Determining research priorities for clinician-initiated trials in infectious diseases

Randomised controlled trials (RCTs) are accepted as the best type of study to assess the effects of health care interventions and therefore have a pivotal role in evidence-based medicine.1 A new paradigm is emerging whereby RCTs are now being undertaken by a network of clinicians.2

Clinician-initiated RCTs have several features that differentiate them from industry-sponsored studies. They are more likely to compare generically available, off-patent medications, or to study processes of care or non-pharmacological interventions. As clinician-initiated trials are financially independent of industry, with their funding source being governmental research organisations (eg, the National Health and Medical Research Council [NHMRC]), the results are viewed by clinicians as more credible.3 The NHMRC has already demonstrated a willingness to fund clinician-initiated RCTs, as shown by the success of networks such as the Australian and New Zealand Intensive Care Society Clinical Trials Group.4–7 The impact of their successfully completed trials on practice change, cost savings and improved patient outcomes has not been formally measured but is likely to be significant.

Another key advantage is that clinician-initiated RCTs tend to investigate issues that clinicians find most important and relevant to their practice. Moreover, the process of engagement with other clinicians is a crucial one. If investigator-initiated studies are to successfully recruit patients, there needs to be an appreciation by other clinicians that the studies have realistic comparators and clinically significant end points.

To facilitate physician engagement and training in clinical trials methodology, the Australasian Society for Infectious Diseases Clinical Research Network (ASID CRN) was established in 2009. This report summarises the results of an online survey of infectious diseases physicians, conducted by the ASID CRN, to establish its research priorities.

Methods

In 2012, a self-reported online questionnaire-based survey was administered on behalf of the steering group of the ASID CRN. The survey was developed by the ASID CRN steering group, who compiled a list of more than 100 potential studies: 42 potential randomised controlled trials, 20 epidemiological studies and 40 observational studies/registries. These studies pertained to bacterial infections (69 of the nominated studies), viral infections (18), fungal infections (10), mycobacterial infections (3) and general aspects of clinical infectious diseases practice (3).

A “short list” of these studies was selected by the ASID CRN steering group to be sent to the entire community of members of ASID, comprising most practising infectious diseases physicians in Australia and New Zealand. The ASID members were asked to rate the proposed studies within each group: (a) RCTs, (b) epidemiological studies, and (c) registries of specific infectious diseases, using a numerical scale (with 1 being of little likely clinical significance and 5 being of greatest clinical significance).

To determine the feasibility of the proposed studies, the physicians were also asked to estimate the number of patients seen at their hospital in the past year with each of the conditions relevant to the proposed clinical trial. Additionally, they were asked to describe barriers to enrolment of study patients at their hospital.

Results

Of the 550 clinicians approached online, 122 (22%) responded to the survey. The RCTs ranked by the ASID members as having most potential clinical significance are listed in Box 1. Foremost among these were RCTs investigating prosthetic joint infections, native joint septic arthritis or osteomyelitis, Staphylococcus aureus bloodstream infections, foot infection in diabetes and serious infections due to gram-negative bacilli. Clinician estimates of case loads per annum, and hence the number of subjects eligible for recruitment into these studies, ranged from 600 to 700 for the studies on prosthetic joint infection and gram-negative bacilli; 1000 to 2000 for those on native joint infections; and 2700 for foot infections in diabetes.

The surveyed clinicians also supported further study of emerging infections (eg, multi- or extensively drug-resistant tuberculosis or unexplained encephalitis) by way of registries or epidemiological studies.

Barriers to performance of clinician-initiated studies are listed in Box 2. The most commonly perceived barrier was lack of funding for conducting studies, followed by absence of infrastructure or study personnel, and lack of time owing to clinical commitments.

Discussion

A number of features dominated the research preferences of Australian and New Zealand infectious diseases physicians. RCTs investigating optimal treatment of commonly encountered infections were highly ranked, highlighting the lack of well conducted RCTs in this area. Investigations into optimal therapy of antibiotic-resistant organisms were also identified as a priority.

Clinician-initiated research presents a number of advantages over research sponsored by pharmaceutical companies. The primary focus of clinician-initiated research is to answer problems of direct clinical relevance, while that of pharmaceutical companies is to obtain regulatory approval for new, patented products. Additionally, the impact of clinician-focused research is, in many cases, cost-savings to the health care system, while that of company-initiated research is the introduction of new and often expensive drugs or devices. As an example, the four highest-ranked RCTs proposed by Australian and New Zealand infectious diseases physicians dealt with reducing the duration of courses of intravenous antibiotics (Box 1). RCTs whereby medications are used less are unlikely to be of interest to industry. RCTs that allow the rigorous evaluation of recommendations in guidelines are likely to be of particular value to clinicians, and those that reduce the duration of intravenous antibiotic courses are likely to reduce costs for governments and, potentially, reduce adverse events for patients.

Steering groups, comprising both researchers and clinicians, have now been established to develop protocols, seek funding for the trials and initiate the studies most highly ranked by clinicians.

Could the methodology and results of our survey of infectious diseases physicians be of use to other clinicians? More than 90 research networks of collaborating clinicians currently exist in Australia (http://australianclinicaltrials.gov.au/). Some of these networks are well established and have been highly productive, completing a number of high-impact studies.4–9 Others are nascent, like our own, and may seek to replicate our methodology.

There are significant challenges in the initiation and conduct of clinician-initiated studies. Foremost of these is funding, which was regarded in our survey as the single largest barrier to studies being conducted. Other potential difficulties included time-consuming processes for (and cost of) ethical approval, and lack of support and infrastructure in cash-strapped hospital systems. Innovative solutions to these barriers should be sought — other research networks (eg, Australian and New Zealand Intensive Care Society Clinical Trials Group) have received funding from foundations and the NHMRC. In addition, the private hospital system may be an untapped resource for clinician and administrative support.

A limitation of our study was the low response rate of 22%. This is to be expected given the nature of online surveys. The research priorities chosen may not necessarily reflect those of all members of ASID.

We have described here a method for giving practising clinicians a central role in the selection of clinical studies. We hope that this will facilitate not just the planning and conduct of these studies, but also their rapid implementation into clinical practice.

