Pharmacodynamics of meropenem in critically ill patients with febrile ...

International Journal of Antimicrobial Agents 38 (2011) 231–236

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Pharmacodynamics of meropenem in critically ill patients with febrile neutropenia and bacteraemia Sutep Jaruratanasirikul a,∗ , Thanya Limapichat a , Monchana Jullangkoon a , Nanchanit Aeinlang a , Natnicha Ingviya b , Wibul Wongpoowarak c a

Department of Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla 90110, Thailand Department of Pathology, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla 90110, Thailand c Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat Yai, Songkhla 90110, Thailand b

a r t i c l e

i n f o

Article history: Received 30 September 2010 Accepted 27 April 2011 Keywords: Carbapenem Pharmacokinetic/pharmacodynamic ␤-Lactam

a b s t r a c t The bactericidal activity of ␤-lactams is determined by the time that concentrations in tissue and serum are above the minimum inhibitory concentration (T > MIC) for the pathogen. The aim of this study was to compare the probability of target attainment (PTA) and the cumulative fraction of response (CFR) for meropenem between administration by bolus injection and a 3-h infusion. The study was a randomised, three-way, cross-over design in eight febrile neutropenic patients with bacteraemia. Each subject received meropenem in three regimens consecutively: (i) a bolus injection of 1 g every 8 h (q8h) for 24 h; (ii) a 3-h infusion of 1 g q8h for 24 h; and (iii) a 3-h infusion of 2 g q8h for 24 h. For pathogens with an MIC of 4 ␮g/mL, the PTA of achieving 40% T > MIC following administration of meropenem by a bolus injection of 1 g q8h, a 3-h infusion of 1 g q8h and a 3-h infusion of 2 g q8h was 75.7%, 99.24% and 99.96%, respectively. Only the 3-h infusion of 2 g q8h achieved a PTA >99% for 40% T > MIC for a MIC of 8 ␮g/mL. By referral to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) MIC distributions, the three regimens of meropenem were predicted to achieve a CFR ≥ 90% against Escherichia coli and Klebsiella spp. In conclusion, a 3-h infusion of 2 g of meropenem q8h resulted in the highest PTA rates. The three regimens of meropenem had high probabilities of achieving optimal impact against E. coli and Klebsiella spp. © 2011 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

1. Introduction Pharmacodynamic (PD) studies suggest that the time course of antimicrobial activity can vary for different classes of antibiotics [1–3]. For ␤-lactam antibiotics, the antimicrobial activity of these agents exhibits primarily time-dependent killing. Therefore, the time that concentrations in tissue and serum are above the minimum inhibitory concentration (T > MIC) is the pharmacokinetic (PK)/PD index that best correlates with efficacy [2,3], and the optimum method to maintain such serum drug concentrations would be to administer the agent by continuous infusion [4–6]. Meropenem, a carbapenem antibacterial agent with a broad spectrum of activity against several pathogens including Gram-negative bacilli, exhibits primarily time-dependent killing [7]. In common with other ␤-lactams, the main PK/PD index that correlates with its therapeutic efficacy is T > MIC, and meropenem can achieve fairly rapid killing for a ␤-lactam. Therefore, administration by continuous infusion is the preferred route to maximise this parameter.

∗ Corresponding author. Tel.: +66 74 451 452; fax: +66 74 429 385. E-mail address: [email protected] (S. Jaruratanasirikul).

However, in tropical countries, the stability of meropenem is an important consideration when continuous infusion is to be used. A previous study showed that meropenem remained 90% stable for MIC than a bolus injection [12,13]. Other studies have found that a 2-h infusion of imipenem and a 4-h infusion of doripenem provide greater values for T > MIC than a bolus injection [14–16]. We have therefore suggested that administration by prolonging intermittent infusion may offer the opportunity to increase the T > MIC within the limitations of stability at room temperature. An earlier study has demonstrated that free drug is available for antimicrobial activity; however, meropenem has low ( MIC both for free and total drug required for bactericidal effect is not much different.

