option,11 but the risk of recurrent HSV hepatitis with overwhelming viral dissemination and concurrent enterococcal sepsis were contraindications in our patient. A high index of suspicion for HSV infection is warranted, as hepatitis can occur without orogenital herpetic lesions. HSV serology, PCR testing for HSV DNA, and vaginal swab cultures are recommended in undifferentiated liver disorders. Liver biopsy should be considered in patients with hepatitis when a definitive aetiology is elusive. Empirical treatment with aciclovir should be considered. 1: Photomicrographs of liver biopsy A: H&E stain, showing significant necrosis of liver parenchyma (lower and lateral edges of micrograph); typical intranuclear herpesvirus inclusions are visible (arrow). Nuclear chromatin is completely effaced and is darkly amphophilic and glazed. Viable hepatocytes are seen uppermost in the photomicrograph. Magnification × 400. B: Immunohistochemical stain for herpes simplex virus, showing strong positive intranuclear staining. Magnification × 400. 2: Lessons from practice Herpes hepatitis can occur without preceding orogenital lesions. Diagnostic tests for herpes simplex infection should be performed in patients with fulminant hepatic failure. Detection of HSV DNA by the polymerase chain reaction, and histological examination of liver tissue, are diagnostic. Empirical treatment with aciclovir may be indicated in patients with liver failure where the aetiology is unclear.

Ramesh Nagappan MD, FRACP · Geoffrey Parkin MB BS, FFICANZCA · Ian Simpson MB BS, FRCPA · William Sievert MD, FRACP

Collaboration between industry and academia is becoming increasingly prevalent and successful in Australia. To encourage and foster these relationships while preventing excesses, Australia needs to act now to create ethical, legal and legislative frameworks for collaboration. As the United States has progressed further than Australia in fostering and controlling collaboration between industry and academia, Australia has the opportunity to learn from the US experience. To speed the pace of development, Australia needs to consider making changes to legislation and increasing the level of government funding, either directly or by the creation of incentives for investment of venture capital and superannuation funds in biotechnology.

Hamilton Moses III MD · Abbey Perumpanani MD, PhD · Jon Nicholson MBA

In 1991, the "organised approach to preventing cancer of the cervix" recommended Pap smears every two years for women aged 18–70 years who have ever been sexually active. The two-year interval was a compromise step towards the scientifically supported three-year interval, as many influential groups were strongly attached to annual screening. When other components of the organised approach were in place, the policy was to be reviewed. Since the safeguards in the "organised approach" have been proven effective, it is appropriate to change the policy to recommend a three-year interval. Increasing the interval would allow more resources to be allocated to enrolling women currently underscreened and to evaluating and improving the program. The age of commencing smears could also be reconsidered to reflect the balance of potential benefits and harm in young women, for whom cancer is very rare but follow-up investigation common. If consensus is not reached within the profession, an evidence-based decision may need to be made at the political level.

James A Dickinson FRACGP, PhD

Commercially available nucleic acid amplification assays (eg, polymerase or ligase chain reaction) are now the "gold standard" tests for genital chlamydial infection and also have a role in screening for gonococcal infection. Single-dose oral antibiotics are available for treatment of Chlamydia trachomatis, Neisseria gonorrhoeae and Trichomonas vaginalis infections. Strains of N. gonorrhoeae in urban Australia are often penicillin resistant, while strains from South East Asia and those in homosexually active men may show high-level resistance to quinolones. Imiquimod, a novel immune-response modifier, is now available for effective, safe, self-administered treatment of genital warts. The Pap smear remains the cornerstone of screening for precursor lesions of cervical cancer, but human papillomavirus genotyping may have a role in clinical decision-making for women with equivocal or early precancerous lesions. Treatment of primary genital herpes changes the clinical course, and long-term suppressive therapy is effective for those with multiple recurrences.

