Publications by authors named "Natasha E Holmes"

57 Publications

Identifying patterns in unplanned hospital admissions during the COVID-19 pandemic: a single-centre retrospective study.

Intern Med J 2021 06;51(6):868-872

Department of General Medicine, Austin Health, Melbourne, Victoria, Australia.

Background: Countries with a high prevalence of COVID-19 have identified a reduction in crude hospital admission rates for non-COVID-19 conditions during the pandemic. There remains a paucity of such data from lower prevalence countries, including Australia.

Aims: To describe the patterns of unplanned hospital daily admission rates during the COVID-19 pandemic in a major Australian metropolitan hospital, with a focus on acute medical presentations including acute coronary syndrome (ACS), stroke and falls.

Methods: This single-centre retrospective analysis analysed hospital admission episodes between 1 March and 30 April 2020 (COVID-19-era) and compared this to a historical cohort during the same period between 2017 and 2019 (pre-COVID-19). Information collected included total admission rates and patient characteristics for ACS, stroke and falls patients.

Results: A total of 12 278 unplanned admissions was identified across the study period. The daily admission rate was lower in the COVID-19-era compared with pre-COVID-19 (46.59 vs 51.56 days, P < 0.001). There was also a reduced average daily admission rate for falls (7.79 vs 9.95 days, P < 0.001); however, similar admission rates for ACS (1.52 vs 1.49 days, P = 0.83) and stroke (1.56 vs 1.76 days, P = 0.33).

Conclusions: Public health interventions have been effective in reducing domestic cases of COVID-19 in Australia. At our tertiary metropolitan hospital, we have observed a significant reduction in unplanned hospital admission rates during the COVID-19-era, particularly for falls. Public health messaging needs to focus on educating the public how to seek medical care safely and promptly in the context of the ongoing COVID-19 crisis.
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http://dx.doi.org/10.1111/imj.15075DOI Listing
June 2021

Successful use of azithromycin for Escherichia coli-associated renal allograft malakoplakia: a report of two cases.

Eur J Clin Microbiol Infect Dis 2021 May 14. Epub 2021 May 14.

Department of Infectious Diseases, Austin Health, 145 Studley Road, Heidelberg, Victoria, 3084, Australia.

Malakoplakia is a chronic granulomatous disease associated with incomplete clearance of bacterial pathogens. A multimodal approach to therapy includes antimicrobials with intracellular activity, reduction in immunosuppression, and debulking of lesions. Azithromycin has an intracellular mechanism of action and enhanced Gram-negative activity compared to other macrolides. Despite some in vitro data to support its use, there are no clinical breakpoints or epidemiological cut-off values for most Enterobacterales from the European Committee on Antimicrobial Susceptibility Testing (EUCAST) or the Clinical and Laboratory Standards Institute (CLSI). We present two cases, previously unreported, of Escherichia coli associated renal allograft malakoplakia successfully treated with azithromycin.
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http://dx.doi.org/10.1007/s10096-021-04270-xDOI Listing
May 2021

CD8 T cells specific for an immunodominant SARS-CoV-2 nucleocapsid epitope display high naive precursor frequency and TCR promiscuity.

Immunity 2021 05 15;54(5):1066-1082.e5. Epub 2021 Apr 15.

Department of Infectious Diseases, Austin Hospital, Heidelberg, VIC 3084, Australia; Department of Medicine and Radiology, The University of Melbourne, Parkville, VIC 3000, Australia; Data Analytics Research and Evaluation (DARE) Centre, Austin Health and The University of Melbourne, Heidelberg, VIC 3084, Australia.

To better understand primary and recall T cell responses during coronavirus disease 2019 (COVID-19), it is important to examine unmanipulated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cells. By using peptide-human leukocyte antigen (HLA) tetramers for direct ex vivo analysis, we characterized CD8 T cells specific for SARS-CoV-2 epitopes in COVID-19 patients and unexposed individuals. Unlike CD8 T cells directed toward subdominant epitopes (B7/N, A2/S, and A24/S) CD8 T cells specific for the immunodominant B7/N epitope were detected at high frequencies in pre-pandemic samples and at increased frequencies during acute COVID-19 and convalescence. SARS-CoV-2-specific CD8 T cells in pre-pandemic samples from children, adults, and elderly individuals predominantly displayed a naive phenotype, indicating a lack of previous cross-reactive exposures. T cell receptor (TCR) analyses revealed diverse TCRαβ repertoires and promiscuous αβ-TCR pairing within B7/NCD8 T cells. Our study demonstrates high naive precursor frequency and TCRαβ diversity within immunodominant B7/N-specific CD8 T cells and provides insight into SARS-CoV-2-specific T cell origins and subsequent responses.
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http://dx.doi.org/10.1016/j.immuni.2021.04.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049468PMC
May 2021

The Role of Immunological and Clinical Biomarkers to Predict Clinical COVID-19 Severity and Response to Therapy-A Prospective Longitudinal Study.

Front Immunol 2021 17;12:646095. Epub 2021 Mar 17.

