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.

Using Artificial Intelligence to Predict Intracranial Hypertension in Patients After Traumatic Brain Injury: A Systematic Review.

Intracranial hypertension (IH) is a key driver of secondary brain injury in patients with traumatic brain injury. Lowering intracranial pressure (ICP) as soon as IH occurs is important, but a preemptive approach would be more beneficial. We systematically reviewed the artificial intelligence (AI) models, variables, performances, risks of bias, and clinical machine learning (ML) readiness levels of IH prediction models using AI. We conducted a systematic search until 12-03-2023 in three databases. Only studies predicting IH or ICP in patients with traumatic brain injury with a validation of the AI model were included. We extracted type of AI model, prediction variables, model performance, validation type, and prediction window length. Risk of bias was assessed with the Prediction Model Risk of Bias Assessment Tool, and we determined the clinical ML readiness level. Eleven out of 399 nonduplicate publications were included. A gaussian processes model using ICP and mean arterial pressure was most common. The maximum reported area under the receiver operating characteristic curve was 0.94. Four studies conducted external validation, and one study a prospective clinical validation. The prediction window length preceding IH varied between 30 and 60 min. Most studies (73%) had high risk of bias. The highest clinical ML readiness level was 6 of 9, indicating "real-time model testing" stage in one study. Several IH prediction models using AI performed well, were externally validated, and appeared ready to be tested in the clinical workflow (clinical ML readiness level 5 of 9). A Gaussian processes model was most used, and ICP and mean arterial pressure were frequently used variables. However, most studies showed a high risk of bias. Our findings may help position AI for IH prediction on the path to ultimate clinical integration and thereby guide researchers plan and design future studies.

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.

Molecular typing of enteroviruses: comparing 5'UTR, VP1 and whole genome sequencing methods.

Enteroviruses (EV) commonly cause hand, foot and mouth disease (HFMD), and can also cause potentially fatal neurological and systemic complications. In our laboratory, sequencing 5' untranslated region (UTR) of the viral genome has been the routine method of genotyping EVs. During a recent localised outbreak of aseptic meningitis, sequencing the 5'UTR identified the causative virus as EV-A71, which did not fit with the clinical syndrome or illness severity. When genotyped using a different target gene, VP1, the result was different. This led us to evaluate the accuracy of the two different target genome regions and compare them against whole genome sequencing (WGS). We aimed to optimise the algorithm for detection and characterisation of EVs in the diagnostic laboratory. We hypothesised that VP1 and WGS genotyping would provide different results than 5'UTR in a subset of samples. Clinical samples from around New South Wales which were positive for EV by commercial polymerase chain reaction (PCR) assays were genotyped by targeting three different viral genome regions: the 5'UTR, VP1 and WGS. Sequencing was performed by Sanger and next generation sequencing. The subtyping results were compared. Of the 74/118 (63%) samples that were successfully typed using both the 5'UTR and the VP1 method, the EV typing result was identical for 46/74 (62%) samples compared to WGS as the gold standard. The same EV group but different EV types were found in 22/74 (30%) samples, and 6/74 (8%) samples belonged to different EV groups depending on typing method used. Genotyping with WGS and VP1 is more accurate than 5'UTR. Genotyping by the 5'UTR method is very sensitive, but less specific.

Multidrug-resistant OXA-48/CTX-M-15 Klebsiella pneumoniae cluster in a COVID-19 intensive care unit: salient lessons for infection prevention and control during the COVID-19 pandemic.

BACKGROUND: Wards caring for COVID-19 patients, including intensive care units (ICUs), have an important focus on preventing transmission of SARS-CoV-2 to other patients and healthcare workers. AIM: To describe an outbreak of carbapenemase-producing Enterobacterales (CPE) in a COVID-19 ICU and to discuss key infection control measures enabling prompt termination of the cluster. METHODS: CPE were isolated from clinical specimens and screening swabs from intensive care patients with COVID-19 disease and from environmental screening. Whole-genome sequencing analysis was instrumental in informing phylogenetic relationships. FINDINGS: Seven clinical isolates and one environmental carbapenemase-producing Klebsiella pneumoniae isolate - all carrying OXA-48, CTX-M-15 and outer membrane porin mutations in ompK35/ompK36 - were identified with ≤1 single nucleotide polymorphism difference, indicative of clonality. A bundle of infection control interventions including careful adherence with contact precautions and hand hygiene, twice weekly screening for multidrug-resistant organisms, strict antimicrobial stewardship, and enhanced cleaning protocols promptly terminated the outbreak. CONCLUSION: Prolonged use of personal protective equipment is common with donning and doffing stations at the ward entrance, leaving healthcare workers prone to reduced hand hygiene practices between patients. Minimizing transmission of pathogens other than SARS-CoV-2 by careful adherence to normal contact precautions including hand hygiene, even during high patient contact manoeuvres, is critical to prevent outbreaks of multidrug-resistant organisms. Appropriate antimicrobial stewardship and screening for multidrug-resistant organisms must also be maintained throughout surge periods to prevent medium-term escalation in antimicrobial resistance rates. Whole-genome sequencing is highly informative for multidrug-resistant Enterobacterales surveillance strategies.

