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

Authors


  • Conflict of interest: The following working group members are consultants or advisory committee members or receive honoraria, fees for service, or travel assistance (independent of research-related meetings) from; or have research or other associations with the organisations listed: Ian Davis – Novartis, Pfizer, GlaxoSmithKline, Schering-Plough; Sue Kirsa – Roche, Schering Plough, Amgen, Hospira, Alphapharm; Senthil Lingaratnam – Victorian Integrated Cancer Services; Orla Morrissey – Gilead, Merck Sharp & Dohme, Orphan, Pfizer, Schering Plough; Monica Slavin – Gilead, Merck Sharp & Dohme, Pfizer, Schering Plough; Karin Thursky – Gilead, Merck Sharp & Dohme, Pfizer, Schering Plough.

Senthil Lingaratnam, Pharmacy Department, Peter MacCallum Cancer Centre, St. Andrew's Place, East Melbourne, Victoria, 3002 Australia. E-mail: Senthil.Lingaratnam@petermac.org

Abstract

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.

Aims:  To describe current clinical practices in Australia, by surveying haematologists, oncologists and infectious diseases physicians involved in cancer care.

Methods:  Clinician members from Australian professional associations, accounting for the vast majority of Australian cancer specialists, were invited to participate in an electronic survey, comprising of a clinical case-based questionnaire. Clinical practice areas explored were: use of risk-assessment and empiric antibiotic strategies across various treatment settings; use of anti-bacterial prophylaxis; and use of granulocyte-colony stimulating factors for established neutropenic fever and for secondary prophylaxis.

Results:  A total of 252 clinicians returned responses (approximately 30% response rate). The majority (>70%) were representative of practices in public, major city, tertiary referral hospitals. Less than half of clinicians were aware of risk-assessment tools and less than quarter currently used ambulatory care strategies. If adequate resources were made available, more than 80% were willing to use risk-assessment tools and 60% more clinicians were likely to use ambulatory care strategies. Most clinicians prescribed dual therapy parenteral antibiotics, even for clinically stable patients (53% haematologists, 56% oncologists). Granulocyte-colony stimulating factor was used frequently as secondary prophylaxis in the breast cancer case (91%), follicular lymphoma case (59%) and non-small cell lung cancer case (31%). Fluoroquinolone prophylaxis was infrequently prescribed (19% oncologists, 30% haematologists).

Conclusions:  Evidence–practice gaps were identified around the use of risk-assessment-based empiric therapy, and help to inform better clinical guidance.

Introduction

Fever in neutropenic patients is the most frequent complication of chemotherapy for cancer.1 Despite the widespread use of haematopoietic colony-stimulating factors and advances in antibiotic therapy, both morbidity and mortality remain substantial. Mortality rates for critically ill patients are 10–20% with rates for patients with Gram-negative bacteraemia as high as 40%.2,3 Critical to patient survival is the timely administration of appropriate empiric antibiotic therapy.4,5 It is therefore crucial that institutional protocols and guidelines exist to elucidate clinical pathways and facilitate prompt and appropriate management of neutropenic fever.

There has been an abundance of new evidence regarding treatment strategies for fever and neutropenia. The emergence of new risk factors in immunocompromised hosts, the constantly changing epidemiology of infections, the increasing trends in bacterial resistance and increasing emphasis on cost-effectiveness for healthcare interventions are reasons for variability in practice across institutions and clinicians alike. We sought to describe current clinical practices in Australia, by surveying Australian oncology and haematology cancer clinicians. Infectious diseases (ID) physicians were also surveyed given their frequent involvement in formulating institutional guidelines around antibiotic use. Four major areas of neutropenic fever management were explored in this survey. These areas include:

  • 1The use of risk stratification in the differential management of high- and low-risk patients, including management in the ambulatory care setting.
  • 2Empiric antibiotic strategies that take into account patient risk and severity of illness.
  • 3The use of anti-bacterial prophylaxis in neutropenic patients.
  • 4The use of recombinant human granulocyte colony stimulating factors (rHu-GCSF) for established neutropenic fever and for secondary prophylaxis.

