Investigation and response to an outbreak of Neisseria meningitidis serogroup Y ST-1466 urogenital infections, Australia.

Abstract: In 2023, an increased number of urogenital and anorectal infections with Neisseria meningitis serogroup Y (MenY) were reported in New South Wales (NSW). Whole genome sequencing (WGS) found a common sequence type (ST-1466), with limited sequence diversity. Confirmed outbreak cases were NSW residents with a N. meningitidis isolate matching the cluster sequence type; probable cases were NSW residents with MenY isolated from a urogenital or anorectal site from 1 July 2023 without WGS testing. Of the 41 cases, most were men (n = 27), of whom six reported recent contact with a female sex worker. Five cases were men who have sex with men and two were female sex workers. Laboratory alerts regarding the outbreak were sent to all Australian jurisdictions through the laboratories in the National Neisseria Network. Two additional states identified urogenital MenY ST-1466 infections detected in late 2023. Genomic analysis showed all MenY ST-1466 sequences were interspersed, suggestive of an Australia-wide outbreak. The incidence of these infections remains unknown, due to varied testing and reporting practices both within and across jurisdictions. Isolates causing invasive meningococcal disease (IMD) in Australia are typed, and there has been no MenY ST-1466 IMD recorded in Australia to end of March 2024. Concerns remain regarding the risk of IMD, given the similarity of these sequences with a MenY ST-1466 IMD strain causing a concurrent outbreak in the United States of America.

Rapid expansion of Neisseria gonorrhoeae ST7827 clone in Australia, with variable ceftriaxone phenotype unexplained by genotype.

BACKGROUND: Neisseria gonorrhoeae is identified as a priority pathogen due to its capacity to rapidly develop antimicrobial resistance (AMR). Following the easing of SARS-CoV-2 pandemic travel restrictions across international borders in the state of New South Wales (NSW), Australia, a surge of gonococcal isolates with raised ceftriaxone MIC values were detected. METHODS: All N. gonorrhoeae isolates (n = 150) with increased ceftriaxone MIC values in NSW between 1 January 2021 and July 2022 from males and females from all sites were sequenced. RESULTS: A new emergence and rapid expansion of an N. gonorrhoeae ST7827 clone was documented within NSW, Australia and provides further evidence of the ability of N. gonorrhoeae to undergo sufficient genomic changes and re-emerge as a geographically restricted subclone. Mapping AMR determinants to MIC results did not reveal any genomic pattern that correlated with MIC values. CONCLUSIONS: The rapid dissemination and establishment of this clone at the population level is a new and concerning demonstration of the agility of this pathogen, and underscores concerns about similar incursions and establishment of MDR clones. Moreover, it is notable that in this context the AMR genotype-phenotype correlates remain unclear, which requires further investigation to enable better understanding of genomic aspects of AMR in N. gonorrhoeae.

Hospital outbreak of New Delhi metallo-ß-lactamase type-1 (NDM-1) in Salmonella enterica with inter-species plasmid transmission.

New Delhi metallo-ß-lactamase (NDM) gene confers high-level resistance to an array of ß-lactams including carbapenems. Short- and long-read sequencing was used to investigate outbreaks of NDM-positive Enterobacterales including a potential horizontal gene transfer (HGT) event of an NDM-positive plasmid between Salmonella enterica and Klebsiella pneumoniae. Genomic analysis demonstrated a high degree of similarity between NDM-carrying plasmids from patient 1 in K. pneumoniae and patient 2 with S. enterica, K. pneumoniae and Klebsiella oxytoca, confirming an inter-species HGT event. The utility of whole-genome sequencing was demonstrated for in-hospital outbreaks, previously undetected using traditional infection-control surveillance.

Establishment of an AUC0-24 Threshold for Nephrotoxicity Is a Step towards Individualized Vancomycin Dosing for Methicillin-Resistant Staphylococcus aureus Bacteremia.

