Consensus guidelines for antifungal stewardship, surveillance and infection prevention, 2021.

Invasive fungal diseases (IFD) are serious infections associated with high mortality, particularly in immunocompromised patients. The prescribing of antifungal agents to prevent and treat IFD is associated with substantial economic burden on the health system, high rates of adverse drug reactions, significant drug-drug interactions and the emergence of antifungal resistance. As the population at risk of IFD continues to grow due to the increased burden of cancer and related factors, the need for hospitals to employ antifungal stewardship (AFS) programmes and measures to monitor and prevent infection has become increasingly important. These guidelines outline the essential components, key interventions and metrics, which can help guide implementation of an AFS programme in order to optimise antifungal prescribing and IFD management. Specific recommendations are provided for quality processes for the prevention of IFD in the setting of outbreaks, during hospital building works, and in the context of Candida auris infection. Recommendations are detailed for the implementation of IFD surveillance to enhance detection of outbreaks, evaluate infection prevention and prophylaxis interventions and to allow benchmarking between hospitals. Areas in which information is still lacking and further research is required are also highlighted.

Fluoroquinolone antibiotics and adverse events.

Fluoroquinolones are broad-spectrum antibiotics with good oral bioavailability. They are used for the treatment of a wide variety of infections, but there are restrictions on prescribing these drugs. Epidemiological studies have reported an increased risk of rare adverse effects. These include tendinopathy and tendon rupture, peripheral neuropathy and aortic aneurysm. Safe prescribing of fluroquinolones requires recognition of patients with risk factors for toxicity. Prompt drug discontinuation is recommended in the event of an adverse reaction. Practising antimicrobial stewardship by prescribing fluoroquinolones only when alternative drugs are unavailable is also key to limiting adverse events and antibiotic resistance.

'Cold and lonely': emergency presentations of patients with hypothermia to a large Australian health network.

BACKGROUND: Extreme heat is a public health priority in Australia with the health effects of cold poorly studied. A record-breaking cold winter prompted an institutional investigation into the epidemiology and outcomes of hypothermic presentations. AIMS: To describe the clinical and epidemiological characteristics of hypothermic emergency presentations including patient outcomes as well as gaps in practice. METHODS: This was a retrospective cohort observational study of hypothermic emergency presentations between 7 July 2009 and 1 September 2016 with a temperature of ≤35°C. Independent predictors for inpatient mortality and characteristics of exposure versus non-exposure presentations were evaluated. RESULTS: There were 217 patients with 226 presentations comprising male gender in 54%, median age 76.5 years (interquartile range (IQR) 53-88) and median initial temperature 33.3°C (IQR 31.2-34.3°C). Non-exposure presentations being found indoors, accounted for 78% overall, with elderly persons ≥65 years (P = 0.002) and multimorbidity (Charlson comorbidity index ≥4, P = 0.013) overrepresented in this subgroup. Among the non-exposure cohort, 55% were pensioners and 42% lived alone. Inpatient mortality was 11% overall and significantly higher in non-exposure versus exposure cohorts (16 vs 2%, P = 0.01). Independent predictors of inpatient mortality included heart failure (P = 0.04), metastatic malignancy (P < 0.01), chronic kidney disease (P < 0.05) and sepsis (P < 0.01). In contrast, exposure-related presentations were characterised by younger patients with intoxication due to alcohol and/or illicit drugs and psychiatric comorbidity. CONCLUSIONS: Hypothermia is a marker of clinical and socioeconomic vulnerability. The dominant presentation of the elderly patient with multimorbidity, and few social supports being found indoors, raises broader questions around the social determinants of health.

A population-based analysis of invasive fungal disease in haematology-oncology patients using data linkage of state-wide registries and administrative databases: 2005 - 2016.