Centre for Antibiotic Allergy and Research, Department of Infectious Diseases, Austin Health, Heidelberg, VIC, Australia.

Background: The association of pro-inflammatory markers such as interleukin-6 (IL-6) and other biomarkers with severe coronavirus disease 2019 (COVID-19) is of increasing interest, however their kinetics, response to current COVID-related treatments, association with disease severity and comparison with other disease states associated with potential cytokine storm (CS) such as Staphylococcus aureus bacteraemia (SAB) are ill-defined.

Methods: A cohort of 55 hospitalized SARS-CoV-2 positive patients was prospectively recruited - blood sampling was performed at baseline, post-treatment and hospital discharge. Serum IL-6, C-reactive protein (CRP) and other laboratory investigations were compared between treatment groups and across timepoints. Acute serum IL-6 and CRP levels were then compared to those with suspected COVID-19 (SCOVID) and age and sex matched patients with SAB and patients hospitalized for any non-infectious condition (NIC).

Results: IL-6 was elevated at admission in the SARS-CoV-2 cohort but at lower levels compared to matched SAB patients. Median (IQR) IL-6 at admission was 73.89 pg/mL (30.9, 126.39) in SARS-CoV-2 compared to 92.76 pg/mL (21.75, 246.55) in SAB (p=0.017); 12.50 pg/mL (3.06, 35.77) in patients with NIC; and 95.51 pg/mL (52.17, 756.67) in SCOVID. Median IL-6 and CRP levels decreased between admission and discharge timepoints. This reduction was amplified in patients treated with remdesivir and/or dexamethasone. CRP and bedside vital signs were the strongest predictors of COVID-19 severity.

Conclusions: Knowledge of the kinetics of IL-6 did not offer enhanced predictive value for disease severity in COVID-19 over common investigations such as CRP and vital signs.
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http://dx.doi.org/10.3389/fimmu.2021.646095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009986PMC
April 2021

Integrated immune dynamics define correlates of COVID-19 severity and antibody responses.

Cell Rep Med 2021 Mar 5;2(3):100208. Epub 2021 Feb 5.

Department of Medicine, Central Clinical School, Monash University, Melbourne, VIC, Australia.

SARS-CoV-2 causes a spectrum of COVID-19 disease, the immunological basis of which remains ill defined. We analyzed 85 SARS-CoV-2-infected individuals at acute and/or convalescent time points, up to 102 days after symptom onset, quantifying 184 immunological parameters. Acute COVID-19 presented with high levels of IL-6, IL-18, and IL-10 and broad activation marked by the upregulation of CD38 on innate and adaptive lymphocytes and myeloid cells. Importantly, activated CXCR3cT1 cells in acute COVID-19 significantly correlate with and predict antibody levels and their avidity at convalescence as well as acute neutralization activity. Strikingly, intensive care unit (ICU) patients with severe COVID-19 display higher levels of soluble IL-6, IL-6R, and IL-18, and hyperactivation of innate, adaptive, and myeloid compartments than patients with moderate disease. Our analyses provide a comprehensive map of longitudinal immunological responses in COVID-19 patients and integrate key cellular pathways of complex immune networks underpinning severe COVID-19, providing important insights into potential biomarkers and immunotherapies.
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http://dx.doi.org/10.1016/j.xcrm.2021.100208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862905PMC
March 2021

Cure of Limb-Threatening XDR Infection: Combining Genome Sequencing, Therapeutic Drug Level Monitoring, and Surgical Debridement.

Open Forum Infect Dis 2021 Jan 26;8(1):ofaa572. Epub 2020 Nov 26.

Department of Infectious Diseases, Austin Health, Melbourne, Australia.

We describe a case of limb-threatening osteomyelitis and metalware infection with carbapenemase-producing extensively drug-resistant successfully cured with aggressive surgical debridement and combined intravenous fosfomycin and colistin. Real-time therapeutic drug monitoring was used to maximize probability of efficacy and minimize potential for toxicity.
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http://dx.doi.org/10.1093/ofid/ofaa572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817083PMC
January 2021

The Role of In Vivo and Ex Vivo Diagnostic Tools in Severe Delayed Immune-Mediated Adverse Antibiotic Drug Reactions.

J Allergy Clin Immunol Pract 2021 05 13;9(5):2010-2015.e4. Epub 2021 Jan 13.

Centre for Antibiotic Allergy and Research, Department of Infectious Diseases, Austin Health, Heidelberg, VIC, Australia; The National Centre for Infections in Cancer, Peter MacCallum Cancer Centre, Parkville, VIC, Australia; Department of Oncology, Peter MacCallum Cancer Centre, The University of Melbourne, Parkville, VIC, Australia; Department of Medicine (Austin Health), The University of Melbourne, Heidelberg, VIC, Australia.

Background: The use of in vivo and ex vivo diagnostic tools for delayed immune-mediated adverse drug reactions is currently ill defined.

Objective: To determine whether the combination of skin testing and/or IFN-γ enzyme-linked immunoSpot assay (ELISpot) can aid diagnosis of these allergy phenotypes.