Unlike vancomycin trough concentrations, data on the utility of vancomycin pharmacokinetic (PK) parameters, namely, the area under the concentration-time curve from 0 to 24 h (AUC0-24), in predicting acute kidney injury (AKI) are limited. Our aim was to investigate this relationship in patients receiving vancomycin therapy for methicillin-resistant Staphylococcus aureus bacteremia (MRSA-B). A single-center retrospective observational cohort study involving 127 consecutive MRSA-B patients was conducted to examine the incidence of AKI (defined as serum creatinine of ≥0.5 mg/liter and a 50% increase from baseline) and vancomycin exposure parameters associated with nephrotoxicity. Bayesian estimation was used to predict individual vancomycin AUC0-24 All patients received vancomycin monotherapy for a minimum of 14 days following the diagnosis of MRSA-B. AKI was observed in 15.7% of patients (20/127). Clinical characteristics were similar between patients with and without AKI. At steady state, higher vancomycin trough concentrations were associated with AKI (17.2 mg/liter versus 13.1 mg/liter; P = 0.003). A vancomycin AUC0-24 threshold for AKI of >563 mg · h/liter was detected by classification and regression tree (CART) analysis; patients with exposures above this threshold were significantly more likely to experience AKI than patients with lower vancomycin exposures (40% [8/20] versus 11.2% [12/107]; P = 0.002). This parameter remained an independent predictor of AKI on multivariate logistic regression (odds ratio [OR], 5.07; 95% confidence interval [CI], 1.57 to 16.29; P = 0.006) and was a better predictor of nephrotoxicity than vancomycin trough concentrations. Overall, AKI is associated with higher vancomycin exposure as measured by AUC0-24 These results suggest that individualized patient dosing may be possible with dose modifications directed toward established pharmacodynamic targets while balancing AKI risks.

MALDI-TOF MS meets WGS in a VRE outbreak investigation.

The use of MALDI-TOF MS (matrix-assisted laser desorption/ ionization-time of flight mass spectrometry) and WGS (whole genome sequencing) has been described for identification and strain relatedness determination. We describe the complementary use of MALDI-TOF MS and WGS in a VRE (vancomycin-resistant enterococci) outbreak investigation, and discuss some of the challenges with defining strain similarity across these two platforms. Although both assays indicated multiple clusters involved in the outbreak of vancomycin resistant Enterococcus faecium isolates from positive blood cultures of four haematology-oncology patients, the small cohort and discrepancies between findings indicate the limitations of MALDI-TOF MS and the cautious interpretation of MALDI-TOF MS dendrograms during outbreaks. For definitive determination of the evolutionary distance between isolates, WGS can be used.

Mucormycosis in Australia: contemporary epidemiology and outcomes.

Mucormycosis is the second most common cause of invasive mould infection and causes disease in diverse hosts, including those who are immuno-competent. We conducted a multicentre retrospective study of proven and probable cases of mucormycosis diagnosed between 2004-2012 to determine the epidemiology and outcome determinants in Australia. Seventy-four cases were identified (63 proven, 11 probable). The majority (54.1%) were caused by Rhizopus spp. Patients who sustained trauma were more likely to have non-Rhizopus infections relative to patients without trauma (OR 9.0, p 0.001, 95% CI 2.1-42.8). Haematological malignancy (48.6%), chemotherapy (42.9%), corticosteroids (52.7%), diabetes mellitus (27%) and trauma (22.9%) were the most common co-morbidities or risk factors. Rheumatological/autoimmune disorders occurred in nine (12.1%) instances. Eight (10.8%) cases had no underlying co-morbidity and were more likely to have associated trauma (7/8; 87.5% versus 10/66; 15.2%; p <0.001). Disseminated infection was common (39.2%). Apophysomyces spp. and Saksenaea spp. caused infection in immuno-competent hosts, most frequently associated with trauma and affected sites other than lung and sinuses. The 180-day mortality was 56.7%. The strongest predictors of mortality were rheumatological/autoimmune disorder (OR = 24.0, p 0.038 95% CI 1.2-481.4), haematological malignancy (OR = 7.7, p 0.001, 95% CI 2.3-25.2) and admission to intensive care unit (OR = 4.2, p 0.02, 95% CI 1.3-13.8). Most deaths occurred within one month. Thereafter we observed divergence in survival between the haematological and non-haematological populations (p 0.006). The mortality of mucormycosis remains particularly high in the immuno-compromised host. Underlying rheumatological/autoimmune disorders are a previously under-appreciated risk for infection and poor outcome.

Survey of antifungal prophylaxis and fungal diagnostic tests employed in malignant haematology and haemopoietic stem cell transplantation (HSCT) in Australia and New Zealand.

