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Annals of Oncology Advance Access originally published online on March 16, 2007
Annals of Oncology 2007 18(6):1080-1084; doi:10.1093/annonc/mdm082
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© 2007 European Society for Medical Oncology

hematologic malignancies

Normal hospital and low-bacterial diet in patients with cytopenia after intensive chemotherapy for hematological malignancy: a study of safety{dagger}

FH van Tiel1,*, MM Harbers1,{ddagger}, PHW Terporten1, RTC van Boxtel3, AG Kessels4, GBWE Voss4,§ and HC Schouten2

1 Maastricht Infection Center, Department of Medical Microbiology
2 Department of Internal Medicine
3 Department of Dietetics
4 Department of Clinical Epidemiology and Medical Technology Assessment, University; Hospital Maastricht, Maastricht, the Netherlands

* Correspondence to: Dr F. H. van Tiel, Medical Microbiology, University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, The Netherlands. Tel: +31-43-3874644; Fax: +31-43-3876643; E-mail: fvt{at}lmib.azm.nl


   Abstract
Top
 Abstract
introduction
 patients and methods
 results
 discussion
 Acknowledgements
 References
 
Background: The purpose of this randomized, controlled pilot study is to address the question whether normal hospital diet (NHD) is safe when compared with low-bacterial diet (LBD) given to prevent infections in cytopenic patients who receive antimicrobial prophylaxis (AP).

Patients and methods: The patients were randomized into two groups: one group to receive AP and LBD, the other to receive the same AP and NHD. The primary outcome parameter is colonization of the digestive tract with aerobic gram-negative bacilli and yeasts. Secondary outcome parameters were infections and total societal costs.

Results: No statistically significant differences between treatment groups were observed regarding the primary outcome parameter, gut colonization by yeasts or gram-negative bacilli, or infections, use of antimicrobials, days with fever and total societal costs.

Conclusion: On the basis of the results of this pilot study, NHD appears to be as safe as LBD in patients with chemotherapy-induced cytopenia. Furthermore, the results indicate that LBD may offer no additional benefit as an infection preventive measure to the measures already implemented, such as AP. Thus, a larger randomized study, powered adequately to determine noninferiority of NHD to LBD is warranted and safe to be carried out.

Key words: chemotherapy, cytopenia, diet, hematological malignancy, infection prevention, protective isolation


   introduction
Top
 Abstract
 introduction
patients and methods
 results
 discussion
 Acknowledgements
 References
 
Patients with hematological malignancies who receive intensive chemotherapy usually develop a period of cytopenia, during which there is an increased risk of infection [1].

Mucositis can also develop in these patients, enabling microorganisms, belonging to the endogenous intestinal flora, to translocate from the intestine to the lymphoid tissue and blood [2]. Therefore, when mucositis and cytopenia develop simultaneously, the risk of infection increases further. In this regard, bloodstream infection by gram-negative bacilli and yeasts are an important cause of serious infections causing considerable morbidity.

In order to reduce the risk of infection, several preventive measures have been adopted [3–5]. Fundamentally, all of these measures were designed to prevent either acquisition of gram-negative bacilli or fungal pathogens from the environment or the translocation of these potential pathogens across the mucosal barrier of the gut. These measures include protective (or reverse) isolation, antibiotic prophylaxis with antibiotics which selectively eradicate the aerobic gram-negative bacilli and yeasts from the gut flora and finally the use of low-bacterial diets (LBDs).

The evidence for the necessity of LBDs is weak. Several studies have documented the frequent isolation of Enterobacteriaceae from food [6, 7] The isolation of gram-negative bacilli, notably Enterobacteriaceae and Pseudomonadaceae, from food together with the increased risk of infection due to these microorganisms provided a theoretical base for avoiding normal hospital food and offering LBD to cytopenic patients. However, to date no randomized controlled studies addressing the question whether LBDs, in addition to antibiotic prophylaxis, are necessary as an infection preventive measure in the treatment of cytopenic patients have been conducted. The need for such trials has been stressed by a number of published, noncontrolled studies [8–14].

