ARTICLE

Randomized Controlled Trial of Once- Versus Thrice-Daily Tobramycin in Febrile Neutropenic Children Undergoing Stem Cell Transplantation

Lillian Sung, L. Lee Dupuis, Bonnie Bliss, Anna Taddio, Mohamed Abdolell, Upton Allen, Martha Rolland, Agnes Tong, Tracey Taylor, John Doyle

Affiliations of authors: Departments of Pediatrics (LS, UA, MR, JD), Health Policy Management and Evaluation (LS, UA), Otolaryngology (BB), Public Health Sciences (MA), and Faculty of Pharmacy (LLD, A. Taddio), University of Toronto, Toronto, Ontario, Canada; Department of Pediatrics, Divisions of Hematology/Oncology (LS, LLD, MR, TT, JD) and Infectious Disease (UA), Departments of Pharmacy (LLD, A. Taddio, TT) and Communication Disorders (BB), and Program in Population Health Sciences (LS, LLD, A. Taddio, UA, A. Tong), Research Institute, The Hospital for Sick Children, Toronto; and Cancer Quality Council of Ontario Secretariat, Cancer Care Ontario, Toronto (MA).

Correspondence to: Lillian Sung, MD, FRCPC, Division of Hematology/Oncology, Hospital for Sick Children, 555 University Ave., Toronto, Ontario, Canada M5G 1X8 (e-mail: lillian.sung{at}sickkids.ca)


    ABSTRACT
 Top
 Notes
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Background: The benefits of aminoglycoside antibiotics, such as tobramycin, administered as a once-daily dose to manage febrile neutropenia, have been demonstrated in many patient populations. However, toxicity and safety data are lacking for pediatric stem cell transplant recipients, who are at especially high risk for aminoglycoside-related toxicity and infectious morbidity. In particular, the relative nephrotoxicity and efficacy of tobramycin administered as a single daily dose or as three daily doses among this patient population is not known. Methods: We conducted a randomized, double-blind controlled study of tobramycin dosing among children 18 years or younger who had fever and neutropenia while undergoing stem cell transplantation. From October 2000 through November 2002, 60 children were randomly assigned to receive intravenous tobramycin, as either a single daily dose (n = 29) or every 8 hours (n = 31), in combination with either piperacillin or ceftazidime (intravenous). Tobramycin doses were adjusted to achieve pharmacokinetic targets. The primary outcome was nephrotoxicity, as represented by the maximal percent increase in serum creatinine concentration throughout the episode of febrile neutropenia relative to the baseline serum creatinine concentration. Efficacy was a secondary outcome and was defined as survival of the episode without modification of the antibacterial regimen. All statistical tests were two-sided. Results: In a modified intent-to-treat analysis, the mean maximal percent increase in serum creatinine concentration was 32% (N = 26) in the once daily dose group and 51% (N = 28) in the every 8 hours dose group (difference = 19%, 95% confidence interval [CI] = 0% to 38%; P = .054). Among patients evaluable for efficacy, 12 (46%) of 26 patients in the once daily dose group and five (19%) of 27 patients in the every 8 hours dose group survived the episode of febrile neutropenia without requiring antibacterial treatment modification (difference = 27%, 95% CI = 4% to 52%; P = .03). There was one death in each group. Conclusions: In febrile neutropenic children undergoing stem cell transplantation, tobramycin may be less nephrotoxic and more efficacious when administered as a once daily dose than when administered every 8 hours.



    INTRODUCTION
 Top
 Notes
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Aminoglycosides are a group of antibiotics commonly used in the management of febrile neutropenia because of their efficacy against gram-negative bacteria. Considerable evidence has suggested that aminoglycosides, such as tobramycin and gentamicin, may be less toxic and more effective if administered as a single daily dose rather than as the traditional three daily doses (i.e., every 8 hours). The higher serum concentration of aminoglycosides that is achieved with once-daily dosing is thought to increase the concentration-dependent killing of bacteria and optimize the capacity of the aminoglycoside to inhibit bacterial growth when serum levels are no longer measurable (i.e., the post-antibiotic effect) (13). By contrast, decreased adaptive resistance to aminoglycosides and the reduction in nephrotoxicity and ototoxicity associated with aminoglycoside administration as a single daily dose are hypothesized to be related to a prolonged drug-free interval (i.e., when serum concentrations of the aminoglycoside are no longer measurable) (13). The results of many randomized controlled trials have been summarized by at least seven meta-analyses (410) that have concluded that administration of aminoglycosides as a single daily dose is associated with improved efficacy (5,8,10) and decreased nephrotoxicity (6,7) compared with administration in multiple daily doses. However, because the vast majority of patients in those randomized controlled trials were immunocompetent adults, the effects of once-daily aminoglycoside dosing in immunocompromised children is not well understood.

Although several randomized controlled trials have also demonstrated the benefits of once-daily dosing of aminoglycosides in patients with febrile neutropenia (1115), most were unable to assess the independent effect of once-daily dosing because the aminoglycoside was combined with different antibiotics in the once daily and the every 8 hours dose groups (for example, ceftriaxone and once-daily-dose aminoglycoside versus ceftazidime and thrice-daily-dose aminoglycoside). In a recent review, Hughes et al. (16) concluded that there are insufficient data to recommend once-daily dosing of aminoglycosides as a standard practice in patients with febrile neutropenia. If nephrotoxicity and efficacy are related to attaining a sufficient drug-free interval and a high peak aminoglycoside level, respectively, it follows that individualized dosing of aminoglycosides administered as a single daily dose may maximize the benefit of this mode of administration. Maximization of benefit is particularly relevant for those at higher risk of toxicity and infectious morbidity. Consequently, we sought to individualize once-daily doses of tobramycin using predefined pharmacokinetic targets in children with fever and neutropenia who were undergoing stem cell transplantation. We expected that this patient population would have a higher degree of infectious morbidity related to myeloablative therapy (17) as well as more nephrotoxicity (18,19) and ototoxicity (20,21) than pediatric patients with febrile neutropenia who were receiving standard-dose chemotherapy regimens.

