a Universitätsklinikum Benjamin Franklin, Hindenburgdamm 30, D 12203, Berlin; b Klinikum Ernst-von-Bergmann, Potsdam; c Klinikum der Philipps-Universität Marburg; d Medizinisches Universitätsklinikum, Freiburg i. Br.; e Klinik für Knochenmarkstransplantation und Hämatologie/Onkologie, Idar-Oberstein; f Institut für Infektionsmedizin, Berlin, Germany
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Abstract |
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Introduction |
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Materials and methods |
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This muticentre study was approved by the Ethics Committee of the Benjamin Franklin
University Hospital in Berlin as well as by the local Ethics Committees of all study centres
involved. Patients were recruited by nine centres in Germany over a period of 18 months.
Inclusion criteria were as follows: (i) patients of at least 18 years of age, (ii) underlying diseases:
leukaemia, malignant lymphoma, agranulocytosis, (iii) neutropenia defined as a granulocyte
count of < 1.0 x 109/L for an expected minimum of 5 days and (iv) fever
defined as two oral temperature readings within 3 h of 38.0°C not explained by
medication or transfusions. Patients were not entered into the study (i) more than once during a
single neutropenic period; (ii) if they were fertile without effective contraceptive methods; (iii)
with known hypersensitivity reactions/allergy or infections due to initially resistant pathogens to
any of the study drugs; (iv) with known HIV infection or renal insufficiency with serum
creatinine values >320 µmol/L; and (v) with any antibiotic pretreatment within 48 h
before entering the study other than oral selective antimicrobial decontamination. Patients who
received fluoroquinolones or co-trimoxazole as part of their antibacterial prevention programme
were not included.
Trial design
This was a prospective, open, randomized multicentre comparative trial with two parallel study arms. After informed consent, hospitalized patients were randomly assigned to receive either ceftazidime in combination with netilmicin or cefotaxime combined with netilmicin for initial management of their febrile episode. The allocation was performed by drawing consecutive sealed envelopes in blocks of four groups. The investigation was surveyed by a study monitor who reviewed data for completeness of entry. The case report forms were examined by the Data Review Committee and the principal investigator.
Antibiotic treatment
Group 1 patients received 1.0 g ceftazidime tid and netilmicin 2 mg/kg bodyweight tid, while group 2 patients were treated with cefotaxime 2.0 g tid and netilmicin 2 mg/kg bodyweight tid. Ceftazidime and cefotaxime were each mixed with 40 mL distilled water and infused intravenously over 30 min, followed by a netilmicin 5-min iv injection in both cases. The aminoglycoside dosage was adjusted to actual renal function according to the recommendations of the manufacturer. Antibiotics were continued until the patient was afebrile (oral temperature <37.5°C) and neutrophil counts exceeded 0.5 x 109/L or for at least 5 days after defervescence if counts persisted below 0.5 x 109/L. In the case of proven infections by resistant non-Gram-negative bacteria or if there was clinical suspicion of infections due to these pathogens the initial regimen could be modified by adding either vancomycin, teicoplanin, flucloxacillin, metronidazole, macrolides or rifampicin. Modification of the initial antibacterial regimen against Gram-negative bacteria was not allowed according to the study protocol.
Investigations
All patients were followed on a daily basis. At entry into the investigation full blood count, biochemical profile and chest X-ray were performed. Blood analyses for haematological and biochemical tests were done at least thrice weekly until completion. Microbiological analysis included venous blood cultures (minimum three bottles and 5 mL blood), blood cultures drawn through intravascular catheters (if present), and any other appropriate specimens. Clinical evaluation was made 2472 h after initiation of the study medication and after discontinuation of the study drugs.
