- Email: [email protected]
tazobactam administered by continuous or intermittent infusion
International Journal of Antimicrobial Agents 33 (2009) 464–468
Contents lists available at ScienceDirect
International Journal of Antimicrobial Agents journal homepage: http://www.elsevier.com/locate/ijantimicag
Short communication
Clinical cure of ventilator-associated pneumonia treated with piperacillin/tazobactam administered by continuous or intermittent infusion Leonardo Lorente a,∗ , Alejandro Jiménez b , María M. Martín a , José Luis Iribarren a , Juan José Jiménez a , María L. Mora a a b
Intensive Care Unit, Hospital Universitario de Canarias, Ofra s/n, La Cuesta, La Laguna 38320, Tenerife, Spain Research Unit, Hospital Universitario de Canarias, Tenerife, Spain
a r t i c l e
i n f o
Article history: Received 10 July 2008 Accepted 23 October 2008 Keywords: Ventilator-associated pneumonia Piperacillin Continuous infusion Intermittent infusion Gram-negative bacilli
a b s t r a c t The standard mode of administration of piperacillin treatment is by intermittent infusion. However, continuous infusion may be advantageous as -lactam antibiotics exhibit time-dependent antibacterial activity. In previous studies, we found a higher rate of clinical cure of ventilator-associated pneumonia (VAP) by continuous infusion rather than intermittent infusion of meropenem and ceftazidime. Therefore, the objective of this historical cohort study was to establish the clinical efficacy of piperacillin/tazobactam (PIP/TAZ) administered by continuous and intermittent infusion in the treatment of VAP in patients without renal failure. Logistic regression analysis showed a higher probability of clinical cure of VAP by continuous compared with intermittent infusion when the microorganism responsible for VAP had a minimum inhibitory concentration (MIC) of 8 g/mL [8/9 (88.9%) vs. 6/15 (40.0%); odds ratio (OR) = 10.79, 95% confidence interval (CI) 1.01–588.24; P = 0.049] or 16 g/mL [7/8 (87.5%) vs. 1/6 (16.7%); OR = 22.89, 95% CI 1.19–1880.78; P = 0.03]. Thus, administration of PIP/TAZ by continuous infusion may be considered more effective than intermittent infusion for the treatment of VAP caused by Gram-negative bacteria when the MIC of the microorganism responsible for VAP is 8–16 g/mL in patients without renal failure. © 2008 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
1. Introduction The standard mode of administration of piperacillin treatment is by intermittent infusion. However, continuous infusion may be advantageous for several reasons: (i) the primary determinant of -lactam antibacterial activity is the duration of time that blood concentrations remain above the minimum inhibitory concentration (MIC) [1]; and (ii) administration of -lactams by continuous infusion provides serum concentrations exceeding the MIC more consistently than has been reported for intermittent infusion [2]. However, there are limited data on the clinical efficacy of piperacillin administered by continuous infusion [3–7]. In previous studies, we found a higher rate of clinical cure of ventilator-associated pneumonia (VAP) by continuous infusion than intermittent infusion of meropenem [8] and ceftazidime [9]. The objective of this study was to establish the clinical efficacy of piperacillin/tazobactam (PIP/TAZ) administered by continuous
∗ Corresponding author. Tel.: +34 922678000. E-mail address: [email protected] (L. Lorente).
infusion compared with intermittent infusion in the treatment of adult patients with VAP caused by Gram-negative bacilli and without renal failure.
2. Patients and methods This historical cohort study was conducted at the Medical–Surgical Intensive Care Unit (ICU) of the Hospital Universitario de Canarias, Tenerife, Spain. The clinical histories of patients with VAP caused by Gramnegative bacteria who received initial empirical antibiotic therapy with PIP/TAZ over a 5-year period (June 2002 to December 2007) were retrieved from the patient database of the ICU. All of the following criteria had to be met for a diagnosis of VAP: chest radiography indicating new or progressive infiltrate; new onset of purulent sputum or a change in sputum character; body temperature >38 ◦ C or <35.5 ◦ C; white blood cell count >10 000 cells/mm3 or <4000 cells/mm3 ; and a significant quantitative pathogen culture from respiratory secretions (tracheal aspirate >106 colony-forming units/mL) or isolation of the same microorganism in blood and respiratory secretions. The respiratory microbiological surveillance protocol in the ICU included obtaining tracheal aspirate at
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L. Lorente et al. / International Journal of Antimicrobial Agents 33 (2009) 464–468