Our primary objective was to examine whether administration of tobramycin as a single daily dose was associated with less nephrotoxicity than tobramycin administered every 8 hours among febrile neutropenic children undergoing stem cell transplantation. Our secondary objectives were to examine whether once-daily dosing of tobramycin was more efficacious and less ototoxic than thrice-daily dosing.


    PATIENTS AND METHODS
 Top
 Notes
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Patients

All children 18 years or younger admitted to The Hospital for Sick Children (Toronto, Canada) for their first stem cell transplantation from October 2000 through November 2002 were evaluated for study eligibility. Children who developed a fever (defined as an oral temperature of 38.0 °C over a 12-hour period on two or more occasions or an oral temperature of 38.5 °C on a single occasion) while experiencing neutropenia (defined as an absolute neutrophil count of <0.5 x 109 cells/mL) were included in our study. Neutropenia was expected to begin around the time of stem cell infusion and resolve approximately 1–4 weeks later. Children who were started on broad-spectrum antibiotic therapy for a clinical infection in the absence of fever and children with fever but without neutropenia but in whom neutropenia was expected were also included in our study. Patients were excluded if they were allergic to piperacillin, ceftazidime, or tobramycin; if they had received aminoglycosides within 2 weeks of study enrollment; or if they presented with septic shock at the onset of fever. Patients participated in our study only once.

Study Design

Written informed consent and assent (when applicable) was obtained from the patient or his or her guardian upon the patient's admission to the stem cell transplantation ward during the conditioning phase. Immediately prior to randomization (i.e., at the onset of febrile neutropenia), we performed a clinical evaluation and obtained cultures from each patient. The cultures consisted of a peripheral blood culture, blood cultures from each lumen of the central venous line, and a urine culture. Patients were then randomly assigned to receive tobramycin (Eli Lilly Canada, Toronto, Canada) intravenously as a single daily dose or every 8 hours. (Specific dosing information is given below.) Randomization was performed by computer allocation, and the randomization sequence was maintained in the pharmacy at The Hospital for Sick Children. The sequence remained concealed from all members of the research team and from those participating in clinical care until conclusion of the study. Randomization was performed in blocks of four or six assignments and stratified by stem cell donor type (allogeneic versus autologous) and patient age (<5 years, 5 to <12 years, and >=12 years).

The study patients and the entire clinical treatment team were blinded to the randomized assignments; only investigators not involved with patient care (L. L. Dupuis and T. Taylor) were unblinded so that they could make adjustments to individual tobramycin doses in response to serum concentrations of tobramycin. To maintain blinding, each tobramycin dose was prepared by the pharmacy staff in a 50-mL syringe, and all patients received a 50-mL injection three times a day (i.e., every 8 hours). Patients assigned to receive tobramycin every 8 hours received tobramycin in each of the three daily syringes, whereas patients assigned to receive a single daily dose of tobramycin received tobramycin in the first syringe and normal saline in the next two syringes. Doses could also be administered in a volume of 25 mL to patients who were fluid restricted. Serum tobramycin levels were available only to the two investigators responsible for adjusting tobramycin dose (L. L. Dupuis and T. Taylor).

According to our institutional protocol, tobramycin for febrile neutropenia was always used in conjunction with a second antibiotic with activity against gram-negative bacteria. However, the specific second antibiotic changed during the course of the study. At the onset of the study, piperacillin (at 50 mg/kg/dose, maximum 2000 mg, injected intravenously every 6 hours) was used. However, in March 2002, piperacillin became unavailable from the supplier (Wyeth-Ayerst Canada, St-Laurent, Quebec) and consequently, ceftazidime (50 mg/kg/dose, maximum 2000 mg, injected intravenously every 8 hours; Eli Lilly Canada, Toronto, Ontario) was substituted.

Each study patient was assessed daily by a clinical evaluation and a complete blood count and chemistry, which included determination of serum creatinine levels, until antibiotic treatment was discontinued. Blood for cultures was drawn on a daily basis from patients with persistent fever. The clinical treatment team made decisions regarding the management of these patients including whether patients required ancillary investigations, modification of antibiotics they were taking, or treatment with antiviral or antifungal medications. A patient could be withdrawn from the study at the discretion of the treatment team if the patient displayed hemodynamic instability; in this event, the patient was placed on open-label tobramycin every 8 hours. Tobramycin was discontinued at the discretion of the treatment team.

Episodes of febrile neutropenia were categorized as microbiologically documented, clinically documented, or as fever of unknown origin, as previously described (22). Filgrastim was given universally except to those patients undergoing autologous stem cell transplantation for acute myeloid leukemia and to those with myelodysplastic syndrome. Three patients in the once daily dose group and two patients in the every 8 hours dose group did not receive filgrastim.

Patients undergoing stem cell transplantation for immune deficiency were treated with prednisone and cyclosporine to prevent graft-versus-host disease; all other patients undergoing allogeneic stem cell transplantation received methotrexate and cyclosporine. This study was approved by the Research Ethics Board of The Hospital for Sick Children.

