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Original Article
Oral Ciprofloxacin Compared with Intravenous Ceftazidim on Low
Risk Febrile Neutropenia in Acute Lymphocytic Leukemia
Hashemi A1, Najafi N2, Behnaz F3, Zare A4

1- Department of Pediatrics, Hematology, Oncology and Genetics Research Center, Shahid Sadoughi University of Medical Sciences and
Health Services, Yazd, Iran
2- General Practitioner, Yazd, Iran
3- Department of Pediatrics, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran
4- MSc Statistics, Hematology, Oncology and genetic research center of Shahid Sadoughi University of Medical Sciences and Health
Services. Yazd, Iran

Abstract
Objective
Fever and neutropenia are a common complication of chemotherapy in cancer. It is usually
managed by hospitalization and empiric administration of antibiotics. Use of Fluroquinolones is
limited because of joint/cartilage toxicity. This study attempted to compare the efficacy of oral
ciprofloxacin with intravenous ceftazidim in low risk febrile neutropenic lymphocytic leukemia.
Methods
Ninety two episodes of febrile neutropenia in 72 patients under 14 years old were studied
prospectively for two years. All the patients received G-CSF plus intravenous ceftazidim 100
mg/kg/d and amikacin 15 mg/kg/d for 24 hours. These episodes randomly allocated into two
groups. Group A received IV ceftazidim and amikacin for at least 3 days. After discharge they
got oral cefixim 8 mg/kg daily. Group B discharged and received oral ciprofloxacin (20
mg/kg.day) for seven days. Failure was defined as temperature higher than 38 °C for more than
72 hours or major complication.
Results
Failure of intravenous ceftazidim plus amikasin for at least 4 days in hospital, in low risk febrile
neutropenic children, was 6.5%, but failure of oral ciprofloxacin for 7 days after 24h intravenous
ceftazidim plus amikasin was 4.3%. There was no arthrotoxicity in patients received
ciprofloxacin.
Conclusion
Empirical therapy with oral ciprofloxacin is safe and effective in children with leukemia and low
risk FN.
Keywords
Ciprofloxacin, Neutropenia, Acute Lymphocytic Leukemia

Corresponding Author:
Hashemi A MD. Hematology, Oncology and Genetics Research Center, Shahid Sadoughi University of
Medical Sciences and Health Services, Yazd, Iran Email: Dr_a_hashemi@yahoo.com
Iranian Journal of Pediatric Hematology and Oncology Vol1. No1.
Introduction
Febrile neutropenia is a common complication of cancer chemotherapy. It is easily managed by
hospitalization and empiric administration of parenteral antibiotics (1). This management clearly
has proved to reduce infection morbidity and mortality and has been considered as the standard
of care. However, recent reports and a previous randomized trial suggested that a low risk subset
of children with febrile neutropenia under chemotherapy might benefit of an oral antibiotic
outpatient approach (2).
Over the past three decades, considerable changes have occurred in the types of bacteria causing
infections in febrile patients with neutropenia and cancer. They include a substantially lower
incidence of gram-negative infections, such as Pseudomonas aeruginosa, and an increase rate of
gram-positive infections, mainly staphylococcus epidermidis and various strains of streptococci
(3). Mortality of the gram-positive coccal bacteremia in neutropenic patients is relatively low.
Gram-negative bacteremic episodes are associated with higher mortality rates, which still
represent 30% of all bacteremias (4). In the past several years, a combination of ceftazidime plus
amikacin has been established as a standard regimen in febrile neutropenia (5,6). Several studies
have used different regimens, either as monotherapy or as combined therapy, which have been
conducted in order to find the most effective regimen (7–10). Ceftazidim is a third-generation
cephalosporin with a broad spectrum of action that is easy to use. Ciprofloxacin is a synthetic 4-
quinolone bactericidal antibiotic against a broad range of gram-positive and gram-negative
organisms, including P. aeruginosa, that has a low rate of nephrotoxicity (11).
The fluoroquinolones are an important group of antibiotics widely used in the treatment of
various infections disease in adults as a result of an excellent spectrum of activity, good tissue
penetration and convenient ways of administration. Their use in children is limited as a result of
possible fluoroquinolone-induced joint cartilage toxicity observed mainly in juvenile animal
researchs (12). With the exception of cystic fibrosis and life endangering infections, the use of
fluoroquinolones in pedietric should be limited to gram-negative neonatal meningitis,
salmonella, and shigella, infections, chronic suppurative otitis media and some cases of
complicated acute otitis media. (12) Unskilled uses of flouroquinolones in children particularly
in community-acquired lower respiratory infection could accelerate the emergence of
pneumococal resistance (12).
Selection of patient with low risk febrile neutropenia is important for the best management.
Low risk patients defined as patient with early signs of bone marrow recovery, short duration of
fever, absence of comorbidity factors, and a predictive period of neutropenia of less than 10 days
(2).
Several randomised controlled trials have addressed the use of haematopoietic growth factors in
febrile neutropenic patients (13). These studies show that granulocyte colony stimulating factor
(GCSF) used in febrile neutropenic patients, consistently shortens the duration of neutropenia,
but does not consistently lead to resolution of infection or shorter time in hospital (14).
This study aimed to compare oral ciprofloxacin in early hospital discharge patients with
intravenous ceftazidim and amikacin for low risk febrile neutropenia.

