A case of subacute sclerosing panencephalitis in a 23-year-old recent immigrant to Australia

A 23-year-old woman presented with a generalised tonic–clonic seizure on a background of 9 months of progressive neurological decline (characterised by involuntary jerks, monocular visual disturbance and reduced speech) resulting in falls, impaired ability to perform activities of daily living and urinary incontinence. Examination showed right-sided myoclonus, bilateral parkinsonism, primitive reflexes present, akinetic mutism and retinal scarring apparent on fundoscopy.

Two years previously, she had migrated to Australia from the Philippines; her family reported that her neurodevelopment was normal and that she had received routine childhood vaccinations.

The results of computed tomography and angiography of the brain were normal. Magnetic resonance imaging of the brain showed cerebral volume loss and extensive white matter changes with ill-defined subcortical T2 hyperintensities. An electroencephalogram showed non-specific focal epilepsy disorder involving frontal regions. Results of extensive investigations for autoimmune, hereditary and infective causes were unremarkable with the exception of cerebrospinal fluid (CSF) analysis, which revealed unmatched oligoclonal IgG. Enzyme immunoassay of CSF and serum (with corrected optical density values of 2.24 and 4.21, respectively) gave a strongly positive result for measles IgG. Intrathecal measles antibody production was confirmed by the concurrent absence of varicella-zoster virus IgG in the CSF, despite it being detected in the serum.

A raised CSF:serum ratio of measles antibodies, oligoclonal IgG in CSF and clinical features of progressive mental deterioration with myoclonus fulfilled Dyken’s diagnostic criteria of probable subacute sclerosing panencephalitis (SSPE), outlined in the Box. Supportive measures were undertaken and isoprinosine treatment for SSPE was initiated. The patient’s neurological condition stabilised but there was no improvement in her condition.

SSPE is a fatal, progressive neurodegenerative disease caused by persistent infection with an altered measles virus. Although rare, SSPE should be considered in the differential diagnosis of subacute neurological deterioration and myoclonus, especially in incompletely vaccinated patients. SSPE is rare following measles infection, with an incidence of 4–22 cases per million measles cases.1 SSPE is rarer in adults, who account for 1–12.7% of cases.2 There is no association with the attenuated measles vaccine and SSPE; no vaccine strains have ever been isolated from tissue specimens of patients with SSPE.3 Vaccination unfortunately does not confer 100% protection against measles infection (and hence against developing SSPE, which may occur after subclinical measles infection). A single dose of MMR vaccine is 95% effective, and two doses are 99% effective for measles protection.

This case is important as it highlights a terrible consequence of a vaccine-preventable disease. Achieving whole-population vaccination is instrumental in preventing measles infections through the development of herd immunity. However, 96–99% of a population are required to be vaccinated to prevent sustained measles transmission. In Australia in 2012, only 91.9% of children aged 5 years had received two doses of measles vaccine.4 Lower immunisation rates have been observed in certain areas, such as parts of the New South Wales north coast. In Australia, there were 154 confirmed measles cases reported in 2013 and 335 cases in 2014.5 Our case highlights one of the possible consequences if measles vaccination rates are not improved.

Box –
Dyken’s criteria for diagnosis of subacute sclerosing panencephalitis1

Criterion

Description

1. Characteristic clinical features

Progressive, subacute mental deterioration with typical signs like myoclonus

2. Electroencephalogram

Periodic, stereotyped high-voltage discharges

3. Cerebrospinal fluid (CSF)

Raised γ-globulin level or oligoclonal pattern

4. Measles antibodies

Raised titre in serum (≥ 1 : 256) and/or CSF (≥ 1 : 4) with a CSF : serum ratio < 1 : 200

5. Brain biopsy or autopsy

Showing typical histopathology and/or culturing altered measles virus and/or detection of measles RNA by polymerase chain reaction

Definitive diagnosis: criterion number 5, plus 3 other criteria. Probable diagnosis: 3 or more of the 5 criteria.

Immunisation for medical researchers: an ethical and practical imperative

Participants in medical research are the most valuable resource within health research, and their wellbeing must be regarded as paramount. Australia’s national statement on ethical conduct in human research1 establishes that the burden is on researchers to safeguard the health, wellbeing and autonomy of their research participants. We argue that additional guidance is required in an area that has not been widely considered in the ethical research literature and policy: immunisation coverage of the research team.

It is acknowledged that health care workers with immunisation-preventable diseases infect their patients.2,3 There is no reason to believe that researchers are exempt from transmitting these diseases to their participants. There are national guidelines4 that provide evidence-based recommendations on immunisation for people at occupational risk, but this guidance does not specifically refer to researchers.

We present a case study to illustrate the issue. We undertook a cross-generational longitudinal study examining environmental, lifestyle and genetic factors influencing health and wellbeing across the lifespan. The study, based at a medical research institute, involved recruiting pregnant women in collaboration with the local health district. University researchers sought honorary appointments for recruitment and data collection in the hospital setting, with the expectation that we would be required to prove immunisation currency, according to relevant state health policy.5 When the resultant honorary researcher appointment applications were approved, we were not required to show any immunisation status. There may be several reasons for this: first that individuals classifying risk may interpret the rules differently; and second, employment status in clinical research studies with multiple researchers from different organisations is complex.

The study researchers reviewed the university immunisation guidelines and found that those on clinical placements in state health facilities required immunisation coverage, but for all others, including researchers, immunisation was voluntary. After careful consideration, we decided that ensuring the research team was fully immunised was the most ethical way to approach our research. In consultation with an infection control specialist at the local health district, we agreed on several immunisations or evidence of serological immunity.

To fulfil our responsibilities as ethical researchers, we believe it is essential that all researchers who have direct contact with participants are fully immunised, using national guidelines, against relevant diseases. The prevention of avoidable harm appears to be an ethical imperative, but we can find no consistent guidance in this area for researchers at a national or international level. We suggest that it is appropriate for the National Health and Medical Research Council to consider guidance on immunisation coverage of researchers who have direct contact with participants, rather than leaving it to individual research ethics committees.

Polymerase chain reaction testing for faecal parasites: risks and alternatives

In this short report, written on behalf of the Australian Society of Infectious Diseases (ASID) and endorsed by its council, we highlight recent changes to stool pathogen testing (particularly for parasites) within Australasian laboratories and alert clinicians to our concerns regarding result interpretation.