Tobramycin Dosing and Pharmacokinetic Considerations

Patients randomly assigned to the once daily dose group received an age-dependent initial dose of tobramycin that was previously determined using the WinNonlin computer simulation program (version 3.1; Pharsight, Mountain View, CA) as previously described (23); the simulation used a pre-existing pharmacokinetic database containing data from more than 100 children with febrile neutropenia treated at The Hospital for Sick Children. Doses of tobramycin were designed to achieve a serum tobramycin concentration at the end of the infusion (Cmax) of 20–22.5 mg/L and a drug-free interval (defined in this study as the time interval during which the tobramycin serum concentration was <1 mg/L) of at least 4 hours during the 24-hour dosing interval. Patients younger than 5 years received 9 mg/kg/dose, those aged at least 5 years but younger than 12 years received 8 mg/kg/dose, and those aged 12 years or older received 7 mg/kg/dose. Patients randomly assigned to the every 8 hours dose group received tobramycin at 2.5 mg/kg/dose (maximum of 120 mg tobramycin per dose prior to serum concentration determination). All tobramycin doses were infused over a 30-minute period that included the time required to flush the intravenous line.

Serum concentrations of tobramycin were analyzed by the Department of Pediatric Laboratory Medicine at The Hospital for Sick Children at 2 hours and 8 hours after the beginning of the first infusion with the use of an Immuno 1 microparticle immunoassay (Bayer, Tarrytown, NY). On the basis of those results, the initial tobramycin dose was adjusted, if necessary, within 24 hours of the initiation of therapy to achieve the target parameters as outlined above for once-daily dosing. For those patients receiving tobramycin every 8 hours, the tobramycin dose was adjusted to achieve a steady-state Cmax of 7–9 mg/L and a steady-state serum tobramycin concentration at the end of the dosing interval (Cmin) of less than 2 mg/L.

After the pharmacokinetic targets were achieved, we monitored the serum tobramycin concentrations at 2 hours and at 6 or 8 hours after a dose at least once weekly and adjusted the tobramycin doses as necessary to ensure continued achievement of the pharmacokinetic targets. We determined serum tobramycin concentrations more frequently for patients with increasing serum creatinine levels or if coadministration of nephrotoxic agents (such as vancomycin or amphotericin B) was initiated.

Pharmacokinetic parameters were calculated using standard first-order, one-compartment equations. Steady-state equations were used to calculate pharmacokinetic parameters in the every 8 hours dose group only when a patient had received at least three equivalent tobramycin doses prior to the determination of serum tobramycin concentration. The area under the curve (AUC) for serum tobramycin concentration versus time was calculated to infinity via the trapezoidal rule using the extrapolated serum tobramycin concentration at the end of the infusion and the serum tobramycin concentration at 2 hours and 6 (or 8) hours after the start of the infusion (24).

Outcome Measures

All outcome measures, with the exception of the audiologic evaluations, were collected and scored by a single investigator (L. Sung) who was blinded to treatment allocation. Audiologic outcomes were evaluated by a second investigator (B. Bliss) who was also blinded to treatment allocation.

The primary outcome measure was nephrotoxicity, which was defined as the maximal percent increase in serum creatinine concentration from the baseline serum creatinine concentration that was measured just prior to the initiation of tobramycin treatment. We chose to use the relative increase in serum creatinine level rather than an absolute increase in serum creatinine level as the primary outcome, because the former accounts for the large differences in baseline creatinine level between smaller and larger children.

The secondary outcome measures were efficacy and ototoxicity. Treatment was considered to be successful if the patient survived the episode of febrile neutropenia without requiring any modification of the assigned antibacterial regimen (25). Treatment was classified as a failure if the patient died of infection, the bacteremia persisted, breakthrough bacteremia occurred, or any modification of the initial antibacterial regimen was made (25). The addition of antiviral or antifungal medications was not considered a failure but was recorded. Recurrences of fever during the episode (defined as an oral temperature of >=38 °C occurring after 48 consecutive hours without a fever) or after discontinuation of tobramycin (within 48 hours and up to 7 days after tobramycin discontinuation) were also not classified as failures but were documented.

Audiologic evaluations were performed prior to stem cell transplantation (baseline) and at 2–4 weeks after the completion of tobramycin treatment (follow-up). Audiometry was performed at 2, 4, and 8 kHz in both ears, and otoacoustic emission (OAE), a sensitive measure of cochlear function, was evaluated if the child was cooperative. A single audiologist (B. Bliss) examined all audiograms and coded each evaluation as normal or abnormal, with abnormal hearing considered a threshold at any frequency of greater than or equal to 20 dB (26). The same audiologist then compared each pair of evaluations for a given child and classified the follow-up audiogram as worse if a decline of at least 15 dB occurred at any frequency compared with the baseline audiogram and not worse if a decline of less than 15dB occurred (27). Paired OAEs were also scored as worse or not worse according to guidelines suggested by others (28). If only the follow-up audiogram or OAE was available, the evaluation was included only if it was classified as normal; in that case, the evaluation was considered to be not worse than baseline.

Statistical Methods

For the primary outcome measure, we assumed that if the mean maximal increase in serum creatinine concentration from baseline was 50% among those receiving tobramycin every 8 hours, we would need a sample size of 48 patients to show a 50% decrease in maximal change in serum creatinine concentration among those receiving a single daily dose of tobramycin given a standard deviation of 30%, an {alpha} of .05, and a {beta} of .20. It was decided a priori that 60 patients would be enrolled to allow for 20% of cases to be nonevaluable.

The prespecified study population evaluated for the primary and secondary outcome measures included the patients from the modified intent-to-treat analyses. The study population evaluated for toxicity outcomes (nephrotoxicity and ototoxicity) included patients who had received tobramycin for at least 48 hours. Patients excluded from the modified intent-to-treat analysis of clinical efficacy were those who had experienced episodes of febrile neutropenia in which a nonbacterial cause of the initial fever was documented, had tobramycin discontinued for a reason unrelated to efficacy (e.g., nephrotoxicity), or were infected with a tobramycin-resistant microorganism. We also performed a separate analysis that included patients who failed treatment because of hemodynamic instability.