Materials and Methods
This prospective, randomized, controlled study was conducted from March 2008 to June 2009.
The aim of this study was to evaluate the safety and efficacy of intravenous ceftazidim plus
amikacin given for 24 hours followed by oral ciprofloxacin, in children with febrile neutropenia
Iranian Journal of Pediatric Hematology and Oncology Vol1. No1. after chemotherapy with ALL. Ninety two episodes of low risk febrile neutropenia in 72 children
(mean age: 7.185 years; range: 0-14 years) were included in randomized controlled single
institution trial.
The inclusion criteria was age under 14 years old, fever (equal or more than 38 °C), sever
neutropenia (absolute neutrophil count less than 500/mm3), negative blood culture, good clinical
condition, control of local infection, remission, and parents’ cooperation. The exclusion criteria
included hemodynamic instability, serious comorbidity, dehydration, sever mucositis,
pneumonia, and bone marrow transplantation (2).
Peripheral blood and urine cultures and chest X-ray were performed for all patients before
treatment. Blood samples from port catheters and peripheral veins for quantitative differential
cultures were taken. Skin and soft tissue infections, diarrhea, pharyngitis, or any suspected
infection were roll out using bacterial cultures. All of the patients received intravenous
ceftazidim 100 mg/kg plus amikacin 15 mg/kg daily, for 24 hours. Then they randomly
allocated to two 46 episodes. Group A received IV ceftazidim & amikacin for at least three days
and discharged with oral cefixim (8 mg/kg/day) for 4 days. Patients in group B were discharged
and received oral ciprofloxacin (20 mg/kg/day) for seven days. All of the patients received G-
CSF.
Failure was defined, as temperature higher than 38 °C for more than 72 hours after antibiotic
therapy. Successful treatment was defined no fever and no re-admission due to a new fever
infection event within 7 days of discharge or a new febrile episode during the same episode of
neutropenia. Outcomes were compared by the Fisher exact test or Chi square test. P value less
than or equal to 0.05 was assumed as significant.

