Infectious diseases

Objective: To describe the epidemiology, clinical features and diagnosis of Mycobacterium ulcerans infection occurring on the Bellarine Peninsula in Victoria. Design, setting and patients: Analysis of prospectively collected data on all patients with confirmed M. ulcerans infection reported from the Bellarine Peninsula and managed at Barwon Health ...

Sarah C Boyd MB BS · Eugene Athan MB BS, FRACP · N Deborah Friedman MB BS, FRACP · Andrew Hughes MB BS, FRACP · Aaron Walton MB BS, FRACP · Peter Callan MB BS, FRACS · Anthony McDonald MB BS, FRACS · Daniel P O’Brien MB BS, FRACP

Objective: To compare the unprecedented 91 cases of melioidosis in the Top End of the Northern Territory of Australia from 1 October 2009 to 30 September 2010 with the 540 cases in the preceding 20 years and postulate reasons for this year of very high melioidosis incidence.Design, setting and participants: Review of prospectively collected data on all patients with culture-confirmed melioidosis at Royal Darwin Hospital, the Top End’s tertiary referral centre, since 1 October 1989.Main outcome measures: Population-based annual incidence of melioidosis; differences in epidemiology, clinical presentations and outcomes for 2009–2010 compared with the preceding 20 years.Results: In 2009–2010, the estimated population-based incidence of melioidosis was 50.2 cases per 100 000 in the Top End population overall, and 102.4 cases per 100 000 in the Top End Indigenous population. The proportion of patients acquiring melioidosis in the Darwin urban area increased from 49% in 1989–2009 to 65% in 2009–2010 (OR, 1.96; 95% CI, 1.20–3.19). Among the 49 Indigenous Australian patients with melioidosis in 2009–2010, 63% acquired the infection in Darwin, compared with 35% of Indigenous patients in the previous 20 years (OR, 3.17; 95% CI, 1.62–6.24).Conclusions: In 2009–2010, the Top End had the highest annual incidence of melioidosis documented from anywhere to date. The prominent increase in cases in Darwin was associated with above average rainfall in Darwin during December 2009 to February 2010. The increase in the proportion of Indigenous Australians who acquired melioidosis in Darwin may reflect movement of some Indigenous people into Darwin from remote communities.

Uma Parameswaran MB BS · Robert W Baird MB BS, FRACP, FRCPA · Linda M Ward BAppSci, MMedSci · Bart J Currie FRACP, FAFPHM, DTMTH

We report the first human case of babesiosis in Australia, thought to be locally acquired Clinical recordA 56-year-old man with serious hepatic, renal and bony injuries was transferred to Canberra Hospital in mid November 2010 following a motor vehicle accident. His medical history included type 1 diabetes mellitus, excessive alcohol and prescription medicine use, depression, hypertension and hypercholesterolaemia. He had no history of injecting drug use. He had been living on the south coast of New South Wales with his son. During the first 4 months of his admission he required surgery, prolonged broad-spectrum antibiotic therapy and total parenteral nutrition. He developed worsening cholestatic liver function, moderate-to-severe thrombocytopenia and fluctuating anaemia. By late March 2011, he was pancytopenic with worsening anaemia due to intravascular haemolysis, lymphopenia and severe thrombocytopenia, and required ongoing blood product transfusions. The result of an HIV test was negative. In early April, the patient was transferred to the intensive care unit because of respiratory and haemodynamic deterioration. On 10 April, intraerythrocytic parasites were incidentally identified during routine examination of blood films taken that morning. Ring-form parasites, initially thought to be a Plasmodium species, were confirmed on thick and thin films. Results of immunochromatographic tests were negative for Plasmodium falciparum; however, intravenous artesunate and primaquine therapy for presumed severe malaria was commenced. Broad-spectrum antibiotic therapy was continued. After 48 hours without clinical improvement, the parasitaemia level had increased from 1.7% to 2.6% infected red blood cells. Re-examination of the blood films and recognition that the organisms did not produce hemozoin led to the presumptive diagnosis of babesiosis infection. This was confirmed by Australian and overseas experts who viewed electronic files of the slides. The patient was then given intravenous quinine (600 mg 8-hourly) and clindamycin (600 mg 6-hourly) for babesiosis. Azithromycin and tigecycline were also added to provide additonal broad-spectrum antimicrobial cover, but clinical deterioration continued, and the levels of parasitaemia, anaemia and thrombocytopenia did not improve. He developed multiorgan failure and required haemodialysis. The parasitaemia peaked at 5.1% infected red blood cells despite ongoing blood transfusions (including 18 units of packed red cells over 8 days). As his condition was too unstable for him to undergo total red cell exchange, an exchange of 500 mL of blood was performed on 16 April. He did not recover from the multiorgan failure, and severe thrombocytopenia contributed to acute gastrointestinal bleeding. On 18 April — 5 days after commencing specific antibabesiosis therapy — he suffered a fatal asystolic arrest. Following the patient’s death, a retrospective study of the blood films taken during his hospital admission was undertaken. Ring-form parasites were detected in very low numbers back to the end of the first week of March 2011, coinciding with the development of severe thrombocytopenia. Initially, the multiple blood products that the patient received during his admission were thought to be the likely cause of his babesiosis. But blood films stored by his local pathology service and taken between September and November 2010 (ie, before his hospital admission) revealed pre-existence of the intraerythrocytic parasite and hyposplenic features. As the patient had not received blood products before his hospital admission in November 2010, the parasitaemia could not have been transfusion related. He had reported being bitten by ticks, but had been too sick to qualify this further. Due to general ill health, he had not worked or left the local area for many years. His only overseas travel had been to New Zealand almost 40 years earlier, a country with no known human babesiosis. It thus seemed unlikely that the babesiosis was acquired from overseas. The patient had lived on the south coast of New South Wales for over 30 years — on a small farm with two horses and two Staffordshire bull terriers for 25 years, and then at a house in a small town with his son and a new Staffordshire bull terrier (acquired from within Australia) for 8 years. The new Staffordshire bull terrier was their only pet and was still living at their south coast home in mid 2011. Both his son (who was asymptomatic) and his Staffordshire bull terrier underwent testing for babesiosis; the results were negative. To identify the organism and further elucidate its source, blood samples and films from the patient were examined at the Centers for Disease Control and Prevention (CDC) in Atlanta, United States, and at the School of Veterinary and Biomedical Sciences, Murdoch University, Western Australia. Both laboratories agreed that the morphological characteristics of the parasites in the blood films were consistent with a small Babesia. Intraerythrocytic organisms were mostly single and measured 1.5–2.5 m in size but were highly polymorphic; pyriform and ovoid forms predominated, bizarre amoeboid forms were also common, and an occasional tetrad (Maltese cross form) was noted (Box 1). Immunofluorescent antibody testing for Babesia microti was performed by the CDC on serum samples from the patient (positive result, with titre of 1 : 256) and his son (negative result). Complete sequencing of the 18S ribosomal RNA gene (18S rDNA) and partial sequencing of the β-tubulin gene (both amplified by polymerase chain reaction) confirmed that the organism in the patient’s blood was B. microti. At the CDC, a nested PCR that specifically amplifies a 154-base-pair fragment from the B. microti 18S rDNA was initially used to confirm the presence of B. microti in the patient’s blood. In addition, sequencing of a 1767-base-pair fragment amplified with primers Crypto FL (5'-AACCTGGTTGATCCTGCCAGTAGTCAT-3') and Crypto RN (5'-GAATGATCCTTCCGCAGGTTCACCTAC-3'), was performed to strengthen the PCR findings.1 The 18S rDNA sequence obtained was 100% similar to the GenBank entry AY693840 obtained from a B. microti isolate 18S rDNA gene. At Murdoch University, two nested sets of universal piroplasm 18S rDNA primers were used, one of which has been published.2 The patient’s son’s blood was used as a negative control. The consensus sequence was 100% homologous to known human-derived Babesia species isolates. In addition, five novel primer sets designed during this study were used to obtain a partial β-tubulin gene fragment (791 base pairs), which confirmed the presence of B. microti in the patient’s blood and showed 100% homology with North American isolates (eg, GenBank entries AB083377 and AY144722). A phylogenetic tree for this locus (produced using the maximum likelihood method) revealed clustering with isolates of B. microti obtained from the tick species Ixodes scapularis (formerly known as Ixodes dammini), humans and voles in North America. DiscussionTo our knowledge, this is the first report of a human case of babesiosis in Australia, which we believe was locally acquired. Human babesiosis is an emerging tick-borne zoonosis. The first human case was reported in Croatia in 1957.3 In 1968, Babesia divergens was identified as the cause of human babesiosis in Europe; this was soon followed by the discovery of human cases of B. microti infection in the US.4 More recently, human cases of babesiosis have emerged from Asia, Africa and South America.5-8 Since B. microti has never been detected in Australia before, its discovery as the cause of infection in this patient, who had no significant history of travel, raises intriguing questions about its natural hosts and epidemiology on this continent. Traditionally, B. microti is considered to have a Holarctic distribution, associated with a variety of small mammalian hosts (rodents, including voles, and shrews), and is transmitted by several Ixodes tick species present throughout the northern hemisphere, with humans becoming infected as accidental hosts. Recent phylogenetic analyses based on complete sequences of the genes encoding 18S ribosomal RNA, β-tubulin and the η subunit of the chaperonin-containing t-complex polypeptide 1 suggest that B. microti represents a genetically diverse species complex that comprises several geographically distinct clusters located in North America, Eurasia and Japan, and is closely related to “Babesia microti-like” species isolated from an ever-expanding range of feral and domesticated mammal hosts.9 In Australia, babesiosis is a well documented disease of cattle (Babesia bigemina and Babesia bovis) and dogs (Babesia canis, Babesia vogeli and Babesia gibsoni), and babesiosis tick vectors have been imported to the continent since European settlement.10,11 Australia also has a diverse variety of native Ixodes ticks, including Ixodes holocyclus (responsible for tick paralysis), and a few Babesia and Theileria species have been described morphologically in native marsupial hosts (but not B. microti).12 Unfortunately, a paucity of molecular studies means that the taxonomy and phylogenetic relationships of the endemic piroplasms (intraerythrocytic tick parasites, including Babesia and Theileria) are not well understood. Based on phylogenetic analysis, the isolate from this patient was most closely related to North American strains of B. microti, so it is unlikely that the piroplasm described here originated from a native Australian mammal, but not impossible. In the absence of transfusion or injecting drug history, the patient must have become infected following a tick bite. Two scenarios seem probable. The patient might have been bitten by an imported tick (contained within clothing or luggage that had recently arrived from an endemic country), but no history suggested such contact. Alternatively, a local tick might have transmitted an autochthonous infection, presumably originating from one or more species of introduced rodent. The natural history of this patient’s infection is notable. Babesia ring forms were detectable on routine blood films taken while he was an outpatient — 7 months before he died. At that time, he was asymptomatic and neither anaemic nor thrombocytopenic, but 6 months later the babesiosis became symptomatic and severe. The parasitaemia of 5.1% around the time of his death was likely to have been an underestimate of the true figure as it would have been diluted by the multiple blood products that he was receiving at the time. Asymptomatic parasitaemia is well described in babesiosis, both in the setting of primary infection and following treatment of symptomatic infection.4 It is unclear what transformed this patient’s chronic asymptomatic infection into a severe symptomatic infection that probably contributed to his death. He did have risk factors for severe babesiosis: hyposplenism, liver impairment and his age;4 however, these were present when the infection was asymptomatic months earlier. It is possible that his chronic hospitalisation, and general deconditioning from the long admission, resulted in significant immunosuppression. Severe babesiosis from B. microti is a serious condition with a case fatality rate of 5%–10%.13 Indeed, this patient’s condition did not improve despite his receiving recommended therapy once the diagnosis of babesiosis was made. Even the artesunate that he received for suspected malaria (immediately before the diagnosis) has been shown to have activity against B. microti in animal models.14 Although the animal host for B. microti is yet to be identified in Australia, the proximity of ticks, other wildlife and human populations along Australia’s eastern seaboard means that further cases may be encountered. Clinicians working in Australia should therefore be aware of the signs and symptoms of babesiosis and how to diagnose it (Box 2). Further investigation into the piroplasms of native mammals, introduced rodents and their ticks is necessary to identify the source of this infection. As transfusion-related babesiosis is well recognised in other countries,15 this case may have future implications for the screening of blood products in Australia. 1 Blood film from a 56-year-old man infected with Babesia microti, showing a tetrad form (black arrow) and single ovoid forms (white arrows) Wright stain; original magnification, 3 100. 2 Diagnosing human babesiosis in Australia When to suspect babesiosis Clinicians should suspect babesiosis in patients in Australia who have haemolytic anaemia, thrombocytopenia, fever, an influenza-like illness and a history of at least one of the following: tick bites outdoor activities putting one at risk of tick bites transfusion of blood products overseas travel to a region where babesiosis is endemic. How to proceed with the diagnosis Thick and thin blood films should be examined for intraerythrocytic parasites (three sets of films should be taken, 8–12 hours apart). If the results of blood films are negative but the diagnosis is still suspected, antibody testing of serum and molecular testing of blood (by polymerase chain reaction) can be done.

