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Clinically important detection of infection as an 'incidental' finding during cancer staging using FDG-PET/CT

Wong PS, Lau WF, Worth LJ, Thursky KA, Drummond E, Slavin MA, et al.

Intern Med J, 2012 Feb;42(2):176-83.
PMID: 21309995 DOI: 10.1111/j.1445-5994.2011.02450.x

BACKGROUND:
FDG-PET/CT is widely used in the management of a variety of malignancies with excellent overall accuracy, despite the potential for false positive results related to infection and inflammation.

AIM:
As cancer patients can develop clinically inapparent infections, we evaluated the prevalence and nature of incidental findings reported to be suggestive of infections that had been identified during clinical cancer staging with FDG-PET/CT.

METHODS:
The study involved a retrospective analysis of 60 patients managed primarily at our facility from a total of 121 cases identified as having possible infection on clinical reporting of more than 4500 cancer staging investigations performed during the calendar year of 2008.

RESULTS:
Occult infections were uncommon overall (≤1%), but most often because of pneumonia (31.6%), upper respiratory tract infections (21.1%) or wound infections (15.8%). Abnormal scans contributed to patients' management in 52.7% of cases. Two out of 13 patients whose scan abnormalities were not investigated further had worsening changes on repeated scan and one of these patients had clinical deterioration.

CONCLUSIONS:
In patients with FDG-PET/CT scans suggestive of infection and in whom a final diagnosis could be reached, the positive predictive value for FDG-PET/CT scans was 89% suggesting that abnormal scans indicative of infection should be investigated further in this population.
Impact of fluorine-18 fluorodeoxyglucose positron emission tomography on diagnosis and antimicrobial utilization in patients with high-risk febrile neutropenia

Koh KC, Slavin MA, Thursky KA, Lau E, Hicks RJ, Drummond E, et al.

Leuk Lymphoma, 2012 Oct;53(10):1889-95.
PMID: 22448920 DOI: 10.3109/10428194.2012.677533

Early and targeted antimicrobial therapy improves outcomes in patients with febrile neutropenia (FN). We evaluated the impact of fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) on antimicrobial utilization in the management of FN. A cohort of patients with FN and hematological malignancy was identified. Cases (in whom FDG-PET was performed, n = 37) were compared with controls (in whom conventional investigations excluding FDG-PET were performed, n = 76). An underlying cause for FN was determined in 94.6% of cases, compared to 69.7% of controls. FDG-PET had a significant impact on antimicrobial utilization compared to conventional imaging (35.1% vs. 11.8%; p = 0.003), and was associated with shorter duration of liposomal amphotericin-B therapy for systemic fungal infection (median 4.0 days cases vs. 10.0 days controls; p = 0.001). Cases had a longer length of hospitalization (p = 0.016). In the management of patients with high-risk FN, FDG-PET improves diagnostic yield and allows rationalization of antifungal therapy. The impact upon healthcare costs associated with antimicrobial therapy for FN requires further evaluation.
Clinical effectiveness of early posaconazole suspension pre-emptive therapy in lung transplant recipients: The Alfred's experience

Jeong W, Snell GI, Levvey BJ, Westall GP, Morrissey CO, Ivulich S, et al.

J Antimicrob Chemother, 2017 Jul 01;72(7):2089-2092.
PMID: 28369489 DOI: 10.1093/jac/dkx085