Result:
Seventy two patients presented 92 episodes of febrile neutropenia, who were entered in this
study. Forty six randomly episodes allocated in two groups A and B. Demographic
characteristics of patients showed in table 1. No significant difference in gender and age was
observed between both groups. Three patients (6.5%) in group A and 2 patients (4.3%) in group
B failed to treat. Forty eight hours after administration of the antibiotics, 24 patients (52%) in
group A and 14 patient (30%) in group B had fever, which difference was significant (P =
0.034). There were no sever complications in two groups. Patients failed the treatment had
fever more than 72 hours. There was no significant difference in ALT, AST, urea and creatinin
levels between two groups before treatment. Liver complication was defined as ALT or AST
equal or more than 40 after treatment. Liver complication was not significantly different between
two groups (ALT P = 0.335, AST P = 0.632). Renal complication was defined as urea equal or
more than 50 mg/dl, or creatinin equal or more than 1mg/dl after treatment. Renal complication
was not significantly different between two groups (urea PV= 0.153, creatinin PV= 0.153). No
arthrotoxicity was seen in patients after treatment.
Iranian Journal of Pediatric Hematology and Oncology Vol1. No1.
Table 1. Demographic characteristics of the two groups.
Characteristic


The table shows differences between two groups were not significant.
Table 2. Clinical course and outcome of the 93 episodes of fever and neutropenia

AST ≥40 after treatment if AST <40 before ALT ≥40 after treatment if ALT <40 before Urea ≥50 after treatment if urea <50 before Cr1 after treatment if Cr <1 before treatment Discussion:
Fever and neutropenia remains a potentially life threatening complication of anticancer
chemotherapy (7). Until recently, all febrile neutropenic patients were hospitalized for the
administration of empiric, broad-spectrum, intravenous antibiotic therapy (2). However, it is
possible to give more convenient treatment and less-intensive care for low risk patients (15).
The careful selection of the lower risk patients was a crucial factor in the success of the new
Iranian Journal of Pediatric Hematology and Oncology Vol1. No1. regimens. Other studies have used similar criteria, affirming their predictive value in the setting
of fever and neutropenia (16,17 and 2).
This study demonstrates that febrile neutropenic children with low risk criteria might be safely
and effectively managed using daily intravenous ceftazidim plus amikacin followed by oral
ciprofloxacin for 7 additional days. In compliant patients, with lower risk criteria, the treatment
could be changed after 1 day of intravenous therapy to an oral antibiotic, such as cefixime,
ciprofloxacin, ofloxacin, clindamycin, or quinolone associated with amoxicillin/clavulanic acid.
The patients could be discharged earlier from the hospital, with careful follow up (2,18)
Amikacin could cause nephrotoxicity. Thus, combination of high, once daily dose of ceftriaxon
with ciprofloxacin, a synthetic 4-quinolone antibiotic, are used. This bactericidal regimen is
against a broad range of gram-positive and gram-negative organisms including P. aeruginosa,
which has a low rate of nephrotoxicity (11). In a study conducted by the EORTC (European
Organization for Research and Treatment of Cancer), the incidence of nephrotoxicity in groups receiving
a single daily dose of amikacin was between 1.2% and 3.0%, while the incidence of ototoxicity
was 9% in the amikacin group receiving a single daily dose compared to 7% in the amikacin
group receiving it every 8 hours (19).
The use of fluoroquinolons in children should be selective and administered more carefully.
These drugs are currently used in pediatrics as second-line antibiotics, mostly in cases in which
all other previous treatment have failed. With the exception of cystic fibrosis and life threatening
infections, their use as first line therapy should be limited to gram-negative neonatal meningitis,
salmonella, and shigella spp. infections, chronic suppurative otitis media and some cases of
complicated acute otitis media non-responsive to initial treatment. Most of the published studies
failed to detect an increased rate of articular adverse effects in children treated with
fluoroquinolons (12). In this study sever complication was not seen but minor complication such
as mild nausea and headache were observed.

