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Randomized controlled trial comparing ciprofloxacin and cefepime in febrile neutropenic patients with hematological malignancies

Open AccessPublished:January 14, 2013DOI:https://doi.org/10.1016/j.ijid.2012.12.005

      Summary

      Background

      Ciprofloxacin (CPFX) is a potential alternative in patients with febrile neutropenia (FN) because of its activity against Gram-negative organisms. We conducted a non-inferiority, open-label, randomized controlled trial comparing intravenous CPFX and cefepime (CFPM) for FN patients with hematological malignancies.

      Methods

      Patients aged from 15 to 79 years with an absolute neutrophil count of <0.500 × 109/l were eligible, and were randomized to receive 300 mg of CPFX or 2 g of CFPM every 12 h. Initial treatment efficacy, overall response, and early toxicity were evaluated.

      Results

      Fifty-one episodes were included in this trial, and 49 episodes (CPFX vs. CFPM: 24 vs. 25) were evaluated. Treatment efficacy at day 7 was significantly higher in the CFPM group (successful clinical response: nine with CPFX and 19 with CFPM; p = 0.007). The response was better in high-risk patients with neutrophil counts of ≤0.100 × 109/l (p = 0.003). The overall response during the study period was similar between the CPFX and CFPM groups (p = 0.64). Adverse events were minimal, and all patients could continue the treatment.

      Conclusions

      We could not prove the non-inferiority of CPFX in comparison with CFPM for the initial treatment of FN. CFPM remains the standard treatment of choice for FN.

      Keywords

      1. Introduction

      The goal of initial empiric antibiotic therapy for febrile neutropenia (FN) with hematologic malignancies is to prevent serious morbidity and mortality due to bacterial pathogens, until the results of blood cultures are available to guide more precise antibiotic choices. Although Gram-positive bacteria have increased as pathogens in FN during the past 20 years, Gram-negative bacteria are associated with a greater mortality.
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      Current trends in the epidemiology of nosocomial bloodstream infections in patients with hematological malignancies and solid neoplasms in hospitals in the United States.
      In particular, Pseudomonas aeruginosa infection is associated with a higher mortality,
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      and coverage of this organism remains an essential component of the initial empiric antibiotic regimen. A commonly used therapy for FN is a combination of β-lactam antibiotic and aminoglycoside, which offers a broad spectrum of initial coverage, including P. aeruginosa.
      • Klastersky J.
      Management of infection in granulocytopenic patients.
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      Empiric antibiotic therapy for granulocytopenic cancer patients.
      Although combination therapy with a β-lactam antibiotic and an aminoglycoside has been reported to be highly effective for neutropenic patients,
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      Management of infection in granulocytopenic patients.
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      Empiric antibiotic therapy for granulocytopenic cancer patients.
      aminoglycosides have some serious adverse effects such as renal dysfunction and ototoxicity. Antibiotics as monotherapy are generally less toxic, less costly, and more convenient to administer to patients than combination therapy,
      • Ramphal R.
      Is monotherapy for febrile neutropenia still a viable alternative?.
      so monotherapy with a fourth-generation cephem or carbapenem has been applied and compared to combination therapy in randomized controlled trials; these did not show diminished effectiveness of monotherapy.
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      • et al.
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      • et al.
      A randomized, open-label, multicenter comparative study of the efficacy and safety of piperacillin–tazobactam and cefepime for the empirical treatment of febrile neutropenic episodes in patients with hematologic malignancies.
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      • et al.
      A multicenter, double-blind, placebo-controlled trial comparing piperacillin–tazobactam with and without amikacin as empiric therapy for febrile neutropenia.
      Monotherapy is now also recommended as standard therapy in the Infectious Diseases Society of America (IDSA) guidelines 2010.
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      • et al.
      Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer—2010 update by the Infectious Diseases Society of America.
      However, the incidence of drug-resistant bacterial species in the institute should be taken into consideration when using monotherapy, because resistant bacteria would tend to result in treatment failure in the case of monotherapy compared with combination therapy.
      • Ramphal R.
      Is monotherapy for febrile neutropenia still a viable alternative?.
      In fact, extended-spectrum β-lactamase (ESBL)- and metallo-β-lactamase-producing Gram-negative bacteria are emerging at an increasing rate, and these cause significant mortality.
      • Senda K.
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      • et al.
      Multifocal outbreaks of metallo-beta-lactamase-producing Pseudomonas aeruginosa resistant to broad-spectrum beta-lactams, including carbapenems.
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      Evolution and epidemiology of extended-spectrum beta-lactamases (ESBLs) and ESBL-producing microorganisms.
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      • et al.
      Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study.
      In this context, alternative effective regimens other than β-lactams are warranted for neutropenic patients to overcome the resistant bacteria.
      Ciprofloxacin (CPFX) is an attractive drug that has wide coverage against Gram-negative organisms including P. aeruginosa, good pharmacokinetic characteristics, and an absence of the need for drug level monitoring.
      • Oliphant C.M.
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      Ciprofloxacin. An updated review of its pharmacology, therapeutic efficacy and tolerability.
      A number of studies have demonstrated that CPFX combined with a β-lactam is effective for neutropenic patients.
      • Peacock J.E.
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      • Lazarus H.M.
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      • et al.
      Ciprofloxacin plus piperacillin compared with tobramycin plus piperacillin as empirical therapy in febrile neutropenic patients. A randomized, double-blind trial.
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      • et al.
      Ciprofloxacin vs an aminoglycoside in combination with a beta-lactam for the treatment of febrile neutropenia: a meta-analysis of randomized controlled trials.
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      • Paesmans M.
      • Gaya H.
      Oral versus intravenous empirical antimicrobial therapy for fever in patients with granulocytopenia who are receiving cancer chemotherapy. International Antimicrobial Therapy Cooperative Group of the European Organization for Research and Treatment of Cancer.
      Furthermore, CPFX inhibits DNA gyrase of prokaryotic organisms,
      • Oliphant C.M.
      • Green G.M.
      Quinolones: a comprehensive review.
      and the drug mechanism is completely different from that of β-lactams. Therefore, CPFX may be active for some organisms resistant to β-lactams and it would be acceptable for those who are allergic to β-lactams.
      • Johnson P.R.
      • Liu Yin J.A.
      • Tooth J.A.
      A randomized trial of high-dose ciprofloxacin versus azlocillin and netilmicin in the empirical therapy of febrile neutropenic patients.
      In this context, CPFX is a potential alternative for the empiric treatment of patients with FN. However, monotherapy with CPFX has been less well reported and is not well established in the treatment of FN patients.
      To assess the possibility of increasing the choice of initial treatment for FN, we designed a randomized controlled trial of intravenous CPFX vs. cefepime (CFPM) in FN patients. This trial aimed to prove its non-inferiority compared to CFPM, a standard therapy for FN.