Sanjaya N Senanayake MB BS, FRACP, MAppEpid · Andrea Paparini MSc, PhD · Maya Latimer MB BS, FRACP, FRCPA · Kerrie Andriolo GradCert (DiagnosticPathology) · Alexandre J Dasilva PhD · Heather Wilson MB BS, PhD · Maniphet V Xayavong BA, MBA · Peter J Collignon MBBS, FRACP, FRCPA · Phillip Jeans MB BS, FRACS · Peter J Irwin BVetMed, PhD, FANZCVSc

Viewing germs through biological and sociological lenses. In 1922, Simon Flexner, the director of the Rockefeller Institute in New York City, observed that “each generation receives its particular impression of epidemic diseases”. After the influenza pandemic of 1918, the postwar medical generation was trying to ...

Warwick H Anderson MD, PhD

To the Editor: A 12-year-old boy presented to a regional emergency department with a 3-day history of progressing bilateral conjunctival injection, fevers (39°C), a widespread erythematous bullous rash, and superficial erosions to his lips, oral mucosa and urethral meatus. The patient was admitted to hospital for management of Stevens–Johnson syndrome (SJS). Initial treatment included intravenous f luids, intravenous ceftriaxone and oral azithromycin before transfer to a tertiary referral hospital. The patient had not taken any oral medications or over-the-counter therapies. He had no preceding viral symptoms. However, 2 weeks before onset of symptoms, he had received vaccination against varicella-zoster virus. On Day 1 of admission, intravenous immunoglobulin (Intragam P, CSL, Melbourne, VIC; batch numbers 3740600696, 3740500668, 3740600690, 3740600679) was administered at a dose of 1 mg/kg and repeated 20 hours later. On Day 2, oral prednisolone therapy (1 mg/kg/day) was initiated and continued for 5 days, and antibiotics were administered for 8 days (cefotaxime [50 mg/kg] and azithromycin [10 mg/kg]). Mycoplasma pneumoniae serological testing of blood samples taken on admission was negative. Bilateral conjunctival ulcers were managed with topical chloramphenicol eye ointment, topical 0.5% prednisone, lubricant drops and normal saline washes. The patient developed further areas of bullae and erosions to his cheeks and ears (Box). He also developed palmar papules, and dusky finger tips and toes. Skin bullous lesions were managed with daily sterile aspiration, and erosions were managed with silver-impregnated silicone dressings (Mepilex Ag, Mölnlycke Health Care, Gothenburg, Sweden). The patient’s rash and fevers abated, and he was discharged on Day 12 with advice from the dietitian and physiotherapy-assisted mobilisation. Sequelae at 2 months included cutaneous post-inflammatory hyperpigmentation. SJS after varicella infection has been reported,1,2 and a single case after varicella vaccination was included in a case series of six possible cases of SJS after vaccinations.3 SJS after medication use or infection with M. pneumoniae is well documented; however, cases where no clear cause can be documented result in increased parental anxiety. This case of SJS was preceded by varicella-zoster vaccination performed as part of school protocol. In the absence of any other obvious cause, it has been reported to alert practitioners of the possibility of a link (Therapeutic Goods Administration adverse drug reaction no. 291111). Patient with Stevens–Johnson syndrome after varicella vaccination

Elizabeth M Christou · Orli Wargon

Incorrect description of microbiological methods: In “Meningitis and pneumonitis caused by pet rodents” in the 20 February 2012 issue of the Journal (Med J Aust 2012; 196: 202-203), there was an error in the clinical record box. The third sentence of the fourth paragraph should have read: “After 24 hours of incubation, light growth of an organism was noted on blood and chocolate agars (Oxoid Australia, Thebarton, SA) which had been incubated anaerobically and in supplemental carbon dioxide.”

