a Department of Internal Medicine I, Division of Infectious Diseases b Department of Internal Medicine I, Intensive Care Unit c Department of Laboratory Medicine, University of Vienna, Waehringer Guertel 18- 20, A-1090 Vienna, Austria
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Abstract |
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Introduction |
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Intermittent administration of a drug results in high peak and low trough serum levels. For ß-lactam antibiotics this method of administration could result in concentrations below the MIC for the target organism over a long period of the dosing interval. During the last decade continuous infusion of ß-lactam antibiotics has been studied in order to exploit these pharmacodynamic properties. Some in-vitro and in-vivo studies of continuous infusion of ceftazidime6,7,8 and meropenem published recently have demonstrated the effectiveness of continuous infusion.9
The present study was performed firstly to compare the pharmacokinetic parameters of meropenem by continuous infusion (CI) and intermittent administration (IA) in critically ill patients and secondly to determine the possibility of achieving therapeutic meropenem concentrations with a 3 g iv CI over 24 h. The third aim was to study the applicability and side-effects of the IA regimen.
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Materials and methods |
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The study was conducted in the intensive care unit of a teaching hospital. In accordance with
ethical requirements, informed consent was obtained from patients or their next of kin. Fifteen
critically ill patients (four females, 11 males; Table I), admitted to the
intensive care unit
suffering from suspected or proven severe community or hospital acquired infection, were
eligible for enrolment in the study. Inclusion criteria demanded at least two of the following: (i)
elevated C-reactive protein of >10 mg/dL (normal <0.5 mg/dL), (ii) at least one positive
blood culture (Gram-negative or Gram-positive bacteria) or two positive blood cultures growing
coagulase-negative staphylococci, (iii) clinical signs of infection, (iv) respiratory tract infection
(new infiltrate on a chest X-ray), or (v) positive urine culture. Predicted duration of treatment had
to be 4 days. Patients with known hypersensitivity to meropenem, imipenem/cilastatin, or
other ß-lactam antibiotics, bleeding disorders, a history of convulsions, or a decreased
creatinine clearance were excluded from the study. Concomitant antimicrobial therapy with
vancomycin was permitted to include cover for methicillin-resistant strains of Staphylococcusspp.
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The study was performed as a prospective, randomized, crossover trial. All patients were randomized to receive either a 2 g iv loading dose of meropenem followed by a daily 3 g continuous infusion (CI; group 1) over 48 h or intermittent administration (IA; group 2) of 2 g of meropenem iv every 8 h for 2 days. After 2 days the patients received the alternative dose regimen. If necessary, vancomycin was added to cover methicillin-resistant staphylococci or enterococci. Steady-state concentrations of meropenem were expected to be achieved on day 2 of administration of CI or IA therapy.
Drug administration
For group 1 meropenem was administered via an infusion pump (Braun Melsungen, Melsungen, Germany). One gram of meropenem (Optinem; Zeneca, Macclesfield, UK) was reconstituted according to the manufacturer's guidelines and then diluted in 50 mL of isotonic saline solution. New solutions were prepared every 8 h. The doses of 2 g of meropenem in group 2 were diluted in 100 mL of isotonic saline solution and administered over 15 min.
Blood and urine sampling
Blood samples were taken at 0, 0.25, 0.5, 1, 2, 3, 6, 12, 24 and 48 h after the start of CI and at 0, 0.5, 8, 8.5, 16, 16.5, 24, 24.5, 32, 32.5, 40, 40.5 and 48 h after the start of IA. All blood samples were drawn from indwelling arterial catheters after discarding the first 10 mL of blood. After centrifugation, serum was stored at 70°C until assayed.
Routine laboratory parameters (e.g. leucocyte and platelet counts, renal and liver function tests) were determined daily by the institution's clinical chemistry department. Creatinine clearance was calculated by standard methods.