      2. Materials and methods

      From January 2005 to December 2009, a non-inferiority, open-label, randomized, multicenter trial was conducted to evaluate the efficacy of intravenous CPFX for FN. The study was approved by both the protocol committee and the institutional review board of each institution. Informed consent was obtained from all patients before registration in this study. The study was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR number: UMIN C000000083) and at ClinicalTrials.gov (identifier: NCT00137787). Randomization was performed automatically, stratified by primary disease and balanced in each institute, at the time of enrollment, on a website operated by the Center for Supporting Hematology-Oncology Trials (C-SHOT) data center.

      3. Definitions

      Fever was defined as an axillary temperature of not less than 38 °C, or of 37.5–38 °C sustained for more than 1 h. Resolution of fever was defined as a maximum temperature of less than 37.5 °C sustained for three successive days, and the first day was defined as the date the fever disappeared. Fever was considered to be worse when at least one of the following criteria was met: more than 1 °C elevation in maximum body temperature, change from remittent fever to continued fever, emergence of new infectious foci, blood culture positivity after administration of antibiotics, more than 10% fall in arterial O2 pressure or oxygen saturation, and a decline of performance status.
      Episodes of fever were classified as microbiologically documented infection, clinically documented infection, or fever of unknown origin (FUO). Microbiologically documented infection was defined as the isolation of microorganisms. Clinically documented infection was considered when there were foci of infection on physical examination or clinical data, without microbiological documentation. FUO was considered when there was no clinical or microbiological evidence of infection in a febrile episode.
      Neutropenia was defined as an absolute neutrophil count (ANC) of <0.500 × 109/l or that from 0.500 × 109/l to 0.100 × 109/l showing a decline compared with the level at the last examination. Recovery of neutropenia was defined as an ANC of ≥0.500 × 109/l sustained for 24 h after ANC had dropped to <0.500 × 109/l. The first day was considered to be the recovery date.

