Safety and cost benefit of an ambulatory program for patients with low-risk neutropenic fever at an Australian centre

Teh BWBrown CJoyce TWorth LJSlavin MAThursky KA.


BACKGROUND: Neutropenic fever (NF) is a common complication of cancer chemotherapy. Patients at low risk of medical complications from NF can be identified using a validated risk assessment and managed in an outpatient setting. This is a new model of care for Australia. This study described the implementation of a sustainable ambulatory program for NF at a tertiary cancer centre over a 12-month period.

METHODS: Peter MacCallum Cancer Centre introduced an ambulatory care program in 2014, which identified low-risk NF patients, promoted early de-escalation to oral antibiotics, and early discharge to a nurse-led ambulatory program. Patients prospectively enrolled in the ambulatory program were compared with a historical-matched cohort of patients from 2011 for analysis. Patient demographics, clinical variables (cancer type, recent chemotherapy, treatment intent, site of presentation) and outcomes were collected and compared. Total cost of inpatient admissions was determined from diagnosis-related group (DRG) codes and applied to both the prospective and historical cohorts to allow comparisons.

RESULTS: Twenty-five patients were managed in the first year of this program with a reduction in hospital median length of stay from 4.0 to 1.1 days and admission cost from Australian dollars ($AUD) 8580 to $AUD2360 compared to the historical cohort. Offsetting salary costs, the ambulatory program had a net cost benefit of $AUD 71895. Readmission for fever was infrequent (8.0%), and no deaths were reported.

CONCLUSION: Of relevance to hospitals providing cancer care, feasibility, safety, and cost benefits of an ambulatory program for low-risk NF patients have been demonstrated.

Support Care Cancer. 2017 Oct 10. doi: 10.1007/s00520-017-3921-3. [Epub ahead of print]


Predicting Risk of Infection in Patients with Newly Diagnosed Multiple Myeloma: Utility of Immune Profiling

Teh BW, Harrison S, Allison CC, Slavin MA, Spelman T, Worth LJ, Thursky KA, Ritchie D, Pellegrini M.


BACKGROUND:A translational study in patients with myeloma to determine the utility of immune profiling to predict infection risk in patients with hematological malignancy was conducted.

METHODS:Baseline, end of induction, and maintenance peripheral blood mononuclear cells from 40 patients were evaluated. Immune cell populations and cytokines released from 1 × 106 cells/ml cultured in the presence of a panel of stimuli (cytomegalovirus, influenza, S. pneumoniae, phorbol myristate acetate/ionomycin) and in media alone were quantified. Patient characteristics and infective episodes were captured from clinical records. Immunological variables associated with increased risk for infection in the 3-month period following sample collection were identified using univariate analysis (p < 0.05) and refined with multivariable analysis to define a predictive immune profile.

RESULTS:525 stimulant samples with 19,950 stimulant-cytokine combinations across three periods were studied, including 61 episodes of infection. Mitogen-stimulated release of IL3 and IL5 were significantly associated with increased risk for subsequent infection during maintenance therapy. A lower Th1/Th2 ratio and higher cytokine response ratios for IL5 and IL13 during maintenance therapy were also significantly associated with increased risk for infection. On multivariable analysis, only IL5 in response to mitogen stimulation was predictive of infection. The lack of cytokine response and numerical value of immune cells were not predictive of infection.

CONCLUSION:Profiling cytokine release in response to mitogen stimulation can assist with predicting subsequent onset of infection in patients with hematological malignancy during maintenance therapy.

Front Immunol. 2017 Oct 5;8:1247. doi: 10.3389/fimmu.2017.01247. eCollection 2017.

PCR-based tests for the early diagnosis of sepsis. Where do we stand?

Ginn, Andrew N.; Halliday, Catriona L.; Douglas, Abby P.; Chen, Sharon C-A.

Current Opinion in Infectious Diseases

doi: 10.1097/QCO.0000000000000407


Purpose of review: Bloodstream infections are a major cause of hospital and ICU admission with high morbidity and mortality; however, early and targeted antimicrobial therapy reduces mortality in high-risk patients. This article focuses on the diagnosis of bloodstream infections by PCR-based approaches at an early stage to enable prompt treatment and prevent organ dysfunction.

Recent findings: PCR systems offering highly multiplexed targeting of bacterial and/or fungal pathogens (in whole blood) offer the best opportunity for clinical impact, as informed decisions can be made within 4-8 h of the blood draw. Although more rapid, these systems are typically associated with lower sensitivity and specificity than postculture detection methods which rely on microbial growth. Additionally, unlike postculture methods, detection directly from blood is not prone to misleading results because of concurrent (or previous) therapy, which limit clinical relevance.

Summary: Rapid and accurate identification of the cause of sepsis is essential in improving patient outcomes. Early identification of these pathogens by nucleic acid detection assays directly from blood samples remains key to achieving this, particularly if taken at the time of presentation. Selection of the most suitable PCR system is typically influenced by local epidemiology and by the resources of the testing laboratory.