0924-8579/$ – see front matter © 2011 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. doi:10.1016/j.ijantimicag.2011.04.019

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S. Jaruratanasirikul et al. / International Journal of Antimicrobial Agents 38 (2011) 231–236

In studies performed on febrile neutropenic patients, PK changes were found for several antimicrobial agents, including meropenem. The volume of distribution of meropenem was significantly greater in this patient population than in healthy subjects. Non-renal clearance in febrile neutropenic patients was similar to that found in young healthy subjects, but was significantly higher than in elderly healthy subjects. Total and renal clearances of patients were not significantly different compared with healthy subjects [18,19]. Therefore, the aims of this study were to assess the pharmacokinetics and pharmacodynamics of meropenem in febrile neutropenic patients with bacteraemia and to compare the probability of target attainment (PTA) and cumulative fraction of response (CFR) for meropenem in three regimens: (i) a bolus injection of 1 g; (ii) a 3-h infusion of 1 g; and (iii) a 3-h infusion of 2 g. 2. Methods 2.1. Subjects This study was conducted in febrile neutropenic patients with bacteraemia. Patients were eligible for the study if they met the following criteria: (i) age >18 years; (ii) body temperature ≥38.3 ◦ C; (iii) neutrophil count MIC attainment represents the whole spectrum of microbial behaviour. 2.9. Minimum inhibitory concentration distributions and cumulative fraction of response MIC distributions were derived from meropenem MIC50 and MIC90 (MICs for 50% and 90% of the organisms, respectively) and MIC range obtained from the European Committee on Antimicrobial Susceptibility Testing (EUCAST; updated 30 August 2010) for Escherichia coli, Klebsiella spp., Pseudomonas aeruginosa and Acinetobacter spp. isolates. MIC distributions were estimated from 8005 strains of E. coli, 729 strains of Klebsiella spp., 57 470 strains of P. aeruginosa and 9403 strains of Acinetobacter spp. The CFRs were determined for each regimen against each population of E. coli, Klebsiella spp., P. aeruginosa and Acinetobacter spp. The optimal CFR was defined as ≥90%. 3. Results Eight patients were enrolled in the study (five males and three females), with a mean age of 43.37 ± 20.54 years (range 18–76 years) and a mean body weight of 50.62 ± 17.96 kg (range 25–82 kg). The characteristics of all patients and the MICs of meropenem for the isolated pathogens are shown in Table 2. PK parameters of meropenem for the three regimens are presented in Table 1. The PK parameters from this study were not significantly different from the PK parameters determined by PhoenixTM WinNonlin® 6.1 (data not shown). All of the tested covariates had no identifiable influence on the PK parameters. The PTAs for the three meropenem regimens achieving 40% T > MIC, 60% T > MIC, 80% T > MIC and 100% T > MIC at specific MICs are shown in Table 3 and Fig. 2. Assessment of CFR for patients who achieved a target of 40% T > MIC for the three meropenem regimens against E. coli, Klebsiella spp., P. aeruginosa and Acinetobacter spp. are shown in Table 4. For pathogens with a MIC of 4 ␮g/mL, the PTA of achieving 40% T > MIC following administration of meropenem by a bolus injection of 1 g q8h, a 3-h infusion of 1 g q8h and a 3-h infusion of 2 g q8h were 75.7%, 99.24% and 99.96%, respectively. For pathogens with a MIC of 2 ␮g/mL, the PTA of achieving 80% T > MIC following administration of meropenem by a bolus injection of 1 g q8h, a 3-h infusion

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Table 2 Characteristics of eight febrile neutropenic patients with bacteraemia and minimum inhibitory concentrations (MICs) of meropenem for the pathogens isolated from blood. Patient

Age (years)

Sex

Body weight (kg)

CLCr (mL/min)

Diagnosis

M-P F-L C-P S-P B-N A-K P-P P-D

18 51 31 56 39 58 76 18

F F M M F M M M

33 40 25 82 50 55 60 60

97.79 70.05 90.36 119.58 76.43 74.57 126.98 67.20

ALL 0 AML 0 AML 198 AML 0 Gastric carcinoma 0 AML 0 MM 0 ALL 0

Neutrophil count (cells/␮L)

Pathogen

MIC (␮g/mL)

Moraxella Pseudomonas aeruginosa P. aeruginosa Klebsiella pneumoniae K. pneumoniae N/A Salmonella group D1 P. aeruginosa

0.094 1.5 0.38 0.094 0.047 N/A 0.032 0.094

CLCr , creatinine clearance; ALL, acute lymphoblastic leukaemia; AML, acute myeloblastic leukaemia; N/A, not available; MM, multiple myeloma. Table 3 Probability of target attainment (PTA) for meropenem regimens achieving 40% T > MIC, 60% T > MIC, 80% T > MIC and 100% T > MIC in eight febrile neutropenic patients after administration of a 1 g bolus injection (BI), a 1 g 3-h infusion and a 2 g 3-h infusion. MIC of the pathogen (␮g/mL)