Differences between the once daily and the every 8 hours dose groups with respect to continuous variables were analyzed using Student's t test for independent groups or Wilcoxon's rank sum test, depending on the distribution of the variable. For example, the difference in the primary outcome measure between patients receiving once-daily dosing and those receiving dosing every 8 hours (i.e., the maximal percent increase in serum creatinine concentration during the episode) was analyzed using Student's t test for independent groups. Categorical variables were compared using the chi-square test or Fisher's exact test as appropriate. Multiple regression analyses were performed when potential confounders were identified. Statistical analyses were performed using SAS-PC software (version 8.0; SAS Institute, Cary, NC) or the Statistical Package for Social Sciences for Windows (version 10.1; SPSS, Chicago, IL). All tests of statistical significance were two-sided, and statistical significance was defined as P<.05.


    RESULTS
 Top
 Notes
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 
From October 2000 through November 2002, we assessed 119 children for study eligibility and excluded 59 children (Fig. 1). The remaining 60 children were enrolled in our study; 29 children were randomly assigned to receive tobramycin as a single daily dose and 31 children were randomly assigned to receive tobramycin every 8 hours. The baseline characteristics of patients in the two treatment groups are shown in Table 1.



View larger version (35K):
[in this window]
[in a new window]
 
Fig. 1. Flow diagram of patients in the study. *In the modified intent-to-treat analysis for toxicity, 26 were included in the once daily dose group and 28 were included in the every 8 hours dose group. In the modified intent-to-treat analysis for efficacy, 26 were included in the once daily dose group and 27 were included in the every 8 hours dose group.

 

View this table:
[in this window]
[in a new window]
 
Table 1. Baseline patient characteristics by treatment arm*

 
Description of Episodes of Febrile Neutropenia

Of the 60 episodes of febrile neutropenia that occurred during our study, 17 (28%) were microbiologically documented, 18 (30%) were clinically documented, and 25 (42%) were fevers of unknown origin (Table 2). The 16 positive blood cultures were positive upon initiation of antibiotic therapy, and all bacteremias resolved by the end of treatment. No cases of breakthrough bacteremia with either the same or a different organism occurred during the study. On average, tobramycin was initiated 4 days after stem cell infusion (range = 2 days before to 11 days after stem cell infusion). Although the two study groups had similar numbers of episodes with a positive blood culture overall, the every 8 hours dose group had more episodes characterized by infection with a gram-positive organism, whereas the once daily dose group had more episodes characterized by infection with a gram-negative organism; however, these differences were not statistically significant.


View this table:
[in this window]
[in a new window]
 
Table 2. Characteristics of episodes of febrile neutropenia by treatment arm*

 
Table 3 shows the serum tobramycin concentrations after the first tobramycin dose was administered and the resulting pharmacokinetic parameters for 22 (76%) of the 29 children in the once daily dose group and 23 (74%) of the 31 children in the every 8 hours dose group. The mean drug-free intervals in the once daily dose group and in the every 8 hours dose group were 16.6 hours and 2.6 hours, respectively (difference = 14.0 hours, 95% CI = 13.0 to 15.1 hours; P<.001). Serum tobramycin concentrations for all other patients were determined later in their course of treatment with the exception of one child in the once daily dose group who never had serum tobramycin concentrations determined because of rapid deterioration soon after antibiotic initiation. This child had blood cultures positive for viridans streptococcus and died from overwhelming sepsis. Most patients (25/28; 89%) who received once-daily tobramycin eventually achieved a Cmax that was greater than the lower limit of the target concentration (i.e., 20 mg/L), and all achieved a Cmax of at least 16 mg/L. Similarly, most patients (29/31; 94%) who received tobramycin every 8 hours eventually achieved a Cmax that was greater than the lower limit of the target concentration (i.e., 7 mg/L). However, the mean time required to achieve the lower limit of the target concentration was statistically significantly shorter for patients in the once daily dose group (3.4 days) than for patients in the every 8 hours dose group (6.4 days; difference = 3.0 days, 95% CI = 0.9 to 5.0 days; P = .005) (data not shown).


View this table:
[in this window]
[in a new window]
 
Table 3. Pharmacokinetic parameters following the first tobramycin dose*

 
Nephrotoxicity

Table 4 presents our results for the primary outcome measure, the maximal percent increase in serum creatinine concentration from the concentration at baseline. Patients in the once daily dose group had a smaller percent increase in peak serum creatinine concentration than patients in the every 8 hours dose group (32% versus 51%; difference = 19%, 95% CI = 0% to 38%; P = .054). There was no statistically significant difference between the once daily dose group and the every 8 hours dose group in the mean number of days from initiation of tobramycin administration to the peak in serum creatinine levels (10 days versus 9 days, respectively; difference = 1 day, 95% CI = -2 days to 5.6 days; P = .5). Fig. 2 illustrates the mean daily serum creatinine levels for each dose group.


View this table:
[in this window]
[in a new window]
 
Table 4. Outcome measures by treatment arm*

 


View larger version (18K):
[in this window]
[in a new window]
 
Fig. 2. Scatter plot of mean daily serum creatinine concentrations with respect to the day of tobramycin administration by treatment group. ODD = once daily dose; Q8H = every 8 hours dose. Error bars represent 95% confidence intervals.

 
Three children in each dose group could not be evaluated for toxicity because they received the study drug for less than 48 hours. The reasons for the early discontinuation of study tobramycin were identical for the two dose groups; one child in each group had tobramycin discontinued because of infection with a tobramycin-resistant organism, and two children in each group had tobramycin discontinued because of hemodynamic instability.

