Prophylaxis of neutropenic fever with ciprofloxacin in patients with acute myeloid leukemia treated with intensive chemotherapy

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1 Asia-Pacific Journal of Clinical Oncology 2016; 12: e11 e15 doi: /ajco ORIGINAL ARTICLE Prophylaxis of neutropenic fever with ciprofloxacin in patients with acute myeloid leukemia treated with intensive chemotherapy Mojtaba GHADIANY, 1 Hossein RAHIMI, 3 Hamid REZVANI, 1 Afshin MOHAMMAD ALIZADEH, 1 Nasim ZAMANI, 2 Mahshid MEHDIZADEH 1 and Mohammad FORATYAZDI 4 1 Department of Oncology, Taleghani Hospital, 2 Department of Clinical Toxicology, Shahid Beheshti University of Medical Sciences, Tehran, 3 Department of Oncology, Hamedan University of Medical Sciences, Hamedan, and 4 Department of Oncology, Yazd University of Medical Sciences, Yazd, Iran Abstract Aims: Neutropenic fever is one of the most serious complications after induction chemotherapy in acute myeloid leukemia (AML). Prophylaxis with antibiotics for prevention of neutropenic fever in AML is controversial and there are few studies on this issue from developing countries. Methods: In this retrospective study, we analyzed the clinical data and outcome of patients with AML who did or did not receive prophylactic ciprofloxacin 500 mg BD for neutropenic fever. Results: A total of 69 AML patients were treated by protocol for their first induction chemotherapy. Prophylaxis was given to 25 of them. Incidence of neutropenic fever was the same in both groups (80% vs 82%). Duration of fever and the mortality rate were also similar in both groups. Conclusion: It seems that in developing countries, using prophylactic ciprofloxacin has no significant effect on the incidence of neutropenic fever and the outcome of the AML patients. Key words: ciprofloxacin, fluoroquinolone, leukemia, neutropenic fever, prophylaxis. INTRODUCTION Acute myeloid leukemia (AML) is a very aggressive malignancy and is mostly treated with aggressive induction chemotherapy. Induction chemotherapy causes profound prolonged neutropenia in almost all patients, and therefore, the risk of infection is very high and neutropenic fever has been reported in 80 90% of these patients. 1 3 During the 1970s, the results of several randomized trials about the effectiveness of trimethoprim/sulfamethoxazole prophylaxis were published. Correspondence: Dr Nasim Zamani MD, Department of Clinical Toxicology, Loghman-Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran , Iran. nasim.zamani@gmail.com Conflict of interest: none Accepted for publication 11 August However, in the 1980s, the focus of antibiotic prophylaxis shifted toward the use of fluoroquinolones. Fluoroquinolones have good oral bioavailability and broad spectrum of gram-negative antimicrobial coverage. In the past two decades, many studies were done about fluoroquinolone prophylaxis during neutropenia in cancer patients. Unfortunately, few were randomized, double-blind, placebo-controlled trials, and even fewer focused specifically on patients with leukemia. 4 Generally, most of the randomized controlled trials on the subject have shown that fluoroquinolone prophylaxis reduces the incidence of gram-negative bacteremia. The issue of prophylaxis is however controversial mainly because none of these studies have shown a mortality benefit and most have failed to address the time-delayed potential emergence of fluoroquinolone-resistant organisms. 4 Although meta-analyses and systematic reviews were done by Van de Wetering and colleagues, and

2 e12 M Ghadiany et al. Gafter-Gvili and associates recommended use of prophylactic antibiotics in cancer patients, unfortunately most of the trials evaluated in these meta-analyses were done on heterogeneous groups of patients including leukemia and non-leukemia patients, few were done 5,6 only on patients with leukemia, and even fewer were done in developing countries. Incidence of fluoroquinolone-resistant Escherichia coli in leukemia patients is significantly more than other malignancies. 