Francis J Bowden FRACP, MD · Sepehr N Tabrizi PhD · Suzanne M Garland MD, FRCPA · Christopher K Fairley FRACP, PhD

A 34-year-old woman (gravida 5, para 2) presented to the Government Hospital in Katsina, northern Nigeria, in 1973. She was in labour and had had no antenatal care. She successfully delivered a live 3.2 kg infant. A 14 cm right adnexal pelvic mass was noted postnatally. An x-ray and hysterosalpingogram (see picture) performed four months after the birth showed the calcified remains of an extrauterine pregnancy. The woman stated that four years earlier she had missed her periods and had consulted a "bush doctor" (local herbalist) about abdominal swelling and pain. The herbs he prescribed to rub on her abdomen had eased the pain, and her periods had returned after seven months. The mass was easily removed from the omentum at subsequent laparotomy. Histology confirmed an advanced lithokelyphopaedion (ie, calcified fetus, membranes and placenta).

Lourdes I St George LRCPS, FRCOG, FRACOG · John St George FRCS, FRCOG, FRACOG

To the Editor: Although treatment with vitamin D has been shown to reduce hip fracture risk in elderly institutionalised people,1 there has been a perception that vitamin D deficiency is generally uncommon in countries with high sunlight exposure such as Australia. We studied the prevalence of vitamin D deficiency in older people in residential aged-care facilities (hostels and nursing homes) in the northern Sydney area as part of the FREE study (Fracture Risk Epidemiology in the Elderly), a prospective study of fracture incidence in more than 2000 participants. Here, we report baseline serum 25(OH) vitamin D concentrations in the first 386 participants, determined in partially purified lipid extracts using a competitive protein binding assay.2 The sample comprised 252 women and 134 men (mean ± SE age, 86.7 ± 0.6 v 81.2 ± 0.7 years, respectively; P < 0.001). The mean serum 25(OH)D level was 17 nmol/L (SD, 12) and median serum 25(OH)D level was 15 nmol/L (interquartile range, 9 to 22). Vitamin D deficiency (defined as a serum 25(OH)D concentration < 28 nmol/L) was present in 86% of women and 68% of men. There was no significant difference in serum vitamin D levels between women in nursing homes versus women in hostels, nor between men in nursing homes versus those in hostels. Although serum vitamin D levels were low throughout the year, a small rise was observed in summer (P < 0.01). Length of stay in the residential facility was not a predictor of serum vitamin D level. Mean parathyroid hormone levels were 93 pg/mL (normal range, 12–72 pg/mL) and rose when vitamin D levels dropped below 21 nmol/L, indicating secondary hyperparathyroidism. A number of previous studies have suggested a high prevalence of vitamin D deficiency in older institutionalised Australians in southern States,2-4 but we are unaware of any published studies in Sydney (latitude 33°S). However, as the prevalence of vitamin D deficiency in older people living in the community in Geelong is low,5 our study suggests that factors like confinement indoors is more important than latitude. Given the relationship between vitamin D status and fracture, with more than 72 500 nursing home residents and 60 200 hostel residents in Australia in 1997, our findings indicate that vitamin D deficiency represents a significant public health problem in elderly institutionalised Australians regardless of geographical location. Importantly, this problem could be solved relatively simply by measures such as a short period of daily sunlight exposure or giving moderate doses of vitamin D annually to nursing home and hostel residents.

Philip N Sambrook · Ian D Cameron · Robert G Cumming · Stephen R Lord · Jennifer M Schwarz · Angelika Trube · Lynnette M March