The mean serum creatinine concentration at baseline was similar in the two study groups (31.0 µmol/L in the once daily dose group and 32.3 µmol/L in the every 8 hours dose group; P = .5) (Table 1). Among patients evaluable for nephrotoxicity, vancomycin was used to treat episodes of febrile neutropenia statistically significantly more frequently in the every 8 hours dose group (17 [61%] of 28 episodes) than in the once daily dose group (seven [27%] of 26 episodes; P = .01). Among patients evaluable for nephrotoxicity, there was no difference between the dose groups in the use of amphotericin B to treat episodes (13 [50%] of 26 episodes in the once daily dose group versus 16 [57%] of 28 episodes in the every 8 hours dose group; P = .6). In multiple regression analyses, patients in the once daily dose group did not have a statistically significant decrease in the maximal percent increase in serum creatinine concentration compared with patients in the every 8 hours dose group, after adjustment for vancomycin use (P = .1) or body surface area (P = .08) (data not shown).

Only one child required hemodialysis for renal failure; that child had been assigned to the every 8 hours dose group. Two children in the every 8 hours dose group required an increase in the dosing interval to every 12 hours because of reduced tobramycin clearance. No children in the once daily dose group required an increase in the dose interval.

Clinical Efficacy

Patients in the once daily dose group had a higher percentage of successful episodes of febrile neutropenia than patients in the every 8 hours dose group (46% versus 19%, difference = 27%, 95% CI = 4% to 52%; P = .03) (Table 4). Among patients evaluable for efficacy, fewer patients in the once daily dose group had vancomycin added to their regimen than patients in the every 8 hours dose group (31% versus 67%; P = .009) (Table 4). Seven episodes were considered unevaluable for the efficacy analysis (three in the once daily dose group and four in the every 8 hours dose group). In the once daily dose group, one episode was not evaluable because of nephrotoxicity, one because of bacteremia involving a tobramycin-resistant organism, and one because the initial fever was caused by a rotavirus infection. In the every 8 hours dose group, three episodes were not evaluable because of nephrotoxicity and one was not evaluable because of bacteremia involving a tobramycin-resistant organism. The median duration of fever for patients in the once daily dose group (3 days, interquartile range = 2–10 days) was similar to that for patients in the every 8 hours dose group (5 days, interquartile range = 2–9 days; P = .3). There were no differences between the two treatment groups in the number of episodes in which the fever recurred after discontinuation of antibiotics (data not shown). There were no statistically significant differences in the drug-free interval or the Cmax between successful episodes and episodes that failed in the once daily dose group (data not shown).

Six patients in the once daily dose group and three patients in the every 8 hours dose group developed cardiovascular instability (i.e., hypotension) while receiving tobramycin. The median time that hypotension developed was on treatment day 5 (range = day 1 to day 11) for patients in the once daily dose group and on treatment day 3 (range = day 2 to day 7) for patients in the every 8 hours dose group (P = .7). Among the six hypotensive patients in the once daily dose group, three patients had positive blood cultures (one child had viridans streptococcus, one child had viridans streptococcus and Klebsiella pneumoniae, and one child had Streptococcus pneumoniae and Escherichia coli). Only one of the three hypotensive patients in the every 8 hours dose group had a positive blood culture; the organism was viridans streptococcus. One patient in each dose group died during an episode of febrile neutropenia. The death in the once daily dose group was attributed to overwhelming sepsis with viridans streptococcus; the death in the every 8 hours dose group was attributed to culture-negative septic shock, with pneumatosis intestinalis found on autopsy.

The three patients who received tobramycin every 8 hours and who became hypotensive had a statistically significantly longer mean drug-free interval after the first tobramycin dose than the 20 patients in this group who were hemodynamically stable throughout treatment (4.3 versus 2.4 hours; difference = 1.9 hours, 95% CI = 0.5 to 3.3 hours; P = .01). Although two of the hypotensive patients never achieved a Cmax within or greater than the target range, the average Cmax for hemodynamically stable patients (6.0 mg/L) was not statistically significantly different from that for hypotensive patients (4.6 mg/L; difference = 1.4 mg/L, 95% CI = -0.9 to 3.7 mg/L; P = .2). There were no statistically significant differences in the drug-free interval or the Cmax between hypotensive and hemodynamically stable patients in the once daily dose group (data not shown).

Ototoxicity

Patients in the two treatment groups had similar proportions of normal audiograms and OAEs at baseline; 12 (67%) of 18 patients in the once daily dose group and 14 (58%) of 24 patients in the every 8 hours dose group had normal audiograms (P = .6), and 10 (83%) of 12 patients in the once daily dose group and 10 (83%) of 12 patients in the every 8 hours dose group had normal OAEs (P = 1.0). There was no statistically significant difference between the treatment groups in the proportion of children with an audiologic evaluation at follow-up that was worse than their evaluation at baseline (Table 4).


    DISCUSSION
 Top
 Notes
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Our results suggest that, in children with febrile neutropenia who are undergoing stem cell transplantation, administration of tobramycin as a single daily dose is associated with less nephrotoxicity and greater efficacy than tobramycin administered every 8 hours. To our knowledge, this study is the first to rigorously evaluate the effects of a single daily dose of tobramycin in a high-risk pediatric population in which individualized dosing based on pharmacokinetic parameters was used.

Compared with tobramycin administered every 8 hours, tobramycin administered as a single daily dose was associated with a 37% reduction in the relative increase in serum creatinine levels. However, this reduction in the maximal increase in serum creatinine concentration relative to baseline may, in part, also be related to lower vancomycin use in the once daily dose group. The once daily dose group also had a higher rate of successful episodes of febrile neutropenia than the every 8 hours dose group (46% versus 19%). Our definition of success (i.e., the patient surviving the episode of febrile neutropenia without requiring modification of the assigned antibiotic regimen) was similar to that proposed by the International Antimicrobial Therapy Cooperative Group of the European Organisation for Research and Treatment of Cancer (25). Our success rates, albeit low, are similar to those observed in other studies (2932) that included patients undergoing stem cell transplantation. For example, one study (29) reported a 27% success rate among 234 patients receiving ciprofloxacin and piperacillin and a 22% success rate among 237 patients receiving tobramycin and piperacillin. It is possible that one factor contributing to our low success rate is that we did not mandate that changes to the initial antibiotic regimen be performed according to a set protocol for patients with persistent fever. We believe that the lack of a protocol for changes to the antimicrobial regimen should not have biased the results because of the blinded nature of the study, and may have improved their generalizability.

