Scandinavian Journal of Infectious Diseases

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Comparison of two oral regimens for the outpatient treatment of low-risk cancer patients with chemotherapy-induced neutropenia and fever: Ciprofloxacin plus cefuroxime axetil versus ciprofloxacin plus amoxicillin/clavulanate Online Publication Date: 01 January 2007 To cite this Article: Sipsas, Nikolaos V., Kosmas, Christos, Ziakas, Panayiotis D., Karabelis, Athanasios, Vadiaka, Maria, Skopelitis, Elias, Kordossis, Theodore and Tsavaris, Nikolaos (2007) 'Comparison of two oral regimens for the outpatient treatment of low-risk cancer patients with chemotherapy-induced neutropenia and fever: Ciprofloxacin plus cefuroxime axetil versus ciprofloxacin plus amoxicillin/clavulanate', Scandinavian Journal of Infectious Diseases, 39:9, 786 - 791 To link to this article: DOI: 10.1080/00365540701367769 URL: http://dx.doi.org/10.1080/00365540701367769

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Scandinavian Journal of Infectious Diseases, 2007; 39: 786 791

ORIGINAL ARTICLE

Comparison of two oral regimens for the outpatient treatment of low-risk cancer patients with chemotherapy-induced neutropenia and fever: Ciprofloxacin plus cefuroxime axetil versus ciprofloxacin plus amoxicillin/clavulanate

NIKOLAOS V. SIPSAS1, CHRISTOS KOSMAS2, PANAYIOTIS D. ZIAKAS1, ATHANASIOS KARABELIS2, MARIA VADIAKA1, ELIAS SKOPELITIS1, THEODORE KORDOSSIS1 & NIKOLAOS TSAVARIS1 From the 1Pathophysiology Department, Laikon General Hospital and Medical School, National and Kapodistrian University of Athens, Athens, and 2Second Division of Medical Oncology, Department of Medicine, ‘Metaxa’ Cancer Hospital, Piraeus, Greece

Abstract The objective of this investigation was to assess retrospectively the safety and the efficacy of oral ciprofloxacin plus cefuroxime axetil compared to the combination of oral ciprofloxacin plus amoxicillin/clavulanate, as initial outpatient treatment, in low-risk cancer patients with fever and neutropenia. We analysed retrospectively 120 episodes of febrile neutropenia, treated on an outpatient basis at 2 different oncology units; 63 episodes were treated with the oral regimen of ciprofloxacin plus amoxicillin/clavulanate and 57 were treated with the combination of oral ciprofloxacin plus cefuroxime. 20 treatment failures were recorded 2 of them among patients receiving ciprofloxacin plus amoxicillin/clavulanate and 18 in the ciprofloxacin plus cefuroxime group. Univariate analysis showed that the administration of ciprofloxacin plus cefuroxime was associated with a worse outcome compared to the regimen ciprofloxacin plus amoxicillin/clavulanate (OR 11, CI 2.42 49.9, p0.002). In the multivariate model, after adjusting for the absolute number of neutrophils and the duration of neutropenia, the effect of the antibiotic regimen on the outcome disappeared, and no significant differences between the 2 regimens were noted, although the regimen of ciprofloxacin plus cefuroxime was associated with a trend to a worse outcome (OR 4.74, CI 0.72 31.1, p0.10). In conclusion, the 2 regimens appeared equally safe and effective but prospective studies are needed to confirm these results.

Introduction Infection continues to be the most common complication of cancer therapy and accounts for the majority of chemotherapy-associated mortality. In neutropenic patients, fever alone is a reliable indicator of invasive bacterial infection and/or bacteraemia, even in the absence of other symptoms or signs [1]. Therefore, for many y the standard of care for cancer patients with fever and neutropenia was hospitalization and administration of broad-spectrum antibiotics intravenously [2]. Recently, it became evident that these patients represent a very heterogeneous population and the majority has a low risk to develop life-threatening infectious complica-

tions [3]. Therefore, efforts were made to develop a risk assessment model in order to identify low-risk patients. The risk assessment system developed by the Multinational Association of Supportive Care in Cancer (MASCC) [4] can safely predict, at the initial presentation, which patients have a less than 5% risk for developing serious complications. These low-risk patients have additional treatment options including totally outpatient treatment with oral antibiotics [5]. It should be pointed out, however, that the MASCC risk-index score has not been validated extensively with large, international, multicentre, prospective studies. Therefore, its clinical application should be undertaken with caution [6].