1 Proposals for randomised-controlled trials ranked highest for clinical significance by infectious diseases physicians

	Mean score*	Protocol title

1	3.97	Early prosthetic joint infections managed with debridement and retention: 6 weeks of intravenous antibiotics versus 2 weeks of intravenous antibiotics and prolonged oral antibiotics
2	3.83	Native joint septic arthritis or osteomyelitis: 6 weeks of intravenous antibiotics versus 2 weeks of intravenous antibiotics and prolonged oral antibiotics
3	3.82	Uncomplicated Staphylococcus aureus bloodstream infections: 2 weeks of intravenous antibiotics versus 1 week of intravenous antibiotics and 1 week of oral antibiotics
4	3.74	All oral antibiotic regimen versus prolonged intravenous antibiotics for diabetic foot infection
5	3.43	Meropenem versus piperacillin–tazobactam for serious infections caused by an extended-spectrum β-lactamase producer
6	3.38	Enterococcal endocarditis: ampicillin–gentamicin versus ampicillin/ceftriaxone
7	3.30	Fosfomycin versus ertapenem for urinary tract infections caused by an extended-spectrum β-lactamase producer
8	3.26	Daptomycin versus vancomycin for methicillin-resistant S. aureus bloodstream infections with a minimum inhibitory concentration of vancomycin of 2 mg/L
9	3.25	Short (2-day) versus standard (5-day) intravenous treatment for cellulitis
10	3.23	14-day versus 7-day antibiotic course for bloodstream infections caused by gram-negative bacilli
11	3.11	β-lactam plus aminoglycoside combination therapy versus β-lactam monotherapy for serious Pseudomonas aeruginosa infections
12	3.09	Topical versus topical plus systemic decolonisation regimen for patients with recurrent S. aureus infections
13	2.75	Extended/continuous infusion versus bolus infusion of β-lactam therapy for infections in patients with neutropenia

* Surveyed infectious diseases physicians were asked to rank each study proposal on a scale of 1–5 (1 = of little likely clinical significance; 5 = of greatest clinical significance). The mean score of 122 surveyed clinicians is given.

2 Ranking of perceived obstacles to clinician-initiated research by infectious diseases physicians

	Mean score*	Perceived obstacle

1	4.26	Lack of funding
2	4.00	Lack of study nurse/coordinator
3	3.92	Limitations of time owing to excessive clinical load
4	2.72	Difficulties with submissions to ethics committees
5	2.67	Difficulties with clinicians in other specialties

* Surveyed infectious diseases physicians were asked to rank obstacles to clinical research on a scale of 1–5 (1 = of no importance; 5 = of greatest importance). The mean score of 122 surveyed clinicians is given.

The doctor and the mask: iatrogenic septic arthritis caused by Streptoccocus mitis

A 72-year-old man developed septic arthritis in a prosthetic shoulder after intra-articular injection of radiographic contrast. This is the first published case in which molecular techniques matched oral commensal organisms cultured from joint aspirate with oral flora from the proceduralist, who was not wearing a mask.

Clinical record

A 72-year-old man presented in 2011 with acute-on-chronic right shoulder pain. Bilateral shoulder replacements had been performed 8 years earlier for osteoarthritis, with no surgical complications.

In the 6 months before presentation, the patient experienced increasing pain and decreased range of movement of the right shoulder. Four days before presentation, a computed tomography (CT) arthrogram of the right shoulder was performed to look for glenoid osteolysis and assess the linear integrity of the shoulder prosthesis. Eight millilitres of radiographic contrast with bupivacaine were injected into the joint space. The proceduralist used an aseptic technique and skin preparation with 0.5% alcoholic chlorhexidine, but did not wear a mask. Within 24 hours, the shoulder pain dramatically worsened and the range of movement became severely impaired.

The patient had a history of hypertension, severe obstructive sleep apnoea, and paroxysmal atrial fibrillation. He was taking indapamide, perindopril and warfarin, and used nocturnal continuous positive airway pressure. In 1993, he had been treated with radiotherapy for prostate cancer and was taking finasteride.

On presentation, the patient was febrile (38.4°C). Clinical examination showed a warm, swollen right shoulder and pain on passive movement of the joint. The C-reactive protein level was elevated at 229 mg/L (reference interval, < 5 mg/L).

Ultrasound-guided aspiration of the joint recovered a highly inflammatory fluid with a white cell count of 174.6 × 109/L, and 1 + gram-positive cocci were identified. Arthroscopic washout was performed, and the patient was given intravenous flucloxacillin 2 g every 6 hours and benzylpenicillin 1.8 g every 6 hours.

Culture yielded light growth on the primary plates of Streptococcus mitis group 1 and scant Haemophilus parainfluenzae. The antibiotic dose was changed to intravenous benzylpenicillin 2.4 g every 6 hours with synergistic gentamicin 240 mg daily for the first 2 weeks. After 4 weeks of intravenous therapy, the patient was switched to oral amoxicillin 1 g three times daily to complete a 3-month course of antibiotics.

Shortly after the patient presented, the proceduralist agreed to provide an oropharyngeal swab. Several organisms were cultured, including multiple viridans Streptococcus species. Pulsed-field gel electrophoresis (PFGE) was performed according to the method of Lefevre et al, with modifications.1 Using two different restriction enzymes (SmaI, ApaI), we found that the patient’s organism and a strain of S. mitis recovered from the proceduralist’s throat showed indistinguishable fragment patterns (Box). This strongly suggested droplet transmission of the proceduralist’s oral flora onto the needle or skin, with subsequent inoculation into the shoulder joint.

Six months after the acute presentation, joint failure, confirmed on arthrogram and by arthroscopy, necessitated full revision of the right shoulder prosthesis. The procedure was uncomplicated, and the patient remains well with no signs of recurrent infection.

Discussion

This is the first published instance of a molecular epidemiology technique showing probable transmission of oral flora from a proceduralist to the joint of a patient, resulting in iatrogenic septic arthritis.

Australian Medicare data for the period 2006–2009 show that an average of 516 562 claims were made annually for joint injections or aspirations.2 The estimated incidence of septic arthritis after intra-articular corticosteroid injection into a native joint is estimated to be between 1 per 3000 and 1 per 16 000 injections.3 Applying these incidence rates to Australian data, we would estimate that between 30 and 180 instances of iatrogenic septic arthritis per year are a result of joint injection or aspiration. It could be safely assumed that even fewer of these could be attributed to omission of a surgical mask. Given this apparently low burden of disease, should a surgical mask be a mandatory requirement of an aseptic technique for this procedure?