Materials and methods

Study population

In July 2009, we made a formal application to several key professional associations, including the Haematology Society of Australia and New Zealand (HSANZ), the Australasian Leukaemia and Lymphoma Group (ALLG), the Medical Oncology Group of Australia (MOGA) and Private Cancer Physicians of Australia (PCPA) to survey their members. All practising haematology-oncologist and/or medical oncologist members from private and public sectors, metropolitan and regional treatment centres were invited by email to complete an online survey. This consisted of 500 HSANZ members, (undeterminable haematology-oncology (HO) membership), 241 ALLG members, 303 MOGA members and 138 PCPA members, accounting for at least 95% of Australian cancer specialists. A further sample of ID physicians who were members of Ozbug (an email discussion group of the Australasian Society of Infectious Diseases) was also surveyed. Clinicians were asked to base their answers on actual practice or policy of their unit, and not on personal opinions. The survey was made available from 12 August to 9 September 2009. A reminder email was sent on day 16 of the survey period.

Survey

A team of ID physicians, haematology and medical oncologists and pharmacists developed the electronic survey tool, with assistance from the health informatics team at the Western and Central Melbourne Integrated Cancer Services. This was piloted within a single institution to ensure validity and reliability of responses. A steering committee that comprised of lead clinicians from key stakeholder organizations who oversaw development of the Australian Neutropenic Fever Guidelines 2010 reviewed and improved the survey tool prior to its distribution.

Separate clinical case-based survey tools were developed for medical oncology (MO) and HO given the risk of infectious complications is inherently different for both types of malignancy. These were aimed at identifying typical treatment pathways for hypothetical scenarios of neutropenic fever. The MO version consisted of questions around a breast cancer patient with low burden of neutropenic fever symptoms (Case 1 MO) and a second case of a lung cancer patient with more severe symptoms (Case 2 MO). This survey was distributed to medical oncologists from MOGA and PCPA. The HO version consisted of questions around three cases; a follicular lymphoma (low-grade non-Hodgkin lymphoma (NHL)) patient with low burden of neutropenic fever symptoms (Case 1 HO), a Burkitt's lymphoma patient with more severe symptoms (Case 2 HO) and an acute leukemic patient presenting for re-induction chemotherapy (Case 3 HO). This survey was presented to HO members of ALLG, HSANZ and PCPA. MO members of MOGA and PCPA who usually treat lymphomas were also invited to answer questions relating to the two lymphoma cases. Both versions were distributed to a sample of ID physicians. Demographics and hospital capacity information were also captured in the survey without identifying respondents or their institutions. Please refer to the appendix for a copy of the survey tool (Appendix I).

Case 1 MO and Case 1 HO provided information needed to calculate a Multinational Association for Supportive Care in Cancer (MASCC) risk score ≥21, suggesting low risk of medical complications. The actual score was not provided in the survey tool. Clinicians were asked whether they considered these cases to be low or high risk of developing medical complications. They were further asked what combination of inpatient and/or ambulatory care strategies and parenteral and/or oral antibiotic regimens would be used, both in current practice and under ideal conditions where ambulatory care infrastructural and clinical resources were optimal. They were also asked to grade factors that influenced such treatment decisions as ‘very important’, ‘somewhat important’, ‘not important’ or’ not applicable/unsure’. Clinicians were also asked about their practices in using rHu-GCSF to treat the episode of neutropenic fever and for secondary prophylaxis.

Case 2 MO and Case 2 HO depicted a patient with more severe symptoms, admitted for parenteral antibiotic therapy. The MASCC risk score could be calculated and was <21, suggesting higher risk of medical complications. Clinicians were queried about their choice of empiric antibiotic regimens, in particular their use of anti-pseudomonal beta-lactam antibiotics, aminoglycosides (e.g. gentamicin) and glycopeptides (e.g. vancomycin). Clinicians answering Case 2 MO were also asked if they would use rHu-GCSF and/or antibiotics for prophylaxis against future events of neutropenic fever.

Case 3 HO depicted a pretreated and refractory acute myeloid leukemic patient at high risk for neutropenic fever. Clinicians were queried about practices in using antibiotic prophylaxis.

Results

Practice settings of respondents

A total of 252 clinician responses were received. For the haematology survey, 120 cancer clinicians returned responses comprising of 105 haematology-oncologists, four medical oncologists and 11 who practised in both fields. This cohort is hereafter referred to as ‘haematology respondents (HR)’. For the MO survey, 94 medical oncologists returned responses, hereafter referred to as ‘oncology respondents (OR)’. There was significant membership overlap across various professional body associations, for example, PCPA and MOGA; PCPA, ALLG and HSANZ. Furthermore, the proportion of haematology-oncologists among haematologists and pathologists from the HSANZ could not be determined. Therefore, only an estimated response rate of 30% could be made for both versions. A further 19 ID physicians returned responses for both versions; these results are summarized separately.