Lito E Papanicolas · Judith M Holds · Narin Bak

Clinical record In 2011, a previously well 26-year-old office worker presented to a large Australian metropolitan hospital with a severe headache. Her illness had begun 3 days earlier with fever and a sore throat, after which she developed a severe, unrelenting occipital headache that was associated with nausea, vomiting, photophobia and neck stiffness. She had no respiratory symptoms such as cough or dyspnoea. The patient had a temperature of 38.5°C, pulse rate of 132 beats/min, respiratory rate of 20 breaths/min and blood pressure of 102/65 mmHg. Clinical examination revealed meningism and tender lymphadenopathy in the anterior cervical chain. Blood tests showed an elevated creatinine level (104 μmol/L; reference interval [RI], 50–100 μmol/L) and leukocytosis with neutrophilia (neutrophil count, 15.56 × 109/L; RI, 1.8–7.5 × 109/L). Lumbar puncture revealed a raised cerebrospinal fluid (CSF) opening pressure of 37 cmH2O (RI, < 18 cmH2O). CSF microscopy showed no cells and no bacteria. No antibiotic therapy was given. Results of a plain computed tomography scan of the patient’s brain and a subsequent computed tomography venogram with contrast were normal. On Day 2, the patient continued to be febrile and two sets of blood cultures were performed. Further tests showed a raised C-reactive protein level (380 mg/L; RI, < 8.0 mg/L) and a mild coagulopathy (international normalised ratio, 1.4; RI, 0.8–1.2) with thrombocytopenia (platelet count, 123 × 109/L; RI, 150–400 × 109/L) suggesting early disseminated intravascular coagulation. That evening, the patient developed respiratory distress and hypoxaemia, with an arterial partial pressure of oxygen of 66 mmHg despite receiving a fraction of inspired oxygen (Fio2) of 80%. She was transferred to the intensive care unit, where she received non-invasive ventilation. A chest x-ray revealed bilateral patchy infiltrates consistent with a pneumonic process (Box 1). Antibiotic treatment with ceftriaxone and azithromycin was initiated. On Day 3, growth was detected in the aerobic bottle from one set of blood cultures after 20 hours of incubation (BACTEC Plus, BD Diagnostics, Sparks, Md, USA), and antibiotic treatment was changed to piperacillin–tazobactam and ciprofloxacin. An initial Gram stain showed a thin gram-negative rod with no distinguishing features. After 24 hours of incubation, light growth of an organism was noted on blood and chocolate agars (Oxoid Australia, Thebarton, SA) which had been incubated anaerobically and in supplemental carbon dioxide. Gram stain of these colonies showed irregular, bulbous gram-negative organisms typical of Streptobacillus moniliformis (Box 2). Antibiotic susceptibility was performed by Etest (bioMérieux, Marcy l’Etoile, France). The organism’s minimum inhibitory concentration to penicillin was 0.016 mg/L and to ceftriaxone was 0.008 mg/L. The organism was definitively identified by 16S rRNA sequencing. This showed a 100% base-pair match with S. moniliformis. The next closest match was a Leptotrichia species with a 94% base-pair match. On Day 5, a blanching macular rash involving all limbs, including palms and soles, became apparent (Box 3). Histological examination of a biopsy sample of a macule from the patient’s hand showed a neutrophilic inflammation of the small dermal vessels consistent with leukocytoclastic vasculitis. By this time, the patient’s respiratory function had improved markedly and she was transferred to a medical ward. Further history-taking revealed that the patient owned two pet rats. Although the animals had never bitten her, she had had close contact with her pets, including cuddling and kissing them. On Day 9, lumbar puncture was repeated to ensure normalisation of pressures; the CSF opening pressure was normal (14 cmH2O), but the CSF showed a pleocytosis with two polymorpho- nucleocytes, 59 monocytes and 75 red cells. There was no growth of bacteria on standard cultures of CSF. Antibiotic therapy was changed to intravenous ceftriaxone (2 g twice daily) for a further 7 days to ensure treatment of possible meningitis. Results of further investigations, including transthoracic echocardiogram, whole-body bone scan and CT pulmonary angiogram, were negative. The patient was discharged home after 17 days in hospital and made a full recovery with no relapse. This case highlights the importance of history-taking and the need to perform blood cultures in patients presenting with fever. The differential diagnoses considered were wide and included bacterial sepsis, viral infection and autoimmune disease. Bacterial sepsis from streptococcal, meningococcal or staphylococcal infection was considered most likely in this patient. Definitive diagnosis was helped by the isolation of S. moniliformis from blood culture, which allowed targeted therapy and improved prognosis. It is possible that our patient was co-infected with an arenavirus such as lymphocytic choriomeningitis virus (LCMV). Although LCMV is rare, it can be acquired by handling pet rodents or their excreta and can cause a flu-like illness with aseptic meningitis.1 Diagnosis of LCMV infection would require molecular testing of blood or CSF in a reference laboratory. S. moniliformis, a causative agent of rat bite fever, is part of the commensal flora of the rat’s oropharynx.2 Another form of rat bite fever — known as “sodoku” — is caused by Spirillum minus, a spirochaete-like organism.2 Sodoku generally differs from S. moniliformis infection by causing induration at the site of the rodent bite and having an incubation period of more than 10 days. The incubation period for S. moniliformis infection is typically fewer than 7 days.2 Rat bite fever, as the name suggests, is usually acquired through a rat bite. However, the disease can result from handling and exposure to excreta or saliva of rodents such as rats or guinea pigs.2,3 S. moniliformis infection can also be caused by ingestion of contaminated milk; in such cases it is known as Haverhill fever, as the first known outbreak (in 1926) occurred in Haverhill, Massachusetts.2 Clinical manifestations of S. moniliformis infection include fever, headache, rash and polyarthritis. The rash typically involves the extremities, including the palms and soles, with a leukocytoclastic vasculitis seen on histology.4 The disease is often mild or self-limiting. However, infection is potentially lethal and can cause rapid death in previously healthy adults.2,5 The overall mortality rate is estimated to be 13%.2 Although less frequently reported than fever, headache, rash and polyarthritis, pneumonitis and endocarditis are common autopsy findings in those who succumb to the disease.5-7 Meningitis due to S. moniliformis is rare, but it has been described in Dutch and Portuguese literature.8,9 Classically, this organism has been described as slow and difficult to grow in the laboratory. This was not the experience in our laboratory as growth occurred within 24 hours, although enriched media and incubation with supplemental carbon dioxide was required. The initial Gram stain was not distinctive, but with subculture the bacteria became irregular and formed bulbar swellings, a feature highly suggestive of S. moniliformis. The standard recommended therapy is penicillin, but S. moniliformis is susceptible to a number of other antibiotics including cephalosporins and macrolides. In cases where the organism has been isolated, in-vitro antibiotic susceptibility testing should be done for any antibiotic being considered for clinical use.2 Systemic illness following rat bite has been recognised for thousands of years. Historically, the disease was associated with squalor and slum-dwelling. However, victims in recent years have included laboratory workers, pet shop employees and, increasingly, owners of pet rats.2,4,5,10 As this case demonstrates, a bite is not necessary for infection — close contact with rodents may be sufficient. As rodents become more popular as household pets, more cases of S. moniliformis infection due to affectionate contact are likely to occur. 1 Chest radiograph (mobile, erect) taken on Day 2, showing diffuse bilateral infiltrates consistent with a pneumonic process 2 Gram stain of Streptobacillus moniliformis cultured from the patient’s blood (100 × magnification) 3 Characteristic rash on the patient’s palms Lessons from practice Rat bite fever caused by Streptobacillus moniliformis is an uncommon but potentially lethal systemic infection. The organism has a distinctive Gram stain appearance which allows for early presumptive identification. A thorough history, including history of animal exposure and pet ownership, should be taken for all febrile patients. Transmission of S. moniliformis can occur by affectionate contact; a bite is not required.

Lito E Papanicolas BM BS · Judith M Holds BLabMed · Narin Bak MB BS, FRACP, MPH

To the Editor: Tenofovir disoproxil fumarate is a nucleotide analogue reverse transcriptase inhibitor that is used in Australia as first-line antiviral treatment for HIV infection.1,2 Tenofovir may be nephrotoxic, particularly affecting proximal tubular function.3 We report a case of tenofovir-associated Fanconi syndrome, which demonstrates the need for vigilance in patients taking tenofovir. A 17-year-old rurally residing boy with perinatally acquired HIV infection presented to a tertiary referral hospital with renal impairment. His serum creatinine level had been normal 4 years previously. He had had severe leg pain and weakness for over a year, and was unable to mobilise without a walking frame. Because of his illness, he had stopped studying. He had commenced antiretroviral therapy in 1996, when he was 3 years old, and at presentation was taking tenofovir plus emtricitabine and lopinavir plus ritonavir. Follow-up with his local clinician was intermittent. The patient’s HIV viral load was undetectable, and he had a CD4 count of 0.62 × 109 cells/L. His serum creatinine level was 150 μmol/L (reference interval, 60–110 μmol/L) and his estimated glomerular filtration rate (eGFR) was 52 mL/min/1.73 m2 (normal value, > 90 mL/min/1.73 m2). He had all the features of Fanconi syndrome — hypophosphataemia with renal phosphate wasting, glycosuria, aminoaciduria, a reduced serum uric acid level and proteinuria (1.93 g/day). He also had hypokalaemia and acidosis, and his urine tested positive for β2-microglobulin. Histological analysis of a renal biopsy specimen showed proximal tubular abnormalities (Box). In addition, he had severely reduced bone mineral density, elevated bone turnover markers and vitamin D deficiency. The patient’s tenofovir therapy was ceased, he was started on an alternative antiretroviral regimen, and he was given phosphate, potassium, bicarbonate and calcium supplementation plus vitamin D and calcitriol therapy. Two months later, his serum creatinine level was 130 μmol/L, his eGFR was > 60 mL/min/1.73 m2, and his proteinuria, glycosuria and aminoaciduria had resolved. His leg pain and weakness resolved within another month. He has since been able to recommence full-time study. The persistent biochemical and renal abnormalities in this patient may have been a result of delayed recognition of Fanconi syndrome leading to prolonged illness. Risk factors for tenofovir-associated nephrotoxicity include a GFR of less than 90 mL/min/1.73 m2, use of nephrotoxic medications, comorbidities (eg, diabetes and hypertension) and use of some protease inhibitors. Patients on tenofovir should be screened at least 6-monthly for eGFR, serum phosphate levels, proteinuria and glycosuria.4 Three-monthly testing is also suggested in the initial year, due to the occurrence of tenofovir-associated nephrotoxicity without risk factors.5 Urinary protein to creatinine ratio is usually increased in tenofovir-associated nephrotoxicity, and tests for some urinary proteins may be useful in subtle cases of the condition.3 Testing for albuminuria (a marker of glomerular disease) and sole reliance on eGFR are insufficient for detecting tenofovir-associated tubular dysfunction.3 Due to potential renal toxicity, optimal outcomes for patients on tenofovir require careful monitoring of patients and close liaison between treating practitioners. Renal biopsy specimens showing proximal tubular abnormalities in a patient with tenofovir-associated Fanconi syndrome A: Prominent changes of acute tubular necrosis (haematoxylin and eosin stain; original magnification, × 4). B: Acute tubular necrosis with proximal tubular eosinophillic inclusions (arrows) representing giant mitochondria visible by light microscopy (haematoxylin and eosin stain; original magnification, × 10).