Classification of febrile episodes
Primary febrile episodes were classified as microbiologically documented infections subdivided into those with and without concomitant bacteraemia; clinically documented infections (clinical evidence of infection, e.g. sinusitis, pneumonia) without microbiological identification of the offending pathogen; unexplained fever; and doubtful infection; according to the IHS consensus report.6
Assessment
Evaluation of response was classified as success without modification of the initial antibiotic regimen, success with modification against non-Gram-negative bacteria (Gram-positive bacteria and anaerobes), failure and not evaluable. Success was resolution of fever and clinical signs of infection and eradication of the causative microorganism. Failure was no response to initial therapy, e.g. the pathogen or fever persisted and the patient's clinical condition did not improve, requiring a change of the antibacterial therapy or death of the patient due to initial infection. There were no restrictions concerning the administration of non-bacterial anti-infective drugs such as aciclovir or amphotericin B. A response was defined as not evaluable if the febrile episode was doubtful, the patient had a viral or fungal infection, or if a relevant protocol violation occurred. Since a low-dosage regimen of unknown efficacy was being tested, early evaluation at 2472 h was chosen for safety reasons.
Toxicity
Overall tolerability of the study drugs was assessed by a semiquantitative score (excellent, good, moderate, poor). Liver toxicity was defined as a two-fold increase in serum aspartate aminotransferase and serum alanine aminotransferase from baseline and nephrotoxicity as a serum creatinine rise of >0.5 mg/dL.
Microbiology
The microbiological evaluation was done by the local microbiology laboratories using
standard identification methods and antibiotic susceptibility tests.7 All relevant organisms at each centre were tested for susceptibility to ceftazidime,
cefotaxime and netilmicin by breakpoint microbouillon dilution in IsoSensitest broth
(Unipath/Oxoid; Wesel, Germany). Isolates were categorized as susceptible (ceftazidime 4
mg/L, cefotaxime
2 mg/L, netilmicin
1 mg/L), intermediate (816 mg/L,
48 mg/ and 24 mg/L, respectively) or resistant to study drugs according to the
breakpoints of DIN 58 940 (Deutsches Institut für Normierung e.V. (DIN) 1990).8 Viridans streptococci (e.g. Streptococcus mitis),
corynebacteria and Streptococcus pneumoniae, were tested with agar diffusion test on
Iso-Sensitest agar with 5% sheep blood according to DIN 58 940. Intermediate susceptibility was
defined as an inhibition diameter of 1620 mm for ceftazidime, 1420 mm for
cefotaxime and 1721 mm for netilmicin.
Statistical analysis
One hundred and fifty patients (2 x 75 per treatment arm) were estimated as needed to
detect a clinically relevant difference of 15% between the two arms concerning the primary
end-point `failure' with an assumed probability error of <0.05 and a
power of 75%.
An intent-to-treat analysis was performed. All data were entered into a dBase IV data bank (ASHTON TATE) and calculated using BIAS. The intervention groups were compared with demographic and other baseline variables. Comparison for categorical data was done by the chi-square test with Yates's correction; the nonparametric Wilcoxon-test was used for continuous variables. The MantelHaenszel test was applied for small numbers (less than five). Statistical significance was defined as P < 0.05.
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Results |
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Of the 186 patients included, 95 received ceftazidime plus netilmicin and 91 cefotaxime plus netilmicin. The two groups were comparable with respect to age, gender, type of underlying malignant disease, type of cytoreductive treatment, initial polymorphonuclear cell count, median duration of neutropenia and median duration of treatment (Table I). In particular, there was no significant difference between the groups in the frequency of acute leukaemia and bone marrow transplantation.
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The clinical and microbiological evaluation is shown in Table II. Despite rigorous microbiological assessment before the initiation of empirical antibiotic therapy, the neutropenic fever could not be explained in most patients. Infection could be documented microbiologically in 54 of 186 (29%) patients; only 14 did not have concomitant bacteraemia. Twelve and 14 patients developed bacteraemia without other documented infectious foci in groups 1 and 2, respectively. Clinically defined infections, e.g. pneumonia or sinusitis, occurred in 30 (16%) patients. In about half of the patients, no infection could be documented either on clinical or microbiological grounds. These cases were defined as fever of unknown origin.
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Only one of 10 (10%) Gram-negative isolates in the ceftazidime group was initially resistant to this agent. Likewise, one of 12 Gram-negative bacteria in patients within the cefotaxime group was resistant to this cephalosporin. One patient with a bacteraemia due to a ceftazidime-resistant Klebsiella pneumoniae died from his infection after 2 days of ceftazidime therapy. One P. aeruginosa isolated in a patient in the cefotaxime group was resistant to this compound; treatment with cefotaxime was unsuccessful.