To the Editor: Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for patients with cardiovascular disease, including those taking perhexiline for severe ischaemic heart disease. Elevated serum perhexiline concentrations have been observed during therapy with the SSRIs fluoxetine and paroxetine, which are known to be strong inhibitors of cytochrome P450 2D6, the enzyme system responsible for the hepatic metabolism of perhexiline.1 The Adverse Drug Reactions Advisory Committee has received five reports of a possible interaction between perhexiline and SSRIs, but none of these involved the SSRIs citalopram or fluvoxamine, which are generally considered to be weak inhibitors of cytochrome P450 2D6. I describe here a case of perhexiline toxicity that occurred within 10 days of starting citalopram therapy. An 82-year-old man was admitted to hospital for drainage of a femoral abscess. His medical history included bilateral hip replacements, ischaemic heart disease, hypertension, renal artery stenosis, renal calculi, gout, gastroesophageal reflux disease and prostate cancer. His medications included (daily) aspirin 100 mg, isosorbide mononitrate 120 mg, pravastatin 40 mg, allopurinol 300 mg, celecoxib 200 mg, lorazepam 2 mg, nitrazepam 10 mg; (twice daily) perhexiline 100 mg; and paracetamol and tramadol as needed. On Day 51 after admission the patient underwent first-stage revision of an infected hip implant under general anaesthesia, and on Day 60 citalopram was commenced (10 mg daily for four days, then 20 mg daily). On Day 70, the patient complained of diarrhoea, nausea and dizziness. Citalopram was discontinued but the nausea was slow to settle. After a perhexiline assay on Day 75 revealed a high serum concentration (see Box), the perhexiline dose was reduced to 100 mg daily and the patient's nausea settled. Previous perhexiline concentrations on a dose of 100 mg twice daily had ranged from 0.29 to 0.34 mg/L over a two-year period. Tests of renal and hepatic function were normal throughout the patient's hospital stay. While in hospital, the patient was given celecoxib (a cytochrome P450 2D6 inhibitor) at a constant dose between Days 1 and 95, and meropenem (not a documented cytochrome P450 2D6 inhibitor) between Days 51 and 95. These patterns of administration suggest that neither of these drugs had a significant effect on perhexiline concentration. On the other hand, the laboratory evidence of a marked inhibition of perhexiline metabolism during treatment with citalopram suggests that caution is required when prescribing citalopram (or any other SSRI) for a patient taking perhexiline.2 Serum concentrations (mg/L) of perhexiline and perhexiline metabolite Day 48 Day 75 Day 95 Perhexiline (therapeutic range, 0.15–0.60 mg/L) 0.37 0.82 0.27 Perhexiline metabolite 3.53 0.37 2.22 Ratio of perhexiline to perhexiline metabolite 0.10 2.22 0.12

Karin Nyfort-Hansen

To the Editor: Hydroxymethylglutaryl coenzyme-A (HMG Co-A) reductase inhibitors (or statins) are widely prescribed, and any class-specific side effect has the potential to affect many thousands of patients. The statin drugs are well recognised as a cause of mild and usually transient hepatitis.1-3 Cholestatic liver injury has been reported with simvastatin4 and atorvastatin,5 but pravastatin has only been implicated as a cause in one report.6 We report a 64-year-old woman who was twice treated with pravastatin sodium and who, on both occasions, demonstrated cholestasis, which, at its peak, was associated with minimal hepatocellular injury. Our patient presented to the liver clinic of the John Hunter Hospital in 2001 for investigation of abnormal liver function test results. She was taking diltiazem, aspirin, irbesartan plus hydrochlorothiazide, and pravastatin as therapy for hypertension and hyperlipidaemia. She consumed less than 10 g alcohol per week. Liver function tests showed a predominant elevation of alkaline phosphatase and γ-glutamyltransferase, with a minimal rise in alanine and aspartate aminotransferases, a picture consistent with cholestasis rather than hepatocellular disease (see Box). She had started taking pravastatin in the three months preceding her referral, and commented that when she was taking the drug in the previous year she had also had abnormal liver test results. Her liver function test results in 1998 were normal. Two ultrasound examinations of the liver, performed after five months of taking pravastatin in the first period and two months after beginning her second period of therapy, showed normal liver size and echogenicity, and no sign of obstructive liver disease. Tissue antibodies, viral studies for hepatitis viruses, α1-antitrypsin and iron studies were all either normal or negative. Renal function was normal throughout. She had no biochemical evidence of impaired hepatocellular function, and for this reason liver biopsy and endoscopic retrograde cholangiopancreatography were not undertaken. In view of the association the patient made between previously ceasing therapy with the drug (because she felt unwell) and improving liver function, therapy (which was recommenced by the cardiologist for hyperlipidaemia) was again suspended and within two months liver test results improved markedly. We believe that in the absence of other markers of liver disease and with improvement of liver function on both occasions that therapy with pravastatin was suspended, it is likely that this patient has twice developed a cholestatic response to pravastatin. Patient's liver function test results during and after two periods of pravastatin therapy Initial period Second period* Normal range Pravastatin No pravastatin Pravastatin No pravastatin Test Month 0 Month 4 Month 5 Month 6 Month 10 Month 0 Month 1 Month 2 Month 3 Bilirubin (µmol/L) < 20 7 13 5 7 10 11 11 7 9 Alkaline phosphatase (U/L) < 115 230 362 220 213 242 291 347 186 171 γ-Glutamyltransferase (U/L) < 25 259 625 353 231 195 297 463 167 126 Alanine aminotransferase (U/L) < 40 26 85 31 25 28 25 49 16 18 * Commenced seven months after initial episode. Patient's results were normal two years before the initial period.