We observed a mean drug-free interval of 16.6 hours among patients who received tobramycin as a single daily dose. This finding was not unexpected given the pharmacokinetics of tobramycin previously observed in adult (3335) and pediatric (3638) oncology patients. We cannot compare the drug-free intervals we observed with those seen in other studies because most other studies of once-daily aminoglycosides did not report the drug-free interval. However, the drug-free intervals we observed are likely to be shorter than the drug-free intervals in other studies of once-daily tobramycin because those studies used lower doses of tobramycin (i.e., 4–7 mg/kg/day) and, unlike in our study, the doses were not adjusted to achieve pharmacokinetic targets (13,39,40). In our study, the length of the drug-free interval was not associated with clinical outcomes among patients who received a single daily dose of tobramycin. However, this lack of an association must be interpreted cautiously, given the small number of patients used in this analysis.

Most of the aminoglycoside-dosing nomograms that have been validated for use in adults do not consider dosing intervals of less than 24 hours (41,42). However, the nomogram created by Urban and Craig (1) suggests that adult patients who have a drug-free interval longer than 16 hours after receiving a single daily dose of tobramycin (aminoglycosides) should receive subsequent doses every 12 hours. Although dosing every 12 hours may achieve theoretical pharmacokinetic targets, the higher success rate we observed for patients in the once daily dose arm of our study suggests that drug administration every 12 hours is not necessary in most patients with febrile neutropenia.

Our results also suggest that once-daily administration of tobramycin, compared with thrice-daily administration, is not associated with adverse effects on hearing. Conversely, a review of eight studies in which audiologic evaluations were performed for children receiving aminoglycosides noted that ototoxicity was observed in seven (4.1%) of 171 children receiving a single daily dose and in two (2.4%) of 83 children treated with traditional (i.e., multiple daily) dosing regimens (43). However, because several of those studies were single-arm trials, it is difficult to directly compare the results of children treated with the different dosing regimens. Therefore, our results are important because they provide an evaluation of ototoxicity among comparable groups of children who received tobramycin either as a single daily dose or every 8 hours, in which the assessor was blinded to the treatment allocation.

Results of at least two studies (15,44) have suggested that monotherapy with agents such as ceftazidime is sufficient for the treatment of febrile neutropenia and thus raise the question of whether aminoglycosides are important at all in this setting. However, two-drug combination therapy remains an acceptable option for patients with febrile neutropenia, and the most commonly used two-drug combinations contain an aminoglycoside (16). There are theoretical advantages to using two-drug combination therapy, such as potential synergism against some gram-negative bacilli (45) and decreased emergence of breakthrough bacteremia due to growth of antibiotic-resistant isolates (46). Our results are important for those clinical centers that continue to use aminoglycosides in the treatment of febrile neutropenia.

Our results must be interpreted in light of several study limitations. First, because efficacy was a secondary outcome measure in our study, results concerning efficacy must be considered to be hypothesis-generating when they are examined in isolation. Second, our analysis of the ototoxicity data was underpowered to detect differences between dose groups. A meta-analysis of all randomized trials at the individual patient level may be better able to determine the relationship between once-daily dosing with aminoglycosides and ototoxicity. Third, our findings are generalizable only to a setting of once-daily dosing in which doses of tobramycin are adjusted to achieve pharmacokinetic targets. In addition, our monitoring and dosing guidelines are only applicable to children with febrile neutropenia; tobramycin single-daily-dose requirements and optimal monitoring schedules are likely to be different in other groups of patients.

In summary, our results suggest that tobramycin administered as a single daily dose is associated with less nephrotoxicity and improved efficacy compared with tobramycin administered every 8 hours. We propose that once-daily dosing with tobramycin should be adopted for children with febrile neutropenia, including children who are undergoing stem cell transplantation.


    NOTES
 Top
 Notes
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 
L. Sung is supported by fellowships from the Canadian Institutes of Health Research (CIHR) and the Hospital for Sick Children Clinician Scientist Program. The project was supported by a seed grant from the Hospital for Sick Children Research Institute.

We thank the nurses, pharmacists, and physicians on the Bone Marrow Transplantation and Oncology Units, the pharmacy staff, and the staff from the Department of Pediatric Laboratory Medicine for their invaluable assistance in completing this study. We also thank Gina Schwamborn for her assistance with data management and the staff of the Canadian Hematology/Oncology Centers who assisted with collection of audiologic assessments.


    REFERENCES
 Top
 Notes
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

1 Urban AW, Craig WA. Daily dosage of aminoglycosides. Curr Clin Top Infect Dis 1997; 17: 236–55.[Medline]

2 Freeman CD, Nicolau DP, Belliveau PP, Nightingale CH. Once-daily dosing of aminoglycosides: review and recommendations for clinical practice. J Antimicrob Chemother 1997; 39: 677–86.[Abstract]

3 Lacy MK, Nicolau DP, Nightingale CH, Quintiliani R. The pharmacodynamics of aminoglycosides. Clin Infect Dis 1998; 27: 23–7.[ISI][Medline]

4 Hatala R, Dinh T, Cook DJ. Once-daily aminoglycoside dosing in immunocompetent adults: a meta-analysis. Ann Intern Med 1996; 124: 717–25.[Abstract/Free Full Text]