Overall response to treatment
Table IV shows the clinical status of patients at the early evaluation (2472 h) and final evaluation 2472 h after termination of the study treatment. In 72% of the patients in the ceftazidime group, success without modification could be seen at the early evaluation versus 55% in the cefotaxime group. There was no difference in the failure rate between the groups during this stage of treatment.
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Table V shows the response rates in patients with microbiologically documented infections and fever of unknown origin. For episodes categorized as microbiologically defined infections, treatment succeeded in 12 out of 20 (63%) patients on ceftazidime versus six out of 22 (28%) of those on cefotaxime. The failure rate was 18.5% with ceftazidime and 31% with cefotaxime (P < 0.05).
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Resistant pathogens and outcome
Detection of resistance against one of the study drugs predicted poor outcome in both treatment arms. For ceftazidime, nine resistant strains were isolated in seven patients. The failure rate was 3/7 patients (43%); in three out of seven patients, the response was recorded only after treatment modification, and one patient died. For cefotaxime, eight resistant strains were found in seven patients. In the latter case the failure rate was even higher (six of eight patients, 75%), but due to the low numbers this difference was not significant.
Superinfections
Bacterial infections developed in 12 patients with 21 different isolates during the first 2472 h after commencement of study drug treatment (Table VI). The type and rate of infection did not differ between the treatment groups. After discontinuation of the study antibiotics, infections with 17 different pathogens were recorded in 14 patients. Likewise, no statistical difference in the rate and type of infection was seen between the two study arms. Emergence of resistance could not be detected in initially sensitive strains but neither serotyping nor DNA fingerprinting of the isolates was performed.
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All 186 patients were evaluated for adverse side-effects and intolerance of study drugs (Table VII). Local and systemic tolerability was excellent/good in 91% for ceftazidime and in 94% for cefotaxime. Forty-five out of 95 (47%) patients in the ceftazidime arm and 44/91 (47%) in the cefotaxime arm had unsuspected events (definitely, probably, possibly and doubtfully related). There was no significant difference in the distribution of the adverse drug events between the study groups.
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Discussion |
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The study protocol providing initial antibiotic combination therapy consisting of an antipseudomonal ß-lactam plus an aminoglycoside was established according to the guidelines published by a working committee of the Infectious Diseases Society of America.1 Advantages of combination therapy are: broader antimicrobial coverage; potential synergic effects against some Gram-negative bacilli and Gram-positive bacteria; and minimal emergence of resistance during therapy.9 Lack of synergic effects against some Gram-positive bacteria, and adverse reactions, e.g. hypokalaemia, ototoxicity and nephrotoxicity associated with the use of aminoglycosides, are the major drawbacks of dual therapy.2,10
Early studies with aminoglycosides demonstrated a better clinical outcome with higher peak serum concentrations.11 In the last 20 years, in-vitro studies and animal experiments have shown that antibacterial efficacy can be maintained even with improving drug tolerability when the daily aminoglycoside dosage is administered od instead of in conventional multiple divided doses.12,13,14
When the protocol was prepared, od dosing of aminoglycosides was not an accepted and evidence-based therapeutic approach in this highly immunosuppressed patient population. As the main interest in this study was to evaluate the clinical efficacy of low-dose ceftazidime (1 g tid) multiple daily dosage was chosen for netilmicin.