intubation, twice weekly thereafter, at extubation and just before administration of empirical antibiotic therapy. The presence of Gram-negative bacteria was confirmed by a significant quantitative culture from respiratory secretions. Criteria for exclusion from the study were: age <18 years; pregnancy or lactation; allergy to -lactam antibiotics; VAP caused by Gram-negative bacteria resistant to PIP/TAZ; acquired immune deficiency syndrome (AIDS); neutropenia (<1000 cells/mm3 ); solid or haematological tumour; and creatinine clearance (CLCr ) <60 mL/min by the Cockcroft–Gault equation [10]. For patients included in the review, the following baseline data were recorded: sex; age; chronic obstructive pulmonary disease (COPD); severity at ICU admission [Acute Physiology and Chronic Health Evaluation (APACHE) II score]; diagnosis group; weight; CLCr ; MIC of the organism responsible for VAP; severity of organ dysfunction at the time of suspected VAP as suspected by Sepsisrelated Organ Failure Assessment [SOFA] score [11]; vasopressor use; and steroid use. A group of staff specialists reviewed each clinical history. The clinical effect of treatment was categorised as cure or failure. Cure was defined as complete resolution of all clinical signs and symptoms of pneumonia. Failure was defined as persistence or progression of any sign or symptom of pneumonia. The type of PIP/TAZ infusion (continuous or intermittent) was blinded to the specialists who reviewed the clinical history. Two groups of patients were compared: those who received PIP/TAZ by continuous infusion and those who received PIP/TAZ
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by intermittent infusion. Administration by continuous or intermittent infusion was at the discretion of the treating physician. Patients treated by intermittent infusion received PIP/TAZ 4/0.5 g infused over 30 min every 6 h. Those treated by continuous infusion received a loading dose of PIP/TAZ 4/0.5 g over 30 min, followed by 4/0.5 g infused over 360 min every 6 h. Once dissolved, PIP/TAZ remains stable for 24–120 h at room temperature [12–14]. However, in our UCI new intravenous admixtures were prepared every 6 h. Each dose of PIP/TAZ was diluted in 100 mL of 0.9% NaCl. All patients included in the study received PIP/TAZ in combination with tobramycin for 14 days. Tobramycin was administered according to the Hartford Hospital once-daily method [15]. The initial dose of tobramycin was 7 mg/24 h, infused over 60 min. The dosing interval was determined based on the Hartford Hospital nomogram. The dosing interval was based on CLCr calculated by the Cockcroft–Gault equation [10]. Tobramycin concentrations in serum were determined at 8–12 h after the first dose and weekly thereafter. Each dose of tobramycin was diluted in 100 mL of 0.9% NaCl and administered over 60 min. Statistical analysis was performed using SPSS 14.0.1 (SPSS Inc., Chicago, IL) and StatXact 5.0.3 (Cytel Inc., Cambridge, MA). Quantitative variables were reported as mean and standard deviation, and comparisons between groups were performed using the Student’s t-test. Qualitative variables were reported as frequencies and percentages. The proportion of patients receiving continuous or intermittent infusion in sex and diagnosis groups was compared
Table 1 Characteristics and outcomes of patients with ventilator-associated pneumonia (VAP) treated with piperacillin/tazobactam administered by continuous or intermittent infusion. Characteristic
Continuous infusion (n = 37)
Intermittent infusion (n = 46)
Sex [n (%)] Male Female
P-value
29 (78.4) 8 (21.6)
36 (78.3) 10 (21.7)
Age [mean (S.D.)] (years) COPD [n (%)] APACHE II score at ICU admission [mean (S.D.)]
63.2 (9.76) 5 (13.5) 16.1 (2.09)
61.8 (9.91) 5 (10.9) 16.2 (2.15)
Diagnosis [n (%)] Cardiac surgery Neurological Trauma Respiratory Cardiologic Digestive
9 (24.3) 8 (21.6) 6 (16.2) 5 (13.5) 5 (13.5) 4 (10.8)
10 (21.7) 8 (17.4) 9 (19.6) 8 (17.4) 4 (8.7) 7 (15.2)
Microorganism responsible for VAP [n (%)] Pseudomonas aeruginosa Acinetobacter baumannii Escherichia coli Klebsiella pneumoniae Enterobacter spp. Serratia marcescens Morganella morganii Haemophilus influenzae Proteus mirabilis Citrobacter spp.
11 (29.7) 2 (5.4) 5 (13.5) 2 (5.4) 4 (10.8) 4 (10.8) 3 (8.1) 4 (10.8) 1 (2.7) 1 (2.7)
13 (28.3) 2 (4.3) 8 (17.4) 2 (4.3) 5 (10.9) 5 (10.9) 3 (6.5) 4 (8.7) 2 (4.3) 2 (4.3)
CLCr [mean (S.D.)] (mL/min) SOFA score at suspicion of VAP [mean (S.D.)] Vasopressor use Steroid use
102.2 (14.54) 9.1 (2.23) 26 (70.3) 14 (37.8)
101.3 (11.80) 8.8 (2.06) 29 (63.0) 15 (32.6)
0.75 0.57 0.64 0.65
Cure of VAP [n (%)] Cure of VAP when MIC = 4 g/mL [n (%)] Cure of VAP when MIC = 8 g/mL [n (%)] Cure of VAP when MIC = 16 g/mL [n (%)]
33/37 (89.2) 18/20 (90.0) 8/9 (88.9) 7/8 (87.5)
26/46 (56.5) 19/25 (76.0) 6/15 (40.0) 1/6 (16.7)
0.001 0.20 0.02 0.02
Mortality rate [n (%)] Duration of mechanical ventilation [mean (S.D.)] (days) ICU stay [mean (S.D.)] (days)
8 (21.6) 17.97 (10.19) 21.81 (12.34)
14 (30.4) 21.65 (18.08) 25.61 (19.84)
0.46 0.61 0.62
0.99
0.53 0.75 0.69 0.94
0.82
S.D., standard deviation; COPD, chronic obstructive pulmonary disease; APACHE, Acute Physiology and Chronic Health Evaluation; ICU, Intensive Care Unit; CLCr , creatinine clearance; SOFA, Sepsis-related Organ Failure Assessment; MIC, minimum inhibitory concentration.
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L. Lorente et al. / International Journal of Antimicrobial Agents 33 (2009) 464–468
Table 2 Multiple Binary Logistic Regression Analysis using type of piperacillin/tazobactam (PIP/TAZ) infusion as the independent variable, clinical cure of ventilator-associated pneumonia as the dependent variable and controlling for minimum inhibitory concentration (MIC). Variable b
Type of PIP/TAZ infusion (continuous) Type of PIP/TAZ infusion (continuous)b when MIC = 4 g/mL Type of PIP/TAZ infusion (continuous)b when MIC = 8 g/mL Type of PIP/TAZ infusion (continuous)b when MIC = 16 g/mL
OR (95% CI)
P-valuea
7.42 (1.96–37.42) 2.78 (0.42–31.67) 10.79 (1.01–588.24) 22.89 (1.19–1880.78)
0.001 0.41 0.049 0.03
OR, odds ratio; CI, confidence interval. a P-values are exact and one-sided. b Reference category: intermittent infusion.
