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Background and Aim: Rates of antimicrobial-resistant Helicobacter pylori infection are rising globally, but little is known about contemporary resistance patterns, virulence factors, and phylogenetic patterns of isolates within Australia. We aimed to characterize antimicrobial resistance and genetic mutations associated with adverse clinical outcomes., Methods: Whole genome sequencing, culturing, and antibiotic sensitivity data for refractory H. pylori isolates at Australian centers were collected between 2013 and 2022. Phylogenetic origins, antibiotic resistance mutations, and virulence factors were examined with phenotypic resistance profiles., Results: One hundred thirty-five isolates underwent culture, with 109 of these undergoing whole genome sequencing. Forty-three isolates were isolated from patients in South Australia and 66 from Western Australia. Isolates originated primarily from hpEurope (59.6%), hpEastAsia (25.7%), and hpNEAfrica (6.4%). Antimicrobial resistance to clarithromycin was seen in 85% of isolates, metronidazole in 52%, levofloxacin in 18%, rifampicin in 14%, and amoxicillin in 9%. Most isolates (59%) were multi-drug resistant. Resistance concordance between genetically determined resistance and phenotypic resistance was 92% for clarithromycin and 94% for levofloxacin. Analysis of virulence factors demonstrated cag pathogenicity island (cagPAI) in 67% of isolates and cagA in 61%, correlating with isolate genetic origin. The most virulent s1m1 vacuolating cytotoxin A genotype was present in 26% of isolates., Conclusion: Refractory H. pylori isolates in Australia emanate from multiple global origins. Strong concordance between genetic and phenotypic antibiotic resistance profiles raises the possibility of utilizing genetic profiling in clinical practice. The dynamic landscape of H. pylori in Australia warrants the establishment of a national database to monitor H. pylori resistance and evolving virulence., (© 2024 The Author(s). Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Abstract: From 1 January 2020 to 31 December 2021, thirty-eight institutions across Australia submitted data to the Australian Group on Antimicrobial Resistance (AGAR) from patients aged < 18 years (AGAR-Kids). Over the two years, 1,679 isolates were reported from 1,611 patients. This AGAR-Kids report aims to describe the population of children and adolescents with bacteraemia reported to AGAR and the proportion of resistant isolates. Overall, there were 902 gram-negative isolates reported: 800 Enterobacterales , 61 Pseudomonas aeruginosa and 41 Acinetobacter spp. Among the Enterobacterales , 12.9% were resistant to third generation cephalosporins; 11.6% to gentamicin/tobramycin; and 11.2% to piperacillin-tazobactam. In total, 14.5% of Enterobacterales were multi-drug resistant (MDR). Only 3.3% of P. aeruginosa were resistant to carbapenems and 4.9% were MDR. Resistance in Acinetobacter spp was uncommon. Of 607 Staphylococcus aureus isolates, 12.9% were methicillin-resistant (MRSA). Almost half of S. aureus isolates from the Northern Territory were MRSA. In S. aureus , resistance to erythromycin was 13.2%; 12.4% to clindamycin; and 5.3% to ciprofloxacin. Resistance to all antibiotics tested was higher in MRSA. Overall, 6.5% of S. aureus were MDR, of which 65% were MRSA. Almost three-quarters of the 170 Enterococcus spp. reported were E. faecalis , and half were from patients < 1 year old. Ampicillin resistance in enterococci was 19.6%. Eight isolates were vancomycin resistant and three isolates were teicoplanin resistant. Five E. faecium isolates were classified as MDR. This AGAR-Kids report highlights clear differences in the geographic distribution of pathogens and resistance profiles across Australia., (© Commonwealth of Australia CC BY-NC-ND.)

Background: Data on the health-related quality of life (HRQoL) for invasive meningococcal disease (IMD) survivors, particularly among adolescents and young adults (AYAs), are limited. This study aimed to investigate the in-depth experiences and impacts of IMD on AYAs., Methods: Participants were recruited from two Australian states, Victoria and South Australia. We conducted qualitative, semi-structured interviews with 30 patients diagnosed with IMD between 2016 and 2021. The interview transcripts were analyzed thematically., Results: Of the participants, 53% were aged 15-19 years old, and 47% were aged 20-24. The majority (70%) were female. Seven themes relating to the participants' experience of IMD were identified: (1) underestimation of the initial symptoms and then rapid escalation of symptoms; (2) reliance on social support for emergency care access; (3) the symptoms prompting seeking medical care varied, with some key symptoms missed; (4) challenges in early medical diagnosis; (5) traumatic and life-changing experience; (6) a lingering impact on HRQoL; and (7) gaps in the continuity of care post-discharge., Conclusion: The themes raised by AYA IMD survivors identify multiple areas that can be addressed during their acute illness and recovery. Increasing awareness of meningococcal symptoms for AYAs may help reduce the time between the first symptoms and the first antibiotic dose, although this remains a challenging area for improvement. After the acute illness, conducting HRQoL assessments and providing multidisciplinary support will assist those who require more intensive and ongoing assistance during their recovery.

