Infectious diseases

TO THE EDITOR: In 2016, there were an estimated 490 000 cases globally of multidrug‐resistant (MDR) tuberculosis exhibiting resistance to isoniazid and rifampicin.1 The first case of MDR tuberculosis diagnosed in Tasmania occurred in 2016 in a Vietnamese‐born person. Vietnam was the second highest reported country of birth for overseas‐born patients with tuberculosis notified in Australia in 2014.2 The patient had previously tested positive for tuberculosis infection in an interferon‐γ release assay test performed in Tasmania in early 2016, but at the time, the patient was asymptomatic and had a normal chest x‐ray and a negative sputum culture. After an episode of colitis, a colon tissue biopsy specimen isolated Mycobacterium tuberculosis. Whole genome sequence of the isolate (TASMDR1), identified high confidence mutations for isoniazid, rifampicin, ethambutol and pyrazinamide, in accordance with the culture‐based drug susceptibility testing, and, in addition, it identified a mutation associated with streptomycin resistance.3 We became aware that a household contact of the Tasmania‐located patient with MDR tuberculosis had been diagnosed with pulmonary tuberculosis in Vietnam in 2012 and requested the drug susceptibility testing data for this isolate (VTB1) from the treating hospital in Ho Chi Minh City. VTB1 was resistant to isoniazid, rifampicin, ethambutol, pyrazinamide and streptomycin in culture‐based drug susceptibility testing. We therefore obtained a genomic DNA preparation of VTB1 to enable direct comparison with the TASMDR1 isolate collected in Tasmania. Next generation sequencing of VTB1 was performed on an Illumina platform and paired‐end reads were mapped to the M. tuberculosis H37Rv reference genome (NC_000962.3). The Box shows variants associated with drug resistance. In addition to drug resistance mutations, VTB1 shared all previously described variants in TASMDR1 with respect to H37Rv3 and, therefore, the two isolates were genetically indistinguishable. This is strongly indicative of transmission involving the two patients based on established single nucleotide polymorphism thresholds.4 It is most probable that the patient diagnosed in Tasmania contracted the MDR strain of M. tuberculosis during the episode of pulmonary disease diagnosed in the household contact in 2012 and that the infection remained latent until reactivating as extrapulmonary MDR tuberculosis in 2016. In conclusion, the global burden of latent tuberculosis infection has been estimated to be 23% of the world's population, which corresponds to about 1.7 billion people.5 Despite the immense prevalence of latent tuberculosis infection, there are few reports in the literature that confirm using genome variant analyses for the translocation of the MDR form of tuberculosis from one jurisdiction to another as a latent infection and its subsequent emergence as active MDR tuberculosis in a new host country. This type of transit of tuberculosis is difficult to detect with pre‐immigration screening practices that are reliant upon a diagnosis of pulmonary tuberculosis based on a chest x‐ray. The international movement of MDR tuberculosis in latent form, as has been determined in this case, is an area of concern and could be a significant challenge for future tuberculosis eradication. The growing application of genome sequencing in tuberculosis diagnostics and surveillance will help establish the level of MDR tuberculosis cases due to reactivation of latent tuberculosis infection. Box – Drug resistance determining mutations in a contact who presented with tuberculosis in Vietnam in 2012 (VTB1) and in the first confirmed patient with multidrug‐resistant (MDR) tuberculosis in Tasmania in 2016 (TASMDR1). The isolate from VTB1 and TASMDR1 share identical drug resistance mutations Isolates Drug Gene Function Mutation Substitution VTB1 and TASMDR1 Rifampicin rpoB (Rv0667) RNA polymerase β‐subunit gAc/gGc, tCg/tTg D435G, S450L Isoniazid katG (Rv1908c) Catalase‐peroxidase aGc/aCc S315T Pyrazinamide pncA (Rv2043c) Pyrazinamidase/nicotinamidase cCg/cTg P62L Ethambutol embB (Rv3795) Arabinosyltransferase B Atg/Gtg M306V Streptomycin rrs (MTB000019) 16S ribosomal RNA a/c a514c* * Substitution located in a non‐protein coding gene. ◆

Sanjay S Gautam · Greg Haug · Louise A Cooley · Micheál Mac Aogáin · Ronan F O'Toole

