THERAPEUTIC NOTE
New study shows oral antibiotics are a safe and effective alternative to IV antibiotics for some cancer patients
A new study published in the current issue of the New England Journal of Medicine (NEJM, July 29, 1999) shows that oral antibiotic ciprofloxacin plus amoxicillin-clavulanic is as effective as the standard intravenous (IV) therapy with ceftriaxone plus amikacin for low risk patients with cancer who have fever and granulocytopenia. This is the first randomized, multicenter clinical trial to establish equivalent efficacy of treatment with oral ciprofloxacin as well as safety. Ciprofloxacin a broad-spectrum fluoroquinolone antibiotic that has established safety and efficacy against a range of bacteria. The study was conducted by the International Antimicrobial Therapy Cooperative Group of the European Organization for Research and Treatment of Cancer (1).
Granulocytopenia is common among many cancer patients receiving chemotherapy. Because of a reduced white blood cell count, these patients are more vulnerable to fever and infection. If fever has developed, these patients are admitted to a hospital and promptly receive broadspectrum IV antibiotics until the fever subsides. Intravenous antibiotics are costly and usually require the patient to be hospitalized, contributing to increased medical expenses and hindering a patient''s quality of life.
AN ALTERNATIVE TO IV
Lead investigator Dr. Winfried V. Kern, Associate Professor, Department of Medicine at the University Hospital Ulm, Germany (2), said. In low risk patients with cancer who have fever and granulocytopenia, oral therapy with ciprofloxacin plus amoxicillin/clavulanic acid has tremendous advantages over intravenous therapy. It''s less invasive; it''s equally safe and effective, it''s less expensive and may lead to early discharge from the hospital or treatment on an outpatient basis. For the patient this means a better quality of life and for the hospital it means reduced costs of treating cancer patients.
In an analysis of 312 patients, the rate of success for oral therapy with ciprofloxacin (CP) amoxicillin-clavulanic acid (AC) was equal to that of IV therapy. Data shows an 86 percent success rate among patients receiving treatment with oral CP plus AC versus an 84 percent success rate among patients receiving treatment with IV ceftriaxone plus amikacin. Previous studies have reported similar rates of success, but have never have been designed to demonstrate equivalence.
This study provides convincing evidence that oral treatment with ciprofloxacin plus amoxicillin-clavulanic acid can be as effective as IV combination therapy in low risk patients, increasing the treatment options available for cancer patients, "said Dr. Kern." The oral formulation of ciprofloxacin was a natural choice for the study, mainly because oral ciprofloxacin is one of the few drugs showing excellent bioavailability and bactericidal activity against gram-negative pathogens including Pseudomonas aeruginosa. The oral and IV formulations are bioequivalent in efficacy and safety. Ciprofloxacin IV has been used with success to treat cancer patients with fever and granulocytopenia, in particular when it was combined with another antibacterial drug to improve the coverage of gram-positive pathogens.
DETERMINING EQUIVALENCE
In order to determine the rate of success of treatment with oral CP plus A-C, investigators of the Kern et al, study monitored fever, infection, and specific pathogens where possible. Primary endpoints included: a normal temperature for three consecutive days, no signs and symptoms of infection at identifiable infection sites, elimination of the primary pathogen, and no recurrence of the primary infection after one week of discontinuing treatment.
STUDY STRUCTURE
The study was a two-year, prospective, open-label, randomized, multicenter clinical trial. Patients with 1,000 granulocytes per cubic millimeter that were expected to last 10 days or less, and who were judged to be clinically stable and had no signs of specific infection, were selected to participate. Any patients with bone marrow transplants, recent treatment with antibiotics, renal failure, respiratory insufficiency or high probability of death within 48 hours were not eligible for participation.
The study included 353 low risk patients with cancer who had fever and granulocytopenia from 25 European hospitals. Of the 353 patients, 177 patients received oral ciprofloxacin (Cipro 750 mg) twice daily plus amoxicillin-clavulanic acid (Augmentin 625 mg) three times daily and 176 patients received IV ceftriaxone (Rocephin 2 g) once daily plus amikacin (20 mg/kg) once daily. All patients were hospitalized until their fever subsided. At the conclusion of the study, 312 patients were included in the final analysis.
ADVERSE EVENTS
During the study approximately one third of patients in each group experienced some adverse reactions. Twenty-six patients receiving oral therapy experienced diarrhea or other gastrointestinal symptoms versus four in the IV group. However, only IV patients experienced catheter problems (11 patients), nephrotoxicity (4 patients), and hypokalemia (4 patients).
There have been reports of increased resistance to fluoroquinolones among patients with cancer who received these drugs for prophylaxis. In this study the risk of failure due to bacterial resistance was small. Bacterial resistance is a serious concern and should be carefully monitored in any treatment regimen helping to prevent increased bacterial resistance in the community and in hospitals.
NEW TREATMENT GUIDELINES
A working committee of the Infectious Disease Society of American recently updated treatment guidelines for all patients with cancer who have fever and granulocytopenia. The guidelines recommend treatment with maximal doses of broad-spectrum intravenous antibiotics in order to guard against infectious complications due to their compromised immune system. The equivalence between oral therapy with CP plus A-C and standard IV therapy as demonstrated by Kern et al, offers physicians a safe, effective and cost-effective alternative to IV therapy in low risk patients.
Bayer AG, a research-based pharmaceutical company, sponsored the study.
(1) The International Antimicrobial Therapy Cooperative Group, founded in 1973, is a clinical trials group of the European Organization for Research and Treatment of Cancer, an international association under Belgian law (http://www.eortc.be).
(2) The University of Ulm (http://www.uni-ulm.de) is one of the four State Universities of the German State of Baden-Württemberg. It was founded in 1967. The University Hospital Ulm is a 1,000-bed hospital with a clinical research focus on hematology, pancreas research, biomaterials, and infectious diseases.