Since 2013, many laboratories in Australasia have changed the technique used for stool parasite detection from subjective, time-consuming microscopy to multiplex polymerase chain reaction (PCR), which can detect multiple enteric bacterial and parasitic pathogens. A turnaround time of under 3 hours increases efficiency and reduces costs.1 Five protozoa are generally included in multiplex PCR assay: Giardia lamblia, Cryptosporidium spp., Entamoeba histolytica, Dientamoeba fragilis and Blastocystis spp.1

ASID and the Royal College of Pathologists of Australasia (RCPA) have significant concerns regarding two parasites included in multiplex PCR assay — D. fragilis and Blastocystis spp. — as their role as putative gastrointestinal pathogens is controversial and unproven. Both D. fragilis and Blastocystis spp., which are of uncertain clinical significance and may be colonising flora, have been detected at much higher rates by PCR than by routine microscopy, with prevalence rates of 17% for D. fragilis and Blastocystis.2 Similar rates have been found in Australian laboratories.3 Children aged under 10 years are the main population affected by the significant increase in detection.2,3 To date the best evidence in children, a double-blind randomised controlled trial, showed no difference between treatment and placebo for dientamoebiasis.4 A second peak occurs at 30–40 years of age, presumably among parents of children who test positive for D. fragilis.2 This has resulted in increased consultations to medical practitioners, unnecessary use of antimicrobials, and anxiety and uncertainty for families. Symptoms are often falsely attributed to these organisms, leading to overtreatment.

The results of these tests as part of the multiplex have resulted in confusion for clinicians. To optimise the use of faecal multiplex PCR in clinical practice and to minimise unwarranted treatment and anxiety, we recommend that practitioners:

do not request stool pathogen assessment (including multiplex faecal PCR) on formed stool samples;
do not request specific testing for D. fragilis or Blastocystis spp.;
should reflect the markedly increased sensitivity with unclear significance in their clinical interpretation of pathology laboratory reports of detection of these parasites;
adhere to comments appended to the laboratory report regarding the significance of D. fragilis and Blastocystis spp. and avoid specific treatment and further testing; and
discuss with a paediatric or adult infectious diseases specialist or medical microbiologist, if clarification is required.

To eliminate uncertainties, the RCPA has released guidelines (http://www.rcpa.edu.au/Library/College-Policies/Guidelines/Faecal-pathogen-testing-by-PCR.aspx) recommending that laboratories do not include D. fragilis or Blastocystis spp. within enteric multiplex PCR testing. Where laboratories continue to test and report such results, ASID and the RCPA recommend that laboratories add a comment regarding the uncertainty of the significance of these organisms.

Shigellosis: high rates of antibiotic resistance necessitate new treatment recommendations

Shigella species cause a potentially severe diarrhoeal illness that is frequently travel-associated and is both foodborne and sexually acquired. There is evidence of increasing antibiotic resistance in Shigella isolates from international studies.1,2 However, there is limited published research on this issue in an Australian context. The current Australian Therapeutic Guidelines recommend either co-trimoxazole or quinolone therapy for suspected or proven shigellosis, but do comment that quinolone resistance is increasing in developing countries and recommend azithromycin as an alternative option, if required.3 Successful treatment of shigellosis reduces the duration of illness and infectivity.

We conducted a study to describe antimicrobial resistance patterns among Shigella isolates in New South Wales during 2013 and 2014, and to identify predictors of resistance using laboratory and epidemiological data from the NSW Notifiable Conditions Information Management System (NCIMS).

A cross-sectional analysis was conducted using cases of shigellosis notified to public health authorities in NSW through NCIMS, with specimens received by the enteric pathogen reference laboratory for NSW — the Institute for Clinical Pathology and Medical Research (ICPMR) at Westmead Hospital — collected from 1 May 2013 to 30 April 2014. During the study period, a notified case was classified as confirmed if there was laboratory definitive evidence (isolation or detection of Shigella species). The study used routinely collected surveillance data from NCIMS collected by NSW Health for the purposes of analysis and reporting, for which ethics committee approval was not required. Susceptibility to azithromycin was measured via Etest (Biomérieux) using a breakpoint of ≤ 16 μg/mL, in line with the method of previous investigators.4 Susceptibility of isolates to all other drugs was tested using the BD Phoenix (BD Diagnostics) automated broth microdilution instrument and interpreted using Clinical and Laboratory Standards Institute criteria.5

Among the 160 Shigella isolates tested, 98% were susceptible to ceftriaxone, 87% to azithromycin, 73% to ampicillin, 65% to ciprofloxacin, and only 24% to co-trimoxazole (Box). Rates of resistance varied with both place of acquisition (overseas or Australia) and method of acquisition (sexual or other). Of note, ciprofloxacin resistance was more common in locally acquired than in overseas acquired infection.

We recommend the use of azithromycin, rather than ciprofloxacin or co-trimoxazole, as the first-line agent in suspected or proven shigellosis, regardless of place or method of acquisition. Our findings indicate that it is time for Therapeutic Guidelines to review its guidelines for the treatment of shigellosis in light of changing resistance patterns. Ceftriaxone remains a suitable option for seriously unwell or hospitalised patients before the availability of susceptibility testing. We strongly recommend culture and susceptibility testing for suspected and proven shigellosis, particularly among men who have sex with men, who have a higher risk of both being infected with a resistant strain and transmitting infection.

Box –
Antimicrobial resistance of Shigella isolates, by antibiotic and place and method of acquisition, 1 May 2013 to 30 April 2014*

	No.	Resistance
	No.	Azithromycin	Ciprofloxacin	Co-trimoxazole	Ampicillin

Total isolates	160	21 (13.1%)	56 (35.0%)	122 (76.3%)	59 (36.9%)
Overseas acquired^†
Yes	55	2 (3.6%)	13 (23.6%)	39 (70.9%)	19 (34.5%)
No	91	13 (14.3%)	37 (40.7%)	72 (79.1%)	32 (35.2%)
Reported sex with faecal exposure
Yes	58^‡	11 (19.0%)	27 (46.6%)	45 (77.6%)	21 (36.2%)
No	102	10 (9.8%)	29 (28.4%)	77 (75.5%)	38 (37.3%)

* Shigella isolates obtained from the New South Wales reference laboratory (Institute for Clinical Pathology and Medical Research, Westmead Hospital). The first isolate for each illness event was used; subsequent isolates were excluded where patients had multiple specimens collected for one illness event. 98% of isolates were susceptible to ceftriaxone. † 14 unknown. ‡ All men, 57 of whom also reported that they were men who have sex with men.