      3.1 Patients

      Patients had to meet all of the following criteria for inclusion in the study: age 15–79 years, at least one episode of fever, neutropenia within 72 h, total bilirubin of 2.0 times the upper limit of normal (ULN) or less, creatinine of 1.5 times ULN or less, and giving informed consent. Patients were excluded if they had a history of allergic reaction to antibiotics, HIV infection, were pregnant or lactating, had a family history of deafness, had received antibiotics in the last 14 days, had received an antifungal or antiviral agent, ketoprofen, or sodium valproate, were infected with bacteria resistant to agents used in this study, were in septic shock, or other inappropriate cases as judged by a physician. If the ANC did not recover to ≥1.000 × 109/l after the last episode of fever, the patient was also ineligible for this study.

      3.2 Treatment

      Patients received 300 mg of CPFX or 2 g of CFPM intravenously every 12 h immediately upon the development of FN. Treatment was continued until patients met the criteria for treatment discontinuation as follows: fever absent for more than 48 h (ANC of ≥0.500 × 109/l) or for more than 5 days (ANC from 0.100 × 109/l to 0.500 × 109/l) without any symptoms. If the associated symptoms worsened or were sustained during the study period, the treatment was modified according to the study protocol (Figure 1). From 72 h to 120 h after the study started, an aminoglycoside was added to the treatment if fever symptoms worsened. From 120 h to 168 h, the initial antibiotic was discontinued and the combination therapy of carbapenem (meropenem or imipenem), aminoglycoside, and antifungal agents was started. After 168 h, patients were allowed to receive any treatment as required if fever persisted. Patients could receive granulocyte colony-stimulating factor, if required, at any time.
      Figure thumbnail gr1
      Figure 1Treatment algorithm for febrile neutropenia. For febrile neutropenia, we treated patients according to the treatment algorithm. Treatment evaluation and treatment modification were performed as shown (CPFX, ciprofloxacin; CFPM, cefepime; ET, endotoxin; β-D, β-D-glucan; X-P, X-ray picture; AMK, aminoglycoside; MEPM, meropenem; IPM/CS, imipenem/cilastatin).

      3.3 Clinical and laboratory evaluations

      Clinical symptoms were monitored daily. Blood cell counts were obtained at least twice a week, and biochemical parameters were measured at least once a week. Blood culture, serum endotoxin, β-d-glucan, and chest radiographs were obtained before starting antibacterial therapy and in the case of a sustained or worsened pattern of fever.

      3.4 Response criteria

      The primary endpoint of this study was the rate of the initial treatment success at day 7. Response to treatment at day 7 was divided into four groups as follows: very effective: fever disappeared with a temperature below 37.5 °C within 4 days and an afebrile state remained for more than 3 days; effective: maximum temperature decreased 1 °C or more within 4 days and an afebrile (below 37.5 °C) state persisted for 7 days; partial response: maximum temperature decreased 1 °C or more within 7 days accompanied by the improvement of clinical symptoms; not effective: maximum temperature did not decrease by 1 °C or more within 7 days and/or no improvement of febrile symptoms. The response to treatment was categorized as a success if patients were included in either the very effective group or the effective group at day 7.
      We also evaluated the overall response rate at day 21 as a secondary endpoint. If patients were able to discontinue the treatment according to the criteria described above, it was considered to be successful.

      3.5 Adverse events

      Adverse events, regardless of whether they appeared to be related to the use of the study medication, were carefully recorded throughout the study. Causal relationships between the study drugs and adverse events were analyzed using six stages: definitive, probable, possible, unlikely, not related, and not assessable. Adverse events were considered related to the study drug if the stage was definitive, probable, or possible. The severity of the adverse events was classified according to the National Cancer Institute Common Toxicity Criteria version 2.0 (http://ctep.cancer.gov/).