Background: In Australia, invasive meningococcal disease (IMD) incidence rapidly increased between 2014 and 2017 due to rising serogroup W (MenW) and MenY infections. We aimed to better understand the genetic diversity of IMD during 2017 and 2018 using whole genome sequencing data., Methods: Whole genome sequencing data from 440 Australian IMD isolates collected during 2017 and 2018 and 1737 international MenW:CC11 isolates collected in Europe, Africa, Asia, North America, and South America between 1974 and 2020 were used in phylogenetic analyses; genetic relatedness was determined from single-nucleotide polymorphisms., Results: Australian isolates were as follows: 181 MenW (41%), 144 MenB (33%), 88 MenY (20%), 16 MenC (4%), 1 MenW/Y (0.2%), and 10 nongenogroupable (2%). Eighteen clonal complexes (CCs) were identified, and 3 (CC11, CC23, CC41/44) accounted for 78% of isolates (343/440). These CCs were associated with specific serogroups: CC11 (n = 199) predominated among MenW (n = 181) and MenC (n = 15), CC23 (n = 80) among MenY (n = 78), and CC41/44 (n = 64) among MenB (n = 64). MenB isolates were highly diverse, MenY were intermediately diverse, and MenW and MenC isolates demonstrated the least genetic diversity. Thirty serogroup and CC-specific genomic clusters were identified. International CC11 comparison revealed diversification of MenW in Australia., Conclusions: Whole genome sequencing comprehensively characterized Australian IMD isolates, indexed their genetic variability, provided increased within-CC resolution, and elucidated the evolution of CC11 in Australia., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Antimicrobial-resistant Klebsiella pneumoniae is one of the predominant pathogens in healthcare settings. However, the prevalence and resistome of this organism within residential aged care facilities (RACFs), which are potential hotspots for antimicrobial resistance, remain unexplored. Here, we provide a phenotypic and molecular characterization of antimicrobial-resistant K. pneumoniae isolated from RACFs. K. pneumoniae was isolated from urine, faecal and wastewater samples and facility swabs. The antimicrobial susceptibility profiles of all the isolates were determined and the genomic basis for resistance was explored with whole-genome sequencing on a subset of isolates. A total of 147 K. pneumoniae were isolated, displaying resistance against multiple antimicrobials. Genotypic analysis revealed the presence of beta-lactamases and the ciprofloxacin-resistance determinant QnrB4 but failed to confirm the basis for the observed cephalosporin resistance. Clonal spread of the multidrug-resistant, widely disseminated sequence types 323 and 661 was observed. This study was the first to examine the resistome of K. pneumoniae isolates from RACFs and demonstrated a complexity between genotypic and phenotypic antimicrobial resistance. The intra-facility dissemination and persistence of multidrug-resistant clones is concerning, given that residents are particularly vulnerable to antimicrobial resistant infections, and it highlights the need for continued surveillance and interventions to reduce the risk of outbreaks.

Background: Nocardia is a ubiquitous saprophyte capable of causing human disease. Disease is primarily respiratory or cutaneous, usually acquired via inhalation or inoculation. Under the influence of environmental and host factors, Nocardia incidence and species distribution demonstrate geographical variation., Aims: To examine for differences in Nocardia incidence within Western Australia (WA) and analyse species distribution in the context of prior published studies. To analyse antibiogram data from a nationwide passive antimicrobial resistance surveillance program., Methods: Retrospective extraction of laboratory data for Western Australian Nocardia isolates over a 21-year period. Analysis of Nocardia antimicrobial susceptibility testing data submitted to the Australian Passive Antimicrobial Resistance Surveillance (APAS) program between 2005 and 2022., Results: Nine hundred sixty WA isolates were identified, giving an annual incidence of 3.03 per 100 000 population with apparent latitudinal variation. The four most common species identified within WA and amongst APAS isolates were N. nova, N. cyriacigeorgica, N. brasiliensis and N. farcinica. APAS data demonstrated that all species exhibited high rates of susceptibility to linezolid (100%) and trimethoprim-sulfamethoxazole (98%). Amikacin (>90% susceptibility for all species except N. transvalensis) was the next most active parenteral agent, superior to both carbapenems and third-generation cephalosporins. Susceptibility to oral antimicrobials (other than linezolid) demonstrated significant interspecies variation., Conclusions: We demonstrate geographical variation in the distribution of Nocardia incidence. Four species predominate in the Australian setting, and nationwide data confirm a high in vitro susceptibility to trimethoprim-sulphamethoxazole and linezolid, justifying their ongoing role as part of first-line empiric therapy., (© 2023 Royal Australasian College of Physicians.)

Background: Invasive fungal disease (IFD) in the early post-allogeneic HSCT (alloHCT) period is associated with increased likelihood of catastrophic outcomes. The utility of oral modified release (MR) posaconazole tablets is limited by reduced drug absorption from gastrointestinal toxicity induced by cytotoxic chemotherapy, necessitating a switch to the IV posaconazole formulation., Objectives: To describe the population pharmacokinetics of posaconazole for oral MR and IV formulations in alloHCT patients and determine dosing regimens likely to achieve therapeutic exposures., Methods: We performed a prospective observational pharmacokinetic study in adult patients in the early post-alloHCT period requiring a change in posaconazole formulation (oral to IV). Samples were analysed using a validated LC-MS/MS method. Population pharmacokinetic analysis and Monte Carlo simulations (n = 1000) were performed using Pmetrics for R., Results: Twenty patients aged between 21 and 70 years were included in the study. A two-compartment model, incorporating mucositis/diarrhoea to modify the bioavailability for oral administration best described the data. To achieve ≥90% PTA, simulations showed that higher than currently recommended doses of oral MR posaconazole were required for prophylaxis Cmin targets (≥0.5 and ≥0.7 mg/L), while increased doses of both formulations were required for IFD treatment PK/PD targets, with patients experiencing oral mucositis/diarrhoea unlikely to achieve these., Conclusions: Increased doses of posaconazole should be considered for both prophylaxis and treatment of IFD to increase the proportion of alloHCT patients achieving therapeutic exposures, particularly the oral formulation in patients with mucositis and/or diarrhoea. Posaconazole therapeutic drug monitoring should be considered for all formulations in this setting., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Complications of diabetes, such as diabetic foot ulcers (DFUs), are common, multifactorial in origin, and costly to treat. DFUs are the cause of nearly 90% of limb amputations among persons with diabetes. In most chronic infections such as DFU, biofilms are involved. Bacteria in biofilms are 100-1000 times more resistant to antibiotics than their planktonic counterparts. Multidrug-resistant (MDR) Staphylococcus aureus and Pseudomonas aeruginosa infections in DFUs may require alternative therapeutic agents such as bacteriophages ("phages"). This study describes the lytic activity of phage cocktails AB-SA01 (3-phage cocktail) and AB-PA01 (4-phage cocktail), which target S. aureus and P. aeruginosa, respectively. The host range and lytic effect of AB-SA01 and AB-PA01 on a planktonic culture, single-species biofilm, and mixed-species biofilm were evaluated. In vitro testing showed that 88.7% of S. aureus and 92.7% of P. aeruginosa isolates were susceptible to AB-SA01 and AB-PA01, respectively, in the planktonic state. The component phages of AB-SA01 and AB-PA01 infected 66% to 94.3% of the bacterial isolates tested. Furthermore, AB-SA01 and AB-PA01 treatment significantly (p < 0.05) reduced the biofilm biomass of their hosts, regardless of the antibiotic-resistant characteristics of the isolates and the presence of a non-susceptible host. In conclusion, the strong lytic activity, broad host range, and significant biofilm biomass reduction of AB-SA01 and AB-PA01 suggest the considerable potential of phages in treating antibiotic-resistant S. aureus and P. aeruginosa infections alone or as coinfections in DFUs., (© 2024. The Author(s).)