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.

Voriconazole plus terbinafine combination antifungal therapy for invasive Lomentospora prolificans infections: analysis of 41 patients from the FungiScope® registry 2008-2019.

OBJECTIVES: Lomentospora prolificans is an emerging cause of serious invasive fungal infections. Optimal treatment of these infections is unknown, although voriconazole-containing treatment regimens are considered the treatment of choice. The objective of this study was to evaluate the role of combination antifungal therapy for L. prolificans infections. METHODS: We performed a retrospective review of medical records of patients with invasive L. prolificans infection diagnosed between 1 January 2008 and 9 September 2019 that were documented in the FungiScope® registry of rare invasive fungal infections. We compared clinical outcomes between antifungal treatment strategies. RESULTS: Over the study period, 41 individuals with invasive L. prolificans infection from eight different countries were documented in the FungiScope® registry. Overall, 17/40 (43%) had treatment response/stable disease and 21/40 (53%) had a fatal outcome attributed to invasive fungal infection. Combination antifungal therapy was associated with increased 28-day survival (15/24 survived versus 4/16 receiving monotherapy; p 0.027) and the combination voriconazole plus terbinafine trended to be associated with higher rates of treatment success (10/16, 63%, 95% CI 35%-85%) compared with other antifungal treatment regimens (7/24, 29%, 95% CI 13%-51%, p 0.053). In Kaplan-Meier survival analysis there was a higher survival probability in individuals receiving the voriconazole/terbinafine combination compared with other antifungal regimens (median survival 150 days versus 17 days). CONCLUSIONS: While overall mortality was high, combination antifungal treatment, and in particular combination therapy with voriconazole plus terbinafine may be associated with improved treatment outcomes compared with other antifungal regimens for the treatment of invasive L. prolificans infections.

Candidaemia and a risk predictive model for overall mortality: a prospective multicentre study.

BACKGROUND: Candidaemia is associated with high mortality. Variables associated with mortality have been published previously, but not developed into a risk predictive model for mortality. We sought to describe the current epidemiology of candidaemia in Australia, analyse predictors of 30-day all-cause mortality, and develop and validate a mortality risk predictive model. METHODS: Adults with candidaemia were studied prospectively over 12 months at eight institutions. Clinical and laboratory variables at time of blood culture-positivity were subject to multivariate analysis for association with 30-day all-cause mortality. A predictive score for mortality was examined by area under receiver operator characteristic curves and a historical data set was used for validation. RESULTS: The median age of 133 patients with candidaemia was 62 years; 76 (57%) were male and 57 (43%) were female. Co-morbidities included underlying haematologic malignancy (n = 20; 15%), and solid organ malignancy in (n = 25; 19%); 55 (41%) were in an intensive care unit (ICU). Non-albicans Candida spp. accounted for 61% of cases (81/133). All-cause 30-day mortality was 31%. A gastrointestinal or unknown source was associated with higher overall mortality than an intravascular or urologic source (p < 0.01). A risk predictive score based on age > 65 years, ICU admission, chronic organ dysfunction, preceding surgery within 30 days, haematological malignancy, source of candidaemia and antibiotic therapy for ≥10 days stratified patients into < 20% or ≥ 20% predicted mortality. The model retained accuracy when validated against a historical dataset (n = 741). CONCLUSIONS: Mortality in patients with candidaemia remains high. A simple mortality risk predictive score stratifying patients with candidaemia into < 20% and ≥ 20% 30-day mortality is presented. This model uses information available at time of candidaemia diagnosis is easy to incorporate into decision support systems. Further validation of this model is warranted.

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.

Clinical effectiveness of itraconazole as antifungal prophylaxis in AML patients undergoing intensive chemotherapy in the modern era.