7 It seems that the results of other malignancies cannot be extended to AML patients. In addition, in developing countries, situation is not the same as in developed countries; so the effect of prophylactic antibiotics may be different in developing countries and we cannot easily extend the results of these studies to the developing countries. We aimed to evaluate the effect of oral prophylaxis with ciprofloxacin in prevention of neutropenic fever in AML patients treated in a developing country. We conducted this retrospective analysis on patients with AML who had been treated in our hospital. MATERIALS AND METHODS The study was conducted on a dataset extracted from patient s files who had been treated in a referral hospital in Tehran, approved by local ethics committee. All patients had signed written consent forms. The hospital files of all AML patients treated from September 2009 to November 2010 were reviewed. All patients bone marrows and peripheral blood smear examinations had been reviewed by a single expert hematologist. Patients with more than 20% blast in their peripheral blood smear or bone marrow and flow cytometric analysis compatible with diagnosis of AML were considered to have AML. Patients who were native and had been treated with intensive induction chemotherapy containing idarubicin 12 mg/m 2 /day for 3 days (days 1 3) and Ara-C mg/m 2 /day as 24-h continuous infusion for 7 days (days 1 7; protocol 3 + 7) were included, and those who had been treated by other protocols or hospitalized for second induction, relapse or consolidation were not included. They were all advised to eat only cooked food and were admitted in a six-bed room with no high efficiency particle air (HEPA) filter. No patient had central venous catheters and all medications and blood products were administered via the peripheral veins. Patients received blood products (red blood cell packed cell, fresh frozen plasma, platelet) and other supportive treatments when indicated. Some of the treating physicians had prophylactically administered ciprofloxacin to their patients (group A; treated with ciprofloxacin tablets, 500 mg twice a day) from day 1 of chemotherapy until day 28. Those who had been treated with antibiotics within 7 days before start of chemotherapy or were febrile on the first day of chemotherapy were excluded. The patients were classified as control group (group B) if their treating physicians had not given them prophylactic antibiotics and were not febrile on the first day of chemotherapy. All neutropenic fever episodes in both groups were treated according to the hospital guidelines, and prophylactic oral ciprofloxacin was discontinued after the first episode of neutropenic fever. Data including the patients demographic data, type of AML, rate of neutropenic fever episodes, microbiologic findings, patterns of resistance and the outcome were extracted from the patients files. Febrile episodes that had happened after induction chemotherapy were used for the analysis. A single oral temperature of more than 38.3 Ċ or a temperature of more than 38 but less that 38.3 Ċ for more than 1 h, with an absolute neutrophil count of less than 500/μL or predicted rapid decline to less than 500/μL, was considered as neutropenic fever. The neutropenic fever episodes were classified as microbiologically documented if culture(s) was(were) positive and clinically suspected if culture was not positive. If the patient received granulocyte colony stimulating factor (G-CSF) before episodes of fever, it was classified as primary G-CSF, and if it was injected after episodes of fever it was classified as secondary G-CSF. Mortality was defined as death from any cause occurring within 28 days of the first day of induction chemotherapy. All data were analyzed using Statistical Package for Social Sciences (SPSS; IBM, Chicago, IL, USA) software package version 17, Student s t-test, Fisher s exact test and chi-square test. Differences were considered statistically significant at the P < 0.05 level (two tailed for all tests). RESULTS From September 2009 to November 2010, 82 patients were evaluated. A total of 28 patients had received oral ciprofloxacin as prophylaxis and 54 did not. Three patients from prophylaxis group were excluded; the reasons for exclusion were reaction to ciprofloxacin, having fever before the initiation of ciprofloxacin and not using ciprofloxacin due to the patient s decision (remaining 25). Among 54 patients who did not receive

