Once-daily oral moxifloxacin works at least as well as twice-daily oral ciprofloxacin plus amoxicillin–clavulanic acid when it comes to treating febrile neutropenia in patients who are at low risk for complications, according to a randomized, double-blind trial reported in the Journal of Clinical Oncology.1 Investigators led by Winfried V. Kern, MD, of the Universitatsklinikum Freiburg, in Freiburg, Germany, found that about four out of five patients given each regimen met criteria for therapy success such as defervescence and improved clinical status, with the difference between groups falling within the predefined cutoff for equivalence.
The two regimens were generally similar in terms of tolerability, safety, and reasons for therapy failure. Patients in the combination therapy group had a somewhat higher rate of gastrointestinal adverse effects, whereas their counterparts in the moxifloxacin group more often had microbiologically documented failures, partly due to more cases of Pseudomonas aeruginosa infection.
Nearly 6 in 10 patients overall were able to go home on their oral regimen, and readmissions in this subset were rare. As the investigators note, such outpatient therapy has numerous potential advantages that include shortened hospital stays, better quality of life, a reduced likelihood of complications from intravenous access devices, and less exposure to hospital pathogens that may be multidrug resistant.
Oncology patients were eligible for the trial, formally known as EORTC (European Organisation for Research and Treatment of Cancer) Infectious Diseases Group Trial XV, if they had febrile neutropenia, a low risk of complications as predicted by a Multinational Association for Supportive Care in Cancer (MASCC) score of greater than 20 (see Table 1 on page 28), and ability to swallow, and had received at most a single intravenous dose of empiric antibiotics.
The patients were assigned to receive either moxifloxacin therapy (400 mg once daily) or combination therapy consisting of ciprofloxacin (750 mg twice daily) plus amoxicillin with clavulanic acid (1,000 mg twice daily). Treating physicians were encouraged to discharge patients early if they met predefined criteria, such as absence of comorbidities requiring monitoring.
The trial was designed to test equivalence of the two regimens. Equivalence was defined as a difference of less than 10% between regimens in the rate of therapy success—defervescence and improvement in clinical status during study drug treatment, freedom from infection relapse, and absence of documented infection caused by bacteria resistant to study drugs.
In terms of characteristics, slightly more than half of the patients studied had a hematologic malignancy. Overall, 43% had a MASCC score of 21 to 23. Twenty-seven percent received an initial (parenteral) antibiotic dose before starting their study therapy.
Main Trial Outcomes
An intention-to-treat analysis among the 333 patients studied showed the rate of therapy success was 80% with moxifloxacin therapy and 82% with combination therapy, with the difference meeting the definition for equivalence. The findings were similar in patient subgroups and in a per-protocol analysis. More than half of patients were afebrile on day 2, and the time to defervescence was statistically indistinguishable between groups. Nearly all patients in both groups (99%) were alive at 30 days.
The two groups had somewhat different reasons for treatment failure. The moxifloxacin group had more microbiologically documented failures, including some cases of P aeruginosa infection; the combination therapy group had more cases of discontinuation because of intolerance and adverse events.
Overall, 59% of the patients were discharged on their assigned therapy; the main reasons for remaining hospitalized were related to transport/logistics and psychosocial problems. Just 5% of the discharged patients were readmitted; the majority of readmissions were due to clinical deterioration and medical complications, including fever and infection.
The rate of any adverse event was 44% with moxifloxacin and 52% with combination therapy, a nonsignificant difference; the leading events were diarrhea and abdominal pain. Overall, 7% of patients experienced serious adverse events, with no significant difference between groups.
The combination therapy group had more cases of diarrhea, whereas the moxifloxacin group had more cases of neurologic events. The groups were similar in terms of liver and cardiac function abnormalities. The moxifloxacin group had a borderline significant lower rate of superinfections (7% vs 14%, P = .05).
“[T]he data from this double-blind trial provide evidence that single-drug oral therapy in low-risk febrile neutropenia with moxifloxacin is equivalent to the combination therapy so far considered standard. Local monitoring, particularly regarding the frequency of P aeruginosa infection and fluoroquinolone resistance among E coli and other Gram-negative enteric bacteria, is advisable and may influence the choice of the best suitable drug for initial therapy,” the investigators concluded.
“The data also represent the first confirmation to our knowledge in a multicenter setting that febrile neutropenic patients with cancer identified with the help of the MASCC score as being low risk and treated with an adequate oral antibiotic regimen can often be discharged and safely treated at home,” they added.
In an accompanying editorial, Monica A. Slavin, MD, MBBS, and Karin A. Thursky, MD, MBBS, both of the Peter MacCallum Cancer Centre in Melbourne, Australia, wrote, “This study has important implications for treatment of fever and neutropenia in patients with cancer but translating these trial findings into clinical practice will require changes to treatment algorithms, the way patients with fever and neutropenia are assessed, and the way antibiotic therapy is delivered in hospitals.”2
They continued, “Key to successful implementation of an outpatient oral antibiotic program will be making the correct choice of patient and antibiotic. Additionally the infrastructure must be in place for follow-up and readmission of outpatients if required as well as for ongoing surveillance of antimicrobial susceptibility in isolates from this patient group.”
Dr. Thursky also told The ASCO Post that “the real significance of this paper is that it was a multicenter prospective validation and application of the MASCC score.” ■
Disclosure: Dr. Kern has received honoraria from Bayer HealthCare Pharmaceuticals, Pfizer, and Sanofi-Aventis, and research funding from Pfizer and Sanofi-Aventis. Drs. Slavin and Thursky reported no potential conflicts of interest. For full disclosures of the other study authors, visit jco.ascopubs.org.
1. Kern WK, Marchetti O, Drgona L, et al: Oral antibiotics for fever in low-risk neutropenic patients with cancer: a double-blind, randomized, multicenter trial comparing single daily moxifloxacin with twice daily ciprofloxacin plus amoxicillin/clavulanic acid combination therapy—EORTC Infectious Diseases Group Trial XV. J Clin Oncol 31:1149-1156, 2013.
2. Slavin MA, Thursky KA: Outpatient therapy for fever and neutropenia is safe but implementation is the key [editorial]. J Clin Oncol 31:1128-1129, 2013.
The EORTC Infectious Diseases Group Trial XV “is a long-awaited study because it finally is an investigation of outpatient management of low-risk fever and neutropenia in a large number of patients,” Alison Freifeld, MD, of the University of Nebraska Medical Center in Omaha, commented in an...