using the Kruskal–Wallis test for singly ordered row by column tables (two-tailed P-values). Kruskal–Wallis test for singly ordered row by column tables was used to compare patients receiving continuous or intermittent infusion in clinical cure rates (onetailed P-values) and microorganism responsible of VAP (two-tailed P-values). The proportion of patients receiving continuous or intermittent infusion was compared according to COPD, vasopressor use, steroid use and mortality using the Jonckheere–Terpstra test for doubly ordered rows by columns tables (two-tailed P-values). The duration of mechanical ventilation and ICU stay for patients receiving continuous or intermittent infusion was compared using the Wilcoxon–Mann–Whitney test (two-tailed P-values). The probability of cure as a function of the type of PIP/TAZ infusion was determined by Multiple Binary Logistic Regression Analysis, controlling for MIC, sex, age, COPD, APACHE II score at ICU admission, diagnosis, weight, CLCr , SOFA score at the time of suspected VAP, vasopressor use and steroid use. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for clinical cure rates. P-values <0.05 were considered statistically significant. 3. Results No significant differences were found between the continuous infusion (n = 37) and intermittent infusion (n = 46) groups in terms of sex, age, COPD, APACHE II score at ICU admission, diagnosis, microorganism responsible for VAP, weight, CLCr , SOFA score at the time of suspected VAP, vasopressor use, steroid use or the MIC of the responsible organism. The continuous infusion group had a significantly higher clinical cure rate than the intermittent infusion group [33/37 (89.2%) vs. 26/46 (56.5%); P = 0.001]. There were no significant differences in mortality rate and duration of mechanical ventilation or ICU stay (Table 1). Multiple Binary Logistic Regression Analysis showed a higher probability of clinical cure of VAP by continuous infusion of PIP/TAZ than by intermittent infusion when the microorganism responsible for VAP had a MIC of 8 g/mL [8/9 (88.9%) vs. 6/15 (40.0%); OR = 10.79, 95% CI 1.01–588.24; P = 0.049] or 16 g/mL [7/8 (87.5%) vs. 1/6 (16.7%); OR = 22.89, 95% CI 1.19–1880.78; P = 0.03] (Table 2). This higher probability of clinical cure of VAP by continuous infusion of PIP/TAZ was found controlling for sex, age, COPD, APACHE II score at ICU admission, diagnosis, weight, CLCr , SOFA score at the time of suspected VAP, vasopressor use and steroid use (data not shown). No antibiotic resistance to PIP/TAZ was observed during the treatment course for either infusion mode. 4. Discussion Administration of PIP/TAZ by continuous infusion as opposed to intermittent infusion may be pharmacodynamically advantageous because the percentage of time during which the PIP/TAZ plasma concentration remains above the MIC (%T > MIC) is higher by continuous infusion [3,7,16].
In a study by Rafati et al. [3], 40 septic critically ill patients were randomised to receive piperacillin by continuous infusion (2 g over 0.5 h as a loading dose, followed by 8 g daily over 24 h) or by intermittent infusion (3 g every 6 h over 0.5 h). When the MIC was 16 mg/L, the %T > MIC was higher by the continuous infusion (100%) than by intermittent infusion (62%). In a study by Bulitta et al. [7], eight adult cystic fibrosis patients received different infusion modes of piperacillin. Those receiving continuous infusion showed a higher %T > MIC when the MIC was >2 mg/L. The doses of piperacillin studied were: short infusion (as a 30-min infusion) of 3 g every 4 h (daily dose 18 g); prolonged infusion (as a 4-h infusion) of 3 g every 8 h (daily dose 9 g); and continuous infusion of 9 g/day. In the Monte Carlo simulation it was found that in the continuous infusion the %T > MIC was 100% for a MIC ≤ 16 mg/L, and in the intermittent infusion the %T > MIC was 100% for a MIC ≤ 2 mg/L, 90% for a MIC of 4 mg/L, 70% for a MIC of 8 mg/L and 55% for a MIC of 16 mg/L. However, there are limited published results on the clinical efficacy of PIP/TAZ administered by continuous or intermittent infusion [3–6]. Grant et al. [4] performed a prospective, open-label, controlled study of 98 hospitalised patients who received PIP/TAZ by continuous (12/1.5 g per day) or intermittent infusion (3/0.375 g every 6 h or 4/0.5 g every 8 h) for community- or hospital-acquired infections. The authors found a trend towards a higher clinical success rate in the continuous infusion group than in the intermittent infusion group (94% vs. 82%; P = 0.081), a trend towards a higher microbiological success rate (89% vs. 73%; P = 0.092), a lower number of days to normalisation of fever (1.2 ± 0.8 days vs. 2.4 ± 1.5 days; P = 0.012) and lower costs per patient ($399 ± 407 vs. $523 ± 526; P = 0.028) encompassing all cost directly related to antibiotic use (drug, preparation, treatment of adverse events, concomitant antibiotics). In the study by Rafati et al. [3], continuous infusion of piperacillin reduced the severity of illness more rapidly, as demonstrated by APACHE II scores, than intermittent infusion (P = 0.04). However, in other randomised controlled trials, significant differences were not found in the cure rates of intraabdominal infections using PIP/TAZ by continuous or intermittent infusion [5,6]. In the present study of VAP caused by Gram-negative bacteria, PIP/TAZ administered by continuous infusion had greater clinical efficacy than administration by intermittent infusion when the MIC of the microorganism responsible for VAP was 8 g/mL or 16 g/mL in patients without renal failure. This finding may be attributed to the fact that the continuous infusion mode achieved a higher %T > MIC when the MIC was 8–16 g/mL. In some studies using piperacillin by continuous infusion, findings included piperacillin plasma concentrations of 21–51 mg/L [3–5,17–19], and a higher fraction of time with PIP/TAZ plasma concentration above the MIC than by intermittent infusion when the MIC was 8–16 mg/L [3,7,16]. In our study, we found a higher clinical efficacy of PIP/TAZ by continuous infusion than by intermittent infusion in patients without renal failure, probably due to the use of a high daily