The majority of responses from both haematology and oncology surveys were representative of practices in public, tertiary referral hospitals, situated in major cities (Table 1). Clinicians who worked in institutions that performed allogeneic transplants accounted for 42% and 22% of the responses for haematology and oncology surveys respectively. Approximately half of the clinicians who represented their clinical practices in the private sector acknowledged that they also worked in the public sector.

Table 1.  Demographics and hospital capacity information of surveyed clinicians
Institution characteristicHaematology respondentsOncology respondentsInfectious diseases physicians
n= 120 (%)n= 94 (%)n= 19 (%)
Institution type   
 Public106(88)74(78)17(89)
 Private14(12)20(22)2(11)
 Metropolitan102(85)81(86)17(89)
 Regional18(15)13(14)2(11)
 Tertiary referral centre98(82)70(74)19(100)
 NSW26(22)31(33)5(26)
 VIC27(23)30(32)4(21)
 QLD24(20)11(12)2(11)
 SA12(10)8(9)1(5)
 WA8(7)6(6)2(11)
 TAS4(3)3(3)3(16)
 ACT1(1)5(5)2(11)
 NT2(2)0(0)0(0)
 NZ12(10)0(0)
Inpatient bed capacity   
 ≤50 beds2(2)1(1)0(0)
 51–200 beds15(13)18(19)1(5)
 201–500 beds58(48)51(54)12(63)
 >500 beds43(36)22(23)5(26)
 Did not answer2(2)2(2)1(5)
Inpatient bed capacity for cancer patients   
 ≤10 beds9(8)1(1)0(0)
 11–30 beds73(61)18(19)10(53)
 31–50 beds26(22)51(54)7(37)
 >50 beds10(8)22(24)1(5)
 Did not answer2(2)2(2)1(5)

Facilities/resources available to respondents (both surveys)

More than 85% of respondents reported that inpatient wards, outpatient clinics, a day facility (less than 8-h stay) and emergency department were available at their institution. Facilities most frequently used for neutropenic febrile patients were inpatient wards (>95%), emergency departments (>80%) and day facilities (50% and 35% for haematology and oncology respectively). Where outpatient clinics, short-stay wards (60–65%) and hospital-in-the-home (HITH) services (57–63%) were available in their institution, less than half of HR and less than one-third of OR used these facilities for neutropenic febrile patients.

Approximately 97% of HR and 86% of OR noted that institutional guidelines for neutropenic fever management were available, and three-quarters believed that they were generally followed. More than half of the respondents without institutional guidelines (12 of 17) were from the private sector.

Knowledge of risk assessment and attitudes to ambulatory care antibiotic therapy

Case 1: low-risk (by Multinational Association for Supportive Care in Cancer score) fever and neutropenia

Approximately 47% (n= 54) of HR and 60% (n= 53) of OR correctly identified Case 1 as low risk of developing medical complications, with most other respondents believing that patient was high-risk. Of those that answered low-risk, more than half would treat as an inpatient until fever resolved and more than one-third until neutropenia resolved. Less than a one-quarter used early discharge strategies and fewer than 5% would manage solely in an outpatient setting. When asked which strategies (or combination of) would be used in ideal conditions of adequately equipped ambulatory care resources, there was greater than 20% increase in preference for early discharge strategies, and similar increases in preferences for outpatient strategies and HITH services. Similar trends are noted for the entire cohort of respondents, regardless of their risk classification of Case 1 (Fig. 1).

Figure 1.

Current and ideal practice preference selected by all clinicians for Case 1 (n= 214). (inline image) current practice (Med Onc); (inline image) ideal practice (Med Onc); (inline image) current practice (Haem); (inline image) ideal practice (Haem). FN, neutropenic fever.

About 44% of clinicians (56% HR and 39% OR) acknowledged they were unaware of risk-assessment tools. However, a large majority of 85% (n= 104 HR and n= 79 OR) would be willing to use such tools to assist with patient assessment.

Factors influencing choice of inpatient versus ambulatory care

The top-ranking factors selected by clinicians as most important reasons for their current practice to admit patients, such as those described in Case 1 (low risk of complications), were (i) hospital capacity to follow up patients in an ambulatory setting and (ii) concern that medical complications would ensue (Fig. 2). Respondents further detailed capacity to meet educational needs of the patient and carer as another important consideration.