Background and Aim: Helicobacter pylori infection is responsible for considerable morbidity and mortality worldwide and eradication rates are falling globally because of increasing antimicrobial resistance. However, there is a paucity of local data to guide the choice of eradication therapy in Australia. This study aimed to evaluate current Australian rates of H. pylori antibiotic resistance in patients who had failed prior eradication therapy., Methods: A retrospective analysis of routine culture and antibiotic susceptibility data from two pathology laboratories servicing multiple tertiary referral hospitals in Western Australia (WA) and South Australia (SA), between 2018 and 2022, was performed. Rates of antimicrobial resistance and prevalence of multiresistant isolates in both SA and WA were calculated and comparison of temporal trends and differences between the two states was conducted., Results: A total of 796 H. pylori isolates revealed a clarithromycin resistance rate of 82%, metronidazole 68%, amoxicillin 4.4% and tetracycline 0.5%. Resistance to levofloxacin was observed in 22% and rifampicin 14%. Rates of resistance to clarithromycin were lower in SA compared with WA (incidence rate ratio [IRR]: 0.69, P = 0.0001). Multiresistant isolates were discovered in 63% of patients, with lower rates in SA compared with WA (IRR: 0.74, P = 0.002)., Conclusion: This first multicentre, multistate study of H. pylori resistance in Australian patients exposed to prior therapy demonstrated high rates of antimicrobial resistance, including levofloxacin (>20%). This raises concern about recommending levofloxacin in empirical second-line therapies. Increased monitoring and awareness of current H. pylori resistance rates in Australia are needed to guide local eradication practices., (© 2023 The Authors. Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Physicians.)

Background: The Combination Antibiotic Therapy for Methicillin-Resistant Staphylococcus aureus (CAMERA2) trial ceased recruitment in July 2018, noting that a higher proportion of patients in the intervention arm (combination therapy) developed acute kidney injury (AKI) compared to the standard therapy (monotherapy) arm. We analyzed the long-term outcomes of participants in CAMERA2 to understand the impact of combination antibiotic therapy and AKI., Methods: Trial sites obtained additional follow-up data. The primary outcome was all-cause mortality, censored at death or the date of last known follow-up. Secondary outcomes included kidney failure or a reduction in kidney function (a 40% reduction in estimated glomerular filtration rate to <60 mL/minute/1.73 m 2 ). To determine independent predictors of mortality in this cohort, adjusted hazard ratios were calculated using a Cox proportional hazards regression model., Results: This post hoc analysis included extended follow-up data for 260 patients. Overall, 123 of 260 (47%) of participants died, with a median population survival estimate of 3.4 years (235 deaths per 1000 person-years). Fifty-five patients died within 90 days after CAMERA2 trial randomization; another 68 deaths occurred after day 90. Using univariable Cox proportional hazards regression, mortality was not associated with either the assigned treatment arm in CAMERA2 (hazard ratio [HR], 0.84 [95% confidence interval [CI], .59-1.19]; P = .33) or experiencing an AKI (HR at 1 year, 1.04 [95% CI, .64-1.68]; P = .88)., Conclusions: In this cohort of patients hospitalized with methicillin-resistant S aureus bacteremia, we found no association between either treatment arm of the CAMERA2 trial or AKI (using CAMERA2 trial definition) and longer-term mortality., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Treatment of cytomegalovirus (CMV) infection in allogeneic hematopoietic stem cell transplantation (alloHCT) patients with ganciclovir is complicated by toxicity and resistance. This study aimed to develop an intravenous ganciclovir population pharmacokinetic model for post-alloHCT patients and to determine dosing regimens likely to achieve suggested therapeutic exposure targets. We performed a prospective observational single-center pharmacokinetic study in adult alloHCT patients requiring treatment with intravenous ganciclovir for CMV viremia or disease. Samples were analyzed using a validated ultraperformance liquid chromatography method. Population pharmacokinetic analysis and Monte Carlo simulations ( n  =   1000) were performed using Pmetrics for R. Twenty patients aged 18 to 69 years were included in the study. A 2-compartment model with linear elimination from the central compartment and between occasion variability best described the data. Incorporating creatinine clearance (CL CR ) estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and presence of continuous renal replacement therapy as covariates for ganciclovir clearance improved the model. Compared to current dosing recommendations, simulations demonstrated loading doses were required to achieve a target AUC 24 of 80 to 120 mg.h/L on day 1 of induction therapy. Increased individualization of post-loading induction and maintenance doses based on CL CR is required to achieve the suggested exposures for efficacy (AUC 24 >80/>40 mg.h/L for induction/maintenance) while remaining below the exposure thresholds for toxicity (AUC 24 <120/<60 mg.h/L for induction/maintenance). Intravenous ganciclovir dosing in alloHCT patients can be guided by CL CR estimated by CKD-EPI. Incorporation of loading doses into induction dosing regimens should be considered for timely achievement of currently suggested exposures.

