Once-daily versus multiple-daily gentamicin in empirical antibiotic therapy of febrile neutropenia following intensive chemotherapy

Fatima El Bakria,*, A. Palletta, A. G. Smithb and A. S. Duncombeb

a Department of Medical Microbiology and b Department of Haematology, Southampton University Hospitals NHS Trust, Southampton, UK


    Abstract
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The clinical efficacy and toxicity of once-daily compared with multiple-daily gentamicin dosing, in combination with azlocillin, were studied retrospectively in febrile neutropenic episodes following intensive chemotherapy. Fifty-two episodes were studied in 28 patients with acute myeloid leukaemia. Reasons for initiation of antibiotic therapy, dose, duration of treatment, organism isolation rates, response, cost comparison and toxicity were studied in the two treatment groups. The main indication for initiation of antibiotic therapy was neutropenic fever without a documented infection (80.8% of episodes). The response rate to once-daily gentamicin dosing and azlocillin was three times higher than to multiple-daily gentamicin dosing and azlocillin (P = 0.0112). The incidence of toxicity was low overall and was slightly but not significantly higher in the once-daily group. In this clinical context once-daily gentamicin at a dose of 7 mg/kg/day is more effective than a multiple-daily dosing regimen but may be more toxic.


    Introduction
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Aminoglycosides remain an important part of the empirical treatment of febrile episodes in neutropenic patients despite the introduction of new broad-spectrum antibiotics. They are usually used in combination with a ß-lactam antibiotic active against Pseudomonas sp. to provide synergy and to cover ß-lactam-resistant pathogens until sensitivity results are known. A regimen that ensures maximum efficacy with minimal toxicity has yet to be described.

Once-daily dosing (od) regimens of aminoglycosides have been studied extensively. They have been shown to be as effective as and no more toxic than multiple-daily dosing (md) regimens in different groups of patients.1,2 Most of the published work on od aminoglycoside dosing was based on clinical trials and meta-analyses and/or tightly controlled models of efficacy and toxicity which used healthy animals.2 Very few studies have involved neutropenic patients and none has evaluated the use of od aminoglycosides in routine clinical practice.

The incidence of toxicity related to od gentamicin use, especially ototoxicity, is difficult to establish because of the small numbers of patients studied and the lack of a standardized means of ascertaining cochlear and vestibular damage.3,4 This study is a sequential, comparative, nonrandomized study of the efficacy and toxicity of the two regimens in febrile neutropenic patients following intensive chemotherapy for acute myeloid leukaemia (AML).


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients eligible for the study were all febrile neutropenic adults with AML, treated with intensive chemotherapy according to MRC trial protocols5 over a 2 year period. In the first year, standard md gentamicin was used and in the second year od was used without change in any other aspect of prophylactic or empirical antibiotic therapy. None of the patients received antibiotic prophylaxis before first-line treatment and none of the patients was receiving a nephrotoxic or ototoxic agent when gentamicin was started.

All patients received gentamicin as part of an antibiotic regimen to treat proven or suspected infections. A total of 28 patients were studied, 16/28 (57.1%) were male and 12/28 (42.9%) were female. The age range was 19–75 years. Subjects were monitored throughout remission induction and consolidation therapy courses (the first three courses). A total of 52 febrile neutropenic episodes were studied: 27 episodes of md and 25 episodes of od therapy with gentamicin.

The first-line regimen in use at the time of the study was a combination of gentamicin and azlocillin (5 g tds). The second-line regimen was teicoplanin (400 mg bd for three doses and 400 mg od subsequently) and ceftazidime (2 g tds).

In the md group a dose of 80 mg tds was used. Trough and peak serum gentamicin concentrations and alteration of the dose were monitored accordingly. The acceptable range for the trough and peak serum concentrations was 1–2 and 6–8 mg/L, respectively. For the od group the Hartford Hospital protocol was used. This recommends a dose of 7 mg/kg/day, with subsequent dosing interval adjustments based on serum concentrations and a nomogram designed using an intravenous infusion model with computer simulation.1

In both treatment groups, patients were monitored for clinical signs of gentamicin toxicity, and audiograms and vestibular function tests were performed when signs of ototoxicity were noted. Serum creatinine was monitored at least twice weekly.

