Infectious Diseases - Research Publications

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    Repurposing antibiotic resistance surveillance data to support treatment of recurrent infections in a remote setting
    Cuningham, W ; Perera, S ; Coulter, S ; Wang, Z ; Tong, SYC ; Wozniak, TM (NATURE PORTFOLIO, 2024-01-29)
    In northern Australia, a region with limited access to healthcare and a substantial population living remotely, antibiotic resistance adds to the complexity of treating infections. Focussing on Escherichia coli urinary tract infections (UTIs) and Staphylococcus aureus skin & soft tissue infections (SSTIs) captured by a northern Australian antibiotic resistance surveillance system, we used logistic regression to investigate predictors of a subsequent resistant isolate during the same infection episode. We also investigated predictors of recurrent infection. Our analysis included 98,651 E. coli isolates and 121,755 S. aureus isolates from 70,851 patients between January 2007 and June 2020. Following an initially susceptible E. coli UTI, subsequent recovery of a cefazolin (8%) or ampicillin (13%) -resistant isolate during the same infection episode was more common than a ceftriaxone-resistant isolate (2%). For an initially susceptible S. aureus SSTI, subsequent recovery of a methicillin-resistant isolate (8%) was more common than a trimethoprim-sulfamethoxazole-resistant isolate (2%). For UTIs and SSTIs, prior infection with a resistant pathogen was a strong predictor of both recurrent infection and resistance in future infection episodes. This multi-centre study demonstrates an association between antibiotic resistance and an increased likelihood of recurrent infection. Particularly in remote areas, a patient's past antibiograms should guide current treatment choices since recurrent infection will most likely be at least as resistant as previous infection episodes. Using population-level surveillance data in this way can also help clinicians decide if they should switch antibiotics for patients with ongoing symptoms, while waiting for diagnostic results.
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    Mosquitoes provide a transmission route between possums and humans for Buruli ulcer in southeastern Australia
    Mee, PT ; Buultjens, AH ; Oliver, J ; Brown, K ; Crowder, JC ; Porter, JL ; Hobbs, EC ; Judd, LM ; Taiaroa, G ; Puttharak, N ; Williamson, DA ; Blasdell, KR ; Tay, EL ; Feldman, R ; Muzari, MO ; Sanders, C ; Larsen, S ; Crouch, SR ; Johnson, PDR ; Wallace, JR ; Price, DJ ; Hoffmann, AA ; Gibney, KB ; Stinear, TP ; Lynch, SE (NATURE PORTFOLIO, 2024-02)
    Buruli ulcer, a chronic subcutaneous infection caused by Mycobacterium ulcerans, is increasing in prevalence in southeastern Australia. Possums are a local wildlife reservoir for M. ulcerans and, although mosquitoes have been implicated in transmission, it remains unclear how humans acquire infection. We conducted extensive field survey analyses of M. ulcerans prevalence among mosquitoes in the Mornington Peninsula region of southeastern Australia. PCR screening of trapped mosquitoes revealed a significant association between M. ulcerans and Aedes notoscriptus. Spatial scanning statistics revealed overlap between clusters of M. ulcerans-positive Ae. notoscriptus, M. ulcerans-positive possum excreta and Buruli ulcer cases, and metabarcoding analyses showed individual mosquitoes had fed on humans and possums. Bacterial genomic analysis confirmed shared single-nucleotide-polymorphism profiles for M. ulcerans detected in mosquitoes, possum excreta and humans. These findings indicate Ae. notoscriptus probably transmit M. ulcerans in southeastern Australia and highlight mosquito control as a Buruli ulcer prevention measure.
