Candida tropicalis-A systematic review to inform the World Health Organization of a fungal priority pathogens list.

In response to the growing global burden of fungal infections with uncertain impact, the World Health Organization (WHO) established an Expert Group to identify priority fungal pathogens and establish the WHO Fungal Priority Pathogens List for future research. This systematic review aimed to evaluate the features and global impact of invasive candidiasis caused by Candida tropicalis. PubMed and Web of Science were searched for studies reporting on criteria of mortality, morbidity (defined as hospitalization and disability), drug resistance, preventability, yearly incidence, diagnostics, treatability, and distribution/emergence from 2011 to 2021. Thirty studies, encompassing 436 patients from 25 countries were included in the analysis. All-cause mortality due to invasive C. tropicalis infections was 55%-60%. Resistance rates to fluconazole, itraconazole, voriconazole and posaconazole up to 40%-80% were observed but C. tropicalis isolates showed low resistance rates to the echinocandins (0%-1%), amphotericin B (0%), and flucytosine (0%-4%). Leukaemia (odds ratio (OR) = 4.77) and chronic lung disease (OR = 2.62) were identified as risk factors for invasive infections. Incidence rates highlight the geographic variability and provide valuable context for understanding the global burden of C. tropicalis infections. C. tropicalis candidiasis is associated with high mortality rates and high rates of resistance to triazoles. To address this emerging threat, concerted efforts are needed to develop novel antifungal agents and therapeutic approaches tailored to C. tropicalis infections. Global surveillance studies could better inform the annual incidence rates, distribution and trends and allow informed evaluation of the global impact of C. tropicalis infections.

One Health Determinants of Escherichia coli Antimicrobial Resistance in Humans in the Community: An Umbrella Review.

To date, the scientific literature on health variables for Escherichia coli antimicrobial resistance (AMR) has been investigated throughout several systematic reviews, often with a focus on only one aspect of the One Health variables: human, animal, or environment. The aim of this umbrella review is to conduct a systematic synthesis of existing evidence on Escherichia coli AMR in humans in the community from a One Health perspective. PubMed, EMBASE, and CINAHL were searched on "antibiotic resistance" and "systematic review" from inception until 25 March 2022 (PROSPERO: CRD42022316431). The methodological quality was assessed, and the importance of identified variables was tabulated across all included reviews. Twenty-three reviews were included in this study, covering 860 primary studies. All reviews were of (critically) low quality. Most reviews focused on humans (20), 3 on animals, and 1 on both human and environmental variables. Antibiotic use, urinary tract infections, diabetes, and international travel were identified as the most important human variables. Poultry farms and swimming in freshwater were identified as potential sources for AMR transmission from the animal and environmental perspectives. This umbrella review highlights a gap in high-quality literature investigating the time between variable exposure, AMR testing, and animal and environmental AMR variables.

Current Epidemiology and Clinical Features of Cryptococcus Infection in Patients Without Human Immunodeficiency Virus: A Multicenter Study in 46 Hospitals in Australia and New Zealand.

BACKGROUND: Patients without human immunodeficiency virus (HIV) are increasingly recognized as being at risk for cryptococcosis. Knowledge of characteristics of cryptococcosis in these patients remains incomplete. METHODS: We conducted a retrospective study of cryptococcosis in 46 Australian and New Zealand hospitals to compare its frequency in patients with and without HIV and describe its characteristics in patients without HIV. Patients with cryptococcosis between January 2015 and December 2019 were included. RESULTS: Of 475 patients with cryptococcosis, 90% were without HIV (426 of 475) with marked predominance in both Cryptococcus neoformans (88.7%) and Cryptococcus gattii cases (94.3%). Most patients without HIV (60.8%) had a known immunocompromising condition: cancer (n = 91), organ transplantation (n = 81), or other immunocompromising condition (n = 97). Cryptococcosis presented as incidental imaging findings in 16.4% of patients (70 of 426). The serum cryptococcal antigen test was positive in 85.1% of tested patients (319 of 375); high titers independently predicted risk of central nervous system involvement. Lumbar puncture was performed in 167 patients to screen for asymptomatic meningitis, with a positivity rate of 13.2% where meningitis could have been predicted by a high serum cryptococcal antigen titer and/or fungemia in 95% of evaluable cases. One-year all-cause mortality was 20.9% in patients without HIV and 21.7% in patients with HIV (P = .89). CONCLUSIONS: Ninety percent of cryptococcosis cases occurred in patients without HIV (89% and 94% for C. neoformans and C. gattii, respectively). Emerging patient risk groups were evident. A high level of awareness is warranted to diagnose cryptococcosis in patients without HIV.