Ebola outbreak in West Africa: considerations for strengthening Australia’s international health emergency response

It is time for a common vision and strategy for deploying Australian expertise to international public health emergencies

An effective response to health emergencies such as the Ebola virus disease outbreak in West Africa relies on global capacity to rapidly surge the supply of skilled workers, particularly when they are limited in affected countries and increasingly depleted during the emergency. Before the Ebola outbreak, health professionals in West Africa were already scarce; for example, in Liberia the doctor-to-population ratio was 1:70 000, compared with 1:300 in Australia.1,2 In addition to clinicians, an effective response to a large outbreak of Ebola virus disease in resource-limited settings requires international technical support across a range of public health and other disciplines, including infection prevention and control, epidemiology, laboratory diagnostics, communication, mental health, anthropology, social mobilisation, logistics, security and coordination.

Early in the Ebola virus disease outbreak in West Africa, many international non-government organisations (NGOs) and several governments established treatment centres and sent public health professionals to provide clinical care and augment control efforts. Timely public health interventions in Ebola-affected rural communities achieved crucial reductions (about 94%) in Ebola transmission.3 The Centers for Disease Control and Prevention (CDC) in the United States is a case study in how governments can deploy significant public health staff to countries affected by health emergencies. At time of writing, the CDC had effected 2206 staff deployments since July 2014 to support the public health response in Ebola-affected countries across a wide range of areas including surveillance, contact tracing, database management, laboratory testing, logistics, communication and health education.4 Most CDC public health staff were deployed into roles with a low risk of Ebola virus infection (ie, non-patient care roles) and none have become infected. In assessing the CDC’s exemplary response, it is important to note its pre-existing Global Health Strategy that clearly articulates the CDC’s vision, rationale, role, strategy, funding, partnerships, staff and areas of expertise for working in international public health, including in health emergencies such as Ebola virus disease.5

In contrast, nearly 6 months into the outbreak — when almost 5000 deaths had already been recorded — the Australian Government was being criticised by public health experts for its lack of substantive assistance to Ebola-affected countries.6 The Public Health Association of Australia called on the government to help strengthen the medical and public health capacity in the region by deploying an Australian Medical Assistance Team (AUSMAT), and by supporting Australians who wanted to volunteer their services through the World Health Organization or international NGOs by encouraging their employers to provide special leave and continuation of entitlements.6 Ultimately, the Australian Government declined to deploy AUSMAT resources, stating it would not consider sending people to Ebola-affected countries until it could get assurances from developed countries closer to West Africa that Australians would be able to be evacuated for treatment in the event they became infected.7 Instead, the Australian Government chose to fund a private contractor to staff a single treatment centre built by British army engineers in Sierra Leone. To date, anecdotal reports suggest no public health professionals have been deployed to Ebola-affected countries by the Australian Government, although the risk of infection is low.

The current and all previous Australian governments have not clearly articulated a vision for providing public health support during an international health emergency. AUSMATs are multidisciplinary health teams of doctors, nurses, paramedics, firefighters (logisticians) and allied health staff such as environmental health workers, radiographers and pharmacists8 who provide timely acute medical relief immediately after disasters in Australia and overseas. Staff of state and territory governments can be members of AUSMATs, and these agencies are reimbursed by the federal government for the salaries of staff who deploy through this mechanism. AUSMATs have a relatively small number of public health professionals on a roster largely drawn from staff of state and territory health authorities, but this list includes only a limited number with relevant outbreak response skills. While AUSMATs have a proven track record in providing emergency medical care in post-disaster settings, they are not currently designed to support the public health response required for a large outbreak.

The decision not to use AUSMAT assets and the lack of federal support for other Australian health professionals who wanted to volunteer to help contain the Ebola outbreak transferred the pressure to institute human resource policies (ie, special leave and continuation of entitlements) to state and territory health authorities. Without the type of financial arrangements that the AUSMATs afford state and territory health authorities, and with a general lack of jurisdiction-funded strategies for their staff engaging in emergency responses overseas, the environment for staff deploying independently was not always supportive.

Despite the challenges, many public health professionals from state and territory health authorities and academic institutions in Australia deployed as volunteers for NGOs or United Nations agencies, including about 15% of the Australian National University Master of Applied Epidemiology (MAE) program’s alumni since 1991 (Martyn Kirk, MAE Program Director, Australian National University, personal communication). Still, only one current Australian MAE participant was deployed, with Médecins Sans Frontières (as of January 2015), compared with 97 from a similar program in the US (the CDC’s Epidemic Intelligence Service), highlighting the missed opportunity for Australia’s next generation of outbreak control experts to get invaluable field experience while providing much needed support.

Now that the Ebola virus disease outbreak is over, Australia needs to examine how well it performed in assisting the WHO to respond to this significant threat to global health, as it was declared by the International Health Regulations Emergency Committee in August 2014.9 We believe it is time for the Australian Government, in consultation with state and territory health authorities and public health training institutions, to establish a common vision and strategy for deploying Australian expertise to international public health emergencies, including Ebola virus disease outbreaks. If AUSMATs (currently the only funded mechanism) are Australia’s preferred approach to responding to international health emergencies, their capacity to support a major public health response should be expanded by including more professionals in relevant disciplines. To maximise the impact of public health professionals deployed through AUSMAT arrangements, personnel should be made available at the beginning of future health emergencies. In addition, formalising support arrangements with members of the Australian Response MAE (ARM) Network10 (created by academic institutions in response to gaps in the coordination of Australia’s public health surge capacity) may be a way for the government to effectively mobilise skilled public health professionals for deployment overseas in response to disease outbreaks. Consideration should also be given to expanding the AUSMAT roster of public health professionals and integrating structures like the ARM Network into the response framework.

The Australian Government missed an important opportunity to contribute timely, valuable technical assistance to Ebola-affected countries; support that was essential to stopping the outbreak at its source at a time when it was needed most. In the end, many Australians stepped up as volunteers in the fight to extinguish this global threat to public health. Australian federal authorities should reflect on this experience and consider it an opportunity to strengthen Australia’s response to future health emergencies and demonstrate leadership on the global stage.