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    Evaluating the cost-effectiveness of [18F]FDG-PET/CT for investigation of persistent or recurrent neutropenic fever in high-risk haematology patients
    Tew, M ; Douglas, AP ; Szer, J ; Bajel, A ; Harrison, SJ ; Tio, SY ; Worth, LJ ; Hicks, RJ ; Ritchie, D ; Slavin, MA ; Thursky, KA ; Dalziel, K (BMC, 2023-12-15)
    BACKGROUND: A recent randomised trial demonstrated [18F]fluorodeoxyglucose positron-emission tomography in combination with low-dose CT (FDG-PET/CT), compared to standard of care computed tomography (CT) imaging, positively impacted antimicrobial management and outcomes of acute leukaemia and haematopoietic stem cell transplant recipients with persistent and recurrent neutropenic fever. We conducted an economic evaluation from a healthcare perspective alongside the clinical trial. METHODS: Unit costs in Australian dollars were applied to all resources used (antimicrobials, diagnostic tests, ICU and hospital bed days). Effectiveness was measured as number of patients with antimicrobial rationalisation, 6-month mortality and quality-adjusted life years (QALYs) derived from patient-reported trial-based health-related quality-of-life. Generalised linear models were used to analyse costs and outcomes. Incremental cost-effectiveness ratios (ICERs) for all outcomes and net monetary benefit (NMB) for QALYs were calculated. We performed bootstrapping with 1000 replications using the recycled predictions method. RESULTS: The adjusted healthcare costs were lower for FDG-PET/CT (mean $49,563; 95%CI 36,867, 65,133) compared to CT (mean $57,574; 95% CI 44,837, 73,347). The difference in QALYs between the two groups was small (0.001; 95% CI -0.001, 0.004). When simulated 1000 times, FDG-PET/CT was the dominant strategy as it was cheaper with better outcomes than the standard CT group in 74% of simulations. The estimated NMBs at willingness-to-pay thresholds of $50,000 and $100,000 per QALY were positive, thus FDG-PET/CT remained cost-effective at these thresholds. CONCLUSIONS: FDG-PET/CT is cost effective when compared to CT for investigation of persistent/recurrent neutropenic fever in high-risk patients, providing further support for incorporation of FDG-PET/CT into clinical guidelines and funding. TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov, NCT03429387.
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    Near-to-patient-testing to inform targeted antibiotic use for sexually transmitted infections in a public sexual health clinic: the NEPTUNE cohort study
    Vodstrcil, LA ; Htaik, K ; Plummer, EL ; De Petra, V ; Sen, MG ; Williamson, DA ; Ong, JJ ; Wu, J ; Owlad, M ; Murray, G ; Chow, EPF ; Fairley, CK ; Bradshawa, CS (ELSEVIER, 2024-03)
    BACKGROUND: Empiric treatment of sexually transmitted infections can cause unnecessary antibiotic use. We determined if near-to-patient-testing (NPT) for Neisseria gonorrhoeae, Chlamydia trachomatis and Mycoplasma genitalium (MG) improved antibiotic-use for a range of clinical presentations. METHODS: Clients attending with non-gonococcal urethritis (NGU), proctitis, as STI-contacts, or for an MG-test-of-cure (MG-TOC) between March and December 2021 were recruited. Participants received near-to-patient-testing (NPT-group) for the three STIs using the GeneXpert® System (Cepheid), and concurrent routine-testing by transcription-mediated-amplification (TMA; Aptima, Hologic). Antibiotic-use among NGU or proctitis cases in the NPT-group was compared to clinic-controls undergoing routine-testing only. The proportion in the NPT-group who notified partners <24 hrs of their STI-specific result was calculated. FINDINGS: Among 904 consults by 808 NPT-participants, ≥1 STI was detected in 63/252 (25.0%) with NGU, 22/51 (43.1%) with proctitis, and 167/527 (31.7%) STI-contacts. MG was detected among 35/157 (22.3%) MG-TOC consults. Among NGU and proctitis cases, fewer in the NPT-group received empiric treatment compared to clinic-controls (29.4% [95% CI: 24.3-34.9%] vs 83.8% [95% CI: 79.2-87.8%], p < 0.001), resulting in more NPT-group cases appropriately treated (STI-specific drug/no drug appropriately; 80.9% [95% CI: 76.0-85.1%] vs 33.0% [95% CI: 27.7-38.6%], p < 0.001) and fewer mistreated (incorrect drug/treated but pathogen-negative; 17.8% [13.7-22.6%] vs 61.4% [55.6-66.9%], p < 0.001). Of 167/264 in the NPT-group with an STI who responded regarding partner-notification, 95.2% notified all/some partners; 85.9% notified them <24 hrs of the STI-specific result. INTERPRETATION: Near-to-patient-testing significantly improved antibiotic use and a high proportion of individuals rapidly notified partners of STI-specific results, highlighting the broad benefits of timely diagnostic strategies for STIs in clinical decision making and partner notification. FUNDING: ARC ITRP Hub-grant; NHMRC.
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    Non-SARS-CoV-2 respiratory viral detection and whole genome sequencing from COVID-19 rapid antigen test devices: a laboratory evaluation study.