3 Neutropenic fever and acute leukemia e13 Table 1 Characteristics Patients characteristics Prophylaxis with ciprofloxacin No prophylaxis with ciprofloxacin No. of patients No. of neutropenic episodes/no. of patients 20/25 (80%) 36/44 (82%) NS Age (years) 41.3 ± ± 9.0 NS Gender (male patients) 16/25 (64%) 31/44 (70%) NS Duration of fever (days) 6.1 ± ± 4.4 NS G-CSF primary 4/25 (16%) 6/44 (14%) NS G-CSF secondary 12/25 (48%) 24/44 (54%) NS Mortality 4/25 (16%) 10/44 (23%) NS Amphotericin 11/20 (55%) 18/36 (50%) NS Positive blood culture 3/20 (15%) 4/36 (11%) NS G-CSF primary, G-CSF started before fever; G-CSF secondary, G-CSF started after fever; NS, not significant. P-value prophylactic antibiotic, 10 were excluded (remaining 44) because they had fever before the administration of chemotherapy. A total of 69 patients (25 in group A and 44 in group B) were finally entered in the study. The characteristics of these two groups are summarized in Table 1. Subtypes of AML were similar in both groups and no patient with AML-M3 was included in the study. No patient had central vein catheter and all patients were treated in rooms with six beds without HEPA filter. Overall, 56 episodes of neutropenic fever were documented. Twenty-one episodes happened while the patients were in hospital and 35 when the patients had been discharged. Mean time of hospitalization was 9 days in the latter group (at least 8 days). Blood culture was positive in five patients; two of them were in prophylactic group and three in the control group. Chest X-ray showed infiltration in 16 patients, seven of whom were in prophylactic group and nine in the control group (with no statistically significant differences). Mean time of fever has been 13 ± 7 days in ciprofloxacin group and 14 ± 8 days in the control group without a significant difference. All patients had received intravenous antibiotics after the initiation of fever. Only seven positive blood cultures were reported so we did not analyze its details. All 56 neutropenic fever episodes were treated with empirical broad spectrum antibiotics including ceftazidime plus amikacin or imipenem with or without amikacin starting immediately when the patient had the criteria of neutropenic fever. Ciprofloxacin group also received vancomycin immediately after neutropenic fever but control group received vancomycin according to the physician s decision. Amphotericin B was added empirically after 7 days if the patients still had fever. Administration of G-CSF was done according to the Table 2 Incidence of febrile episodes in neutropenic patients with fluoroquinolone prophylaxis compared with no prophylaxis groups in previous studies physician s decision. Prophylactic administration of ciprofloxacin was discontinued when empirical antibiotic therapy was started. DISCUSSION Neutropenic fever Fluoroquinolone Control NF/NP (%) NF/NP (%) P-value 48/62 (77%) 8 46/57 (81%) NS 13/17 (76%) 9 15/18 (83%) NS 38/52 (73%) 10 44/51 (86%) NS 123/183 (67%) /165 (88%) < /46 (83%) 12 44/49 (90%) NS 34/50 (68%) 13 47/50 (94%) NS NF, number of neutropenic fever; NP, number of patients; NS, not significant. Infection is the main cause of mortality and morbidity in AML patients treated with intensive chemotherapy. Because few studies have only focused on patients with leukemia and fewer have been done in developing countries, we need more studies that focus on leukemia patients and, more importantly, in developing countries. We summarized the results of six studies that we found about prophylaxis with fluoroquinolones in AML patients in Table 2. Unlike most retrospective studies that usually have historical controls, our study has a control group that was treated at the same time and at the same ward. In

4 e14 M Ghadiany et al. our study, only patients with AML treated for first induction chemotherapy were included, and therefore, there are homogenous case and control groups. Although the number of patients in our study is not enough to make a good power, it seems acceptable in comparison with most of other studies. Neutropenic fever happened in 82% of our patients who had not received ciprofloxacin prophylaxis. This rate is a bit more than the rate reported by Rahman and George but less than that reported by others (Table 2). It seems that the rate of neutropenic fever in AML patients without ciprofloxacin prophylaxis is in the range of 78 94%. Incidence of neutropenic fever was 80% in our patients who had received ciprofloxacin. This rate is only 2% less than the control group and the difference is not statistically significant (P = 0.5). Although in most other studies the rate of neutropenic fever in prophylactic group was less than the control group, the difference was not statistically significant in five of seven studies (Table 2). In a study from India, neuropenic fever happened in 68% when patients were treated as inpatient with prophylaxis and in 52% when patients were treated as outpatients. 