Time-to-positivity in bloodstream infection for Candida species as a prognostic marker for mortality.

Time-to-positivity (TTP) may assist in predicting the outcome of candidaemia. We analysed a candidaemia dataset collected prospectively in Australia over 1 year (2014-2015). TTP was defined as the period from blood culture sampling to the blood culture flagging positive. Of 415 candidaemia episodes, overall, 30-day mortality was 29% (120/415); mortality with Candida albicans was 35% (59/169), C. glabrata complex, 37% (43/115), C. tropicalis, 43% (10/23), Pichia kudriavzevii 25% (3/12), and C. parapsilosis complex 7% (5/71). Each day of increased TTP multiplied the odds ratio (OR) of survival at 30 days by a factor of 1.32 [95% confidence interval (CI) 1.06-1.69]. Shorter TTP was associated with increased mortality, with 1-day TTP associated with 30-day mortality 37% (41/112) (95%CI: 28%-46%) and 5-day TTP 11% (2/18) (95%CI: 2%-36%).

Time-to-positivity is a measure that is available to clinicians when patients are identified as having candida in their bloodstream. Our data support the association of a shorter time to positivity with higher mortality.

Multi-year antimicrobial-resistance trends in urine Escherichia coli isolates from both community-based and hospital-based laboratories of an Australian local health district.

OBJECTIVES: Efforts to monitor and combat antimicrobial resistance (AMR) are typically focused on the hospital-based laboratory setting. The aim of this study was to longitudinally examine and compare trends in AMR among urine Escherichia coli isolates from a private community-based laboratory and a public hospital-based laboratory in an Australian local health district. METHODS: A total of 108 262 urine E. coli isolates from a public hospital-based laboratory (N = 34 103) and a private community-based laboratory (N = 74 159) in a single health district between 2007-2019 were analysed. Linear regression was used to identify significance of change in AMR rates in both laboratories independently and detect any significant interaction of each setting in proportional change over the study period. RESULTS: Similar AMR trends were detected among urinary E. coli isolates in private community-based laboratory and public hospital-based laboratory settings over 12 y. AMR rates were consistently higher in the public hospital-based setting. Ampicillin was the only antibiotic for which the E. coli resistance trend did not significantly change over the time period in either laboratory setting. All other antibiotics showed a significant increase in AMR rates over time in both settings. CONCLUSIONS: AMR rates in both the private community-based laboratory and public hospital-based laboratory settings increased over time and were consistently higher in the public hospital-based laboratory setting. Since private laboratories handle the vast majority of pathology volumes in community outpatient settings in Australia, interventions incorporating the community-based laboratory setting are critical to addressing AMR in the community.

Whole Genome Sequencing Shows Genetic Diversity, as Well as Clonal Complex and Gene Polymorphisms Associated with Fluconazole Non-Susceptible Isolates of Candida tropicalis.

Resistance to azoles in Candida tropicalis is increasing and may be mediated by genetic characteristics. Using whole genome sequencing (WGS), we examined the genetic diversity of 82 bloodstream C. tropicalis isolates from two countries and one ATCC strain in a global context. Multilocus sequence typing (MLST) and single nucleotide polymorphism (SNP)-based phylogenies were generated. Minimum inhibitory concentrations (MIC) for antifungal agents were determined using Sensititre YeastOne YO10. Eleven (13.2%) isolates were fluconazole-resistant and 17 (20.5%) were classified as fluconazole-non susceptible (FNS). Together with four Canadian isolates, the genomes of 12 fluconazole-resistant (18 FNS) and 69 fluconazole-susceptible strains were examined for gene mutations associated with drug resistance. Fluconazole-resistant isolates contained a mean of 56 non-synonymous SNPs per isolate in contrast to 36 SNPs in fluconazole-susceptible isolates (interquartile range [IQR] 46−59 vs. 31−48 respectively; p < 0.001). Ten of 18 FNS isolates contained missense ERG11 mutations (amino acid substitutions S154F, Y132F, Y257H). Two echinocandin-non susceptible isolates had homozygous FKS1 mutations (S30P). MLST identified high genetic diversity with 61 diploid sequence types (DSTs), including 53 new DSTs. All four isolates in DST 773 were fluconazole-resistant within clonal complex 2. WGS showed high genetic variation in invasive C. tropicalis; azole resistance was distributed across different lineages but with DST 773 associated with in vitro fluconazole resistance.

What's New in Cryptococcus gattii: From Bench to Bedside and Beyond.