David M Gracey · Mangalee Fernando · John Ziegler · Christopher P White · Jeffrey J Post

Murray Valley encephalitis virus (MVEV) is a mosquito-borne virus that is found across Australia, Papua New Guinea and Irian Jaya.MVEV is endemic to northern Australia and causes occasional outbreaks across south-eastern Australia.2011 saw a dramatic increase in MVEV activity in endemic regions and the re-emergence of MVEV in ...

James Knox BSc(Med), MBBS, DTM · Raquel U Cowan MB BS, PhD · Joseph S Doyle MB BS, MSc, FRACP · Matthew K Ligtermoet MB BS, BMed Sci · John S Archer MB BS, FRACP, PhD · James N C Burrow MB BS, FRACP · Steven Y C Tong MB BS, FRACP, PhD · Bart J Currie FRACP, FAFPHM, DTM · John S Mackenzie PhD, FASM, FACTM · David W Smith MB BS, FRCPA, FACTM · Mike Catton BSc(Hons), MB ChB, FRCPA · Rodney J Moran · Craig A Aboltins MB BS(Hons), FRACP · Jack S Richards MB BS, FRACP, PhD

To the Editor: We read with interest the article by Pinto and colleagues regarding colonisation of reusable tourniquets by multiresistant organisms (MROs).1 We highlight that surgical adhesive tape also has the potential to act as a significant fomite in health care settings. We collected partially used surgical tape rolls from several clinical areas of three hospitals in the Hunter New England Area Health Service. Using hands disinfected with alcohol gel, tape rolls from different locations in each area were placed into 21 clean collection bags (up to three tapes per bag). Tapes from each batch were placed in 21 sterile containers with 15 mL of brain–heart infusion broth and incubated overnight at 35°C in carbon dioxide. The broths were subcultured onto Columbia horse-blood agar (Oxoid Australia, Adelaide, SA), MacConkey agar (Oxoid) and differential selective media to detect vancomycin-resistant enterococci (VRE) (chromID VRE; bioMérieux, Marcy L’Étoile, France), methicillin-resistant Staphylococcus aureus (MRSA) (Brilliance MRSA; Oxoid) and multiresistant gram-negative bacteria (chromID ESBL; bioMérieux). A multiplex tandem polymerase chain reaction assay (MRSA4; AusDiagnostics, Sydney, NSW) to detect MRSA and methicillin-susceptible S. aureus (MSSA) was also performed on all broth cultures. Routine species level identification was performed (VITEK MS; bioMérieux). Susceptibility was determined in accordance with Clinical and Laboratory Standards Institute criteria.2 In 11 of the 21 tape batches, MRSA and/or VRE were identified. Of these, four were positive for MRSA and 10 for VRE, with three positive for both. MSSA was identified in two, both in association with VRE. All batches showed evidence of contamination with other bacteria such as Bacillus cereus, coagulase-negative staphylococci, non-multiresistant Enterobacteriaceae, Pseudomonas spp, Acinetobacter spp and other enterococci. Our results indicate that surgical adhesive tapes are frequently contaminated with MROs. Interpretation of these results is limited by the small number of tapes and clinical areas sampled, and the difficulty of proving a relationship to clinical infection. However, items such as intravenous cannulae, surgical drains and wound dressings are frequently fixed using surgical adhesive tape. This may lead to colonisation and subsequent infection. Furthermore, tape rolls are often left lying on contaminated surfaces, are handled by multiple individuals and cannot be disinfected. Surgical adhesive tape is a potential reservoir of pathogenic bacteria3 and fungi4 and was implicated in a prolonged S. aureus outbreak in a neonatal unit.5 The role of surgical tape as a potential fomite was reported in 19746 but has not been widely acknowledged since. Removing the outer layer of the tape roll is unlikely to reduce contamination, given visible contamination of the side of many rolls (Figure).3 Short rolls of surgical adhesive tape should be supplied in sealed packets and used for individual patients, only after hand disinfection, and discarded after use.

Patrick N A Harris · Chris Ashhurst-Smith · Sandy J Berenger · Alison Shoobert · John K Ferguson

To the Editor: Antimicrobial resistance has been identified as a major concern in Australia, particularly as few new antimicrobial agents are being developed.1 Studies suggest that up to half of antimicrobial agents prescribed in hospitals are inappropriate.2-4 Antimicrobial stewardship interventions, including dissemination of clinical guidelines and restrictions on antimicrobial formularies, may not be fully able to account for the complex indications for antimicrobial use in hospitalised patients. We instituted a rapid clinical audit and feedback system of patients on one of 14 restricted antimicrobial agents as a component of antimicrobial stewardship activities in 2011 at the Alfred Hospital in Melbourne. Multidisciplinary antimicrobial stewardship ward rounds involving a senior clinical pharmacist, an infectious diseases (ID) registrar and an ID physician were performed on weekdays. Patients in units (respiratory, haematology/bone marrow transplantation, burns and intensive care) who had existing liaison ID services were excluded from our analysis. Patients included in the analysis were prescribed a restricted antimicrobial, either for an indication outside hospital policies, or where approval had not been obtained through a web-based antimicrobial approval system. Between January and April 2011, 473 patients were identified as requiring review by the antimicrobial stewardship team. In total, 236 recommendations (Box) were made for 158 patients across all 18 units (73% surgical, 27% medical). For other patients, antimicrobial use was deemed clinically justified or the antimicrobial agent had been ceased at the time of review. Recommended changes to therapy involved ceftriaxone (n = 70), piperacillin/tazobactam (n = 23), ciprofloxacin (n = 22) and vancomycin (n = 18). A formal referral to the ID consultation service was made for 11 of the 236 patients (5%). Recommendations were followed in 78% (184/236) of cases; acceptance of recommendations was higher when review involved the ID physician (146/176, 83%) than when it did not (38/60, 63%; P = 0.002). Rapid clinical review by a multidisciplinary antimicrobial stewardship team was able to assess large numbers of patients requiring restricted antimicrobial agents. Postprescribing evaluation has been reported mainly in North American studies, but has not been reported in Australian hospitals.5 In most patients, agreement was reached with the treating clinicians to cease or reduce the use of antimicrobial agents, suggesting that their ongoing use was not clinically justified. In addition, regular ward rounds by the team supported compliance with the antimicrobial approval system, provided education to junior medical staff and identified antimicrobial use protocols that had no basis in evidence. Proportion of the antimicrobial stewardship team’s recommendations accepted Recommendation Accepted Stop antimicrobial agent 72% (56/78) Change drug dose 75% (33/44) De-escalate antimicrobial cover 83% (25/30) Change to oral antimicrobial agents 90% (26/29) Change drug to alternative 88% (21/24) Formal infectious diseases consult 64% (7/11) Initiate antimicrobial 73% (8/11) Additional management 100% (4/4) Additional diagnostic procedures 67% (2/3) Therapeutic drug monitoring 100% (2/2) Total 78% (184/236)

Kelly A Cairns · Adam W J Jenney · Sushena Krishnaswamy · Michael J Dooley · Orla Morrissey · Sharon R Lewin · Allen C Cheng

To describe the clinical outcomes for all HIV-serodiscordant couples attending an assisted reproduction program.

on behalf of the CVI Study Group

Objective: To report outcomes from the first 2 years of the National Hand Hygiene Initiative (NHHI), a hand hygiene (HH) culture-change program implemented in all Australian hospitals to improve health care workers’ HH compliance, increase use of alcohol-based hand rub and reduce the risk of health care-associated infections.

