Continuous infusion versus intermittent administration of meropenem in critically ill patients

Florian Thalhammera,*, Friedericke Traunmüllera, Ibrahim El Menyawia, Michael Frassb, Ursula M. Hollensteina, Gottfried J. Lockerb, Brigitte Stoiserb, Thomas Staudingerb, Renate Thalhammer-Scherrerc and Heinz Burgmanna

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


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
This prospective crossover study compared the pharmacokinetics of meropenem by continuous infusion and by intermittent administration in critically ill patients. Fifteen patients were randomized to receive meropenem either as a 2 g iv loading dose, followed by a 3 g continuous infusion (CI) over 24 h, or by intermittent administration (IA) of 2 g iv every 8 h (q8h). Each regimen was followed for a period of 2 days, succeeded by crossover to the alternative regimen for the same period. Pharmacokinetic parameters (mean ± SD) of CI included the following: concentration at steady state (CSS) was 11.9 ± 5.0 mg/L; area under the curve (AUC) was 117.5 ± 12.9 mg/L·h. The maximum and minimum serum concentrations of meropenem (C max, Cmin) and total meropenem clearance (Cl tot) for IA were 110.1 ± 6.9 mg/L, 8.5 ± 1.0 mg/L and 9.4 ± 1.2 L/h, respectively. The AUC during the IA regimen was larger than the AUC during CI (P< 0.001). In both treatment groups, meropenem serum concentrations remained above the MICs for the most common bacterial pathogens. We conclude that CI of meropenem is equivalent to the IA regimen and is therefore suitable for treating critically ill patients. Further studies are necessary to compare the clinical effects of CI and IA in this patient group.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The optimal mode of administration of ß-lactam antibiotics in the treatment of bacterial infections remains controversial. Unlike aminoglycosides, which exhibit concentration-dependent killing rates, ß-lactam antibiotics achieve maximal killing at concentrations four or five times the MIC.1,2 Serum concentrations of ß-lactam antibiotics exceeding these values show no additional benefit. The bactericidal activity does not increase. In addition, the significance of a carbapenem post-antibiotic effect (PAE) against Gram-negative bacteria is highly disputed.3,4 The bactericidal effect of ß-lactams is closely related to the time during which the serum concentration of the antibiotic remains above the MIC (T > MIC). 5

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.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Patients

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.


View this table:
[in this window]
[in a new window]
 
Table I. Patient's characteristics
 
Study design

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.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Fifteen patients (age 55.3 ± 14.3 years, body weight 83.7 ± 15.4 kg) suffering from pneumonia (n = 7), sepsis (n = 3), or systemic inflammatory distress syndrome (n = 5) were enrolled in the study (Table II). Their creatinine clearance was 83.7 ± 53.1 mL/min, the white blood cell count was 16.5 ± 11.5 G/L (normal range 4- 10 G/L) and the C-reactive protein level was 19.8 ± 7.0 mg/100 mL. No pathogens, with the exception of a coagulase-negative staphylococcus in one blood culture, were isolated during the study; no underlying infection was detected by microbiological tests.


View this table:
[in this window]
[in a new window]
 
Table II. Pharmacokinetic parameters
 
The pharmacokinetic parameters for continuous and intermittent administration of meropenem are presented in Table II and the Figure. AUC and total meropenem clearance (Cltot) showed statistically significant differences between groups 1 and 2. The IA group achieved an AUC of 193.8 ± 21.1 mg/L·h compared with 117.5 ± 12.9 mg/L·h for the CI group (P , 0.001). The Cl tot in the two patient groups was 9.4 ± 1.2 L/h (IA) and 7.7 ± 1.4 L/h (CI), respectively (P = 0.01). A continuous infusion of meropenem 3 g/24 h achieved a steady-state concentration of 11.9 ± 5.0 mg/L (Figure). The minimum concentration in the IA group was 8.5 ± 1.0 mg/L. In both treatment groups the T> MIC was 100% for the most common bacterial strains found in ICU patients, throughout the observation period.



View larger version (22K):
[in this window]
[in a new window]
 
Figure Mean serum meropenem concentrations with SD (bars). ({blacklozenge}), intermittent administration; ({blacktriangleup}), continuous infusion.

 
No adverse effects were observed in any patient during the study period.


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Constant concentrations of ß-lactam antibiotics above the MICs for target organisms can be achieved in vivo by administering these compounds via a continuous infusion. Concentration-independent bacterial killing is also a property of ß-lactams. The pharmacodynamic parameter correlating best with clinical outcome for these antibiotics is the time of serum concentration above the MIC (T > MIC).5,11 Intermittent administration is associated with very high peak concentrations, which provide little additional bactericidal activity but may be associated with more side-effects. In between the doses, serum concentrations often fall below the MIC for the specific pathogen for a considerable time. Most authors agree that T> MIC has to be at least 40- 50% of the dosing interval to achieve clinical effectiveness. Maximum killing is seen when T> MIC is at least 60–70%.12

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.


View this table:
[in this window]
[in a new window]
 
Table III. In-vitro activity of meropenem for clinically important Gram-positive and Gram-negative pathogens18
 
A recent study by Benko et al.7 compared a 3 g ceftazidime CI with 2 g q8h IA in critically ill patients, with similar results. In both treatment groups serum concentrations exceeded the MIC by four to five times. The serum bactericidal titres were equal in both regimens. The latter study and other clinical trials with ceftazidime, demonstrated the effectiveness of CI and confirmed our results. 6,14 ,19 Furthermore, Keil & Wiedemann described an in-vitro dynamic model to compare the antimicrobial effects of CI versus IA of carbapenem antibiotics.9 The evaluation of the corresponding kill curves for the two administration regimens showed improved antimicrobial activity of CI (1 g per 24 h) compared with IA (1 g q8h).

