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JAC Advance Access published online on February 27, 2007
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkm003
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Tobramycin once versus three times daily, given with penicillin G, to febrile neutropenic cancer patients in Norway: a prospective, randomized, multicentre trial

Dag Torfoss1,*, E. Arne Høiby2,3, Jon Magnus Tangen4, Harald Holte1, Kåre Bø5, Peter Meyer6, Kjell Grøttum7, Kjetil Weyde8, Grete Fossum Lauritzsen1, Berit Sandstad1,9, Anne-Birgitte Jacobsen1, Harald Olsen2 and Stein Kvaløy1

1 Cancer Clinic, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway 2 Laboratory Clinic, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway 3 Norwegian Institute of Public Health, Oslo, Norway 4 Department of Hematology, Ullevaal University Hospital, Oslo, Norway 5 Department of Internal Medicine, Buskerud Hospital Trust, Drammen, Norway 6 Department of Hematology and Oncology, Stavanger University Hospital, Stavanger, Norway 7 Department of Internal Medicine, Sørlandet Hospital Trust, Kristiansand, Norway 8 Department of Internal Medicine, Innlandet Hospital Trust, Gjøvik, Norway 9 The Norwegian Cancer Society, Oslo, Norway

* Corresponding author. Tel: +47-22-93-51-36; Fax: +47-22-73-07-25; E-mail: dag.torfoss{at}radiumhospitalet.no

Received 10 September 2006; returned 15 October 2006; revised 9 January 2007; accepted 10 January 2007


   Abstract
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Objectives: Penicillin G with an aminoglycoside is the standard initial empirical treatment in febrile neutropenia in Norway. It has been argued that giving the aminoglycoside once daily to neutropenic patients with Gram-negative bacteraemia may be hazardous when penicillin G is the ß-lactam antibiotic. We questioned this argument and hypothesized that tobramycin once daily was as efficacious as three times daily.

Methods: We conducted a randomized prospective multicentre study, comparing the efficacy of tobramycin 6 mg/kg once (arm A) versus three times (arm B) daily, plus penicillin G 5 million IU x4, in febrile neutropenic cancer patients. Primary outcome: modification of the antibiotic regimen.

Results: One hundred and seventy-four patients were evaluable for intention-to-treat analyses. One hundred and fifty-five patients had lymphoma or leukaemia as the underlying cancer diagnosis. In arm A, 35 of 88 patients and in arm B, 34 of 86 patients, that is 40% in both arms had no modification of the antibiotic regimen. No patients died while participating in the study. Upon modification of the antibiotic regimen, all patients were successfully treated. The increase in serum creatinine was modest and similar in the two treatment groups.

Conclusions: When administered with penicillin G, tobramycin given once daily was as efficacious and safe as tobramycin given three times daily in cancer patients with febrile neutropenia in Norway, provided the regimen was modified according to the clinical response.

Key Words: neutropenia , fever , antibiotics


   Introduction
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Antibiotic consumption in Norway is low compared with most other western countries.1–3 In 2005, the total consumption of antibiotics was 18.2 defined daily doses/1000 inhabitants;1 which is about half of what was used in Southern Europe. In addition, penicillins, mainly penicillins G and V, accounted for 41%, whereas fluoroquinolones accounted for only 3% of the total consumption. The only penicillin combination in Norway, piperacillin/tazobactam, accounted for <0.1%.1

Increased use of broad-spectrum antibiotics causes increased antimicrobial resistance and a shift in the microbiological flora towards more resistant organisms.4–8 Antibiotic resistance in Norway is low.1 In blood culture isolates in 2005, no Staphylococcus aureus was resistant to methicillin (MRSA); none of the Enterococcus species were resistant to vancomycin; and 2.1% of Streptococcus pneumoniae showed reduced susceptibility to penicillin G. Escherichia coli and Klebsiella showed reduced susceptibility towards gentamicin in 2.5% of the isolates, and 0.5% of them possessed extended-spectrum ß-lactamases.1

