Pediatr Blood Cancer 2007;49:682–686
Oral Gatifloxacin in the Outpatient Treatment of Children With Cancer Fever and Neutropenia Antonio Se´rgio Petrilli, MD, PhD,1* Fabianne Altruda Carlesse, Background. Fever in neutropenic (FN) patients requires immediate broad-spectrum antibiotics, however, such patients do not represent a homogeneous population and the majority of them are at low risk of developing complication. Gatifloxacin (GA) is an alternative, though it has not been thoroughly studied in Pediatrics yet. The aim of this study was to evaluate oral GA in oncology pediatric patients with FN and low risk of infectious complications. Methods. We conducted a prospective study in patients submitted to chemotherapy and FN, from the ages of 3 to 21 years old, with solid tumors, acute lymphoid leukemia, and lymphomas without comorbidities and treated as outpatient with oral GA. Safety and adverse effects were monitored. Results. We evaluated 108 patients with 201 episodes of FN. The average age was 10.8 years, 64.8% of the
Key words:
MD,
1
and Carlos Alberto Pires Pereira,
MD
1,2
patients were male. Osteosarcoma accounted for 22% of the episodes, rhabdomyosarcoma for 13%, acute lymphoid leukemia, lymphomas and Ewing sarcoma, for 11% each. Among the 174 episodes exclusively treated as outpatients, the average duration of neutropenia was 4.8 days, the average duration of fever was 2.4 days; the average duration of the treatment was 8.1 days. The treatment was successful in 75.9%, analyzing only the first episodes. No patient died during the study. Adverse events included diarrhea, vomiting, increased liver enzymes, arthralgia, and ECG changes. Conclusion. Oral GA is effective and safe in the management of oncology pediatric patients with FN at low risk of infectious complications in the outpatient setting. Pediatr Blood Cancer 2007;49:682–686. ß 2007 Wiley-Liss, Inc.
febrile neutropenia; gatifloxacin; low risk of infection
INTRODUCTION Fever often signals the presence of infection in a high percentage of neutropenic patients, requiring immediate broad-spectrum antibiotics [1]. This empiric therapy in cancer patients who develop fever and neutropenia is widely accepted [2,3]. Febrile neutropenia (FN) patients do not form a homogeneous group. Identifying which of them are at greater risk of life-threatening illnesses at the time of presentation is challenging, partly because neutropenia changes the inflammatory response to infections [3]. Features that help define low risk patients include early signs of marrow recovery, short periods of fever, absence of comorbidities, and neutropenia for less than 10 days [4]. Recent advances, such as the availability of oral antibiotics active against common pathogens isolated from these patients, made it possible to study the feasibility of outpatient management of lower risk FN episodes [5–11]. Quinolones have been included in antibiotics regimens for the treatment of Pediatric or childhood FN with good results [10,12]. Some limitations for fluoroquinolones include inadequate coverage of Gram-positive organisms. Gatifloxacin (GA) represents an important contribution due to potent activity against Gram-positive, Gram-negative, and atypical pathogens. However, GA has not been approved yet for neither children nor FN treatment [11]. The objective of this study was to evaluate the efficacy and toxicity of the therapy with oral GA in children and adolescents at low risk of infectious complications.
ments between 37.58 and 388C, at intervals of at least 4 hr, within a 24-hr; (3) Neutropenia, defined as an absolute neutrophil count (ANC) of less than 500 cells/mm3, or between 500 and 1,000/mm3 before the nadir of chemotherapy; (4) Patients with solid tumors (ST), or acute lymphoblastic leukemia (ALL) and lymphomas (L) in remission and without comorbidities. Exclusion criteria: (1) severe comorbidities: hypotension, respiratory failure, renal insufficiency, hepatic dysfunction, sepsis, poor clinical status, facial, perineal, or catheter-associated cellulitis, evidence of enteritis or severe mucositis, intensive chemotherapy (based on the expected severity of medullar suppression) and progressive disease, (2) allergic reaction to quinolones, (3) pregnancy or breastfeeding, (4) fever during or immediately after blood transfusion, (5) bone marrow transplantation. Initial assessment included complete medical history and physical examination, chest and knee X-rays, electrocardiogram (ECG), blood and urine cultures, CBC, serum creatinine, blood urea nitrogen, AST, ALT, and urinalysis. Blood samples from catheters and peripheral veins for cultures were also taken. Also, cultures of the presumptive site of infection were obtained in cases with skin and soft tissue infections, diarrhea, or any localized infections. Cerebrospinal fluid examination was performed as clinically indicated. After the initial workup, patients were started on GA 15 mg/kg body weight/day (maximum 600 mg/day), orally, once a day. Safety and adverse effects were monitored at the beginning and then every 7 days during treatment.