This article reports the findings of a survey developed to assess the current use of antifungal prophylaxis among haematology and infectious disease clinicians across Australia and New Zealand, and their alignment with existing consensus guidelines for the use of antifungal agents in the haematology/oncology setting (published 2008). Surveyed clinicians largely followed the current recommendations for prophylaxis in the setting of induction chemotherapy for acute myeloid leukaemia, as well as autologous and low-risk allogeneic haemopoietic stem cell transplantation (HSCT). In keeping with guideline recommendations, posaconazole was the agent used by most centres for high-risk allogeneic HSCT. However, its routine continuation for 75-100 days post-transplantation without de-escalation suggested use beyond those indications described in the 2008 guidelines, namely pre-engraftment neutropenia and graft-versus-host disease. Variations in practice were observed in other settings, such as acute lymphoblastic leukaemia and myelodysplastic syndrome, reflecting the general lack of evidence for antifungal prophylaxis in these patient populations and changing perceptions of risk. With regard to the availability of testing in cases of suspected breakthrough IFD, 40% of centres did not have access to investigative bronchoscopy within 48 h of referral, and results of Aspergillus galactomannan (GM), fungal polymerase chain reaction and therapeutic drug monitoring (TDM) were not available within 48 h in 83%, 90% and 85% of centres respectively. The survey's findings will influence the recommendations provided in the updated 2014 consensus guidelines for the use of antifungal agents in the haematology/oncology setting.

Consensus guidelines for antifungal prophylaxis in haematological malignancy and haemopoietic stem cell transplantation, 2014.

There is a strong argument for the use of antifungal prophylaxis in high-risk patients given the significant mortality associated with invasive fungal disease, the late identification of these infections, and the availability of safe and well-tolerated prophylactic medications. Clinical decisions about which patients should receive prophylaxis and choice of antifungal agent should be guided by risk stratification, knowledge of local fungal epidemiology, the efficacy and tolerability profile of available agents, and estimates such as number needed to treat and number needed to harm. There have been substantial changes in practice since the 2008 guidelines were published. These include the availability of new medications and/or formulations, and a focus on refining and simplifying patient risk stratification. Used in context, these guidelines aim to assist clinicians in providing optimal preventive care to this vulnerable patient demographic.

Consensus guidelines for optimising antifungal drug delivery and monitoring to avoid toxicity and improve outcomes in patients with haematological malignancy, 2014.

Antifungal agents may be associated with significant toxicity or drug interactions leading to sub-therapeutic antifungal drug concentrations and poorer clinical outcomes for patients with haematological malignancy. These risks may be minimised by clinical assessment, laboratory monitoring, avoidance of particular drug combinations and dose modification. Specific measures, such as the optimal timing of oral drug administration in relation to meals, use of pre-hydration and electrolyte supplementation may also be required. Therapeutic drug monitoring (TDM) of antifungal agents is warranted, especially where non-compliance, non-linear pharmacokinetics, inadequate absorption, a narrow therapeutic window, suspected drug interaction or unexpected toxicity are encountered. Recommended indications for voriconazole and posaconazole TDM in the clinical management of haematology patients are provided. With emerging knowledge regarding the impact of pharmacogenomics upon metabolism of azole agents (particularly voriconazole), potential applications of pharmacogenomic evaluation to clinical practice are proposed.

Impact of source of infection and vancomycin AUC0-24/MICBMD targets on treatment failure in patients with methicillin-resistant Staphylococcus aureus bacteraemia.

Despite recent controversies about toxicity and reduced efficacy, vancomycin remains the current treatment of choice for methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia. The parameter associated with treatment success is the vancomycin 24-h area under concentration-time curve to MIC ratio (AUC0-24/MIC). We aimed to determine the utility of calculated AUCs and explore the optimal AUC0-24/MIC targets associated with treatment success. In this single-centre retrospective observational cohort study of 127 patients with MRSA bacteraemia, forty-five (35.4%) did not respond to vancomycin treatment. Patient characteristics were essentially the same between those who did not respond to vancomycin treatment and those with treatment success, with independent predictors of treatment failure being source of bacteraemia (odds ratio (OR), 4.29; 95% confidence interval (CI), 1.50-12.26; p 0.007) and not achieving an AUC0-24/MICBMD (using broth microdilution) target of ≥398 (OR, 11.4; 95% CI, 4.57-28.46; p< 0.001). Bacteraemic source-specific thresholds were observed with a higher AUC0-24/MICBMD target of 440 required for high-risk sources (e.g. infective endocarditis) compared with 330 for low-risk sources (line related bacteraemia). Overall treatment success in patients with MRSA bacteraemia was associated with a vancomycin AUC0-24/MICBMD target of ≥398, with source-specific targets observed. Future vancomycin practice guidelines will need to take into account MIC methodology, source of bacteraemia and patient populations prior to setting targets and monitoring recommendations.