L. Lorente et al. / International Journal of Antimicrobial Agents 33 (2009) 464–468
dosage of PIP/TAZ of 16/2 g. In a study by Boselli et al. [20], 40 patients with microbiologically documented VAP were randomised to receive PIP/TAZ daily continuous infusions of 12/1.5 g or 16/2 g and the serum and alveolar PIP/TAZ concentrations were determined. In patients with no/mild renal failure, the continuous daily dose of PIP/TAZ 12/1.5 g achieved a median serum piperacillin concentration of 25.3 mg/L (range 23.1–32.6 mg/L) and a median alveolar piperacillin concentration of 12.7 mg/L (range 6.7–18.0 mg/L); and the continuous daily dose of PIP/TAZ 16/2 g reached a median serum piperacillin concentration of 38.9 mg/L (range 32.9–59.6 mg/L) and a median alveolar piperacillin concentration of 19.1 mg/L (range 14.0–21.5 mg/L). In patients with moderate/advanced renal failure, the continuous daily dose of PIP/TAZ 12/1.5 g reached a median serum piperacillin concentration of 102.4 mg/L (range 97.4–112.6 mg/L) and a median alveolar piperacillin concentration of 44.1 mg/L (range 33.4–48.3 mg/L); and the continuous daily dose of PIP/TAZ 16/2 g achieved a median serum piperacillin concentration of 135.3 mg/L (range 119.5–146.2 mg/L) and a median alveolar piperacillin concentration of 54.9 mg/L (range 45.2–110.3 mg/L). Thus, the alveolar percentage penetration was 40–50% for piperacillin and 65–85% for tazobactam. The authors suggested that a target piperacillin serum concentration of at least 35–40 mg/L is probably required to provide alveolar concentrations exceeding the susceptibility breakpoint for Gram-negative bacteria (16 mg/L) during VAP. In patients with no/mild renal failure, a continuous daily dose of PIP/TAZ 16/2 g allows this target concentration to be reached, which might be not achieved with 12/1.5 g per day, and the authors suggested that this is probably due to the fact that the volume distribution of antimicrobial agents varies with illness severity and is therefore wider in critically ill septic patients. In patients with moderate/advanced renal failure, both dosages (16/2 g and 12/1.5 g) achieve serum concentrations far above the 35–40 mg/L threshold. The findings of the present study were similar to those of two retrospective studies published by our research group comparing administration of other -lactams by continuous and intermittent infusion [8,9]. We found a greater clinical cure rate of VAP caused by Gram-negative bacteria treated with meropenem administered by continuous infusion (loading dose of 1 g over 30 min followed by 1 g every 6 h infused over 360 min) than by intermittent infusion (1 g over 30 min every 6 h) [38/42 (90.47%) vs. 28/47 (59.57%); OR = 6.44, 95% CI 1.97–21.05; P < 0.001] [8]. Moreover, we found a higher clinical cure rate of VAP caused by Gram-negative bacteria in patients receiving ceftazidime by continuous infusion (loading dose of 1 g over 30 min, followed by 2 g infused over 720 min every 12 h) than by intermittent infusion (2 g infused over 30 min every 12 h) [50/56 (89.3%) vs. 34/65 (52.3%); OR = 12.2, 95% CI 3.47–43.21; P < 0.001] [9]. This study has three important limitations. First, the two modes of administration were not compared using a randomised design. Second, PIP/TAZ serum concentrations were not determined. Third, patients with renal failure were excluded, so the conclusions should be restricted to patients without renal failure. Despite these limitations, the results of our study may contribute to an interest in the use of -lactam antibiotics by continuous infusion.
5. Conclusion In this retrospective study of patients without renal failure, administration of PIP/TAZ by continuous infusion showed a higher rate of clinical cure than intermittent infusion for the treatment of VAP caused by Gram-negative bacteria when the MIC of the causative microorganism was 8–16 g/mL. Thus, administration of PIP/TAZ by continuous infusion may be con-
467
sidered more effective than intermittent infusion. However, before changing the standard mode of administering -lactams, randomised clinical trials are required to confirm these findings and to establish the potential benefit of administering -lactams by continuous infusion according to the MIC of the microorganism responsible, the ratio of tissue and serum concentration, the volume of distribution of the antimicrobial agent and the stability of the antimicrobial agent once dissolved. Funding: Hospital Universitario de Canarias, Tenerife, Spain. Competing interests: None declared. Ethical approval: Institutional Review Board of the Hospital Universitario de Canarias, Tenerife, Spain.
References [1] Turnidge JD. The pharmacodynamics of beta-lactams. Clin Infect Dis 1998;27:10–22. [2] Lipman J, Gomersall CD, Gin T, Joynt GM, Young RJ. Continuous infusion ceftazidime in intensive care: a randomized controlled trial. J Antimicrob Chemother 1999;43:309–11. [3] Rafati MR, Rouini MR, Mojtahedzadeh M, Najafi A, Tavakoli H, Gholami K, et al. Clinical efficacy of continuous infusion of piperacillin compared with intermittent dosing in septic critically ill patients. Int J Antimicrob Agents 2006;28:122–7. [4] Grant EM, Kuti JL, Nicolau DP, Nigthtingale Ch, Quintiliani R. Clinical efficacy and pharmacoeconomics of a continuous infusion piperacillin–tazobactam program in a large community teaching hospital. Pharmacotherapy 2002;22:471–83. [5] Li C, Kuti JL, Nightingale CH, Mansfield DL, Dana A, Nicolau DP. Population pharmacokinetics and pharmacodynamics of piperacillin/tazobactam in patients with complicated intra-abdominal infection. J Antimicrob Chemother 2005;56:388–95. [6] Lau WK, Mercer D, Itani M, Nicolau DP, Kuti JL, Mansfield D, et al. Randomized, open-label, comparative study of piperacillin–tazobactam administered by continuous infusion versus intermittent infusion for treatment of hospitalized patients with complicated intra-abdominal infection. Antimicrob Agents Chemother 2006;50:3556–61. [7] Bulitta