TO THE EDITOR: We commend Heldens and colleagues1 for publishing their data on the incidence and in‐hospital mortality of sepsis and septic shock among patients admitted to Australian intensive care units (ICUs). The incidence of sepsis and septic shock in ICUs is estimated to be 101.8 and 19.3 per 100 000 patient‐years, respectively, at an attributable cost of $32 421.2 We concur that sepsis cases captured using the Australian and New Zealand Intensive Care Society Centre for Outcome and Resource Evaluation database criteria, compared with prospective clinical diagnoses,3 has poor sensitivity for sepsis case ascertainment. Notwithstanding, we propose that the application of a third surveillance metric using coded discharge data could be a viable alternative for sepsis case ascertainment and monitoring in ICUs. International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, Australian Modification (ICD‐10‐AM) diagnostic coding data are feasible to collect with a reduced risk of sampling bias and minimal loss to follow‐up. Using tandem dataset comparison following the implementation of a hospital‐wide sepsis pathway,4 we explored the utility of coding data for sepsis surveillance. We noted that 78% and 74% of ICU cases were designated an ICD‐10‐AM code denoting sepsis at admission and patient level, respectively (Box). Alarmingly, the concordance rate between coded administrative data and clinically verified sepsis diagnoses was even lower in non‐ICU settings. These data are in keeping with international reports.2 Robust and reproducible data are required to evaluate quality improvement regarding sepsis management. Given the poor sensitivity of research criteria and coding data, used in isolation for sepsis identification, a multifaceted approach is required. We hypothesise that the combination of administrative coding data and electronic medical record data, augmented with sepsis screening algorithms, may improve the sensitivity for sepsis case ascertainment in both cancer and non‐cancer settings.5 We encourage Heldens and colleagues to consider these suggestions as an alternative reproducible method needed to elucidate the incidence of sepsis and septic shock in Australian ICUs. Box – Relationship between sepsis cases satisfying clinical criteria and designated coded discharge data in intensive care unit (ICU) and non‐ICU settings, 2012–2014 Year Admission level ICU Non‐ICU All new admissions* ICD‐10‐AM captured cases Concordance All new admissions* ICD‐10‐AM captured cases Concordance 2012 38 27 71% 70 62 89% 2013 39 34 87% 175 103 59% 2014 81 61 75% 331 149 45% Mean (± SD) – – 78% (± 8.3%) – – 64% (± 22%) ICD‐10‐AM = International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, Australian Modification; SD = standard deviation. * Clinically diagnosed sepsis cases according to consensus diagnostic criteria.◆

Jake C Valentine · Gabrielle Haeusler · Leon Worth · Karin Thursky

TO THE EDITOR: We congratulate Heldens and colleagues1 for their work investigating the prevalence and mortality of sepsis within a tertiary hospital intensive care unit (ICU). As the authors rightly point out in their article and podcast, this requires careful screening, consistent diagnostic criteria, and considerable time and effort. The Australian and New Zealand Intensive Care Society (ANZICS) registry provides a highly specific, widely applicable, cost‐effective, timely and practical epidemiological measure of the prevalence and outcomes of sepsis and septic shock as a primary cause of ICU admissions throughout Australia and New Zealand.2 Findings from the registry appear consistent with those of Heldens and colleagues.1 However, their article confirms that there are more patients with sepsis within our ICUs than those who enter with this as an admission diagnosis. Between January 2016 and June 2018, 11.6% (43 529/374 442) of the ICU admissions reported to the ANZICS Adult Patient Database were due to sepsis as defined by the international Sepsis‐3 taskforce.3 In tertiary hospital ICUs, this was slightly higher at 12.1% (19 204/159 067), which is between 14.0% (121/864) by clinical criteria and 11.3% (98/864) by database criteria found within the first 24 hours of ICU admission by Heldens et al. With the recent addition of information about vasopressors and lactate levels, ANZICS can also now confidently identify patients with septic shock. Of 59 069 ICU admissions with available information, 3.3% (1978) had septic shock, again similar to the findings of Heldens et al. ICU admissions in the ANZICS registry due to sepsis or septic shock were associated with mortality of 15.1% and 26.7%, respectively. Heldens et al reported a similar mortality of 24% (8/33) with septic shock identified in the first 24 hours of admission (Appendix, table 4). The study by Heldens et al and the findings from the ANZICS registry are complementary. Together they highlight how the measurement of sepsis depends on the exact definition applied, and the population under consideration, which may vary between clinical practice, prospective observational and interventional studies, and widespread epidemiological comparisons.

