LInezolid Monitoring to MInimise Toxicity (LIMMIT1): A multicentre retrospective review of patients receiving linezolid therapy and the impact of therapeutic drug monitoring.

BACKGROUND: Linezolid is a broad-spectrum antimicrobial with limited use due to toxicity. This study aimed to evaluate linezolid toxicity in a large multicentre cohort. Secondary objectives were to identify factors contributing to toxicity, including the impact of therapeutic drug monitoring (TDM). METHODS: Patients administered linezolid between January 2017 and December 2019 were retrospectively reviewed. Data were collected on patient characteristics, linezolid therapy and outcomes. Descriptive statistics were performed on all patients, and statistical comparisons were undertaken between those who did and did not experience linezolid toxicity. A multivariable logistic regression model was constructed to identify any covariates that correlated with toxicity. RESULTS: Linezolid was administered to 1050 patients; of these, 381 did not meet the inclusion criteria and 47 were excluded as therapy ceased for non-toxicity reasons. There were 105 of 622 (16.9%) patients assessed to have linezolid toxicity. Patients who experienced toxicity displayed a higher baseline creatinine (96.5 µmol/L vs. 79 µmol/L; P = 0.025), lower baseline platelet count (225 × 109/L vs. 278.5 × 109/L; P = 0.002) and received a longer course (median 21 vs. 14 days; P < 0.001) than those who did not. Linezolid TDM was performed in 144 patients (23%). Multivariable logistic regression demonstrated that TDM-guided appropriate dose adjustment significantly reduced the odds of linezolid toxicity (aOR = 0.45; 95% CI 0.21-0.96; P = 0.038) and a treatment duration > 28 days was no longer significantly associated with toxicity. CONCLUSIONS: This study confirmed that linezolid treatment-limiting toxicity remains a problem and suggests that TDM-guided dose optimisation may reduce the risk of toxicity and facilitate prolonged courses beyond 28 days.

Emerging therapeutic drug monitoring of anti-infective agents in Australian hospitals: Availability, performance and barriers to implementation.

AIMS: The purpose of the study was to assess the status of emerging therapeutic drug monitoring (TDM) of anti-infective agents in Australian hospitals. METHODS: A nationwide cross-sectional survey of all Australian hospitals operating in the public and private health sector was conducted between August and September 2019. The survey consisted of questions regarding institutional TDM practice for anti-infective agents and clinical vignettes specific to ß-lactam antibiotics. RESULTS: Responses were received from 82 unique institutions, representing all Australian states and territories. All 29 (100%) of principal referral (major) hospitals in Australia participated. Five surveys were partially complete. Only 25% (20/80) of hospitals had TDM testing available on-site for any of the eight emerging TDM candidates considered: ß-lactam antibiotics, anti-tuberculous agents, flucytosine, fluoroquinolones, ganciclovir, human immunodeficiency virus (HIV) drugs, linezolid and teicoplanin. A considerable time lag was noted between TDM sampling and reporting of results. With respect to ß-lactam antibiotic TDM, variable indications, pharmacodynamic targets and sampling times were identified. The three greatest barriers to local TDM performance were found to be (1) lack of timely assays/results, (2) lack of institutional-wide expertise and/or training and (3) lack of guidelines to inform ordering of TDM and interpretation of results. The majority of respondents favoured establishing national TDM guidelines and increasing access to dose prediction software, at rates of 89% and 96%, respectively. CONCLUSION: Translating emerging TDM evidence into daily clinical practice is slow. Concerted efforts are required to address the barriers identified and facilitate the implementation of standardised practice.

Consensus guidelines for optimising antifungal drug delivery and monitoring to avoid toxicity and improve outcomes in patients with haematological malignancy and haemopoietic stem cell transplant recipients, 2021.