Introduction: There has been renewed interest in the therapeutic use of bacteriophages (phages); however, standardised therapeutic protocols are lacking, and there is a paucity of rigorous clinical trial data assessing efficacy., Methods and Analysis: We propose an open-label, single-arm trial investigating a standardised treatment and monitoring protocol for phage therapy. Patients included will have exhausted other therapeutic options for control of their infection and phage therapy will be administered under Australia's Therapeutic Goods Administration Special Access Scheme. A phage product with high in vitro activity against the targeted pathogen(s) must be available in line with relevant regulatory requirements. We aim to recruit 50-100 patients over 5 years, from any public or private hospitals in Australia. The standardised protocol will specify clinical assessments and biological sampling at scheduled time points. The primary outcome is safety at day 29, assessed by the frequency of adverse events, and overseen by an independent Data Safety Monitoring Board. Secondary outcomes include long-term safety (frequency of adverse events until at least 6 months following phage therapy), and feasibility, measured as the proportion of participants with>80% of minimum data available for analysis. Additional endpoints assessed include clinical response, patient/guardian reported quality of life measures, phage pharmacokinetics, human host immune responses and microbiome analysis. All trial outcomes will be summarised and presented using standard descriptive statistics., Ethics and Dissemination: Participant inclusion will be dependent on obtaining written informed consent from the patient or guardian. The trial protocol was approved by the Sydney Children's Hospitals Network Human Research Ethics Committee in December 2021 (Reference 2021/ETH11861). In addition to publication in a peer-reviewed scientific journal, a lay summary of study outcomes will be made available for participants and the public on the Phage Australia website (https://www.phageaustralia.org/)., Trial Registration Number: Registered on ANZCTR, 10 November 2021 (ACTRN12621001526864; WHO Universal Trial Number: U1111-1269-6000)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Limited consensus exists on the optimal use of antifungal agents to prevent invasive fungal infection in the early post allogeneic hematopoietic stem cell transplant (alloHCT) period, particularly when patients cannot tolerate oral medication administration., Methods: We undertook a retrospective observational cohort study to assess the tolerability, efficacy, and cost of a new antifungal prophylaxis pathway at a major tertiary alloHCT centre. Patients aged ≥16 years who underwent alloHCT between February 2018 and October 2019 (cohort 1) or between April 2020 and November 2021 (cohort 2) were included. In both cohorts, first line prophylactic therapy was oral posaconazole. The second line drugs where oral therapy was unable to be administered were intravenous voriconazole (cohort 1) versus intravenous posaconazole (cohort 2)., Results: There were 142 patients enrolled in the study, 71 in each cohort. The proportion of patients remaining on first-line prophylaxis or progressing to second-, third-, and fourth-line options was 22.5%, 39.4%, 29.6%, and 8.5% in cohort 1 and 39.4%, 59.2%, 1.4%, and 0% in cohort 2, respectively. The frequency of neuropsychiatric adverse events was significantly higher in cohort 1 compared to cohort 2 (49.3% vs. 19.8%, p = .0004). Occurrence of proven and probable fungal infections was not significantly different between cohorts. Antifungal drug expenditure was $359 935 (AUD) more in cohort 1 ($830 486 AUD) compared to cohort 2 ($477 149 AUD)., Conclusion: The antifungal prophylaxis pathway used in cohort 2 resulted in reduced antifungal-associated adverse effects, less patients requiring progression to 3rd and 4th line prophylaxis and reduced antifungal drug costs., (© 2022 The Authors. Transplant Infectious Disease published by Wiley Periodicals LLC.)

Background: Helicobacter pylori infection is responsible for considerable morbidity and mortality worldwide, and eradication rates are falling in many countries, primarily due to clarithromycin and metronidazole resistance., Aims: There is a paucity of contemporary Australian data, which we sought to address by evaluating local rates of resistance of H. pylori to amoxicillin, clarithromycin, metronidazole and tetracycline over the past 20 years., Methods: All gastric biopsy specimens collected at endoscopy to detect H. pylori infection at a single centre underwent routine culture and antibiotic susceptibility testing between 1998 and 2017. Specimens from 12 842 patients were cultured for H. pylori, of which 1473 positive cultures were tested for antibiotic susceptibility., Results: Antibiotic resistance to clarithromycin increased by 3.7% per year (incidence rate ratio [IRR] 1.037; P = 0.014) over 20 years, with a corresponding 5.0% annual increase in minimum inhibitory concentration (MIC) (odds ratio 1.050; P < 0.001). Since 2010, average clarithromycin resistance has exceeded 20%, with >25% of isolates resistant in the past 2 years of data capture. In contrast, rates of resistance to metronidazole (35.3%), amoxicillin (0.14%) and tetracycline (0.34%) and their MIC have remained stable. Review of a representative sample (n = 120; 8%) of these patients revealed that only 5% had documented prior H. pylori eradication therapy., Conclusions: Over the past 20 years there has been a substantial rise in clarithromycin resistance, with stable metronidazole resistance and low rates of resistance to amoxicillin and tetracycline. Current first-line H. pylori eradication therapy may fail to achieve adequate eradication rates, and optimal first-line therapy in Australia should be revisited., (© 2021 Royal Australasian College of Physicians.)