What, where and why: exploring fluorodeoxyglucose-PET's ability to localise and differentiate infection from cancer

Douglas A1, Lau E, Thursky K, Slavin M.

Curr Opin Infect Dis. 2017 Sep 15. 



PURPOSE OF REVIEW: To review the utility of FDG-PET imaging in detecting the cause of fever and infection in patients with cancer.

RECENT FINDINGS: FDG-PET has been shown to have high sensitivity and accuracy for causes of neutropenic fever, leading to higher diagnostic certainty in this group. Recent advances in pathogen-specific labelling in PET to identify Aspergillus spp. and Yersinia spp. infections in mice, as well as differentiating between Gram-positive, Gram-negative and mycobacterial infections are promising.

SUMMARY: Patients with cancer are vulnerable to infection and fever, and the causes of these are frequently unclear using conventional diagnostic methods leading to high morbidity and mortality, length of stay and costs of care. FDG-PET/CT, with its unique complementary functional and anatomical information as well as its whole-body imaging capability, has demonstrated use in detecting occult infection in immunocompromised patients, including invasive fungal and occult bacterial infections, as well as defining extent of infection. By demonstrating disease resolution following treatment and allowing earlier cessation of therapy, FDG-PET acts as a key tool for antimicrobial and antifungal stewardship. Limitations include at times poor differentiation between infection, malignancy and sterile inflammation, however, exciting new technologies specific to infectious pathogens may help alleviate that issue. Further prospective randomised research is needed to explore these benefits in a nonbiased fashion.

DOI: 10.1097/QCO.0000000000000405


Urbancic KF, Ierino F, Phillips E, Mount PF, Mahony A, Trubiano JA.


While trimethoprim-sulfamethoxazole is considered first-line therapy for Pneumocystis pneumonia prevention in renal transplant recipients, reported adverse drug reactions may limit use and increase reliance on costly and less effective alternatives, often aerosolized pentamidine. We report our experience implementing a protocolized approach to trimethoprim-sulfamethoxazole adverse drug reaction assessment and rechallenge to optimize prophylaxis in this patient cohort. We retrospectively reviewed 119 patients receiving Pneumocystis pneumoniaprophylaxis prior to and after protocol implementation. Forty-two patients (35%) had 48 trimethoprim-sulfamethoxazole adverse drug reactions documented either at baseline or during the prophylaxis period, of which 83% were non-immune-mediated and 17% were immune-mediated. Significantly more patients underwent trimethoprim-sulfamethoxazole rechallenge after protocol implementation (4/22 vs. 23/27; P=0.0001), with no recurrence of adverse drug reactions in 74%. In those who experienced a new or recurrent reaction (26%), all were mild and self-limiting with only 1 recurrence of an immune-mediated reaction. After protocol implementation, aerosolized pentamidine-associated costs were reduced. The introduction of a standard approach to trimethoprim-sulfamethoxazole rechallenge in the context of both prior immune and non-immune-mediated reactions was safe and successful in improving the uptake of first-line Pneumocystis pneumoniaprophylaxis in renal transplant recipients. This article is protected by copyright. All rights reserved.

Am J Transplant. 2017 Sep 12. doi: 10.1111/ajt.14498. [Epub ahead of print]


Haeusler GM, Thursky KA, Slavin MA, Mechinaud F, Babl FE, Bryant P, De Abreu Lourenco R, Phillips R.



Fever and neutropenia (FN) clinical decision rules (CDRs) are recommended to help distinguish children with cancer at high and low risk of severe infection. The aim of this study was to validate existing pediatric FN CDRs, designed to stratify children with cancer at high or low risk of serious infection or medical complication.


Pediatric CDRs suitable for validation were identified from a literature search. Relevant data were extracted from an existing dataset of 650 retrospective FN episodes in children with cancer. The sensitivity and specificity of each of the CDR were compared with the derivation studies to assess reproducibility.


Six CDRs were identified for validation: two were designed to predict bacteremia and four to predict adverse events. Five CDRs exhibited reproducibility in our cohort. A rule predicting bacteremia had the highest sensitivity (100%; 95% confidence interval (CI) 93-100%) although poor specificity (17%) with only 15% identified as low risk. For adverse events, the highest sensitivity achieved was 84% (95% CI, 75-90%) with specificity of 29% and 27% identified as low risk. A rule intended for application after a 24-hour period of inpatient observation yielded a sensitivity of 80% (95% CI, 73-86) and specificity of 46%, with 44% identified as low-risk.


Five CDRs were reproducible although not all can be recommended for implementation because of either inadequate sensitivity or failure to identify a clinically meaningful number of low-risk patients. The 24-hour rule arguably exhibits the best balance between sensitivity and specificity in our population.

Pediatr Infect Dis J. 2017 Sep 5. doi: 10.1097/INF.0000000000001777. [Epub ahead of print]



Trubiano JA, Stone CA, Lindsay Grayson M, Urbancic K, Slavin MA, Thursky KA, Phillips EJ.