BACKGROUND: Little is known about the morbidity and mortality of invasive fungal disease (IFD) at a population level. The aim of this study was to determine the incidence, trends and outcomes of IFD in all haematology-oncology patients by linking Victorian hospital data to state-based registries. METHODS: Episodes of IFD complicating adult haematological malignancy (HM) and haematopoietic stem cell transplantation (HSCT) patients admitted to Victorian hospitals from 1st July 2005 to 30th June 2016 were extracted from the Victorian Admitted Episodes Dataset and linked to the date of HM diagnosis from the Victorian Cancer Registry and mortality from the Victorian Death Index. Descriptive analyses and regression modelling were used. RESULTS: There were 619,702 inpatient-episodes among 32,815 HM and 1,765 HSCT-patients. IFD occurring twelve-months from HM-diagnosis was detected in 669 (2.04%) HM-patients and 111 (6.29%) HSCT-recipients, respectively. Median time to IFD-diagnosis was 3, 5, 15 and 22 months in acute myeloid leukaemia, acute lymphoblastic leukaemia, Hodgkin lymphoma and multiple myeloma, respectively. Median survival from IFD-diagnosis was 7, 7 and 3 months for invasive aspergillosis, invasive candidiasis and mucormycosis, respectively. From 2005-2016, IFD incidence decreased 0.28% per 1,000 bed-days. Fungal incidence coincided with spring peaks on time-series analysis. CONCLUSIONS: Data linkage is an efficient means of evaluating the epidemiology of a rare disease, however the burden of IFD is likely underestimated, arguing for better quality hospital level surveillance data to improve management strategies.

Primary antifungal prophylaxis in adult patients with acute lymphoblastic leukaemia: a multicentre audit.

OBJECTIVES: The primary objectives were to investigate the prescribing practices of primary antifungal prophylaxis (PAP) and incidence of invasive fungal disease (IFD) in adult patients with ALL receiving induction-consolidation chemotherapy. Secondary objectives were to determine risk factors for IFD and resource utilization associated with IFD. METHODS: A retrospective chart review of adult patients with ALL from commencement of induction until completion of consolidation chemotherapy was undertaken from January 2008 to June 2013 in four hospitals in Melbourne, Australia. IFD was classified according to the revised European Organisation for Research and Treatment of Cancer criteria. Cost analysis was performed from an Australian public hospital perspective. RESULTS: Ninety-eight patients were included in the audit; 83 (85%) received PAP. Most patients (49/83, 59%) switched between two different antifungal agents, predominantly between liposomal amphotericin B and an azole. Five proven/probable and six possible IFD cases were identified. Proven/probable IFD was most common in patients receiving the BFM95 chemotherapy protocol. The incidence of proven/probable IFD was significantly lower in patients receiving PAP compared with those who did not (2/78, 2.6% versus 3/14, 21.4%; P = 0.024). For every five patients receiving PAP, one proven/probable IFD case would be prevented. Proven/probable IFD was associated with an additional median cost of 121,520 Australian dollars (95% CI: 90,781-180,141 Australian dollars; P < 0.001) compared with patients without IFD. CONCLUSIONS: This is the first multicentre study evaluating PAP use in patients with ALL. With the caveats of interpretation of retrospective, non-randomized data, PAP was associated with a reduced IFD risk.

Safety, clinical effectiveness and trough plasma concentrations of intravenous posaconazole in patients with haematological malignancies and/or undergoing allogeneic haematopoietic stem cell transplantation: off-trial experience.

OBJECTIVES: This study describes the safety, clinical effectiveness and trough plasma concentration (Cmin) of intravenous (iv) posaconazole, provided as part of Merck Sharp and Dohme Australia's Named Patient Programme (NPP) in non-clinical trial settings. METHODS: A multicentre, retrospective study on the NPP use of iv posaconazole between July 2014 and March 2015 across seven Australian hospitals. RESULTS: Seventy courses of iv posaconazole were prescribed and evaluated in 61 patients receiving treatment for haematological malignancy. Sixty-one courses were prescribed for prophylaxis against invasive fungal disease (IFD), the majority of which (59) were initiated in patients with gastrointestinal disturbances and/or intolerance to previous antifungals. The median (IQR) duration for prophylaxis was 10 (6-15) days. No breakthrough IFD was observed during or at cessation of iv posaconazole. Nine courses of iv posaconazole were prescribed for treatment of IFD with a median (IQR) duration of 19 (7-30) days. Improvement in signs and symptoms of IFD was observed in five cases at cessation of, and six cases at 30 days post-iv posaconazole. Cmin was measured in 39 courses of iv posaconazole, with the initial level taken [median (IQR)] 4 (3-7) days after commencing iv posaconazole. The median (IQR) of initial Cmin was 1.16 (0.69-2.06) mg/L. No severe adverse events specifically attributed to iv posaconazole were documented, although six courses were curtailed due to potential toxicity. CONCLUSIONS: This non-clinical trial experience suggests that iv posaconazole appeared to be safe and clinically effective for prophylaxis or treatment of IFD in patients receiving treatment for haematological malignancies.

Automatic detection of patients with invasive fungal disease from free-text computed tomography (CT) scans.