JB, Duffull SB, Kinzig-Schippers M, Holzgrabe U, Stephan U, Drusano GL, et al. Systematic comparison of the population pharmacokinetics and pharmacodynamics of piperacillin in cystic fibrosis patients and healthy volunteers. Antimicrob Agents Chemother 2007;51:2497–507. [8] Lorente L, Lorenzo L, Martín MM, Jiménez A, Mora ML. Meropenem by continuous versus intermittent infusion in ventilator-associated pneumonia due to Gram-negative bacilli. Ann Pharmacother 2006;40:219–23. [9] Lorente L, Jiménez A, Palmero S, Jimenez JJ, Iribarren JL, Santana M, et al. Comparison of clinical cure rates in adults with ventilator-associated pneumonia treated with intravenous ceftazidime administered by continuous or intermittent infusion: a retrospective, nonrandomized, open-label, historical chart review. Clin Ther 2007;29:2433–9. [10] Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31–41. [11] Vincent JL, Moreno R, Takala J, Willatts S, De Mendonc¸a A, Bruining H, et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-related Problems of the European Society of Intensive Care Medicine. Intensive Care Med 1996;22:707–10. [12] Mathew M, Das Gupta V, Bethea C. Stability of piperacillin sodium in the presence of tazobactam sodium in 5% dextrose and normal saline injections. J Clin Pharm Ther 1994;19:397–9. [13] Viaene E, Chanteux H, Servais H, Mingeot-Leclercq MP, Tulkens PM. Comparative stability studies of antipseudomonal -lactams for potential administration through portable elastomeric pumps (home therapy for cystic fibrosis patients) and motor-operated syringes (intensive care units). Antimicrob Agents Chemother 2002;46:2327–32. [14] Zhang Y, Trissel LA. Stability of piperacillin and ticarcillin in AutoDose infusion system bags. Ann Pharmacother 2001;35:1360–3. [15] Nicolau DP, Freeman CD, Belliveau PP, Nightingale CH, Ross JW, Quintiliani R. Experience with a once-daily aminoglycoside program administered to 2184 adult patients. Antimicrob Agents Chemother 1995;39:650–5. [16] Kim A, Sutherland CA, Kuti JL, Nicolau DP. Optimal dosing of piperacillin–tazobactam for the treatment of Pseudomonas aeruginosa infections: prolonged or continuous infusion? Pharmacotherapy 2007;27: 1490–7. [17] Burgess DS, Waldrep T. Pharmacokinetics and pharmacodynamics of piperacillin/tazobactam when administered by continuous infusion and intermittent dosing. Clin Ther 2002;24:1090–104. [18] Buck C, Bertram N, Ackermann T, Sauerbruch T, Derendorf H, Paar WD. Pharmacokinetics of piperacillin–tazobactam: intermittent dosing versus continuous infusion. Int J Antimicrob Agents 2005;25:62–7.
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Contents lists available at ScienceDirect
International Journal of Antimicrobial Agents journal homepage: http://www.elsevier.com/locate/ijantimicag
Short communication
Clinical cure of ventilator-associated pneumonia treated with piperacillin/tazobactam administered by continuous or intermittent infusion Leonardo Lorente a,∗ , Alejandro Jiménez b , María M. Martín a , José Luis Iribarren a , Juan José Jiménez a , María L. Mora a a b
Intensive Care Unit, Hospital Universitario de Canarias, Ofra s/n, La Cuesta, La Laguna 38320, Tenerife, Spain Research Unit, Hospital Universitario de Canarias, Tenerife, Spain
a r t i c l e
i n f o
Article history: Received 10 July 2008 Accepted 23 October 2008 Keywords: Ventilator-associated pneumonia Piperacillin Continuous infusion Intermittent infusion Gram-negative bacilli
a b s t r a c t The standard mode of administration of piperacillin treatment is by intermittent infusion. However, continuous infusion may be advantageous as -lactam antibiotics exhibit time-dependent antibacterial activity. In previous studies, we found a higher rate of clinical cure of ventilator-associated pneumonia (VAP) by continuous infusion rather than intermittent infusion of meropenem and ceftazidime. Therefore, the objective of this historical cohort study was to establish the clinical efficacy of piperacillin/tazobactam (PIP/TAZ) administered by continuous and intermittent infusion in the treatment of VAP in patients without renal failure. Logistic regression analysis showed a higher probability of clinical cure of VAP by continuous compared with intermittent infusion when the microorganism responsible for VAP had a minimum inhibitory concentration (MIC) of 8 g/mL [8/9 (88.9%) vs. 6/15 (40.0%); odds ratio (OR) = 10.79, 95% confidence interval (CI) 1.01–588.24; P = 0.049] or 16 g/mL [7/8 (87.5%) vs. 1/6 (16.7%); OR = 22.89, 95% CI 1.19–1880.78; P = 0.03]. Thus, administration of PIP/TAZ by continuous infusion may be considered more effective than intermittent infusion for the treatment of VAP caused by Gram-negative bacteria when the MIC of the microorganism responsible for VAP is 8–16 g/mL in patients without renal failure. © 2008 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
1. Introduction The standard mode of administration of piperacillin treatment is by intermittent infusion. However, continuous infusion may be advantageous for several reasons: (i) the primary determinant of -lactam antibacterial activity is the duration of time that blood concentrations remain above the minimum inhibitory concentration (MIC) [1]; and (ii) administration of -lactams by continuous infusion provides serum concentrations exceeding the MIC more consistently than has been reported for intermittent infusion [2]. However, there are limited data on the clinical efficacy of piperacillin administered by continuous infusion [3–7]. In previous studies, we found a higher rate of clinical cure of ventilator-associated pneumonia (VAP) by continuous infusion than intermittent infusion of meropenem [8] and ceftazidime [9]. The objective of this study was to establish the clinical efficacy of piperacillin/tazobactam (PIP/TAZ) administered by continuous
∗ Corresponding author. Tel.: +34 922678000. E-mail address: [email protected] (L. Lorente).
infusion compared with intermittent infusion in the treatment of adult patients with VAP caused by Gram-negative bacilli and without renal failure.