Robert G Batey · Michelle Harvey

To the Editor: A potentially important, if somewhat crude, means of suicide prevention involves restricting the availability of commonly used methods. In 1967, for example, restrictions on barbiturate prescribing in Australia led to declines in its use for suicide and in overall suicides.1 A crucial concern with this approach is that distressed individuals might use alternative, more lethal, methods. In Britain, there is just such a concern in relation to recent legislation restricting the availability of paracetamol.2 Analysis of the natural experiment investigated by Balit and colleagues3 does not, however, provide useful insights into the impact of paracetamol sales restrictions. Their most consistent finding was that, despite restricted availability for the period studied, paracetamol accounted for about 10% of all contacts with the two poisons information centres in both time periods. In Britain, in 1998, paracetamol purchases from chemists and supermarkets were restricted rather than banned.4 Up to 16 g (32 tablets) may be purchased from pharmacies and 8 g from supermarkets. The aim was not to prevent overdose but to reduce its severity. Presumably, over the periods studied by Balit et al, paracetamol was simply unavailable. As their analysis is based on calls to poisons information centres rather than on the clinical records of people presenting to hospital, they could not assess whether changes in paracetamol availability influenced indicators of severe poisoning — death and liver damage. A decline in the number of severe paracetamol poisonings, without a change in total episodes of paracetamol overdose, might be considered the most important end-point. Attention is drawn to statistically significant rises in calls concerning ibuprofen in one centre and aspirin in the other. The clinical significance of these observations is questionable. Overdoses of ibuprofen are less harmful than paracetamol,5 and the significant rise in aspirin overdose represents an increase from two calls per year to five per year — an increase of only three calls. Of note is the fact that the largest absolute decline in calls related to paracetamol (from 423 per year in 1997–1999 to 370 per year in 2000). Furthermore, as only two time points are compared, it is impossible to determine whether the increases reflect year-on-year changes in use of particular drugs for overdose, as might occur with increased ibuprofen sales. Legislation seeking to influence patterns of harm through changing the availability of drugs which are beneficial when used safely should be monitored carefully.4 Balit et al do not provide convincing evidence concerning the effects of paracetamol sales restrictions on population health.

Corrine R Balit BPharm · Geoffrey K Isbister BSc, MB BS · Andrew H Dawson FRCP(Ed), FRACP · Ian M Whyte MB BS, FRACP

To the Editor: In their recent article,1 Balit et al concluded "restriction of paracetamol-containing products may inadvertently increase poisoning with potentially more toxic agents". As manufacturers of one brand of ibuprofen tablets and the only brand of ibuprofen suspension in Australia, we would like to comment on the article and its conclusion. We understand that the objective of the audit was to determine whether the occurrence of paracetamol and non-paracetamol analgesic deliberate self-poisoning and accidental paediatric poisoning was affected by two periods of recall of paracetamol products. However, our concern is that the article's conclusion — "may inadvertently increase poisoning with potentially more toxic agents" — is not linked to any long term outcomes nor any follow-up regarding ongoing sequelae. This conclusion might give the impression that ibuprofen is more toxic than paracetamol when taken in an overdose situation, whether deliberate or accidental. It might also give the impression that overdoses of ibuprofen leave the patient with ongoing morbidity. In addition, we note that the percentage change in deliberate self-poisonings at both the NSW Poisons Information Centre (PIC) and the Hunter Area Toxicology Service for the periods when paracetamol was restricted, although seemingly large and statistically significant for the PIC, both came from a very low base (0.9% and 0.8% of all calls, respectively).