Methods: Patients with antibiotic-associated severe delayed immune-mediated adverse drug reaction hypersensitivity, including Stevens-Johnson syndrome and toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis, generalized bullous fixed drug eruption, and severe maculopapular exanthema, were prospectively recruited. In vivo testing was completed to the implicated drug(s), and ex vivo testing was performed with the patient's PBMCs stimulated with the relevant antibiotic concentrations for IFN-γ release ELISpot measurement.

Results: Eighty-one patients met the inclusion criteria, with DRESS (42; 51.9%) accounting for most cases. Among the 63 (78%) who had an ELISpot assay performed, 34 (54%) were positive to at least 1 implicated antibiotic (median spot-forming units/million cells, 99.5; interquartile range, 68-187), with glycopeptide being a strong predictor of positivity (adjusted odds ratio, 6.11; 95% CI, 1.74-21.42). In combination (in vivo and ex vivo), 51 (63%) of those tested were positive to an implicated antibiotic. For DRESS and severe maculopapular exanthema associated with penicillins and cephalosporins, this combination confirmed the culprit agent in 11 of the 12 cases and in 6 of 7 for DRESS associated with glycopeptides.

Conclusions: This study demonstrates that using in vivo in combination with ex vivo testing can enhance the diagnostic approach in these severe phenotypes by assisting with the identification of possible culprit antibiotics.
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http://dx.doi.org/10.1016/j.jaip.2020.12.052DOI Listing
May 2021

Complete recovery from COVID-19 of a kidney-pancreas transplant recipient: potential benefit from everolimus?

BMJ Case Rep 2021 Jan 11;14(1). Epub 2021 Jan 11.

Department of Nephrology, Austin Health, Heidelberg, Victoria, Australia

We present a kidney-pancreas transplant recipient who achieved complete recovery from COVID-19. A 45-year-old patient with T3 paraplegia underwent kidney-pancreas transplantation 18 years ago, followed by a subsequent kidney transplant 9 years ago, and presented with fever, hypoxia and hypotension after exposure to two confirmed cases of COVID-19. History of solid organ transplant, pre-existing renal impairment, asthma and an elevated D-dimer were identified as established risk factors for severe COVID-19. Supportive management was provided, baseline immunosuppression with everolimus was continued, and oral prednisolone was increased. A complete recovery was observed. Given the favourable outcome despite risk factors for severe COVID-19, we identify and review the potential mitigating roles of immunosuppression and mammalian target of rapamycin (mTOR) inhibitors in this disease. Further investigation is required to establish whether mTOR inhibitors could be used as therapeutic agents to treat COVID-19, or as alternative immunosuppression implemented early in the COVID-19 disease course.
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http://dx.doi.org/10.1136/bcr-2020-238413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802699PMC
January 2021

COVID-MATCH65-A prospectively derived clinical decision rule for severe acute respiratory syndrome coronavirus 2.

PLoS One 2020 9;15(12):e0243414. Epub 2020 Dec 9.

Department of Infectious Diseases, Austin Health, Heidelberg, Australia.

Objectives: We report on the key clinical predictors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and present a clinical decision rule that can risk stratify patients for COVID-19.

Design, Participants And Setting: A prospective cohort of patients assessed for COVID-19 at a screening clinic in Melbourne, Australia. The primary outcome was a positive COVID-19 test from nasopharyngeal swab. A backwards stepwise logistic regression was used to derive a model of clinical variables predictive of a positive COVID-19 test. Internal validation of the final model was performed using bootstrapped samples and the model scoring derived from the coefficients, with modelling performed for increasing prevalence.

Results: Of 4226 patients with suspected COVID-19 who were assessed, 2976 patients underwent SARS-CoV-2 testing (n = 108 SARS-CoV-2 positive) and were used to determine factors associated with a positive COVID-19 test. The 7 features associated with a positive COVID-19 test on multivariable analysis were: COVID-19 patient exposure or international travel, Myalgia/malaise, Anosmia or ageusia, Temperature, Coryza/sore throat, Hypoxia-oxygen saturation < 97%, 65 years or older-summarized in the mnemonic COVID-MATCH65. Internal validation showed an AUC of 0.836. A cut-off of ≥ 1.5 points was associated with a 92.6% sensitivity and 99.5% negative predictive value (NPV) for COVID-19.

Conclusions: From the largest prospective outpatient cohort of suspected COVID-19 we define the clinical factors predictive of a positive SARS-CoV-2 test. The subsequent clinical decision rule, COVID-MATCH65, has a high sensitivity and NPV for SARS-CoV-2 and can be employed in the pandemic, adjusted for disease prevalence, to aid COVID-19 risk-assessment and vital testing resource allocation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243414PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725390PMC
December 2020

Comprehensive Genomic Investigation of Adaptive Mutations Driving the Low-Level Oxacillin Resistance Phenotype in Staphylococcus aureus.

mBio 2020 12 8;11(6). Epub 2020 Dec 8.