BACKGROUND: Invasive fungal diseases (IFDs) are associated with considerable health and economic costs. Surveillance of the more diagnostically challenging invasive fungal diseases, specifically of the sino-pulmonary system, is not feasible for many hospitals because case finding is a costly and labour intensive exercise. We developed text classifiers for detecting such IFDs from free-text radiology (CT) reports, using machine-learning techniques. METHOD: We obtained free-text reports of CT scans performed over a specific hospitalisation period (2003-2011), for 264 IFD and 289 control patients from three tertiary hospitals. We analysed IFD evidence at patient, report, and sentence levels. Three infectious disease experts annotated the reports of 73 IFD-positive patients for language suggestive of IFD at sentence level, and graded the sentences as to whether they suggested or excluded the presence of IFD. Reliable agreement between annotators was obtained and this was used as training data for our classifiers. We tested a variety of Machine Learning (ML), rule based, and hybrid systems, with feature types including bags of words, bags of phrases, and bags of concepts, as well as report-level structured features. Evaluation was carried out over a robust framework with separate Development and Held-Out datasets. RESULTS: The best systems (using Support Vector Machines) achieved very high recall at report- and patient-levels over unseen data: 95% and 100% respectively. Precision at report-level over held-out data was 71%; however, most of the associated false-positive reports (53%) belonged to patients who had a previous positive report appropriately flagged by the classifier, reducing negative impact in practice. CONCLUSIONS: Our machine learning application holds the potential for developing systematic IFD surveillance systems for hospital populations.

Making sense of posaconazole therapeutic drug monitoring: a practical approach.

PURPOSE OF REVIEW: Therapeutic drug monitoring (TDM) may be an important adjunct to optimizing the use of posaconazole. RECENT FINDINGS: Limited clinical studies suggest that an exposure-response relationship for posaconazole exists for the treatment of established invasive fungal diseases (IFDs), with emerging but less compelling data supporting its role in prophylaxis. The high prevalence of subtherapeutic levels has not translated to high prophylactic failure rates perhaps because of preferential uptake by effector cells important in the front-line defence against Aspergillus species. Nevertheless, TDM would appear prudent in patients deemed at highest risk for IFD with correction of patient modifiable factors and attention to drug administration important in optimizing drug exposure. TDM performed within a few days after commencing posaconazole may be predictive of steady-state levels, thus minimizing the delay in obtaining results in addition to identifying a subset of patients who may remain persistently subtherapeutic and also resistant to dose-escalation. Trough levels may be supplanted by untimed levels at steady state, thereby expanding the practicalities of TDM. We propose that TDM becomes one of the several measures in an integrated approach to IFD prevention combining screening of high-risk haematology patients for invasive aspergillosis at presentation, together with prospective surveillance for IFD, explicit criteria for switching to an alternative prophylactic agent and adherence to infection control practices. SUMMARY: Growing evidence supports the value of TDM for posaconazole to identify patients who may benefit from correction of modifiable factors impacting bioavailability, dosage adjustment or switch to an alternative agent.

The case for antifungal stewardship.

PURPOSE OF REVIEW: Antimicrobial stewardship (AMS) has overwhelmingly focussed on antibiotics while antifungal agents have been largely neglected despite the few published audits of antifungal drug use demonstrating clear deficiencies in prescribing behaviour. In this review, we outline not only the elements of antifungal stewardship (AFS) in common with AMS but also features specific to antifungal drugs, combined with insights from our experience in AFS. RECENT FINDINGS: Invasive fungal diseases (IFDs) have a lower institutional incidence relative to infections caused by multiresistant bacteria, but their health and economic burden are substantial. Pharmacy costs inclusive of antifungal agents are a major determinant of IFD-attributable hospital cost. High drug costs and the toxicities of antifungal agents are the principal rationale for AFS while antifungal resistance is an emerging but less prevalent issue. The high mortality/morbidity associated with IFDs, including adverse impact on curative chemotherapy, combined with suboptimal diagnostic tools, has driven the overuse of antifungal drugs. De-escalation of empiric therapy is one of the most challenging aspects of AFS to implement. Nonculture-based tests may enhance AFS, but refinement of both target populations and clinical pathways incorporating their use is required. Performance indicators including structural, process and outcome measures are integral for demonstrating the value of AFS programmes. SUMMARY: Practice guidelines adapted to the local context are the cornerstone of AFS. Local epidemiology informs the choice of antifungal agents for the prevention and management of IFDs, underscoring the need for surveillance. Adherence to minimum standards of prescribing ensures that clinical outcomes are optimized and drug toxicities minimized, thus meeting healthcare quality and safety goals.