M Lindsay Grayson MD, FRACP, FAFPHM · Philip L Russo MClinEpid, BN · Marilyn Cruickshank RN, PhD, FRCNA · Jacqui L Bear BEc, MLitt, GradCertMgmt · Christine A Gee MBA · Clifford F Hughes AO, FRACS, FACS · Paul D R Johnson MB BS, PhD, FRACP · Rebecca McCann BSc(Nursing) · Alison J McMillan MBA, BEd, RN · Brett G Mitchell RN, MAdvPrac, DTN · Christine E Selvey MB BS, MSc · Robin E Smith MBA · Irene J Wilkinson BSc(Hons), MPH

Take another look at the cover of this issue of the MJA and you will see just how close Papua New Guinea (PNG) is to Australia’s Boigu Island. In 2004, Queensland Health established tuberculosis (TB) clinics on Boigu and Saibai islands in the Torres Strait to provide medical care for PNG residents with multidrug-resistant TB (MDR-TB) (Queensland Health spokesman, personal communication, Oct 2011). The strategy has been extremely effective in treating these difficult cases and has, as Vincent states, been credited with “there being no MDR-TB cases detected in the Australian population in this region”. It is not surprising, then, that TB experts are working to lobby the government to reconsider its decision to close these clinics by February 2012 and hand over care of these patients to services provided by PNG. PNG is a desperately poor country, ranked 137 out of 169 countries in the United Nations Human Development Index (http://hdr.undp.org/en/statistics). Its health services are largely in disarray. The position statement in this issue of the Journal (Reynolds et al) invokes the World Health Organization ethical guidelines for care of patients with TB to call for free, equal and comprehensive care for patients with TB who present within our borders. It insists that transfer to the home country for ongoing care should only be contemplated when it is known that adequate care will be available. It recommends that Australia provide financial and technical support to neighbouring countries with endemic TB. The authors of the position statement cite sound economic and scientific reasons, as well as the obvious humanitarian arguments, for their stand. For example, the WHO estimates that the cost of treating a patient with MDR-TB is about 100 times greater than that of treating a patient with drug-susceptible TB. According to the authors, substandard care of patients with TB is “the greatest contributing factor to the development of MDR-TB”. Brolan and colleagues examine the Torres Strait treaty as it affects the provision of health care by Australian clinics to residents of PNG. They point out that, while providing such care is not strictly allowed, the practice meets our humanitarian obligations while offering protection to vulnerable Aboriginal communities in north Queensland. While the Australian Government has pledged a large slab of financial support to improve PNG-based health services, and particularly to assist with providing TB treatment facilities in PNG’s Western Province (http://www.health.gov.au/internet/ministers/publishing.nsf/Content/mr-yr11-nr-nr175.htm), more time is needed. As Vincent says, effective TB control requires prompt identification and treatment as well as monitoring and contact screening. Only when PNG clinics can provide all this should care be transferred. It seems extremely unlikely that this will occur by the planned date of February 2012. Australia enjoys one of the lowest rates of TB in the world. King and colleagues, also in this issue, argue that this can in part be attributed to premigration screening, which they say benefits applicants, by earlier detection of their disease, and the Australian population, by avoiding exposure to people with active TB. Their argument of substantial cost savings with this approach is compelling. While it is impossible to completely protect Australia from TB coming to our shores, the two strategies of continuing to treat PNG residents and conducting premigration screening appear to be effective at reducing this risk and should be supported.

Annette Katelaris

The growing infection control challenges facing an ageing population In this issue of the Journal, a study of multiresistant bacterial intestinal carriage by Stuart and colleagues adds important detail to the emerging picture of multiple antibiotic resistance in non-hospital settings.1 The higher colonisation rate they found for Escherichia coli than for vancomycin-resistant enterococci (VRE) or Clostridium difficile in residential aged care facilities is a timely reminder that our surveillance and infection control resources should not be exclusively targeted at VRE or C. difficile. The simultaneous presence of these potential pathogens in the same aged care population raises the ugly spectre of carriage of two or more resistant organisms. The risk of contemporaneous multiresistant E. coli, C. difficile-associated diarrhoea and faecal incontinence might be considered the perfect infection control storm. As Stuart and colleagues rightly point out, data are lacking on the prevalence of community-acquired multiresistant gram-negative bacteria in Australia. By extrapolation from northern hemisphere studies, it appears that nursing homes and other long-term care facilities can function as potent reservoirs of multiresistant E. coli.2 Measuring the duration of enteric carriage after initial colonisation by a multiresistant strain may help determine the potential window for onward transmission, but we can anticipate variable and possibly strain-dependent transmissibility. The relatively small size of Stuart et al’s study, the presence of a single-strain case cluster and other specific features make it difficult to generalise from their results. However, observation of a dominant genotype of multiresistant E. coli in one aged care facility concords with a previous observation of single genotype clusters in long-term care facilities.3 The observed dominance of CTX-M (cefotaxime-hydrolysing) β-lactamase-mediated resistance is also consistent with the wider international trend, as noted in a recent nationwide study from Belgium.4 The mechanism of antibiotic resistance designated CTX-M-15 has been particularly successful on a global scale — the result of carriage of resistance-determining genes on multireplicon plasmids, combined with international travel.5 CTX-M-15 has become a prominent multiresistance determinant detected in the faeces of international travellers, particularly those returning from the Indian subcontinent or Africa.6 The route followed by multiresistant gram-negative bacteria brought to Australia by healthy, young international travellers to reach the residents of aged care facilities is unclear. But once aged care residents are colonised, Stuart et al’s data suggest spread of resistance among them, possibly assisted by transmissible bacterial genetic elements.1,3 In a survey of resistant E. coli in western Sydney, where CTX-M-15 predominates, 11 different conjugative plasmids were found, most of which had multiresistance regions.7 The challenges of aged care are many and will continue to grow as the number of people in need of residential care expands. There are many potential contributors to the emergence of multiresistant bacteria in residents of aged care facilities: multiple hospital admissions, excessive use of antibiotics (in terms of courses, duration and antimicrobial spectrum), incontinence, dementia, venous stasis ulcers, and difficulty implementing infection control practices in institutions where residents are free to move outside their rooms and mingle with others. Well established multiresistant bacteria such as community-acquired methicillin-resistant Staphylococcus aureus (MRSA) pose a significant problem in some aged care facilities and other long-term care units. Our failure to hold the MRSA threat at bay, even with the most stringent measures, should make us wary of trying to apply failed control strategies to a group of bacteria with a substantially different ecology. The “search-and-destroy” approach to infection control, with its heavy reliance on screening swabs and decolonisation, risks interfering with movement of aged care facility residents to and from hospital (when admission or discharge depends on documented screening status or completion of decolonisation) for little, if any, demonstrable benefit. The value of alternative approaches is also uncertain. To date, attempts to control intestinal carriage of multiresistant E. coli in long-term care residents using probiotic E. coli have been unsuccessful.8 This indicates the durability of multiresistant E. coli as a gastrointestinal coloniser. A control method for multiresistant bacteria that relies on surveillance and targeted infection control measures may seem appealing, but in reality is likely to be costly, impractical and ineffective. An alternative strategy9 is to use multiple measures targeting improvements in the skilled nursing care of those at identifiably higher risk of multiresistant bacterial infection, without prior surveillance culture. We recognise that this proposal will not sit comfortably with those who have long advocated a post-hoc, species-specific, search-and-destroy approach to organisms of interest. But with an estimated multimillion dollar annual cost of multiresistant bacteria control measures, and a residential aged care sector facing many challenges, we will be forced to explore all options. This should include considering a more public health-based approach, as long-term care facilities lie outside the remit of conventional hospital infection control. These options cannot be properly debated without additional, nationally representative data addressing the key questions raised by Stuart and colleagues, particularly the duration of gastrointestinal colonisation, the relationship between colonisation and subsequent infection, and the consistency of epidemiological data across a wider range of residential aged care facilities. Their timely study highlights a need for informed discussion of new measures to control multiresistant gram-negative bacteria in long-term residential care facilities. This could include a gamut of aged care measures aimed at reducing transmission, such as decreasing long-term care facility–hospital transfers through the use of advance care planning10 and hospital-in-the-home treatment.

Timothy J J Inglis DM, PhD, FRCPA · Christopher D Beer MB BS, PhD, FRACP

To the Editor: Recent articles in the Journal have noted the first case of extensively drug-resistant tuberculosis (TB) in New Zealand,1 and emphasised the exponential increase in cost and complexity of managing drug-resistant TB.2 We thus wish to caution against the proposed premature closure of TB treatment services for Papua New Guinea (PNG) citizens who access health care in the Torres Strait Islands. A Protected Zone under the Torres Strait Island Treaty allows selected inhabitants from the South Fly District of Western Province, PNG, to conduct traditional practices in the outer Torres Strait Islands. Because access to health care in the South Fly District is difficult and local TB control is poor, many of these people use TB services in the Torres Strait Islands, which are under Australian jurisdiction. Around 60 PNG patients, 50 of whom have multidrug-resistant TB, currently receive treatment from Australian TB services for humanitarian and public health reasons — to limit the transmission of TB into Australia. This is especially important given the high rates of transmissible drug-resistant disease.3,4 We thus support the strategy of the Australian and Queensland governments, which aims to strengthen PNG TB control as the best long-term solution. However, establishing effective TB control in resource-poor settings such as PNG is complex and confounded by competing health priorities. We are very concerned by the assumption that care of all PNG patients with TB should be transferred back to PNG by February 2012. To avoid making TB control in this area even harder, and particularly to avert the emergence of extensively drug-resistant TB, with subsequent transmission to Australia, we believe that such transfer of care should be based on an objective assessment of the capacity of services to manage the increasing number of patients and the complexity of their treatment. The National Tuberculosis Advisory Committee — a subcommittee of the national Department of Health and Ageing’s Communicable Disease Network Australia — and the International Union Against Tuberculosis and Lung Disease, endorse the World Health Organization Stop TB Strategy,5 which places the responsibility for TB management on the jurisdiction where the case was diagnosed. This strategy should also be adopted by the federal and Queensland governments so that patients diagnosed within Australia are only transferred to places where they are likely to complete effective treatment, in accordance with International standards for tuberculosis care.6 This is the situation for illegal immigrants who are diagnosed with TB at the United States–Mexico border. We therefore recommend that: federal government funding to develop TB services in PNG should include operational research to identify the most cost-effective and pragmatic long-term solutions; and current Australian services within the Torres Strait be maintained to ensure cross-jurisdictional management of TB, with a gradual transfer only as capacity within PNG is increased. This position is widely supported by Australian clinicians involved in TB control.7