David Gunnell · Anthea Steans

In reply: There appears to be some misunderstanding about both the conclusions and the methodology of our study.1 We showed that when the availability of one analgesic (paracetamol) decreased, the use of the next most available analgesic increased in deliberate and accidental self-poisonings. We did not look at the relative toxicity of the analgesics, but referred to the published literature on acute paracetamol and ibuprofen overdoses in children, noting that serious complications of acute overdose in children have only been reported with ibuprofen.2-4 Data reported in the study not only included a poisons information centre, but also included data from hospital presentations. The Hunter Area Toxicology Service (HATS) manages all patients with poisoning in the Newcastle region and is based at the Newcastle Mater Misericordiae Hospital. The limitation of the small sample size in the HATS data was discussed in the article, highlighting the fact that, as this was an opportunistic study, it was not possible to increase the sample size. However, the conclusions drawn were based on two different data sets, with a much larger sample size for the NSW Poisons Information Centre data. Overdose is a significant public health problem that requires appropriate post-marketing vigilance. For drugs that are commonly taken in overdose, it is important to take advantage of opportunities to assess the potential effect of any change in availability.

David Gunnell

To the Editor: We read with interest the case report of Ward and colleagues, describing methicillin-resistant Staphylococcus aureus with reduced susceptibility to vancomycin in a patient being treated for lower-limb ischaemia.1 We conclude that this antibiotic resistance may not have developed if the patient had been treated with conventional vascular therapy. The patient had diabetes, was haemodialysis-dependent and continued to smoke. Bilateral lower-limb ischaemia in such a patient is an indication for early vascular assessment, including angiography, debridement of non-viable tissue and, if possible, revascularisation. The option of early below-knee amputation should always be considered for such a patient. Broad-spectrum antibiotics administered over a long period to patients with ischaemic tissue can provide the ideal medium for development of multiresistant organisms. In this patient, 41 days of chronic infection, combined with the decreasing nutritional status typical of haemodialysis patients, contributed to the breakdown of both below-knee amputation sites and the ongoing sepsis. The difficult decision to preserve or amputate an ischaemic limb is best made by a vascular surgeon in consultation with the patient. Amputation should not be seen as treatment failure but as another stage of vascular disease. Early amputation preserves the physical condition and nutrition of patients and allows earlier transfer to rehabilitation units, with an improved result.2

Anthony J Grabs · Reginald SA Lord

To the Editor: The Lipid management guidelines — 2001 supplement1 is no doubt full of cardiovascular wisdom. Unfortunately, the authors appear oblivious to the fact that people are more than just cardiovascular systems. I found no mention of the risks of violent deaths associated with low cholesterol levels, which in some studies have been found to offset the decreased cardiovascular mortality benefits.2 In 1995, Engstrom et al neatly reviewed the relevant issues for those interested in populations of whole people. They cite studies which found low cholesterol levels to be associated with homicidal offenders with habitual violent tendencies when under the influence of alcohol, boys with aggressive conduct disorder, and criminals with antisocial personality, as well as with increased depressive symptoms in men aged 50–89 years. Further, an evaluation of six primary prevention trials found a significant increase in violent deaths in groups receiving interventions to reduce serum cholesterol levels.2 Engstrom et al also reviewed studies which found increased aggression in cynomolgus monkeys fed a low-fat diet. This appeared related to reduced serotonin activity, as serotonin is widely known to reduce aggression. In fairness, Engstrom and colleagues also cited studies which have not found an association between low cholesterol levels and aggression. If the increase in violent deaths associated with changing the dietary habits of whole populations turns out to be more than a red herring, the ethical and financial implications will be staggering. This evidence is not so conclusive as to have made me change my own relatively low-fat diet, but they do make me wonder if my irritation about the oversight in the Lipid management guidelines — 20011 might have something to do with my low fat intake!