Background and Aim: Rates of antimicrobial-resistant Helicobacter pylori infection are rising globally; however, geospatial location and its interaction with risk factors for infection have not been closely examined., Methods: Gastric biopsy specimens were collected to detect H. pylori infection at multiple centers in Adelaide, South Australia, between 1998 and 2017. The geospatial distribution of antibiotic-resistant H. pylori in the Greater Adelaide region was plotted using choropleth maps. Moran's I was used to assess geospatial correlation, and multivariate linear regression (MLR) was used to examine associations between migration status, socioeconomic status, age, gender, and rates of H. pylori positivity and antibiotic resistance. Geographically weighted regression (GWR) was used to determine the extent to which the associations varied according to geospatial location., Results: Of 20 108 biopsies across 136 postcodes within the Greater Adelaide region, 1901 (9.45%) were H. pylori positive. Of these, 797 (41.9%) displayed clarithromycin, tetracycline, metronidazole, or amoxicillin resistance. In MLR, migration status was associated with the rate of H. pylori positivity (β = 3.85% per 10% increase in a postcode's migrant population; P < 0.001). H. pylori positivity and resistance to any antibiotic were geospatially clustered (Moran's I = 0.571 and 0.280, respectively; P < 0.001 for both). In GWR, there was significant geospatial variation in the strength of the migrant association for both H. pylori positivity and antibiotic resistance., Conclusion: Our study demonstrates the heterogeneous geospatial distribution of H. pylori positivity and antibiotic resistance, as well as its interaction with migrant status. Geographic location and migrant status are important factors to consider for H. pylori eradication therapy., (© 2022 The Authors. Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Clonal complex 398 (CC398) livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) has been reported worldwide in a variety of food-animal species. Although CC398 is synonymous with LA-MRSA, community-associated MRSA (CA-MRSA) variants have emerged, including the Panton-Valentine leukocidin (PVL)-positive ST398-V and ST398 single-locus variant ST1232-V, and the PVL-negative ST398-V clones. Using comparative genomic analysis, we determined whether ten CC398 MRSA bacteraemia episodes recently identified in Australia were due to LA-MRSA or CA-MRSA CC398. Isolates were sourced from the Australian Group on Antimicrobial Resistance S. aureus surveillance programme and episodes occurred across Australia. Whole-genome sequencing (WGS) and phylogenetic comparison of the ten CC398 bacteraemia isolates with previously published CC398 MRSA whole-genome sequences identified that the Australian CC398 isolates were closely related to the human-associated II-GOI clade and the livestock-associated IIa clade. The identified CC398 MRSA clones were: PVL-positive ST1232-V (5C2&5), PVL-negative community-associated ST398-V (5C2&5) and livestock-associated ST398-V (5C2&5). Our findings demonstrate the importance of using WGS and comparing the sequences with international sequences to distinguish between CC398 CA-MRSA and LA-MRSA and to determine the isolates' origin. Furthermore, our findings suggest that CC398 CA-MRSA has become established in the Australian community and that ST398-V (5C2&5) LA-MRSA is now widespread in Australian piggeries. Our study emphasises the need for national One Health antimicrobial resistance surveillance programmes to assist in monitoring the ongoing epidemiology of MRSA and other clinically significant antimicrobial-resistant organisms., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Infection control is critical to safe hospital care. However, how bacteria within nosocomial environments relate to space utilisation and occupancy remains poorly understood. Our aim was to characterise the hospital microbiome in the context of the closure of a tertiary hospital and the opening of a new facility., Methods: Environmental swabs were collected from common and inpatient areas in the old and new hospitals during a 12-month transition period. Microbiota characteristics were determined by 16S rRNA gene sequencing and quantitative (q)PCR. Targeted assays were used to detect Methicillin-resistant Staphylococcus aureus (MRSA) and vanB-positive Vancomycin-Resistant Enterococci (VRE)., Results: The transition to full occupancy in the new facility was associated with an increase in bacterial load (inpatient areas, 3 months p = 0.001; common areas, 6 months p = 0.039) and a change in microbiota composition (baseline-12 months, PERMANOVA p = 0.002). These changes were characterised by an increase in human microbiota-associated taxa, including Acinetobacter and Veillonella. Closure of the existing facility was associated with a decrease in bacterial load (p = 0.040). Detection of MRSA did not differ significantly between sites., Conclusions: Occupancy is a major determinant of bacterial dispersion within hospital environments. Steady-state bacterial levels and microbiota composition provide a basis for assessment of infection control measures., Competing Interests: Declaration of Competing Interest The authors of this manuscript have no conflicts of interest to disclose as described by the Journal of Infection., (Copyright © 2021. Published by Elsevier Ltd.)

Microsporum canis is a dermatophyte known to cause superficial skin infections. In immunocompromised patients, it can lead to invasive dermatophytosis. We present a case of biopsy-proven left knee mycetoma caused by M canis in a renal transplant patient. Identification of M canis was achieved via sequencing of the internal transcribed spacer regions. Treatment involved surgical debridement, oral posaconazole, and reduction in immunosuppression. In addition, we provide a review of current literature on invasive M canis infections., (© 2020 Wiley Periodicals LLC.)

Background: Antimicrobial resistance (AMR) represents a profound global health threat. Reducing AMR spread requires the identification of transmission pathways. The extent to which hospital wards represent a venue for substantial AMR transmission in low- and middle-income countries settings is poorly understood., Methods: Rectal swabs were obtained from adult male inpatients in a "Nightingale" model general medicine ward in Yangon, Myanmar. Resistome characteristics were characterised by metagenomic sequencing. AMR gene carriage was related to inter-patient distance (representing inter-patient interaction) using distance-based linear models. Clinical predictors of AMR patterns were identified through univariate and multivariate regression., Results: Resistome similarity showed a weak but significant positive correlation with inter-patient distance (r = 0.12, p = 0.04). Nineteen AMR determinants contributed significantly to this relationship, including those encoding β-lactamase activity (OXA-1, NDM-7; adjusted p < 0.003), trimethoprim resistance (dfrA14, adjusted p = 0.0495), and chloramphenicol resistance (catB3, adjusted p = 0.002). Clinical traits of co-located patients carrying specific AMR genes were not random. Specifically, AMR genes that contributed to distance-resistome relationships (OXA-1, catB3, dfrA14) mapped to tuberculosis patients, who were placed together according to ward policy. In contrast, patients with sepsis were not placed together, and carried AMR genes that were not spatially significant or consistent with shared antibiotic exposure., Conclusions: AMR dispersion patterns primarily reflect the placement of particular patients by their condition, rather than AMR transmission. The proportion of AMR determinants that varied with inter-patient distance was limited, suggesting that nosocomial transmission is a relatively minor contributor to population-level carriage.

The ability of influenza A virus to evolve, coupled with increasing antimicrobial resistance, could trigger an influenza pandemic with great morbidity and mortality. Much of the 1918 influenza pandemic mortality was likely due to bacterial coinfection, including Staphylococcus aureus pneumonia. S. aureus resists many antibiotics. The lack of new antibiotics suggests alternative antimicrobials, such as bacteriophages, are needed. Potential delivery routes for bacteriophage therapy (BT) include inhalation and intravenous injection. BT has recently been used successfully in compassionate access pulmonary infection cases. Phage lysins, enzymes that hydrolyze bacterial cell walls and which are bactericidal, are efficacious in animal pneumonia models. Clinical trials will be needed to determine whether BT can ameliorate disease in influenza and S. aureus coinfection.