Antifungal prophylaxis regimens vary between centres, informed by local epidemiology and antifungal stewardship practices. The advantages of itraconazole over posaconazole prophylaxis include maintaining the utility of azole therapy for suspected breakthrough invasive fungal infection (bIFI). We examined the effectiveness and tolerability of itraconazole as prophylaxis in acute myeloid leukaemia (AML) patients. We sought to determine the rate of probable and proven bIFI in the context of itraconazole prophylaxis in a real-life setting. Eighty-four patients corresponded to 175 episodes of primary antifungal prophylaxis with itraconazole solution (200 mg twice daily) as prophylaxis supported by a dedicated clinical pharmacist during induction, re-induction and consolidation chemotherapy for AML between January 2010 and January 2014. Assessment of clinical course included blinded review of all radiology scans. Episodes of bIFI were categorised according to consensus criteria. A low rate of bIFI (6/175, 3.4 %) occurred with the use of itraconazole. Tolerance was excellent with adverse events consisting predominantly of deranged liver function tests reported in 7/175 (4 %). Therapeutic drug monitoring performed at clinicians' discretion demonstrated appropriate levels in 12/14 (86 %). Persisting fever and suspicion of invasive fungal infection (IFI) led to empiric antifungal therapy with voriconazole or caspofungin in 33/175 episodes (19 %), ceased after a median of 5 days following investigation in 16/175 (9 %). In this setting, itraconazole is effective and well-tolerated as prophylaxis. An additional benefit was seen in empiric therapy of suspected bIFI with amphotericin formulations kept in reserve. Local epidemiology is vital in guiding prophylaxis strategy.

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.

Combination antibiotic treatment of serious methicillin-resistant Staphylococcus aureus infections.

Outcomes from methicillin-resistant Staphylococcus aureus (MRSA) infections are relatively poor, at least in part due to the limitations of vancomycin (the current standard treatment for MRSA). Combination antibiotic treatment for MRSA infections is an attractive alternative as it could address most of vancomycin's shortcomings, including poor tissue penetration, slow bacterial killing, and emerging resistance in some strains of MRSA. However, the theoretical promise of combination therapy for MRSA infections has not been borne out in most in vitro and animal studies. Multiple combinations have been tested and have been either antagonistic, indifferent, or have had conflicting findings in various studies. This includes combinations of two primarily active agents (such as vancomycin plus daptomycin or linezolid), or the addition of gentamicin or rifampin to either vancomycin or daptomycin. However, hope on this front has come from an unexpected quarter. Although MRSA is by definition inherently resistant to nearly all ß-lactam antibiotics, this class of drugs has consistently shown evidence of synergy with either daptomycin or vancomycin in over 25 separate in vitro studies, and a limited number of animal and human observational studies. However, there are currently insufficient data to recommend ß-lactam combination therapy in routine clinical use. Results of current and planned randomized controlled trials of this strategy are awaited.

Invasive infections due to filamentous fungi other than Aspergillus: epidemiology and determinants of mortality.

The epidemiology of invasive fungal disease (IFD) due to filamentous fungi other than Aspergillus may be changing. We analysed clinical, microbiological and outcome data in Australian patients to determine the predisposing factors and identify determinants of mortality. Proven and probable non-Aspergillus mould infections (defined according to modified European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria) from 2004 to 2012 were evaluated in a multicentre study. Variables associated with infection and mortality were determined. Of 162 episodes of non-Aspergillus IFD, 145 (89.5%) were proven infections and 17 (10.5%) were probable infections. The pathogens included 29 fungal species/species complexes; mucormycetes (45.7%) and Scedosporium species (33.3%) were most common. The commonest comorbidities were haematological malignancies (HMs) (46.3%) diabetes mellitus (23.5%), and chronic pulmonary disease (16%); antecedent trauma was present in 21% of cases. Twenty-five (15.4%) patients had no immunocompromised status or comorbidity, and were more likely to have acquired infection following major trauma (p <0.01); 61 (37.7%) of cases affected patients without HMs or transplantation. Antifungal therapy was administered to 93.2% of patients (median 68 days, interquartile range 19-275), and adjunctive surgery was performed in 58.6%. The all-cause 90-day mortality was 44.4%; HMs and intensive-care admission were the strongest predictors of death (both p <0.001). Survival varied by fungal group, with the risk of death being significantly lower in patients with dematiaceous mould infections than in patients with other non-Aspergillus mould infections. Non-Aspergillus IFD affected diverse patient groups, including non-immunocompromised hosts and those outside traditional risk groups; therefore, definitions of IFD in these patients are required. Given the high mortality, increased recognition of infections and accurate identification of the causative agent are required.

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.