1 2 4 8

PTA 40% T > MIC

PTA 60% T > MIC

PTA 80% T > MIC

PTA 100% T > MIC

BI

BI

3-h infusion

BI

BI

1g

2g

84.02 56.74 20.16 0.37

99.93 98.12 73.73 9.26

100 99.95 98.06 74.76

99.7 97.07 75.7 17.83

3-h infusion 1g

2g

99.99 99.92 99.24 78.79

100 100 99.96 99.24

49.01 22.88 3.97 0

3-h infusion 1g

2g

87.01 57.95 17.56 0.1

97.56 87.18 59.77 16.82

25.43 8.98 0.68 0

3-h infusion 1g

2g

0 0 0 0

3.35 0 0 0

MIC, minimum inhibitory concentration; T > MIC, time that concentrations in tissue and serum are above the MIC.

of 1 g q8h and a 3-h infusion of 2 g q8h were 22.88%, 57.95% and 87.18%, respectively. The predicted CFRs for PTA achieving a target of 40% T > MIC for E. coli following administration of meropenem by a bolus injection of 1 g q8h, a 3-h infusion of 1 g q8h and a 3-h infusion of 2 g q8h were 97.03%, 99.88% and 99.96%, respectively. The predicted CFRs for PTA achieving a target of 40% T > MIC for Klebsiella spp. were 97.07%, 99.92% and 100%, respectively. All three regimens were well tolerated and no adverse events were reported. 4. Discussion For ␤-lactam antibiotics, the bactericidal activity is determined by the T > MIC for the pathogens. High peak concentrations do not enhance the bactericidal activity of these agents and once the concentration falls below the MIC, bacterial growth resumes immediately [2,3]. In addition, T > MIC is the best predictor of bacterial eradication or clinical success [28]. Studies in animal infection models have shown that for most ␤-lactams concentrations do not need to exceed the MIC for 100% of the dosing interval to achieve a significant antibacterial effect [2,3]. Bacteriostatic effects of carbapenems against E. coli and P. aeruginosa in a murine thigh

Table 4 Cumulative fraction of response (CFR) for a 1 g bolus injection, a 1 g 3-h infusion and a 2 g 3-h infusion of meropenem against Escherichia coli, Klebsiella spp., Pseudomonas aeruginosa and Acinetobacter spp. at a probability of target attainment achieving 40% T > MIC in febrile neutropenic patients with bacteraemia. Organism

% Susceptiblea

CFR (%) Bolus injection

E. coli Klebsiella spp. P. aeruginosa Acinetobacter spp.

99.96 100 79.38 78.07

97.03 97.07 77.05 75.78

3-h infusion 1g

2g

99.88 99.92 79.31 78.01

99.96 100 79.38 78.07

T > MIC, time that concentrations in tissue and serum are above the minimum inhibitory concentration. a Susceptibility determined using 2010 European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints (2 ␮g/mL for meropenem).