Therefore, we carried out a prospective randomized pilot study on the safety of normal hospital diet (NHD) in comparison with LBD with regards to gut colonization by aerobic gram-negative bacilli and yeasts and the occurrence of infections. In addition, the total costs of hospital care were documented in order to identify potential cost savings by the use of either diet.


   patients and methods
Top
 Abstract
 introduction
 patients and methods
results
 discussion
 Acknowledgements
 References
 
patients
From February to December 2003, 20 adult patients (five women and 15 men) with acute leukemia receiving remission induction chemotherapy fulfilled the entry criteria and were included into the study after having given informed consent. The study protocol was approved by the Medical Ethics Committee of the University Hospital Maastricht, The Netherlands.

The patients were randomized into two groups according to a predetermined randomization schedule produced by a computerized randomization program. One group received antimicrobial prophylaxis (AP) and the LBD; the other group received the same AP and NHD.

AP included ciprofloxacin (Bayer Pharmaceuticals, Mijdrecht, The Netherlands); (500 mg every 12 h, orally) and fluconazole (Pfizer bv, Capelle aan de Ijssel, The Netherlands) (50 mg every 24 h, orally). AP was adjusted or switched to alternative drugs according to results of the surveillance cultures. The AP was started before initiation of chemotherapy and discontinued, when leukocyte counts had recovered to 1000/mm3 or higher. ‘Chemotherapy cycle’ was defined for the first cycle as the period from starting AP, before induction chemotherapy, until leukocyte counts recover to at least 1000/mm3 or AP was discontinued. For subsequent periods, chemotherapy cycle was defined as the period from the first day the patient was not only hospitalized but also receiving AP and with leukocyte counts <1000/mm3 until the day on which AP was discontinued or leukocyte counts recovered to 1000/mm3 or higher. Once randomized the patient remained in the same study group.

diets
For patients randomized into the NHD or LBD group, the diet was either changed to the designated diet or continued, whichever was appropriate, as soon as possible after inclusion. The LBD at our institution omits raw vegetables, salads, soft cheeses, raw meat products, most fresh fruits, tap water and spices added after cooking. Furthermore, bread, cheese and ham are individually packed and yogurt deserts, soda drinks and soups are served in single serving containers.

sampling and processing of fecal samples
During chemotherapy cycles, fecal samples were collected daily, if possible. Fecal samples were diluted (10–1) and homogenized in 1% (mass/vol) peptone water supplemented with 20% mass/vol glycerol and stored at –20°C until analysis.

Amounts of 0.037 ml of the diluted samples were inoculated onto solid agar media, with and without antibiotics, using a spiral plater (Lameris Laboratorium BV, Breukelen, The Netherlands). Violet Red Bile Glucose (VRBG) agar (OXOID LTD, Basingstoke, Hampshire, UK) was used for the detection of aerobic gram-negative bacilli. ChromAgar Candida plates (ChromAgar, Paris, France) were used for the detection of yeasts. VRBG agar plates were incubated for 24 h at 37°C. The ChromAgar Candida plates were incubated for 48 h at 37°C. With this method, the lower limit of detection was around 268 colony-forming units (CFU)/g feces. After incubation, different colony types were counted, isolated in pure culture and identified. In order to detect gram-negative bacilli and Candida spp. at amounts <102 CFU/g feces, tubes containing 5 ml Brilliant Green Bile (2%) broth (BGB broth) (Oxoid Ltd, Basingstoke, Hampshire, UK) and tubes containing 5 ml Sabouraud (Sab) broth (glucose, 20 g/l supplemented with bacteriological peptone, 10 g/l, Oxoid Ltd) were inoculated with 0.5 ml of the samples containing 0.05 g of feces and stored overnight at 37°C. To detect growth 20 µl of the BGB broth and Sab broth, overnight cultures were inoculated onto VRBG and ChromAgar Candida plates, respectively, and incubated for another 24 h at 37°C. After incubation, growth was recorded and different colony types were isolated in pure culture and identified. When growth of Candida spp. or gram-negative bacilli was present in the overnight cultures but absent on the regular agar plates inoculated with the spiral plater, the colony count was set at 134 CFU/g feces (half the value of the detection limit).