David Pilcher · Sue Huckson · Peter Hicks

To the Editor: In 2007 and again in 2012, we highlighted in the Medical Journal of Australia1,2 the limited access Australian prisoners had to essential health protection measures. Six years on, we can only report that progress has been minimal (Box). In August 2012, the Australian Capital Territory Chief Minister announced the implementation of a needle exchange program for prisoners in the ACT; 6 years later, the ACT government retracted its commitment. Canada has recently agreed to a pilot prison-based needle exchange, with a commitment to national implementation in 2019. Human immunodeficiency virus (HIV) is still not a concern in Australian prisons, although bleach provision and condoms are still severely restricted in Queensland and the Northern Territory, and effectively not available in Victoria and Tasmania. Hepatitis B immunisation coverage continues to improve, and chronic hepatitis B infection is not increasing among Aboriginal and Torres Strait Islander prisoners.3 The availability of direct-acting antiviral treatments for hepatitis C infection for all Australians, including prisoners, has some Australian prisons already reporting treatment achievements commensurate to international treatment targets for 20304 — the term “micro-elimination” has been applied to facility by facility reduction of burden of this infection. However, despite reductions in hepatitis C in Australian prisons, the risk of transmission is ever present.5 The predictors of successful return to the community include housing, employment and maintenance of relationships;6 yet, private family (conjugal) visits are only allowed in some Victorian prisons and in one South Australian prison farm. Visits are definitely not available to ACT prisoners, since previous enabling policy was repealed in 2014. Safer sex is still an elusive aspiration for the majority of Australian prisoners and their families. Tattoo and body piercing programs are being implemented in prisons in Luxembourg and Catalonia, Spain. Despite this activity being successfully regulated in the community, there are still no verifiable reports of sanctioned programs in Australian prisons. In 2012, we questioned Australia’s commitment to protecting the health of prisoners.2 With changes in prison harm reduction programs internationally (notably, Canada) underpinned by legal challenges, we foresee that similar proceedings could have a place in finally driving reform in Australia. Box – Progress in Australian prisoners’ access to essential health protection measures Jurisdiction Changes since 2012 Australian Capital Territory Bleach available in single unit sachets; micro-elimination of hepatitis C from the only prison; private family visits ceased; support for a prison needle exchange program withdrawn New South Wales Micro-elimination of hepatitis C from several prisons Northern Territory No notable changes Queensland Still considering opiate replacement therapy; micro-elimination of hepatitis C from one prison South Australia Private visits available at one prison farm Tasmania Micro-elimination of hepatitis C from one prison Victoria Micro-elimination of hepatitis C from several prisons Western Australia Poor uptake of hepatitis C treatment

Michael H Levy · Carla J Treloar

To the Editor: Primary meningococcal conjunctivitis (PMC) is a rare presentation of Neisseria meningitidis.1 Before antibiotics, N. meningitidis conjunctivitis was a recognised harbinger of cerebrospinal meningitis due to systemic infection.1-3 Secondary N. meningitidis conjunctivitis is now uncommon.1 PMC seeds exogenously from mucosal secretions, causing a primary infection of the ocular surface without systemic infection,4 and it is characterised by purulent conjunctivitis and periorbital oedema.3,4 Untreated PMC spreads systemically in 10–18% of cases,1,3,5 and early diagnosis is essential to prevent visual loss and life-threatening complications.1,3,5 In September 2017, the Northern Territory experienced an outbreak of N. meningitidis serogroup W strain. Presentations were atypical and, consequently, the threshold was low for empirical treatment. We report the case of a 4-year-old girl who presented to a remote clinic with a 24-hour history of rapidly progressive pain, erythema and discharge from both eyes. Her medical history was unremarkable. She had bilateral conjunctival injection with profuse yellow mucopurulent discharge (Box, A). Systemic examination was unremarkable. Considering the meningococcal outbreak, conjunctival swabs were sent for urgent Gram stain, which showed gram-negative diplococci with characteristic N. meningitidis appearance (Box, B). Ceftriaxone and topical ofloxacin were commenced as empirical meningococcal treatment. Ocular culture and polymerase chain reaction (PCR) were positive for N. meningitidis-W. Three blood cultures and serum PCR were negative. After 48 hours, the purulent discharge and eye pain resolved. On Day 4 of treatment, her conjunctivae normalised and she was asymptomatic (Box, C). Her family members received prophylactic treatment with ciprofloxacin. She was discharged from hospital on Day 6 and had an unremarkable follow-up. To our knowledge, this is the first reported case of N. meningitidis-W PMC. Since presentations of PMC in contemporary society are rare,1,3,4 clinicians may overlook PMC as a differential diagnosis to the patient’s detriment. Given the highly virulent nature of the N. meningitidis-W, the importance of early treatment and contact tracing is paramount, so that antimicrobial prophylaxis can be offered to close patient contacts, especially direct household members. To preserve vision and prevent systemic infection, a high suspicion of atypical microorganisms must be entertained, especially during an outbreak. Box – Primary meningococcal conjunctivitis due to Neisseria meningitidis: bilateral conjunctival injection with profuse yellow mucopurulent discharge (A), gram-negative diplococci with characteristic Neisseria appearance (B), and normalised conjunctivae (C)