In Norway, penicillin G with an aminoglycoside is recommended as the initial empirical antibiotic therapy in cancer patients with febrile neutropenia; unless the patient is in septic shock, then a combination of a broad-spectrum ß-lactam antibiotic with an aminoglycoside is the routine therapy.9–11 We found reason to believe that the antibiotic combination of penicillin G plus an aminoglycoside, as opposed to an initial broad-spectrum ß-lactam, contributes to a low rate of resistance, without compromising the care of the patients.9–12

Tobramycin and gentamicin are the two most used aminoglycosides in Norway. Their half-lives in serum are 2–3 h, and their post-antibiotic effect lasts 5–6 h, depending on the bacteria.13,14 It has been argued that an aminoglycoside given once daily, in combination with penicillin G, may be hazardous in febrile neutropenic patients, as penicillin G alone does not have activity against Gram-negative bacilli. The administration of an aminoglycoside once daily may thus leave the patients without antibiotic coverage for a long period of time between doses.13 We questioned this argument and hypothesized that tobramycin given once daily might be at least as efficacious as tobramycin three times daily, when given with penicillin G, to febrile neutropenic cancer patients.


   Materials and methods
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We conducted a prospective, randomized, multicentre trial. From September 2001 to March 2005, 210 episodes of febrile neutropenia were randomized in 11 Norwegian hospitals. The study was approved by the local institutional review board and the regional committee for medical research ethics and conducted in accordance with the ethical standards of the Helsinki Declaration. (The Regional Committee for Medical Research Ethics, Health Region South, Norway, approved the study protocol on 25 May 2001 and gave it the reference number S-01111.)

An external institution (Smerud Medical Research Norway Ltd, Oslo, Norway) monitored the patients' medical charts and verified that the information in the database was identical to the information in the charts. A case review committee composed of four participants from the project group evaluated classification of febrile episodes and outcomes of the treatment.

Eligibility criteria

Inclusion criteria were cancer and febrile neutropenia. Neutropenia was defined as a neutrophil granulocyte count ≤0.5 x 109/L, and it had to be present 24 h after randomization at the latest. Fever was defined as a temperature ≥38.0°C. Age limits were 16–70 years. A signed, informed consent was mandatory.

Exclusion criteria were allergy to penicillins or aminoglycosides, serum creatinine level >100 µmol/L in women, or >120 µmol/L in men, massive ascites, neurogenically decreased hearing or a vestibular dysfunction, treatment with nephrotoxic medications, such as cis-platinum, treatment with an aminoglycoside within 4 weeks prior to randomization, parenteral antibacterial therapy within the last 4 days, pregnancy or nursing, or a haemodynamically unstable condition.

Participants

The doctors on call at the different participating centres identified potential candidates, presented the study to them and asked for a written informed consent. The study was conducted without any support from the pharmaceutical industry and without any research infrastructural help in the form of study nurses or other support.

Intervention

Antibiotic therapy was started immediately after randomization. The patients received tobramycin 6 mg/kg of body weight intravenously either once daily (arm A) or divided into three daily doses, with the first dose being doubled (arm B). All patients in both arms received penicillin G 5 million IU intravenously every 6 h.

Outcomes

The primary outcome variable was defined related to modification of the antibiotic regimen. The outcome ‘no-modification’ implied eradication of any isolated blood culture pathogen and no modification of the antimicrobial regimen, except for adjustments of the tobramycin dose (addition of metronidazole and any antifungal or antiviral medication was allowed).

Modification of the antibiotic regimen was done in the cases of inadequate clinical or bacteriological response, toxicity or allergy. Patient death and persisting bacteraemia for >24 h were defined as treatment failure and would define the outcome as ‘modification’.