Antifungal agents can have complex dosing and the potential for drug interaction, both of which can lead to subtherapeutic antifungal drug concentrations and poorer clinical outcomes for patients with haematological malignancy and haemopoietic stem cell transplant recipients. Antifungal agents can also be associated with significant toxicities when drug concentrations are too high. Suboptimal dosing can be minimised by clinical assessment, laboratory monitoring, avoidance of interacting drugs, and dose modification. Therapeutic drug monitoring (TDM) plays an increasingly important role in antifungal therapy, particularly for antifungal agents that have an established exposure-response relationship with either a narrow therapeutic window, large dose-exposure variability, cytochrome P450 gene polymorphism affecting drug metabolism, the presence of antifungal drug interactions or unexpected toxicity, and/or concerns for non-compliance or inadequate absorption of oral antifungals. These guidelines provide recommendations on antifungal drug monitoring and TDM-guided dosing adjustment for selected antifungal agents, and include suggested resources for identifying and analysing antifungal drug interactions. Recommended competencies for optimal interpretation of antifungal TDM and dose recommendations are also provided.

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.

Therapeutic drug monitoring of commonly used anti-infective agents: A nationwide cross-sectional survey of Australian hospital practices.

When performed according to best-practice principles, therapeutic drug monitoring (TDM) can optimise anti-infective treatment and directly benefit clinical outcomes. We evaluated TDM performance and clinical decision-making for established anti-infective agents amongst Australian hospitals. A nationwide cross-sectional survey was conducted between August and September 2019. The survey consisted of multiple-choice questions regarding TDM of anti-infective agents in general as well as clinical vignettes specific to vancomycin, gentamicin and voriconazole. We sought to survey all Australian hospitals operating both in the public and private health sectors. Responses were captured from 85 unique institutions, from all Australian states and territories. Regarding guidelines, 26% of hospitals did not have endorsed guidelines to advise on the ordering, sampling and interpretation of TDM for any anti-infective agent. Admitting teams were predominantly responsible for ordering TDM (85%) and interpreting results (76%). Only 51% of hospitals had access to dose prediction software, with access generally better amongst principal referral (69%) (P = 0.01) and children's hospitals (100%) (P = 0.04). Whenever a laboratory-derived minimum inhibitory concentration (MIC) was not available to guide dosing decisions, a surrogate target MIC was assumed in 77% of hospitals. This was based on a 'worst-case' scenario infection in 11% of hospitals. The rates of clinical practice consistent with current guideline recommendations across all aspects of TDM were demonstrated to be 0% for vancomycin, 4% for gentamicin and 35% for voriconazole. At present, there is significant institutional variability in the clinical practice of TDM for anti-infective agents in Australia for established TDM drugs.

Antimicrobial stewardship in remote primary healthcare across northern Australia.

BACKGROUND: The high burden of infectious disease and associated antimicrobial use likely contribute to the emergence of antimicrobial resistance in remote Australian Aboriginal communities. We aimed to develop and apply context-specific tools to audit antimicrobial use in the remote primary healthcare setting. METHODS: We adapted the General Practice version of the National Antimicrobial Prescribing Survey (GP NAPS) tool to audit antimicrobial use over 2-3 weeks in 15 remote primary healthcare clinics across the Kimberley region of Western Australia (03/2018-06/2018), Top End of the Northern Territory (08/2017-09/2017) and far north Queensland (05/2018-06/2018). At each clinic we reviewed consecutive clinic presentations until 30 presentations where antimicrobials had been used were included in the audit. Data recorded included the antimicrobials used, indications and treating health professional. We assessed the appropriateness of antimicrobial use and functionality of the tool. RESULTS: We audited the use of 668 antimicrobials. Skin and soft tissue infections were the dominant treatment indications (WA: 35%; NT: 29%; QLD: 40%). Compared with other settings in Australia, narrow spectrum antimicrobials like benzathine benzylpenicillin were commonly given and the appropriateness of use was high (WA: 91%; NT: 82%; QLD: 65%). While the audit was informative, non-integration with practice software made the process manually intensive. CONCLUSIONS: Patterns of antimicrobial use in remote primary care are different from other settings in Australia. The adapted GP NAPS tool functioned well in this pilot study and has the potential for integration into clinical care. Regular stewardship audits would be facilitated by improved data extraction systems.

Two carbapenemase-producing Enterobacteriaceae outbreaks detected retrospectively by whole-genome sequencing at an Australian tertiary hospital.