Multidrug-resistant tuberculosis in Australia and our region

MDR-TB threatens TB control programs in Australia’s region and will not diminish without concerted efforts

Tuberculosis (TB) is one of the world’s great killers, but Australia has been relatively protected because of its strong public health system. Of 1300 cases reported in Australia each year, almost 90% occur in the overseas born, although Indigenous Australians are also disproportionately affected. Most cases arise in the large immigrant communities from India, Vietnam, the Philippines, China and Nepal, but high rates are also reported from Papua New Guinea (PNG), Ethiopia, Somalia and Myanmar. These cases occur primarily in permanent residents and students, rather than in refugees or those on humanitarian visas.1

Many countries are now reporting significant rates of drug-resistant tuberculosis, with at least 480 000 cases worldwide now attributable to multidrug-resistant TB (MDR-TB; defined as resistance to the two most effective first-line agents, isoniazid and rifampicin).2 However, countries with the highest rates of drug resistance often have the poorest quality data, largely due to the lack of resistance testing. Globally, MDR-TB was estimated to constitute 3.3% of new and 20% of retreatment cases in 2014. Although the deployment of molecular diagnostics to detect resistance is progressing, only a quarter of these cases were correctly identified. For example, in PNG, MDR-TB rates are similar to those described globally, but a nationwide drug-resistance survey has not been undertaken and other data sources suggest that the rates could be underestimates.3 Extensively drug-resistant TB (XDR-TB; resistant to isoniazid, rifampicin and the most effective second-line agents, quinolones and injectables) has also been sporadically reported in Australia from PNG.4 For Australian clinicians, for whom diagnostics are widely available, the rise of MDR-TB makes definitive strain identification through culture even more important.

Traditional second-line agents to treat the handful of MDR-TB cases in Australia are generally available, but prolonged courses of toxic and expensive drug combinations are required. The agents used to treat MDR-TB depend on the remaining susceptibilities, but ototoxicity (aminogylcosides), nausea (p-aminosalicylic acid) and neuropsychiatric reactions (cycloserine) are among many common side effects. It is therefore unsurprising that globally, treatment outcomes are poor, with only about half of identified patients completing the 2-year treatment course, such that only around 10% of all incident cases complete treatment worldwide.2 Meta-analyses demonstrate that the chance of treatment success diminishes as the number of drugs to which a strain is resistant increases.5 Alarmingly, there are now data on outcomes for patients with “beyond XDR”-TB, with treatment success rates comparable to the pre-antibiotic era natural history of TB.6

There is a resurgence of interest in new treatments for TB, with the first new drugs in 40 years now proceeding through development, including bedaquiline, delamanid and pretomanid. As important as individual agents is the development of new regimens that can be deployed programmatically, such as the 9-month Bangladesh regimen (comprising gatifloxacin, clofazimine, ethambutol and pyrazinamide, with prothionamide, kanamycin and high-dose isoniazid added for the intensive phase).7 There is also interest in off-label use of existing antibiotics with anti-TB activity, such as linezolid and meropenem–clavulanate, and new strategies to minimise toxicity, such as therapeutic drug monitoring. However, even if new regimens become established, significant barriers exist to providing treatment for MDR-TB in the countries that need them most. MDR-TB is both a cause and symptom of poor communicable disease control programs, with MDR-TB regimens costing around tenfold that of drug-susceptible cases.8

MDR-TB is not a problem that will just go away. Policy makers may prefer to treat the problem they can address — focusing on improving programs for drug-susceptible TB to prevent resistance amplification. However, modelling has consistently demonstrated that cases of MDR-TB predominantly arise from community transmission rather than from resistance amplification in previously susceptible strains,9 such that only targeted control programs will achieve reduction in the disease burden attributable to MDR-TB.10

As global TB rates slowly decline, the contribution of late reactivation of latent infection to incidence is likely to increase. While this makes treatment for latent MDR-TB a key consideration, evidence for effective treatments remains scarce and clinical trials are ongoing.

The ambitious post-2015 targets for TB control, which replace the relatively modest Millennium Development Goals, present an opportunity for Australian leadership. In our setting, with most TB imported and the emergence of MDR-TB so dependent on the strength of health systems, Australia has a critical role to play in supporting developing countries of our region to improve TB control programs and their health systems generally. A vision for an expanded international response, coordinated with global partners, governments, multinational organisations, affected individuals and communities is provided by the United States National Action Plan for Combating MDR-TB.11 Given that 57% of MDR-TB cases occur in the Asia–Pacific region,2 a similar response to improve clinical diagnostics and management in our region would help keep MDR-TB from our shores.

The ASID test

The Australasian Society for Infectious Diseases view on infectious diseases challenges in 2016 and beyond

This year, 2016, is a historic year for the Australasian Society for Infectious Diseases (ASID), being the 40th anniversary of the formation of the society. It is an opportunity not only to celebrate our achievements in infectious diseases and microbiology over the past 4 decades but also to anticipate future challenges. Principal among these are antimicrobial resistance (AMR) and the emergence or re-emergence of previously controlled or unrecognised diseases.

Although infectious diseases were thought to have been conquered as public health problems 40 years ago, our complacency has been repeatedly challenged by new and re-emerging threats. In this issue of the MJA, we read about re-emergence of Ebola virus,1 preparedness for Zika virus2 and local transmission for hepatitis E3 as salient examples. Williams and colleagues also describe the diagnosis of subacute sclerosing panencephalitis in a 23-year-old man,4 a timely reminder that high levels of herd immunity are required to prevent measles outbreaks, which still occur in parts of Australia with suboptimal immunisation rates.5 But emerging infections are not only viral. In this issue, Mandrawa et al discuss carbapenem-resistant Klebsiella,6 which highlights the serious impact of AMR on clinical practice.

AMR remains a global challenge. It results in about 2000 attributable deaths per year in Australia and a projected 10 million globally by 2050.7 As antibiotics become less effective, old diseases re-emerge, many in Australia’s near neighbours. Tuberculosis (TB) remains one of the most lethal infectious diseases with a third of the world’s population being infected, and over 1.5 million annual TB-related deaths worldwide.8 In this issue, Cheng and Trauer report on the increase in multidrug-resistant TB in Australia and the region.9 Another disease from times past, gonorrhoea, is also re-emerging as increases in AMR result in treatment failures. In 2015, the National Neisseria Network reported a marked increase in rates of gonococcal disease, with the highest ever proportion of strains on record with reduced susceptibility to ceftriaxone, and high-level resistance to azithromycin recorded for the first time.10 These patterns reflect trends around the world, and as noted by Lahra and colleagues, suggest that Neisseria gonorrhoeae is emerging as a global public health threat.10 Both TB and N. gonorrhoeae emphasise our need for national, coordinated AMR surveillance in humans and animals so we can monitor and respond to these trends.