Department of Microbiology and Immunology, The University of Melbourne at the Doherty Institute for Infection and Immunity, Melbourne, Australia

Antistaphylococcal penicillins such as oxacillin are the key antibiotics in the treatment of invasive methicillin-susceptible (MSSA) infections; however, gene-independent resistance adaptation can cause treatment failure. Despite its clinical relevance, the basis of this phenomenon remains poorly understood. Here, we investigated the genomic adaptation to oxacillin at an unprecedented scale using a large collection of 503 clinical -negative isolates and 30 -adapted isolates from independent oxacillin exposures. By combining comparative genomics, evolutionary convergence, and genome-wide association analysis, we found 21 genetic loci associated with low-level oxacillin resistance, underscoring the polygenic nature of this phenotype. Evidence of adaptation was particularly strong for the c-di-AMP signal transduction pathways ( and ) and in the chaperone-protease complex. The role of mutations in in conferring low-level oxacillin resistance was confirmed by allele-swapping experiments. We found that resistance to oxacillin emerges at high frequency (median, 2.9 × 10; interquartile range [IQR], 1.9 × 10 to 3.9 × 10), which is consistent with a recurrent minimum inhibitory concentration (MIC) increase across the global phylogeny of clinical isolates. Nevertheless, adaptation in clinical isolates appears sporadically, with no stably adapted lineages, suggesting a high fitness cost of resistance, confirmed by growth assessment of mutants in rich media. Our data provide a broader understanding of the emergence and dynamics of oxacillin resistance adaptation in and a framework for future surveillance of this clinically important phenomenon. The majority of strains causing human disease are methicillin-susceptible (MSSA) and can be treated with antistaphylococcal penicillins (such as oxacillin). While acquisition of the gene represents the main resistance mechanism to oxacillin, can acquire low-level resistance through adaptive mutations in other genes. In this study, we used genomic approaches to understand the basis of adaption to oxacillin and its dynamic at the population level. By combining a genome analysis of clinical isolates from persistent MSSA infections, selection of oxacillin resistance, and genome-wide association analysis on a large collection of isolates, we identified 21 genes linked to secondary oxacillin resistance. Adaptive mutations in these genes were easy to select when was exposed to oxacillin, but they also came at a substantial cost in terms of bacterial fitness, suggesting that this phenotype emerges preferentially in the setting of sustained antibiotic exposure.
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http://dx.doi.org/10.1128/mBio.02882-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733948PMC
December 2020

Are surgical masks manufactured from sterilisation wrap safe?

Infect Dis Health 2021 05 19;26(2):104-109. Epub 2020 Nov 19.

Department of Intensive Care, Austin Hospital, Victoria, 3084, Australia.

Background: Due to regional shortages some health services have proposed using surgical masks manufactured from sterilisation wrap. However, there has been little assessment of the safety of this practice. Therefore, we developed our own prototypes and evaluated whether they met regulatory standards.

Methods: Surgical mask prototypes were manufactured from two thickness grades of commercial sterilisation wrap. Safety was assessed in the context of regulatory standards. As it was not previously reported, we developed and performed differential pressure and synthetic blood penetration resistance experiments in accordance with official methodology.

Results: Bacterial filtration efficiency was comparable between sterilisation wrap and commercial surgical masks. Both prototypes met regulatory standards for synthetic blood resistance, whilst only our thinner mask fulfilled acceptable differential pressure ('breathability') thresholds.

Conclusion: Acceptable barrier and breathability properties can be achieved with surgical masks produced from sterilisation wrap. Therefore, this may be a reasonable method to supplement stock if required. Unless there are shortages mandating alternatives, health-care workers should always use approved personal protective equipment.
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http://dx.doi.org/10.1016/j.idh.2020.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674969PMC
May 2021

Clinical evaluation of four commercial immunoassays for the detection of antibodies against established SARS-CoV-2 infection.

Pathology 2020 Dec 21;52(7):778-782. Epub 2020 Sep 21.

Austin Pathology, Austin Health, Heidelberg, Vic, Australia.

A comparison of the clinical performance of the Elecsys Anti-SARS-CoV-2, Liaison SARS-CoV-2 S1/S2 IgG, Access SARS-CoV-2 IgG and Vitros Immunodiagnostic Products Anti-SARS-CoV-2 IgG immunoassays for the diagnosis of COVID-19 infection was performed. Patient sera were collected at least 6 weeks following onset of COVID-19 infection symptoms. Negative control specimens were stored specimens from those without COVID-19, collected in April-May 2019. Sensitivity and specificity with 95% confidence intervals (CI) were calculated. Linear regression was used to examine the relationship between the magnitude of serological response and clinical characteristics. There were 80 patients from whom 86 sera specimens were collected; six patients had duplicate specimens. There were 95 negative control specimens from 95 patients. The clinical sensitivity of the Elecsys assay was 98.84% (95% CI 93.69-99.97), specificity was 100% (95% CI 96.19-100.00); the Liaison assay clinical sensitivity was 96.51% (95% CI 90.14-99.27), specificity was 97.89% (95% CI 92.60-99.74); the Access assay clinical sensitivity was 84.88% (95% CI 75.54-91.70), specificity was 98.95% (95% CI 94.27-99.97); and the Vitros assay clinical sensitivity was 97.67% (95% CI 91.85-99.72), specificity was 100% (95% CI 96.15-100.00). A requirement for hospitalisation for COVID-19 infection was associated with a larger Vitros, Liaison and Access IgG response whilst fever was associated with a larger Elecsys response. All assays evaluated with the exception of the Access assay demonstrated similar performance. The Elecsys assay demonstrated the highest sensitivity and specificity.
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http://dx.doi.org/10.1016/j.pathol.2020.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505602PMC
December 2020

Matched Case-Control Study of the Long-Term Impact of Beta-Lactam Antibiotic Allergy Testing.