In 2014, two genetically-linked cases of carbapenemase-producing Enterobacteriaceae (CPE) were detected at the Canberra Hospital (TCH), prompting an investigation and response that appeared to contain transmission. We report a 2017 retrospective investigation into cases of CPE in the Australian Capital Territory (ACT) that aimed to identify clusters and transmission mechanisms. Cases detected between 2012 and 2016 were identified from the hospital laboratory information system. Whole-genome sequencing (WGS) was performed retrospectively on stored isolates. Seventy-two cases were identified, with nearly 90% of isolates containing blaIMP genes. Using multilocus sequence type (ST) data, we identified two small outbreaks of CPE containing blaIMP-4 (Enterobacter cloacae complex ST24, n = 7; Citrobacter freundii ST8, n = 10), each spanning over three years. Epidemiological and environmental evidence implicate environmental reservoirs and carriers undetected by routine infection prevention and control investigations.

Vancomycin-resistant Enterococcus (VRE) outbreak in a neonatal intensive care unit and special care nursery at a tertiary-care hospital in Australia-A retrospective case-control study.

OBJECTIVE: We investigated the risk factors and origins of the first known occurrence of VRE colonization in the neonatal intensive care unit (NICU) at the Canberra Hospital. DESIGN: A retrospective case-control study. SETTING: A 21-bed neonatal intensive care unit (NICU) and a 15-bed special care nursey (SCN) in a tertiary-care adult and pediatric hospital in Australia. PATIENTS: All patients admitted to the NICU and SCN over the outbreak period: January-May 2017. Of these, 14 were colonized with vancomycin-resistant Enterococcus (VRE) and 77 were noncolonized. METHODS: Demographic and clinical variables of cases and controls were compared to evaluate potential risk factors for VRE colonization. Whole-genome sequencing of the VRE isolates was used to determine the origin of the outbreak strain. RESULTS: Swift implementation of wide-ranging infection control measures brought the outbreak under control. Multivariate logistic regression revealed a strong association between early gestational age and VRE colonization (odds ratio [OR], 3.68; 95% confidence interval [CI], 1.94-7.00). Whole-genome sequencing showed the isolates to be highly clonal Enterococcus faecium ST1421 harboring a vanA gene and to be closely related to other ST1421 previously sequenced from the Canberra Hospital and the Australian Capital Territory. CONCLUSION: The colonization of NICU patients was with a highly successful clone endemic to the Canberra Hospital likely introduced into the NICU environment from other wards, with subsequent cross-contamination spreading among the neonate patients. Use of routine surveillance screening may have identified colonization at an earlier stage and have now been implemented on a 6-monthly schedule.

Chlorhexidine washing in intensive care does not reduce bloodstream infections, blood culture contamination and drug-resistant microorganism acquisition: an interrupted time series analysis.

BACKGROUND: Health care-associated infections are a major cause of morbidity and mortality in intensive care patients. The effect of daily washing with chlorhexidine on these infections is controversial. METHODS: Single-centre, retrospective, open-label, sequential period, interrupted time series (ITS) analysis in a 31-bed tertiary referral mixed intensive care unit (ICU), comparing daily washing with water and soap (from January 2011 to August 2013) with chlorhexidine washing (from November 2013 to December 2015), after the introduction of a unit-level policy of chlorhexidine washing. All patients in the ICU were included in the study, except: if they were under 18 years of age, if their ICU stay was less than 24 hours (to ensure that all studied patients had at least one exposure to the daily wash intervention), or if patients had a known allergy to chlorhexidine. Outcome measures included: clinically significant positive blood cultures attributable to the ICU stay; contaminated blood cultures; newly acquired multidrug-resistant microorganisms (MDRO) such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococcus (VRE) or multidrug-resistant gram-negative (MRGN) isolates attributable to ICU from clinical and screening cultures; and newly acquired Clostridium difficile infections (CDIs). Incidence rates of these outcomes were calculated per 1000 patient days. MDRO acquisition rates were corrected for background hospital period prevalence rates of MDRO. RESULTS: A total of 6634 patients were included in the study. ITS analysis showed no significant level or slope changes in any of the outcome measures after implementation of chlorhexidine washing. The incidence rate of clinically significant positive blood cultures during the chlorhexidine period compared with the water and soap period was 3.6 v 4.7 (P =0.37); blood culture contamination rates were 11.8 v 9.5 (P =0.56); incidence rates of new ICU-associated MDRO acquisitions were 3.22 v 3.69 (P =0.27); incidence rates of new CDI were 2.01 v 0.79 (P =0.16). Outcomes after adjustment for known and potential confounders were similar. CONCLUSIONS: In this real-world, long term ICU study, implementation of a unit-level policy of daily washing with chlorhexidine impregnated cloths was not associated with a reduction in the rates of ICU-associated clinically significant positive blood cultures, blood culture contamination, newly acquired MDRO isolates, and CDIs.