Surveillance alone will be ineffective if there is not a clear plan to reduce the AMR threat, as well as a coordinated mechanism to implement this plan across jurisdictions (which is currently lacking). The federal government released its national AMR strategy in late 2015.11 A key element is the need to develop a “one health” approach to antimicrobial stewardship, including capture of prescription data in both humans and animals, and regulation of antimicrobial use and national antimicrobial guidelines for veterinary practice and agriculture. Guideline development in animals and humans needs to be supported by implementation science to improve uptake and adherence. We also need to reduce the unnecessary use of antibiotics, which is estimated to occur in up to 75% of antibiotic prescriptions in Australia,12 the bulk of which are dispensed in primary care. There needs to be coordination of strategies to address this problem across stakeholders including professional colleges and societies. ASID, led by Professor Denis Spelman, and the Royal College of Pathologists Australasia have collaborated with the Royal Australasian College of Physicians’ EVOLVE campaign to list the top five low value interventions in infectious diseases and microbiology practice.13 These include the use of antibiotics for asymptomatic bacteriuria, leg ulcers without clinical infection, uncomplicated upper respiratory tract infections, and faecal pathogens in the absence of gastrointestinal symptoms (with some exceptions). Avoiding inappropriate diagnostic tests is one important aspect of reducing antibiotic prescribing for these conditions. For example, as Bowen et al report in this issue,14 faecal multiplex polymerase chain reaction testing results in high rates of reporting of the non-pathogenic parasites Dientamoeba fragilis and Blastocystis spp., which could lead to unnecessary antibiotic use in patients who test positive.

Another benefit of reducing unnecessary antibiotic use is reduction of adverse events. In their study of medical inpatients at a Melbourne hospital, Trubiano and colleagues found that almost one in four had a serious antibiotic allergy, most commonly associated with overuse of broad spectrum agents.15 Of particular concern was poor documentation of allergies in patient records and charts.

Over the past 40 years, members and affiliates of ASID have contributed to paradigm-shifting approaches to infectious diseases and microbiology — including the elimination of smallpox and the link between Helicobacter pylori infection and duodenal ulcers. Who knows what challenges lie ahead. We are on the cusp of personalised medicine that will predict our risk of disease, inform our likely response and guide our therapy. We must, however, remain mindful of key lessons from the past, so that history does not repeat itself. As Kurt Vonnegut, Jr wrote: “History is merely a list of surprises. It can only prepare us to be surprised yet again.”

Zika preparedness in Australia

Our comprehensive national response encompasses prevention and surveillance, as well as monitoring and controlling Aedes aegypti in Australia

The spectrum of clinical illness for Zika virus infection is generally not severe — about 80% of cases are asymptomatic1 — and the infection was not previously thought to be cause for serious public health concern. There is no specific treatment for, nor a vaccine against, a Zika infection.

Recent disquiet has been raised by emerging evidence of possible vertical transmission of Zika, the development of severe congenital abnormalities, including microcephaly,2,3 and of a possible link to fetal deaths.4 In addition, a possible link to Guillain–Barré syndrome has been reported.5,6 The World Health Organization declared the clusters of microcephaly and neurological disorders a Public Health Emergency of International Concern on 1 February 2016.7 Knowledge about any causal link between Zika virus and effects in utero is still evolving; however, given the serious implications, should there be one, Australian guidance for managing pregnant women returning from Zika-affected areas and for preventing the spread of the disease has been prepared.

In almost all cases, the Zika flavivirus is transmitted by mosquitoes (particularly by Aedes aegypti). The Zika virus was first isolated from a monkey in Uganda in 1947,8 and serological evidence of past infections in humans has been reported since 1952 in Africa and since 1981 in South-East Asia.9,10 Outbreaks in the Pacific Islands were first reported in Yap State, Micronesia, in 20071 and in French Polynesia from 2013,11 with spread to many Pacific islands between 2013 and 2016.12,13 Zika has spread rapidly across the Americas since late 2015, after being first confirmed in Brazil in 2015.14 In November 2015 the international community was alerted to the possibility of severe congenital malformations, with an International Health Regulations notification about an increase in cases of microcephaly in Brazil with geographical and temporal links to Zika.15 At that time, further information was also provided by health authorities in French Polynesia about congenital malformations, also with geographical and temporal links to Zika.15

In Australia, sporadic cases of Zika have been detected since 2012 in 35 returning travellers (to 29 February 2016), and there is a continuing risk of imported Zika infections from overseas. With the number of affected overseas areas increasing, as is greater awareness among the public and health professionals, an increase in the detection of imported cases could be expected.

The low risk of local transmission of Zika in Australia is restricted to areas of Queensland where the most suitable vector, A. aegypti, is continually present. Queensland has well developed and practised plans and resources for controlling dengue (also carried by the A. aegypti mosquito) that are also applicable to Zika. Through routine vector monitoring and control activities, and the deployment of Dengue Action Response Teams (DARTs), the Queensland government has prevented dengue from becoming endemic, despite regular importations. The Queensland government recently announced a package of measures to strengthen preparedness, including enhanced laboratory capacity in Townsville. Queensland Health remains on the alert for imported cases and subsequent local transmission.

A program of mosquito surveillance and control, coordinated by the federal Department of Agriculture and Water Resources, is in place at Australia’s air and sea ports to prevent incursions of exotic mosquitoes from overseas. While foreign mosquitoes are detected during the summer months, well established programs prevent their establishing breeding populations. There is also a specific program conducted by Queensland Health in the Torres Strait for controlling A. albopictus (a potential alternative vector for the Zika virus16), active in this area since 2005. The program has been successful in preventing its spread to the mainland and in reducing the numbers of A. albopictus and, at the same time, of A. aegypti in the transport hubs of the Torres Strait.

In February 2016, the Australian Health Protection Principal Committee issued advice on the management of pregnant women returning from Zika-affected countries and on preventing sexual transmission of Zika. A public health guideline on Zika is being finalised, and advice for travellers was issued in January 2016.17 Until more is known about the link between the virus and microcephaly, Australia recommends that women who are pregnant or planning to become pregnant should consider postponing travel to areas with ongoing transmission of Zika. If they do decide to travel, they should consistently adhere to mosquito avoidance measures. This recommendation is in line with major public health agencies around the world.