James Sterrey · Farshad Abedi · Tim RM Henderson

To the Editor: We are concerned about the emergence of antibiotic-resistant gonorrhoea in Australia. On 17 April 2018, the Commonwealth’s Chief Medical Officer Brendan Murphy released a statement about two cases of multidrug-resistant gonorrhoea that had recently been detected in Australia1 — at least one of these patients acquired the infection in Southeast Asia. These particular cases were similar to the one recently reported in the United Kingdom,2 where the patient was reported3 as having high level resistance to azithromycin and to ceftriaxone — the cornerstone of treatment. Also notable in that case was treatment failure using spectinomycin, with ongoing detection of the bacterium on throat swab. Treatment with intravenous ertapenem was successful. It should be of concern that gonorrhoea may only have the option of intravenous treatment, but the real problem here is that we may be on the precipice of untreatable gonorrhoea. With almost 750 000 short term resident returns every month,4 and over 200 000 of these being returns from Southeast Asia, the likelihood of repeated introductions is real. In the current context of rising gonorrhoea rates in Australia,5 further importation, transmission and spread of these resistant organisms will add substantial challenges to the disease control, especially in men who have sex with men and in Indigenous Australians. Such spread will incur significant health and health care costs for the sexual and reproductive health of Australians. There is an urgent need for all treating doctors to ensure that swabs for culture are taken for all symptomatic patients, as well as for those with an initial positive polymerase chain reaction result; for travellers to be aware of the risks of having unprotected sex; and for any multidrug-resistant patients and contacts to be referred for expert advice to ensure testing and treatment.

Brett Sutton · Mihaela Ivan

To the Editor:A recent article by O’Brien and colleagues1 highlights the worsening epidemic of Buruli ulcer in Australia. The steep rise in both the incidence and severity of the disease is associated with estimated health care costs of over $2.5 million per year in Victoria.1 The increase in Buruli ulcer cases in Australia parallels the increase in non-tuberculous mycobacterial (NTM) infections, especially lymphadenitis and Buruli ulcer, reported worldwide. Although this rise might be partly attributable to improved awareness and diagnostic methods, it might also be related to the discontinuation of universal bacillus Calmette–Guérin (BCG) vaccination in settings where the rate of tuberculosis has declined. Routine vaccination with BCG through the school program was discontinued in Victoria in the mid-1980s. The live-attenuated strain of Mycobacterium bovis contained in BCG vaccine shares epitopes with NTM, which makes cross-protection plausible. Our recently published meta-analysis indicates that BCG vaccination has a protective effect against NTM.2 In particular, two randomised controlled trials provide strong evidence for protection against Mycobacterium ulcerans.3,4 However, immunity might only be short lived, as the highest protection was observed in the first year after vaccination. Nevertheless, studies also report that compared with BCG-naive individuals, those who have received the BCG vaccine have smaller skin lesions,4 a shorter duration to healing5 and protection against severe forms of Buruli ulcer with multiple skin lesions.6 Buruli ulcer is a serious condition, which, despite prolonged antibiotic treatment and surgical intervention, can lead to complications such as osteomyelitis and other crippling sequelae. In light of the worsening epidemic, the protective effect of BCG vaccination should not be overlooked.