infection model are observed when serum drug concentrations are above the MIC for 20% of the dosing interval, whereas the T > MIC required for bactericidal activity is 40% of the dosing interval [29]. Moreover, optimum killing properties have been observed in critically ill patients when concentrations are maintained at 4× MIC, with higher concentrations providing little added benefit [30,31]. Our previous PK/PD study of meropenem in patients with VAP found that a 3-h infusion of meropenem resulted in greater T > MIC values than a bolus injection, suggesting that a 3-h infusion may be an appropriate mode of administration for meropenem in tropical countries, and a 3-h infusion of 2 g of meropenem q8h provided mean concentrations in serum >4× the MIC of 4 ␮g/mL (i.e. >16 ␮g/mL) for almost 60% of an 8-h interval [13]. Another previous PD study in patients with intra-abdominal infections, community-acquired pneumonia or VAP showed that at a MIC of 4 ␮g/mL, prolonging the infusion time from 30 min to 3 h for 1 g of meropenem increased the PTA achieving 40% T > MIC from 64% to 90% [32]. In the current study, we examined pharmacokinetics/pharmacodynamics in febrile neutropenic patients with bacteraemia, and a Monte Carlo simulation was performed to determine the probability of attaining a specific PD target using various regimens. The probabilities of 3-h meropenem infusion regimens achieving a target of 40% T > MIC, 60% T > MIC and 80% T > MIC were all superior to a bolus injection of meropenem regimen and the highest PTA rates were obtained with a 3-h infusion of 2 g of meropenem q8h. The high PTA (≥90%) achieving 40% T > MIC for MICs of 2 ␮g/mL was observed when meropenem was administered by all three regimens. For pathogens with MICs of 4 ␮g/mL, the high PTA (≥90%) was achieved when meropenem was administered as a prolonged infusion. However, only a 3-h infusion of 2 g of meropenem q8h regimen achieved >99% PTA of 40% T > MIC for a MIC of 8 ␮g/mL. Therefore, from these data it appears that a 3-h infusion of 1 g of meropenem q8h can provide good coverage for pathogens with MICs of ≤4 ␮g/mL. However, against pathogens less susceptible to meropenem with MICs >4 ␮g/mL, the dosage administered through a 3-h prolonged infusion should be increased to a maximum of 2 g q8h to achieve almost 100% PTA (40% T > MIC) for a MIC of 8 ␮g/mL. A previous study of meropenem in critically ill patients with sepsis found that against the less


Fig. 2. Probability of target attainment (PTA) for meropenem regimens achieving (A) 40% T > MIC, (B) 60% T > MIC, (C) 80% T > MIC and (D) 100% T > MIC (D) at specific minimum inhibitory concentrations (MICs) in eight febrile neutropenic patients after administration of a 1 g bolus injection (), a 3-h infusion of 1 g () and a 3-h infusion of 2 g (). The broken line represents 90% PTA. T > MIC, time that concentrations in tissue and serum are above the MIC.

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susceptible P. aeruginosa (MIC90 = 8 ␮g/mL) and Acinetobacter spp. (MIC90 = 16 ␮g/mL), administration by extended infusion of 2 g q8h or continuous infusion of 6 g/day had superior achievement of PD targets than a bolus injection of the same daily dose [33]. The current study used susceptibility patterns obtained from EUCAST. All three regimens of meropenem had high probabilities of achieving optimal exposure against E. coli or Klebsiella spp., and the prolonged infusion of meropenem regimens did not have a significant advantage over the bolus injection regimen. However, against P. aeruginosa and Acinetobacter spp., neither a prolonged infusion nor a bolus injection regimen achieved bactericidal targets (CFR ≥ 90%). Because Gram-negative bacilli bacteraemia is a serious infection with a high mortality rate in febrile neutropenic patients, appropriate antibiotic therapy and optimum dosing regimens are required for maximal bacterial killing. A previous clinical study in febrile neutropenic patients was conducted to investigate the relationship between the PK/PD index of T > MIC of meropenem and clinical outcome. The results clearly demonstrated that an optimum clinical response was shown when the percentages of T > MIC of meropenem exceeded 75% of the dosing interval [34]. Another previous study evaluated T > MIC as a predictor of outcome for cefepime and ceftazidime in critically ill patients with serious bacterial infections, finding that patients with T > MIC of 100% had a significantly greater clinical cure rate and bacteriological eradication than patients with T > MIC of MIC for maximal bacterial killing in this patient population. The results showed that at a MIC of 2 ␮g/mL, a bolus injection of 1 g q8h, a 3-h infusion of 1 g q8h and a 3-h infusion of 2 g q8h achieved 23%, 58% and 87% PTA, respectively. Therefore, for treatment of infections in critically ill patients such as bacteraemia in febrile neutropenic patients, the meropenem dosage administered by a 3-h infusion should be increased to a maximum of 2 g q8h. The outcome of meropenem treatment by 3-h infusion and bolus injection regimens could not be fully evaluated owing to the short duration of the study treatment, however the MICs of all isolated pathogens in this study were ≤1 ␮g/mL, except for one isolated pathogen (P. aeruginosa), and after 14 days of antibiotic treatment haemocultures were negative in all patients. Therefore, in this study the meropenem dosage administered by a 3-h infusion may be decreased to a 1 g q8h regimen. During meropenem administration in this study, no major adverse events related to the use of either the 3-h infusion or the bolus injection were observed. This study has a few limitations that must be noted. First, the small number of patients could be considered a potential limitation. However, in the absence of data from a larger sample size, a Monte Carlo simulation based on a small number of patients such as in this study can be instructive in illuminating the effects of different dosing approaches [36]. Second, the Cockcroft–Gault method used for estimating CLCr is known to have certain limitations in severely ill patients [37]. Third, the results of this study could be difficult to extrapolate to other situations because the low body weight of the patients could have had an effect on volume of distribution (Vd ) and total clearance (CL). And lastly, the wide range of confidence intervals for these parameters imply that the confidence intervals of simulation predictions would also be wide. This would be an imposing constraint for its use in situations that require low confidence interval ranges of PK parameters such as in the case of cytotoxic chemotherapy modelling. However, the aim of this study was to nullify ineffective regimens, so the wider ranges of confidence intervals could be considered as useful rather than an impediment. In conclusion, it was found that a 3-h infusion of meropenem resulted in higher PTA rates than after a bolus injection, and the highest PTA rates were obtained with a 3-h infusion of 2 g q8h. In addition, for the treatment of infections in critically ill patients who