Infection control practices during the injection of sterile sites vary substantially across specialties and depend on the type of procedure and where it is performed (general practice, wards, operating theatres). Several studies confirm the anecdotal evidence that mask-wearing while injecting into sterile sites is not standard practice across a number of specialties, including rheumatology,4 obstetric anaesthesia5 and general practice.6 In some series, the rate is as low as 11%, and a debate exists in the surgical literature about whether surgical masks should be used at all in operating theatres.6

However, there is good microbiological evidence that oral bacterial flora, of which oral (viridans) streptococci predominate, can be deposited on an agar plate held at 30 cm from a speaking subject’s mouth for a period of 5 minutes.7 Thus, if a mask is omitted, procedures such as spinal anaesthesia, or any teaching procedure that can involve speaking to the patient or observers, may result in increased risk of contamination of the sterile field.

In the context of iatrogenic septic arthritis, viridans streptococci are infrequently identified as pathogens.8 They are regarded as low virulence organisms and are often dismissed as contaminants when recovered from joint aspirates. This may lead to an underestimation of their significance as pathogens in this context.

However, viridans streptococci have been implicated in other settings as nosocomial pathogens, most spectacularly with bacterial meningitis after spinal anaesthesia or myelography. A review of 179 cases of iatrogenic meningitis provides corroborative evidence that low virulence organisms can be dispersed from the oropharynx to sterile sites and cause infection.9 The evidence indicates that the risk of meningitis is far higher when there is inoculation into a sterile site (eg, spinal anaesthesia) than simple needle puncture of the site (eg, lumbar puncture). Similarly, the risk of iatrogenic septic arthritis is likely to be greater with inoculation than aspiration alone. That a low virulence organism can cause such morbidity, and occasionally death from meningitis, likely relates to the breach of usual host immune defences by direct inoculation into the site of infection. On rare occasions molecular confirmation of the source, using either PFGE or polymerase chain reaction, has been documented after recovery of identical organisms from the oropharynx of the proceduralist.10

It is always challenging to prove relatedness of bacterial strains, as typing techniques are often dependent on the specific bacterial species. PFGE has been shown to be a reliable technique for differentiating strains of S. mitis in other studies.11,12 In our case, the use of two different restriction endonucleases with identical results adds robustness to the data. While molecular methods can only ever prove two bacterial strains are different, there are established criteria for relatedness.13 The combination of our two pulsed-field gels satisfies the Tenover criteria for indistinguishable strains.

For most procedures, it is highly improbable that oral flora from the patient are the source of contamination, simply because of the physical configuration of the patient’s mouth relative to the sterile field. In addition, the microbiological similarity between iatrogenic septic arthritis and post-lumbar puncture meningitis (where contamination by the patient’s oral flora cannot reasonably be asserted) is compelling. Other sources of contamination from patients, such as skin flora or groin organisms, are unlikely given the preponderance of viridans streptococci and the striking absence of gram-negative bacilli and Staphylococcus species. We did not feel it necessary to take a mouth swab from the patient in this case.

Although no reports to date have been able to link a proceduralist’s oral flora to the causative pathogen in nosocomial septic arthritis, we consider the transmission of an oral Streptococcus species to a sterile joint space as analogous to the demonstration of identical organisms in iatrogenic meningitis.

Some authors have suggested that the efficacy of surgical masks is unproven, and that viridans streptococci may be introduced in ways other than direct contamination from the oropharynx.14 In particular, it has been suggested that transmission could be explained by more general deficiencies in aseptic technique, including contamination of the equipment during set-up or improper skin sterilisation. However, the compelling evidence that oral commensal bacteria can be aerosolised, and molecular confirmation of the source in several cases, including our own, would suggest that a surgical mask serves a role in aseptic technique.

Based on this case, we would recommend that clinicians seek a history of recent joint intervention in circumstances in which viridans streptococci are isolated from joint culture, particularly when the organism grows from the direct inoculum as well as the enrichment medium. We consider a surgical mask to be a low-cost, simple addition to the aseptic technique that may assist in prevention of nosocomial septic arthritis.

Pulsed-field gel electrophoresis dendrogram: Streptococcus mitis isolates from the patient’s joint fluid (Lane 1), and the proceduralist’s oropharynx (Lane 2 and Lane 3), showing an indistinguishable restriction fragment pattern. The lanes below are other oral Streptococcus isolates from the proceduralist along with control organisms

Antimicrobial resistance: global problems need global solutions

Much has been written about antimicrobial resistance and the measures we must take to prevent an era in which infections become untreatable. Despite these longstanding concerns, there has been a steady rise in antimicrobial resistance globally, threatening the effectiveness of increasing numbers of antimicrobial classes against broadening species of microorganisms.

Do we continue on our current path until no effective antimicrobials are available, the pressure on microorganisms is slowly reduced, and resistance wanes over time? If so, we face a period during which many people will die with untreatable infections. Or do we act now?

In the spirit of optimism that action now can still make a difference, we publish in this issue several articles to be presented at this week’s combined Australasian Society for Infectious Diseases (ASID) and Communicable Disease Control conference, which address the breadth of antimicrobial resistance issues we currently face.

In their editorial, Looke and colleagues from the ASID Council (doi: 10.5694/mja13.10190) describe the growing threat of multiresistant gram-negative bacteria, a new “Red Plague”, engendered by the ability of resistance genes to move freely between bacterial species, across borders and, through global travel and trade, around the world. An example of a multiresistant gram-negative pathogen causing disseminated infection after a routine surgical procedure is described by Roberts and colleagues (doi: 10.5694/mja12.11719). This infection was caused by an organism thought to have been acquired innocuously during regular overseas travel. In the same vein, research by Kotsanas and colleagues (doi: 10.5694/mja12.11757) describes the difficulty in eliminating an environmental source of resistance-carrying plasmids that had been implicated in several clusters of infection in an intensive care unit.