Support for the EUCAST and revised CLSI fluconazole clinical breakpoints by Sensititre® YeastOne® for Candida albicans: a prospective observational cohort study.

OBJECTIVES: Species-specific clinical breakpoints (CBPs) for Candida spp. were established following consideration of clinical outcomes in patients with oesophageal candidiasis. We sought to further determine the validity of the current CBPs based on data from a prospective candidaemia study. PATIENTS AND METHODS: All Candida albicans candidaemia episodes in patients enrolled in the Australian Candidaemia Study and who were treated with fluconazole monotherapy were included. Fluconazole MICs were established using Sensititre(®) YeastOne(®). RESULTS: Two hundred and seventeen evaluable episodes were identified, 93.5% of which occurred in adult patients. Fluconazole was commenced within 72 h of blood culture positivity in 96.3% (209/217) of episodes. Fluconazole doses were appropriate in 89.9% (195/217) of episodes and the median duration of therapy was 14 days (IQR 8-21 days) for the whole cohort. The all-cause 30 day mortality was 19.8% (43/217), with 37.2% (16/43) of deaths attributed to candidaemia. Classification and regression tree (CART) analysis identified a fluconazole MIC target of ≥2 mg/L for infection-related mortality and ≥4 mg/L for overall 30 day mortality. Overall mortality was no different in episodes with isolates above or below the identified MIC target, although there was a trend towards significance (P = 0.051). On univariate analysis, infection-related mortality was significantly increased in C. albicans episodes with an MIC ≥2 mg/L compared with those below this MIC target (20.6% versus 4.9%; P = 0.001). This target remained an independent predictor of infection-related mortality (OR 8.2; 95% CI 2.3-29.7; P = 0.001). CONCLUSIONS: We observed a direct relationship between infection-related mortality and rising fluconazole MIC for C. albicans candidaemia; overall, the data support the EUCAST and revised CLSI fluconazole clinical breakpoints.

Systematic review and meta-analysis of vancomycin-induced nephrotoxicity associated with dosing schedules that maintain troughs between 15 and 20 milligrams per liter.

In an effort to maximize outcomes, recent expert guidelines recommend more-intensive vancomycin dosing schedules to maintain vancomycin troughs between 15 and 20 mg/liter. The widespread use of these more-intensive regimens has been associated with an increase in vancomycin-induced nephrotoxicity reports. The purpose of this systematic literature review is to determine the nephrotoxicity potential of maintaining higher troughs in clinical practice. All studies pertaining to vancomycin-induced nephrotoxicity between 1996 and April 2012 were identified from PubMed, Embase, Cochrane Controlled Trial Registry, and Medline databases and analyzed according to Cochrane guidelines. Of the initial 240 studies identified, 38 were reviewed, and 15 studies met the inclusion criteria. Overall, higher troughs (≥ 15 mg/liter) were associated with increased odds of nephrotoxicity (odds ratio [OR], 2.67; 95% confidence interval [CI], 1.95 to 3.65) relative to lower troughs of <15 mg/liter. The relationship between a trough of ≥ 15 mg/liter and nephrotoxicity persisted when the analysis was restricted to studies that examined only initial trough concentrations (OR, 3.12; 95% CI, 1.81 to 5.37). The relationship between troughs of ≥ 15 mg/liter and nephrotoxicity persisted after adjustment for covariates known to independently increase the risk of a nephrotoxicity event. An incremental increase in nephrotoxicity was also observed with longer durations of vancomycin administration. Vancomycin-induced nephrotoxicity was reversible in the majority of cases, with short-term dialysis required only in 3% of nephrotoxic episodes. The collective literature indicates that an exposure-nephrotoxicity relationship for vancomycin exists. The probability of a nephrotoxic event increased as a function of the trough concentration and duration of therapy.