Antimicrob Agents Chemother 2020 11 17;64(12). Epub 2020 Nov 17.

Centre for Antibiotic Allergy and Research, Department of Infectious Diseases, Austin Health, Melbourne, Australia.

Whereas the short-term impacts of antibiotic allergy testing on delabeling and antibiotic usage have been demonstrated, the long-term impacts have been less well defined. In a single-center matched case-control study from Melbourne, Australia, we demonstrate that a beta-lactam antibiotic allergy testing program has a significant impact on antibiotic usage and infection-related outcomes. This study supports implementation of an antibiotic allergy testing program as a standard of care of antimicrobial stewardship programs.
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http://dx.doi.org/10.1128/AAC.01823-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674060PMC
November 2020

Identification and management of congenital parvovirus B19 infection.

Prenat Diagn 2020 12 30;40(13):1722-1731. Epub 2020 Sep 30.

Department of Perinatal Medicine, Mercy Hospital for Women, Melbourne, Victoria, Australia.

Parvovirus B19 (B19V) infection is well known for its mild, self-limiting clinical presentations in children, such as erythema infectiosum. Approximately 40% of women of childbearing age are susceptible to B19V infection. While maternal B19V infection usually has a good prognosis, B19V can cause severe fetal anaemia and pregnancy loss due to its ability to suppress erythroid progenitor cells. Non-invasive ultrasound monitoring for fetal anaemia is usually performed if maternal seroconversion occurs in the first 20 weeks of gestation, with amniocentesis for fetal infection reserved for those who first present with fetal anaemia or hydrops of unknown cause. Intrauterine transfusion is the standard treatment for severe fetal anaemia and is associated with a significant improvement in survival. However, survivors of hydrops fetalis may have a higher rate of long-term neurodevelopmental complications compared with non-hydropic survivors. This review aims to synthesise published data on the diagnosis, surveillance and outcomes of congenital parvovirus infection to assist clinicians in diagnosing and managing this important condition.
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http://dx.doi.org/10.1002/pd.5819DOI Listing
December 2020

The Penicillin Allergy Delabeling Program: A Multicenter Whole-of-Hospital Health Services Intervention and Comparative Effectiveness Study.

Clin Infect Dis 2020 Aug 5. Epub 2020 Aug 5.

Department of Infectious Diseases and Centre for Antibiotic Allergy and Research, Austin Health, Heidelberg, Australia.

Background: Penicillin allergies are associated with inferior patient and antimicrobial stewardship outcomes. We implemented a whole-of-hospital program to assess the efficacy of inpatient delabeling for low-risk penicillin allergies in hospitalized inpatients.

Methods: Patients ≥ 18 years of age with a low-risk penicillin allergy were offered a single-dose oral penicillin challenge or direct label removal based on history (direct delabeling). The primary endpoint was the proportion of patients delabeled. Key secondary endpoints were antibiotic utilization pre- (index admission) and post-delabeling (index admission and 90 days).

Results: Between 21 January 2019 and 31 August 2019, we assessed 1791 patients reporting 2315 antibiotic allergies, 1225 with a penicillin allergy. Three hundred fifty-five patients were delabeled: 161 by direct delabeling and 194 via oral penicillin challenge. Ninety-seven percent (194/200) of patients were negative upon oral penicillin challenge. In the delabeled patients, we observed an increase in narrow-spectrum penicillin usage (adjusted odds ratio [OR], 10.51 [95% confidence interval {CI}, 5.39-20.48]), improved appropriate antibiotic prescribing (adjusted OR, 2.13 [95% CI, 1.45-3.13]), and a reduction in restricted antibiotic usage (adjusted OR, 0.38 [95% CI, .27-.54]). In the propensity score analysis, there was an increase in narrow-spectrum penicillins (OR, 10.89 [95% CI, 5.09-23.31]) and β-lactam/β-lactamase inhibitors (OR, 6.68 [95% CI, 3.94-11.35]) and a reduction in restricted antibiotic use (OR, 0.52 [95% CI, .36-.74]) and inappropriate prescriptions (relative risk ratio, 0.43 [95% CI, .26-.72]) in the delabeled group compared with the group who retained their allergy label.

Conclusions: This health services program using a combination of direct delabeling and oral penicillin challenge resulted in significant impacts on the use of preferred antibiotics and appropriate prescribing.
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http://dx.doi.org/10.1093/cid/ciaa653DOI Listing
August 2020

Duration of Respiratory and Gastrointestinal Viral Shedding in Children With SARS-CoV-2: A Systematic Review and Synthesis of Data.