Anastasios Konstantinos · Graham Simpson · Tania C Sorrell · Ben J Marais

Position statement from the Thoracic Society of Australia and New Zealand, Australian Society for Microbiology, Australasian Society for Infectious Diseases and Public Health Association of Australia Many high-income countries with a low incidence of tuberculosis (TB) are confronting the complicated issue of the cross-border movement of people with TB from neighbouring low-income countries with a high burden of TB. Well documented examples where this is an issue include the United States–Mexico border and Scandinavian countries adjacent to Russia and the Baltic States.1,2 In Australia, we face similar dilemmas, not only with Papua New Guinea (PNG) nationals crossing into the Torres Strait Protected Zone, but also with fisherpersons illegally entering our territory, temporary residents on short-term work visas and students attending tertiary education institutions. Cross-border communicable diseases present a complex mix of clinical, public health, humanitarian, ethical, political and financial issues for governments and health care providers. Fortunately, international organisations have provided guiding principles that should underpin a country’s response to cross-border TB cases. For example, the World Health Organization (WHO) has published ethical guidelines for care of patients with TB and control of the disease.3 This document states that: . . . all governments have a fundamental obligation to provide universal access to high-quality TB diagnosis and treatment . . . universal access to TB care implies a duty to ensure the quality of that care . . . The international community must provide financial and technical assistance to countries that lack the resources to satisfy this obligation on their own. These ethical guidelines are based on numerous values including equity, solidarity, and common good (as providing effective TB treatment prevents ongoing transmission of disease, and thereby benefits everyone). Similar recommendations are made by two complementary documents, The patient’s charter for tuberculosis care (PCTC) and International standards for tuberculosis care (ISTC).4,5 These principles are also embodied in the final draft of the Australian National TB Strategic Plan (2011–2016), which is expected to be published in early 2012. In view of these international ethical guidelines, the Thoracic Society of Australia and New Zealand (TSANZ), the Australian Society for Microbiology (ASM), the Australasian Society for Infectious Diseases (ASID) and the Public Health Association of Australia (PHAA) believe that Australia’s response to any situation involving cross-border TB cases should be based on the following four principles. All patients with TB who present to health care services within Australia’s borders should have free and equal access to TB care from diagnosis to completion of treatment, irrespective of their legal status or other demographic characteristics as outlined in the PCTC.4 Health professionals dealing with these complex issues must have enough support from the relevant Australian state and federal health agencies to enable them to implement best-practice care, and should be closely engaged in the process of consultation about service delivery. Patients should only be transferred to their home country for ongoing care when the TB service in the responsible Australian state is satisfied that the patient’s ongoing care will be of a suitable standard that meets the ISTC.5 Australia should provide financial and technical support to neighbouring countries where TB is endemic, so that they can develop national TB programs meeting the ISTC standards to which Australia’s TB services can confidently return international patients, who are increasingly mobile. The development of these programs may demand an ongoing investment over many years. The complexity and cost of treating multidrug-resistant tuberculosis (MDR-TB) or TB/HIV co-infection compound the dilemmas in providing cross-border TB care. WHO estimates that the cost of treating a patient with MDR-TB is about 100 times greater than for treating a patient with drug-susceptible TB.6 Poor standards of care of patients with cross-border mobility place nations on both sides of the border at risk of dissemination of untreatable drug-resistant disease. Based on the same values of equity, solidarity and common good, the international ethical guidelines argue that the universal right to receive medical advice and treatment must extend to patients with MDR-TB and/or HIV infection.3,4 The TSANZ, ASM, ASID and PHAA therefore recommend that the above four principles should also apply to cross-border patients with MDR-TB or TB with HIV co-infection. Initial substandard care of patients with drug-susceptible TB is the greatest contributing factor to the development of MDR-TB and extensively drug-resistant TB. MDR-TB in expatriates therefore suggests that the national tuberculosis program in their home country is failing. Hence, health care professionals and governments who propose repatriating patients with MDR-TB must be wary of the level of care that will be available when those patients arrive home. The Green Light Committee, an MDR-TB working group that advises WHO and evaluates applications from countries for access to second-line antituberculosis drugs, has developed a set of criteria for assessing nascent MDR-TB treatment programs in low-income countries.7 These criteria include the level of government commitment and funding, the availability of medical personnel trained and experienced in managing MDR-TB, access to supporting laboratory services that are externally quality controlled, the reliability of second-line drug supplies, and existing strategies to assure patient adherence to treatment regimens. Australian governments and state TB services should use the same criteria when determining whether cross-border patients with MDR-TB can be safely returned to their home country for ongoing care. Although they are ethically justified, the above four principles for the care of cross-border patients with TB may appear financially onerous. Interestingly, modelling has found that increasing United States investment in TB programs in Mexico, Haiti and the Dominican Republic could reduce tuberculosis-related morbidity and mortality among migrants, and produce net cost savings for the US.8 The TSANZ, ASM, ASID and PHAA therefore strongly support the four principles described above for the care of cross-border patients with TB on ethical, clinical and public health grounds (including the protection of Australian citizens), and we believe this approach is economically justified. It is critical that all parties involved in providing care of cross-border patients with TB work together to ensure that the necessary outcomes are achieved.

Paul N Reynolds MD, PhD, FRACP · John D Turnidge MB BS, FRACP, FRCPA · Thomas Gottlieb MB BS, FRACP, FRCPA · Michael J Moore BA, DipEd, MPopHealth

Objective: To assess the frequency of, and risk factors for, colonisation with vancomycin-resistant enterococci (VRE), Clostridium difficile and extended-spectrum β-lactamase (ESBL)-producing organisms in residential aged care facilities (RACFs).Design, setting and participants: We conducted a point prevalence survey in October – November 2010 in three RACFs associated with our health service. A single faecal sample was collected from each participating resident and screened for the presence of VRE, C. difficile and ESBL-producing organisms. Presence of risk factors for antibiotic-resistant organisms was identified using a questionnaire.Main outcome measures: Prevalence of colonisation with VRE, C. difficile and ESBL-producing organisms; molecular typing of ESBL-producing organisms; prevalence of risk factors including presence of a urinary catheter, recent inpatient stay in an acute care setting and recent antibiotic consumption.Results: Of 164 residents in the three facilities, 119 (73%) were screened. Mean age of screened residents was 79.2 years, and 61% were women; 74% had resided in the RACF for > 12 months, 21% had been given antibiotics within the past month and 12% had been in an acute care centre within the past 3 months. Overall rates of VRE (2%) and C. difficile (1%) colonisation were low, but ESBL-producing Escherichia coli was detected in 14 residents (12%) overall, with half of these residing in one wing of an RACF (27% of wing residents tested). Ten of the 14 ESBL-producing isolates had identical molecular typing patterns and belonged to genotye CTX-M-9. Eight of 13 residents had persistent colonisation on repeat testing 3 months later.Conclusion: We found a high prevalence of multiresistant ESBL-producing E. coli in RACF residents. A clonal relatedness of isolates suggests possible transmission within the facility. RACFs should have programs emphasising processes that will limit spread of these organisms, namely good hand hygiene compliance, enhanced environmental cleaning and dedicated antimicrobial stewardship programs.