2. Patients and methods This historical cohort study was conducted at the Medical–Surgical Intensive Care Unit (ICU) of the Hospital Universitario de Canarias, Tenerife, Spain. The clinical histories of patients with VAP caused by Gramnegative bacteria who received initial empirical antibiotic therapy with PIP/TAZ over a 5-year period (June 2002 to December 2007) were retrieved from the patient database of the ICU. All of the following criteria had to be met for a diagnosis of VAP: chest radiography indicating new or progressive infiltrate; new onset of purulent sputum or a change in sputum character; body temperature >38 ◦ C or <35.5 ◦ C; white blood cell count >10 000 cells/mm3 or <4000 cells/mm3 ; and a significant quantitative pathogen culture from respiratory secretions (tracheal aspirate >106 colony-forming units/mL) or isolation of the same microorganism in blood and respiratory secretions. The respiratory microbiological surveillance protocol in the ICU included obtaining tracheal aspirate at
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L. Lorente et al. / International Journal of Antimicrobial Agents 33 (2009) 464–468
intubation, twice weekly thereafter, at extubation and just before administration of empirical antibiotic therapy. The presence of Gram-negative bacteria was confirmed by a significant quantitative culture from respiratory secretions. Criteria for exclusion from the study were: age <18 years; pregnancy or lactation; allergy to -lactam antibiotics; VAP caused by Gram-negative bacteria resistant to PIP/TAZ; acquired immune deficiency syndrome (AIDS); neutropenia (<1000 cells/mm3 ); solid or haematological tumour; and creatinine clearance (CLCr ) <60 mL/min by the Cockcroft–Gault equation [10]. For patients included in the review, the following baseline data were recorded: sex; age; chronic obstructive pulmonary disease (COPD); severity at ICU admission [Acute Physiology and Chronic Health Evaluation (APACHE) II score]; diagnosis group; weight; CLCr ; MIC of the organism responsible for VAP; severity of organ dysfunction at the time of suspected VAP as suspected by Sepsisrelated Organ Failure Assessment [SOFA] score [11]; vasopressor use; and steroid use. A group of staff specialists reviewed each clinical history. The clinical effect of treatment was categorised as cure or failure. Cure was defined as complete resolution of all clinical signs and symptoms of pneumonia. Failure was defined as persistence or progression of any sign or symptom of pneumonia. The type of PIP/TAZ infusion (continuous or intermittent) was blinded to the specialists who reviewed the clinical history. Two groups of patients were compared: those who received PIP/TAZ by continuous infusion and those who received PIP/TAZ
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by intermittent infusion. Administration by continuous or intermittent infusion was at the discretion of the treating physician. Patients treated by intermittent infusion received PIP/TAZ 4/0.5 g infused over 30 min every 6 h. Those treated by continuous infusion received a loading dose of PIP/TAZ 4/0.5 g over 30 min, followed by 4/0.5 g infused over 360 min every 6 h. Once dissolved, PIP/TAZ remains stable for 24–120 h at room temperature [12–14]. However, in our UCI new intravenous admixtures were prepared every 6 h. Each dose of PIP/TAZ was diluted in 100 mL of 0.9% NaCl. All patients included in the study received PIP/TAZ in combination with tobramycin for 14 days. Tobramycin was administered according to the Hartford Hospital once-daily method [15]. The initial dose of tobramycin was 7 mg/24 h, infused over 60 min. The dosing interval was determined based on the Hartford Hospital nomogram. The dosing interval was based on CLCr calculated by the Cockcroft–Gault equation [10]. Tobramycin concentrations in serum were determined at 8–12 h after the first dose and weekly thereafter. Each dose of tobramycin was diluted in 100 mL of 0.9% NaCl and administered over 60 min. Statistical analysis was performed using SPSS 14.0.1 (SPSS Inc., Chicago, IL) and StatXact 5.0.3 (Cytel Inc., Cambridge, MA). Quantitative variables were reported as mean and standard deviation, and comparisons between groups were performed using the Student’s t-test. Qualitative variables were reported as frequencies and percentages. The proportion of patients receiving continuous or intermittent infusion in sex and diagnosis groups was compared
Table 1 Characteristics and outcomes of patients with ventilator-associated pneumonia (VAP) treated with piperacillin/tazobactam administered by continuous or intermittent infusion. Characteristic
Continuous infusion (n = 37)
Intermittent infusion (n = 46)
Sex [n (%)] Male Female
P-value
29 (78.4) 8 (21.6)
36 (78.3) 10 (21.7)
Age [mean (S.D.)] (years) COPD [n (%)] APACHE II score at ICU admission [mean (S.D.)]
63.2 (9.76) 5 (13.5) 16.1 (2.09)
61.8 (9.91) 5 (10.9) 16.2 (2.15)
Diagnosis [n (%)] Cardiac surgery Neurological Trauma Respiratory Cardiologic Digestive
9 (24.3) 8 (21.6) 6 (16.2) 5 (13.5) 5 (13.5) 4 (10.8)
10 (21.7) 8 (17.4) 9 (19.6) 8 (17.4) 4 (8.7) 7 (15.2)
Microorganism responsible for VAP [n (%)] Pseudomonas aeruginosa Acinetobacter baumannii Escherichia coli Klebsiella pneumoniae Enterobacter spp. Serratia marcescens Morganella morganii Haemophilus influenzae Proteus mirabilis Citrobacter spp.
11 (29.7) 2 (5.4) 5 (13.5) 2 (5.4) 4 (10.8) 4 (10.8) 3 (8.1) 4 (10.8) 1 (2.7) 1 (2.7)
13 (28.3) 2 (4.3) 8 (17.4) 2 (4.3) 5 (10.9) 5 (10.9) 3 (6.5) 4 (8.7) 2 (4.3) 2 (4.3)
CLCr [mean (S.D.)] (mL/min) SOFA score at suspicion of VAP [mean (S.D.)] Vasopressor use Steroid use
102.2 (14.54) 9.1 (2.23) 26 (70.3) 14 (37.8)
101.3 (11.80) 8.8 (2.06) 29 (63.0) 15 (32.6)
0.75 0.57 0.64 0.65
Cure of VAP [n (%)] Cure of VAP when MIC = 4 g/mL [n (%)] Cure of VAP when MIC = 8 g/mL [n (%)] Cure of VAP when MIC = 16 g/mL [n (%)]
33/37 (89.2) 18/20 (90.0) 8/9 (88.9) 7/8 (87.5)
26/46 (56.5) 19/25 (76.0) 6/15 (40.0) 1/6 (16.7)
0.001 0.20 0.02 0.02
Mortality rate [n (%)] Duration of mechanical ventilation [mean (S.D.)] (days) ICU stay [mean (S.D.)] (days)
8 (21.6) 17.97 (10.19) 21.81 (12.34)
14 (30.4) 21.65 (18.08) 25.61 (19.84)
0.46 0.61 0.62
0.99
0.53 0.75 0.69 0.94
0.82
S.D., standard deviation; COPD, chronic obstructive pulmonary disease; APACHE, Acute Physiology and Chronic Health Evaluation; ICU, Intensive Care Unit; CLCr , creatinine clearance; SOFA, Sepsis-related Organ Failure Assessment; MIC, minimum inhibitory concentration.