Secondary outcome variables were hours to defervescence, number of days before modification of the antibiotic regimen and further antibiotic therapy, and changes in the serum creatinine levels. The highest serum creatinine level in the time period between randomization and up to 4 days after tobramycin was stopped was recorded. Later elevations in serum creatinine were considered to have other causes than medication with tobramycin. In some patients, serum creatinine levels decreased after randomization. Their increase in serum creatinine was 0 µmol/L. Ototoxicity was recorded as present or absent on the basis of a clinical evaluation.

Sample size

To estimate the sample size, we supposed that the ‘no-modification’ outcome would occur in 30% to 50% of the patients receiving tobramycin three times daily. If we accepted 20% difference in response between tobramycin given once daily and three times daily as equivalence, we would need 78 patients in each arm to complete the study according to protocol. Assuming that ~25% of the patients would not complete the study per protocol, we decided to randomize 210 episodes. Computations were done in nQuery Advisor 5.0.

Randomization

The patients were stratified by study centre and by three combined diagnosis and treatment groups: (i) acute-leukaemia-receiving-intensive-chemotherapy; (ii) malignant-lymphoma-undergoing-intensive-chemotherapy-with-autologous-stem-cell-support; (iii) other-cancer-patients, including leukaemia and lymphoma patients not receiving the above-mentioned therapies. Block randomization was done by the computer using random block sizes of four and six episodes and presented at the participating centres in sealed, consecutive, pre-numbered envelopes. The envelope with the lowest number was drawn when an eligible patient developed febrile neutropenia.

Blinding

Owing to the lack of resources, no blinding was performed. At the earliest, the local physician in charge of the patient could change the antibiotic regimen at his discretion when the first dose of the assigned regimen had been given.

Statistical methods

Continuous variables are presented as mean values with 95% confidence intervals (CI). Differences between the treatment groups were tested using two-sample t-tests. For binary variables, numbers and percentages of group totals, relative risks with 95% CI and {chi}2 tests were presented. Analyses were performed using SPSS 13.0.


   Results
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Participant flow

Two hundred and ten febrile episodes in 199 patients were randomized (Figure 1).


Figure 1
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  		Figure 1.. Flow chart of the randomization process. For the per protocol analyses, we accepted in arm A patients who received at least 5 mg/kg per day of tobramycin. In arm B, we accepted patients who received at least 5 mg/kg per day and a first doubled dose of tobramycin. We accepted into the per protocol analyses the following patients: one patient who received penicillin G 2 million IU four times daily for 2 days, increasing to 5 million IU four times daily, and two other patients who received penicillin G 5 million IU three times daily.

 
We were generally not able to keep track of possible candidates to the trial who were not asked to participate, except for one hospital, where 90% of those asked to take part in the trial signed the informed consent.

Even though the protocol allowed for patients to be randomized several times, only the first randomization was included in the analyses, to avoid speculation that outcome of one episode of febrile neutropenia could affect the outcome of a subsequent episode in the same patient. Fifteen episodes were multiple randomizations. In 20 other patients, the inclusion and/or exclusion criteria were violated (Figure 1), leaving 175 patients for the intention-to-treat analyses. One patient was lost to follow-up. The results presented in this article are based on the remaining 174 patients, unless otherwise indicated.

Patient characteristics

There were no differences in patient demographic and baseline medical characteristics at the time of randomization comparing the two arms (Table 1).


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  		Table 1.. Patient demographic and medical characteristics at the time of randomization according to tobramycin given once daily or three times daily for the patients in the intention-to-treat group

 
Neutropenia lasted ≥7 days in 108 of 174 patients (62%). The mean duration of neutropenia was 9.2 days (95% CI: 8.3–10.1 days), with no difference between the two arms. Tobramycin was given for a mean of 6.5 days (95% CI: 6.0–7.0 days) and penicillin G for a mean of 5.9 days (95% CI: 5.4–6.4 days), with no difference between the two arms. The tobramycin peak concentration samples were taken half an hour after the infusions were completed. In arm A, the first tobramycin mean peak and trough concentrations were 16.9 µmol/L (95% CI: 15.5–18.4 µmol/L) and 0.3 µmol/L (95% CI: 0.2–0.4 µmol/L), respectively. In arm B, the first tobramycin peak and trough concentrations were 6.4 µmol/L (95% CI: 6.0–6.8 µmol/L) and 0.9 µmol/L (95% CI: 0.8–1.0 µmol/L), respectively.