The rationale of the present trial was two-fold: (i) economic reasons for reducing antibiotic-related costs and (ii) pharmacokinetic and pharmacodynamic considerations, arguing for a dose reduction without jeopardizing the safety and potency of ceftazidime. Compared with cefotaxime, ceftazidime has a longer half-life leading to prolonged time periods in which serum concentrations exceed MICs for relevant bacterial pathogens.3 For ß-lactam antibiotics the duration of free antibacterial concentrations remain above the MIC has been shown to exert the most important influence on clinical outcome.15,16,17 Reducing the dose of an antibiotic will ultimately result in lowering the peak concentrations and shortening of the percentage of time the concentrations are well above the MIC for a given pathogen. From a theoretical standpoint, this might have a negative impact on the clinical performance of this antibiotic and may augment the emergence of resistance.16
According to the data of Paradis,18 1 g of ceftazidime will ensure that serum concentrations remain above the MIC for P. aeruginosa for approximately 80% of the dosing interval. Data derived from animal studies indicate that bacteriostasis can be achieved at concentrations of ß-lactam antibiotics above the MIC for 5060% of the dosage interval.19,20
Concerning cost containment, several approaches have been applied to reduce the expense of treating neutropenic patients: (i) early discontinuation of empirical antibiotic treatment in situations where fever was not felt to reflect an infectious process;21 (ii) early discharge of patients at lower risk for life-threatening infection-related complications;22 and (iii) avoidance or shortening of hospital-based treatment by outpatient parenteral or oral antibiotic therapy.23,24 In terms of cost-effectiveness, drug acquisition costs alone are of limited value. The most important issues are the relative effectiveness, the rate of side-effects, and the follow-up costs (e.g. modification of treatment, therapy of adverse events, prolonged hospitalization).2
In our study, the overall response rates and the response in patients with documented or `possible infections' corresponded to those published in numerous antibiotic treatment studies performed in comparable high-risk populations.2 Although relevant differences in the patient populations, the definitions of infection and the responses/cures, respectively, must be considered when comparing results of different studies, most trials have demonstrated an improvement rate well above 60% for ceftazidime 2 g tid plus an aminoglycoside even in high-risk groups, including bone marrow transplant recipients.25,26,27 Interestingly, the same response rates were seen with ceftazidime monotherapy, leading to the consensus of a working panel of the Infectious Disease Society of America that this compound may be used as monotherapy in most cases.2 Some studies successfully applied lower doses of 1.0 g ceftazidime every 8 h in patients with an expected shorter period of neutropenia.28 Marie et al.29,30 have published a series of studies using ceftazidime 1 g tid as monotherapy. One of these studies included a high-risk population with a prolonged neutropenic period of 21 ± 13 days.30 The response rate without modification (e.g. adding vancomycin) was unacceptably low at only 13%. Because of the high rate of superinfections by Gram-positive bacteria, the authors concluded that satisfactory coverage of Gram-negative bacterial infections is achieved with low-dose ceftazidime. For safety reasons, they recommended an initial antibiotic regimen of low-dose ceftazidime combined with an aminoglycoside and the addition of vancomycin in non-responding febrile patients (for better Gram-positive coverage), as in the present study.
The clinical results in the cefotaxime + netilmicin group were inferior in terms of failure rates for patients with microbiologically proven and possible infections. The European Organization for Research on Treatment of Cancer (EORTC) published a prospective study in 1986 examining the difference between the extended-spectrum antibiotics azlocillin, ticarcillin and cefotaxime, each combined with amikacin.31 Response rates were significantly lower in the cefotaxime group than in the azlocillin group due to the different susceptibility of the isolates to the drugs being used. A more recent study revealed that monotherapy with imipenem-cilastatin (3 x 0.5 g/d) was superior to a combination regimen, including cefotaxime plus piperacillin, in primary bacteraemias.32 Considering the above mentioned pharmacodynamic implications, an additional explanation for these inferior clinical results may be the underdosing of cefotaxime due to its short half-life of approximately 60 min. Nevertheless, the results of this study are in agreement with the more favourable kinetic properties and the broader antimicrobial spectrum of ceftazidime, as well as the superior clinical data in neutropenic patients published so far.33,34
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Acknowledgments |
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Notes |
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Additional members of the Multicentre Study Group: principal
investigator (number of
patients). Fauser, A., Idar-Oberstein (n = 28); Finke, J., Freiburg (n
= 30); Grüneisen, A., Berlin(n = 6); Höfeler, H., Witten (n = 6); Pasold, R., Potsdam (n = 59); Petrasch, S., Bochum (n = 3); Pflüger, K.H., Marburg (n = 30); Respondek, M.,
Stuttgart (n = 2); Thiel, E./Höffken, G., Berlin (n = 22).
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References |
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Received 9 December 1998; returned 3 March 1999; revised 7 April 1999; accepted 19 April 1999