Correspondence: N.V. Sipsas, Department of Pathophysiology, Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, Athens 11527, Greece. (Tel: 30 210 7462667. Fax: 30 210 7462664. E-mail: [email protected])

(Received 24 November 2006; accepted 6 March 2007) ISSN 0036-5548 print/ISSN 1651-1980 online # 2007 Taylor & Francis DOI: 10.1080/00365540701367769


Outpatient treatment of febrile neutropenia The oral regimens that were better evaluated included a quinolone (ciprofloxacin, ofloxacin or moxifloxacin) alone or in combination with amoxicillin or amoxicillin/clavulanate [6]. Quinolones are the backbone of any oral regimen for low-risk patients with febrile neutropenia, because they confer coverage against Gram-negative pathogens, especially pseudomonas. On the other hand, there is some controversy on the selection of the second complementary antibiotic of the combination, which ideally should have an excellent activity against Gram-positive agents and low toxicity. Agents that were evaluated have several disadvantages such as diarrhoea (clindamycin and ampicillin/sulbactam), narrow spectrum (penicillin), and high rates of bacterial resistance [7]. Furthermore, they have a complicated dosing schedule (i.e. 3 4 times per d) not compatible with that of quinolones. Cefuroxime axetil is a second-generation cephalosporin, with increased potency against Grampositive pathogens and significant activity against many Gram–negative pathogens [8]. Cefuroxime axetil is a broad-spectrum antibacterial agent with a pharmacokinetic profile that permits twice-daily administration. The drug is an effective and welltolerated treatment in patients with various infections. It has a convenient dosing schedule (2 times per d) and it can be taken along with a quinolone, allowing thus an increased compliance of the patients to the regimen. In addition, it has a low incidence of adverse effects, and few drug interactions [8]. The aim of the study was to assess retrospectively the safety and the efficacy of oral ciprofloxacin plus cefuroxime axetil compared to the standard combination of oral ciprofloxacin plus amoxicillin/clavulanate. Materials and methods In this report, we analysed retrospectively 120 episodes of febrile neutropenia in low-risk cancer patients, treated on an outpatient basis at 2 different oncology units. The 2 units were located in 2 tertiary care hospitals, serving the area of Athens and the nearby city of Piraeus, respectively. The participating units were similar regarding facilities and the personnel. 57 episodes were treated at the first institution with the oral regimen of ciprofloxacin plus amoxicillin/clavulanate and 63 were treated at the other institution with the combination of oral ciprofloxacin plus cefuroxime axetil. Eligible for inclusion in our study were patients with histologically-confirmed solid tumours, who were at least 15 y of age, and who developed fever and neutropenia after receiving chemotherapy. We

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excluded from the study all the patients with haematological malignancies and those who had undergone haematopoietic stem cell transplantation. The reason was that both units were specialized in patients with solid tumours; therefore there were only 2 patients with lymphoproliferative disorders, who were not included in the analysis. More specifically, we analysed the records of patients who had undergone chemotherapy and were presented at the outpatient department with fever (a single core temperature 38.38C, or a sustained temperature 38.08C for at least 1 h, without other mitigating environmental causes) and neutropenia (absolute neutrophil countB500 cells/ml, or B1000 cells/ml when a further and/or prolonged decrease was expected). Patients who had developed fever while in the hospital or those who were taking antibiotics within the previous week were not eligible for the study. According to the standard policy of both participating oncology units, outpatient treatment was offered to patients with a performance status 52, and an adequate hepatic function (defined as aminotransferase values that were less than 5 times the normal values) and renal function (defined as a creatinine clearance of at least 30 ml per min). Patients were admitted to the hospital if they had hypothermia and/or hypotension, altered mental status, abnormal chest X-ray, nausea and vomiting, diarrhoea, inability to swallow pills, abdominal pain, or intravascular-catheter infection. A history was obtained at the initial presentation of the patient and a meticulous physical examination was performed. The baseline laboratory evaluation included a complete blood count and differential; measurement of serum levels of creatinine, urea nitrogen, and transaminases; electrolyte levels; 3 sets of blood cultures; urinalysis and urine culture; and chest X-ray. After the initial evaluation, risk assessment of the patient was performed using the MASCC scoring system [4]. Patients with a risk-index score of 521 were considered as low-risk patients and were assigned to take 1 of the 2 study regimens. The policy of 1 of the 2 oncology units was to prescribe ciprofloxacin (500 mg, twice daily) plus amoxicillin/ clavulanate (500125 mg, 3 times daily), while the policy of the second unit was to prescribe ciprofloxacin (500 mg, twice daily) plus cefuroxime axetil (500 mg, twice daily). The dose of ciprofloxacin was lower than the dose used in other similar studies (i.e. 750 mg b.i.d. or t.i.d.) [9,10] in order to minimize the side-effects. All patients were also given growth factors (granulocyte-colony stimulating factor, 5 mg/kg, subcutaneously daily) at the onset of neutropenia. In both units the first dose of the oral regimen was given at the outpatient department. No