MATERIALS AND METHODS
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We conducted a prospective open label study, between March 2003 and July 2004, to evaluate the safety and efficacy of oral GA in children with FN and low risk of infection complications after chemotherapy at the Pediatric Oncology Institute—Federal University of Sa˜o Paulo, Sa˜o Paulo, Brazil. The Ethics Committee approved the protocol, and informed consent was obtained from each parent or legal guardian. Inclusion criteria: (1) Age between 3 and 21 years, (2) Fever, defined by axillary temperature higher than 388C or three measure-
ß 2007 Wiley-Liss, Inc. DOI 10.1002/pbc.21124
Pediatric Oncology Institute—GRAACC—Federal University of Sa˜o Paulo (UNIFESP-EPM), Sa˜o Paulo, SP, Brazil; 2Infectious Diseases Department, Federal University of Sa˜o Paulo (UNIFESP-EPM), Sa˜o Paulo, SP, Brazil Grant sponsor: Bristol-Myers Squibb. *Correspondence to: Antonio Se´rgio Petrilli, Instituto de Oncologia Pedia´trica, Universidade Federal de Sa˜o Paulo, Escola Paulista de Medicina, Rua Botucatu, 743, Zip Code 04023-062-Sa˜o Paulo, SP, Brazil. E-mail:
[email protected] Received 12 July 2006; Accepted 7 November 2006
Oral Gatifloxacin in Febrile Neutropenia Patients returned to the clinic on a daily basis for physical examination, blood cultures (if fever persisted), and other tests as required, and to receive GA under the supervision of a nursing staff. Follow-up evaluations also included CBC every other day, weekly blood chemistries (when necessary) and, a chest X-ray. Knee X-rays (days 0, 7, 14, as well as 15 and 30 days after the end of treatment and 3 and 6 months thereafter) and ECG (day 0, 7, 14, or at the end of treatment). Therapy was modified with the inclusion of new antibiotics, antifungal, or antiviral agents according to clinical status, development of clinically or microbiologically documented infections or fever persistence. Amphotericin B was started if patients persisted with FN for more than 5 days, or earlier, in case of suspected or documented fungal infection. Antibiotics were discontinued after the second consecutive day without fever in patients with ANC > 500/mm3 but without an identified source of infection. Clinically and microbiologically documented infections were treated with GA—for as long as it was required (maximum 14 days). Bacteriological isolates were identified according to standard techniques and antibiotic susceptibilities were determined by the disk diffusion, according to the National Committee for Clinical Laboratory Standards [13]. The FN episodes were classified at the end of treatment as (1) Microbiologically documented infection, including bacteremia (MDI); (2) Clinically documented infection (CDI), and (3) Fever of unknown origin (FUO), if no clinical or microbiological infection was identified. Clinically or MDI were treated with GA as long as required (maximum 14 days). Therapeutic success was defined as resolution of all signs and symptoms without modification of the initial empirical antibacterial regimen; and failure as death due to infection or the administration of any additional antibacterial agent for persistent fever, persistent fever in a patient with signs of clinical deterioration, microbiological reason, clinical progression of the presumed infection, or adverse event associated with the GA [14,15]. Fever was considered as an isolated cause of failure only after 7 days of treatment, 2 days after the introduction of amphotericin B. In all patients who needed hospitalization, the initial treatment was modified to cefepime. We also used the definition of therapeutic success with modification if FN resolved without hospitalization but with the association of another antibiotic, antiviral, or antifungal agent to the initial monotherapy. Super-infection was defined as any infection occurring from 72 hr after treatment initiation to 1 week after discontinuation of the antibiotic therapy [16].
Statistical Analysis Student’s t-test was used to evaluate the difference between two mean values (age). Chi-square test with Yates correction was used to evaluate differences in the distribution, gender, race, underlying disease (UD), activity of the UD, and presence of a central venous catheter (CVC), comparing patients and episodes. A P-value