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.


    Notes
 
* Corresponding author. Tel: +43-1-40400-4440; Fax: +49-89-66617-18696; E-mail: florian.thalhammer{at}akh-wien.ac.at Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1 . Craig, W. A. & Ebert, S. C. (1990). Killing and regrowth of bacteria in vitro : a review. Scandinavian Journal of Infectious Diseases 74 , Suppl., 63–70.

2 . Soriano, F. (1992). Optimal dosage of ß-lactam antibiotics: time above the MIC and inoculum effect. Journal of Antimicrobial Chemotherapy 30, 566–9.[ISI][Medline]

3 . Odenholt-Tornqvist, I. (1993). Studies on the postantibiotic effect and the postantibiotic sub-MIC effect of meropenem. Journal of Antimicrobial Chemotherapy 31, 881–92.[Abstract]

4 . Hanberger, H., Svensson, E., Nilsson, L. E. & Nilsson, M. (1995). Pharmacodynamic effects of meropenem on Gram-negative bacteria. European Journal of Clinical Microbiology and Infectious Diseases 14 ,383 –90.[ISI][Medline]

5 . Drusano, G. L. (1988). Role of pharmacokinetics in the outcome of infections. Antimicrobial Agents and Chemotherapy 32, 289–97.[ISI][Medline]

6 . Daenen, S., Erjavec, Z., Uges, D. R. A., De Vries-Hospers, H. G., De Jonge, P. & Halie, M. R. (1995). Continuous infusion of ceftazidime in febrile neutropenic patients with acute myeloid leukemia. European Journal of Clinical Microbiology and Infectious Diseases 14, 188–92.[ISI][Medline]

7 . Benko, A. S., Cappelletty, D. M., Kruse, J. A. & Rybak, M. J. (1996). Continuous infusion versus intermittent administration of ceftazidime in critically ill patients with suspected Gram-negative infections. Antimicrobial Agents and Chemotherapy 40, 691–5.[Abstract]

8 . Mouton, J. W., Vinks, A. A. T. M. M. & Punt, N. C. (1997). Pharmacokinetic-pharmacodynamic modeling of activity of ceftazidime during continuous and intermittent infusion. Antimicrobial Agents and Chemotherapy 41, 733–8.[Abstract]

9 . Keil, S. & Wiedemann, B. (1997). Antimicrobial effects of continuous versus intermittent administration of carbapenem antibiotics in an in vitro dynamic model. Antimicrobial Agents and Chemotherapy 41, 1215–9.[Abstract]

10 . Thalhammer, F., Schenk, P., Burgmann, H., El Menyawi, I., Hollenstein, U. M., Rosenkranz, A. R. et al. (1998). Single-dose pharmacokinetics of meropenem during continuous venovenous hemofiltration. Antimicrobial Agents and Chemotherapy 42, 2417–20.[Abstract/Free Full Text]

11 . Hatano, K., Wakai, Y., Watanabe, Y. & Mine, Y. (1994). Simulation of human plasma levels of ß-lactams in mice by multiple dosing and the relationship between the therapeutic efficacy and pharmacodynamic parameters. Chemotherapy 40, 1–7.

12 . Craig, W. A. (1998). Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clinical Infectious Diseases 26 ,1 –12.[ISI][Medline]

13 . Craig, W. A. & Ebert, S. C. (1992). Continuous infusion of ß-lactam antibiotics. Antimicrobial Agents and Chemotherapy 36, 2577–83.[ISI][Medline]

14 . Visser, L. G., Arnouts, P., van Furth, R., Mattie, H. & van den Broek, P. J. (1993). Clinical pharmacokinetics of continuous intravenous administration of penicillins. Clinical Infectious Diseases 17, 491–5.[ISI][Medline]

15 . Nicolau, D. P., Nightingale, C. H., Banevicius, M. A., Fu, Q. & Quintiliani, R. (1996). Serum bactericidal activity of ceftazidime: continuous infusion versus intermittent injections. Antimicrobial Agents and Chemotherapy 40, 61–4.[Abstract]

16 . James, J. K., Palmer, S. M., Levine, D. P. & Rybak, M. J. (1996). Comparison of conventional dosing versus continuous-infusion vancomycin therapy for patients with suspected or documented Gram-positive infections. Antimicrobial Agents and Chemotherapy 40 , 696–700.[Abstract]

17 . Di Filippo, A., De Gaudio, A. R., Novelli, A., Paternostro, E., Pelagatti, C., Livi, P. et al. (1998). Continuous infusion of vancomycin in methicillin-resistant staphylococcus infection. Chemotherapy 44, 63–8.[ISI][Medline]

18 . Pryka, R. D. & Haig, G. M. (1994). Meropenem: a new carbapenem antimicrobial. Annals of Pharmacotherapy 28, 1045–54.[Abstract]

19 . Kuzemko, J. & Crawford, C. (1989). Continuous infusion of ceftazidime in cystic fibrosis. Lancet ii, 385.

20 . Craig, W. A. (1995). Antibiotic selection factors and description of a hospital-based outpatient antibiotic therapy program in the USA. European Journal of Clinical Microbiology and Infectious Diseases 14, 636–42.[ISI][Medline]

Received 9 July 1998; returned 8 October 1998; revised 26 October 1998; accepted 1 December 1998