Study design and setting
The present one was an observational study conducted in the Department of Hematology of Dhaka, Medical College Hospital, Dhaka, Bangladesh, from July 2020 to June 2021.
Adult FN patients (aged 16 years or older) with hematological malignancy who had not undergone allogeneic stem cell transplantation were included in the present study. FN was defined as an axillary temperature ≥ 37.5 °C or oral temperature ≥ 38 °C and an absolute neutrophil count (ANC) < 1000 × 106/L with no other infectious signs. Exclusion criteria were patients with (1) previous identified bacteria considered to be resistant to the initial drug before study entry; (2) severe cardiac, hepatic, or renal dysfunction; (3) history of hypersensitivity to β-lactam or drugs; (4) positive intradermal reaction to the antimicrobials tested; (6) inappropriateness for efficacy evaluation because of old age; (7) pregnancy, possible pregnancy, or lactation; or (8) judgment by the investigator of ineligibility for the study.
Based on a reported efficacy rate of 57% for cefepime therapy in FN, the calculated sample size was 30 per arm to detect any significant difference with an α of 0.05 and 80% power on the assumption that the expected efficacy rates of meropenem and piperacillin/tazobactam would be 80%. Assuming 10% dropout rate, we considered a total of 99 patients (33 patients per arm).
Before enrollment in the study, all patients who met the inclusion criteria and gave informed written consent underwent following laboratory tests: hematology, biochemistry, chest X-ray, and specimen culture (blood, urine, or nasopharyngeal aspirate as required). Eligibility was assessed based on the results of these tests, and all eligible patients were registered in the central registry of the Dhaka Medical College Hospital and randomly assigned to three treatment arms.
The study method is illustrated in Fig. 1. Cefepime, meropenem, or piperacillin/tazobactam was administered 8 hourly by intravenous infusion at a dose of 2 g, 1 g, and 4.5 g 8 hourly (if body weight < 40 kg) or 50 mg/kg, 20 mg/kg, and 112.5/kg 8 hourly (if body weight is 40 kg or above) respectively along with other supportive care measures. A patient who showed improvement in symptoms (e.g., defervescence) or in laboratory values including neutrophil counts on day 3 after the initiation of the therapy was considered as “very responsive,” and the therapy was continued for another 4 days and then followed up. A patient whose fever tended to defervesce and whose symptoms or laboratory values improved without full recovery on day 3 after the initiation of therapy was treated with the same antibiotic for another 4 days. If defervescence with further improvement in symptoms or laboratory values occurred on day 7 after the initiation of therapy, the patient was considered as “responsive.” If a tendency toward improvement was observed without full recovery on day 7, the patient was characterized as “somewhat responsive.” If no improvement with progressive disease was observed on day 3 after the initiation of therapy, the patient was considered as “unresponsive,” and switching to another antimicrobial regimen was considered.
Defervescence, in this study, was defined as normal body temperature (< 37° C) for at least 3 consecutive days. The definition of tendency to defervesce is additionally stated as normal body temperature (< 37° C) for 2 consecutive days. The antibiotic sensitivity of any pathogen isolated from blood, urine, or other samples was tested, and the choice of antimicrobials was based on the test results. When no defervescence occurred on day 7, blood culture, fungal serological tests (β-D-glucan, etc.), chest X-ray, and C-reactive protein (CRP) assay were performed.
The percentage efficacy on days 3 and 7 after the initiation of therapy was calculated from the number of “very responsive” cases and the summative number of “very responsive” and “responsive” cases relative to the number of evaluable cases respectively.
Patients unresponsive to initial therapy with no pathogen isolated were treated with the same antimicrobial agent plus aminoglycosides (amikacin) or quinolone (ciprofloxacin, moxifloxacin) additionally administered twice daily for another 2 days. The respective physician determined the antibiotic to be used. Reassessment of body temperature, symptoms, and laboratory values, including neutrophil counts, was performed 48 h after the addition of subsequent therapy. If defervescence with further improvement in symptoms or laboratory values occurred, the same therapy is continued for subsequent 2 days. If no improvement was observed, changing beta-lactam drug and test for fungal infection and addition of antifungal drug were considered. On the other hand, patients unresponsive to initial therapy with isolated causative organism, treatment modification on the basis of susceptibility test was considered.
During the study, patients were closely monitored for any concomitant symptoms or abnormal changes in laboratory values. For each such symptom or abnormal change, the date of onset, severity, treatment, treatment course (outcome), and causal relationship with the study drug were recorded in detail. Blood, hepatic function, renal function, and fungus testing were carried out routinely.
Descriptive statistics was used to represent the findings. Patients’ background characteristics of different treatment groups were compared by chi-square test. Chi-square test and Fisher’s exact test were used to compare the efficacy of the treatment regimens on day 3 and 7 as well as efficacy according to the underlying disease, cause of fever, and neutrophil counts. STATA version 17.0 was used to perform the analyses.
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