[Pediatric Reports 2011; 3:e3] [page 9]

Antibacterial prophylaxis inneutropenic children with cancerAngelica BaronePediatric Hematology and Oncology Unit,Department of Pediatrics, AziendaOspedaliero-Universitaria di Parma, Italy

Abstract

During the period of neutropenia induced bychemotherapy, patients have a high risk ofinfection. The use of antibiotic prophylaxis toreduce neutropenia-related complications inpatients with cancer is still disputed. Recentmeta-analysis and clinical trials demonstratedthat antibiotic prophylaxis with quinolonesreduces febrile episodes, bacterial infectionsand mortality in adult oncological patients withneutropenia induced by chemotherapy inacute leukaemia. In paediatric patients, theonly randomized, double-blind, prospectivestudy until now suggests that amoxicillin/clavulanate may represent an effective prophy-lactic treatment in reducing fever and infec-tions in oncological children with neutropenia,with an efficacy that is statistically demon-strated only in patients with acute leukaemia.Considering the risk of resistances, antibiotic-prophylaxis should be used only in selectedpatients.

Introduction

During the period of neutropenia induced bychemotherapy, patients have a high risk ofinfections, with a risk-rate related to the leveland duration of neutropenia.1 Bacterial infec-tions, proved in a minority of cases, are amajor cause of disease and death in neu-tropenic patients, with some differencesaccording to the aggressiveness of chemother-apy.2,3 The use of antibiotic prophylaxis toreduce neutropenia-related infectious compli-cations in patients with cancer, mostly used inadults, is still disputed. These antimicrobialagents are given to patients at the beginningof neutropenia, without fever or other signs ofinfection.4 Neutropenia is defined as anabsolute neutrophil count lower than 500/mmcor under 1.000/mmc if rapidly decreasing.5 Therisk is higher if neutropenia lasts longer than7 days. Fever is defined by body temperatureequal to or higher than 38.5°C or a tempera-ture of 38°C lasting for more than an hour or38°C or more measured at least twice in 12hours.5,6

Methods

The terms neutropenia & similar, antibiotic& similar, prophylaxis & similar, cancer & sim-ilar, fever & similar were crossed in theCochrane Library, MEDLINE and EMBASEfrom January 1980 to October 2010.

Results

Considering that 80% of infections in neu-tropenic patients originate from endogenousbacterial flora, and about half of these areacquired in the hospital,7 the first approachwas the reduction of intestinal flora throughthe use of non-absorbable antibiotics.Intestinal decontamination was either total orpartial, if anaerobic flora was preserved.Antibiotics mostly used were gentamicin, van-comycin, colistin or neomycin/polymyxin.8However, a poor patient compliance associatedwith the risk of resettlement by opportunisticor resistant bacteria led to the failure of theprophylaxis.9 Selective decontaminationrequired careful monitoring of the intestinalflora. Afterwards the drug of choice becameTMP-SMX, frequently used in association withnystatin or amphotericin B, even if it some-times lengthened neutropenia.10 However theadministration of TMP-SMX was a systemicprophylaxis, as far as it is an adsorbable antibi-otic. Fluoroquinolones are interesting drugsfor oral prophylaxis, due to their bioavailabili-ty, wide antibacterial spectrum, sparing of theanaerobic intestinal flora, bactericide action,good tolerance and absence of myelosuppres-sive effect.11 However, their use is contraindi-cated for prophylaxis in patients under 18years of age because of their possible interfer-ence with osteocartilagineous development.

Guidelines from the Infectious DiseasesSociety of America (IDSA) in 2002 recom-mended the use of antibiotic prophylaxis for aperiod as short as possible and in a small num-ber of patients, in order to avoid the risk ofddeveloping bacterial resistance and beacuseof the unproven reduction in mortality despitethe decreased rate of fever episodes.5 Howeversome meta-analysis and clinical trials showedthat prophylaxis with fluoroquinolonesreduces fever episodes, clinically and microbi-ologically proven bacterial infections, infec-tion-related and overall mortality in adultpatients with acute leukaemia.2,12,13 A largeclinical trial in adult patients with solidtumours undergoing standard chemotherapydid not show the same results.14 Guidelinesfrom ECIL (European Conference onInfections in Leukaemia) and NCCN (US-National Comprehensive Cancer Network) rec-ommend prophylaxis with quinolones in adult

patients undergoing chemotherapy for acuteleukaemia.15,16 According to other Authors, pro-phylaxis with quinolones should also be con-sidered in patients with solid tumour or lym-phoma at the first block of chemotherapy sinceit is frequently associated with a 4°-degreeneutropenia.17-19