The classification of febrile episodes was similar in the two arms (Table 2).


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  		Table 2.. Classification of febrile episodes in the intention-to-treat group of febrile neutropenic patients

 
Primary outcome

Table 3 presents the primary outcomes. In the intention-to-treat group (n = 174), the ‘no-modification’ outcome was recorded in 35 of 88 patients in arm A and in 34 of 86 patients in arm B; that is 40% of the patients in both arms. One patient received gentamicin instead of tobramycin from day 4 through day 7. No other modification was done. This patient was evaluated to have a ‘no-modification’ outcome.


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  		Table 3.. Primary outcome in absolute numbers: no-modification of the antibiotic regimen in the intention-to-treat group

 
Table 4 presents the primary outcome results as relative risks with the upper and lower limits of the 95% confidence intervals for the intention-to-treat group, the three stratification groups, the subset of patients with prolonged neutropenia and for the group of patients who completed the study ‘per protocol’ (for definition of per protocol, see Figure 1 subtext). The relative risk was not significantly different from 1 in any of the tested groups.


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  		Table 4.. Results presented as relative risks with 95% confidence intervals in the intention-to-treat group

 
Thirty-one patients (18%) had growth in blood cultures. Ten patients had Gram-negative bacteraemia (9 patients with E. coli and 1 patient with Klebsiella pneumoniae and E. coli) and 21 patients had Gram-positive bacteraemia.

‘Inadequate clinical or bacteriological response’ was the reason for modification of the antibiotic regimen in 104 of 105 patients. One patient had the regimen modified because of a rash considered to be a side effect of penicillin. Two out of the 105 patients also had persisting bacteraemias 24 h or later after randomization. No patients died while participating in the study. During the first 30 days after randomization, one patient died on day 29, 3 weeks after discharge from the hospital.

Secondary outcome variables

The mean number of hours to defervescence in the patients with a ‘no-modification’ outcome (n = 63) was 59 h (range: 8–216 h), with no difference between the two arms.

One hundred and five patients had modifications of the antibiotic regimen. The mean time until treatment modification after randomization (n = 99) was 5 days (range: 0–17 days), with no difference between the two arms. Early modifications occurred in 18 patients (2 patients on day 0, 4 patients on day 1 and 12 patients on day 2). Seventy patients received ceftazidime for a mean of 6 days (95% CI: 5–6 days), and 35 patients received a carbapenem for a mean of 9 days (95% CI: 7–11 days), with no differences between the two arms, respectively. Other broad-spectrum ß-lactams and fluoroquinolones were unusual.

The highest mean serum creatinine after therapy with tobramycin (n = 172) was 69 µmol/L (95% CI: 66–71 µmol/L) and the mean increase in serum creatinine (n = 169) was 7 µmol/L (95% CI: 6–9 µmol/L), with no difference between the two arms. The highest absolute elevation in serum creatinine was 47 µmol/L. No ototoxicity or other side effects of tobramycin were reported.


   Discussion
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This study found that giving tobramycin once daily was as efficacious and safe as giving it three times daily, when administered with penicillin G, to cancer patients with febrile neutropenia. Forty percent of the patients in both arms recovered uneventfully, without modification of the antibiotic regimen. The patients were stratified according to expected duration of neutropenia and risk of complications. There was no difference between the two arms in any of these subgroups (Tables 3 and 4). However, the rate of modification of the antibiotic regimen varied from 16% in the lymphoma/autologous stem cell group to 65% in the group of other cancer patients. Patients with a positive blood culture and patients with a long duration of neutropenia had no-modification rates of 19% and 24%, respectively. No patients died while participating in the study.