Objectives: This study describes the clinical outcomes and therapeutic drug monitoring (TDM) following posaconazole suspension pre-emptive therapy in lung transplant (LTx) recipients.
Methods: This was a single-centre, retrospective cohort study evaluating posaconazole suspension pre-emptive therapy in LTx recipients between January 2009 and December 2015.
Results: Forty-two LTx recipients were prescribed posaconazole suspension pre-emptively. Aspergillus fumigatus was the most commonly isolated fungal organism. Of the patients receiving posaconazole suspension as the initial antifungal post-LTx, 93% had eradication of colonization at 6 months after commencing therapy. In contrast, only 61% had eradication of fungal colonization when posaconazole suspension was administered following initial therapy with voriconazole. Posaconazole suspension appeared to be well tolerated, although one case was curtailed following concern about abnormal liver function and another due to nausea/vomiting. TDM was performed in 37 patients. The initial median (IQR) trough plasma concentration ( C min ) following 400 mg twice-daily posaconazole suspension was 0.78 (0.46-1.19) mg/L. Doses beyond 800 mg daily did not appear to result in a higher median C min.
Conclusions: Early initiation of posaconazole suspension pre-emptive therapy in LTx recipients appears to be well tolerated and may potentially afford favourable clinical outcomes.
Lung transplant recipients receiving voriconazole and skin squamous cell carcinoma risk in Australia

Neoh CF, Snell GI, Levvey B, Kotsimbos T, Morrissey O, Slavin MA, et al.

Med J Aust, 2014 Nov 03;201(9):543-4.
PMID: 25358582
Single-centre study of therapeutic drug monitoring of posaconazole in lung transplant recipients: factors affecting trough plasma concentrations

Jeong W, Snell GI, Levvey BJ, Westall GP, Morrissey CO, Wolfe R, et al.

J Antimicrob Chemother, 2018 Mar 01;73(3):748-756.
PMID: 29211913 DOI: 10.1093/jac/dkx440

Objectives: This study describes therapeutic drug monitoring (TDM) of posaconazole suspension and modified release (MR) tablets in lung transplant (LTx) recipients and evaluates factors that may affect posaconazole trough plasma concentration (Cmin).
Methods: A single-centre, retrospective study evaluating posaconazole Cmin in LTx recipients receiving posaconazole suspension or MR tablets between January 2014 and December 2016.
Results: Forty-seven LTx patients received posaconazole suspension, and 78 received the MR tablet formulation; a total of 421 and 617 Cmin measurements were made, respectively. Posaconazole was concurrently administered with proton pump inhibitor in ≥ 90% of patients. The median (IQR) of initial posaconazole Cmin following 300 mg daily of posaconazole tablet was significantly higher than that of 800 mg daily of posaconazole suspension [1.65 (0.97-2.13) mg/L versus 0.81 (0.48-1.15) mg/L, P
A protocol for an international, multicentre pharmacokinetic study for Screening Antifungal Exposure in Intensive Care Units: The SAFE-ICU study

Roberts JA, Sime F, Lipman J, Hernández-Mitre MP, Baptista JP, Brüggemann RJ, et al.

Crit Care Resusc, 2023 Mar;25(1):1-5.
PMID: 37876989 DOI: 10.1016/j.ccrj.2023.04.002

OBJECTIVE: To describe whether contemporary dosing of antifungal drugs achieves therapeutic exposures in critically ill patients that are associated with optimal outcomes. Adequate antifungal therapy is a key determinant of survival of critically ill patients with fungal infections. Critical illness can alter an antifungal agents' pharmacokinetics, increasing the risk of inappropriate antifungal exposure that may lead to treatment failure and/or toxicity.
DESIGN SETTING AND PARTICIPANTS: This international, multicentre, observational pharmacokinetic study will comprise adult critically ill patients prescribed antifungal agents including fluconazole, voriconazole, posaconazole, isavuconazole, caspofungin, micafungin, anidulafungin, and amphotericin B for the treatment or prophylaxis of invasive fungal disease. A minimum of 12 patients are targeted for enrolment for each antifungal agent, across 12 countries and 30 intensive care units to perform descriptive pharmacokinetics. Pharmacokinetic sampling will occur during two dosing intervals (occasions): firstly, between days 1 and 3, and secondly, between days 4 and 7 of the antifungal course, collecting three samples per occasion. Patients' demographic and clinical data will be collected.
MAIN OUTCOME MEASURES: The primary endpoint of the study is attainment of pharmacokinetic/pharmacodynamic target exposures that are associated with optimal efficacy. Thirty-day mortality will also be measured.
RESULTS AND CONCLUSIONS: This study will describe whether contemporary antifungal drug dosing achieves drug exposures associated with optimal outcomes. Data will also be used for the development of antifungal dosing algorithms for critically ill patients. Optimised drug dosing should be considered a priority for improving clinical outcomes for critically ill patients with fungal infections.
Fulltext Multilocus Sequence Typing Reveals Extensive Genetic Diversity of the Emerging Fungal Pathogen Scedosporium aurantiacum

Harun A, Kan A, Schwabenbauer K, Gilgado F, Perdomo H, Firacative C, et al.