Comparative clinical effectiveness of prophylactic voriconazole/posaconazole to fluconazole/itraconazole in patients with acute myeloid leukemia/myelodysplastic syndrome undergoing cytotoxic chemotherapy over a 12-year period.

Post-induction aplasia for acute myeloid leukemia/myelodysplastic syndrome is a high-risk period for invasive fungal diseases. The effectiveness of fluconazole, itraconazole solution, voriconazole and posaconazole prophylaxis used consecutively from December 1998 to January 2010 in patients with acute myeloid leukemia/myelodysplastic syndrome undergoing remission-induction chemotherapy was retrospectively evaluated. A total of 216 consecutive patients received 573 prophylaxis courses. Breakthrough-invasive fungal disease incidence in fluconazole, itraconazole, voriconazole, posaconazole recipients was 25%, 16%, 14% and 3%, respectively. Voriconazole/posconazole versus fluconazole/itraconazole combined was associated with significant reductions in breakthrough-invasive fungal disease incidence (20% vs. 8%, P=0.011), premature discontinuations (46% vs. 22% P<0.001) and empiric antifungal treatment (31% vs. 8.5%, P<0.001). Microbiologically confirmed infections were molds. Posaconazole compared to other drugs was associated with fewer courses requiring computed-tomography (43% vs. 26%, P<0.001). Adoption of voriconazole/posaconazole has decreased invasive fungal disease incidence, empiric antifungal treatment and for posaconazole, computed-tomography demand, with effectiveness of posaconazole comparable to clinical trial experience.

Attributable hospital cost and antifungal treatment of invasive fungal diseases in high-risk hematology patients: an economic modeling approach.

Studies using patient-level data to determine the attributable cost of invasive fungal diseases (IFDs) are few. Using a case-control study with activity-based costing of patients admitted to a quaternary hospital from 2002 to 2007, we determined attributable hospitalization cost (and 12 weeks thereafter), length of stay (LOS), and costly antifungal treatment (C-AT; liposomal amphotericin B, voriconazole, posaconazole, caspofungin), expressed as defined daily doses (DDDs) per IFD episode, in patients with hematological malignancies and hematopoietic stem cell recipients. Matching criteria and median regression modeling controlled for confounding variables, including LOS prior to IFD onset. Multiple mycoses were identified in 43 matched case-control pairs (n=86). A separate sensitivity analysis included 22 unmatched patients. IFD status was associated with a median excess cost of AU$30,957 (95% confidence interval [CI]=AU$2,368 to AU$59,546; P=0.034), approximating at purchasing power parity US$21,203 (95% CI=US$1,622 to US$40,784) and €15,788 (95% CI=€1,208 to €30,368), increasing to AU$80,291 (95% CI=AU$33,636 to AU$126,946; P=0.001), i.e., US$54,993 (95% CI=US$23,038 to US$86,948) and €40,948 (95% CI=€17,154 to €64,742), with intensive care unit (ICU) requirement. Cost determinants were pharmacy costs (64%; P<0.001) inclusive of antifungal treatment (27%; P<0.001) and ward costs (27%; P=0.091), with proportions persisting through 12 weeks for 25 surviving matched pairs (pharmacy, 60% [P=0.12]; ward, 31% [P=0.21]). Median LOS was not significantly increased unless unmatched patients were included (8 days, 95% CI=1.8 to 14 days; P=0.012). Excess C-ATs were 17 DDDs (95% CI=15 to 19 DDDs; P<0.001) per case patient and 19 DDDs (95% CI=16 to 22 DDDs; P<0.001) per ICU patient. The sensitivity analysis was confirmatory (for median cost, AU$29,441, 95% CI=AU$5,571 to AU$53,310, P=0.016; for C-AT, 17 DDDs, 95% CI=16 to 18 DDDs, P<0.001). IFD results in increased hospital and ICU costs, with pharmacy costs, including antifungal treatment, being major determinants. Consumption of costly antifungal drugs may be a novel resource metric with wider generalizability than cost alone.

Ushering in Antifungal Stewardship: Perspectives of the Hematology Multidisciplinary Team Navigating Competing Demands, Constraints, and Uncertainty.