The ways to deal with resistance are seemingly straightforward: halting unnecessary use of antimicrobials, limiting broad-spectrum antimicrobial use through stewardship programs, and enforcing basic preventive infection control measures that relate to hygiene, sterile technique and isolation of infectious carriers, as well as reducing antimicrobial use in veterinary and animal production sectors. As of January 2013, antimicrobial stewardship programs are a requirement for hospital accreditation in Australia, but do they actually work? Cairns and colleagues (doi: 10.5694/mja12.11683) describe an audit of antimicrobial use before and after an antimicrobial stewardship program in a tertiary hospital in Victoria. While immediately successful in reducing broad-spectrum antibiotic use, there was a trend towards a subsequent rebound, the venture has not yet been proven cost-effective, and long-term outcomes such as reductions in antimicrobial resistance cannot yet be shown. More work may be needed to convince all stakeholders of the importance of implementing these measures.

It may yet be the simplest preventive measures that have the greatest effect for the least cost. Coatsworth and colleagues (doi: 10.5694/mja12.11695) describe a case of probable iatrogenic prosthetic shoulder infection attributable to an intra-articular injection performed by a proceduralist not wearing a mask. Have we come to depend so much on the panacea of the antimicrobial that we have forgotten the lessons of Semmelweis, Pasteur and Lister? Prevention of infection must be as important as treatment, and this will require effort on a global scale. In the developing world, resistance is becoming endemic and our global interactions mean we cannot act in isolation and expect resistance to disappear.

Ghafur (doi: 10.5694/mja13.10099) urges us to behave like microbes and “unite or perish”. He calls for global, cross-border action and describes efforts in India to tackle the now very serious threat of gram-negative resistance by bringing together members from across the medical, political, industrial and community divide to create the Chennai Declaration.

We can all learn from this effort, but the real challenge is to institute the measures we know are needed and to show that they can work. If we do, we may one day write about the success story that is global collaboration, reduced resistance, better infection control and improved human health.

Gram-negative resistance: can we combat the coming of a new “Red Plague”?

Coordinated action is urgently needed to tackle a looming public health crisis

Everybody knows that pestilences have a way of recurring in the world; yet somehow we find it hard to believe in ones that crash down on our heads from a blue sky. There have been as many plagues as wars in history; yet always plagues and wars take people equally by surprise. Albert Camus, The plague, Part 11

Infectious diseases scourges in history have had devastating effects on unprepared human populations. Bubonic plague, or the “Black Death”, killed more than a third of Europe’s population from 1346 to 1351, and the “White Plague” (tuberculosis) became epidemic in Europe throughout the 19th century. These plagues provide many lessons from which we can learn if we are to contain the spread of gram-negative resistance — the coming of a new “Red Plague”.

In 1884, Danish bacteriologist Hans Christian Gram published a stain method for distinguishing bacteria. Gram-negative bacteria do not retain a blue dye (crystal violet) and are stained pink or red by use of a counterstain, hence the term “red”. In clinical use, “gram-negative” largely refers to the common human pathogens such as Escherichia, Klebsiella, Enterobacter, Proteus and Pseudomonas species. These organisms cause infections such as urinary tract infections, peritonitis, biliary tract infection, hospital-acquired pneumonia, and less common but more serious infections such as liver abscess and neonatal meningitis, among others.

While antimicrobial agents were initially highly successful in treating these infections, their unfettered use in both humans and animals has seen rates of antimicrobial resistance rise alarmingly, especially in the developing world. In a 2009 study, > 50% of Escherichia coli in China and > 70% in India were extended-spectrum β-lactamase-producing strains, indicative of high-level resistance.2 It is now estimated that up to 100–200 million people in India may harbour gram-negative bacteria that carry the New Delhi metallo-β-lactamase (NDM-1) enzyme that renders the bacteria virtually untreatable.3 It is not known how many have experienced infections from these organisms. Poor sanitation and uncontrolled antibiotic overuse in health and agriculture are the likely culprits.

Australia and the rest of the developed world are not immune to these developments. Antibiotic-resistant gram-negative bacterial infections were once thought to be simply “hospital-acquired infections”, but people with community-acquired multiresistant gram-negative bacterial infections are now presenting to general practices and emergency departments. Comprehensive Australia-wide surveillance of resistance trends in gram-negative bacilli is lacking, however. Though rates of resistance are lower in Australia than in the United States, southern Europe and much of Asia, resistance (eg, to third-generation cephalosporins and fluoroquinolones) is rising. The Australian Group on Antimicrobial Resistance surveillance of community-acquired gram-negative isolates has shown that multiresistant E. coli isolates rose from 4.5% in 2008 to 7.2% in 2010.4 Moreover, virtually all key mechanisms of multidrug-resistance in gram-negative bacilli found worldwide have now been detected in Australia.5–8

Establishment of gram-negative resistance in Australia is likely to have several consequences, including the need to treat previously simple infections, such as uncomplicated urinary tract infections, with intravenous instead of oral antimicrobial therapy; the need to treat severe community-acquired sepsis with antibiotics of last resort up-front, and a growing ineffectiveness of surgical antibiotic prophylaxis. The impact of increased resistance would be seen across all age groups, leading to significant costs to the community in both human and economic terms. This shift has already become apparent in children and adults with no prior hospital exposure presenting with infections acquired during travel to countries where resistance is endemic.9 The impact on health care-associated sepsis is likely to be substantial.

Are new antibiotics waiting in the wings to save the day? Unfortunately, antibiotic development has all but stalled, and candidate antibiotics in development have limited activity against these resistant pathogens. Two basic strategies remain: enhancing traditional infection control, including hand hygiene and isolation of carriers in hospital; and antibiotic stewardship, where “selection pressure” on bacterial flora is mitigated by reduction in the volume of antibiotics used in clinical practice. Infection control and antibiotic stewardship programs are now mandated in all hospitals through accreditation, but their effectiveness in halting the spread of gram-negative resistance is unknown.

What must be done?

Without a coordinated effort at government level across all human and animal health care sectors, we are likely doomed to failure. We need to implement national surveillance to map and track the true extent and impact of these infections. We need to proactively implement the principles of stewardship across all sectors from “high-tech” hospitals to country general practices, to eliminate the many, mostly non-evidence-based, ways that antimicrobials and disinfectant products are used within the community, hospitals and industry. We need to support and fund research into new antimicrobial compounds and other innovative strategies to combat resistance. We need to think outside the square and embrace innovative trials of preventive strategies, such as vaccines; newer methods of disease treatment, such as using interventional radiology and minimalist surgical techniques instead of traditional surgery; and farm production methods developed with techniques that do not require antimicrobial agents. Most importantly, we need to appreciate the significance of this growing outbreak of gram-negative resistance in the same way that we appreciate and plan for outbreaks of infections such as avian influenza.