Figure 2.

Factors governing clinician decision to treat as inpatient or within ambulatory care setting (n= 212; two did not answer). (inline image) very important (Haem); (inline image) somewhat important (Haem); (inline image) very important (Med Onc); (inline image) somewhat important (Med Onc).

Current use of oral antibiotic therapy

Fewer than 15% (14% OR and 10% HR) would prescribe oral antibiotics for Case 1 at presentation, of which more than three-quarters would prescribe a combination of ciprofloxacin and amoxicillin/clavulanate. Of the proportion that would prescribe parenteral antibiotics, 75% of OR and 85% of HR would switch to oral antibiotics during the course of the episode. Important factors in the decision to switch to oral antibiotics were whether patients were clinically well and afebrile (Fig. 3). Compared with HR, OR placed greater emphasis on patients needing to be free of, or have had their central venous catheters removed (P < 0.01), and less emphasis on the need to remain an inpatient after oral switch for a period of observation (P < 0.05) (Fig. 3).

Figure 3.

Factors, prioritized by importance, governing clinician decision to switch to oral antibiotics (n= 187). (inline image) very important (Haem); (inline image) somewhat important (Haem); (inline image) very important (Med Onc); (inline image) somewhat important (Med Onc).

Discharge planning

When respondents were asked when Case 1 was likely to be discharged, regardless of whether oral switch occurred, approximately 80% of HR and OR said after fevers abate and when neutrophil count recovers above 0.5 × 109 cells/L (42% OR, 51% HR) or above 1.0 × 109 cells/L (32% OR, 12%HR). The remainder would discharge Case 1 as soon as oral antibiotics were started (10% OR and HR) and/or at least 24 h (calculated median) of being clinically stable on oral antibiotics (10% OR and 18% HR). If ambulatory infrastructure was adequate and ideal, then 10% fewer OR and 20% fewer HR required complete resolution of fevers, and 21% fewer OR required that a patient's neutrophil count recover above 1 × 109 cells/L. In addition, 10% more OR and 22% more HR would discharge patients either as soon as oral antibiotics were initiated and/or after a period of 24 h (calculated median) of the patient being stable on an antibiotic regimen.

Parenteral therapy

Case 1: low-risk (by Multinational Association for Supportive Care in Cancer score) fever and neutropenia

The majority that selected parenteral therapy for Case 1 (90% HR and 86% OR) were mixed in their use of mono-therapy (β-lactam antibiotic) and dual therapy (β-lactam antibiotic combined with an aminoglycoside or ciprofloxacin). The most frequently prescribed dual therapy regimen by OR was ticarcillin/clavulanate and gentamicin (43%). Just under half (47% HR, 44% OR) used mono-therapy; single-agent antibiotics most frequently prescribed by OR were cefepime (25%) followed by piperacillin/tazobactam (17%) while the reverse order was true for HR (14% and 28% respectively).

Case 2: high-risk (by Multinational Association for Supportive Care in Cancer score) fever and neutropenia with hypotension

More than 85% of clinicians prescribed dual therapy for Case 2 (presenting with more severe symptoms). OR most commonly prescribed gentamicin with ticarcillin/clavulanate (51%) or cefepime (28%) or piperacillin/tazobactam (18%). HR most commonly selected gentamicin with piperacillin/tazobactam (46%) or ticarcillin/clavulanate (30%) or cefepime (15%).

The majority of clinicians (56% HR and 81% OR) would avoid using vancomycin upfront with empiric therapy.

Factors influencing choice of dual therapy over mono-therapy and use of glycopeptides

The most commonly ranked important factors for clinicians prescribing dual therapy over mono-therapy were severe sepsis, suspected pseudomonal infection and previous resistance profiles (Fig. 4). Another factor cited was the presence of comorbidities.

Figure 4.

Factors, prioritized by importance, that influence clinician decision to use dual therapy over mono-therapy (n= 198; 16 did not answer). (inline image) very important (Haem); (inline image) somewhat important (Haem); (inline image) very important (Med Onc); (inline image) somewhat important (Med Onc).