Cryptococcus species are a major cause of life-threatening infections in immunocompromised and immunocompetent hosts. While most disease is caused by Cryptococcus neoformans, Cryptococcus gattii, a genotypically and phenotypically distinct species, is responsible for 11-33% of global cases of cryptococcosis. Despite best treatment, C. gattii infections are associated with early mortality rates of 10-25%. The World Health Organization's recently released Fungal Priority Pathogen List classified C. gattii as a medium-priority pathogen due to the lack of effective therapies and robust clinical and epidemiological data. This narrative review summarizes the latest research on the taxonomy, epidemiology, pathogenesis, laboratory testing, and management of C. gattii infections.

Consensus guidelines for the diagnosis and management of invasive candidiasis in haematology, oncology and intensive care settings, 2021.

Patients with haematological malignancies, haemopoietic stem cell transplant recipients and patients requiring admission to intensive care settings are at high risk for invasive candidiasis (IC). Over the past decade, there has been increased reporting of non-albicans species and fluconazole resistance in Australia. These guidelines provide updated evidence-based recommendations for the diagnosis and management of IC in adult and paediatric haematology, oncology and intensive care settings. Optimal pharmacological and non-pharmacological management are discussed. Recent studies strengthen the recommendation for an echinocandin agent as first-line therapy for high-risk patients with IC. Mortality benefit has also been demonstrated for non-pharmacological management, including removal of central venous catheters, infectious diseases consultation and use of care bundles. Healthcare facilities managing immunocompromised patient populations should therefore adopt implementation strategies for these multimodal interventions.

A vanA vancomycin-resistant Enterococcus faecium ST80 outbreak resulting from a single importation event.

BACKGROUND: A marked genotype shift among vancomycin-resistant Enterococcus faecium (VREfm) from vanB to vanA in Australia between 2011 and 2015 is a well-known phenomenon. It is hypothesized that this was caused by multiple independent clones emerging simultaneously in different settings and/or regions. OBJECTIVES: To gain insights into the circumstances surrounding the shift from vanB to vanA VREfm in one Australian hospital. METHODS: The genomes of 69 vanA VREfm isolates from St George Hospital collected between 2009 and 2018 were studied. An expansion of ST80 vanA VREfm was noted following a single introduction. ST80 isolates were thus further characterized using hybrid sequencing and contextualized through comparisons with other published Australian ST80 isolates. Phylogenies were constructed with plasmid sequences compared with the index isolate. RESULTS: The 2011 expansion of ST80 vanA VREfm isolates in our institution originated from the 2009 index isolate, from a patient transferred from overseas. Phylogenetic analysis with other Australian ST80 vanA VREfm isolates showed that the 2011 expansion event was unique, with limited spread to adjacent local health districts. Plasmid analysis showed multiple variants, which can also be traced back to the 2009 isolate, consistent with ongoing plasmid adaptation over time. CONCLUSIONS: These findings confirm an expansion event following a VREfm introduction event leading to a sustained clonal and plasmid outbreak over several years. Moreover, it demonstrates the complexity of countrywide replacement events. This study also highlights the use of hybrid sequencing in establishing an epidemiological relationship to the index isolate that was initially inapparent.

Risk factors for candidaemia: A prospective multi-centre case-control study.

OBJECTIVES: Candidaemia carries a mortality of up to 40% and may be related to increasing complexity of medical care. Here, we determined risk factors for the development of candidaemia. METHODS: We conducted a prospective, multi-centre, case-control study over 12 months. Cases were aged ≥18 years with at least one blood culture positive for Candida spp. Each case was matched with two controls, by age within 10 years, admission within 6 months, admitting unit, and admission duration at least as long as the time between admission and onset of candidaemia. RESULTS: A total of 118 incident cases and 236 matched controls were compared. By multivariate analysis, risk factors for candidaemia included neutropenia, solid organ transplant, significant liver, respiratory or cardiovascular disease, recent gastrointestinal, biliary or urological surgery, central venous access device, intravenous drug use, urinary catheter and carbapenem receipt. CONCLUSIONS: Risk factors for candidaemia derive from the infection source, carbapenem use, host immune function and organ-based co-morbidities. Preventive strategies should target iatrogenic disruption of mucocutaneous barriers and intravenous drug use.

Preventing Early-Onset Group B Streptococcus neonatal infection and reducing antibiotic exposure using a rapid PCR test in term prelabour rupture of membranes.