Aim: The objective was to study the long-term (lifetime) cost effectiveness of four different hepatitis C virus (HCV) treatment models of care (MOC) with directly acting antiviral drugs., Methods: A cohort Markov model-based probabilistic cost-effectiveness analysis (CEA) was undertaken extrapolating to up to 30 years from cost and outcome data collected from a primary study involving a real-life Australian cohort. In this study, noncirrhotic patients treated for HCV from 1 March 2016 to 28 February 2017 at four major public hospitals and liaising sites in South Australia were studied retrospectively. The MOC were classified depending on the person providing patient workup, treatment and monitoring into MOC1 (specialist), MOC2 (mixed specialist and hepatitis nurse), MOC3 (hepatitis nurse) and MOC4 (general practitioner, GP). Incremental costs were estimated from the Medicare perspective. Incremental outcomes were estimated based on the quality-adjusted life years (QALY) gained by achieving a sustained virological response. A cost-effectiveness threshold of Australian dollar 50 000 per QALY gained, the implicit criterion used for assessing the cost-effectiveness of new pharmaceuticals and medical services in Australia was assumed. Net monetary benefit (NMB) estimates based on this threshold were calculated., Results: A total of 1373 patients, 64% males, mean age 50 (SD ±11) years, were studied. In the CEA, MOC4 and MOC2 clearly dominated MOC1 over 30 years with lower costs and higher QALYs. Similarly, NMB was the highest in MOC4, followed by MOC2., Conclusion: Decentralized care using GP and mixed consultant nurse models were cost-effective ways of promoting HCV treatment uptake in the setting of unrestricted access to new antivirals.

Background: Diabetic foot ulcer (DFU) is a serious complication of diabetes mellitus. Antibiotic-resistant Staphylococcus aureus is frequently isolated from DFU infections. Bacteriophages (phages) represent an alternative or adjunct treatment to antibiotic therapy. Here we describe the efficacy of AB-SA01, a cocktail of three S. aureus Myoviridae phages, made to current good manufacturing practice (cGMP) standards, and which has undergone two phase I clinical trials, in treatment of multidrug-resistant (MDR) S. aureus infections., Results: Wounds of saline-treated mice showed no healing, but expanded and became inflamed, ulcerated, and suppurating. In contrast, AB-SA01 treatment decreased the bacterial load with efficacy similar or superior to vancomycin treatment. At the end of the treatment period, there was a significant decrease (p < 0.001) in bacterial load and wound size in infected phage- and vancomycin-treated groups compared with infected saline-treated mice. In phage-treated mice, wound healing was seen similar to vancomycin treatment. No mortality was recorded associated with infections, and post-mortem examinations did not show any evident pathological lesions other than the skin wounds. No adverse effects related to the application of phages were observed., Conclusion: Topical application of phage cocktail AB-SA01 is effective, as shown by bacterial load reduction and wound closure, in the treatment of diabetic wound infections caused by MDR S. aureus. Our results suggest that topical phage cocktail treatment may be effective in treating antibiotic-resistant S. aureus DFU infections.

The efficacy of phages in multispecies infections has been poorly examined. The in vitro lytic efficacies of phage cocktails AB-SA01, AB-PA01, which target Staphylococcus aureus and Pseudomonas aeruginosa, respectively, and their combination against their hosts were evaluated in S. aureus and P. aeruginosa mixed-species planktonic and biofilm cultures. Green fluorescent protein (GFP)-labelled P. aeruginosa PAO1 and mCherry-labelled S. aureus KUB7 laboratory strains and clinical isolates were used as target bacteria. During real-time monitoring using fluorescence spectrophotometry, the density of mCherry S. aureus KUB7 and GFP P. aeruginosa PAO1 significantly decreased when treated by their respective phage cocktail, a mixture of phage cocktails, and gentamicin. The decrease in bacterial density measured by relative fluorescence strongly associated with the decline in bacterial cell counts. This microplate-based mixed-species culture treatment monitoring through spectrophotometry combine reproducibility, rapidity, and ease of management. It is amenable to high-throughput screening for phage cocktail efficacy evaluation. Each phage cocktail, the combination of the two phage cocktails, and tetracycline produced significant biofilm biomass reduction in mixed-species biofilms. This study result shows that these phage cocktails lyse their hosts in the presence of non-susceptible bacteria. These data support the use of phage cocktails therapy in infections with multiple bacterial species.