      3.6 Statistical analysis

      Percentages of comparability of the treatment arms, treatment response, and treatment modification were compared by Chi-square test or Fisher's exact test. Quantitative variables were analyzed by Mann–Whitney test.
      The success rates of the CFPM and CPFX arms were estimated to be 50% and 60%, respectively.
      • Tamura K.
      • Imajo K.
      • Akiyama N.
      • Suzuki K.
      • Urabe A.
      • Ohyashiki K.
      • et al.
      Randomized trial of cefepime monotherapy or cefepime in combination with amikacin as empirical therapy for febrile neutropenia.
      The δ value of non-inferiority was set to be −15% in accordance with previous reports. The CFPM arm was the reference. To prove the non-inferiority of the CPFX arm, the lower limit of the 95% confidence interval (CI) of the difference of efficacy should exceed the δ value. With a statistical power of 90% and a one-sided type I error of 2.5%, the number of patients required for this study was calculated to be 82 in each arm using a binominal analysis method. Therefore, the total number of accrual was planned to be 100 patients in each arm.

      4. Results

      4.1 Characteristics of the study population

      From January 2005 to December 2009, 51 patients were registered from seven participating institutes in Japan. Forty-nine patients (24 in the CPFX arm and 25 in the CFPM arm) were eligible for assessment, but two patients were excluded because they did not meet the inclusion criteria. Ten patients were enrolled in the study more than once via different episodes of FN. Although we planned to include 200 patients, this study was closed in December 2009 due to slow accrual.
      The clinical characteristics of the patients in both treatment arms are listed in Table 1. The distribution of patient sex, diagnosis, treatment for primary disease, neutrophil count at randomization, and duration of neutropenia did not differ between the arms. Acute leukemia was the most common disease in this study (55.1%). Patient age was younger in the CPFX arm than in the CFPM arm (median age 53 vs. 61 years; p = 0.02). Four patients were excluded from further analysis of the duration of neutropenia because their neutrophil counts did not exceed 0.500 × 109/l (n = 3), or their neutrophil counts did not drop below 0.500 × 109/l (n = 1).
      Table 1Characteristics of patients enrolled in the study
      CharacteristicCPFX (n = 24)CFPM (n = 25)p-Value
      Patient sex
       Male16 (67%)14 (56%)0.44
       Female8 (33%)11 (44%)
      Patient age
       Median53610.02
       Range21–6521–79
      Diagnosis
       AML9 (38%)11 (44%)0.72
       ALL4 (17%)3 (12%)
       CML3 (13%)2 (8%)
       MDS1 (4%)0
       ML5 (21%)5 (20%)
       MM1 (4%)3 (12%)
       ATLL01 (4%)
       Myeloid sarcoma1 (4%)0
      Treatment for primary disease
       HSCT01 (4%)0.32
       Chemotherapy24 (100%)24 (96%)
      Neutrophil count at start of study
       <0.100 × 109/l15 (63%)18 (72%)0.19
       0.100–0.500 × 109/l6 (25%)7 (28%)
       0.501–1.000 × 109/l3 (13%)0
      Duration of neutropenia
       ≤7 days5 (24%)7 (29%)0.75
       >7days16 (76%)17 (71%)
      CPFX, ciprofloxacin; CFPM, cefepime; AML, acute myeloid leukemia; ALL, acute lymphoblastic leukemia; CML, chronic myelogenous leukemia; MDS, myelodysplastic syndrome; ML, malignant lymphoma; MM, multiple myeloma; ATLL, adult T-cell leukemia/lymphoma; HSCT, hematopoietic stem cell transplantation.

      4.2 Type of infection and microbiological outcomes

      Of 49 episodes, the responsible bacterium was identified in 11 (22.4%). A Gram-positive coccus was cultured in eight episodes, consisting of one each of methicillin-sensitive Staphylococcus aureus, Staphylococcus haemolyticus, and Staphylococcus epidermidis, and five Streptococcus species (Table 2). A Gram-negative bacillus was isolated in three episodes: one each for P. aeruginosa, Klebsiella pneumoniae, and Pasteurella (Table 2). Ten of the 11 episodes were diagnosed with sepsis and one with meningitis. The other two clinically documented episodes were diagnosed with pneumonia and peritonitis, but no responsible organisms were identified.
      Table 2Microbiological blood culture results on day 0
      Infecting microorganismsCPFX (n = 24)CFPM (n = 25)
      Gram-positive organisms5 (21%)3 (12%)
       Coagulase-positive Staphylococcus1 (4%)-
       Coagulase-negative Staphylococcus2 (8%)-
       Streptococcus2 (8%)3 (12%)
      Gram-negative organisms-3 (12%)
      Pseudomonas aeruginosa-1 (4%)
      Klebsiella pneumoniae-1 (4%)
      Pasteurella species-1 (4%)
      CPFX, ciprofloxacin; CFPM, cefepime.

