Senthil Lingaratnam

Use of empiric antimicrobial therapy in neutropenic fever

Administration of empiric antimicrobial therapy is standard practice in the management of neutropenic fever, but there remains considerable debate about the selection of an optimal regimen. In view of emerging evidence regarding efficacy and toxicity differences between empiric treatment regimens, and strong evidence of heterogeneity in clinical practice, the current guidelines were developed to provide Australian clinicians with comprehensive guidance for selecting an appropriate empiric strategy in the setting of neutropenic fever. Beta‐lactam monotherapy is presented as the treatment of choice for all clinically stable patients while early treatment with combination antibiotic therapy is considered for patients at higher risk. Due consideration is given to the appropriate use of glycopeptides in this setting. Several clinical caveats, accounting for institution‐ and patient‐specific risk factors, are provided to help guide the judicious use of the agents described. Detailed recommendations are also provided regarding time to first dose, timing of blood cultures, selection of a first‐line antibiotic regimen, subsequent modification of antibiotic choice and cessation of therapy.

Use of risk stratification to guide ambulatory management of neutropenic fever

Utilization of risk‐stratification tools in the setting of neutropenic fever is currently limited by inadequate knowledge and lack of awareness. Within this context, the approach to management of low‐risk patients with neutropenic fever is inconsistent with the available evidence across many Australian treating centres. These clinical guidelines define and clarify an accepted standard of care for this patient group given the current evidence base. The Multinational Association for Supportive Care in Cancer risk index is presented as the preferred risk assessment tool for determining patient risk. Suitability of ambulatory care within specific patient populations is discussed, with defined eligibility criteria provided to guide clinical decision‐making. Detailed recommendations for implementing appropriate ambulatory strategies, such as early discharge and outpatient antibiotic therapy, are also provided. Due consideration is given to infrastructural requirements and other supportive measures at a resourcing and operational level. An analysis of the relevant health economics is also presented.

Use of antibacterial prophylaxis for patients with neutropenia

The use of oral prophylactic antibiotics in patients with neutropenia is controversial and not recommended by this group because of a lack of evidence showing a reduction in mortality and concerns that such practice promotes antimicrobial resistance. Recent evidence has demonstrated non‐significant but consistent, improvement in all‐cause mortality when fluoroquinolones (FQs) are used as primary prophylaxis. However, the consensus was that this evidence was not strong enough to recommend prophylaxis. The evidence base for FQ prophylaxis is presented alongside current consensus opinion to guide the appropriate and judicious use of these agents. Due consideration is given to patient risk, as it pertains to specific patient populations, as well as the net effect on selective pressure from antibiotics if FQ prophylaxis is routinely used in a target population. The potential costs and consequences of emerging FQ resistance, particularly among Escherichia coli, Clostridium difficile and Gram‐positive organisms, are considered. As FQ prophylaxis has been advocated in some chemotherapy protocols, specific regard is given to whether FQ prophylaxis should be used to support these regimens. The group also provides recommendations for monitoring and surveillance of emerging resistance in those centres that have adopted FQ prophylaxis.

An Australian survey of clinical practices in management of neutropenic fever in adult cancer patients 2009

Background:  An abundance of new evidence regarding treatment strategies for neutropenic fever is likely to contribute to variability in practice across institutions and clinicians alike.

The disease and economic burden of neutropenic fever in adult patients in Australian cancer treatment centres 2008: analysis of the Victorian Admitted Episodes Dataset

Background:  Although the incidence of neutropenic fever (FN) is estimated to be up to 80% for some malignancies, the epidemiological characteristics and economic burden are not well understood for Australian patients.

Late‐onset Pneumocystis jirovecii pneumonia post–fludarabine, cyclophosphamide and rituximab: implications for prophylaxis

Fludarabine, cyclophosphamide and rituximab (FCR) therapy for lymphoid malignancies has historically been associated with a low reported incidence of Pneumocystis jirovecii pneumonia (PJP). However, prophylaxis was routinely used in early studies, and molecular diagnostic tools were not employed. The objective of this study was to review the incidence of PJP during and post‐FCR in the era of highly sensitive molecular diagnostics and 18F‐fluorodeoxyglucose (FDG) positron emission tomography (PET)–computerised tomography (CT).

Use of empiric antimicrobial therapy in neutropenic fever. Australian Consensus Guidelines 2011 Steering Committee.

Administration of empiric antimicrobial therapy is standard practice in the management of neutropenic fever, but there remains considerable debate about the selection of an optimal regimen. In view of emerging evidence regarding efficacy and toxicity differences between empiric treatment regimens, and strong evidence of heterogeneity in clinical practice, the current guidelines were developed to provide Australian clinicians with comprehensive guidance for selecting an appropriate empiric strategy in the setting of neutropenic fever. Beta‐lactam monotherapy is presented as the treatment of choice for all clinically stable patients while early treatment with combination antibiotic therapy is considered for patients at higher risk. Due consideration is given to the appropriate use of glycopeptides in this setting. Several clinical caveats, accounting for institution‐ and patient‐specific risk factors, are provided to help guide the judicious use of the agents described. Detailed recommendations are also provided regarding time to first dose, timing of blood cultures, selection of a first‐line antibiotic regimen, subsequent modification of antibiotic choice and cessation of therapy.