Pediatr Infect Dis J 2020 09;39(9):e249-e256

From the Department of Infectious Diseases, Austin Hospital, Heidelberg.

Background: Children with coronavirus disease 2019 (COVID-19) are more likely to have mild or no symptoms compared with adults and may represent important vectors for transmitting the virus. Little is known about the duration of respiratory and gastrointestinal viral shedding in children with COVID-19.

Objective: To determine the average shedding times of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) via the respiratory and gastrointestinal tracts in children.

Methods: We performed a systematic search of Ovid MEDLINE, Embase and Cochrane CENTRAL databases for studies reporting real-time reverse transcriptase polymerase chain reaction (rt-PCR) results in children with COVID-19, then extracted and synthesized data on duration of viral shedding from symptom onset in respiratory and gastrointestinal samples.

Results: Based on data compiled from 69 pediatric cases, the duration of viral shedding through the respiratory tract is up to 24 days from symptom onset with a mean of 11.1 ± 5.8 days. Of the children who underwent testing with stool PCR, rectal swab or anal swab, 86% returned a positive result. The mean duration of viral shedding via the gastrointestinal tract was 23.6 ± 8.8 days from symptom onset. In 89% of cases, viral shedding via the gastrointestinal tract persisted after nasopharyngeal or throat swabs became negative, for as long as 4 weeks.

Conclusions: To our knowledge, this is the first attempt to systematically review the duration of respiratory and gastrointestinal viral shedding of SARS-CoV-2 in pediatric patients. These findings may have important implications for infection control strategies during the COVID-19 pandemic.
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http://dx.doi.org/10.1097/INF.0000000000002814DOI Listing
September 2020

Adverse reactions to vancomycin and cross-reactivity with other antibiotics.

Curr Opin Allergy Clin Immunol 2020 08;20(4):352-361

Department of Infectious Diseases, Centre for Antibiotic Allergy and Research, Austin Health.

Purpose Of Review: Glycopeptide antibiotics such as vancomycin are frequently utilized to treat resistant Gram-positive infections such as methicillin-resistant Staphylococcus aureus. The current literature on glycopeptide and lipoglycopeptide structure, hypersensitivity and potential cross-reactivity was reviewed, highlighting implications for safe prescribing.

Recent Findings: Structurally similar, glycopeptides could theoretically cross-react. Immediate reactions to vancomycin include non-IgE-mediated reactions (e.g. red man syndrome) and IgE-mediated hypersensitivity (e.g. anaphylaxis), sharing clinical features. Vancomycin can activate mast cells via MAS-related G-protein-coupled receptor X2, an IgE-independent receptor implicated in non-IgE reactions. In-vivo and in-vitro testing for suspected IgE-mediated reactions to glycopeptides remain ill-defined. Vancomycin is increasingly recognized to cause severe cutaneous adverse reactions (SCAR), with drug reaction with eosinophilia and systemic symptoms (DRESS) predominantly reported. Vancomycin DRESS has been associated with HLA-A32:-01, with a number needed to prevent of 1 in 74. Data demonstrating cross-reactivity amongst glycopeptides and lipoglycopeptides is limited to case reports/series.

Summary: Further studies and in-vivo/in-vitro diagnostics are required for better differentiation between IgE and non-IgE glycopeptide reactions. Despite its association with vanomycin DRESS, utility of pharmacogenomic screening for HLA-A32: 01 is ill-defined. Although HLA-A32:01 has been associated with vancomycin DRESS, its utility for pharmacogenomic screening is ill defined. Further clinical and immunological cross-reactivity data for glycopeptide/lipoglycopeptide antibiotics is required.
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http://dx.doi.org/10.1097/ACI.0000000000000665DOI Listing
August 2020

Cross-reactivity between vancomycin, teicoplanin, and telavancin in patients with HLA-A∗32:01-positive vancomycin-induced DRESS sharing an HLA class II haplotype.

J Allergy Clin Immunol 2021 Jan 19;147(1):403-405. Epub 2020 May 19.

Vanderbilt University Medical Center, Nashville, Tenn; Institute for Immunology and Infectious Diseases, Murdoch University, Perth, Australia. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2020.04.056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674263PMC
January 2021

Delayed hypersensitivity associated with amoxicillin-clavulanate.

Allergy 2020 10 26;75(10):2700-2702. Epub 2020 May 26.

Centre for Antibiotic Allergy and Research, Department of Infectious Diseases, Austin Health, Heidelberg, Vic, Australia.

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http://dx.doi.org/10.1111/all.14359DOI Listing
October 2020

Development and Validation of a Penicillin Allergy Clinical Decision Rule.

JAMA Intern Med 2020 05;180(5):745-752

Department of Infectious Diseases, Vanderbilt University Medical Centre, Nashville, Tennessee.

Importance: Penicillin allergy is a significant public health issue for patients, antimicrobial stewardship programs, and health services. Validated clinical decision rules are urgently needed to identify low-risk penicillin allergies that potentially do not require penicillin skin testing by a specialist.