      4.3 Treatment modification

      Ten patients (41.7%) treated with CPFX and 15 patients (60.0%) treated with CFPM received the same treatment without modification (Table 3). For the patients who were judged as febrile by physicians, treatment modifications were performed according to the algorithm described in Figure 1. In the CPFX arm, an aminoglycoside was added to the treatment regimen for 13 patients (54.2%) and CPFX was replaced by other antibiotics for 10 patients (41.7%). In the CFPM arm, an aminoglycoside was added for eight patients (32.0%) and CFPM was replaced for five patients (20.0%). Vancomycin was added for four patients (16.7%) in the CPFX arm, but not in the CFPM arm.
      Table 3Treatment modification
      Treatment modificationCPFX (n = 24)CFPM (n = 25)p-Value
      Initial treatment continued10 (42%)15 (60%)0.20
      Modification
       Initial treatment replaced10 (42%)5 (20%)0.10
       Add aminoglycoside13 (54%)8 (32%)0.12
       Add vancomycin4 (17%)00.05
       Add antifungal agents8 (33%)7 (28%)0.69
       Add antiviral agents2 (8%)1 (4%)0.61
      CPFX, ciprofloxacin; CFPM, cefepime.

      4.4 Efficacy of CPFX and CFPM

      The treatment was effective in nine patients (37.5%) in the CPFX arm and 19 (76.0%) in the CFPM arm at day 7 (Figure 2). The difference of the effective proportion was −38.5% (95% CI −64% to −13%), and the lower limit (−64%) did not exceed the δ value of −15%. Furthermore, the efficacy was significantly lower in the CPFX arm (p = 0.007). However, the overall efficacy at day 21 was similar between the two arms (CPFX 83.3% vs. CFPM 88.0%, p = 0.64). Patients for whom treatment failed were rescued by treatment modification.
      Figure thumbnail gr2
      Figure 2Clinical efficacy of ciprofloxacin and cefepime. Initial treatment evaluation showed a significantly better response in the CFPM arm than in the CPFX arm (76.0% vs. 37.5%, p = 0.007). Overall, treatment evaluation showed almost the same efficacy between the two arms (CPFX, ciprofloxacin; CFPM, cefepime).
      For patients from whom the responsible bacteria were isolated, a treatment response at day 7 was achieved in 20.0% in the CPFX arm and 66.7% in the CFPM arm (p = 0.12, Table 4). Gram-positive coccus infection (16.3%) was more common than Gram-negative bacillus infection (6.1%). The efficacy was better in the CFPM arm (66.7%) than in the CPFX arm (20.0%), but the difference was not statistically significant (p = 0.12). For patients retaining FUO, a treatment response was achieved in 47.1% of patients in the CPFX arm and 78.9% of patients in the CFPM arm (p = 0.05, Table 4).
      Table 4Response at day 7 by the cause of fever and severity of neutropenia
      CPFXCFPMp-Value
      Cause of fever
       Microbiologically documented infection1/5 (20%)4/6 (67%)0.12
        Sepsis1/4 (25%)4/6 (67%)
        Meningitis0/1-
       Clinically documented infection (pneumonia and peritonitis)0/2--
       Unknown origin8/17 (47%)15/19 (79%)0.05
      Duration of neutropenia
      Four patients were excluded from the analysis because the neutrophil count did not recover to 0.500×109/l (n=3), or the neutrophil count did not drop to <0.500×109/l (n=1).
       >7 days5/16 (31%)13/17 (77%)0.02
       ≤7 days3/5 (60%)5/7 (71%)0.68
      Baseline neutrophil count
       ≤0.100 × 109/l5/15 (33%)15/18 (83%)0.003
       >0.100 × 109/l4/9 (44%)4/7 (57%)0.61
      CPFX, ciprofloxacin; CFPM, cefepime.
      a Four patients were excluded from the analysis because the neutrophil count did not recover to 0.500 × 109/l (n = 3), or the neutrophil count did not drop to <0.500 × 109/l (n = 1).
      Since patients with prolonged neutropenia of more than 7 days or profound neutropenia (ANC of ≤0.100 × 109/l) are regarded as at high risk in the IDSA guidelines 2010,
      • Freifeld A.G.
      • Bow E.J.
      • Sepkowitz K.A.
      • Boeckh M.J.
      • Ito J.I.
      • Mullen C.A.
      • et al.
      Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer—2010 update by the Infectious Diseases Society of America.
      a subgroup analysis of this population was also conducted. Fewer patients in the CPFX arm than in the CFPM arm had a good clinical response (Table 4).