14 The incidence of neutropenic fever in our patients was much higher than that reported by Naithani et al. 14 In most studies, fluoroquinolone prophylaxis reduced documented bacterial infections; but in our study the rate of documented bacterial infection was very low and the difference was not statistically significant between the two groups. Because of low rate of documented bacterial infections in our study, we cannot compare this rate in our study with other studies. We found few studies from developing countries using fluoroquinolones as prophylaxis in AML patients. Rahman and Khan published a randomized clinical trial about levofloxacin prophylaxis in AML patients. In this study, the rate of neutropenic fever (78% vs 68%) and isolation of the pathogenic bacteria (30.43% vs 16%) in the placebo group was higher than the levofloxacin group. They concluded that levofloxacin reduced the bacterial infections and delayed the onset of fever in chemotherapy-induced neutropenia especially in short duration (<7 days). 15 They suggested that more prudent use of antibiotic prophylaxis might be reasonable even in patients at high risk for developing infection. In a study from Korea, the incidence of fever in nonprophylactic group was 91.6% and 82.6% in prophylactic group with a nonsignificant difference. Incidence of documented bacterial infection was not significantly different between the two groups either. 12 In summary, according to most studies performed only on AML patients especially from developing countries, using prophylactic ciprofloxacin has no statistically significant effect on the rate of neutropenic fever and the outcome of AML patients. We need larger randomized trials especially in developing countries to evaluate the effects of prophylactic antibiotic administration in AML patients. REFERENCES 1 Hämäläinen S, Kuittinen T, Matinlauri I, Nousiainen T, Koivula I, Jantunen E. Neutropenic fever and severe sepsis in adult acute myeloid leukemia (AML) patients receiving intensive chemotherapy: causes and consequences. Leuk Lymphoma 2008; 49: Douer D, Ben-Bassat I, Singer A, Ramot B. Treatment of acute myeloid leukemia in a special hematology unit. Harefuah 1999; 118: Yoshida M, Tsubaki K, Kobayashi T, Tanimoto M, Kuriyama K et al. 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Available from: divisions/pharmaco/rounds/anderson pdf 8 Talbot GH, Cassileth PA, Paradiso L, Correa-Coronas R, Bond L. Oral enoxacin for infection prevention in adults with acute nonlymphocytic leukemia. Antimicrob Agents Chemother 1993; 37: Imran H, Tleyjeh IM. The use of fluoroquinolones as prophylaxis in neutropenia [cited September 1993]. Retrieved from: artsrv2009_5.pdf 10 Yamada T, Dan K, Nomura T. Prevention of bacterial and fungal infections in acute leukemia patients: a new and potent combination of oral norfloxacin and amphotericin B. Intern Med 1993; 32:

5 Neutropenic fever and acute leukemia e15 11 Bucaneve G, Micozzi A, Menichetti F et al. Levofloxacin to prevent bacterial infection in patients with cancer and neutropenia. N Engl J Med 2005; 353: Lee DG, Choi SM, Choi JH et al. Selective bowel decontamination for the prevention of infection in acute myelogenous leukemia: a prospective randomized trial. Korean J Intern Med 2002; 17: López A, Soler JA, Juliá A, Novo A, Bueno J. Prophylaxis with ciprofloxacin in postchemotherapy neutropenia in acute myeloid leukemia. Med Clin (Barc) 1994; 102: Naithani R, Kumar R, Mahapatra M, Agrawal N, Mishra P. Early discharge from hospital after consolidation chemotherapy in acute myeloid leukemia in remission: febrile neutropenic episodes and their outcome in a resource poor setting. Haematologica 2008; 93: Rahman MM, Khan MA. Levofloxacin prophylaxis to prevent bacterial infection in chemotherapy-induced neutropenia in acute leukemia. Bangladesh Med Res Counc Bull 2009; 35: 91 4.