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antibiotics were given intravenously. The patients were sent home with specific instructions to return immediately to the hospital if they were unable to take their medications or their condition was deteriorating. Each patient should live with a reliable adult within close distance from a hospital and should have telephone access. The follow-up visits were arranged on d 3 and 7, and included a complete physical examination and any laboratory test that was considered necessary. All side-effects of the antibiotics, reported by the patients, were recorded. In our retrospective analysis, treatment failure was defined as death during febrile episode, change of the antibiotic regimen, persistence of fever for more than 5 d and hospitalization for any cause (including for administration of intravenous antibiotics). Treatment success was defined as the resolution of fever within 5 d, without recurrence during the following week. The protocol of the study has been approved by the ethics committees of both participating institutions, and permission to use data from the medical records was granted, on condition that there would be no breach in patient information confidentiality.

Statistical analysis Categorical variables were compared using the x2 test. Continuous variables were compared using the Wilcoxon rank sum test. Univariate and multivariate logistic regression models were used to estimate the impact of independent covariates on the outcome, and odds ratios (ORs) with their corresponding confidence intervals (CIs) were reported. Only the significant covariates of the univariate analysis were included in the multivariate model. Significance was set to 0.05 and Stata V8 software package was used for the analysis. Results We retrospectively analysed the records of 110 cancer patients with chemotherapy-associated neutropenia, who developed 120 episodes of fever and were treated with either ciprofloxacin plus amoxicillin/clavulanate (n 57) or ciprofloxacin plus cefuroxime (n 63). The underlying malignancy for the majority of patients was non-small-cell lung cancer (36 patients) followed by breast cancer (17 patients) and colon cancer (12 patients). 67 (55.8%) of the 120 episodes of fever occurred in males and 53 in females. The median age at entry was 63 (range 31 73) y, the median neutrophil count was 500 (range 100 900)/mm3 and the median duration of neutropenia was 5 (range 115) d. The majority of patients (78/120, 65%) had fever of unknown origin. In 28

cases of clinically documented infection, the lower respiratory tract (11 patients) and the urinary tract (10 patients) were the most common sources of infection, whereas there were 6 cases of skin and soft tissue infections, and 1 case of gastrointestinal infection. There were also 14 patients with bacteraemia; the isolated pathogens were Pseudomonas aeruginosa (6 cases), Staphylococcus aureus or epidermidis (3 cases), Klebsiella pneumoniae (2 cases), Escherichia coli (2 cases) and Streptococcus pneumoniae (1 case). It is noteworthy that 8 out of the 14 patients with bacteraemia were hospitalized. Patient demographic characteristics after stratification for oral antibiotic regimen are summarized in Table I. Statistical analysis showed that the group of patients receiving ciprofloxacin plus cefuroxime had at study entry significantly lower numbers of neutrophils and a significantly longer period of neutropenia. The 2 groups did not differ statistically with regard to the type of infection. Both regimens were well tolerated by the patients. Mild nausea developed in 8 patients (4 in each group) and WHO grade 1 diarrhoea in 3 patients. These side-effects were resolved without discontinuation or modification of the treatment. 20 treatment failures were recorded, 2 of them among patients receiving ciprofloxacin plus amoxicillin/clavulanate and 18 in the ciprofloxacin plus cefuroxime group (Table I). Among those patients who failed to respond, 14 were hospitalized (2 in the ciprofloxacin plus amoxicillin/clavulanate and 12 in the ciprofloxacin plus cefuroxime group) for a mean duration of 10.795.0 d. The reasons for hospitalization were persistent fever (5 d) and/or deteriorating condition. Two patients were hospitalized on the second d, and died 6 and 4 d, respectively, after the onset of fever. No autopsies were performed. The treating physicians recorded the cause of death as septic shock. However, this assumption should be interpreted cautiously because both patients were elderly with extensive metastatic cancer and other comorbidities. Therefore, the lack of autopsy does not allow concluding definitely whether infection was the cause of death or not. These 2 deaths represent also the 30-d-mortality of our study. In univariate analysis (Table II) the absolute number of neutrophils at onset of fever appeared as a significant predictor for outcome, as a 100/mm3 rise decreased the risk of failure (OR 0.40, CI 0.26 0.62). Duration of neutropenia predicted an unfavourable outcome, as 1 d prolongation of neutropenia almost tripled the risk of failure (OR 2.44, CI 1.70 3.50). Univariate analysis also showed that the administration of ciprofloxacin plus cefuroxime was associated with a worse outcome compared to the regimen ciprofloxacin plus amoxicillin/clavulanate (OR 11,