In 2011, the World Health Organization declared antimicrobial resistance to be the theme for World Health Day, and governments around the world have begun to face up to this threat. A major positive step has been taken by the Australian Government with the recent formation of the Antimicrobial Resistance Standing Committee, which reports to the Australian Health Protection Committee. This, for the first time, has created a dialogue that allows involved agencies and groups to tackle this challenge together.

All of us — government and public health institutions, universities, human and animal health professional groups, and the community — have to recognise gram-negative resistance as a looming public health crisis and a social challenge: a new plague. We need to be brave enough to make difficult decisions to re-regulate antibiotics. Without intervention, many of the greatest advances in the practice of medicine — such as transplantation, joint replacement surgery or critical care medicine — will be under significant threat.

We have one great advantage over the past plagues of history: we need not be caught unprepared. We have the vast armamentarium of science now working for us. Using this knowledge, we have the capacity to counter ignorant practices and galvanise public and governmental action. Past plagues teach us to take effective steps before it is too late.

Updated Creutzfeldt–Jakob disease infection control guidelines: sifting facts from fiction

New guidelines aimed at reducing iatrogenic disease and discrimination against patients

Creutzfeldt–Jakob disease (CJD) is a rare neurodegenerative disorder which causes the death of about 25–30 Australians each year, giving an average mortality rate of 1.2 cases/million/year.1 It is untreatable. CJD is the commonest human form of prion disease2 and is a notifiable disease in all Australian states and territories, with notification to the relevant jurisdictional health department required for all cases in which a strong clinical suspicion for CJD exists.

CJD may be acquired through medical intervention (iatrogenic CJD), for example, from the use of cadaver-derived pituitary hormones; or it may be inherited in an autosomal dominant pattern with high penetrance (familial CJD, occurring in about 10%–15% of cases); but in at least 85% of cases it occurs sporadically (sporadic CJD),2 with the person having no recognised cause for the disease. Variant CJD (vCJD) is the form zoonotically linked to bovine spongiform encephalopathy (mad cow disease), with a median age at death of around 28 years.2,3

Iatrogenic transmission is generally most likely when infectious material is placed in direct contact with the brain.4 CJD is not transmitted through respiratory, casual or sexual contact, and bloodborne transmission has only been confirmed for vCJD.5 Whether CJD has been transmitted through surgery not involving the central nervous system remains debatable.6,7 Worldwide, there have been two major iatrogenic outbreaks of CJD, one caused by contaminated pituitary hormone extracts (226 cases),8 and the other related to dura mater grafts (228 cases),9 mostly associated with a single brand (Lyodura), when these products were derived from human cadavers with unrecognised CJD. In Australia, the most recent human-derived pituitary gonadotrophin-related CJD death occurred in 1991, and the most recent Lyodura-related CJD death occurred in 2000,1 although new cases were reported overseas in 2011.

The Communicable Diseases Network Australia has recently completed a revision of the Australian CJD Infection Control Guidelines (CJD ICG).10 These guidelines continue to be primarily aimed at preventing iatrogenic cases of CJD, and they differ from the previous version by being considerably more streamlined in order to enhance useability. They give up-to-date information on diagnosis (including associated genetic mutations), contain much more detail on management of surgical instruments, dealing with high- and low-risk people and procedures, and give new advice on postmortem and funeral industry practices. The updated guidelines apply a clear risk stratification approach to minimise the risk of iatrogenic disease until a blood test or other screening test for the detection of preclinical infection becomes available. vCJD has not occurred in Australia to date,1 with most cases reported in the United Kingdom, and modelling suggesting that cases will be unlikely to occur here. Therefore vCJD is not considered in the scope of the revised guidelines.

We believe the updated CJD ICG will be of interest for two reasons. First, they serve as a reminder, that despite the relative rarity of confirmed cases, CJD is not infrequently considered in the differential diagnosis of progressive neurological disease in a variety of health care settings. Second, they contribute to equity in medical care by aiming to overcome ignorance coupled with suboptimal implementation of previous CJD ICG, which have sometimes led to discrimination, against not only sufferers of CJD, but also their family members. To illustrate these concerns: the family of one suspected CJD patient was told not to return to a particular general practice, because the general practitioner did not want “other people at the practice to become infected”; and numerous asymptomatic people at above “background” risk of CJD (due to possible iatrogenic exposure) have been refused routine endoscopies or been told they will have to pay for replacement colonoscopes, and some have been refused surgery such as hip replacement. Such occurrences lead to inordinate distress and, more insidiously, drive some patients to present to another facility where they conceal risk status in order to have a procedure performed.

We would like to highlight the information and advice in these guidelines in the hope that clinicians follow practices which are based on science and reflect the real and manageable risks surrounding CJD.

The Australian National CJD Registry (ANCJDR) has been funded by the federal government since 1993 to evaluate all suspect and proven cases of prion disease in Australia. The ANCJDR tries to follow all suspect cases until the most accurate case classification is achieved, with brain neuropathological examination being the gold standard for a definitive diagnosis. Beyond comprehensive epidemiological surveillance of all cases of prion disease in the Australian population, the ANCJDR also provides additional nationwide infection control advice, diagnostic services, and advice to families and clinicians.

Progressive multifocal leukoencephalopathy caused by BK virus?

The evidence is provocative but not definitive; nonetheless, it should serve as a stimulus to further research

In this issue of the Journal, Daveson and colleagues1 describe a case of progressive multifocal leukoencephalopathy (PML) possibly caused by BK virus rather than JC virus. This finding is potentially very significant. The polyomaviruses BK and JC commonly infect humans and remain latent in immunocomptent individuals. Both are associated with clinical disease in the setting of immunosuppression. However, only JC virus has been causally associated with PML; BK virus has been causally associated with nephropathy, ureteric stenosis and cystitis. There have been previous case reports of BK virus causing a meningoencephalitis and PML as detailed by Daveson et al, but the evidence for causality has been tenuous, largely because of the lack of confirmation in tissue. The data provided by Daveson et al are more convincing, although not definitive.