Front Cell Infect Microbiol, 2021;11:761596.
PMID: 35024355 DOI: 10.3389/fcimb.2021.761596

Scedosporium spp. are the second most prevalent filamentous fungi after Aspergillus spp. recovered from cystic fibrosis (CF) patients in various regions of the world. Although invasive infection is uncommon prior to lung transplantation, fungal colonization may be a risk factor for invasive disease with attendant high mortality post-transplantation. Abundant in the environment, Scedosporium aurantiacum has emerged as an important fungal pathogen in a range of clinical settings. To investigate the population genetic structure of S. aurantiacum, a MultiLocus Sequence Typing (MLST) scheme was developed, screening 24 genetic loci for polymorphisms on a tester strain set. The six most polymorphic loci were selected to form the S. aurantiacum MLST scheme: actin (ACT), calmodulin (CAL), elongation factor-1α (EF1α), RNA polymerase subunit II (RPB2), manganese superoxide dismutase (SOD2), and β-tubulin (TUB). Among 188 global clinical, veterinary, and environmental strains, 5 to 18 variable sites per locus were revealed, resulting in 8 to 23 alleles per locus. MLST analysis observed a markedly high genetic diversity, reflected by 159 unique sequence types. Network analysis revealed a separation between Australian and non-Australian strains. Phylogenetic analysis showed two major clusters, indicating correlation with geographic origin. Linkage disequilibrium analysis revealed evidence of recombination. There was no clustering according to the source of the strains: clinical, veterinary, or environmental. The high diversity, especially amongst the Australian strains, suggests that S. aurantiacum may have originated within the Australian continent and was subsequently dispersed to other regions, as shown by the close phylogenetic relationships between some of the Australian sequence types and those found in other parts of the world. The MLST data are accessible at http://mlst.mycologylab.org. This is a joined publication of the ISHAM/ECMM working groups on "Scedosporium/Pseudallescheria Infections" and "Fungal Respiratory Infections in Cystic Fibrosis".
Global guideline for the diagnosis and management of rare mould infections: an initiative of the European Confederation of Medical Mycology in cooperation with the International Society for Human and Animal Mycology and the American Society for Microbiology

Hoenigl M, Salmanton-García J, Walsh TJ, Nucci M, Neoh CF, Jenks JD, et al.

Lancet Infect Dis, 2021 Aug;21(8):e246-e257.
PMID: 33606997 DOI: 10.1016/S1473-3099(20)30784-2

With increasing numbers of patients needing intensive care or who are immunosuppressed, infections caused by moulds other than Aspergillus spp or Mucorales are increasing. Although antifungal prophylaxis has shown effectiveness in preventing many invasive fungal infections, selective pressure has caused an increase of breakthrough infections caused by Fusarium, Lomentospora, and Scedosporium species, as well as by dematiaceous moulds, Rasamsonia, Schizophyllum, Scopulariopsis, Paecilomyces, Penicillium, Talaromyces and Purpureocillium species. Guidance on the complex multidisciplinary management of infections caused by these pathogens has the potential to improve prognosis. Management routes depend on the availability of diagnostic and therapeutic options. The present recommendations are part of the One World-One Guideline initiative to incorporate regional differences in the epidemiology and management of rare mould infections. Experts from 24 countries contributed their knowledge and analysed published evidence on the diagnosis and treatment of rare mould infections. This consensus document intends to provide practical guidance in clinical decision making by engaging physicians and scientists involved in various aspects of clinical management. Moreover, we identify areas of uncertainty and constraints in optimising this management.