In 2/25 od episodes (8%) the patients had received one course of md gentamicin previously and in 1/25 od episodes (4%) the patient had received two courses of md gentamicin previously. All other patients in the remaining od gentamicin episodes had not previously been treated with md gentamicin.

Response to antibiotics was defined as complete resolution of symptoms and signs of infection for 48 h, regardless of the neutrophil count. The duration of antibiotic treatment was determined by clinical response as well as the neutrophil count. Neutropenia was defined as an absolute neutrophil count of <0.5 x 109/L. An infective episode was defined as febrile illness with or without signs of focal infection requiring antibiotic treatment, with or without a positive microbiological result. Nephrotoxicity was defined as an increase in the baseline serum creatinine by >=25%. Auditory toxicity was defined as signs of hearing loss with >15 dB perception deficit at any frequency on audiometric examination. Vestibular toxicity was defined as clinical symptoms of dizziness or vertigo and signs of balance disturbance with or without abnormal vestibular function tests.

The following information was collected: (i) reasons for initiation of antibiotic therapy, (ii) concurrent treatment with other nephrotoxic agents, (iii) dose and duration of treatment, (iv) renal function at the start of and during therapy, (v) gentamicin serum levels, (vi) clinical response and (vii) toxicity.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Analysis of results from the whole group

In 42/52 episodes (80.8%), antibiotics were started as empirical treatment for neutropenic fever. Antibiotics were started for a microbiologically documented infection in 8/52 episodes (15.4%). In five of these episodes (9.6%) organisms were isolated from blood cultures (Pseudomonas aeruginosa, Klebsiella pneumoniae and Enterococcus faecalis) and all were sensitive to first-line antibiotics. In the remaining episodes during which bacteria were isolated (5.8%), Staphylococcus aureus was isolated from other infected sites, leading to the addition of flucloxacillin to first-line antibiotics.

For a microbiologically documented infection, antibiotics were changed after treatment with first-line antibiotics for >=7 days in 3/52 episodes (5.8%). The organisms isolated were Stenotrophomonas maltophilia, Enterobacter cloacae and coagulase-negative staphylococci. Isolation of these organisms was related to central venous catheter infections in all cases and all were resistant to first-line antibiotics.

Analysis of comparative results

The mean duration of treatment was 10.4 days in the od group and 7.0 days in the md group (P = 0.026; 95% CI = 0.4191). The response rate to azlocillin and od gentamicin was approximately three times higher than to azlocillin and md gentamicin (52% and 18.2%, respectively; P = 0.0112). Table IGo shows the outcome of treatment with the two regimens.


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Table I. Outcome of treatment with azlocillin and gentamicin
 
The peak serum gentamicin concentrations of patients treated with md gentamicin were subtherapeutic in 11/27 episodes (40.7%) and were subsequently increased in 8/27 episodes (29.6%). Subsequent alteration of the doses did not improve the response and antibiotics were switched to the second-line combination according to unit policy.

In 2/27 episodes in which md gentamicin (7.4%) was in use, both trough and peak serum gentamicin concentrations were high and dose and/or frequency were adjusted accordingly. The frequency and hence dose/day of od gentamicin was reduced according to the Hartford Hospital nomogram in 6/25 episodes (24%) owing to high gentamicin concentrations. None of these patients developed nephrotoxicity or ototoxicity. In both treatment groups adjustment of the dose was guided by serum gentamicin and creatinine concentrations.

The cost of azlocillin and od gentamicin per patient per day was £21.85 at the time of the study, and the cost of teicoplanin and ceftazidime per patient per day (the second-line treatment in use) was £89.00. A cost comparison carried out on the above data showed that a saving of £67.15 per patient per day was made in net antibiotic expenditure, a change to second-line antibiotics being required less frequently. This can also be expressed as an overall saving of approximately £537.20 per day resulting from the improved response rate (32% episodes).