The factors ranked as most important by more than 80% of HR and OR in influencing their decision to use empiric vancomycin were suspected line-related sepsis, positive results of blood culture for Gram-positive bacteria and persistent fevers for 48–72 h after initiating parenteral antibiotics. Other less commonly selected factors (60–80% by HR and OR) ranked as highly important were known colonization with penicillin-resistant organisms, for example methicillin-resistant Staphylococcus aureus and shock.

Granulocyte-colony stimulating factor for treatment and prophylaxis and fluoroquinolones for prophylaxis

Oncology respondents

In Case 1 MO, 91% of 81 respondents to this question reported they would use rHu-GCSF for secondary prophylaxis while 7% would also use rHu-GCSF to treat that particular episode of neutropenic fever. In Case 2 MO, 53% of 79 respondents would use rHu-GCSF (31% secondary prophylaxis alone, 13% secondary prophylaxis and therapeutic rHu-GCSF, 9% therapeutic rHu-GCSF alone).

When questioned about the use of prophylactic antibiotics, 19% of 80 respondents noted they would use fluoroquinolones. The most commonly reported considerations in whether or not to use prophylactic antibiotics were the development of superinfections (46%) and emergence of antibiotic resistance (42%).

Haematology respondents

In Case 1 HO, 93% of 100 respondents would use rHu-GCSF (59% secondary prophylaxis alone, 27% secondary prophylaxis and therapeutic rHu-GCSF, 7% therapeutic rHu-GCSF alone). When asked what factors were influential in their decision to use secondary prophylaxis rHu-GCSF, 48% required that the indication satisfy requirements of Section 100 and the Pharmaceutical Benefits Scheme (PBS), 57% considered such use for patients at high risk of infection-related complications. Other factors listed were whether treatment intent was curative and dependant on maintaining chemotherapy dose intensity.

For Case 3 HO, 70% of HR (21 did not answer) would avoid using prophylactic fluoroquinolone antibiotics. Of those that used fluoroquinolones (30 of 99), 18% would use this in an outpatient setting for afebrile neutropenic patients. Emergence of antibiotic resistance and concern over development of superinfections were listed by more than 90% of HR as an important factor that influenced their decision. The lowest-ranking factors of consideration were the effect on patient's quality of life and compromise to chemotherapy dose density.

Summary of responses from infectious diseases physicians

More ID physicians reported they were aware of risk-stratification tools (69% HO cases and 59% MO cases). Correspondingly, more respondents identified Case 1 as low-risk (65% HO cases and 80% MO cases, P= 0.05). Similar to MR and HR, optimization of resources was identified as the most important factor influencing ID physicians' decision to use ambulatory care strategies. ID physicians also noted predicted neutrophil recovery for the HO survey, and awareness of evidence supporting ambulatory care strategies and effect on patient's quality of life for the MO survey to be highly ranked factors. More than half ID respondents (56% HO, 58% MO) would avoid using vancomycin for Case 2. More than 95% would avoid using fluoroquinolone prophylaxis in MO Case 2, while 85% would avoid use in HO Case 3.

Summary of responses from private clinicians (n= 36)

This proportion of clinicians represented their practices in the private sector. Compared with other clinicians, private HR more frequently identified Case 1 as low-risk (70%, P < 0.05). Private clinicians more frequently selected parenteral mono-therapy (60%) for Case 1 MO and HO (P < 0.05), the most commonly prescribed being cefepime (80%). Another point of difference was that private clinicians did not rank adherence to institutional guidelines highly or as influential in determining the use of dual therapy over mono-therapy (P < 0.05). Private OR also differed in their use of anti-bacterial prophylaxis; 35% private OR would use fluoroquinolone prophylaxis for Case 2 MO (compared with 20% from OR), citing reduction in hospitalizations as the most influential factor governing their decision to use fluoroquinolones.

Discussion

Given that there was significant membership overlap across professional body associations, only an estimated response rate of 30% could be made. Despite a moderate response rate, this dataset of 252 responses from haematology, oncology and ID physicians is the largest representation of clinical practices in management of neutropenic fever across various states and institution types within Australia. Although the introductory note stressed that the survey was not aimed at testing clinicians' knowledge, there is still likely to be an element of non-response from clinicians who are not familiar with current evidence. Another limitation is that few responses were received from private cancer clinicians hampering any ability to draw firm parallels or differences with public sector practices. Current clinical practices described in this study were widely representative of public, tertiary hospitals from metropolitan or major city centres.