BACKGROUND: The social, contextual, and behavioral determinants that influence care in patients at risk for invasive fungal diseases (IFD) are poorly understood. This knowledge gap is a barrier to the implementation of emerging antifungal stewardship (AFS) programs. We aimed to understand the barriers and enablers to AFS, opportunities for improvement, and perspectives of AFS for hematology patients at a major medical center in Australia. METHODS: Semistructured, face-to-face interviews were conducted with 35 clinicians from 6 specialties (hematology, infectious diseases, pharmacy, nursing, radiology, respiratory), followed by thematic analysis mapped to a behavioral change framework. RESULTS: Access to fungal diagnostics including bronchoscopy was identified as the key barrier to rational prescribing. Collective decision making was the norm, aided by an embedded stewardship model with on-demand access to infectious diseases expertise. Poor self-efficacy/knowledge among prescribers was actually an enabler of AFS, because clinicians willingly deferred to infectious diseases for advice. A growing outpatient population characterized by frequent care transitions was seen as an opportunity for AFS but neglected by an inpatient focused model, as was keeping pace with emerging fungal risks. Ad hoc surveillance, audit, and feedback practices frustrated population-level quality improvement for all actors. Antifungal stewardship was perceived as a specialized area that should be integrated within antimicrobial stewardship but aligned with the cultural expectations of hematologists. CONCLUSIONS: Antifungal stewardship is multifaceted, with fungal diagnostics a critical gap and outpatients a neglected area. Formal surveillance, audit, and feedback mechanisms are essential for population-level quality improvement. Resourcing is the next challenge because complex immunocompromised patients require personalized attention and audit of clinical outcomes including IFD is difficult.

Renal safety of short-term empiric gentamicin therapy in aged patients.

OBJECTIVE: To determine the incidence of acute kidney injury (AKI) in aged patients receiving empiric gentamicin therapy. METHODS: Patients aged ≥65 years receiving gentamicin upon admission between 2013 and 2015 at two Australian hospitals were retrospectively studied. AKI was defined as a rise in creatinine by ≥50% and/or ≥26.5 µmol/L. RESULTS: Most patients (95%) received a single dose of gentamicin. The incidence of AKI was 15% (36/242 patients). A composite outcome of persistent kidney injury, requirement for renal replacement therapy or inpatient death in a patient with AKI occurred in 10 (4%) patients. Patients who developed AKI were older (median 80.5 vs 78 years, P = 0.03), had higher Charlson Co-morbidity Index (median 7 vs 5, P = 0.0004) and had more advanced chronic kidney disease at baseline (Stages IV and V) (OR 4.38, 95% confidence interval 1.45-13.2, P = 0.01). CONCLUSION: Empiric gentamicin use in patients with advancing age is associated with low rates of predominantly transient renal impairment.

Toward Electronic Surveillance of Invasive Mold Diseases in Hematology-Oncology Patients: An Expert System Combining Natural Language Processing of Chest Computed Tomography Reports, Microbiology, and Antifungal Drug Data.

PURPOSE: Prospective epidemiologic surveillance of invasive mold disease (IMD) in hematology patients is hampered by the absence of a reliable laboratory prompt. This study develops an expert system for electronic surveillance of IMD that combines probabilities using natural language processing (NLP) of computed tomography (CT) reports with microbiology and antifungal drug data to improve prediction of IMD. METHODS: Microbiology indicators and antifungal drug-dispensing data were extracted from hospital information systems at three tertiary hospitals for 123 hematology-oncology patients. Of this group, 64 case patients had 26 probable/proven IMD according to international definitions, and 59 patients were uninfected controls. Derived probabilities from NLP combined with medical expertise identified patients at high likelihood of IMD, with remaining patients processed by a machine-learning classifier trained on all available features. RESULTS: Compared with the baseline text classifier, the expert system that incorporated the best performing algorithm (naïve Bayes) improved specificity from 50.8% (95% CI, 37.5% to 64.1%) to 74.6% (95% CI, 61.6% to 85.0%), reducing false positives by 48% from 29 to 15; improved sensitivity slightly from 96.9% (95% CI, 89.2% to 99.6%) to 98.4% (95% CI, 91.6% to 100%); and improved receiver operating characteristic area from 73.9% (95% CI, 67.1% to 80.6%) to 92.8% (95% CI, 88% to 97.5%). CONCLUSION: An expert system that uses multiple sources of data (CT reports, microbiology, antifungal drug dispensing) is a promising approach to continuous prospective surveillance of IMD in the hospital, and demonstrates reduced false notifications (positives) compared with NLP of CT reports alone. Our expert system could provide decision support for IMD surveillance, which is critical to antifungal stewardship and improving supportive care in cancer.