    Moso, MA ; Taiaroa, G ; Steinig, E ; Zhanduisenov, M ; Butel-Simoes, G ; Savic, I ; Taouk, ML ; Chea, S ; Moselen, J ; O'Keefe, J ; Prestedge, J ; Pollock, GL ; Khan, M ; Soloczynskyj, K ; Fernando, J ; Martin, GE ; Caly, L ; Barr, IG ; Tran, T ; Druce, J ; Lim, CK ; Williamson, DA (Elsevier BV, 2024-02-07)
    BACKGROUND: There has been high uptake of rapid antigen test device use for point-of-care COVID-19 diagnosis. Individuals who are symptomatic but test negative on COVID-19 rapid antigen test devices might have a different respiratory viral infection. We aimed to detect and sequence non-SARS-CoV-2 respiratory viruses from rapid antigen test devices, which could assist in the characterisation and surveillance of circulating respiratory viruses in the community. METHODS: We applied archival clinical nose and throat swabs collected between Jan 1, 2015, and Dec 31, 2022, that previously tested positive for a common respiratory virus (adenovirus, influenza, metapneumovirus, parainfluenza, rhinovirus, respiratory syncytial virus [RSV], or seasonal coronavirus; 132 swabs and 140 viral targets) on PCR to two commercially available COVID-19 rapid antigen test devices, the Panbio COVID-19 Ag Rapid Test Device and Roche SARS-CoV-2 Antigen Self-Test. In addition, we collected 31 COVID-19 rapid antigen test devices used to test patients who were symptomatic at The Royal Melbourne Hospital emergency department in Melbourne, Australia. We extracted total nucleic acid from the device paper test strips and assessed viral recovery using multiplex real-time PCR (rtPCR) and capture-based whole genome sequencing. Sequence and genome data were analysed through custom computational pipelines, including subtyping. FINDINGS: Of the 140 respiratory viral targets from archival samples, 89 (64%) and 88 (63%) were positive on rtPCR for the relevant taxa following extraction from Panbio or Roche rapid antigen test devices, respectively. Recovery was variable across taxa: we detected influenza A in nine of 18 samples from Panbio and seven of 18 from Roche devices; parainfluenza in 11 of 20 samples from Panbio and 12 of 20 from Roche devices; human metapneumovirus in 11 of 16 from Panbio and 14 of 16 from Roche devices; seasonal coronavirus in eight of 19 from Panbio and two of 19 from Roche devices; rhinovirus in 24 of 28 from Panbio and 27 of 28 from Roche devices; influenza B in four of 15 in both devices; and RSV in 16 of 18 in both devices. Of the 31 COVID-19 devices collected from The Royal Melbourne Hospital emergency department, 11 tested positive for a respiratory virus on rtPCR, including one device positive for influenza A virus, one positive for RSV, four positive for rhinovirus, and five positive for SARS-CoV-2. Sequences of target respiratory viruses from archival samples were detected in 55 (98·2%) of 56 samples from Panbio and 48 (85·7%) of 56 from Roche rapid antigen test devices. 98 (87·5%) of 112 viral genomes were completely assembled from these data, enabling subtyping for RSV and influenza viruses. All 11 samples collected from the emergency department had viral sequences detected, with near-complete genomes assembled for influenza A and RSV. INTERPRETATION: Non-SARS-CoV-2 respiratory viruses can be detected and sequenced from COVID-19 rapid antigen devices. Recovery of near full-length viral sequences from these devices provides a valuable opportunity to expand genomic surveillance programmes for public health monitoring of circulating respiratory viruses. FUNDING: Australian Government Medical Research Future Fund and Australian National Health and Medical Research Council.