Toxicity

In 3/25 (12%) od gentamicin episodes the patient developed toxicity. One patient developed nephrotoxicity, one developed ototoxicity and a third developed both. In 1/27 (3.7%) md episodes the patient developed mild nephrotoxicity but not ototoxicity.

In the od group, the three patients who developed toxicity were 43, 64 and 41 years old; two were male and one was female. They all received a dose of 7 mg/kg/day and the duration of treatment was 12, 15 and 21 days, respectively. One patient had received two courses of md gentamicin previously. The other two developed toxicity following the first course of od gentamicin treatment for their first febrile neutropenic episode. The total mg/kg doses administered to these three patients, respectively, were: (i) 151.5 mg/kg over a total of 39 days (80 mg tds per day for 23 days during the first febrile neutropenic episode, 80 mg tds per day for three days after the second and 500 mg/day for 12 days after the third); (ii) 105.0 mg/kg over 15 days continuously and (iii) 147 mg/kg over 21 days continuously.

Details of the toxicities and relevant laboratory results are shown in Table IIGo. In all the patients who developed toxicity related to gentamicin treatment the serum gentamicin levels remained within the therapeutic range and did not predict or reflect toxicity.


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Table II. Details of toxicities in both regimens
 
In the od group the mean duration of treatment for the patients who developed toxicity compared with those who did not was 16 and 9.7 days, respectively (P = 0.066). In the md group it was 3 and 7.4 days, respectively.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
In this study the microbiological documentation of infection during febrile neutropenic episodes was low in both groups. This was despite the use of an automated blood culture system (Bact-alert, Organon-Teknika-Akzo Nobel-Kembridge) and optimum blood volumes, and the collection of peripheral and central blood cultures (from each lumen of the central venous catheter). Although this rate is less than those published in trials (40–60%),6 it is consistent with rates from our centre.

The organisms isolated were predominantly Gramnegative, possibly because prophylactic ciprofloxacin was not in use for these patients; its use was introduced subsequently.

Compliance with local policy was good in both groups and was consistent with rates reported by others.7 These rates reflect the efficacy of planned progressive therapy protocols for neutropenic patients, despite institutional variations in the choice of antibiotics. Constant review of local policies is essential to take into account changes in nosocomial flora and toxicities of antibiotics used.

The difference in response rate between the od dosing regimen and an md regimen was 32%. This was not only statistically significant (P = 0.0112) but was greater than differences reported previously.1,2 The failure to achieve therapeutic levels in the first 48 h of md gentamicin treatment contributed to the poor response rate in this group, leading to switching to second-line combinations.8

The actual response rate to od gentamicin was lower than other published results, with most trials reporting rates of 80–95%. This may be explained by differences in the patient groups studied and the nature of the underlying disease.2 The homogeneous group of patients in this study was a very high-risk group, with prolonged absolute neutropenia following toxic chemotherapy.

The improved efficacy resulted in significant cost savings in addition to the savings made by less frequent dosing and monitoring of one rather than two serum concentrations. This was despite the longer duration of treatment in the od group, which resulted from the improved response rate to first-line treatment (P = 0.026). A large study from another centre showed similar results.9

Previous studies evaluating od gentamicin-related toxicity suggested that its incidence is similar to or less than that associated with an md regimen.2 However, in many patients hearing was not tested, different methods of investigating ototoxicity were used, or various doses (range 3–7 mg/kg/ day) were employed. In this study the incidence of od gentamicin-related toxicity was high (12%), but statistical significance was not attained because of the small numbers studied (P = 0.3409). Cases of ototoxicity were severe and irreversible.