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Table 2 Multiple Binary Logistic Regression Analysis using type of piperacillin/tazobactam (PIP/TAZ) infusion as the independent variable, clinical cure of ventilator-associated pneumonia as the dependent variable and controlling for minimum inhibitory concentration (MIC). Variable b
Type of PIP/TAZ infusion (continuous) Type of PIP/TAZ infusion (continuous)b when MIC = 4 g/mL Type of PIP/TAZ infusion (continuous)b when MIC = 8 g/mL Type of PIP/TAZ infusion (continuous)b when MIC = 16 g/mL
OR (95% CI)
P-valuea
7.42 (1.96–37.42) 2.78 (0.42–31.67) 10.79 (1.01–588.24) 22.89 (1.19–1880.78)
0.001 0.41 0.049 0.03
OR, odds ratio; CI, confidence interval. a P-values are exact and one-sided. b Reference category: intermittent infusion.
using the Kruskal–Wallis test for singly ordered row by column tables (two-tailed P-values). Kruskal–Wallis test for singly ordered row by column tables was used to compare patients receiving continuous or intermittent infusion in clinical cure rates (onetailed P-values) and microorganism responsible of VAP (two-tailed P-values). The proportion of patients receiving continuous or intermittent infusion was compared according to COPD, vasopressor use, steroid use and mortality using the Jonckheere–Terpstra test for doubly ordered rows by columns tables (two-tailed P-values). The duration of mechanical ventilation and ICU stay for patients receiving continuous or intermittent infusion was compared using the Wilcoxon–Mann–Whitney test (two-tailed P-values). The probability of cure as a function of the type of PIP/TAZ infusion was determined by Multiple Binary Logistic Regression Analysis, controlling for MIC, sex, age, COPD, APACHE II score at ICU admission, diagnosis, weight, CLCr , SOFA score at the time of suspected VAP, vasopressor use and steroid use. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for clinical cure rates. P-values <0.05 were considered statistically significant. 3. Results No significant differences were found between the continuous infusion (n = 37) and intermittent infusion (n = 46) groups in terms of sex, age, COPD, APACHE II score at ICU admission, diagnosis, microorganism responsible for VAP, weight, CLCr , SOFA score at the time of suspected VAP, vasopressor use, steroid use or the MIC of the responsible organism. The continuous infusion group had a significantly higher clinical cure rate than the intermittent infusion group [33/37 (89.2%) vs. 26/46 (56.5%); P = 0.001]. There were no significant differences in mortality rate and duration of mechanical ventilation or ICU stay (Table 1). Multiple Binary Logistic Regression Analysis showed a higher probability of clinical cure of VAP by continuous infusion of PIP/TAZ than by intermittent infusion when the microorganism responsible for VAP had a MIC of 8 g/mL [8/9 (88.9%) vs. 6/15 (40.0%); OR = 10.79, 95% CI 1.01–588.24; P = 0.049] or 16 g/mL [7/8 (87.5%) vs. 1/6 (16.7%); OR = 22.89, 95% CI 1.19–1880.78; P = 0.03] (Table 2). This higher probability of clinical cure of VAP by continuous infusion of PIP/TAZ was found controlling for sex, age, COPD, APACHE II score at ICU admission, diagnosis, weight, CLCr , SOFA score at the time of suspected VAP, vasopressor use and steroid use (data not shown). No antibiotic resistance to PIP/TAZ was observed during the treatment course for either infusion mode. 4. Discussion Administration of PIP/TAZ by continuous infusion as opposed to intermittent infusion may be pharmacodynamically advantageous because the percentage of time during which the PIP/TAZ plasma concentration remains above the MIC (%T > MIC) is higher by continuous infusion [3,7,16].