References:

1- Mullen CA,Petropoulos D,Roberts WM,Rytting M,Zipf T,Chan KW,et al. Outpatient treatment of fever and neutropenia for low risk pediatric cancer patients. Cancer, 1999; 86(1):126-34. 2-. et al. Oral ciprofloxacin in the management of children with cancer with lower risk febrile neutropenia. 2001; 91(8):1563-7. 3-Zinner SH. Changing epidemiology of infections in patients with neutropenia and cancer Clin Infect Dis. 1999; 29:490–4. 4- Feld R. Vancomycin as part of initial empirical antibiotic therapy for febrile neutropenia in patients with cancer: pros and cons. Clin Infect Dis. 1999;29:503–7. 5- Nucci M, Pulcheri WA, Spector N, de Oliveira HP. Ceftazidime and amikacin as empirical treatment of febrile episodes in neutropenic patients. J Infect. 1994; 28:335–6. 6- Santhosh-Kumar CR, Ajarim DS, Harakati MS, al Momen AK, al Mohareb F, Zeitany RG. Ceftazidime and amikacin as empiric treatment of febrile episodes in neutropenic patients in Saudi Arabia. J Infect 1992;25:11–9. 7- De Pauw BE, Deresinski SC, Feld R, Lane-Allman EF, Donnelly JP. Ceftazidime compared with piperacillin and tobramycin for the empiric treatment of fever in neutropenic patients with cancer. Ann Intern Med. 1994; 120:834–44. 8- Bodey GP, Rolston KV, Raad II. Ciprofloxacin versus tobramycin for neutropenic fevers. Ann Intern Med 2003; 138:435:436. 9- Pérez C, Sirham M, Labarca J, Grebe G, Lira P, Oliva J, et al. Imipenem/cilastatin versus ceftazidime-amikacin in the treatment of febrile neutropenic patients. Rev Med Chil 1995; 123(3):312–20. Iranian Journal of Pediatric Hematology and Oncology Vol1. No1. 10- Hazel DL, Graham J, Dickinson JP, Newland AC, Kelsey SM.Piperacillin-tazobactam as empiric monotherapy in febrile neutropenic patients with haematological malignancies. J Chemother 1997; 9: 267–72. 11- Metallidis S, Kollaras AP, Giannakakis P, Seitanidis B, Kordosis K, Nikolaidis K, et al. A prospective, controlled, randomized, non-blind, comparative study of the efficacy and safety of a once daily high dose of ceftriaxone plus ciprofloxacin versus thrice daily ceftazidime plus amikacin in empirical therapy for febrile neutropenic patients,European Journal of Internal Medicine 2008;19: 619–624. 12-Leibovitz E. The use of fluoroquinolones in children.Current Opinion in Pediatrics February, 2006 :64-70. 13-Ozer H, Armitage JO, Bennett CL, et al. 2000 update of recommendations for the use of heamatopoietic colonystimulating factors. J Clin Oncol 2000; 18:3558–85. 14-Sheila M. Lane, Janice A. Kohler, The management of febrile neutropenia, Current Paediatrics. 2005; 15:400–405. 15- Oral antibiotics with early hospital discharge compared with in-patient intravenous antibiotics for low-risk febrile neutropenia in patients with cancer.2003; 89(1):43-9. 16-Kern WV, Cometta A, de Bock R, Langenaeken J, Paesmans M, Gaya H, et al. Oral versus intravenous empirical antimicrobial therapy for fever in patients with granulocytopenia who are receiving cancer chemotherapy. N Engl J Med 1999; 341:312–8. 17. Mullen CA, Petropoulos D, Roberts M, Rytting M, Zipf T, Chan KW, et al. Outpatient treatment of fever and neutropenia for low risk pediatric cancer patients. Cancer 1999; 86: 126–34. 18- et al . A double-blind comparison of empirical oral and intravenous antibiotic therapy for low-risk febrile patients with neutropenia during cancer chemotherapy.1999; 341(5):305-1. 19- Calandra T. Efficacy and toxicity of single-daily doses of amikacin and ceftriaxone versus multiple daily doses of amikacin and ceftazidime for infection in patients with cancer and granulocytopenia. Ann Intern Med 1993: 584–93. Iranian Journal of Pediatric Hematology and Oncology Vol1. No1.

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