In a sequential, comparative, non-randomized study comparing two antibiotics or dosing regimens of the same antibiotic, there is a risk of multiple exposures in the same patient. This can result from overlap of the two antibiotics or dosing regimens leading to an increased incidence of toxicity in the second group. Detailed evaluation of all cases of toxicity related to od gentamicin use encountered during this study revealed that 2/3 patients who developed toxicity had no previous exposure to gentamicin. All three had a total exposure of >100 mg/kg. This appears to reflect the longer duration of treatment in these patients compared with the rest of the group. The difference in the mean duration of treatment was not statistically significant (P = 0.066) in this small study. Larger studies are needed to evaluate duration of treatment as a risk factor for od gentamicin-related toxicity. The dose of 7 mg/kg/day recommended by the Hartford Hospital group is larger than that used by most centres and may have contributed to the high incidence of toxicity in this study.

There is no general agreement as to how and when serum gentamicin concentrations should be monitored. Although monitoring was regular in this centre, the development of toxicity was not predicted. One of the methods of monitoring serum concentrations, based on the area under a time–concentration curve, appears to be more sensitive than the Hartford Hospital nomogram method. This method requires monitoring of two or more levels, and the analysis of results is more labour intensive.10

Aminoglycosides constitute an important part of the antibiotic treatment of febrile neutropenic episodes, but the optimal dosing and monitoring regimens remain to be determined.


    Notes
 
* Correspondence address. Public Health Laboratory, Level B South Laboratory and Pathology Block, Southampton General Hospital, Southampton SO16 6YD, UK. Tel: +44-1703-796-408; Fax: +44-173-702-530. Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1 . Nicolau, D. P., Freeman, C. D., Belliveau, P. P., Nightingale, C. H., Ross, J. W. & Quintiliani, R. (1995). Experience with a once-daily aminoglycoside program administered to 2,184 adult patients. Antimicrobial Agents and Chemotherapy 39, 650–5.[Abstract]

2 . Gilbert, D. N. (1997). Meta-analyses are no longer required for determining the efficacy of single daily dosing of aminoglycosides. Clinical Infectious Diseases 24, 816–9.[ISI][Medline]

3 . Singer, C., Smith, C. & Krieff, D. (1996). Once-daily aminoglycoside therapy: potential ototoxicity. Antimicrobial Agents and Chemotherapy 40, 2209–11.[Abstract]

4 . El Bakri, F., Pallett, A., Smith, A. G. & Duncombe, A. S. (1998). Ototoxicity induced by once-daily gentamicin. Lancet 351, 1407–8.[ISI][Medline]

5 . Hann, I. M., Stevens, R. F., Goldstone, A. H., Rees, J. K., Wheatley, K., Gray, R. G. et al. (1997). Randomized comparison of DAT versus ADE as induction chemotherapy in children and younger adults with acute myeloid leukemia. Results of the Medical Research Council's 10th AML trial (MRC AML 10). Blood 89, 2311–8.[Abstract/Free Full Text]

6 . Hughes, W. T., Armstrong, D., Bodey, G. P., Brown, A. E., Edwards, J. E., Feld, R. et al. (1997). 1997 guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever. Infectious Diseases Society of America. Clinical Infectious Diseases 25, 551–73.[ISI][Medline]

7 . De Pauw, B. E. & Dompeling, E. C. (1996). Antibiotic strategy after the empiric phase in patients treated for a haematological malignancy. Annals of Haematology 72, 273–9.

8 . Moore, R. D., Lietman, P. S. & Smith, C. R. (1987). Clinical response to aminoglycoside therapy: importance of the ratio of peak concentration to minimal inhibitory concentration. Journal of Infectious Diseases 155, 93–9.[Medline]

9 . Nicolau, D. P., Wu, A. H., Finocchiaro, S., Udeh, E., Chow, M. S., Quintiliani, R. et al. (1996). Once-daily aminoglycoside dosing: impact on requests and costs for therapeutic drug monitoring. Therapeutic Drug Monitoring 18, 263–6.[ISI][Medline]

10 . Duffull, S. B., Kirkpatrick, C. M. & Begg, E. J. (1997). Comparison of two Bayesian approaches to dose-individualisation for once-daily aminoglycoside regimens. British Journal of Clinical Pharmacology 43, 125–35.[ISI][Medline]

Received 22 February 1999; returned 9 August 1999; revised 22 September 1999; accepted 11 November 1999