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Outpatient treatment of febrile neutropenia Table I. Baseline data and outcome. Antibiotic regimen Ciprofloxacin cefuroxime

Ciprofloxacinamoxicillin/ clavulanate

p

Number of FN episodes Median age (range)

63 63 (43 73)

57 63 (31 73)

NS NS

Gender Male Female

35 28

32 25

NS NS

Solid tumour Ovarian Lung Head and Neck Gastrointestinal Breast Other

5 25 2 12 7 12

2 16 2 17 10 10

NS NS NS NS NS NS

Median ANC (neutrophils/ml) at the onset of fever (range) Patients with ANCB100/ml Median duration of neutropenia (d) Successful treatment Deaths Hospitalization Median duration of fever (d, range)

400 (100 800) 3 5.5 (1 15)

600 (100 900) 1 4 (3 10)

45 (71.43%) 2 12 4 (2 10)

0.01 NS B0.001

55 (96.5%) 0 2 3 (2 8)

0.002 0.27 0.004 0.002

FN: febrile neutropenia; ANC: absolute neutrophil count; G-CSF: granulocyte-colony stimulating factor; p : p -value; Htc: haematocrit.

CI 2.42 49.9, p 0.002). However, in the multivariate model (Table II), after adjusting for all other significant covariates, the effect of the antibiotic regimen on the outcome disappeared, and no significant differences between the 2 regimens were noted. Nevertheless, the administration of ciprofloxacin plus cefuroxime was associated with a trend to a worse outcome (OR 4.74, CI 0.72 31.1, p 0.10). Duration of neutropenia appeared to be the only important predictor of outcome (OR 2.07, CI 1.30 3.29). Discussion Treatment of low-risk cancer patients with fever and neutropenia with oral antibiotics on an outpatient basis has many advantages over conventional hospitalization, including lower cost, avoidance of cathe-

ter use/infection, better quality of life, and lower risk for colonization and superinfection with resistant nosocomial organisms [5]. However, many physicians were reluctant to adopt this strategy because it might present safety problems [11]. These concerns were addressed by early studies [12 14] and 2 well designed randomized controlled prospective studies [9,10], which have shown that oral antibiotics may be safely substituted for intravenous antibiotics in low-risk patients with febrile neutropenia. A recent meta-analysis summarizing the findings of all the randomized controlled clinical trials comparing oral with intravenous antibiotics, confirmed the feasibility of treatment with oral antibiotics in low-risk patients [7]. Historically, Gram-negative pathogens, especially pseudomonas, have been the prominent pathogens

Table II. Variables associated with treatment outcome by univariate and multivariate analysis. Univariate analysis. OR Gender (F vs M) Age (y) Second vs first episode Absolute neutrophil count at entry (100/mm3) Duration of neutropenia (B500/ml) (d) Regimen (CC vs CAC)

1.04 0.95 1.28 0.40 2.44 11.00

95% CI 0.39 0.91 0.25 0.26 1.70 2.42

to to to to to to

2.73 1.00 6.52 0.62 3.50 49.9

Multivariate analysis p

OR

95% CI

p

0.93 0.11 0.76 B0.001 B0.001 0.002

0.85 2.07 4.74

0.49 to 1.45 1.30 to 3.29 0.72 to 31.1

0.55 0.002 0.10

CC: ciprofloxacin-cefuroxime; CAC: ciprofloxacin plus amoxicillin/clavulanate; OR: odds ratio; p : p -value; CI: confidence intervals; F: female; M: male.