The Interim recommendations for assessment of pregnant women returning from Zika virus-affected areas18 encourage health care providers to ask all pregnant women about their recent travel history. Those who have travelled to a Zika-affected country during their pregnancy should be evaluated and tested. Any woman who tests positive for Zika virus should be referred for specialist obstetric care. The Royal Australian and New Zealand College of Obstetricians and Gynaecologists has issued guidance on the care of women with confirmed Zika virus infection during pregnancy in Australia.19

Further concerns for pregnant women and their unborn babies have been triggered by the possibility of sexual transmission of Zika virus. Initially, two instances of likely sexual transmission were reported internationally, one in 2008 and the other in 2016,20,21 and two instances of Zika virus being detected by polymerase chain reaction in semen — including one 62 days after the onset of symptoms — although virus isolation was not performed, so that it was not determined whether viable virus was present.22,23 There is evidence from the United States that sexual transmission of Zika may be more common than previously reported.23 To date, all reports of suspected or confirmed sexual transmission of Zika have involved a symptomatic man transmitting the virus to a woman. It is still unknown how long the virus can persist in semen, or how infectious this may be. Mosquitoes remain the overwhelmingly predominant mode of transmission. The Australian advice, Interim recommendations for reducing the risk of sexual transmission of Zika virus,25 recommends that men with a confirmed Zika virus infection and whose partner is pregnant should abstain from sex or consistently use a condom during sex for the duration of the pregnancy. Men with a confirmed Zika infection who do not have a pregnant partner should abstain from sex or consistently use a condom during sex for 3 months after leaving a Zika-affected country.

All recommendations about travel, testing and management require definition of the countries that have current local transmission. The list of affected countries is assessed daily by the Department of Health, based on agreed criteria. This, however, is not straightforward, and differences between overseas surveillance systems mean that a variety of sources must be checked to assess whether local transmission of Zika virus is happening in a particular country.

While unease about Zika is high, there remains a lack of high quality evidence for a causative link between infection and the development of microcephaly, and there is a general lack of data on the pathogenesis and epidemiology of the disease. Further studies are urgently required, and are underway. The need to formulate recommendations despite a paucity of data and evidence is not new in public health. However, it does pose particular challenges and risks, in that we may have to modify recommendations frequently. Expert consultations and the experiences and recommendations of other agencies internationally are important in the development of such recommendations. A key component of preparedness for communicable disease outbreaks in Australia is developing nationally consistent advice across the states and territories, and harnessing the expertise that is present throughout our country.

Australia has robust systems in place that can be adapted as required to enable a rapid response to communicable diseases such as Zika, with excellent laboratory capacity, public health response capability and communicable disease surveillance systems, as well as established vector surveillance and control programs. As the situation evolves, ongoing monitoring will continue, with information and recommendations updated as necessary. Zika is the latest communicable disease threat to challenge us. Each new threat offers an opportunity for enhancing core elements of communicable disease control and for ensuring readiness for the next emerging infectious disease.

Aileen Joy Plant

Professor Aileen Plant (1948–2007) was a renowned medical epidemiologist and an outstanding global public health leader

In mid-March 2003, hurrying through Perth Airport on her way to a World Health Organization assignment, Professor Aileen Plant paused to write out her will. She asked the airline staff to witness it before boarding a plane for Hanoi. Her task was to lead a team trying to bring Vietnam out of its sudden nightmare of the deadly disease of severe acute respiratory syndrome (SARS), an illness that no one knew the cause of, nor how it spread. The person she was replacing, Dr Carlo Urbani — who had identified the new syndrome — lay sickened by it in a hospital in Bangkok.

Aileen knew that speed was essential. The effectiveness of the tasks of early detection and prevention of transmission would require a cohesive and willing team, which in turn would require the trust of the Vietnamese Ministry and the Vietnamese health care workers. This, she achieved.

On 29 March, Dr Carlo Urbani died. Dr Katrin Leitmeyer, virologist, recalls how Aileen rallied everyone, “gluing extreme characters from all around the world together under difficult psychological circumstances”.

The 3-week mission became 11 weeks. Vietnam had 69 cases of SARS and five deaths, mostly in staff and patients of the Hanoi French Hospital. During this time, Aileen’s sister, Kaye, became gravely ill in Perth. Aileen was desperate to be with her but knew that, even if she did return to Australia, she would not be allowed into any hospital.

Under her leadership, the Hanoi team characterised the clinical features of the disease, its incubation period and possible routes of transmission, and made important observations about the effectiveness of case isolation and infection control in halting transmission. On 28 April, Vietnam was declared SARS-free, the first country to eradicate the disease. The Vietnamese government awarded Professor Plant its highest award, the National Medal of Honour.

Aileen said of her experience that two things stood out. The first was that the Vietnamese government agreed that external help should be sought — an extraordinary admission in communist Vietnam at that time. The second was the dedication of the Vietnamese staff, who quarantined themselves in the hospital and worked with little in the way of modern technology or resources. Aileen thought they should have been awarded the Medal, rather than her. Her own keen sense of family no doubt contributed to her great respect for the grief and isolation of any individual. Finally, in June, Aileen was able to return home to her recovering sister.

Other WHO assignments in which Aileen was involved included investigating an HIV outbreak in children in Libya, childhood dermal fibromatosis in Vietnam, yellow fever outbreaks in Africa, tuberculosis trends in Indonesia and the emergence of avian influenza in Asia. She also began seminal work with the WHO on the International Health Regulations (IHR), to frame the relationship between countries and the WHO in regard to preparation and response for public health events of international concern, and continued work on the Global Outbreak and Alert Response Network (GOARN), which she had helped establish in 2000. Both are key tools in global biosecurity today.

Aileen came from a large family and left school at the age of 15 to work on her parents’ farm in Denmark, Western Australia. She became interested in infectious diseases, telling her father that an animal had died of eastern equine encephalitis. This became a family joke, as the animal in question was a cow. She took up work as a bank teller for 5 years but became determined to study medicine, putting herself though technical school and gaining entrance to the University of Western Australia.

Her early years as a resident doctor in the Northern Territory sparked her interest in Aboriginal health. She became firm in her belief that it was essential for the overall health of humanity to understand and care for vulnerable populations. Already evident to her colleagues by this time were her razor-sharp “bullshit detector”, her interest in all matters and her keen sense of humour.

Professor Aileen Plant with Professor Lance Jennings on a World Health Organization mission to investigate a cluster of H5N1 influenza cases in Vietnam in 2005.

Aileen went on to study at the London School of Hygiene and Tropical Medicine. On returning to Australia, she obtained a Master of Public Health at the University of Sydney, eventually joining the faculty as a lecturer, while also working with the New South Wales Department of Health.