This is the first prospective, randomized trial comparing the clinical efficacy and safety of antibiotic regimens based on an aminoglycoside and penicillin G. Two retrospective studies9,10 and one prospective observational study11 in cancer patients with febrile neutropenia found response rates of the combination of an aminoglycoside and penicillin G comparable to the results of this trial.

The small number of patients with positive blood cultures (10 patients with Gram-negative bacteraemia) made it difficult to draw any significant conclusions concerning the antimicrobial efficacy of the antibiotic regimens. Patients with Gram-negative bacteraemia were of major concern in the discussion about the efficacy of giving the aminoglycoside once daily when penicillin G was the ß-lactam. More information on the outcomes in the patients with bacteraemia is available in the Appendix [available as Supplementary data at JAC Online (http://jac.oxfordjournals.org/)].

No patient died while participating in this trial. In recent studies on febrile neutropenia, the fatality rates have been ~5%.15 Our patients may have been selected for less severity by the exclusion criterion ‘a haemodynamically unstable condition’. Unfortunately, this made the results less easy to generalize. On the other hand, this restriction was according to Norwegian antibiotic guidelines.

The inclusion process was not optimal. Many patients with febrile neutropenia were admitted to the participating hospitals without being considered for participation in the trial. The reason for this was mainly lack of resources to identify and include patients, not selection bias.

Thirty-five episodes of febrile neutropenia turned out to be not evaluable. When the protocol was written, we allowed for patients to be randomized several times, according to the common practice in earlier EORTC trials in febrile neutropenia.16,17 However, during the trial, strong recommendations against multiple randomizations appeared in the literature.18 The project group consequently decided to omit the 15 cases of multiple randomizations from the analyses. It is possible that the inclusion and exclusion criteria were too strict. Two patients were considered not evaluable because they were not febrile at the time of randomization, even though the doctor on call felt the patient was developing an infection and needed antibiotic therapy.

The primary response parameter in this study was related to modification of the antibiotic regimen. Important earlier studies19–22 had defined failure as a combination of modification of the antibiotic regimen and mortality. None of the patients in this trial died. We felt uncomfortable defining modification of the antibiotic regimen as a failure as long as the patient recovered from the febrile neutropenic episode.

Modification of the antibiotic regimen was an objective response parameter, easy to record and count. However, the decision to modify the antibiotic regimen was the responsibility of the doctor on call, and this decision was made on the basis of best clinical judgement. Varying clinical experience with febrile neutropenic patients may explain some of the differences in response rates between the leukaemia/intensive-therapy and the lymphoma/autologous-stem-cell-support groups. It is still interesting to notice that in spite of this possible bias, there was no difference between the two arms of the study.

We chose to use tobramycin as the aminoglycoside for this trial. Tobramycin was the aminoglycoside of choice at the hospitals participating in the preliminary preparations for the study. The antimicrobial spectra of tobramycin and gentamicin are similar, with few exceptions. For empirical use in febrile neutropenia, we believe that both these aminoglycosides are useful and relatively equivalent.

Several trials in cancer patients with febrile neutropenia have compared aminoglycosides given once daily or several times daily with a broad-spectrum ß-lactam,23,24 all concluding that giving the aminoglycoside once daily is both efficacious and safe. However, these trials cannot be directly compared with our study. In most cases, the broad-spectrum ß-lactam would be a sufficient therapy alone, with good or excellent antimicrobial effect against both the Gram-negative and the Gram-positive microbes. In our trial, monotherapy with a broad-spectrum ß-lactam antibiotic was the most common drug used when modification of the antibiotic regimen was needed.