Australian consensus guidelines for the safe handling of monoclonal antibodies for cancer treatment by healthcare personnel

These consensus guidelines provide recommendations for the safe handling of monoclonal antibodies. Definitive recommendations are given for the minimum safe handling requirements to protect healthcare personnel. The seven recommendations cover: (i) appropriate determinants for evaluating occupational exposure risk; (ii) occupational risk level compared with other hazardous and non‐hazardous drugs; (iii) stratification of risk based on healthcare personnel factors; (iv) waste products; (v) interventions and safeguards; (vi) operational and clinical factors and (vii) handling recommendations. The seventh recommendation includes a risk assessment model and flow chart for institutions to consider and evaluate clinical and operational factors unique to individual healthcare services. These guidelines specifically evaluated monoclonal antibodies used in the Australian cancer clinical practice setting; however, the principles may be applicable to monoclonal antibodies used in non‐cancer settings. The guidelines are only applicable to parenterally administered agents.

Introduction to the Australian consensus guidelines for the management of neutropenic fever in adult cancer patients, 2010/2011

The current consensus guidelines were developed to standardize the clinical approach to the management of neutropenic fever in adult cancer patients throughout Australian treating centres. The three areas of clinical practice covered by the guidelines, the process for developing consensus opinion, and the system used to grade the evidence and relative strength of recommendations are described. The health economics implications of establishing clinical guidance are also discussed.

Fluoroquinolone prophylaxis: a word of caution

The recent audit of treatment outcomes of fluor-oquinolone (FQ) prophylaxis from a tertiary hospitalin Singapore [1] highlights important considerationsfor the use of FQ prophylaxis in patients withhematologic–oncologic disease. A hospital preva-lence of FQ resistance in Escherichia coli isolatedfrom internal medicine patients above 20% has beenreported to be associated with significant loss of FQprophylaxis efficacy in patients with hematologic–oncologic disease, such that the protective effect ofFQ prophylaxis on reducing febrile episodes anddocumented infections is severely blunted [2,3]. Thishas been well demonstrated in the study by Ng et al.,where the rate of resistance in E. coli was 34.4% [1].As the authors indicate, the role of FQ prophylaxisrequires further evaluation in areas of the worldwhere FQ resistance is prevalent amongst gram-negative isolates, such as parts of South and LatinAmerica, and South East Asia [4].Although not all countries have such rates of FQresistance, no appropriately designed time-seriesanalyses have effectively evaluated the relationshipbetween FQ prophylaxis and rates of infection byFQ-resistant bacteria in oncology patients. Attemptsto do so [5] have been limited by study design,inadequate duration of surveillance, and incompletereporting. There is concern that widespread use ofFQ prophylaxis may result in increased rates ofresistance, and this has recently been demonstratedin a single center in allogeneic transplant recipientsreceiving levofloxacin prophylaxis [6,7].FQ prophylaxis alters colonizing flora, particularlyof the gastrointestinal tract. This may occur byindividual exposure to FQs or by horizontaltransmission of biologically fit, FQ-resistant bacteria(such as E. coli, Pseudomonas aeruginosa, and coagu-lase-negative staphylococci) such that, over time, themajority of a hospital’s patient population maydevelop colonization with FQ-resistant organisms.Support for these concepts comes from ecologicalstudies that have shown selection of FQ-resistantstrains results from selective pressure of antibiotics,mainly (but not limited to) excessive use of fluor-oquinolones, and this may take many months (up toa year) to manifest within a hospital setting [8].Further, FQ prophylaxis has been consistentlyassociated with FQ resistance in (but not limitedto) gram-negative bacteria (GNB), particularly E. coli[3,9]. There also appears to be an association withFQ use and FQ resistance in viridans groupstreptococci, coagulase-negative staphylococci, Sta-phylococcus aureus, and outbreaks of Clostridiumdifficile, including the hypervirulent strain [10].Although FQ prophylaxis is advocated in someclinical practice guidelines [11], the evidence for amortality benefit is not conclusive. Gafter-Gvili et al.,in a large systematic review (SR) (which includedpseudo-randomized controlled trials), demonstratedreduced overall mortality [5]. However, many of theincluded studies were small, were of variable quality(i.e. not always blinded), and spanned over a longtime period (e.g. 1987–2005), during which practicesrelated to empiric antibiotic therapy are likely to havechanged. No mortality benefit could be shown in asub-analysis of good-quality randomized controlledtrials (RCTs). In contrast, a number of RCTs andSRs have consistently shown significant reductions infebrile neutropenia episodes and microbiologically