Petra Zimmermann · Adam Finn · Nigel Curtis

To the Editor:Salmonella infection manifests as enteritis and enteric fever, predominantly acquired overseas. When required, therapy with azithromycin, ciprofloxacin or ceftriaxone is recommended by the Therapeutic guidelines: antibiotic;1 however, reduced susceptibility to fluoroquinolones in Asia limits the use of ciprofloxacin unless susceptibility is confirmed.2 The Australian Bureau of Statistics recorded a 546% increase in short term departures to Indonesia over 10 years, with 1.2 million nationally in 2016.3 A 31-year-old man was taking long term azithromycin 250 mg daily to prevent bronchiolitis obliterans syndrome after a bilateral lung transplant several years earlier for cystic fibrosis. Three weeks after returning from Bali, he was admitted with fatigue, fever, diarrhoea and abdominal pain. He had acute kidney injury. His C-reactive protein level was 190 mg/L (reference interval [RI], < 5 mg/L) and procalcitonin concentration was 3.5 μg/L (RI, < 0.05 μg/L). A single set of blood cultures was negative. Stool culture isolated Salmonella enterica serovar Paratyphi B var Java, sensitive to ceftriaxone and ciprofloxacin, with a raised azithromycin minimum inhibitory concentration (MIC) of 64 mg/L by ETEST (bioMérieux); an MIC > 16 mg/L indicates non-wild-type4 and is associated with treatment failures. Owing to his immunocompromised state, the patient received a 14-day course of ciprofloxacin (MIC, 0.016 mg/L). Our review of 2015–2017 data from the Western Australian public pathology provider revealed that two of 31 typhoidal Salmonella isolates (Salmonella Paratyphi A and Salmonella Typhi bacteraemia, each acquired in India) and one of 15 non-typhoidal Salmonella isolates (S. typhimurium, no clinical details provided) had an azithromycin MIC > 16 mg/L. Ceftriaxone resistance was low at 0% (0/117) of typhoidal Salmonella and 0.4% (7/1648) of non-typhoidal Salmonella; ciprofloxacin resistance was higher at 48.0% (47/98) of typhoidal Salmonella and 6.8% (94/1384) of non-typhoidal Salmonella. By comparison, azithromycin MIC > 16 mg/L was found in 16.1% of typhoidal Salmonella from travellers returning to the Netherlands,5 and in 1.3% of non-typhoidal Salmonella in the United States.4 Azithromycin use while travelling probably selected for resistant Salmonella infection in this case. However, our data show that azithromycin susceptibility cannot be assumed in Salmonella infections; testing should therefore occur in serious cases, along with ongoing surveillance for evolving resistance.

Alan J Rogers · Gar-hing A Lee · Peter Boan

To the Editor:Tick-borne infectious diseases, including rickettsial infections, acquired in Australia or after international travel remain a diagnostic challenge.1 A 68-year-old man presented with umbilical pain 10 days after returning from a 2-month camping trip through the south-west of the United States (ie, Texas, New Mexico, Arizona, Colorado and Utah). On examination, a live tick was detected and removed from the patient’s umbilicus (Box). The umbilical pain resolved after tick removal. There was no development of fevers, constitutional symptoms, or rash to suggest a tick-borne illness. Laboratory investigations were unremarkable. He was educated about the signs and symptoms of tick-borne illnesses and prescribed a single dose of doxycycline 200 mg for prophylaxis due to his high risk exposure. The tick was identified as Dermacentor andersoni (Rocky Mountain wood tick), which is endemic to North America and not known to occur in Australia.2 D. andersoni adult ticks are principal vectors of Rickettsia rickettsii (the cause of Rocky Mountain spotted fever), and are associated with transmission of other pathogens to humans, including Colorado tick fever virus and Francisella tularensis (the cause of tularemia).2,3 Although isolated from D. andersoni ticks, transmission of Coxiella burnetii (the cause of Q fever) is uncommon. D. andersoni is not known to transmit Lyme disease.2 Analysis of the tick for rickettsial DNA was positive. No Borrelia DNA was detected. Rickettsia was isolated in cell culture and identified as Rickettsia peacockii based on sequencing of the 17kDa, OmpB, gltA and Sca4 genes. R. peacockii is a member of the spotted fever group of rickettsiae.3,4 The presence of R. peacockii in ticks is correlated with reduced prevalence of R. rickettsii.2,3 R. peacockii is closely related to R. rickettsii, and deletion or mutation of genes, possibly resulting in loss of virulence in R. peacockii, have been identified.3 R. peacockii is not known to be a pathogen of humans or other animals.3,4 Rickettsial serology 10 weeks after the tick bite showed detectable antibodies (titre, 1/256), predominantly to the spotted fever group of Rickettsia, compatible with exposure to R. peacockii identified in the tick. Unfortunately, definitive seroconversion or a rising antibody titre was not able to be demonstrated as no earlier sera were available for parallel testing. Pre-existing antibodies from a distant rickettsial exposure from his tick-prone lifestyle (history of extensive international camping trips) cannot be excluded. The patient remains asymptomatic 9 months later and is still an avid traveller. Tick-borne rickettsial infections in Australia include Queensland tick typhus (Rickettsia australis), Flinders Island spotted fever and Australian spotted fever (Rickettsia honei) and Q fever transmitted by ticks including Ixodes spp., Amblyomma triguttatum and Bothriocroton hydrosauri.1 With increasing international travel, recognition of tick-borne rickettsial diseases is becoming more important. Dermacentor ticks have been detected on livestock exported from North America into Europe.5 This case shows the ability of human ectoparasites, and their potentially pathogenic bacteria, to bypass stringent Australian quarantine controls. Further studies of Australian and imported tick-borne infections are required to increase understanding of these emerging infectious diseases. Box – Dermacentor andersoni removed from the patient’s umbilicus

Sadid F Khan · Mythili Tadepalli · John Stenos · Stephen R Graves · Tony M Korman