5 Munckhof WJ, Grayson ML, Turnidge JD. A meta-analysis of studies on the safety and efficacy of aminoglycosides given either once daily or as divided doses. J Antimicrob Chemother 1996; 37: 645–63.[Abstract]

6 Barza M, Ioannidis JP, Cappelleri JC, Lau J. Single or multiple daily doses of aminoglycosides: a meta-analysis. BMJ 1996; 312: 338–45.[Abstract/Free Full Text]

7 Freeman CD, Strayer AH. Mega-analysis of meta-analysis: an examination of meta-analysis with an emphasis on once-daily aminoglycoside comparative trials. Pharmacotherapy 1996; 16: 1093–102.[ISI][Medline]

8 Ali MZ, Goetz MB. A meta-analysis of the relative efficacy and toxicity of single daily dosing versus multiple daily dosing of aminoglycosides. Clin Infect Dis 1997; 24: 796–809.[ISI][Medline]

9 Ferriols-Lisart R, Alos-Alminana M. Effectiveness and safety of once-daily aminoglycosides: a meta-analysis. Am J Health Syst Pharm 1996; 53: 1141–50.[ISI][Medline]

10 Bailey TC, Little JR, Littenberg B, Reichley RM, Dunagan WC. A meta-analysis of extended-interval dosing versus multiple daily dosing of aminoglycosides. Clin Infect Dis 1997; 24: 786–95.[ISI][Medline]

11 Charnas R, Luthi AR, Ruch W. Once daily ceftriaxone plus amikacin vs. three times daily ceftazidime plus amikacin for treatment of febrile neutropenic children with cancer. Writing Committee for the International Collaboration on Antimicrobial Treatment of Febrile Neutropenia in Children. Pediatr Infect Dis J 1997; 16: 346–53.[CrossRef][ISI][Medline]

12 Ariffin H, Arasu A, Mahfuzah M, Ariffin WA, Chan LL, Lin HP. Single-daily ceftriaxone plus amikacin versus thrice-daily ceftazidime plus amikacin as empirical treatment of febrile neutropenia in children with cancer. J Paediatr Child Health 2001; 37: 38–43.[CrossRef][ISI][Medline]

13 Postovsky S, Ben Arush MW, Kassis E, Elhasid R, Krivoy N. Pharmacokinetic analysis of gentamicin thrice and single daily dosage in pediatric cancer patients. Pediatr Hematol Oncol 1997; 14: 547–54.[ISI][Medline]

14 Efficacy and toxicity of single daily doses of amikacin and ceftriaxone versus multiple daily doses of amikacin and ceftazidime for infection in patients with cancer and granulocytopenia. The International Antimicrobial Therapy Cooperative Group of the European Organization for Research and Treatment of Cancer. Ann Intern Med 1993; 119: 584–93.[Abstract/Free Full Text]

15 Rubinstein E, Lode H, Grassi C. Ceftazidime monotherapy vs. ceftriaxone/tobramycin for serious hospital-acquired gram-negative infections. Antibiotic Study Group. Clin Infect Dis 1995; 20: 1217–28.[ISI][Medline]

16 Hughes WT, Armstrong D, Bodey GP, Bow EJ, Brown AE, Calandra T, et al. 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis 2002; 34: 730–51.[CrossRef][ISI][Medline]

17 Bodey GP, Buckley M, Sathe YS, Freireich EJ. Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia. Ann Intern Med 1966; 64: 328–40.[ISI][Medline]

18 Zager RA, O'Quigley J, Zager BK, Alpers CE, Shulman HM, Gamelin LM, et al. Acute renal failure following bone marrow transplantation: a retrospective study of 272 patients. Am J Kidney Dis 1989; 13: 210–6.[ISI][Medline]

19 Kist-van Holthe JE, van Zwet JM, Brand R, van Weel MH, Vossen JM, van der Heijden AJ. Bone marrow transplantation in children: consequences for renal function shortly after and 1 year post-BMT. Bone Marrow Transplant 1998; 22: 559–64.[CrossRef][ISI][Medline]

20 Freilich RJ, Kraus DH, Budnick AS, Bayer LA, Finlay JL. Hearing loss in children with brain tumors treated with cisplatin and carboplatin-based high-dose chemotherapy with autologous bone marrow rescue. Med Pediatr Oncol 1996; 26: 95–100.[CrossRef][ISI][Medline]

21 Parsons SK, Neault MW, Lehmann LE, Brennan LL, Eickhoff CE, Kretschmar CS, et al. Severe ototoxicity following carboplatin-containing conditioning regimen for autologous marrow transplantation for neuroblastoma. Bone Marrow Transplant 1998; 22: 669–74.[CrossRef][ISI][Medline]

22 Hughes WT, Pizzo PA, Wade JC, Armstrong D, Webb CD, Young LS. Evaluation of new anti-infective drugs for the treatment of febrile episodes in neutropenic patients. Infectious Diseases Society of America and the Food and Drug Administration. Clin Infect Dis 1992; 15 Suppl 1: S206–15.[ISI][Medline]

23 Dupuis LL, Taddio A, Sung L, Abdolell M, Allen U, Doyle JJ. Determination of an appropriate once daily tobramycin dose for pediatric bone marrow transplant patients [abstract]. Pharmacotherapy 2000; 20: 1258.

24 Gibaldi M. Biopharmaceutics and clinical pharmacokinetics. 4th ed. Philadelphia (PA): Lea & Febiger; 1991. p. 377–8.

25 Viscoli C, Bruzzi P, Glauser M. An approach to the design and implementation of clinical trials of empirical antibiotic therapy in febrile and neutropenic cancer patients. Eur J Cancer 1995 Nov; 31A(12): 2013–22.[CrossRef][ISI][Medline]

26 Guidelines for screening for hearing impairment and middle-ear disorders. Working Group on Acoustic Immittance Measurements and the Committee on Audiologic Evaluation. American Speech-Language-Hearing Association. ASHA Suppl 1990 Apr;(2): 17–24.