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in the neutropenic patient with fever [1517]. However, during the last decade many cancer centres have experienced a decrease in Gram-negative bacteraemia and an increase in infections due to Gram-positive cocci [18]. Accordingly, the ideal oral regimen for the outpatient treatment of lowrisk patients with fever and neutropenia should offer coverage against both Gram-negative (including pseudomonas) and Gram-positive pathogens. Therefore, all the oral regimens that were evaluated in the bibliography included a quinolone (ciprofloxacin, ofloxacin or moxifloxacin) alone or in combination with a second antibiotic with good activity against Gram-positive agents such as amoxicillin, amoxicillin/clavulanate, clindamycin, ampicillin/sulbactam, and penicillin [7]. Cefixime is another option of oral antibiotic therapy because of its broad spectrum of activity, comparable to that of ceftriaxone [19]. In the present investigation we took advantage of the different antibiotic prescribing policies of 2 oncology units, in order to study retrospectively the safety and the efficacy of oral ciprofloxacin plus cefuroxime axetil compared to the combination of oral ciprofloxacin plus amoxicillin/clavulanate, as initial outpatient treatment in low-risk cancer patients with fever and chemotherapy-induced neutropenia. Our univariate analysis showed that significantly more treatment failures were observed among patients receiving the combination of ciprofloxacin plus cefuroxime axetil compared to those receiving ciprofloxacin plus amoxicillin/clavulanate. However, this finding should be interpreted cautiously, taking into consideration the design of the study. More specifically, the lack of randomization, due to the retrospective nature of our study, resulted in 2 treatment groups that differed significantly regarding the number of neutrophils and the duration of neutropenia. Thus, the patients treated with ciprofloxacin-cefuroxime axetil had significantly lower neutrophil counts and significantly longer duration of neutropenia at the onset of fever. Both profound neutropenia and prolongation of neutropenia are associated with an unfavourable outcome, according to the bibliography [20] and the findings of the univariate analysis in our study. Therefore, the increased absolute number of treatment failures in the ciprofloxacin-cefuroxime axetil group should be attributed to the differences in the neutrophil counts and the duration of neutropenia between the 2 groups. Indeed, in the multivariate analysis, after adjusting for all other significant covariates, the effect of the antibiotic regimen on the outcome disappeared, and no significant differences between the 2 regimens were noted. With regard to the side- effects, both

regimens were well tolerated, with mild side-effects not requiring discontinuation of the treatment. In the present report, the mortality rate was 1.8% (2 deaths among 110 patients) and the hospitalization rate was 11.7% (14 hospitalizations for 120 episodes of febrile neutropenia). The 2 deaths and the majority of hospitalizations (12/14, 85.7%) occurred among patients receiving cefuroxime. This finding is noteworthy, even though the multivariate analysis showed no statistical significance between the 2 groups. Other studies of low-risk cancer patients with fever and neutropenia treated as outpatients reported 30-d mortality rates ranging from 0% [9,21] to 4.7% [10] and hospitalization rates up to 9.1% [21]. It is clear that the safety of this treatment strategy is an issue not fully addressed yet. Cefuroxime axetil is a broad-spectrum antibacterial agent with a pharmacokinetic profile that permits convenient twice-daily administration [8]. The retrospective nature of our study did not allow assessment of compliance among the patients receiving the 2 regimens; yet a review of studies that measured compliance using electronic monitoring confirmed that the prescribed number of doses per d is inversely related to compliance [22]. Simpler, less frequent dosing regimens resulted in better compliance across a variety of therapeutic classes. The advantage of cefuroxime axetil’s simpler dosing schedule is counterbalanced by amoxicillin’s better pharmacokinetic profile. Cefuroxime axetil is an ester of cefuroxime. Only 30 50% of an oral dose is absorbed and the drug is then hydrolysed to cefuroxime; resultant concentrations in plasma are variable [8]. In contrast, amoxicillin is completely absorbed from the gastrointestinal tract after oral administration. In conclusion, our retrospective analysis showed significantly more treatment failures among low-risk cancer patients with fever and neutropenia receiving, as outpatients, the combination of ciprofloxacin plus cefuroxime axetil compared to those receiving ciprofloxacin plus amoxicillin/clavulanate. However, after adjusting for parameters such as the absolute number of neutrophils and the duration of neutropenia, the 2 regimens appeared equally safe and effective. The retrospective nature of our study, the lack of randomization and the small size of the cohort, do not allow definite conclusions to be reached. Welldesigned prospective studies comparing the efficacy of the 2 regimens are needed to confirm our results.

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