Antibiotic allergy labeling is highly prevalent and negatively impacts patient outcomes and antibiotic appropriateness. Reducing the prevalence and burden of antibiotic allergies requires the engagement of key stakeholders such as allergists, immunologists, pharmacists, and infectious diseases physicians. To help address this burden of antibiotic allergy overlabeling, we review 3 key antibiotic allergy domains: (1) antibiotic allergy classification, (2) antibiotic cross-reactivity, and (3) multidisciplinary collaboration. We review the available evidence and research gaps of currently used adverse drug reaction classification systems, antibiotic allergy cross-reactivity, and current and future models of antibiotic allergy care.

Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

J Allergy Clin Immunol Pract. 2017 Aug 23. pii: S2213-2198(17)30501-9. 

Cytomegalovirus Reactivation Is Associated with Increased Risk of Late-Onset Invasive Fungal Disease after Allogeneic Hematopoietic Stem Cell Transplantation: A Multicenter Study in the Current Era of Viral Load Monitoring.

Yong MK, Ananda-Rajah M, Cameron PU, Morrissey CO, Spencer A, Ritchie D, Cheng AC, Lewin SR, Slavin M.

Biol Blood Marrow Transplant. 2017 Aug 7. pii: S1083-8791(17)30621-3. 


Opportunistic infections such as cytomegalovirus (CMV) reactivation and invasive fungal disease (IFD) cause significant morbidity and mortality to recipients of hematopoietic stem cell transplant (HSCT). We aimed to characterize the risk and relationship of CMV reactivation post-HSCT to IFD in the current era of CMV viral load monitoring using highly sensitive plasma DNA. A multicenter, retrospective, cohort study was conducted of consecutive patients undergoing allogeneic HSCT from January 2006 to December 2010 in Melbourne, Australia. CMV reactivation was defined as detection of plasma CMV DNA ≥ 546 IU/mL or development of CMV disease. IFD was classified in accordance with current international consensus guidelines. Of the 419 study participants, the median age was 44 years (IQR, 34 to 54), and CMV reactivation occurred in 106 participants (25%) at a median time of 56 days (IQR, 45 to 79). Thirty-eight participants (9.1%) were identified with 41 cases of IFD (n = 22 proven, n = 8 probable, n = 11 possible) at a median time of 76 days (IQR, 24 to 344). The incidence of IFD was higher in participants with CMV reactivation compared with no CMV reactivation (15% versus 7%, P = .012). In a multivariate analysis CMV reactivation remained an independent risk factor for IFD (hazard ratio, 3.7; 95% CI, 1.6% to 8.5%; P = .002). The cumulative incidence of all IFD in patients with and without CMV reactivation using a competing risk regression was a hazard ratio of 2.2 (95% CI, 1.2 to 4.1; P = .017) and for late-onset IFD was a hazard ratio of 3.95 (95% CI, 1.7 to 9; P = .001). The median time to IFD onset was longer in participants with than without CMV reactivation (184 versus 37 days, P = .03). The peak viral load, detection of any level of viremia, and experiencing more than 1 episode of CMV reactivation were not associated with development of IFD. CMV reactivation in HSCT recipients in the post-transplant period is associated with an increased risk of developing late-onset IFD. Further research is warranted to understand the interaction between these 2 important infectious complications.

Copyright © 2017. Published by Elsevier Inc.


Colombo AL, de Almeida Júnior JN, Slavin MA, Chen SC, Sorrell TC.


Critically ill patients and patients with haematological cancer are HIV-negative populations at high risk of invasive fungal infections. In intensive-care units, candidaemia and intra-abdominal candidiasis predominate, but aspergillosis has emerged as a lethal, under-recognised cause of pneumonia. In patients with haematological malignancies or who have undergone stem-cell transplantations, pulmonary disease due to aspergillus and other mould diseases predominate. In this Series paper, we provide an update on risk assessment, new diagnostic strategies, and therapeutic approaches. New concepts have emerged for use of risk prediction rules and an evidence base now exists for inclusion of biomarkers (eg, galactomannan, 1,3-β-D-glucan, and PCR assays for Aspergillus spp) into early diagnostic and therapeutic strategies. Imaging techniques remain helpful for early diagnosis of pulmonary mould diseases, with PET techniques offering potential improvements in diagnostic specificity and evaluation of clinical response. Echinocandins and triazoles have been validated extensively for prophylaxis, empirical therapy, and targeted therapy, but an increase in intrinsically resistant fungi and emergence of secondary resistance as a result of drug-induced selection pressure are of major concern. Echinocandins remain a major component of treatment of invasive candidiasis and new triazoles are the best alternative for prophylaxis and therapy of invasive aspergillosis.

Copyright © 2017 Elsevier Ltd. All rights reserved.

Lancet Infect Dis. 2017 Jul 31. pii: S1473-3099(17)30304-3.