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Tobramycin Once versus 3 Times Daily Equally Effective in Cancer Patients With Febrile Neutropenia: Presented at ECCMID

By Chris Berrie

NICE, FRANCE -- April 5, 2006 -- There is no significant clinical difference between the use of penicillin G with tobramycin either once a day or 3 times a day to prevent clinical deterioration in patients with leukaemia, lymphoma or solid tumour who require treatment for febrile neutropenia, according to results of a multicentre, prospective, randomised trial.

Principal investigator Dag Torfoss, MD, consultant in infectious disease, The Norwegian Radium Hospital, Oslo, Norway, presented the results here on April 4^th at the 16^th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID).

Antibiotic consumption remains low in Norway compared to most other countries, with the total consumption of 17.2 defined daily doses per 1000 inhabitants per day in 2004 being about half of that in southern Europe. Penicillins G and V account for some 40% of this, in Norway, which may well have a positive contribution to this country's low antibiotic resistance, Dr. Torfoss noted.

For patients with febrile neutropenia, the treatment in Norway has traditionally been with the narrow-spectrum beta-lactam penicillin G and with an aminoglycoside, such as tobramycin, which is generally administered 3 times daily to avoid long periods of minimal antibiotics coverage.

However, Dr. Torfoss said, "Since we use penicillin G as the beta-lactam, which is basically only covering the Gram-positives, there have been discussions whether giving the aminoglycoside once a day would be adequate therapy, as the patient would be without adequate antibiotic coverage for a significant part of the day."

His research team therefore conducted a study to determine if there is indeed a difference between once-a-day tobramycin (Tobra1) versus 3 times daily (Tobra3) in patients with cancer and granulocytopenia. The study's primary outcome of success or change in the antibiotic treatment. The secondary outcomes were time to defervescence, number of days before modification of antibiotic regimen, and increase in the serum creatinine levels. Successful outcome was defined as resolution of fever and signs of infection without modification of the antibiotic regimen.

Granulocytopenia was defined as 0.5 x10⁹ cells/L or less within 24 hours of randomization.

Of the 210 patients who were originally randomized, 145 were included in the final analysis, with 73 patients in the Tobra1 arm and 72 in the Tobra3 arm. Tobramycin was dosed at 6 mg/kg body weight, and penicillin G was dosed at 5 million IU every 6 hours. The first tobramycin dose was given as double the standard dose, and the physicians were free to change the antibiotic regimen at their discretion after this first dose.

Patients' demographic characteristics were not significantly different between the two treatment groups (mean age, 58 vs. 53 years; male, 60.3% vs. 69.4%; temperature, 38.8 vs. 3.8 °C, respectively), as also seen for the underlying cancer diagnoses (leukaemia, 23% vs. 17%; lymphoma, 64% vs. 75%; solid tumour, 12% vs. 8%) and the febrile episodes classification (microbiologically documented infection, 28% vs. 28%; clinically documented infection, 14% vs. 15%; fever of unknown origin, 58% vs. 57%).

Successful outcome was not significantly different between the Tobra1 and Tobra3 groups, reaching 36% and 39%, respectively. No significant differences were seen across all of the variables calculated (intensive/less intensive chemotherapy and positive blood cultures). The primary reason for treatment failure was inadequate clinical or bacteriological response leading to modification of the antibiotic regimen in all of the patients.

The secondary endpoints also showed no significant difference across the two groups, with an overall mean time to defervescence of 60 hours, an overall mean time to treatment modification of 4.5 days, and a mean serum creatinine increase of 7.9 mcM/L.

Dr. Torfoss indicated that their demonstration of no significant clinical differences between the use of penicillin G with tobramycin either once a day or three times a day in the prevention of clinical deterioration in patients with cancers under treatment for febrile neutropenia has already led to a change to the once-a-day regimen in his hospital.

"Once-a-day is also easier to administer, less costly, and shows a saving of resources and nursing time," he added.


[Presentation title: Tobramycin Once versus Three Times a Day, Given With Penicillin G, to Cancer Patients With Febrile Neutropenia: a Prospective Randomised Multicentre Trial. Abstract P698]

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