How could their evidence change clinical practice? First, the significance of PML being caused by BK virus is that the diagnosis of PML has until now only focused on the detection of JC virus.2,3 A large number of patients have or are presumed to have PML as a consequence of immunosuppression from cytotoxic chemotherapy (especially rituximab), from immunodeficiency related to HIV disease, or from immunomodulation related to the multiple sclerosis drug natalizumab.3 In a reasonable number of cases, JC virus is not detected in the cerebrospinal fluid or brain biopsy. This has been considered a consequence of insensitive assay tools, sampling error, or episodes of immune restoration inflammatory syndrome that may reduce viral DNA load before collection of cerebrospinal fluid.2,3 It is now conceivable that some of these PML cases may be caused by BK virus. Such cases would potentially be amenable to therapy: some evidence exists for efficacy with cidofovir, fluoroquinolones such as ciprofloxacin, and leflunomide.4,5 Further, risk stratification for PML in natalizumab-treated patients is currently heavily weighted towards the presence or absence of JC virus on serological testing.6 If BK virus truly can cause PML, such risk stratification strategies would need to include assessment for BK virus antibodies.

Given the potential importance of BK virus causing PML, how robust is the evidence of the causal link in Daveson et al’s report? While the authors did not find evidence for JC virus, it would have been helpful to have negative serology results for JC virus. The presence of enhancing lesions on magnetic resonance imaging is somewhat unusual for PML unless the patient has immune restoration inflammatory syndrome. Nonetheless, it can occur and has been recorded in about 10% of non-natalizumab-treated patients.2 The detection of BK virus in brain tissue, especially in the context of inflammation, raises the possibility that it was imported into the brain in inflammatory cells and that it is an “innocent bystander”. This is certainly possible but, on the other hand, no other cause was found and, in particular, JC virus was not detected by polymerase chain reaction. Further, it would be reassuring to know that the BK virus antibodies did not cross react with JC virus. Last, the case for BK virus causing PML would have been strengthened if there were data showing BK viraemia or viruria. Nonetheless, the BK viral DNA load in the cerebrospinal fluid was high, at 11 975 copies/mL; a level in the plasma of > 10 000 copies/mL is associated with a 93% specificity for presence of BK virus nephropathy.7 This level was quoted in recent guidelines by the Kidney Disease Improving Global Outcomes Transplant Work Group for the diagnosis of BK virus nephropathy.8 Given the implications of this observation, confirmation by an independent laboratory with validated and certified assays for these viruses could be reassuring.

The case for a causal link between BK virus and PML is still not solid, yet the details of the case report are highly suggestive. We consider the implications to be substantial. The report should prompt further research and meticulous analysis of future PML cases with particular attention to the issues we have outlined here.

Beyond injecting drug use: investigation of a Victorian cluster of hepatitis C among HIV-infected men who have sex with men

Hepatitis C virus (HCV) has emerged worldwide as a major infectious disease. An estimated 221 000 Australians (about 1% of the population) were living with chronic hepatitis C by the end of 2010, and HCV infection is now the most common indication for liver transplantation.1,2 While HCV diagnosis rates have declined nationally over the past 10 years, the persistence of risk behaviours, and the relatively limited uptake of HCV treatment (only 3760 Australians were treated for HCV infection in 2010) suggest that the epidemic is ongoing.1

Public health measures to curb HCV infection in Australia have focused on harm reduction. Injecting drug use (IDU) remains the predominant risk factor,3 but there has been accumulating evidence of sexual (permucosal) transmission over the past decade. Two per cent of the 899 newly acquired Australian cases from 1997 to 2000 were considered related to sexual contact,4 and more recent recognition of HCV–HIV co-infection in men who have sex with men (MSM) has prompted reconsideration of what constitutes blood-to-blood contact.5–7 Several studies of HIV-infected MSM have identified specific risk factors for HCV transmission: group sex, unprotected intercourse, fisting (inserting a hand into the rectum), non-injecting (ie, nasal or rectal) drug use, use of sex toys, and concurrent genital ulceration.6,8–10 Notably, reports of sexually transmitted HCV in HIV-negative MSM remain rare. Nonetheless, with the accelerated progression of liver fibrosis in patients co-infected with HCV–HIV now well established, co-infection has become a key issue, with liver disease-related mortality ranking as one of the leading causes of death among HIV-infected individuals in the developed world.11,12

The prevalence of HCV co-infection in Australians living with HIV was estimated at 13.1% in 2002 and 9.9% in 2010, with most co-infected individuals reporting IDU as a risk factor.1,13 One Melbourne sexual health clinic, however, identified 24 patients with newly acquired HCV without a history of IDU among 620 HIV-infected MSM over an 8-year period up to March 2010.14 We aimed to examine HCV acquisition among HIV-infected MSM in Victoria and to determine the relevance of novel risk factors within this group.

Methods

We undertook a retrospective review of all cases of HCV notified to the Victorian Department of Health from 1 April 2010 to 30 June 2011. The investigation began in April 2011, with subsequent cases examined prospectively. Hepatitis C is a nationally notifiable disease; in Victoria, medical practitioners and laboratories are legally required to notify the Department of Health. From these notifications we delineated a case series of newly acquired HCV infection in MSM infected with HIV (Box 1).

High-caseload centres were the focus of our investigation, including general practitioner clinics specialising in HIV medicine and infectious diseases services. All notifications from these centres were crosschecked with the Victorian HIV Registry (Centre for Population Health, Burnet Institute, Melbourne) to identify patients with co-infection. We undertook the same process for any doctors’ notifications where MSM behaviour was indicated. A standard definition of newly acquired HCV was used, based on any one of: antibody seroconversion in the previous 24 months, new viraemia with a negative antibody test in the previous 24 months, or unexplained alanine aminotransaminase (ALT) elevation (at least 350 U/L; reference interval, 5–50 U/L) at first positive antibody or HCV RNA detection.15

For these patients, we gathered epidemiological data from the following sources:

Enhanced surveillance data from notifications of hepatitis C by clinicians;16

The Victorian Infectious Diseases Reference Laboratory (VIDRL) for HCV genotyping, HIV viral loads, CD4+ lymphocyte counts and results of syphilis serology. We defined recent HIV monitoring as any results within 3 months of HCV diagnosis. We looked for syphilis serology results indicating infectiousness (a fourfold or greater rise in rapid plasma reagin titre plus a reactive specific treponemal test);

The Department of Health Notifiable Infectious Diseases Surveillance database, to identify sexually transmitted infection (STI) notifications in the 12 months before hepatitis C notification;

A cluster-specific questionnaire examining risk factors for HCV acquisition, which was designed by the authors, the Sexual Health and Viral Hepatitis team at the Department of Health, and the Partner Notification Officers (PNOs). Patients were first contacted by their treating doctor to seek informed consent. The PNOs then conducted the questionnaire by telephone with consenting patients who had been de-identified.