outcome parameters and statistics
The primary outcome parameter is colonization of feces with gram-negative bacilli or Candida spp. In order to take both duration and numbers of colonizing gram-negative bacilli and yeasts into account a degree of colonization was defined as the ({sum}10log CFU of yeasts or of aerobic gram-negative bacilli) x (duration of chemotherapy cycle/number of cultures). The degree of colonization in the two groups was compared for the first and second cycles separately, using the Student's t-test for two independent samples (crude value). To correct for differences in patient characteristics in the two diet groups, the degree of colonization was compared for the first and second cycles using a multivariate analysis of variance (adjusted value). To obtain geometric mean numbers of CFU per feces sample per patient, the degree of colonization was converted back to CFU per gram feces per patient. The covariables studied in this analysis were the number of days on parenteral nutrition, days on which additional antibiotics and antifungal agents were administered, days on chemotherapy, yeast colonization (for analysis of colonization with gram-negative bacilli) and colonization with gram-negative bacilli (for analysis of colonization with yeasts). A P value <0.05 was considered statistically significant.

Infection, a secondary outcome parameter, was defined as a temperature of ≥38.5°C or <36.0°C with a single measurement for which empiric antibiotics were administered. The number of infections was registered during the chemotherapy cycle and calculated per cycle. Cases of invasive aspergillosis were classified as ‘definite’, ‘probable’ and ‘possible’ according to the criteria published by the Invasive Fungal Infections Cooperative Group of the European Organization for Research and Treatment of Cancer and the NIAID Mycosis Study Group of the National Institute of Allergy and Infectious Diseases [15]. Also, the number of days with temperature of ≥38.5°C or <36.0°C and number of days during which antibiotic or antimycotic therapy was administered, besides AP, were evaluated during chemotherapy cycles.

Differences in the occurrence of infection were tested with Fisher's exact test. Differences in median number of days per chemotherapy cycle with temperature of ≥38.5°C or <36.0°C and of days during which antibiotic or antimycotic therapy was administered were tested with the Mann–Whitney test. A P value <0.05 was considered statistically significant.

cost analysis
Starting at hospitalization for the first chemotherapy cycle until 28 days after discharge after the last chemotherapy cycle, total societal costs were calculated for each patient. The societal costs include hospital and other health sector costs as well as costs due to time lost from paid and unpaid work and informal care. Total costs can be divided in costs during hospitalization and costs after discharge.

Costs of hospital days and hospital procedures were calculated from data derived from the hospital information system, including volumina and prices. Prices were calculated according to the hospital's unit price methodology and using national guidelines for hospital cost calculation [16]. Medication costs were calculated from the medication records of the hospital pharmacy and the medication prices given by the Dutch Board for health care insurance. Extra costs due to LBD were estimated on the basis of expert opinion and additional unit cost calculations. Costs of visits to the outpatient clinic and outpatient procedures were calculated until 4 weeks after discharge with data from the hospital information system, including volumina and unit prices calculated according to the hospital's unit price methodology. Costs due to time lost from paid work were estimated using the friction cost method [17]. Data on costs after discharge from hospital were obtained with a cost questionnaire which was completed at home between subsequent chemotherapy cycles and for 2 weeks following the last chemotherapy cycle. The Mann–Whitney test was used to compare total societal costs between treatment groups. A one-sided P value <0.05 was considered statistically significant.

For cost analysis ‘cycle’ was defined as the time period from the time AP was started, before initiation of chemotherapy, continuing beyond the point of time the AP was discontinued, and including the period after discharge, at home, until the start of the next AP cycle or for 4 weeks after the final discharge from hospital. All available cycles were used for the cost analysis.


   results
Top
 Abstract
 introduction
 patients and methods
 results
discussion
 Acknowledgements
 References
 
patients
Patients in the two study groups were comparable with regard to age, sex, number of chemotherapy cycles and median number of days per cycle (Tables 1 and 3). On entry to the study, patients had a mean weight of 82.2 kg (range 64.5–116 kg) and a mean age of 53 (range 30–69). Five patients were diagnosed with acute lymphocytic leukemia and 15 patients with acute myeloid leukemia. More patients with ALL and less patients with acute myelogenous leukemia were randomized in the LBD group as compared with the NHD group. Twenty chemotherapy cycles were analyzed in the LBD group. During one of the chemotherapy cycles, leukocytes remained above the threshold of 1000/mm3, but this cycle was nevertheless included in the analysis. One patient of the NHD group was not analyzed for colonization, because not enough feces specimens were collected, due to constipation.