BACKGROUND: How best to target intrapartum antibiotic prophylaxis (IAP) to minimise both Early-Onset Group B Streptococcus (EOGBS) neonatal infection and maternal/fetal antibiotic exposure is uncertain, with both routine-screening and risk-factor approaches available. AIMS: This retrospective cohort study was undertaken to examine the outcomes of a hybrid risk-and-screen approach to EOGBS prevention using GBS polymerase chain reaction (PCR). The target population was women with term prelabour rupture of membranes (TermPROM) having the risk factor of prolonged rupture of membranes (ROM) ≥18 h. MATERIALS AND METHODS: Non-labouring TermPROM women had rapid GBS PCR testing at presentation. GBS screen-positive women proceeded to induction of labour and received IAP. GBS screen-negative women were allowed home to await spontaneous labour and not given IAP regardless of duration of ROM, unless other risk factors developed. For all other women, the risk-factor approach was followed. RESULTS: From 2009 to 2018, there were 20 cases of culture-positive EOGBS, a rate of 0.36/1000 live births (95% CI 0.22-0.56/1000), comparable to other recent reports. Over 2010-2018 when laboratory data were available, 1120 TermPROM women with ROM ≥18 h avoided antibiotics because they were GBS PCR-negative (2.3% of all births, 3.6% of vaginal births) while 338 TermPROM women with ROM <18 h received targeted antibiotics for being GBS-positive. No cases of EOGBS occurred in TermPROM women, those with ROM ≥18 h, or due to protocol-compliance failure. CONCLUSIONS: A hybrid approach involving risk-factor-based IAP and intrapartum GBS PCR screening of non-labouring TermPROM women delivers acceptably low rates of EOGBS while minimising and better targeting antibiotic exposure.

Cellulitis in older people over 75 years - are there differences?

AIM: To examine differences in risk factors, clinical features and outcomes of cellulitis between those 75 + years and those <75 years admitted to a metropolitan hospital. METHODS: A prospective study of patients with limb cellulitis requiring intravenous antibiotics conducted at Bankstown-Lidcombe Hospital, Australia from June 2014 to April 2015. RESULTS: Thirty one patients were 75 + years and 69 less than 75 years. A greater proportion of older patients resided in nursing home (25.8% vs 2.9% respectively, p = 0.001) and mobilized with walking aid(s) (58.1% vs 11.6% respectively, p < 0.001). Significantly more older patients had documented hypertension (45.2% vs 23.2% respectively p = 0.035), atrial fibrillation (33.5% vs 5.8% respectively, p < 0.001), dementia (22.6% vs 1.4% respectively, p = 0.001) and malignancy (16.1% vs 1.4% respectively, p = 0.010). The clinical presentation of cellulitis and cellulitis severity (Eron classification) did not significantly differ in both groups; however older patients were more likely to have dependent edema (OR 4.0, 95%CI 1.3-12.6, p = 0.018) and less likely to be obese (OR 0.3, 95%CI 0.1-0.8, p = 0.012) or had a past history of cellulitis (OR 0.3, 95%CI 0.1-1.0, p = 0.044) on presentation. Despite the age difference, there were no major differences in intravenous antibiotic choice, hospital length of stay, and hospital readmission rates in both groups. Older patients however, were more likely to experience complications such as falls and/or decreased mobility (38.7% vs 15.9% respectively, p = 0.020) during the cellulitis episode. CONCLUSION: There are minor differences in the risk factors and clinical features of cellulitis in older patients as compared to the young. Outcomes are similar except for a higher incidence of hospital related complications.

Out Of Hospital And In Hospital Management Of Cellulitis Requiring Intravenous Therapy.

BACKGROUND: Cellulitis requiring intravenous therapy can be managed via out of hospital programs, but a high number of patients are still admitted to hospital. OBJECTIVE: We aimed to review the clinical features, management and outcomes of patients with cellulitis requiring intravenous therapy in a Hospital in the Home (HITH) program compared to patients who are admitted to hospital. METHODS: A prospective cohort study of patients with limb cellulitis requiring intravenous antibiotics was conducted at a metropolitan principal referral hospital. RESULTS: A total of 100 patients out of 113 eligible patients were recruited. Forty-eight were treated entirely in hospital and 52 were treated entirely or partially via HITH. Patients treated in hospital were older (mean 69.2 vs 56.7 years, p<0.001), less mobile, have more comorbidities (Charlson Comorbidity Index mean 2.2 vs 1.2, P=0.005) and more associated active illness. All patients with Eron Class III were admitted to hospital. Patients treated in hospital had a higher incidence of acute renal failure (27.1% vs 3.8%, p=0.001), nosocomial infection (10.4% vs 0.0%, P=0.023), and a higher 28-day hospital readmission rate (10.4% vs 0.0%, P=0.023). CONCLUSION: Approximately half of the patients who require intravenous therapy can be treated via an out of hospital program. Patients admitted to hospital were more unwell and more likely to suffer complications. The presence of comorbid illness does not necessarily exclude participation in HITH and careful selection is essential to ensure safe outcomes.