Rhonda L Stuart MB BS, FRACP, PhD · Despina Kotsanas BSc(Hons), MClinEpi · Brooke Webb BAppSc(Lab Med) · Susan Vandergraaf BN · Elizabeth E Gillespie BN, MPubHlth · Geoffrey G Hogg MB BS, FRACP, FRCPA · Tony M Korman MB BS, FRACP, FRCPA

Objective: To determine whether premigration screening for tuberculosis is worth undertaking in visa applicants, and whether screening resources are being appropriately directed towards intending migrants at highest risk of tuberculosis.Design, setting and participants: A 12-month survey of all intending migrants with tuberculosis necessitating treatment detected during the premigration health assessment process, whose medical examinations were submitted to the Department of Immigration and Citizenship’s Global Health Branch for assessment by a Medical Officer of the Commonwealth between 1 July 2009 and 30 June 2010.Main outcome measures: Individuals diagnosed with active tuberculosis; proportions diagnosed by sputum smear and culture tests or clinically, and with susceptibility test results; distribution of visa types among people diagnosed.Results: In premigration assessments, 519 people were diagnosed with active tuberculosis (prevalence, 137 per 100 000 in examined population). The top source countries for people with tuberculosis were the Philippines (21.8%), India (16.8%), Vietnam (16.2%) and China (8.3%). Positive sputum smear test results were submitted for 67 cases (12.9%). Positive culture test results were obtained in 230 cases (44.3%), but only 95 of these (41.3%) had susceptibility test results, with 83 fully susceptible. Four people had multidrug-resistant tuberculosis (prevalence, 1.06 per 100 000 population). Five people had both active tuberculosis and HIV infection. Of all those diagnosed with tuberculosis, 162 (31.2%) were intending students, 82 (15.8%) were intending visitors, and 53 (10.2%) were applicants for humanitarian (refugee and Special Humanitarian Program) visas.Conclusions: Premigration health screening of intending migrants is identifying substantial numbers of people who would have required treatment for tuberculosis after arrival in Australia. The high proportion of students, visitors and refugee and humanitarian entrants with tuberculosis validates the current screening program. The screening is of benefit to the applicants, whose tuberculosis is treated earlier than it otherwise would have been, and to the Australian population, by averting exposure to people with active tuberculosis.

Kathleen King BSc(Hons), MB ChB, FRCPath · Paul J Douglas MB BS, MHA, FRACMA · Ken Beath BE, MAppStat, PhD

To the Editor: We would like to congratulate the Central Line Associated Bacteraemia in NSW Intensive Care Units Collaborative for reducing central line-associated bacteraemia (CLAB), and showing that this reduction was associated with compliance with evidence-based aseptic central venous line (CVL) insertion, which included a patient bundle and a clinician bundle, as reported by Burrell and colleagues.1 As part of a quality improvement program in Western Australia, we conducted a collaborative cohort study (unpublished) in two major Perth teaching hospitals with adult intensive care units (ICUs), from April 2007 to September 2008, covering 36 ICU-months and 15 459 catheter-days. Both ICUs implemented the WA Safety and Quality Investment for Reform central line bundle.2 Compliance was monitored by an observer with a checklist. Adherence to all components of the central line bundle was required for compliance to be recorded. This measure was reported monthly. CLAB and catheter-days were monitored by the hospitals’ infection control practitioners. Compliance with the bundle increased from a mean of 10% to greater than 90%. Infection rates declined over the study period from more than six infections per 1000 catheter-days to zero (P = 0.019 for Hospital 1 and P = 0.10 for Hospital 2). In the final 8 ICU-months (4 months in both hospitals), there was no CLAB. The New South Wales study demonstrated the importance of the clinician bundle components over the patient bundle components, which should inform future quality improvement initiatives. We note the comment that the hat, mask and eyewear components of the bundle were unpopular with clinicians. However, there is a risk of recontaminating disinfected skin with aerosolised organisms from the clinician’s hair and upper respiratory tract, whereas eyewear is principally intended to protect the clinician from splash injury and potential blood-borne virus infection. Maximal sterile barrier precautions are endorsed by the 2010 National Health and Medical Research Council guidelines,3 the 2011 Centers for Disease Control and Prevention guidelines,4 and the epic2 study in the National Health Service in England.5

Chantal S Ferguson · Victoria C D’Abrera · Helen J Van Gessel · Dorothy Jones

Fever is an important mechanism of intrinsic resistance against infectious disease. A variety of studies point to a potential detrimental effect of temperature lowering in infectious disorders, but high-quality evidence from randomised controlled trials is lacking. In ambulatory care settings, we need to know whether antipyretics influence the severity and duration of illnesses and, in critically ill patients, whether antipyretics affect mortality.

Paul J Young BSc(Hons), MB ChB, FCICM · Manoj K Saxena MB BChir, FRACP, FCICM · Richard W Beasley MB ChB, DSc, FRACP

Clinical recordA frail 68-year-old woman of European ancestry presented to the emergency department with partial seizures of her left hand and mild left hemiparesis. Magnetic resonance imaging (MRI) scans of the brain revealed a non-enhancing lesion in the right precentral gyrus that was thought to represent infarction (Box, A and B). Over the following 2 months the lesion increased in size. A brain biopsy was performed, as the patient experienced ongoing seizure activity despite anticonvulsant therapy. The patient was married to a retired police officer and had three children. She had been raised in a country town and her father had kept cattle, pigs and sheep on their property and slaughtered meat. She had trained as a nurse and had worked in a tuberculosis ward. During early adulthood she had visited Papua New Guinea for 2 months. The patient’s background medical history was extensive. Coeliac disease was diagnosed 16 years before her current presentation. Within the past 4 years she was diagnosed with ulcerative proctitis, was twice hospitalised for pneumonia, was treated for bronchiectasis and required bone resorptive therapy for osteoporosis. She had had a hysterectomy 25 years previously. Results of the brain biopsy were inconclusive; it showed an unusual lymphoid infiltrate and the presence of cytological atypia. There was no evidence of necrosis, malignancy or granulomas; and no organisms were noted on stains for bacteria, fungi, mycobacteria and parasites. The slides were referred for a second opinion. Dexamethasone therapy was added to help reduce the frequency of seizures. A chest x-ray showed right apical pleural thickening consistent with past tuberculosis exposure, and a computed tomography (CT) scan of the abdomen showed small axillary and intra-abdominal lymph nodes; no hepatosplenomegaly or mass lesions were seen. A positron emission tomography scan showed a focus in the bowel. She was referred to a haematologist due to suspicion of lymphoma. The patient was cachectic and weighed 38 kg. Clinical examination showed no evidence of lymphadenopathy or hepatosplenomegaly. Results of serum biochemical analysis were normal except for a low albumin level of 30 g/L (reference range, [RR], 37–46 g/L). She had a haemoglobin concentration of 82 g/L (RR, 115–160 g/L) and a normal white cell count. A blood film showed some atypical lymphocytes. Iron studies were not suggestive of iron deficiency and there was no haemolysis present. The C-reactive protein level was 15 mg/L (RR, < 5 mg/L) and the erythrocyte sedimentation rate was 100 mm/h (RR, < 15 mm/h). Paraprotein was not observed on immune electrophoresis. An HIV test was positive on two occasions with a confirmatory western blot immunoassay. The CD4 count was 214 × 106 cells/L with a plasma HIV viral load of 382 000 copies/mL (log10 5.58). Serological testing was negative for hepatitis B, hepatitis C, syphilis, Toxoplasma gondii infection, cryptococcal infection, hydatid disease, toxocariasis and schistosomiasis, although there was evidence of past exposure to Epstein–Barr virus and cytomegalovirus. HIV infection was likely to have been acquired during a blood transfusion after her hysterectomy 25 years earlier. Subsequently, an Australian Red Cross Blood Service lookback confirmed that one of two units she received was from a blood donor who subsequently died of HIV-related complications. Her husband was a regular blood donor and had repeatedly screened negative for HIV infection at each donation. Upon further review, the brain biopsies were thought to be consistent with progressive multifocal leukoencephalopathy (PML) with a florid mononuclear infiltrate, atypical astrocytes and prominent eosinophils. Immunohistochemical analysis was positive for John Cunningham virus (JCV). The patient’s cerebrospinal fluid (CSF) was acellular and had normal biochemical features, but the HIV viral load was 51 200 copies/mL, suggesting significant HIV replication in the brain. Polymerase chain reaction did not detect JCV DNA in the CSF. Follow-up gastroscopy revealed lymphocytic gastritis and moderate villous atrophy of the small bowel mucosa, but no malignancy or parasitic infection. Colonoscopy revealed synchronous adenocarcinomas. After careful consideration, the patient underwent proctocolectomy with ileostomy formation. Histopathology revealed tumour–node–metastasis (TNM) stage III disease with clear margins of excision and minimal node involvement. The colon had a diffuse chronic inflammatory mucosal infiltrate but this was not suggestive of ulcerative colitis, and there was no parasitic or opportunistic infection. She was assessed as not requiring adjuvant chemotherapy. After surgery, the patient began highly active antiretroviral therapy (HAART) with a regimen comprising Trizivir (abacavir, lamivudine and zidovudine) and ritonavir-boosted indinavir. She experienced symptomatic improvement, weight gain and reduced partial seizures within a few weeks. The plasma HIV viral load was undetectable within 8 weeks of commencing HAART and a repeat MRI scan at that time confirmed a significant reduction in size of the cerebral lesion (Box, C). Unfortunately, at the same time, routine biochemistry revealed acute renal failure with an elevated serum creatinine of 295 μmol/L (RR, 50–90 μmol/L). An abdominal CT scan showed hypodense liver lesions, a large peripancreatic lesion, an enhancing lesion in the left renal collecting system, and a mass lesion encasing the left ureter. There was a significant amount of abdominal ascites. A fine-needle aspirate confirmed the presence of metastatic adenocarcinoma. Comfort measures were instituted and the patient died 4 days later. The last case of HIV transmission from an infected blood transfusion in Australia was recognised by the Blood Service 9 years before this one (Australian Red Cross Blood Service, personal communication), and further cases from the prescreening era (before 1985) were thought unlikely to be identified due to the passage of time. This case of transfusion-acquired HIV infection was missed by routine Blood Service tracking and the family of the deceased patient were eligible for compensation. DiscussionOur patient presented with PML as her AIDS-defining illness with synchronous colonic neoplasms on a background of multiple medical conditions. With hindsight, these conditions were all linked to immunosuppression due to unrecognised HIV infection. It is likely that prolonged HIV replication in sanctuary sites, such as the gastrointestinal tract and brain, were responsible for her small bowel, colonic and central nervous system (CNS) disease manifestations. Impaired immune dysregulation may have contributed to the aggressiveness of the tumour behaviour. PML is a demyelinating disease of the CNS caused by JCV, a human polyomavirus. The condition generally occurs in the setting of prolonged immunosuppression among individuals with decreased cell-mediated immunity, such as HIV infection.1 In the pre-HAART era, the prognosis for PML was very poor, with median survival times no greater than 6 months.2 With the advent of HAART, the survival time has improved to 15 months or more, but mortality rates can still be as high as 30% to 50%.3 PML has also been documented among patients who receive certain immunosuppressive drugs, such as fludarabine, rituximab, corticosteroids,2 and shortly after the introduction of HAART as a form of immune-reconstitution inflammatory syndrome.4 In HIV infection, HAART is the only therapeutic option for PML, but the efficacy of these agents in controlling JCV replication in the CNS is variable and clinical response is not uniform. Antiretroviral agents with good CNS penetration have been used to optimise therapy for patients with PML.3 Previous studies have suggested the mean time to AIDS diagnosis from HIV acquisition after transfusion was 7 years,5 although a cohort of “non-progressors” who acquired a variant strain of HIV containing the nef gene deletion has been well documented.6 Our patient had delayed progression to AIDS, even in the absence of HAART, a clinical pattern that has been linked to several other genetic factors, including chemokine coreceptor type 5 (CCR5) status.7, 8 CCR5 is a coreceptor required for HIV to enter T cells and macrophages. Homozygosity for the Δ32 gene deletion in the CCR5 gene (CCR5-Δ32) is associated with resistance to HIV infection (although people can still be infected with T-tropic strains of the virus, which use the CXC chemokine receptor type 4 for cell entry), whereas heterozygosity confers delayed progression to disease. Our patient was confirmed as being heterozygous for CCR5-Δ32. In the United States, the frequency of the allele is 11% among white people and 1.7% among black people.8 Targeting the CCR5 receptor to interrupt HIV transmission offers new therapeutic possibilities. Maraviroc, a CCR5 inhibitor, has been introduced with success when used as part of a HAART regimen for patients with R5 (M-tropic) virus.9 Transplantation of stem cells from a donor homozygous for CCR5-Δ32 to a patient with acute myeloid leukaemia and HIV infection resulted in continued virological suppression after transplantation in the transplant recipient and discontinuation of HAART.10 Our case highlights problems associated with delayed diagnosis of HIV infection due to the absence of perceived risk factors. In Australia, rates of HIV screening in the community, outpatient and inpatient clinical settings appear to remain suboptimal. Factors associated with decreased uptake of HIV testing include issues surrounding consent and counselling, or lack of appreciation of risk exposures by doctors and patients. A reduced threshold for performing HIV testing in these settings is required. We recommend an HIV screening test in the workup of all patients with cerebral lesions or an unusual illness pattern when the diagnosis is not easily apparent. One approach to help identify individuals who are unaware that they have HIV infection is the “opt-out” HIV testing strategy proposed by the US Centers for Disease Control and Prevention in 2006.11 All people aged 13–64 years in health care settings would have routine HIV testing. Importantly, pretest counselling and signed consent would not be required, and the test would be performed unless the patient declined. Patients with known risks for HIV infection should be tested annually.11 This testing strategy would allow undiagnosed patients earlier access to medical care with an anticipated reduction in HIV transmission and infection related morbidity and mortality.12 The World Health Organization endorsed these recommendations in 2007, expanding the scope of uptake to the developing world.13 Drawbacks to this approach include concerns about stigmatisation and discrimination of individuals with HIV,14 and increased cost implications15 for health authorities from increased test numbers, including confirmatory immunoblot assays, and a requirement for more expertise to interpret true and indeterminate results. We encourage further debate about improved uptake of HIV testing for the Australian health setting by the appropriate governing bodies. Magnetic resonance imaging of the brain A: T2 coronal sequence at initial presentation. B: Axial fluid-attenuated inversion recovery (FLAIR) sequence at initial presentation. C: Axial FLAIR sequence after 2 months of highly active antiretroviral therapy.