Vancomycin therapeutics and monitoring: a contemporary approach.

Vancomycin remains a clinically useful antibiotic despite the advent of several alternative drugs. Optimising vancomycin therapy with therapeutic drug monitoring is widely recommended. The aim of therapeutic drug monitoring is to help the clinician to achieve target pharmacodynamic parameters in the case of vancomycin, an area under the concentration time curve/minimum inhibitory concentration ratio of ≥400. Vancomycin monitoring methods can be categorised into four categories: empiric trough concentrations; linear regression analysis (one-compartment model), population methods and Bayesian estimation procedures. Although the empiric trough concentrations and population methods are easy to use and require minimal resources, there are large differences in the published vancomycin model parameters. This demonstrates that there is great variance in pharmacokinetic parameters between the models and a single vancomycin model cannot be applied to all patient populations. The linear regression and Bayesian methods recommended more accurate dosage regimens; however, they require additional resources such as information technology and healthcare personnel with background training in pharmacokinetics. The Bayesian methods offered additional advantages such as calculation of doses based on a single-serum concentration and optimisation of the patient's previous pharmacokinetic data to determine subsequent dosage regimens. Computerised programs, utilising the Bayesian estimation procedures, are able to achieve target concentrations in a greater percentage of patients earlier in the course of therapy than the empiric trough concentrations and population methods. We recommend the use of these programs providing there is appropriate expertise available to make appropriate recommendations.

Carriage of an ACME II variant may have contributed to methicillin-resistant Staphylococcus aureus sequence type 239-like strain replacement in Liverpool Hospital, Sydney, Australia.

Approximately 39% of methicillin-resistant Staphylococcus aureus (MRSA) sequence type 239 (ST239)-like bloodstream isolates from Liverpool Hospital (obtained between 1997 and 2008) carry an arginine catabolic mobile element (ACME). Whole-genome sequencing revealed that an ACME II variant is located between orfX and SCCmec III, and based on pulsed-field gel electrophoresis patterns and temporal relationships of all ST239-like isolates (n = 360), ACME carriage may have contributed to subpulsotype strain replacement.

The clinical significance of vancomycin minimum inhibitory concentration in Staphylococcus aureus infections: a systematic review and meta-analysis.

BACKGROUND: Emerging data suggest that vancomycin may be less effective against serious methicillin-resistant Staphylococcus aureus (MRSA) infections with minimum inhibitory concentration (MIC) values at the higher end of the susceptibility range. The purpose of this review is to examine the strength of these associations. METHODS: All relevant studies pertaining to treatment outcomes or mortality associated with vancomycin MIC were retrieved from the medical literature from January 1996 through August 2011 and analyzed according to Cochrane guidelines. RESULTS: Of the 270 studies identified, 48 studies were reviewed, with 22 studies included in the final meta-analysis. Vancomycin MIC was significantly associated with mortality for MRSA infection irrespective of the source of infection or MIC methodology (odds ratio [OR], 1.64; 95% confidence interval [CI], 1.14-2.37; P < .01). This mortality association was predominantly driven by bloodstream infections (BSIs; OR, 1.58; 95% CI, 1.06-2.37; P = .03) and isolates with a vancomycin MIC of 2 µg/mL by Etest (OR, 1.72; 95% CI, 1.34-2.21; P < .01). Vancomycin MIC was significantly associated with treatment failure irrespective of source of infection or MIC methodology (OR, 2.69; 95% CI, 1.60-4.51; P < .01). CONCLUSION: High vancomycin MIC was associated with a higher mortality rate in MRSA BSI. Thus, institutions should consider conducting Etest MICs on all MRSA BSI isolates. Although these data highlight concerns about vancomycin, currently, there are no data to support better survival rates with alternative antibiotics. Data are sorely needed to determine whether other agents can remedy these outcomes observed with vancomycin for MRSA infections with elevated vancomycin MIC values.

Emergence of daptomycin resistance following vancomycin-unresponsive Staphylococcus aureus bacteraemia in a daptomycin-naïve patient--a review of the literature.