Monotherapy with an aminoglycoside in febrile neutropenia was known to be suboptimal.25 However, the notion ‘suboptimal’ implied that no further modification of the antibiotic regimen was done. In the 1970s, when the trials with gentamicin monotherapy were conducted, the options for antibiotic modifications were limited.26–29 Today, the many efficient alternatives for modification may explain why all the patients had a complete response upon modification in this trial.

Most current guidelines30 recommend initial empirical monotherapy with a broad-spectrum ß-lactam antibiotic in febrile neutropenia. However, penicillin G with an aminoglycoside is a regimen that probably causes less antibiotic resistance than regimens based on broad-spectrum ß-lactams.12 In this trial, 40% of the patients received penicillin G and tobramycin as their only antibiotic treatment; the rest had modifications after several days, resulting in a reduced total exposure to broad-spectrum ß-lactam antibiotics. Moreover, current Norwegian guidelines recommend penicillin G and an aminoglycoside as the initial empirical therapy in febrile neutropenic patients as well as in immunocompetent patients with sepsis. This study found that giving tobramycin once daily was as efficacious and safe as giving it three times daily, when penicillin G was the ß-lactam. This finding may facilitate aminoglycoside administration and strengthen the Norwegian tradition of choosing an aminoglycoside and penicillin G as the initial empirical regimen in febrile neutropenia.


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None to declare.


   Supplementary data
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The Appendix is available as Supplementary data at JAC Online (http://jac.oxfordjournals.org/).


   Acknowledgements
 
We acknowledge Professor Kenneth V. I. Rolston at The MD Anderson Cancer Center, Houston, Texas, for valuable advice and inspiration during the preparation of this report. We thank Anders Andersen at The Rikshospitalet-Radiumhospitalet Medical Center for help in preparing the manuscript in the electronic form. We thank the microbiological laboratories at the participating centres for performing identification and resistance determinations of the bacterial isolates presented in the Appendix to this report [available as Supplementary data at JAC Online (http://jac.oxfordjournals.org/)]. We give a special thanks to the study secretariat. Without their support, the trial could not have been conducted. External Funding: research funds from Rikshospitalet-Radiumhospitalet Medical Center, Oslo, and from the government-owned Norwegian Southern Health Corporation (which in turn owns Rikshospitalet-Radiumhospitalet Medical Center), as well as a fund from The Norwegian Association for Infectious Diseases, supported the study financially. The study secretariat is financed by The Norwegian Cancer Society. The study was conducted without any participation or support of the pharmaceutical industry. Interpretation of results and decisions about publication were done solely by the clinical investigators.

Members of the study group: Rikshospitalet-Radiumhospitalet Medical Center, Oslo (100): H. Holte*, E. A. Høiby*, A. B. Jacobsen, S. Kvaløy*, B. Kvisgaard, G. F. Lauritzsen, H. Olsen, B. Sandstad, P. Sandven#, E. Skovlund##, D. Torfoss* (principal investigator); Asker and Bærum Hospital Trust (3): S. Sarvari; Buskerud Hospital Trust, Drammen (39): K. Bø, T. Kalager; Innlandet Hospital Trust, Lillehammer, (1): I. J. Hagen; Innlandet Hospital Trust, Gjøvik, (10): K. Weyde, Ø. Undseth; Innlandet Hospital Trust, Hamar, (1): Ø. Steinum; Stavanger University Hospital, Stavanger (9): P. Meyer; Sørlandet Hospital Trust, Arendal, (3): Y. Benestad; Sørlandet Hospital Trust, Kristiansand, (12): K. Grøttum; Ullevål University Hospital, Oslo (29): J. M. Tangen; Vestfold Hospital Trust, Tønsberg, (3): E. Muller. (The number of episodes randomized at each hospital is given in parentheses. * = member of the Case Review Committee. Current affiliations: # = Norwegian Institute of Public Health, Oslo, ## = Norwegian Medicines Agency, Oslo.)


   References
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 Abstract
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 Discussion
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