Archie A Darbar MB BS, FRACP, FRCPA · Luke A Coyle MB BS, FRACP, FRCPA

Aspiration pneumonia occurs most commonly in patients with a predisposition to aspiration (eg, those with neurological bulbar dysfunction). There is limited evidence regarding the involvement of anaerobes in most cases of aspiration pneumonia. Most patients respond to treatment for aspiration pneumonia without specific anti-anaerobic therapy such as metronidazole. Metronidazole has adverse side effects, and widespread use where not indicated can promote carriage of multiresistant intestinal flora such as vancomycin-resistant enterococci. Use of metronidazole may be appropriate in patients with aspiration pneumonia and evidence of a lung abscess, necrotising pneumonia, putrid sputum or severe periodontal disease.

Jason C Kwong MB BS, BMedSci · Benjamin P Howden MB BS, PhD, FRACP · Patrick G P Charles MB BS, PhD, FRACP

To the Editor: A 38-year-old man with genotype 1b chronic hepatitis C infection had been treated with 48 weeks of pegylated interferon (IFN)-α and ribavirin. Autoimmune serology performed just before treatment showed positive perinuclear antineutrophil cytoplasmic antibodies (ANCA) accompanied by an elevated antimyeloperoxidase antibody level (22 U/mL; reference range [RR], < 5 U/mL). Notably, the patient was ANCA-negative 12 months previously. The treatment course was uneventful. One month after the completion of therapy, the patient presented with a subacute onset of fever, haemoptysis, breathlessness and generalised arthralgia. Laboratory investigations demonstrated raised levels of C-reactive protein (128 mg/L; RR, < 5 mg/L) and creatinine (159 μmol/L; RR, 64–104 μmol/L), low albumin concentration (28 g/L; RR, 35–46 g/L), a low haemoglobin level (64 g/L; RR, 135–180 g/L), and microcytic hypochromic anaemia. Autoimmune serology showed persistence of a positive ANCA and an elevated antimyeloperoxidase antibody level (29 U/mL). A high-resolution computed tomography scan of the chest showed features of interstitial lung disease (Figure, A) and a renal biopsy demonstrated pauci-immune necrotising glomerulonephritis (Figure, B). These findings were consistent with a diagnosis of microscopic polyangiitis. Despite treatment with intravenous cyclophosphamide and pulse methylprednisolone, the patient deteriorated and was admitted to the intensive care unit for ventilatory support, haemodialysis and plasmapheresis. This admission lasted 4 weeks and was complicated by line-related sepsis and persistent anaemia requiring multiple blood transfusions. The patient remains clinically well 14 months after discharge, with negative ANCA and negative hepatitis C virus RNA polymerase chain reaction consistent with a sustained viral response. Autoimmune disease is a well recognised complication of IFN-α therapy in chronic hepatitis C infection. The clinical manifestations of IFN-α-related autoimmune disease can be either organ-specific (thyroiditis, psoriasis) or, less commonly, systemic (rheumatoid arthritis, lupus-like disease, sarcoidosis).1 IFN-α-based treatment in chronic hepatitis C infection unmasks silent autoimmune processes, or induces de novo autoimmune diseases or autoantibodies.2 A predisposition to autoimmunity, together with the presence of baseline auto-antibodies, has been demonstrated in most instances of IFN-α-mediated autoimmune diseases,1 as observed in our case. Although rare, the diagnosis of microscopic polyangiitis needs to be considered in patients treated with IFN-α-based therapy for chronic hepatitis C infection presenting with skin rash, fevers, arthritis, an active urine sediment, renal failure or pulmonary haemorrhage. One could consider reducing the duration of therapy in patients who achieve negative RNA polymerase chain reaction at Week 4 of treatment. There is emerging evidence that 24 weeks of response-guided therapy in genotype 1b chronic hepatitis C infection is as effective as the standard-of-care treatment for 48 weeks in rapid responders.3 We also suggest that, in the presence of a positive ANCA at baseline screening, a chest x-ray and urinalysis be performed before initiating IFN-α-based treatment, and that patients be monitored clinically and with urinalysis during treatment. A chest x-ray should also be performed at the completion of treatment. The presence of auto-antibodies alone is not a contraindication to IFN-α therapy, but it does mandate careful monitoring and a high index of suspicion of an immune diathesis. A: High-resolution computed tomography scan of the patient’s chest showing patchy foci of ground glass opacification and nodules bilaterally. B: Renal biopsy showing focal crescentic necrotising glomerulonephritis (haematoxylin-eosin stain; original magnification x 400).

Stephen Y Oh · Brett E Jones · Suran L Fernando