In a study by Rafati et al. [3], 40 septic critically ill patients were randomised to receive piperacillin by continuous infusion (2 g over 0.5 h as a loading dose, followed by 8 g daily over 24 h) or by intermittent infusion (3 g every 6 h over 0.5 h). When the MIC was 16 mg/L, the %T > MIC was higher by the continuous infusion (100%) than by intermittent infusion (62%). In a study by Bulitta et al. [7], eight adult cystic fibrosis patients received different infusion modes of piperacillin. Those receiving continuous infusion showed a higher %T > MIC when the MIC was >2 mg/L. The doses of piperacillin studied were: short infusion (as a 30-min infusion) of 3 g every 4 h (daily dose 18 g); prolonged infusion (as a 4-h infusion) of 3 g every 8 h (daily dose 9 g); and continuous infusion of 9 g/day. In the Monte Carlo simulation it was found that in the continuous infusion the %T > MIC was 100% for a MIC ≤ 16 mg/L, and in the intermittent infusion the %T > MIC was 100% for a MIC ≤ 2 mg/L, 90% for a MIC of 4 mg/L, 70% for a MIC of 8 mg/L and 55% for a MIC of 16 mg/L. However, there are limited published results on the clinical efficacy of PIP/TAZ administered by continuous or intermittent infusion [3–6]. Grant et al. [4] performed a prospective, open-label, controlled study of 98 hospitalised patients who received PIP/TAZ by continuous (12/1.5 g per day) or intermittent infusion (3/0.375 g every 6 h or 4/0.5 g every 8 h) for community- or hospital-acquired infections. The authors found a trend towards a higher clinical success rate in the continuous infusion group than in the intermittent infusion group (94% vs. 82%; P = 0.081), a trend towards a higher microbiological success rate (89% vs. 73%; P = 0.092), a lower number of days to normalisation of fever (1.2 ± 0.8 days vs. 2.4 ± 1.5 days; P = 0.012) and lower costs per patient ($399 ± 407 vs. $523 ± 526; P = 0.028) encompassing all cost directly related to antibiotic use (drug, preparation, treatment of adverse events, concomitant antibiotics). In the study by Rafati et al. [3], continuous infusion of piperacillin reduced the severity of illness more rapidly, as demonstrated by APACHE II scores, than intermittent infusion (P = 0.04). However, in other randomised controlled trials, significant differences were not found in the cure rates of intraabdominal infections using PIP/TAZ by continuous or intermittent infusion [5,6]. In the present study of VAP caused by Gram-negative bacteria, PIP/TAZ administered by continuous infusion had greater clinical efficacy than administration by intermittent infusion when the MIC of the microorganism responsible for VAP was 8 g/mL or 16 g/mL in patients without renal failure. This finding may be attributed to the fact that the continuous infusion mode achieved a higher %T > MIC when the MIC was 8–16 g/mL. In some studies using piperacillin by continuous infusion, findings included piperacillin plasma concentrations of 21–51 mg/L [3–5,17–19], and a higher fraction of time with PIP/TAZ plasma concentration above the MIC than by intermittent infusion when the MIC was 8–16 mg/L [3,7,16]. In our study, we found a higher clinical efficacy of PIP/TAZ by continuous infusion than by intermittent infusion in patients without renal failure, probably due to the use of a high daily
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dosage of PIP/TAZ of 16/2 g. In a study by Boselli et al. [20], 40 patients with microbiologically documented VAP were randomised to receive PIP/TAZ daily continuous infusions of 12/1.5 g or 16/2 g and the serum and alveolar PIP/TAZ concentrations were determined. In patients with no/mild renal failure, the continuous daily dose of PIP/TAZ 12/1.5 g achieved a median serum piperacillin concentration of 25.3 mg/L (range 23.1–32.6 mg/L) and a median alveolar piperacillin concentration of 12.7 mg/L (range 6.7–18.0 mg/L); and the continuous daily dose of PIP/TAZ 16/2 g reached a median serum piperacillin concentration of 38.9 mg/L (range 32.9–59.6 mg/L) and a median alveolar piperacillin concentration of 19.1 mg/L (range 14.0–21.5 mg/L). In patients with moderate/advanced renal failure, the continuous daily dose of PIP/TAZ 12/1.5 g reached a median serum piperacillin concentration of 102.4 mg/L (range 97.4–112.6 mg/L) and a median alveolar piperacillin concentration of 44.1 mg/L (range 33.4–48.3 mg/L); and the continuous daily dose of PIP/TAZ 16/2 g achieved a median serum piperacillin concentration of 135.3 mg/L (range 119.5–146.2 mg/L) and a median alveolar piperacillin concentration of 54.9 mg/L (range 45.2–110.3 mg/L). Thus, the alveolar percentage penetration was 40–50% for piperacillin and 65–85% for tazobactam. The authors suggested that a target piperacillin serum concentration of at least 35–40 mg/L is probably required to provide alveolar concentrations exceeding the susceptibility breakpoint for Gram-negative bacteria (16 mg/L) during VAP. In patients with no/mild renal failure, a continuous daily dose of PIP/TAZ 16/2 g allows this target concentration to be reached, which might be not achieved with 12/1.5 g per day, and the authors suggested that this is probably due to the fact that the volume distribution of antimicrobial agents varies with illness severity and is therefore wider in critically ill septic patients. In patients with moderate/advanced renal failure, both dosages (16/2 g and 12/1.5 g) achieve serum concentrations far above the 35–40 mg/L threshold. The findings of the present study were similar to those of two retrospective studies published by our research group comparing administration of other -lactams by continuous and intermittent infusion [8,9]. We found a greater clinical cure rate of VAP caused by Gram-negative bacteria treated with meropenem administered by continuous infusion (loading dose of 1 g over 30 min followed by 1 g every 6 h infused over 360 min) than by intermittent infusion (1 g over 30 min every 6 h) [38/42 (90.47%) vs. 28/47 (59.57%); OR = 6.44, 95% CI 1.97–21.05; P < 0.001] [8]. Moreover, we found a higher clinical cure rate of VAP caused by Gram-negative bacteria in patients receiving ceftazidime by continuous infusion (loading dose of 1 g over 30 min, followed by 2 g infused over 720 min every 12 h) than by intermittent infusion (2 g infused over 30 min every 12 h) [50/56 (89.3%) vs. 34/65 (52.3%); OR = 12.2, 95% CI 3.47–43.21; P < 0.001] [9]. This study has three important limitations. First, the two modes of administration were not compared using a randomised design. Second, PIP/TAZ serum concentrations were not determined. Third, patients with renal failure were excluded, so the conclusions should be restricted to patients without renal failure. Despite these limitations, the results of our study may contribute to an interest in the use of -lactam antibiotics by continuous infusion.
5. Conclusion In this retrospective study of patients without renal failure, administration of PIP/TAZ by continuous infusion showed a higher rate of clinical cure than intermittent infusion for the treatment of VAP caused by Gram-negative bacteria when the MIC of the causative microorganism was 8–16 g/mL. Thus, administration of PIP/TAZ by continuous infusion may be con-
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sidered more effective than intermittent infusion. However, before changing the standard mode of administering -lactams, randomised clinical trials are required to confirm these findings and to establish the potential benefit of administering -lactams by continuous infusion according to the MIC of the microorganism responsible, the ratio of tissue and serum concentration, the volume of distribution of the antimicrobial agent and the stability of the antimicrobial agent once dissolved. Funding: Hospital Universitario de Canarias, Tenerife, Spain. Competing interests: None declared. Ethical approval: Institutional Review Board of the Hospital Universitario de Canarias, Tenerife, Spain.
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