In 1989, Aileen took up the position of Chief Health Officer in the NT. Although frustrated by politics, she kept her focus on Aboriginal health, pointing out the flaws in census methods and analysing a decade of data demonstrating health trends and causes of premature mortality in Aboriginal communities.1,2 Her 1995 report called for a whole-of-community and government approach to the poor health trends in Aboriginal and Torres Strait Islander populations.1

Among Aileen’s gifts was the ability to see the truth, or the way to the truth, in science, diplomacy and politics. Science was her bedrock, and diplomacy she saw as an everyday necessity from which wonderful friendships could grow. Bad science and politics tired her, perhaps due to the famous bullshit detector constantly being triggered.

In 1992, Aileen took up the position of Director of the Master of Applied Epidemiology (MAE) Program at the Australian National University, a program she had played a key role in initiating and developing. During her 3 years there, she completed her own PhD, guided many masters and doctoral students, and worked with her colleagues to develop a program on Indigenous health and in attracting Indigenous students. She convinced a colleague in the NT, Dr Mahomed Patel, to join her, developing pathways for international students and obtaining overseas placements for Australian trainees, including deployments with the WHO and establishing MAE-like programs in India, China, Malaysia and Vietnam.

The MAE Program has served the world exceedingly well, with many of its students, staff and graduates contributing to the control of SARS, avian influenza and other public health emergencies. Many of Aileen’s students are now leaders in public health, nationally and internationally.

In 1995, Aileen moved back to Perth to be with her much loved extended family. She worked initially as a senior lecturer at the University of Western Australia before becoming professor of international health at Curtin University in 2000. Together with Professor John Mackenzie, a world-renowned virologist, she compiled an ambitious bid to establish a cooperative research centre (CRC) with a focus on emerging infectious diseases. After two arduous attempts, their bid was successful. The Australian Biosecurity CRC for Emerging Infectious Disease was established in 2003, bringing animal, human and environmental disciplines together in research. Over 7 years, the CRC had many high-impact achievements, including extensive research into the ecology of disease emergence, the development and application of diagnostic tools and systems, and important work on Hendra virus, coronaviruses and influenza viruses. Translational research — taking research into action and policy — was a centrepiece. The CRC awarded over 60 postgraduate scholarships to students in Australia and South-East Asia.

During this time, Aileen continued to assist the Australian Government Department of Health and Ageing, including in emergencies such as the Asian tsunami, where her ability to see the path forward encompassed areas beyond public health. In 2008, the Department named its new crisis response centre the Aileen Plant National Incident Room.

Aileen’s comments usually went to the heart of the matter. Radio host Phillip Adams, interviewing Aileen on ABC RN Late Night Live, asked her whether authoritarian or democratic governments would be better at handling outbreaks. She replied that it depended on the characteristics of the disease and its transmission mode. Diseases like SARS, she noted, are shown to be well handled by authoritarian governments if backed up by a good public health system, but something like HIV–AIDS, which requires behavioural change, is better handled by democracies. She repeated the point, “Wherever they are, infectious diseases always make poor people poorer”.3

Aileen continued to work with the WHO on finalising the IHR, which were endorsed in 2005 and are now signed by over 190 countries. Many of the articles of the IHR reflect the cooperation and information exchange exemplified by Aileen’s time in Vietnam.

Professor Aileen Plant with Professors John Mackenzie (Curtin University), Mal Nairn (Charles Darwin University) and Charles Watson (Curtin University) at the opening of the Queensland node of the Australian Biosecurity Cooperative Research Centre in 2004.

In addition to 90 scientific articles and numerous book contributions, Aileen co-authored a book on the impact of SARS and another on the approach to communicable diseases.4,5 Aileen’s delight was to do projects with her friends and family, and their interests were hers, be they research projects, scientific books, teaching friends’ children to swim, writing creative fiction or designing tree farms.

Aileen died suddenly at Jakarta Airport on 27 March 2007, while travelling home from a WHO meeting, where she had helped to bring about consensus on the issues of sharing avian influenza viruses and access to influenza vaccine for developing countries.

Her spirit and values live on in her colleagues and her students. The Australian Science Communicators honoured Professor Plant as the 2007 Unsung Hero of Australian Science. The University of NSW introduced the yearly Aileen Plant Memorial Prize in Infectious Diseases Epidemiology, an honour for emerging researchers. The Public Health Association of Australia, together with three other peak public health bodies, awards the Aileen Plant Medal for Contributions to Population Health at every Population Health Congress (4-yearly), and Curtin University grants Aileen Plant Memorial Scholarships for Indigenous students and conducts an annual oration, the Aileen Plant Memorial Lecture.

Aileen’s sister Teen, arriving at Jakarta Airport in 2007, remarked, “This is where Aileen died”. Another sister, Caro, replied, “No, she was in departures”. Even in their deep sorrow, they both laughed, as they realised how much Aileen would have liked that quip.

Editor’s note: We hope you are enjoying our series on remarkable and talented Australian medical women. We would love to hear your suggestions about subjects for future articles. Please email your ideas to us at mja@mja.com.au.

Carbapenemase-producing Klebsiella pneumoniae: a major clinical challenge

Clinical record

A 59-year-old man from rural Victoria, with no hospital contact for 15 years or recent history of international travel, presented to his local hospital with severe acute pancreatitis secondary to gallstones. He was transferred to a metropolitan hospital for further management, including intermittent admissions to the intensive care unit (ICU) for haemodynamic support. On Day 4 of admission, empirical antibiotics were prescribed for severe pancreatitis and concurrent nosocomial pneumonia, according to hospital guidelines and advice from the infectious diseases team; initially ceftriaxone, later changed to piperacillin–tazobactam and then meropenem, due to clinical deterioration. Diagnostic microbiology did not reveal any significant pathogens.

Serial computed tomography demonstrated persistent peri-pancreatic fluid collections despite repeated percutaneous drainage and broad-spectrum antibiotics. One month into admission, vancomycin-resistant Enterococcus faecium, Candida albicans and Stenotrophomonas maltophilia were identified in peri-pancreatic fluid. Contact precautions were implemented, and an infectious diseases physician recommended piperacillin–tazobactam, fluconazole, co-trimoxazole and linezolid (later changed to teicoplanin) to cover these organisms. Teicoplanin, co-trimoxazole and fluconazole were ceased after 8 weeks of treatment.

Pancreatic debridement performed 2 months into admission due to persistent pancreatic infection identified carbapenem-resistant Klebsiella pneumoniae in the pancreatic tissue. Testing by polymerase chain reaction detected the bla_KPC-2 gene. Antimicrobial-susceptibility results are shown in the Box. Surrounding patients were screened.