Infections in pregnancy.

Infections in pregnancy represent a challenging and often underappreciated area of concern for many specialists and general practitioners and can cause serious sequelae. Antenatal status should be highlighted on pathology request forms, as this serves to alert the laboratory of the need to store serum for an extended period. Prior antenatal specimens can be forwarded to other laboratories to enable testing in parallel with the more recent sample. Women with a confirmed, potentially vertically transmissible infection should be referred to a specialist with expertise in the management of perinatal infections. Cytomegalovirus infection is the most common congenital infection. Women who care for young children are at greater risk of exposure to the virus. Preventive steps including hand hygiene and avoiding contact with children's urine, mucous and saliva are recommended for all pregnant women. The incidence of parvovirus B19 infection in pregnancy is unknown. This infection is highly contagious and may result in fetal loss; particularly in the first half of pregnancy, pregnant women should avoid contact with adults or children who may have an infection.

Contemporary management and clinical outcomes of mucormycosis: A systematic review and meta-analysis of case reports.

With the advent of newer antifungals, optimum treatment of mucormycosis remains to be fully elucidated. This study systematically evaluated the contemporary management and outcomes of mucormycosis. Mucormycosis cases in patients aged ≥18 years published between January 2000 and January 2017 were identified through Ovid MEDLINE and Embase. Of the 3619 articles identified, 600 (851 individual patient cases) were included in the review. Of the 851 patient cases, antifungal treatment details were available for 785. Intravenous (i.v.) amphotericin B formulations remained the most commonly prescribed first-line antifungals (760/785; 96.8%): 88.2% (670/760) were initiated as monotherapy and 11.8% (90/760) as combination antifungal therapy. Posaconazole oral suspension monotherapy was prescribed as an initial antifungal in 11 cases. It was also administered as maintenance or salvage therapy in 39 and 25 cases, respectively. Itraconazole capsule monotherapy (n = 10) was prescribed primarily for cutaneous disease in patients not receiving any immunosuppressive therapy. All-cause 90-day mortality was 41.0% (349/851). Initial treatment with combination antifungals did not reduce 90-day mortality compared with i.v. conventional amphotericin B or i.v. liposomal amphotericin B monotherapy [35/90 (38.9%) vs. 146/369 (39.6%) vs. 91/258 (35.3%), respectively; P = 0.541]. Concomitant surgical and antifungal therapy was associated with significantly lower 90-day mortality compared with treatment with antifungals alone (OR = 0.23, 95% CI 0.13-0.41; P < 0.001). The findings suggest that first-line antifungals with good efficacy remain an urgent unmet need. Whilst surgery is fundamental to improving survival, the clinical utility of combination antifungal therapy or posaconazole monotherapy requires further investigation.

A series of three cases of severe Clostridium difficile infection in Australia associated with a binary toxin producing clade 2 ribotype 251 strain.

Three patients with severe Clostridium difficile infection (CDI) caused by an unusual strain of C. difficile, PCR ribotype (RT) 251, were identified in New South Wales, Australia. All cases presented with severe diarrhoea, two had multiple recurrences and one died following a colectomy. C. difficile RT251 strains were isolated by toxigenic culture. Genetic characterisation was performed using techniques including toxin gene profiling, PCR ribotyping, whole genome sequencing (WGS), in-silico multi-locus-sequence-typing (MLST) and core-genome single nucleotide variant (SNV) analyses. Antimicrobial susceptibility was determined using an agar incorporation method. In vitro toxin production was confirmed by Vero cell cytotoxicity assay and pathogenicity was assessed in a murine model of CDI. All RT251 isolates contained toxin A (tcdA), toxin B (tcdB) and binary toxin (cdtA and cdtB) genes. Core-genome analyses revealed the RT251 strains were clonal, with 0-5 SNVs between isolates. WGS and MLST clustered RT251 in the same evolutionary clade (clade 2) as RT027. Despite comparatively lower levels of in vitro toxin production, in the murine model RT251 infection resembled RT027 infection. Mice showed marked weight loss, severe disease within 48 h post-infection and death. All isolates were susceptible to metronidazole and vancomycin. Our observations suggest C. difficile RT251 causes severe disease and emphasise the importance of ongoing surveillance for new and emerging strains of C. difficile with enhanced virulence.

Anncaliia algerae Microsporidial Myositis, New South Wales, Australia.

We describe the successful management of Anncaliia algerae microsporidial myositis in a man with graft versus host disease after hemopoietic stem cell transplantation. We also summarize clinical presentation and management approaches and discuss the importance of research into the acquisition of this infection and strategies for prevention.