To examine whether specific strains of HCV were being transmitted, VIDRL staff performed sequence analysis of HCV isolates from a random selection of patients. The HCV genotype and subtype of samples were determined using a commercially available assay, VERSANT Hepatitis C Virus Genotype Assay (LiPA) version 2.0 (Siemens Healthcare Diagnostics). Further discrimination was carried out by sequence analysis of the HCV core region.17 Sequences were aligned with references using ClustalW and BioEdit (http://www.mbio. ncsu.edu/BioEdit/bioedit.html).

This study was approved as an investigation into an emerging outbreak of HCV in Victoria under the direction of the then Deputy Chief Health Officer (RL) in accordance with the Public Health and Wellbeing Act 2008 (Vic).

Results

Newly acquired HCV co-infection in MSM was identified in 31 patients (Box 1). Demographics of this group are shown in Box 2. The median ALT level at diagnosis was 580 U/L (range, 52 –1715 U/L). Nineteen patients (61%) had HCV antibody seroconversion, all within 18 months; six patients (19%) had positive polymerase chain reaction (PCR) test results for HCV with a concurrent negative antibody test consistent with newly acquired HCV; and six patients (19%) tested positive for HCV antibodies, with markedly elevated ALT levels. Of the 29 patients who had their HIV viral load measured around the time of HCV diagnosis, 13 (45%) had a detectable HIV viral load. Intercurrent STI diagnoses are listed in Box 3. The distribution of cases over time is shown in Box 4.

Fourteen patients completed the questionnaire. These patients had similar demographics and clinical characteristics to the total group. Frequencies of traditional and novel risk factors for HCV transmission are shown in Box 5. IDU was confirmed to be a risk factor in the minority (five patients), compared with potential sexual modes of transmission (at least 10 patients). Only five patients had been aware of the potential for HCV to be sexually transmitted before their diagnosis with HCV. Twelve patients reported changing their sexual practices since being diagnosed.

HCV genotyping results were available for 29 patients. Genotype 1a was identified in 21 patients, genotype 3a in seven, and one patient had spontaneous clearance of virus. Nine test samples (six HCV genotype 1a and three genotype 3a) were further characterised by sequencing of the HCV core region. Nucleotide sequence alignments showed that two of the HCV 1a samples shared 100% identity with each other, as did the three HCV 3a isolates. At least one patient within each cluster participated in our questionnaire and had not injected drugs in the 12 months before diagnosis with HCV.

Discussion

This study described the epidemiology of acute HCV in HIV-infected MSM in Victoria and confirmed the importance of transmission risk factors other than IDU. This has direct relevance to testing strategies and prevention messages for HIV-infected MSM.

The 31 cases of newly acquired HCV co-infection represent a relatively small proportion (0.9%) of the total HCV cases statewide. However, among the estimated 5722 Victorians living with HIV at the end of 2010 (about 0.1% of the population), 31 cases of HCV is disproportionately high.18,19 While other Australian studies have reported instances of HIV–HCV co-infection — particularly the Australian Trial in Acute Hepatitis C (ATAHC), with 50 cases nationwide, 23 in MSM with sexual exposure20 — the density of cases in our study’s single jurisdiction is concerning. The sequencing results support the hypothesis that overlapping risk factors contributed to HCV transmission, and related sequences suggest that at least two common lineages of HCV are circulating in this group.

Within this case series, IDU was a relatively uncommon risk factor for HCV acquisition, with 39% of the 31 men reporting any previous history of IDU, and five of 14 patients interviewed confirming IDU in the 12 months before HCV diagnosis. Conversely, sexual risk factors were highly prevalent. Inconsistent condom use with multiple sexual partners was universal among the men who completed the questionnaire, and correlates with the high proportion of STIs in the cluster (15/31 patients). Unprotected sex has become the paradoxical reaction to the success story of anti-retroviral therapy (ART).21 Potentially traumatic sexual practices combined with non-injecting drug use were frequently reported and were probably synergistic in HCV transmission.6 While it is likely that IDU introduces HCV into a sexual network, there is now evidence that sexual transmission in HIV-infected MSM does occur, irrespective of CD4+ lymphocyte counts.9,10,20,22 Serosorting, or selection of sexual partners on the basis of their HIV status, then concentrates HCV transmission within this population.

This study reaffirms the need for periodic HCV testing in HIV-infected MSM, particularly where history-taking reveals high-risk sexual behaviours. Based on our study, we would also argue that any diagnosis of STI in this group should prompt discussion around HCV transmission. Most cases were identified because abnormal LFTs were detected during routine management of ART. Given that HCV infection is commonly asymptomatic, there may be more MSM in the community with undiagnosed HCV who are not aware of the risk to sexual partners. Further, there is a risk of HCV re-infection after treatment or spontaneous clearance, necessitating continued HCV RNA testing to detect possible re-infection.23 This highlights the need for effective education campaigns to circumvent repeated courses of therapy that are both toxic and expensive. There is a much higher response to early treatment with current HCV therapy even in HIV co-infected patients, which again emphasises the need for frequent testing and timely identification and treatment.24

This study has a number of limitations. It is possible that the case-finding strategy may have missed potential patients who underwent their HCV testing elsewhere. The increase in notifications of cases may have been the result of increased testing. An alert was issued by the Chief Health Officer advising of an increase in hepatitis C in HIV-positive men in May 2011, which may have contributed to this.25 The retrospective 12-month period of interest used for the questionnaire may have introduced error resulting from inaccuracy in patients’ recollections of activities undertaken. Finally, only 14 patients participated in the questionnaire. While this group was representative of the cluster on demographic variables, we can only assume that this also applied to sexual risk factors.