Objective: To develop and validate a penicillin allergy clinical decision rule that enables point-of-care risk assessment of patient-reported penicillin allergies.

Design, Setting, And Participants: In this diagnostic study, a multicenter prospective antibiotic allergy-tested cohort of 622 patients from 2 tertiary care sites in Melbourne, Australia (Austin Health and Peter MacCallum Cancer Centre) was used for derivation and internal validation of a penicillin allergy decision rule. Backward stepwise logistic regression was used to derive the model, including clinical variables predictive of a positive penicillin allergy test result. Internal validation of the final model used bootstrapped samples and the model scoring derived from the coefficients. External validation was performed in retrospective penicillin allergy-tested cohorts consisting of 945 patients from Sydney and Perth, Australia, and Nashville, Tennessee. Patients who reported a penicillin allergy underwent penicillin allergy testing using skin prick, intradermal, or patch testing and/or oral challenge (direct or after skin testing). Data were collected from June 26, 2008, to June 3, 2019, and analyzed from January 9 to 12, 2019.

Main Outcomes And Measures: The primary outcome for the model was any positive result of penicillin allergy testing performed during outpatient or inpatient assessment.

Results: From an internal derivation and validation cohort of 622 patients (367 female [59.0%]; median age, 60 [interquartile range{IQR}, 48-71] years) and an external validation cohort of 945 patients (662 female [70.1%]; median age, 55 [IQR, 38-68] years), the 4 features associated with a positive penicillin allergy test result on multivariable analysis were summarized in the mnemonic PEN-FAST: penicillin allergy, five or fewer years ago, anaphylaxis/angioedema, severe cutaneous adverse reaction (SCAR), and treatment required for allergy episode. The major criteria included an allergy event occurring 5 or fewer years ago (2 points) and anaphylaxis/angioedema or SCAR (2 points); the minor criterion (1 point), treatment required for an allergy episode. Internal validation showed minimal mean optimism of 0.003 with internally validated area under the curve of 0.805. A cutoff of less than 3 points for PEN-FAST was chosen to classify a low risk of penicillin allergy, for which only 17 of 460 patients (3.7%) had positive results of allergy testing, with a negative predictive value of 96.3% (95% CI, 94.1%-97.8%). External validation resulted in similar findings.

Conclusions And Relevance: In this study, PEN-FAST was found to be a simple rule that accurately identified low-risk penicillin allergies that do not require formal allergy testing. The results suggest that a PEN-FAST score of less than 3, associated with a high negative predictive value, could be used by clinicians and antimicrobial stewardship programs to identify low-risk penicillin allergies at the point of care.
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http://dx.doi.org/10.1001/jamainternmed.2020.0403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076536PMC
May 2020

Effect of Vancomycin or Daptomycin With vs Without an Antistaphylococcal β-Lactam on Mortality, Bacteremia, Relapse, or Treatment Failure in Patients With MRSA Bacteremia: A Randomized Clinical Trial.

JAMA 2020 02;323(6):527-537

National Centre for Infectious Diseases, Singapore.

Importance: Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is associated with mortality of more than 20%. Combining standard therapy with a β-lactam antibiotic has been associated with reduced mortality, although adequately powered randomized clinical trials of this intervention have not been conducted.

Objective: To determine whether combining an antistaphylococcal β-lactam with standard therapy is more effective than standard therapy alone in patients with MRSA bacteremia.

Design, Setting, And Participants: Open-label, randomized clinical trial conducted at 27 hospital sites in 4 countries from August 2015 to July 2018 among 352 hospitalized adults with MRSA bacteremia. Follow-up was complete on October 23, 2018.

Interventions: Participants were randomized to standard therapy (intravenous vancomycin or daptomycin) plus an antistaphylococcal β-lactam (intravenous flucloxacillin, cloxacillin, or cefazolin) (n = 174) or standard therapy alone (n = 178). Total duration of therapy was determined by treating clinicians and the β-lactam was administered for 7 days.

Main Outcomes And Measures: The primary end point was a 90-day composite of mortality, persistent bacteremia at day 5, microbiological relapse, and microbiological treatment failure. Secondary outcomes included mortality at days 14, 42, and 90; persistent bacteremia at days 2 and 5; acute kidney injury (AKI); microbiological relapse; microbiological treatment failure; and duration of intravenous antibiotics.

Results: The data and safety monitoring board recommended early termination of the study prior to enrollment of 440 patients because of safety. Among 352 patients randomized (mean age, 62.2 [SD, 17.7] years; 121 women [34.4%]), 345 (98%) completed the trial. The primary end point was met by 59 (35%) with combination therapy and 68 (39%) with standard therapy (absolute difference, -4.2%; 95% CI, -14.3% to 6.0%). Seven of 9 prespecified secondary end points showed no significant difference. For the combination therapy vs standard therapy groups, all-cause 90-day mortality occurred in 35 (21%) vs 28 (16%) (difference, 4.5%; 95% CI, -3.7% to 12.7%); persistent bacteremia at day 5 was observed in 19 of 166 (11%) vs 35 of 172 (20%) (difference, -8.9%; 95% CI, -16.6% to -1.2%); and, excluding patients receiving dialysis at baseline, AKI occurred in 34 of 145 (23%) vs 9 of 145 (6%) (difference, 17.2%; 95% CI, 9.3%-25.2%).