Importance: Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is associated with mortality of more than 20%. Combining standard therapy with a β-lactam antibiotic has been associated with reduced mortality, although adequately powered randomized clinical trials of this intervention have not been conducted., Objective: To determine whether combining an antistaphylococcal β-lactam with standard therapy is more effective than standard therapy alone in patients with MRSA bacteremia., Design, Setting, and Participants: Open-label, randomized clinical trial conducted at 27 hospital sites in 4 countries from August 2015 to July 2018 among 352 hospitalized adults with MRSA bacteremia. Follow-up was complete on October 23, 2018., Interventions: Participants were randomized to standard therapy (intravenous vancomycin or daptomycin) plus an antistaphylococcal β-lactam (intravenous flucloxacillin, cloxacillin, or cefazolin) (n = 174) or standard therapy alone (n = 178). Total duration of therapy was determined by treating clinicians and the β-lactam was administered for 7 days., Main Outcomes and Measures: The primary end point was a 90-day composite of mortality, persistent bacteremia at day 5, microbiological relapse, and microbiological treatment failure. Secondary outcomes included mortality at days 14, 42, and 90; persistent bacteremia at days 2 and 5; acute kidney injury (AKI); microbiological relapse; microbiological treatment failure; and duration of intravenous antibiotics., Results: The data and safety monitoring board recommended early termination of the study prior to enrollment of 440 patients because of safety. Among 352 patients randomized (mean age, 62.2 [SD, 17.7] years; 121 women [34.4%]), 345 (98%) completed the trial. The primary end point was met by 59 (35%) with combination therapy and 68 (39%) with standard therapy (absolute difference, -4.2%; 95% CI, -14.3% to 6.0%). Seven of 9 prespecified secondary end points showed no significant difference. For the combination therapy vs standard therapy groups, all-cause 90-day mortality occurred in 35 (21%) vs 28 (16%) (difference, 4.5%; 95% CI, -3.7% to 12.7%); persistent bacteremia at day 5 was observed in 19 of 166 (11%) vs 35 of 172 (20%) (difference, -8.9%; 95% CI, -16.6% to -1.2%); and, excluding patients receiving dialysis at baseline, AKI occurred in 34 of 145 (23%) vs 9 of 145 (6%) (difference, 17.2%; 95% CI, 9.3%-25.2%)., Conclusions and Relevance: Among patients with MRSA bacteremia, addition of an antistaphylococcal β-lactam to standard antibiotic therapy with vancomycin or daptomycin did not result in significant improvement in the primary composite end point of mortality, persistent bacteremia, relapse, or treatment failure. Early trial termination for safety concerns and the possibility that the study was underpowered to detect clinically important differences in favor of the intervention should be considered when interpreting the findings., Trial Registration: ClinicalTrials.gov Identifier: NCT02365493.

Changes in the pharmacokinetics of piperacillin in febrile neutropenic patients have been reported to result in suboptimal exposures. This study aimed to develop a population pharmacokinetic model for piperacillin and perform dosing simulation to describe optimal dosing regimens for hematological malignancy patients with febrile neutropenia. Concentration-time data were obtained from previous prospective observational pharmacokinetic and interventional therapeutic drug monitoring studies. Nonparametric population pharmacokinetic analysis and Monte Carlo dosing simulations were performed with the Pmetrics package for R. A two-compartment model, with between-subject variability for clearance (CL), adequately described the data from 37 patients (21 males, age of 59 ± 12 years [means ± standard deviations] and weight of 77 ± 16 kg). Parameter estimates were CL of 18.0 ± 4.8 liters/h, volume of distribution of the central compartment of 14.3 ± 7.3 liters, rate constant for piperacillin distribution from the central to peripheral compartment of 1.40 ± 1.35 h -1 , and rate constant for piperacillin distribution from the peripheral to central compartment of 4.99 ± 7.81 h -1 High creatinine clearance (CL CR ) was associated with reduced probability of target attainment (PTA). Extended and continuous infusion regimens achieved a high PTA of >90% for an unbound concentration of piperacillin remaining above the MIC ( fT >MIC ) of 50%. Only continuous regimens achieved >90% PTA for 100% fT >MIC when CL CR was high. The cumulative fraction of response (FTA, for fractional target attainment) was suboptimal (<85%) for conventional regimens for both empirical and directed therapy considering 50% and 100% fT >MIC FTA was maximized with prolonged infusions. Overall, changes in piperacillin pharmacokinetics and the consequences on therapeutic dosing requirements appear similar to those observed in intensive care patients. Guidelines should address the altered dosing needs of febrile neutropenic patients exhibiting high CL CR or with known/presumed infections from high-MIC bacteria., (Copyright © 2017 American Society for Microbiology.)

Objectives: Inappropriate antimicrobial use drives antimicrobial resistance and is a global public health problem. This study examined whether withholding antimicrobial susceptibilities in combination with interpretive comments on microbiological reports influenced the decision to inappropriately prescribe antibiotics in a controlled survey., Methods: Seventy junior doctors attending educational sessions were given one of two surveys describing four clinical case vignettes (scenarios) in which antimicrobial treatment was not indicated. They were asked to select their preferred treatment from multiple choices. In the scenarios labelled 'A', the laboratory report did not report antibiotic susceptibilities, but included comments from the microbiologist. In the scenarios labelled 'B', the laboratory report included full organism identification and susceptibility results without additional comments., Results: For scenarios 1, 2 and 3 there was a significantly higher probability ( P  <   0.01) that the doctor selected an answer involving antibiotic treatment if he/she received the 'B' version of the scenario where reports included antimicrobial susceptibilities, but no interpretive comments. This was significant in both interns and more senior doctors. In scenario 4, of which there were two versions, there was no difference seen in the answers between the groups given scenario A or B., Conclusions: The results of this survey suggest that withholding antimicrobial susceptibility results in combination with interpretive comments on microbiology reports significantly influences the decision of junior doctors to prescribe antibiotics in low-acuity outpatient setting scenarios (represented in scenarios 1-3), but not in inpatient scenarios (represented in scenario 4)., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