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required a target of higher than 40% T > MIC, a prolonged infusion of 2 g of meropenem q8h had more advantages than a bolus injection, indicating that a prolonged infusion may be an appropriate mode of administration of meropenem in febrile neutropenic patients. However, it should be remembered that susceptibility patterns of bacteria to antibiotics can vary between regions or countries, and a smaller meropenem dosage may be appropriate in some areas. All three regimens of meropenem had high probabilities of achieving optimal exposure against E. coli and Klebsiella spp., however against P. aeruginosa and Acinetobacter spp. neither a prolonged infusion nor a bolus injection regimen achieved the bactericidal targets (CFR ≥ 90%). However, further well-defined, large, randomised controlled trials comparing 3-h infusion and bolus injection regimens in this patient population are still necessary to confirm these clinical findings. Acknowledgments Meropenem (Meronem® ) was generously donated by AstraZeneca (Bangkok, Thailand). The authors thank Mr David Patterson for checking the English of the manuscript. Funding: This work was supported by a faculty grant from the Faculty of Medicine, Prince of Songkla University (Hat Yai, Thailand). Competing interests: None declared. Ethical approval: This study was approved by the Ethics Committee of Songklanagarind Hospital (Prince of Songkla University, Hat Yai, Thailand). The study was conducted following the guidelines of the Declaration of Helsinki. Judgement reference no. EC. 52-031-14-1-1. References [1] Nicolau D, Quintiliani R, Nightingale CH. Once-daily aminoglycosides. Conn Med 1992;56:561–3. Erratum in: Conn Med 1992;56:694. [2] Craig WA. Interrelationship between pharmacokinetics and pharmacodynamics in determining dosage regimens for broad-spectrum cephalosporins. Diagn Microbiol Infect Dis 1995;22:89–96. [3] Vogelman B, Gudmundsson S, Leggett J, Turnidge J, Ebert S, Craig WA. Correlation of antimicrobial pharmacokinetic parameters with therapeutic efficacy in an animal model. J Infect Dis 1988;158:831–47. [4] Craig WA, Ebert SC. Continuous infusion of ␤-lactam antibiotics. Antimicrob Agents Chemother 1992;36:2577–83. [5] 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. [6] Mouton JW, den Hollander JG. Killing of Pseudomonas aeruginosa during continuous and intermittent infusion of ceftazidime in an in vitro pharmacokinetic model. Antimicrob Agents Chemother 1994;38:931–6. [7] Wiseman LR, Wagstaff AJ, Brogden RN, Bryson HM. Meropenem: a review of its antibacterial activity, pharmacokinetic properties and clinical efficacy. Drugs 1995;50:73–101. [8] 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. [9] Dandekar PK, Maglio D, Sutherland CA, Nightingale CH, Nicolau DP. Pharmacokinetics of meropenem 0.5 and 2 g every 8 hours as a 3-hour infusion. Pharmacotherapy 2003;23:988–91. [10] Kuti JL, Dandekar PK, Nightingale CH, Nicolau DP. Use of Monte Carlo simulation to design an optimized pharmacodynamic dosing strategy for meropenem. J Clin Pharmacol 2003;43:1116–23. [11] Lomaestro BM, Drusano GL. Pharmacodynamic evaluation of extending the administration time of meropenem using a Monte Carlo simulation. Antimicrob Agents Chemother 2005;49:461–3.

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