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    Interim results from a phase I randomized, placebo-controlled trial of novel SARS-CoV-2 beta variant receptor-binding domain recombinant protein and mRNA vaccines as a 4th dose booster
    Nolan, TM ; Deliyannis, G ; Griffith, M ; Braat, S ; Allen, LF ; Audsley, J ; Chung, AW ; Ciula, M ; Gherardin, NA ; Giles, ML ; Gordon, TP ; Grimley, SL ; Horng, L ; Jackson, DC ; Juno, JA ; Kedzierska, K ; Kent, SJ ; Lewin, SR ; Littlejohn, M ; McQuilten, HA ; Mordant, FL ; Nguyen, THO ; Soo, VP ; Price, B ; Purcell, DFJ ; Ramanathan, P ; Redmond, SJ ; Rockman, S ; Ruan, Z ; Sasadeusz, J ; Simpson, JA ; Subbarao, K ; Fabb, SA ; Payne, TJ ; Takanashi, A ; Tan, CW ; Torresi, J ; Wang, JJ ; Wang, L-F ; Al-Wassiti, H ; Wong, CY ; Zaloumis, S ; Pouton, CW ; Godfrey, DI (ELSEVIER, 2023-12)
    BACKGROUND: SARS-CoV-2 booster vaccination should ideally enhance protection against variants and minimise immune imprinting. This Phase I trial evaluated two vaccines targeting SARS-CoV-2 beta-variant receptor-binding domain (RBD): a recombinant dimeric RBD-human IgG1 Fc-fusion protein, and an mRNA encoding a membrane-anchored RBD. METHODS: 76 healthy adults aged 18-64 y, previously triple vaccinated with licensed SARS-CoV-2 vaccines, were randomised to receive a 4th dose of either an adjuvanted (MF59®, CSL Seqirus) protein vaccine (5, 15 or 45 μg, N = 32), mRNA vaccine (10, 20, or 50 μg, N = 32), or placebo (saline, N = 12) at least 90 days after a 3rd boost vaccination or SARS-CoV-2 infection. Bleeds occurred on days 1 (prior to vaccination), 8, and 29. CLINICALTRIALS: govNCT05272605. FINDINGS: No vaccine-related serious or medically-attended adverse events occurred. The protein vaccine reactogenicity was mild, whereas the mRNA vaccine was moderately reactogenic at higher dose levels. Best anti-RBD antibody responses resulted from the higher doses of each vaccine. A similar pattern was seen with live virus neutralisation and surrogate, and pseudovirus neutralisation assays. Breadth of immune response was demonstrated against BA.5 and more recent omicron subvariants (XBB, XBB.1.5 and BQ.1.1). Binding antibody titres for both vaccines were comparable to those of a licensed bivalent mRNA vaccine. Both vaccines enhanced CD4+ and CD8+ T cell activation. INTERPRETATION: There were no safety concerns and the reactogenicity profile was mild and similar to licensed SARS-CoV-2 vaccines. Both vaccines showed strong immune boosting against beta, ancestral and omicron strains. FUNDING: Australian Government Medical Research Future Fund, and philanthropies Jack Ma Foundation and IFM investors.
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    Whole genome sequencing of drug-resistant Mycobacterium tuberculosis isolates in Victoria, Australia
    Dorji, T ; Horan, K ; Sherry, NL ; Tay, EL ; Globan, M ; Viberg, L ; Bond, K ; Denholm, JT ; Howden, BP ; Andersson, P (ELSEVIER SCI LTD, 2024-01)
    OBJECTIVES: Whole genome sequencing (WGS) can identify clusters, transmission patterns, and drug resistance mutations. This is important in low-burden settings such as Australia, as it can assist in efficient contact tracing and surveillance. METHODS: We conducted a retrospective cohort study using WGS from 155 genomically defined drug-resistant Mycobacterium tuberculosis (DR-TB) isolates collected between 2018-2021 in Victoria, Australia. Bioinformatic analysis was performed to identify resistance-conferring mutations, lineages, clusters and understand how local sequences compared with international context. RESULTS: Of the 155 sequences, 42% were identified as lineage 2 and 35% as lineage 1; 65.8% (102/155) were isoniazid mono-resistant, 8.4% were multi-drug resistant TB and 5.8% were pre-extensively drug-resistant / extensively drug-resistant TB. The most common mutations were observed in katG and fabG1 genes, especially at Ser315Thr and fabG1 -15 C>T for first-line drugs. Ser450Leu was the most frequent mutation in rpoB gene. Phylogenetic analysis confirmed that Victorian DR-TB were associated with importation events. There was little evidence of local transmission with only five isolate pairs. CONCLUSION: Isoniazid-resistant TB is the commonest DR-TB in Victoria, and the mutation profile is similar to global circulating DR-TB. Most cases are diagnosed among migrants with limited transmission. This study highlights the value of WGS in identification of clusters and resistance-conferring mutations. This information is crucial in supporting disease mitigation and treatment strategies.