Conclusions And Relevance: Among patients with MRSA bacteremia, addition of an antistaphylococcal β-lactam to standard antibiotic therapy with vancomycin or daptomycin did not result in significant improvement in the primary composite end point of mortality, persistent bacteremia, relapse, or treatment failure. Early trial termination for safety concerns and the possibility that the study was underpowered to detect clinically important differences in favor of the intervention should be considered when interpreting the findings.

Trial Registration: ClinicalTrials.gov Identifier: NCT02365493.
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http://dx.doi.org/10.1001/jama.2020.0103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042887PMC
February 2020

Clinical manifestations of invasive meningococcal disease in Victoria with the emergence of serogroup W and serogroup Y Neisseria meningitidis.

Intern Med J 2021 Mar;51(3):390-397

Department of Infectious Diseases, Austin Health, Melbourne, Victoria, Australia.

Background: Historically, Australian cases of invasive meningococcal disease (IMD) have been most frequently caused by Neisseria meningitidis serogroup B, but recently an increase in cases due to serogroup W (MenW) and serogroup Y (MenY) has occurred.

Aim: To determine whether clinical manifestations of IMD have changed due to increased incidence of MenW and MenY.

Methods: We performed a retrospective review of IMD cases notified to the Department of Health and Human Services in Victoria, Australia. We compared the period between January 2013 and June 2015 (defined as P1) immediately before the increase in MenW and MenY was noted, with the equal time period of July 2015 to December 2017 (P2), when this increase was observed.

Results: IMD was notified more frequently in P2 than P1 (1.24 vs 0.53 per 100 000 person-years, P < 0.001). IMD cases in P2 were older (46 vs 19 years, P < 0.001), and more likely due to MenW (92/187, 49.2% vs 11/80, 13.8%, P < 0.001) or MenY (31/187, 16.6% vs 4/80, 5.0%, P = 0.01). IMD cases from P2 were more likely bacteraemic (151/187, 80.7% vs 55/80, 68.8%, P = 0.04), while meningitis (68/187, 36.4% vs 41/80, 51.3%, P = 0.03) and rash (65/181, 35.9% vs 45/78, 57.7%, P = 0.002) were less frequent. Intensive care unit admission rates and in-hospital mortality were unchanged.

Conclusion: Alongside an increase in IMD in Victoria, the proliferation of cases of MenW and MenY occurred in older patients, and were more often identified through bacteraemia rather than meningitis or purpura fulminans. Clinicians should be aware of these changes to facilitate earlier identification and treatment of IMD.
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http://dx.doi.org/10.1111/imj.14771DOI Listing
March 2021

Using language descriptors to recognise delirium: a survey of clinicians and medical coders to identify delirium-suggestive words.

Crit Care Resusc 2019 Dec;21(4):299-302

Data Analytics Research and Evaluation Centre, University of Melbourne and Austin Hospital, Melbourne, VIC, Australia.

Objective: To develop a library of delirium-suggestive words.

Design: Cross-sectional survey.

Setting: Single tertiary referral hospital.

Participants: Medical, nursing and allied health staff and medical coders.

Main Outcome Measures: Frequency of graded response on a 5-point Likert scale to individual delirium-suggestive words.

Results: Two-hundred and three complete responses were received from 227 survey respondents; the majority were medical and nursing staff (42.4% and 43.8% respectively), followed by allied health practitioners and medical coders (10.3% and 3.4%). Words that were "very likely" to suggest delirium were "confused/ confusion", "delirious", "disoriented/disorientation" and "fluctuating conscious state". Differences in word selection were noted based on occupational background, prior knowledge of delirium, and experience in caring for intensive care unit patients. Distractor words included in the survey were rated as "unlikely" or "very unlikely" by respondents as expected. Textual responses identified several other descriptors of delirium-suggestive words.

Conclusion: A comprehensive repertoire of delirium-suggestive words was validated using a multidisciplinary survey and new words suggested by respondents were added. The use of natural language processing algorithms may allow for earlier detection of delirium using our delirium library and be deployed for real-time decision making and clinical care.
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December 2019

Safety of cephalosporins in penicillin class severe delayed hypersensitivity reactions.

J Allergy Clin Immunol Pract 2020 03 31;8(3):1142-1146.e4. Epub 2019 Oct 31.

Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, WA, Australia; Department of Infectious Diseases, Vanderbilt University, Nashville, Tenn. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2019.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064395PMC
March 2020

Immunosuppressed Returned Traveler With Ulcerating Skin Lesion and Fever.

Clin Infect Dis 2019 05;68(10):1747-1749

Department of Infectious Diseases, Austin Health, Heidelberg.

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http://dx.doi.org/10.1093/cid/ciy518DOI Listing
May 2019