A patient developed a daptomycin-resistant methicillin-resistant Staphylococcus aureus (MRSA) infection, despite being daptomycin-naïve, in the setting of persistent bacteraemia secondary to vertebral osteomyelitis. Modified population analysis profiling of sequential MRSA blood culture isolates revealed transition from a vancomycin-susceptible phenotype to a vancomycin-intermediate S. aureus (VISA) phenotype through a vancomycin-heteroresistant S. aureus (hVISA) intermediary. Increased cell wall thickening, determined by transmission electron microscopy, correlated with the emergence of daptomycin resistance. This case supports the current hypothesis that MRSA with reduced glycopeptide susceptibility are less susceptible to daptomycin because of a thickened cell wall. This may have significance for the use of daptomycin in salvage therapy. Other predictors of daptomycin resistance include bacteraemic persistence and the presence of high inoculum infections. As resistance may appear de novo and be unstable in vivo, all isolates should have daptomycin susceptibility testing performed. The optimal antibiotic option for salvage therapy of these daptomycin-resistant infections is unknown. However, these findings emphasise the importance of optimising management, including the consideration of early surgical intervention to avoid the emergence of daptomycin resistance, especially in high inoculum infections.

Voriconazole concentrations and outcome of invasive fungal infections.

Twenty-five patients with proven or probable invasive fungal infections (IFIs) who experienced two or more episodes of voriconazole therapeutic drug monitoring (TDM) at a tertiary referral hospital were reviewed to explore the association between serum trough concentrations and outcomes of IFI. Microbiological and/or clinical success, in addition to IFI-related mortality, was assessed. We performed two separate analyses, one based on the initial trough voriconazole concentration at steady state, and the other on the median trough voriconazole concentration (derived from repeated TDM episodes) for each patient. Large interpatient and intrapatient variability of trough plasma voriconazole concentrations was observed, with no correlation between dose and concentration (r = 0.065). Classification and regression tree analysis revealed an association between IFI-related mortality and initial trough voriconazole concentrations, with patients more likely to die when their initial steady-state concentration was ≤0.35 mg/L (p 0.004; OR 11, 95% CI 2.9-41.2). Successful outcomes were more likely among patients with a median trough voriconazole concentration >2.2 mg/L (p 0.003; OR 2.7, 95% CI 1.4-5). Nineteen adverse events, with four severe events, were documented in 14 patients. Patients with severe adverse events had higher median voriconazole concentrations than the remaining cohort (2.38 mg/L vs. 1.30 mg/L; p <0.04). All adverse events resolved after cessation of voriconazole treatment. Our data suggest that voriconazole TDM is appropriate for all patients as soon as steady state is achieved. For non-responding patients with low trough concentrations, the association with IFI-related mortality indicates the need for dose adjustments to achieve and sustain voriconazole concentrations.

Candidemia following solid organ transplantation in the era of antifungal prophylaxis: the Australian experience.

Solid organ transplant (SOT) recipients have high rates of invasive fungal infections, with Candida species the most commonly isolated fungi. The aim of this study was to identify differences between incidence rates, risk factors, clinical presentations, and outcomes of candidemia in SOT recipients and non-SOT patients. Data from the multicenter prospective Australian Candidaemia Study were examined. From August 2001 to July 2004, 24 episodes (2.2%; 24/1068) of candidemia were identified in SOT recipients. During this period, the numbers of transplanted organs included liver (n=455), kidney (n=1605), single lung (n=57), bilateral lung (n=183), heart and lung (n=18), heart (n=157), and pancreas (n=62). The overall annual estimated incidence of candidemia in SOT recipients was higher (3 per 1000 transplant admissions) than in non-SOT patients (incidence 0.21 per 1000 admissions; P<0.001). The incidence and timing of candidemia post transplant was influenced by the transplanted organ type, with the majority of episodes (n=14, 54%) occurring >6 months after renal transplantation. Risk factors for candidemia in the month preceding diagnosis were similar to non-SOT recipients except for corticosteroid therapy (P<0.001). Antifungal prophylaxis did not select for more resistant or non-albicans Candida species in the SOT group. The 30-day all-cause mortality was similar to non-SOT patients with candidemia and remains high at 21%. All deaths in SOT recipients occurred early (within 5 days of diagnosis), underlining a need for better diagnostic tests, targeted prevention, and early treatment strategies.