The MASCC score is validated in the international setting for an adult patient population of solid tumour and lymphoma types. International guidelines have long since recognized and advocated its use for selecting low-risk patients.6,7 This survey, however, revealed that in Australia, utilization of risk-stratification tools, such as the MASCC score, may be limited by reduced awareness, rather than a reluctance to apply the score in clinical practice. Only half of responding clinicians deemed Case 1 was low risk of medical complications suggesting that risk stratification is not currently performed according to accepted standardized criteria (MASCC score). The MASCC model identifies seven risk factors as critical predictors for the development of serious complications during neutropenic fever. Each factor is given a weighted score and the sum of these yields a number predictive of high risk of complications (if MASCC score < 21) or low risk of complications (if MASCC score ≥ 21). It is understood that a misclassification risk of 5% is inherent within the model; low-risk patients with MASCC scores closer to 21 are more likely to be misclassified. Factors not included in the model are the underlying tumour type or burden and predicted duration of neutropenia, which from this survey was rated highly in influencing clinician decision to use ambulatory strategies (Fig. 2). With increasing utilization of more immunosuppressive chemotherapy schedules in some solid tumour and lymphoma patients, such factors should be further evaluated in the context of the MASCC model for an Australian setting.

The approach to management of patients identified as low-risk was also inconsistent with the available evidence, as most clinicians elected to use parenteral antibiotics and manage this patient in hospital until complete resolution of fever and neutropenia. Most considered switching to oral antibiotics but only if clinically well and afebrile. Although oral antibiotic therapy has long been recognized as safe and effective as parenteral therapy,8–10 the success of ambulatory care management of select patients is heavily dependant on availability of comprehensive and well-resourced outpatient programmes.11,12 Such concerns were reflected in the survey findings. While ambulatory care offers several advantages, namely potential cost savings, improved quality of life, reduced opportunity costs (by freeing bed space for sicker cases) and reduced exposure to nosocomial infections, these were rated with lower importance by clinicians. Instead, clinicians identified availability of optimal ambulatory care resources, hospital guidelines and concern that complications would ensue as the main barriers for using ambulatory care strategies (Fig. 2). This highlights the need to establish clinical guidance around the use of risk-assessment tools particularly to identify suitable groups of patients for ambulatory care in the Australian setting. More importantly, adequate infrastructural and clinical resources need to be made available so we can ensure adequate and close supervision of these patients if managed in an ambulatory setting instead of in hospital.

The survey found at least half of respondents would treat clinically stable and low-risk patients with a combination of β-lactam antibiotic and aminoglycoside, indicating a significant knowledge gap between practice and best evidence. The safety and efficacy of β-lactam mono-therapy has long been recognized in randomized controlled trials (RCTs) and advocated in international guidelines.6,13 More recent meta-analyses have further confirmed that dual therapy combinations confer a higher risk of nephrotoxicity without any appreciable benefit over standard mono-therapy agents for neutropenic febrile patients.14 Furthermore, the costs associated with monitoring and administration of aminoglycosides and treating aminoglycoside toxicities can be significant. The relevance of increased antibiotic selective pressure on emergence of resistance as a contributing factor to choice of mono- or dual therapy was not assessed in this survey. Notably, the dual therapy combination of ticarcillin/clavulanate and gentamicin featured prominently among OR more so than their haematology counterparts. While β-lactamase inhibitors are frequently touted as necessary inclusions in empiric therapy to cover extended spectrum β-lactamase producing pathogens and the combination antibiotics (of penicillin and β-lactamase inhibitor) additionally cover anaerobic pathogens, there remains no evidence for the use of ticarcillin/clavulanate mono-therapy in neutropenic febrile patients. In contrast, evidence for mono-therapy with another agent containing a β-lactamase inhibitor, piperacillin/tazobactam, is strong.15 However, in patients with severe sepsis or shock and/or with resistant Gram-negative pathogens, the safety and efficacy of mono-therapy has not been confirmed as most RCTs excluded severely shocked or septic patients.14 Such concerns may be the reason that respondents more commonly prescribed dual therapy for sicker patients (85%).