      4.5 Adverse events

      Table 5 shows all adverse events within 21 days in both arms. Six events in the CPFX arm compared to two in the CFPM arm were associated with the drug. The most common toxicity was liver dysfunction (16.7% in the CPFX arm and 8.0% in the CFPM arm). Two severe adverse events of grade 3 were observed in the CPFX arm (liver dysfunction and skin rash), and one event in the CFPM arm (liver dysfunction). All patients could continue the study medication without cessation of the therapy due to adverse events.
      Table 5Adverse events within 21 days
      Adverse events
      Adverse events grade is based on the National Cancer Institute (NCI) Common Toxicity Criteria version 2.0.
      GradeNumber of patients in CPFX group (n = 24)Number of patients in CFPM group (n = 26)
      Cardiovascular102
      Gastrointestinal123
      211
      321
      410
      Liver15 (2)
      Numbers in the parenthesis indicate the drug-associated events (judged as ‘possible’ or more).
      10 (1)
      Numbers in the parenthesis indicate the drug-associated events (judged as ‘possible’ or more).
      24 (2)
      Numbers in the parenthesis indicate the drug-associated events (judged as ‘possible’ or more).
      0
      31 (1)
      Numbers in the parenthesis indicate the drug-associated events (judged as ‘possible’ or more).
      1 (1)
      Numbers in the parenthesis indicate the drug-associated events (judged as ‘possible’ or more).
      Renal110
      Blood sugar123
      220
      Electrolytes134
      211
      320
      Neurological111
      201
      300
      310
      Cutaneous101
      221
      31 (1)
      Numbers in the parenthesis indicate the drug-associated events (judged as ‘possible’ or more).
      0
      CPFX, ciprofloxacin; CFPM, cefepime.
      a Numbers in the parenthesis indicate the drug-associated events (judged as ‘possible’ or more).
      b Adverse events grade is based on the National Cancer Institute (NCI) Common Toxicity Criteria version 2.0.