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  		Table 1. Characteristics of 20 patients

 

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  		Table 3. Characteristics related to infections during chemotherapy cycles

 
colonization
The crude and adjusted value of colonization with yeasts was not significantly different between treatment groups, either for the first or for the second chemotherapy cycle (Table 2). For aerobic gram-negative bacilli, the crude and adjusted value of colonization was not significantly different between treatment groups, either for the first or for the second chemotherapy cycle (Table 2). The differences remained not significant when the maximum count of CFU per chemotherapy cycle or duration of colonization instead of colonization degrees were compared between treatment groups (data not presented).


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  		Table 2. Geometric mean numbers of CFU per feces sample per patient (95% CI)

 
infections
No significant differences in the number of chemotherapy cycles with total infections as well as the number of chemotherapy cycles with microbiologically confirmed and unconfirmed infections were found (Table 3). One patient in the LBD group was diagnosed with candidemia, due to Candida tropicalis, whereas in the NHD diet group, one patient had a single positive blood culture for Candida glabrata. Only two cases of possible invasive aspergillosis occurred in the NHD group.

The number of days with temperature of ≥38.5°C or <36.0°C, the number of days with empiric antibiotic therapy and the number of days with antimycotic therapy were not significantly different between treatment groups (Table 3).

cost analysis
Total societal costs were not significantly different between treatment groups (Table 4). Total costs during hospitalization and total costs after discharge were also not significantly different between treatment groups.


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  		Table 4. Mean societal costs in euro's per cycle according to treatment group

 

   discussion
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
Acknowledgements
 References
 
This pilot study is the first randomized controlled study addressing the safety of NHD compared with LBD in cytopenic patients after intensive chemotherapy and was carried out with an interest in the feasibility of home care. The study was intended to prepare for a future larger trial addressing the question whether NHD can replace LBD given as an infection preventive measure to patients receiving antibiotic prophylaxis.

Overall, no significant differences between LBD and NHD were found regarding colonization by yeasts and gram-negative bacilli based on comparison of colonization degrees.

Regarding all chosen parameters of infection, no significant differences between treatment groups were found. Although there was an increase in the use of antibiotics and number of days with temperature of ≥38.5°C or <36.0°C in the NHD group, in comparison with the LBD group, this increase was not statistically significant. In addition, the higher number of cytopenic days in these patients, an additional possible explanation for the mentioned increases, was also not significant. Total societal costs and total costs during hospitalization were not significantly different between the treatment groups.

Despite the lack of scientific evidence, a survey by Smith and Besser [8], among 156 cancer centers showed that 120 (78%) use some form of dietary restrictions for patients with neutropenia. However, practices vary regarding the types of restricted foods as well as the criteria for initiating the LBD [8, 10]. In our hospital, the LBD is somewhat more strict than the LBD indicated by the Centers for Disease Control [18]. One reason may be that, although several studies have examined bacterial counts in food, no limits for tolerated numbers of CFU have been set for food of neutropenic patients [7, 19].

The results of this study, which indicate that there is no difference between NHD and LBD regarding colonization with potential pathogens, occurrence of infections and societal costs, may rekindle the discussion on the evidence for the necessity of LBD as infection preventive measure. Since less stringent dietary restrictions will facilitate home care of cytopenic cancer patients, these results are promising. Thus, a larger randomized study adequately powered to compare infection rates between NHD and LBD and to determine noninferiority of NHD to LBD is needed and safe to carry out.


   Acknowledgements
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
 Acknowledgements
References
 
We acknowledge the unflinching support of our colleague Ellen E. Stobberingh during the entire study. This work was financially supported by a grant awarded by the Dutch Board for health care insurance and by the Profileringsfonds of the University Hospital of Maastricht.


   Footnotes
 
{dagger} The authors hereby declare that this work is original and had not been published in anther journal, nor is submitted for publication to another journal. Data from this study have been presented as poster and published as an abstract: Back

1. Harbers MM, Schouten HC, van Boxtel HTC et al. 2003. Low bacterial diet in patients with cytopenia after intensive chemotherapy for hematological malignancy: a study of efficacy. In Abstracts of the 43rd ICAAC, Chicago 2003; 380 (Abstr K-1372).