In paediatric patients, the only randomized,double-blind 2-year multicentric AIEOP(Italian Association of Pediatric Hematologyand Oncology) prospective study on 173 chil-dren suggested that amoxicillin/clavulanatemay be an effective prophylactic treatment inreducing fever and infections in neutropenicchildren with cancer, although its efficacy hasbeen statistically demonstrated only inpatients with acute leukaemia and lymphoma.In the general population a clinically signifi-cant reduction (12%) in fever and infectionswas observed, comparing to the placebo group,although not statistically significant. Authorsconcluded that, due to the risk of developingresistances, antibiotic prophylaxis should beused with caution in a selected group ofpatients and for short periods of time.20

Another paediatric study assessed the use ofciprofloxacin in 69 children with acute lym-phoblastic leukaemia during reinduction phas-es, observing a statistically significant reduc-tion in the incidence of Gram-negative bacter-aemias and related admissions to the hospital;however the design of the study consideredprevious patients as control group.21 A retro-spective study conducted by the St. Jude groupon antibiotic prophylaxis in 78 consecutivepaediatric patients with acute myeloidleukaemia undergoing chemotherapy showeda significant reduction in incidence and mor-tality by septicaemia after prophylaxis with

Pediatric Reports 2011; volume 3:e3

Correspondence: Angelica Barone, PediatricHematology and Oncology Unit, Department of Pediatrics, Azienda Ospedaliero-Universitariadi Parma, via Gramsci 14 - 43100 Parma, Italy.Tel. +39.0521.702210 - Fax: +39.0521.702360. E-mail: abarone@ao.pr.it

Key words: neutropenia, antibiotic, prophylaxis,cancer, fever.

Conflict of interest: the authors report no con-flicts of interest.

Received for publication: 16 November 2010.Revision received: 21 January 2011.Accepted for publication: 21 January 2011.

This work is licensed under a Creative CommonsAttribution 3.0 License (by-nc 3.0).

©Copyright A. Barone, 2011Licensee PAGEPress, ItalyPediatric Reports 2011; 3:e3doi:10.4081/pr.2011.e3

[page 10] [Pediatric Reports 2011; 3:e3]

intravenous cefepime or intravenous van-comycin associated with oral ciprofloxacin.4

There are few data on what concerns repeat-ed neutropenic periods in the same patients.The positive effect of antibacterial prophylaxisreported in a meta-analysis considered ran-domized trials including only one neutropenicperiod per patient.2 This beneficial effect ofprophylaxis may disappear in patients withrepeated neutropenic periods as shown byCastagnola3,20 and Cullen.14 In order to evaluatethe efficacy of repeated cycles of antibiotic pro-phylaxis, the number of multicenter clinicaltrials with a very large number of oncologicalpatients should be increased.

The prolonged administration of wide spec-trum antibiotics can cause either the onset ofbacterial resistance and toxicity. The onset ofresistant strains is a justified concern, and hasbeen reported by centres using prophylaxiswith fluoroquinolones.22-24 However a large andrecent meta-analysis was not able to demon-strate a significant increase in colonizationand infections caused by fluoroquinolone-resistant bacteria in patients undergoing pro-phylaxis.25 However these results are limitedby the lack of data reported in trials: in lessthan half of the studies microbiologic surveil-lance was assessed and data on resistant bac-teria colonization were reported; less than athird reported data on quinolone-resistant bac-teria infections. Observation length was notprolonged enough to properly evaluate theeffect of antibiotic prophylaxis on resistances.Therefore, at the moment, long-term effects ofantibiotic prophylaxis on microbiologic resist-ances are still unknown.12,26

Discussion

There are some patient groups that maybenefit from antibiotic prophylaxis. However,the wide and prolonged use of antibiotic pro-phylaxis can lead to the onset of resistant bac-teria, nullifying the effect of prophylaxis.Therefore, antibiotic prophylaxis in pediatricpatients with cancer should be used only inselected cases of acute leukaemia, with amox-icillin/clavulanate (at a dose of 25 mg/kg twicea day), at the end of chemotherapy blocks,since quinolones are contraindicated inpatients under 18 years of age. The choice of aprophylaxis policy for patients at higher risk ofinfections requires the adoption or the imple-mentation of a microbiological surveillanceprogram.

References

1. Pizzo PA. Management of fever in patientswith cancer and treatment-induced neu-tropenia. N Engl J Med 1993;328:1323-32.

2. Gafter-Gvili A, Fraser A, Paul M, LeiboviciL. Met-Analysis: antibiotic prophylaxisreduces mortality in neutropenic patients.Ann Intern Med 2005;142:979-95.

3. Castagnola E, Fontana V, Caviglia I, et al. Aprospective study on the epidemiology offebrile episodes during chemotherapy-induced neutropenia in children with can-cer or after hemopoietic stem cell trans-plantation. Clin Infect Dis 2007;45:1296-304.