Isavuconazole: a new extended spectrum triazole for invasive mold diseases.

Isavuconazole is the first broad spectrum prodrug triazole with efficacy against invasive fungal diseases including aspergillosis and mucormycosis. Characteristics include linear dose-proportional pharmacokinetics, intravenous and oral formulations allowing therapeutic streamlining, once daily dosing, absence of nephrotoxic solubilizing agents and excellent oral bioavailability independent of prandial status and gastric acidity. An open label noncomparator study demonstrated encouraging results for isavuconazole as primary or salvage therapy for a range of fungi including mucormycosis. Isavuconazole had fewer premature drug discontinuations and adverse events in the eye, hepatobiliary and psychiatry systems than the comparator agent, voriconazole in a randomized double-blind clinical trial. Cross-resistance of isavuconazole best correlates with voriconazole. In vitro resistance is not invariably predictive of clinical failure. Isavuconazole signals progress in pharmacokinetics, bioavailability and toxicity/tolerability supported by clinical efficacy from Phase III trials.

Facilitating surveillance of pulmonary invasive mold diseases in patients with haematological malignancies by screening computed tomography reports using natural language processing.

PURPOSE: Prospective surveillance of invasive mold diseases (IMDs) in haematology patients should be standard of care but is hampered by the absence of a reliable laboratory prompt and the difficulty of manual surveillance. We used a high throughput technology, natural language processing (NLP), to develop a classifier based on machine learning techniques to screen computed tomography (CT) reports supportive for IMDs. PATIENTS AND METHODS: We conducted a retrospective case-control study of CT reports from the clinical encounter and up to 12-weeks after, from a random subset of 79 of 270 case patients with 33 probable/proven IMDs by international definitions, and 68 of 257 uninfected-control patients identified from 3 tertiary haematology centres. The classifier was trained and tested on a reference standard of 449 physician annotated reports including a development subset (n = 366), from a total of 1880 reports, using 10-fold cross validation, comparing binary and probabilistic predictions to the reference standard to generate sensitivity, specificity and area under the receiver-operating-curve (ROC). RESULTS: For the development subset, sensitivity/specificity was 91% (95%CI 86% to 94%)/79% (95%CI 71% to 84%) and ROC area was 0.92 (95%CI 89% to 94%). Of 25 (5.6%) missed notifications, only 4 (0.9%) reports were regarded as clinically significant. CONCLUSION: CT reports are a readily available and timely resource that may be exploited by NLP to facilitate continuous prospective IMD surveillance with translational benefits beyond surveillance alone.

The role of general quality improvement measures in decreasing the burden of endemic MRSA in a medical-surgical intensive care unit.

PURPOSE: To determine whether any of several quality improvement interventions with none specifically targeting methicillin-resistant Staphylococcus aureus (MRSA) were associated with a decline in endemic MRSA prevalence in an intensive care unit (ICU) where active screening and contact isolation precautions for known MRSA colonised patients are not practised. SETTING: Medical-surgical ICU with 2,000 admissions/year. DESIGN: 8.5-year retrospective time-series analysis. INTERVENTIONS: ICU re-location, antibiotic stewardship utilising computerised decision-support and infectious-diseases physician rounds, dedicated ICU infection control practitioners, alcohol-based hand rub solution (ABHRS). METHOD: Regression modelling was used to evaluate trends in S. aureus prevalence density (monthly clinical isolates per 1,000 patient-days), antibiotic consumption, infection control consumables, ABHRS and their temporal relationship with MRSA prevalence. RESULTS: Methicillin-resistant S. aureus prevalence density decreased by 83% [95% confidence interval (CI) -68% to -91%, p < 0.001]. Rates of MRSA bacteraemia decreased 89% (95% CI -79% to -94%, p = 0.001) with no statistically significant change in methicillin-sensitive S. aureus bacteraemia. Hospital MRSA prevalence density decreased 17% (95% CI -5% to -27%, p = 0.005), suggesting that ICU was not shifting MRSA elsewhere. In ICU, broad-spectrum antibiotic use decreased by 26% (95% CI -12% to -38%, p = 0.008), coinciding with a decrease in MRSA, but time-series analysis did not show a significant association. On multivariate analysis, only ABHRS was significantly associated with a decrease in MRSA, but it was formally introduced late in the study period when MRSA was already in decline. CONCLUSION: General quality improvement measures were associated with a decrease in endemic MRSA in a high-risk setting without use of resource-intensive active surveillance and isolation practices.