Owing to limited antibiotic options, gentamicin combined with dual carbapenems (high-dose prolonged meropenem infusion three times a day combined with daily ertapenem) was prescribed for the K. pneumoniae. Gentamicin was continued for 3 weeks in conjunction with repeated pancreatic debridements in an attempt to control infection. Oliguric renal failure and sepsis developed, requiring ICU transfer, renal replacement therapy and cessation of gentamicin.

Three months into admission, following further attempted pancreatic debridement, multiple blood cultures grew bla_KPC-2-producing K. pneumoniae that now demonstrated intermediate gentamicin susceptibility (minimum inhibitory concentration, 8 μg/L). Renal replacement therapy continued, all intravenous lines were replaced, two doses of gentamicin were administered and intravenous doxycycline was added to meropenem, ertapenem and fluconazole. Repeat blood cultures were negative. Application for compassionate access to ceftazidime–avibactam was made (to which the isolate was susceptible) and it was supplied 1 week later.

Because of further deterioration and isolation of doxycycline-resistant K. pneumoniae from abdominal fluid, antibiotics were changed to ceftazidime–avibactam (adjusted for renal function), metronidazole and teicoplanin. Over the next 3 weeks while receiving these agents, the patient had resolution of fever, a decrease in serum inflammatory markers, reduction in vasopressor requirements and radiological improvement of the peri-pancreatic collections. No side effects were reported from ceftazidime–avibactam.

During the fifth month, a laparotomy was performed in a final attempt to control pancreatic infection, but was unsuccessful due to the compromised state of pancreatic and peri-pancreatic tissues. Intra-abdominal drain tube fluid continued to grow bla_KPC-2-producing K. pneumoniae that was susceptible to ceftazidime–avibactam. Shortly after this, and following discussion with the patient, family and treating teams, the patient was discharged home for palliation and died soon after.

Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae have been responsible for nosocomial outbreaks worldwide and have become endemic in several countries. These organisms provide immense challenges for healthcare systems, health care providers and patients. Reports of KPC-producing organisms in Australia have been uncommon, with most cases found to be imported from endemic countries.1 Genes responsible for KPC production (eg, bla_KPC-2) are acquired via transferable plasmids and, when expressed, result in enzymatic hydrolysis of all β-lactams including carbapenems.2 Additional antimicrobial resistance genes frequently accompany carbapenem-resistance mechanisms, limiting the choice of effective antimicrobials.2

Multiple risk factors have been associated with carbapenem-resistant Enterobacteriaceae (CRE) acquisition. These include prolonged duration of hospital stay, receipt of broad-spectrum antibiotics, presence of invasive devices, use of mechanical ventilation, total parental nutrition or nasogastric feeds, and colonisation pressure.3

Such infections pose management challenges given their propensity for causing severe sepsis in patients with multiple comorbidities. Many remaining active antibiotics have limitations in terms of efficacy (eg, tigecycline is not ideal for bacteraemia or urinary tract infections) and toxicity (eg, colistin can have significant nephrotoxicity).

There is a paucity of evidence to guide management decisions, and optimal antibiotic treatment is unknown.4,5 Current expert recommendations are largely based on retrospective observational data. These suggest that combination therapy with two or three active agents should be used. Antibiotic classes including fluoroquinolones and sulphonamides are usually inactive against these organisms. Despite the inherent presence of carbapenemases, inclusion of meropenem (usually high-dose extended infusions) in treatment regimens is usually recommended.4,5 However, more recent studies have suggested that a benefit may be restricted to isolates with only low-level carbapenem resistance (minimum inhibitory concentration, ≤ 8 μg/mL).4 At the time of this case, a small number of reports used dual carbapenems as salvage therapy for pandrug-resistant K. pneumoniae, which informed the decision to use combination ertapenem and meropenem. However, the clinical value of this practice remains uncertain.6,7

Ceftazidime–avibactam plus metronidazole has been shown in Phase II studies to have similar efficacy in complicated intra-abdominal infections when compared with meropenem,8 and has been approved for this indication in the United States by the Food and Drug Administration. Avibactam is a new β-lactamase inhibitor in the diazabicyclooctane class and, in combination with ceftazidime, retains activity against some KPC-producing Enterobacteriaceae in vitro.9 There is a paucity of clinical data relating specifically to its efficacy in infections caused by KPC-producing Enterobacteriaceae. Our patient demonstrated a clinical, biochemical and radiological response after administration of ceftazidime–avibactam, metronidazole and teicoplanin, with no development of in vitro resistance after 6 weeks of treatment. However, microbiological clearance was not achieved. Given that early treatment may be effective in managing CRE infections, timely access to antibiotics such as ceftazidime–avibactam and associated antibiotic susceptibility testing in Australia is crucial.

CRE infections are an increasing problem that Australian hospitals are facing; now in both local residents and returned travellers.10 Combination strategies and newer agents under investigation, such as ceftazidime–avibactam, are potential treatment options.

Lessons from practice

Carbapenem-resistant Enterobacteriaceae (CRE) infections pose a clinical challenge for management with limited effective antibiotics available.
New strategies, and new antibiotics, will be required to manage the increasing threat of CRE.
Ceftazidime–avibactam, a novel antimicrobial combination with activity against many CRE, may be a future option for treating such infections.

Box –
Initial Klebsiella pneumoniae antimicrobial-susceptibility results*

Antibiotic

Resistance

MIC (μg/mL)

Amoxycillin-clavulanic acid

≥ 32

Piperacillin–tazobactam

≥ 128

Ceftriaxone

≥ 64

Cefepime

≥ 64

Cefoxitin

≥ 64

Ciprofloxacin

≥ 4

Meropenem

≥ 16

Amikacin

≥ 64

Tobramycin

≥ 16

Gentamicin

Co-trimoxazole

≥ 320

Nitrofurantoin

≥ 512

Colistin^†

Fosfomycin^†

≥ 1024

Tigecycline^†

Tetracycline–doxycycline

MIC = minimum inhibitory concentration. R = resistant. S = susceptible. * Using Vitek 2 gram-negative antibiotic susceptibility cards (bioMérieux) according to Clinical and Laboratory Standards Institute (CLSI) interpretative criteria, unless otherwise indicated. † Etest (bioMérieux), according to European Committee on Antimicrobial Susceptibility Testing interpretative criteria (CLSI interpretative criteria not available).