      5. Discussion

      The efficacy and safety of CPFX monotherapy for neutropenic patients has not been well investigated. One study showed that patients treated with CPFX had a significantly lower overall success rate than those treated with piperacillin plus amikacin.
      • Meunier F.
      • Zinner S.H.
      • Gaya H.
      • Calandra T.
      • Viscoli C.
      • Klastersky J.
      • et al.
      Prospective randomized evaluation of ciprofloxacin versus piperacillin plus amikacin for empiric antibiotic therapy of febrile granulocytopenic cancer patients with lymphomas and solid tumors. The European Organization for Research on Treatment of Cancer International Antimicrobial Therapy Cooperative Group.
      In contrast, another study comparing CPFX monotherapy with β-lactam plus aminoglycoside showed that the response rate was similar.
      • Johnson P.R.
      • Liu Yin J.A.
      • Tooth J.A.
      A randomized trial of high-dose ciprofloxacin versus azlocillin and netilmicin in the empirical therapy of febrile neutropenic patients.
      Furthermore, a prospective randomized study comparing ceftazidime and CPFX as initial therapy also demonstrated that the levels of efficacy were equal.
      • Bayston K.F.
      • Want S.
      • Cohen J.
      A prospective, randomized comparison of ceftazidime and ciprofloxacin as initial empiric therapy in neutropenic patients with fever.
      These results imply that the role of CPFX monotherapy for FN has been controversial and needs further assessment because β-lactam-resistant organisms are on the increase.
      In this randomized, controlled, open-label trial, we could not prove the non-inferiority of CPFX monotherapy compared with CFPM. One of the possible reasons for this is that, although CPFX has strong activity against Gram-negative rods, the coverage and activity for Gram-positive cocci including viridans were insufficient.
      • Hoogkamp-Korstanje J.A.
      In-vitro activities of ciprofloxacin, levofloxacin, lomefloxacin, ofloxacin, pefloxacin, sparfloxacin and trovafloxacin against Gram-positive and Gram-negative pathogens from respiratory tract infections.
      • Kayser F.H.
      • Novak J.
      In vitro activity of ciprofloxacin against Gram-positive bacteria. An overview.
      In fact, our microbiological data show that the treatment success rate for Gram-positive organisms tended to be inferior in the CPFX arm, and the use of vancomycin was applied only in the CPFX arm.
      Another possible reason is that the blood concentration of CPFX might not be adequate because CPFX was administered at a dose of 600 mg/day in this study, a dose that is allowed under the health insurance system in Japan. A recent study demonstrated that only high-dose CPFX (regimens of 400 mg every 8 h or 400 mg every 12 h) can provide good coverage for pathogens with a minimum inhibitory concentration (MIC) of 0.5 μg/ml.
      • Saengsuwan P.
      • Jaruratanasirikul S.
      • Jullangkoon M.
      • Aeinlang N.
      Comparative study of pharmacokinetics/pharmacodynamics of ciprofloxacin between 400 mg intravenously every 8 h and 400 mg intravenously every 12 h in patients with Gram negative bacilli bacteremia.
      This was also confirmed by previous clinical studies, in which monotherapy with CPFX at a low dose (400 mg/day) was not comparable to the standard therapies, but CPFX at a relatively high dose (600 mg/day) was equally effective.
      • Johnson P.R.
      • Liu Yin J.A.
      • Tooth J.A.
      A randomized trial of high-dose ciprofloxacin versus azlocillin and netilmicin in the empirical therapy of febrile neutropenic patients.
      • Meunier F.
      • Zinner S.H.
      • Gaya H.
      • Calandra T.
      • Viscoli C.
      • Klastersky J.
      • et al.
      Prospective randomized evaluation of ciprofloxacin versus piperacillin plus amikacin for empiric antibiotic therapy of febrile granulocytopenic cancer patients with lymphomas and solid tumors. The European Organization for Research on Treatment of Cancer International Antimicrobial Therapy Cooperative Group.
      • Johnson P.R.
      • Yin J.A.
      • Tooth J.A.
      High dose intravenous ciprofloxacin in febrile neutropenic patients.
      A precise pharmacokinetic study and the provision of an appropriate concentration of CPFX might have led to a better response for FN.
      • Forrest A.
      • Nix D.E.
      • Ballow C.H.
      • Goss T.F.
      • Birmingham M.C.
      • Schentag J.J.
      Pharmacodynamics of intravenous ciprofloxacin in seriously ill patients.
      Previous studies have demonstrated that various therapies of CPFX combined with β-lactams such as benzylpenicillin,
      • Kelsey S.M.
      • Wood M.E.
      • Shaw E.
      • Jenkins G.C.
      • Newland A.C.
      A comparative study of intravenous ciprofloxacin and benzylpenicillin versus netilmicin and piperacillin for the empirical treatment of fever in neutropenic patients.
      teicoplanin,
      • Kelsey S.M.
      • Collins P.W.
      • Delord C.
      • Weinhard B.
      • Newland A.C.
      A randomized study of teicoplanin plus ciprofloxacin versus gentamicin plus piperacillin for the empirical treatment of fever in neutropenic patients.