27 Suter AH. NHCA guidelines for revision of baseline audiograms. 4th ed. Milwaukee (WI): Council for Accreditation in Occupational Hearing Conservation; 1993.

28 Gorga MP, Neely ST, Ohlrich B, Hoover B, Redner J, Peters J. From laboratory to clinic: a large scale study of distortion product otoacoustic emissions in ears with normal hearing and ears with hearing loss. Ear Hear 1997; 18: 440–55.[ISI][Medline]

29 Peacock JE, Herrington DA, Wade JC, Lazarus HM, Reed MD, Sinclair JW, et al. Ciprofloxacin plus piperacillin compared with tobramycin plus piperacillin as empirical therapy in febrile neutropenic patients. A randomized, double-blind trial. Ann Intern Med 2002; 137: 77–87. Summary for patients in: Ann Intern Med 2002;137:120.[Abstract/Free Full Text]

30 Nucci M, Biasoli I, Braggio S, Portugal R, Schaffel R, Maiolino A, et al. Ceftazidime plus amikacin plus teicoplanin or vancomycin in the empirical antibiotic therapy in febrile neutropenic cancer patients. Oncol Rep 1998; 5: 1205–9.[ISI][Medline]

31 Sanz MA, Lopez J, Lahuerta JJ, Rovira M, Batlle M, Perez C, et al. Cefepime plus amikacin versus piperacillin-tazobactam plus amikacin for initial antibiotic therapy in haematology patients with febrile neutropenia: results of an open, randomized, multicentre trial. J Antimicrob Chemother 2002; 50: 79–88.[Abstract/Free Full Text]

32 Antabli BA, Bross P, Siegel RS, Small CD, Tabbara IA. Empiric antimicrobial therapy of febrile neutropenic patients undergoing haematopoietic stem cell transplantation. Int J Antimicrob Agents 1999; 13: 127–30.[CrossRef][ISI][Medline]

33 Zeitany RG, el Saghir NS, Santhosh-Kumar CR, Sigmon MA. Increased aminoglycoside dosage requirements in hematologic malignancy. Antimicrob Agents Chemother 1990; 34: 702–8.[ISI][Medline]

34 Manny RP, Hutson PR. Aminoglycoside volume of distribution in hematology-oncology patients. Clin Pharm 1986; 5: 629, 632.[ISI][Medline]

35 Phillips JK, Spearing RL, Crome DJ, Davies JM. Gentamicin volumes of distribution in patients with hematologic disorders. N Engl J Med 1988; 319: 1290.[ISI][Medline]

36 Ho K, Bryson S, Leson C, Morris A. High dose requirements for gentamicin in pediatric oncology patients. Can J Hosp Pharm 1990; 43: 289–92.

37 Hoecker JL, Pickering LK, Swaney J, Kramer WG, van Eys J, Feldman S, et al. Clinical pharmacology of tobramycin in children. J Infect Dis 1978; 137: 592–6.[ISI][Medline]

38 Dupuis L, Kutti R, Mahoney J, Taylor T. Prospective evaluation of gentamicin requirements in febrile, neutropenic children with leukemia [abstract]. Can J Hosp Pharm 1997; 50: 93.

39 Fleischhack G, Schmidt-Niemann M, Wulff B, Havers W, Marklein G, Hasan C, et al. Piperacillin, beta-lactam inhibitor plus gentamicin as empirical therapy of a sequential regimen in febrile neutropenia of pediatric cancer patients. Support Care Cancer 2001; 9: 372–9.[CrossRef][ISI][Medline]

40 Tomlinson RJ, Ronghe M, Goodbourne C, Price C, Lilleyman JS, Das S, et al. Once daily ceftriaxone and gentamicin for the treatment of febrile neutropenia. Arch Dis Child 1999; 80: 125–31.[Abstract/Free Full Text]

41 Nicolau DP, Freeman CD, Belliveau PP, Nightingale CH, Ross JW, Quintiliani R. Experience with a once-daily aminoglycoside program administered to 2,184 adult patients. Antimicrob Agents Chemother 1995; 39: 650–5.[Abstract]

42 Prins JM, Weverling GJ, de Blok K, van Ketel RJ, Speelman P. Validation and nephrotoxicity of a simplified once-daily aminoglycoside dosing schedule and guidelines for monitoring therapy. Antimicrob Agents Chemother 1996; 40: 2494–9.[Abstract]

43 Knoderer CA, Everett JA, Buss WF. Clinical issues surrounding once-daily aminoglycoside dosing in children. Pharmacotherapy 2003; 23: 44–56.[ISI][Medline]

44 De Pauw BE, Deresinski SC, Feld R, Lane-Allman EF, Donnelly JP. Ceftazidime compared with piperacillin and tobramycin for the empiric treatment of fever in neutropenic patients with cancer. A multicenter randomized trial. The Intercontinental Antimicrobial Study Group. Ann Intern Med 1994; 120: 834–44.[Abstract/Free Full Text]

45 Klastersky J, Vamecq G, Cappel R, Swings G, Vandenborre L. Effects of the combination of gentamicin and carbenicillin on the bactericidal activity of serum. J Infect Dis 1972; 125: 183–6.[ISI][Medline]

46 Sepkowitz KA, Brown AE, Armstrong D. Empirical therapy for febrile, neutropenic patients: persistence of susceptibility of gram-negative bacilli to aminoglycoside antibiotics. Clin Infect Dis 1994; 19: 810–1.[ISI][Medline]

Manuscript received June 19, 2003; revised October 8, 2003; accepted October 17, 2003.



             
Copyright © 2003 Oxford University Press (unless otherwise stated)
Oxford University Press Privacy Policy and Legal Statement