Christopher H Cantor

Bacterial housing Biofilm has been shown to be important in prosthetic infections, dental plaque and cystic fibrosis; it has now been found in an animal model of otitis media (OM). Researchers in the United States injected H. influenzae into the middle ears of chinchillas. Starting treatment with ampicillin 72 hours later rendered any effusion culturally sterile. Pairs of chinchillas were killed at 10 intervals, three hours to three weeks after being infected, and their eardrums removed. Scanning electron microscopy showed biofilm formation in all of the animals which had developed middle ear effusions. Microcolony formation was evident after 24 hours, and by five days mature biofilm was present, with tower-type structures consisting of many layers of bacteria in an exopolysaccharide matrix. Frozen specimens were stained (so that, with confocal laser scanning microscopy, live bacterial cells appeared green and dead cells red), showing viable bacteria within the biofilm. JAMA 2002; 287: 1710-1715 Screening blasted Overseas research supports the Australian approach of not screening infants for neuroblastoma. Screening of urine for catecholamine metabolites was offered to 476 654 children in Quebec, Canada,1 between May 1989 and April 1994; 92% were screened at age three weeks and/or six months. Neuroblastoma was detected in 43 infants, who were all still alive in April 2000. However, 22 children in the target population died from neuroblastoma during the 6–11 years’ follow-up (diagnosed aged < 3 weeks, 3; screened negative, 18; not screened, 1). Based on comparisons with other populations (eg, Ontario, Minnesota, Florida), rates of death due to neuroblastoma in children under eight years had not been reduced. In Germany,2 urine screening was offered to 2.5 million children in 6 out of 16 states from 1995 to 2000 (1 475 773 children were tested). The screening detected 149 cases; to date three children have died, all from complications of treatment. By June 2001, 55 children with negative screening results had presented with neuroblastoma, 14 of whom had died. Children in the screened group and in the control states had similar rates of both stage 4 and fatal neuroblastoma. The Canadian group1 note that a body of evidence points to at least two clinical and biological entities. Very few cases of neuroblastoma detected by screening have unfavourable biological features, and there is a high rate of spontaneous regression or maturation into benign ganglioneuromas. On the other hand, disease with an unfavourable prognosis is rarely detectable by screening. 1. N Engl J Med 2002; 346: 1041-1046 2. N Engl J Med 2002; 346: 1047-1053 Stop smoking In a Swiss study, training young physicians to identify patients’ readiness to stop smoking, then implement stage-specific strategies, resulted in improved rates of smoking cessation among their outpatients. The eight hours of training included video demonstrations of motivational interviewing, role-playing, practice interviews and written materials. Doctors were told that a survey of cardiovascular risk factors was being done; they were not aware that they had been randomly assigned to training in smoking cessation (n =17) or a talk on managing dyslipidaemia (controls, n =18). Both the research assistants and the patients (aged 36614 years) whom they interviewed after their outpatient clinic appointment were blind to key elements of the study. At one-year follow-up, 15 of 115 patients treated by intervention group doctors reported not having smoked in the previous week, compared to 7 of 136 control group patients (13% [95% CI, 7%–21%] v 5% [95% CI, 1%–9%]; P = 0.005). Ann Intern Med 2002; 136: 429-437 Placebo power The results of a review of antidepressant trials in outpatients with major depressive disorder confirm the necessity of establishing the efficacy of any new antidepressant against placebo. A systematic search identified 75 randomised, placebo-controlled trials published between 1981 and 2000. Entry to most studies required > 2 weeks of symptoms and a defined minimum score on the Hamilton Rating Scale for Depression (HRSD), and response was a reduction of ≥ 50% in HRSD score. Overall, response to placebo was 29.7% (SD, 8.3%; range, 12.5%–51.8%), and to antidepressant 50.1% (SD, 9%; range, 31.6%–70.4%). Although both response rates increased with year of publication, the association for placebo response rates was stronger. The researchers, from Columbia University, could not identify other factors that accounted for the increase in placebo response. JAMA 2002; 287: 1840-1847

Med J Aust 2002; 176 (11 Suppl).