Antifungal susceptibilities of non-Aspergillus filamentous fungi causing invasive infection in Australia: support for current antifungal guideline recommendations.

Antifungal susceptibilities of non-Aspergillus filamentous fungal pathogens cannot always be inferred from their identification. Here we determined, using the Sensititre(®) YeastOne(®) YO10 panel, the in vitro activities of nine antifungal agents against 52 clinical isolates of emergent non-Aspergillus moulds representing 17 fungal groups in Australia. Isolates comprised Mucorales (n = 14), Scedosporium/Lomentospora spp. (n = 18) and a range of hyaline hyphomycetes (n = 9) and other dematiaceous fungi (n = 11). Excluding Verruconis gallopava, echinocandins demonstrated poor activity (MICs generally >8 mg/L) against these moulds. Lomentospora prolificans (n = 4) and Fusarium spp. (n = 6) demonstrated raised MICs to all antifungal drugs tested, with the lowest being to voriconazole and amphotericin B (AmB), respectively (geometric mean MICs of 3.4 mg/L and 2.2 mg/L, respectively). All Scedosporium apiospermum complex isolates (n = 14) were inhibited by voriconazole concentrations of ≤0.25 mg/L, followed by posaconazole and itraconazole at ≤1 mg/L. Posaconazole and AmB were the most active agents against the Mucorales, with MIC90 values of 1 mg/L and 2 mg/L, respectively, for Rhizopus spp. For dematiaceous fungi, all isolates were inhibited by itraconazole and posaconazole concentrations of ≤0.5 mg/L (MIC90, 0.12 mg/L and 0.25 mg/L, respectively), but voriconazole and AmB also had in vitro activity (MIC90, 0.5 mg/L and 1 mg/L, respectively). Differences in antifungal susceptibility within species and between species within genera support the need for testing individual patient isolates to guide therapy. The Sensititre(®) YeastOne(®) offers a practical alternative to the reference methodology for susceptibility testing of moulds.

Clinical impact of reducing routine blood culture incubation time from 7 to 5 days.

The aim of this study was to determine the clinical impact of reducing the blood culture incubation protocol from 7 to 5 days.A laboratory data extraction identified positive blood cultures occurring after 5 or more days of incubation at Canberra Hospital, Australia between 1 January 2001 and 31 August 2011. Isolates were identified as clinically significant using a pre-existing prospective bacteraemia database. Medical records review determined whether the positive result affected clinical management.Positive blood cultures after 5 or more days of incubation accounted for 2.65% (423/15979) of all positive blood cultures, although the majority were false positives or contaminants. Eighty-five were significant/indeterminate, representing an average of eight cases per year or 0.47% (85/15979) of all positive blood cultures sets. Forty-three were isolated for the first time, representing 1.1% of all significant/indeterminate blood culture episodes. Fungi and anaerobic bacteria compromised over 50% of isolates. In 26 cases (2.4 cases per year), the culture result led to a change in patient management.A 7 day incubation protocol is preferable due to late isolation of organisms; however, if space is required to accommodate increasing blood culture numbers, reducing to a 5 or 6 day protocol would miss only a small percentage of clinically significant isolates.

The Australasian Society for Infectious Diseases Annual Scientific Meeting 2010.

The 2010 Australasian Society for Infectious Diseases Annual Scientific Meeting took place in May in the Northern Territory (Australia) and focussed on infections in the region. The meeting highlights included the changing spectrum of malaria and dengue in endemic regions, the latest on influenza epidemiology, multidrug-resistant organisms and infectious diseases in the Australian indigenous population. This was complemented by subspeciality interest group research encompassing mycobacterial disease, infection control, mycology and virology.