While guidelines recommend empirical cefepime therapy in febrile neutropenia, the mortality benefit of cefepime has been controversial. In light of this, recent reports on pharmacokinetic changes for several antibiotics in febrile neutropenia and the consequent suboptimal exposure call for a pharmacokinetic/pharmacodynamic evaluation of current dosing. This study aimed to assess pharmacokinetic/pharmacodynamic target attainment from a 2-g intravenous (i.v.) every 8 h (q8h) cefepime regimen in febrile neutropenic patients with hematological malignancies. Cefepime plasma concentrations were measured in the 3rd, 6th, and 9th dosing intervals at 60% of the interval and/or trough point. The selected pharmacokinetic/pharmacodynamic targets were the proportion of the dosing interval (60% and 100%) for which the free drug concentration remains above the MIC (fT>MIC). Target attainment was assessed in reference to the MIC of isolated organisms if available or empirical breakpoints if not. The percentage of fT>MIC was also estimated by log-linear regression analysis. All patients achieved >60% fT>MIC in the 3rd and 6th dosing intervals. A 100% fT>MIC was not attained in 6/12, 4/10, and 4/9 patients in the 3rd, 6th, and 9th dose intervals, respectively, or in 14/31 (45%) of the dosing intervals investigated. On the other hand, 29/31 (94%) of trough concentrations were at or above 4 mg/liter. In conclusion, for patients with normal renal function, a high-dose 2-g i.v. q8h cefepime regimen appears to provide appropriate exposure if the MIC of the organism is ≤4 mg/liter but may fail to cover less susceptible organisms., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Objectives: The objectives of this study were to describe piperacillin exposure in febrile neutropenia patients and determine whether therapeutic drug monitoring (TDM) can be used to increase the achievement of pharmacokinetic (PK)/pharmacodynamic (PD) targets., Methods: In a prospective randomized controlled study (Australian New Zealand Registry, ACTRN12615000086561), patients were subjected to TDM for 3 consecutive days. Dose was adjusted in the intervention group to achieve a free drug concentration above the MIC for 100% of the dose interval (100% fT>MIC), which was also the primary outcome measure. The secondary PK/PD target was 50% fT>MIC. Duration of fever and days to recovery from neutropenia were recorded., Results: Thirty-two patients were enrolled. Initially, patients received 4.5 g of piperacillin/tazobactam every 8 h or every 6 h along with gentamicin co-therapy in 30/32 (94%) patients. At the first TDM, 7/32 (22%) patients achieved 100% fT>MIC and 12/32 (38%) patients achieved 50% fT>MIC. Following dose adjustment, 11/16 (69%) of intervention patients versus 3/16 (19%) of control patients (P = 0.012) attained 100% fT>MIC, and 15/16 (94%) of intervention patients versus 5/16 (31%) of control patients (P = 0.001) achieved 50% fT>MIC. After the third TDM, the proportion of patients attaining 100% fT>MIC improved from a baseline 3/16 (19%) to 11/15 (73%) in the intervention group, while it declined from 4/16 (25%) to 1/15 (7%) in the control group. No difference was noted in the duration of fever and days to recovery from neutropenia., Conclusions: Conventional doses of piperacillin/tazobactam may not offer adequate piperacillin exposure in febrile neutropenic patients. TDM provides useful feedback of dosing adequacy to guide dose optimization., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

This study assessed the pharmacokinetics and dosing adequacy of piperacillin in febrile neutropenic patients after the first dose. Pharmacokinetic analysis was performed using noncompartmental methods. We observed an elevated volume of distribution (29.7 ± 8.0 liters [mean ± standard deviation]) and clearance (20.2 ± 7.5 liters/h) compared to data from other patient populations. Antibiotic exposure did not consistently result in therapeutic targets. We conclude that alternative dosing strategies guided by therapeutic drug monitoring may be required to optimize exposure., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

Purpose: Clinical patterns of Klebsiella pneumoniae bacteraemia vary geographically. An invasive syndrome involving abscess formation has emerged in recent years. Putative virulence factors associated with this syndrome include colony hypermucoviscosity, and magA and rmpA genes. We studied epidemiologic and microbiologic characteristics of K. pneumoniae bacteraemia at two South Australian hospitals and identified cases of K. pneumoniae invasive syndrome. We determined the frequency of the hypermucoviscosity, magA and rmpA genes among bacteraemic and selected non-bacteraemic isolates., Methods: Thirty-one patients with K. pneumoniae bacteraemia treated between June 2010 and July 2011 were included. Existing records were examined for relevant clinical and microbiological data. Urinary and wound isolates were also examined. Hypermucoviscosity was identified by a positive string test, whilst polymerase chain reaction detected magA and rmpA positive isolates., Results: Of 31 blood culture isolates, 22 were associated with community-acquired infection. Biliary infection was the commonest source, occurring in ten patients. Three patients had K. pneumoniae invasive syndrome, all of Asian extraction (p = 0.0044). Four blood isolates demonstrated one or more of hypermucoviscosity, magA or rmpA; three were from patients with liver abscesses. Liver abscess isolates were all K1 serotype and had similar PFGE profiles., Conclusions: This study augments understanding of local epidemiology and microbiology of K. pneumoniae bacteraemia. It confirms local emergence of K. pneumoniae invasive syndrome and implicates the role of magA and rmpA genes in its pathogenesis.

Sudden and unexpected nontraumatic death in individuals with asplenia or hyposplenia is usually due to fulminant bacterial sepsis, most often involving Streptococcus pneumoniae, Neisseria meningitidis, and Hemophilus influenzae. We report a case of a previously well 40-year-old man who died 5 hours after hospital admission. At autopsy Waterhouse-Friderichsen syndrome was identified and Capnocytophaga canimorsus was subsequently isolated on antemortem blood cultures. Infection of humans with this organism is most often due to dog bite or contact. Upon specific inquiry it was ascertained that 2 days before admission the deceased had suffered a superficial bite to his hand by his pet Staffordshire Bullterrier dog. His relevant history included a previous splenectomy following blunt abdominal trauma. Asplenia and hyposplenia at autopsy should prompt microbiological testing with consideration of unusual organisms such as C. canimorsus. Although histories of animal contact or injury are often not available at the time of autopsy, this should also be considered in cases of apparent fulminant sepsis. In individuals with asplenia or hyposplenia, dog bites do not have to involve excessive tissue trauma, vascular compromise, or blood loss to be lethal.

Lemierre syndrome refers to necrotizing infections of the head due to Fusobacterium necrophorum and has been called the 'forgotten disease' due to its rarity in the antibiotic era. Recently, however, more cases have been documented in the literature suggesting that there has been an increase in incidence. A 10-year-old boy is reported who had a five-day history of ear infection, with the development of fever, drowsiness and ipsilateral neck swelling. Unexpected cardiac arrest occurred soon after medical assessment. At autopsy, right otitis media was demonstrated with extension of suppurative infection into subcutaneous tissues behind the ear and also into the extradural space at the lateral end of the petrous temporal bone. There was also septic thrombophlebitis of the adjacent sigmoid sinus, but no evidence of meningitis. This case demonstrates yet another infectious condition that may be associated with rapid deterioration and unexpected death in childhood. An autopsy approach to suspected sepsis in childhood is outlined.