4. Kurt B, Flynn P, Shenep JL, et al.Prophylactic antibiotics reduce morbiditydue to septicemia during intensive treat-ment for pediatric acute myeloidleukemia. Cancer 2008;113:376-82.

5. Hughes WT, Armstrong D, Bodey GP, et al.2002 Guidelines for the use of antimicro-bial agents in neutropenic patients withcancer. Clin Infect Dis 2002;34:730-51.

6. Viscoli C, Castagnola E. Prophylaxis andempirical therapy of infection in cancerpatients. In: Mandell, Douglas andBennett’. Principles and Practice ofInfectious Diseases. 6th ed. ChurchillLivingstone; 2005; p. 3442-62.

7. Schimpff SC, Young V, Green E, et al.Origin of infection in acute non-lympho-cytic leukemia: significance of hospitalacquisition of potential pathogens. Ann IntMed 1972;77:707-15.

8. Hawthorn JW. Critical appraisal of antimi-crobials for prevention of infections inimmunocompromised hosts. HematolOncol Clin N Am 1993;7:1051-99.

9. Guiot HF, van der Broek J, van dee MeerJW, van Furth R. Selective antimicrobialmodulation of the intestinal flora ofpatients with acute nonlymphocyticleukemia: a double blind, placebo-con-trolled study. J Infect Dis 1983;147:615-23.

10. Gualtieri RJ, Donowitz GR, Kaiser DL, etal. Double-blind randomized study of pro-phylactic trimethoprim/sulfametoxazolein granulocytopenic patients with hemato-logic malignancies. Am J Med 1983;74:934-40.

11. Engels EA, Lau J, Barza M. Efficacy ofquinolone prophylaxis in neutropenic can-cer patients: a meta-analysis. J Clin Oncol1998;16:1179-87.

12. Bucaneve G, Micozzi A, Menichetti F, et al.Levofloxacin to prevent bacterial infectionin patients with cancer and neutropenia. NEngl J Med 2005;353:977-87.

13. Leibovici L, Paul M, Cullen M, et al.Antibacterial prophylaxis in neutropenic

patients. Cancer 2006;107:1743-51. 14. Cullen M, Steven N, Billingham L, et al.

Antibacterial prophylaxis after chemother-apy for solid tumors and lymphomas. NEngl J Med 2005;353:988-98.

15. Meunier F, Lukan C. The first EuropeanConference on Infections in Leukaemia.Eur J Cancer 2008;44:2112-7.

16. Segal BH, Freifeld AG, Baden LR, et al.Prevention and treatment of cancer-relat-ed infections. J Natl Compr Cancer Netw2008;6:122-74.

17. Cullen M, Billingham L, Gaunt C et al.Rational selection of patients for antibac-terial prophylaxis following chemotherapy.J Clin Oncol 2007;25:4821-8.

18. Pascoe J and Steven N. Antibiotics for theprevention of febrile neutropenia. CurrOpinion Hematol 2009;16:48-52.

19. Cullen M and Baijal S. Prevention offebrile neutropenia: use of prophylacticantibiotics. British J Cancer 2009;101:S11-14.

20. Castagnola E, Boni L, Giacchino M, et al. Amulticenter, randomized, double-blindplacebo-controlled trial of amoxicillin/clavulanate for the prophylaxis of feverand infection in neutropenic children withcancer. Pediatr Infect Dis J 2003;22:359-65.

21. Yousef AA, Fryer CJH, Chedid FD, et al. Apilot study of prophylactic ciprofloxacinduring delayed intensification in childrenwith acute lymphoblastic leukaemia.Pediatr Blood Cancer 2004;43:637-43.

22. Castagnola E, Haupt R, Micozzi A, et al.Differences in the proportions of fluoro-quinolone-resistant Gram-negative bacte-ria isolated from bacteraemic childrenwith cancer in two Italian centres. ClinMicrobiol Infect 2005;11:505-7.

23. Kern WV, Klose K, Jellen-Ritter AS.Fluoroquinolone resistance of Escherichiacoli at a cancer centre: epidemiologicalevolution and effects of discontinuing andre-introducing quinolone use in neu-tropenic patients with leukaemia. Eur JClin Microb Infect Dis 2005;24:111-8.

24. Ito JI, Tegtmeier BR, O’Donnell MR.Antibacterial prophylaxis in children withcancer and neutropenia. N Engl J Med2006;354;1.

25. Gafter-Gvili A, Paul M, Fraser A, LeiboviciL. Effect of quinolone prophylaxis inafebrile neutropenic patients on microbialresistance: systematic review and meta-analysis. J Antimicrobial Chemotherapy2007;59:5-22.

26. Viscoli C. Antibacterial prophylaxis in neu-tropenic patients. Int J AntimicrobialAgents 2007;305:560-5.

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