      and azlocillin,
      • Philpott-Howard J.N.
      • Barker K.F.
      • Wade J.J.
      • Kaczmarski R.S.
      • Smedley J.C.
      • Mufti G.J.
      Randomized multicentre study of ciprofloxacin and azlocillin versus gentamicin and azlocillin in the treatment of febrile neutropenic patients.
      are comparable with the standard therapy for neutropenic patients. In a meta-analysis comparing CPFX plus β-lactam and aminoglycoside plus β-lactam, the former showed better outcomes.
      • Bliziotis I.A.
      • Michalopoulos A.
      • Kasiakou S.K.
      • Samonis G.
      • Christodoulou C.
      • Chrysanthopoulou S.
      • et al.
      Ciprofloxacin vs an aminoglycoside in combination with a beta-lactam for the treatment of febrile neutropenia: a meta-analysis of randomized controlled trials.
      Furthermore, CPFX plus β-lactam is reported to be less toxic in terms of nephro- and oto-toxicities.
      • Ball P.
      Ciprofloxacin: an overview of adverse experiences.
      These results suggest that the combination of CPFX with a β-lactam may be a valuable alternative to the more commonly used aminoglycoside plus β-lactam combination in the management of FN.
      Assessment of the risk of complications in severe infection is important to determine the type of empiric antibiotic therapy (oral vs. intravenous), the venue for treatment (inpatient vs. outpatient), and the duration of antibiotic therapy.
      • Freifeld A.G.
      • Bow E.J.
      • Sepkowitz K.A.
      • Boeckh M.J.
      • Ito J.I.
      • Mullen C.A.
      • et al.
      Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer—2010 update by the Infectious Diseases Society of America.
      The IDSA guidelines have demonstrated that monotherapy with oral CPFX is acceptable for low-risk patients.
      • Freifeld A.G.
      • Bow E.J.
      • Sepkowitz K.A.
      • Boeckh M.J.
      • Ito J.I.
      • Mullen C.A.
      • et al.
      Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer—2010 update by the Infectious Diseases Society of America.
      • Freifeld A.
      • Marchigiani D.
      • Walsh T.
      • Chanock S.
      • Lewis L.
      • Hiemenz J.
      • et al.
      A double-blind comparison of empirical oral and intravenous antibiotic therapy for low-risk febrile patients with neutropenia during cancer chemotherapy.
      On the other hand, the guidelines do not recommend monotherapy with CPFX as standard therapy for high-risk patients.
      • Freifeld A.G.
      • Bow E.J.
      • Sepkowitz K.A.
      • Boeckh M.J.
      • Ito J.I.
      • Mullen C.A.
      • et al.
      Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer—2010 update by the Infectious Diseases Society of America.
      We further tried to assess the link between initial treatment response and risk status using both the duration of neutropenia and the neutrophil count as simple biomarkers.
      • Tamura K.
      • Imajo K.
      • Akiyama N.
      • Suzuki K.
      • Urabe A.
      • Ohyashiki K.
      • et al.
      Randomized trial of cefepime monotherapy or cefepime in combination with amikacin as empirical therapy for febrile neutropenia.
      Our subgroup analysis showed that among patients at a ‘high risk’ of neutropenia, those who received CPFX had significantly lower response rates at day 7. In contrast, no significant difference was found for low-risk patients. These results suggest that CPFX monotherapy might be applicable for low-risk FN.
      In terms of safety, the two agents appear to have similar safety profiles. The most common adverse event possibly related to the therapies was liver dysfunction, and all the patients could continue therapy.
      This trial was prematurely terminated due to slow patient accrual, but not by the predefined early stopping-rule of superiority of CFPM. Prophylactic oral CPFX was not allowed in this study, which might have hindered the accrual. The significance of prophylactic CPFX has been legitimized in recent years.
      • Freifeld A.G.
      • Bow E.J.
      • Sepkowitz K.A.
      • Boeckh M.J.
      • Ito J.I.
      • Mullen C.A.
      • et al.
      Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer—2010 update by the Infectious Diseases Society of America.
      Another possible reason is that this was an open-label randomized controlled trial. Since physicians were able to observe the efficacy of the allocated agents, their impressions might have influenced the slow accrual. Furthermore, the randomization procedure was cumbersome for physicians because fever could occur at any time.
      In conclusion, we could not verify the non-inferiority of monotherapy with CPFX to that with CFPM at day 7, although the overall response was similar in both arms. When selecting monotherapy for the treatment of neutropenic patients, CFPM remains the standard initial treatment of choice. CPFX is better for prophylactic than empiric use.

      Acknowledgements

      We thank all the collaborating institutions and their staff for providing the patient data. This study was funded by the Center for Supporting Hematology-Oncology Trials.
      Conflict of interest: The authors declare no conflicts of interest.

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