Although more oncologists than haematologists avoided upfront vancomycin, most clinicians surprisingly ranked persistent fever equally if not more influential than shock, in prompting their decision to use upfront vancomycin. Available evidence has neither shown mortality benefit nor a reduction in time to defervescence with addition of vancomycin in neutropenic patients who had persistent fever 48–60 h after initiation of empiric therapy, or in patients with bacteraemia or skin and soft tissue infections associated with Gram-positive bacteria.16–18 In contrast, certain Gram-positive organisms particularly viridans Group Streptococci have been associated with poor outcome and high mortality in shocked patients.5,19 Timely administration of empirical vancomycin in this context is likely to improve survival particularly if the initial empiric regimen has poorer cover of these organisms, for example ceftazidime, although this benefit has also been seen in shocked patients with penicillin susceptible organisms receiving other β-lactam mono-therapy.4,17,20 Given most clinicians comply with their institutional guidelines, it is crucial that these guidelines reflect appropriate indications for use of vancomycin (e.g. use in shocked patients and not for persistent fevers in clinically well patients). In the international setting, the availability and implementation of such guidelines have significantly curbed unnecessary use of glycopeptides.21

The survey findings with respect to use of rHu-GCSF reflected that current practices differ from available evidence-based algorithms prescribed by international guidelines22,23 and Australian reimbursement requirements stipulated by the PBS. Although recent updates of international guidelines have advocated broadening the indication for prophylactic rHu-GCSF, guidelines do not advocate use of secondary prophylaxis rHu-GCSF outside of adjuvant breast cancer, lymphoma, myeloma and TPF chemotherapy for head and neck cancer. Therefore, while use of secondary prophylaxis rHu-GCSF may be justified (at the time this survey was conducted) for Case 1 MO and Case 1 HO, the evidence for use of secondary prophylaxis rHu-GCSF in non-small cell lung cancer (NSCLC) (Case 2 MO) is lacking.

The survey also found a strikingly high rate of use of therapeutic rHu-GCSF for the low-risk NHL patient (Case 1 HO) and the NSCLC patient (Case 2 MO). Available guidelines (as at the time of this survey) do not endorse the therapeutic use of rHu-GCSF outside of severe neutropenia (absolute neutrophil count <0.1 × 109 cells/L), severe sepsis syndrome or other patient risk factors predictive of poor clinical outcome. Particularly for the low-risk patients (Case 1), it is unlikely that there is significant clinical utility or cost-effectiveness in adding rHu-GCSF to empiric antibiotic therapy.

In the international setting, utilization of fluoroquinolone prophylaxis in haematology patients is common. However, significant concerns about the emergence of antibiotic resistance and superinfections and the evidence suggesting mortality benefit have been raised, as was reflected in the haematology survey. The clinical benefits of fluoroquinolone prophylaxis in solid tumour patients (who have an expected duration of neutropenia less than 7–10 days) have been reported as smaller.24 Furthermore, the use of fluoroquinolones as prophylaxis renders oral antibiotic therapy an unsuitable option for future episodes of neutropenic fever. Despite this, more oncologists, particularly from the private sector, were supportive of fluoroquinolone prophylaxis. They were more influenced by the need to maintain chemotherapy dose-intensity in the NSCLC case, which despite having disease with low likelihood of cure, may have presented with arguably, more favourable prognostic factors. This may also be a reason for the high utilization of rHu-GCSF secondary prophylaxis in this case, which is otherwise not funded under the PBS.

Conclusions

In summary, this survey highlighted several evidence–practice gaps. While there is significant scope for employing ambulatory care strategies in select patients, considerable investment into optimizing necessary infrastructural and supportive resources is required, such as the provision of outpatient or emergency department space and staff dedicated to clinically evaluating, educating and monitoring neutropenic febrile patients in the outpatient setting. The cost of implementing and evaluating such a programme in cancer treatment centres is likely to be offset very quickly by significant cost-savings realized from reduced inpatient stay. In recognizing that neutropenic febrile patients are a heterogeneous group who exhibit a vast spectrum of risk for infection-related complications, better guidance around use of risk-assessment tools is needed. A paradigm shift towards more targeted empiric antibiotic strategies, based on patient risk factors and clinical syndromes must be realized in order to optimize patient health outcomes and minimize opportunity costs faced by treatment centres. Embracing such a paradigm shift will help ensure more judicial use of hospital beds, antibiotics (aminoglycosides, vancomycin and fluoroquinolones) and rHu-GCSF. This survey showed that treatment approaches for management of neutropenic fever are currently varied across different disciplines and different sectors of cancer care. Consequently, wide representation is needed for guideline development, as has been our approach in formulating the ‘Australian Consensus Guidelines for Management of Neutropenic Fever in Adult Cancer Patients 2010’.

Ancillary