There is a pressing need for the development and rollout of health promotion strategies to increase awareness of HCV sexual transmission and risk mitigation in Australia, in conjunction with the affected community. This is particularly important given that we as practitioners have previously generally delivered a message that HCV was not effectively sexually transmitted. We have continued to monitor the incidence of HCV–HIV co-infection in Victoria, and are aware of at least 13 further cases in the second half of 2011 (data not shown). Prospective data collection should measure changes in risk behaviours in response to prevention campaigns. Without intervention, however, the tide of HCV–HIV co-infection has the potential to erode the revolutionary gains made in the health of HIV-infected men.

1 Process of identifying cases of newly acquired hepatitis C virus (HCV) in
HIV-infected men who have sex with men (MSM) in Victoria from 1 April 2010
to 30 June 2011

* We searched for previous HCV antibody results at four Victorian pathology services and the Victorian Infectious Diseases Reference Laboratory. † Two patients had false-positive results of polymerase chain reaction (PCR) tests with normal liver function tests; the remaining 25 patients
did not meet the seroconversion or alanine aminotransaminase (ALT) criteria.

2 Patient characteristics and results of investigations in 31 HIV-infected men who have sex with men who had newly acquired hepatitis C virus (HCV) infection in Victoria, 1 April 2010 to 30 June 2011

Patient characteristics and investigations

Results

Median age of patients at time of diagnosis with HCV (range)

42 years (26–57 years)

Region of residence

Patients residing in metropolitan areas (%)

27 (87%)

Patients residing in rural areas (%)

4 (13%)

Country of birth

Patients born in Australia (%)

27 (87%)

Patients born overseas (%)

4 (13%)

Reason for HCV testing

Patients with symptoms of acute hepatitis (%)

3 (10%)

Patients who were asymptomatic with abnormal results of liver function tests (%)

28 (90%)

Median time between HIV and HCV diagnoses (range)

22 months (2 months – 17 years)*

Median CD4+ lymphocyte cell count (range); and CD4 percentage of total lymphocytes around time of HCV diagnosis (range)

535/μL (198–822/μL);
25%† (16%–42%)

Median HIV viral load around time of HCV diagnosis (range)

< 50 copies/mL
(< 50 to > 100 000 copies/mL)†

Patients who reported injecting drugs ever (%)

12 (39%)

Patients who reported having sexual contact with a known HCV-positive partner (%)

10 (32%)

* Three patients were outside Victoria at the time of their HIV diagnosis, so the time between HIV and HCV diagnoses could not be determined.
† Two patients had not had recent HIV monitoring in Victoria at the time of their HCV diagnosis.

3 Sexually transmitted infections (STIs) acquired between HIV and hepatitis C virus (HCV) diagnoses by 31 HIV-infected men who have sex with men who had newly acquired HCV infection in Victoria

STI*	Total patients with STIs diagnosed after HIV diagnosis	Patients with STIs diagnosed in the 12 months before HCV diagnosis

Any notifiable sexually transmitted infection	19	15
Chlamydia trachomatis	14	7
Neisseria gonorrhoeae	10	7
Syphilis, infectious	8	4†

* None of the patients had been diagnosed with chancroid, donovanosis or hepatitis A, and one patient had been diagnosed with hepatitis B. † Syphilis serology tests were done for 26 patients in the 12 months before HCV diagnosis.

4 Distribution of cases of newly acquired hepatitis C virus (HCV) infection in
HIV-infected men who have sex with men in Victoria by month of notification from 1 April 2010 to 30 June 2011

5 Risk factors for hepatitis C virus (HCV) acquisition in the 12 months before diagnosis in 14 HIV-infected men who have sex with men

Risk factor	Patients

Injecting drug use	5 (36%)
Sharing of injecting paraphernalia (eg, syringe, tourniquet, spoon) (proportion of injecting drug users)	3 (60%)
Tattoo or piercing
Any	6 (43%)
Performed overseas (proportion of those with tattoos or piercings)	2 (33%)
Sexual contact with known HCV-positive partner	4 (29%)
Sexual activity where blood visibly present	3 (21%)
Serosorting (selection of sexual partner by HIV status)	12 (86%)
Non-injecting drug use
Any	11 (79%)
Ice	4 (29%)
γ-hydroxybutyrate (GHB)	4 (29%)
Cannabis	4 (29%)
Non-injecting drug use before or during sexual activity	11 (79%)
Number of sexual partners
0	0 (
1	0 (
2–9	4 (29%)
10–29	5 (36%)
≥ 30	5 (36%)
Condom use
Always	0 (
Usually	5 (36%)
Sometimes	3 (21%)
Occasionally	3 (21%)
Never	3 (21%)
Group sex participant	12 (86%)
Frequency of episodes of group sex in the 12 months before diagnosis
0	2 (14%)
1–2	3 (21%)
3–5	3 (21%)
6–10	2 (14%)
> 10	5 (36%)
Use of insertive sex toys	10 (71%)
Sharing of toys between partners (proportion of those using insertive sex toys)	7 (70%)
Use of condoms over sex toys (proportion of those using insertive sex toys)	2 (20%)
Washing of toys between partners (proportion of those using insertive sex toys)	2 (20%)
Fisting	10 (71%)

Chromoblastomycosis in a Solomon Islander

To the Editor: I read with great interest the recent article by Knox and Marshall.1 Chromoblastomycosis may result in a number of rare systemic complications that may be associated with significant morbidity.

For instance, chromoblastomycosis may affect the cornea. This usually follows cataract surgery. Cladophialophora carrionii is the aetiological agent involved in corneal chromoblastomycosis.2 Keratitis occurs, resulting in ocular pain and decreased visual acuity. Topical and systemic antifungal therapy may be successful in treating the condition, but usually surgical procedures such as penetrating keratoplasty are required.

Rarely, malignancies such as squamous cell carcinomas may develop in the affected area. This is more common in the extremities and in men over the age of 60 years. Rarely, amputation may be required in this scenario. This complication usually affects patients with a 20–30-year history of chronic untreated or undertreated chromoblastomycosis.3

Chromoblastomycosis may also affect the genitalia, resulting in genital elephantiasis. Chromoblastomycosis may rarely affect the skeletal system, resulting in osteomyelitis.4 Septic arthritis has also been reported. Treatment requires arthrotomy and debridement followed by antimycotic therapy.

Chromoblastomycosis may also affect the central nervous system. For instance, mycotic granulomas in the medullary region of the brain have been reported.5 This is usually seen in intravenous drug users and may be fatal.

These examples clearly illustrate the necessity of identifying and treating chromblastomycosis in a timely manner.