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    Evolution of Humoral and Cellular Immunity Post-Breakthrough Coronavirus Disease 2019 in Vaccinated Patients With Hematologic Malignancy Receiving Tixagevimab-Cilgavimab
    Hall, VG ; Nguyen, THO ; Allen, LF ; Rowntree, LC ; Kedzierski, L ; Chua, BY ; Lim, C ; Saunders, NR ; Klimevski, E ; Tennakoon, GS ; Seymour, JF ; Wadhwa, V ; Cain, N ; Vo, KL ; Nicholson, S ; Karapanagiotidis, T ; Williamson, DA ; Thursky, KA ; Spelman, T ; Yong, MK ; Slavin, MA ; Kedzierska, K ; Teh, BW (OXFORD UNIV PRESS INC, 2023-11-01)
    BACKGROUND: In-depth immunogenicity studies of tixagevimab-cilgavimab (T-C) are lacking, including following breakthrough coronavirus disease 2019 (COVID-19) in vaccinated patients with hematologic malignancy (HM) receiving T-C as pre-exposure prophylaxis. METHODS: We performed a prospective, observational cohort study and detailed immunological analyses of 93 patients with HM who received T-C from May 2022, with and without breakthrough infection, during a follow-up period of 6 months and dominant Omicron BA.5 variant. RESULTS: In 93 patients who received T-C, there was an increase in Omicron BA.4/5 receptor-binding domain (RBD) immunoglobulin G (IgG) antibody titers that persisted for 6 months and was equivalent to 3-dose-vaccinated uninfected healthy controls at 1 month postinjection. Omicron BA.4/5 neutralizing antibody was lower in patients receiving B-cell-depleting therapy within 12 months despite receipt of T-C. COVID-19 vaccination during T-C treatment did not incrementally improve RBD or neutralizing antibody levels. In 16 patients with predominantly mild breakthrough infection, no change in serum neutralization of Omicron BA.4/5 postinfection was detected. Activation-induced marker assay revealed an increase in CD4+ (but not CD8+) T cells post infection, comparable to previously infected healthy controls. CONCLUSIONS: Our study provides proof-of-principle for a pre-exposure prophylaxis strategy and highlights the importance of humoral and cellular immunity post-breakthrough COVID-19 in vaccinated patients with HM.
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    Resistance to first-line antibiotic therapy among patients with uncomplicated acute cystitis in Melbourne, Australia: prevalence, predictors and clinical impact.
    Curtis, SJ ; Kwong, JC ; Chaung, YL ; Mazza, D ; Walsh, CJ ; Chua, KY ; Stewardson, AJ (Oxford University Press (OUP), 2024-02)
    BACKGROUND: Australian guidelines recommend trimethoprim or nitrofurantoin as first-line agents for uncomplicated urinary tract infections (UTIs). Laboratory surveillance indicates high rates of trimethoprim resistance among urinary bacterial isolates, but there are scant local clinical data about risk factors and impact of trimethoprim resistance. OBJECTIVES: To determine the prevalence, risk factors, mechanism and impact of resistance to first-line antibiotic therapy for uncomplicated UTIs in the community setting. METHODS: A prospective observational study from October 2019 to November 2021 in four general practices in Melbourne, Australia. Female adult patients prescribed an antibiotic for suspected or confirmed uncomplicated acute cystitis were eligible. Primary outcome was urine isolates with resistance to trimethoprim and/or nitrofurantoin. RESULTS: We recruited 87 participants across 102 UTI episodes with median (IQR) age of 63 (47-76) years. Escherichia coli was the most common uropathogen cultured (48/62; 77%); 27% (13/48) were resistant to trimethoprim (mediated by a dfrA gene) and none were resistant to nitrofurantoin. Isolates with resistance to a first-line therapy were more common among patients reporting a history of recurrent UTIs [risk ratio (RR): 2.08 (95% CI: 1.24-3.51)] and antibiotic use in the previous 6 months [RR: 1.89 (95% CI: 1.36-2.62)]. Uropathogen resistance to empirical therapy was not associated with worse clinical outcomes. CONCLUSIONS: Resistance to trimethoprim is common in uncomplicated UTIs in Australia but may not impact clinical outcomes. Further research is warranted on the appropriateness of trimethoprim as empirical therapy, particularly for patients with antimicrobial resistance risk factors.
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    The APPRISE Virtual Biobank for Infectious Diseases
    Smith, MZ ; Turner, M ; Haurat, J ; Thevarajan, I ; Denholm, J ; Tong, SYC ; Matthews, G ; Bull, RA ; Martinello, M ; Mcmahon, J ; Imrie, A ; Pillai, PE (AUSTRALIAN GOVERNMENT, DEPT HEALTH & AGEING, 2023-11-16)
    The Australian Partnership for Preparedness Research on InfectiouS disease Emergencies (APPRISE) has developed a virtual biobank to support infectious disease research in Australia. The virtual biobank (https://apprise.biogrid.org.au) integrates access to existing distributed infectious disease biospecimen collections comprising multiple specimen types, including plasma, serum, and peripheral blood mononuclear cells. Through the development of a common data model, multiple collections can be searched simultaneously via a secure web portal. The portal enhances the visibility and searchability of existing collections within their current governance and custodianship arrangements. The portal is easily scalable for integration of additional collections.