Determination of meropenem concentration
The concentration of meropenem in serum was determined by HPLC as described previously. 10 The limit of detection in serum was defined as the lowest concentration of meropenem resulting in a signal-to-noise ratio of 3:1. The lowest detection limit was 0.1 mg/L serum. The percentage recoveries from sera were 94.6 ± 3.1%, 92.4 ± 4.3%, 95.2 ± 3.0% and 91.9 ± 4.0% with coefficients of variation (CV) of 2.7%, 3.0%, 2.5% and 5.5% for assays of 5.0, 10.0, 50.0 and 100.0 mg/L serum, respectively. The intra-assay reproducibility characterized by CV was 4.3%, 3.57% and 5.0% for assays of 5, 100 and 250 mg/L, respectively. The interassay reproducibility precision values calculated by CV were 3.5%, 4.7% and 5.6% for assays of 5.0, 100.0 and 250.0 mg/L, respectively.
Interference studies were carried out with many substances that might be administered with meropenem: ß-lactam antibiotics (penicillins, imipenem), aminoglycosides (gentamicin, tobramycin). None of these compounds was coeluted with meropenem during chromatography. During specificity studies all chromatograms were carefully checked for skewed shouldering, or tailing peaks.
Pharmacokinetic analysis
Meropenem data were analysed with a curve-fitting computer program, KINETICA 2.0 (MicroPharm International, Champs sur Marne, France). The volume of distribution at steady state (VSS), elimination rate constant (kel), concentration at steady state (CSS), serum half-life (t ½), total meropenem clearance (Cltot) and the area under the concentration-time curve over the dosing interval (AUC) were calculated for each patient.
Statistical analysis
Results are given as mean values ± standard deviation. Pharmacokinetic parameters were compared with the two-tailed Student's t-test. Significance was defined as P < 0.05.
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Results |
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Discussion |
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The most effective administration mode of parenteral antibiotics remains controversial. Administration of ß- lactam antibiotics by CI results in constant serum levels which can be maintained above the MIC for the target organisms to promote maximal bactericidal activity. 12 The extent of tissue penetration following CI appears to be similar to that following intermittent administration. 13 Although the advantages of such a therapy are often discussed, only a few clinical trials have been performed. 6,7,14,15,16,17 The main objectives of this study were to investigate the pharmacokinetics of continuous infusion versus intermittent administration of meropenem, in ICU patients with severe infections, to determine the applicability of CI and to compare the side-effects and cost- effectiveness of the two treatment regimens.
In this study, a loading dose of 2 g of meropenem was used followed by a CI of 36 ± 8.4 mg/kg per day. Mean meropenem serum concentrations in the CI group at steady state were 11.9 ± 5.0 mg/L, compared with trough levels of 8.5 ± 1.0 mg/L in the IA group (P < 0.001). Serum levels well above the MIC for most pathogens were achieved in both groups (Table III).18 In addition, continuous bactericidal activity during CI was achieved with only 50% of the meropenem dose used for the intermittent regimen. Therefore, the use of CI could lower the costs of antimicrobial therapy.
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The stability of an antibiotic is an important consideration if CI administration is to be used.
At room temperature most dissolved antimicrobials are stable for 24 h.
20 However, the manufacturer's guidelines state
that once meropenem is reconstituted in isotonic saline solution it is stable at room temperature
for 8 h. Thus, in this study, the antibiotic solution was changed every 8 h for the CI group. No
problems with stability occurred during the study period. This characteristic reduces the
applicability of meropenem for CI for outpatient parenteral antibiotic therapy.
In conclusion, the rationale for using meropenem as CI is supported by the pharmacokinetic data of our study. Serum concentrations remained above the MIC for most likely target pathogens in all patients. A loading dose of 2 g of meropenem should be given initially to attain bactericidal drug concentrations as rapidly as possible. During continuous infusion, no major adverse events related to the use of CI were observed. Thus, meropenem can be administered safely by CI. Additionally, a CI regimen can save costs, bactericidal serum levels being achieved with only 50% of the amount of drug used for IA. This study did not evaluate the clinical efficacy of the two different antibiotic treatment schedules. Further investigations are required to evaluate pharmacodynamic and economic perspectives in the clinical setting.
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Notes |
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References |
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Received 9 July 1998; returned 8 October 1998; revised 26 October 1998; accepted 1 December 1998