2. Schouten HC, Harbers MM, Terporten PHW et al. Role of low-bacterial diet (LBD) in infection prevention in acute leukemia patients with chemotherapy induced cytopenia receiving antibiotic prophylaxis (AP). Blood 2003; 102 (11): 233B–234B (Abstr 4657) Part 2.

{ddagger} Present address: Centre for Public Health Forecasting, National Institute of Public Health and the Environment, Bilthoven, The Netherlands. Back

§ Present address: Clinical Trial Center Maastricht, University Hospital Maastricht, Maastricht, The Netherlands. Back

Received for publication December 15, 2006. Accepted for publication February 2, 2007.


   References
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
 Acknowledgements
 References
 
1. Bodey GP, Buckley M, Sathe YS, et al. Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia. Ann Intern Med (1966) 64:328–340.[Abstract/Free Full Text]

2. Khan SA, Wingard JR. Infection and mucosal injury in cancer treatment. J Natl Cancer Inst Monogr (2001) 29:31–36.[Abstract/Free Full Text]

3. Schwartz SA, Perry S. Patient protection in cancer chemotherapy. JAMA (1966) 197:623–627.[Abstract/Free Full Text]

4. James KW, Jameson B, Kay HE, et al. Some practical aspects of intensive cytotoxic therapy. Lancet (1967) 1:1045–1049.[Web of Science][Medline]

5. Bodey GP, Hart J, Freireich EJ, et al. Studies of a patient isolator unit and prophylactic antibiotics in cancer chemotherapy. General techniques and preliminary results. Cancer (1968) 22:1018–1026.[CrossRef][Web of Science][Medline]

6. Hamilton-Miller JM, Shah S. Identity and antibiotic susceptibility of enterobacterial flora of salad vegetables. Int J Antimicrob Agents (2001) 18:81–83.[CrossRef][Web of Science][Medline]

7. Pizzo PA, Purvis DS, Waters C. Microbiological evaluation of food items. For patients undergoing gastrointestinal decontamination and protected isolation. J Am Diet Assoc (1982) 81:272–279.[Web of Science][Medline]

8. Smith LH, Besser SG. Dietary restrictions for patients with neutropenia: a survey of institutional practices. Oncol Nurs Forum (2000) 27:515–520.[Medline]

9. Somerville ET. Special diets for neutropenic patients: do they make a difference? Semin Oncol Nurs (1986) 2:55–58.[CrossRef][Medline]

10. Todd J, Schmidt M, Christain J, et al. The low-bacteria diet for immunocompromised patients. Reasonable prudence or clinical superstition? Cancer Pract (1999) 7:205–207.[CrossRef][Web of Science][Medline]

11. Wilson BJ. Dietary recommendations for neutropenic patients. Semin Oncol Nurs (2002) 18:44–49.[CrossRef][Medline]

12. Moody K, Charlson ME, Finlay J. The neutropenic diet: what's the evidence? J Pediatr Hematol Oncol (2002) 24:717–721.[CrossRef][Web of Science][Medline]

13. Henry L. Immunocompromised patients and nutrition. Prof Nurse (1997) 12:655–659.[Medline]

14. French MR, Levy-Milne R, Zibrik D. A survey of the use of low microbial diets in pediatric bone marrow transplant programs. J Am Diet Assoc (2001) 101:1194–1198.[CrossRef][Web of Science][Medline]

15. Ascioglu S, Rex JH, de Pauw B, et al. Defining opportunistic fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus. Clin Infect Dis (2002) 34:7–14.[CrossRef][Web of Science][Medline]

16. Oostenbrink JB, Koopmanschap MA, Rutten FFH. Handleiding voor kostenonderzoek: methoden en richtlijnprijzen voor economische evaluaties in de gezondheidszorg. (1999) Apeldoorn, The Netherlands: VDA Groep.

17. Koopmanschap MA, Rutten FF, van Ineveld BM, et al. The friction cost method for measuring indirect costs of disease. J Health Econ (1995) 14:171–189.[CrossRef][Web of Science][Medline]

18. CDC, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. MMWR Recomm Rep (2000) 49:1–125.[Medline]

19. Moe G. Low-microbial diets for patients with granulocytopenia. In: Nutrition Management of the Cancer Patient—Bloch AS, ed. (1990) Rockville, MD: Aspen Publishing. 125–134.


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