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pharmacodynamic profile of linezolid in severely ill Intensive Care Unit patients
International Journal of Antimicrobial Agents 38 (2011) 296–300
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International Journal of Antimicrobial Agents journal homepage: http://www.elsevier.com/locate/ijantimicag
Clinical pharmacokinetic/pharmacodynamic profile of linezolid in severely ill Intensive Care Unit patients Haiyan Dong a,1 , Xue Wang b,1 , Yalin Dong a,∗ , Jin’e Lei c , Hao Li b , Haisheng You a , Maoyi Wang a , Jianfeng Xing d , Jinyao Sun a , Huifang Zhu a a
Department of Pharmacy, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China Central Intensive Care Unit, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China c Department of Laboratory, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China d Department of Pharmacy, Medical School of Xi’an Jiaotong University, Xi’an 710061, China b
a r t i c l e
i n f o
Article history: Received 3 March 2011 Accepted 5 May 2011 Keywords: Pharmacokinetic/pharmacodynamic (PK/PD) Linezolid Severely ill patients Gram-positive bacteria Intensive Care Unit (ICU)
a b s t r a c t Severely ill Intensive Care Unit (ICU) patients have an increased risk of developing multiresistant Gram-positive infections, largely due to the inappropriate use of antimicrobials. In this study, the pharmacokinetic/pharmacodynamic (PK/PD) profile of linezolid, an antibiotic against Gram-positive infections, was characterised in eight critically ill patients admitted to the ICU. Remarkable variation amongst patients in the PK parameters of linezolid was observed, including a 5–7-fold difference in peak serum concentration (Cmax ) (mean ± standard deviation 15.70 ± 6.58 mg/L) and 12-h area under the serum concentration–time curve (AUC0–12 ) (96.73 ± 56.45 mg h/L), although the minimum inhibitory concentration (MIC) was similar amongst patients. In particular, variation amongst patients was found in the ratio of AUC0–24 /MIC (range 31.66–216.82, mean 96.73) and the percentage of time that the serum concentration exceeded the MIC (T > MIC) (range 53.4–100%), two parameters used to predict linezolid efficacy. These variations highlight the importance of individual monitoring of linezolid PK/PD properties in critically ill patients. Furthermore, it was observed that regardless of AUC0–24 /MIC and T > MIC values, the clinical and microbiological responses of patients were primarily affected by the individual’s pathophysiological condition. In summary, these findings point to highly variable PK/PD properties of linezolid in severely ill patients, providing the rationale for targeting linezolid dosage to each individual patient’s specific properties. An optimal dosage regimen based on individual PK/PD properties and pathophysiological conditions will help reduce the occurrence of resistance in Gram-positive bacteria. © 2011 Published by Elsevier B.V. and the International Society of Chemotherapy.
1. Introduction Severely ill patients in the Intensive Care Unit (ICU) are often at risk of developing multiresistant Gram-positive bacterial infections. In fact, the growing incidence of the appearance and spread of multiresistant Gram-positive infections in the ICU constitutes a significant health problem in many countries [1,2]. In developed countries, up to 52% of ICU patients with bacteraemia have attributable mortality, more than two-fold that of the general population (23%) [1]. Incorrect use of antimicrobials is a major risk factor contributing to the generation of multidrug-resistant microorganisms, thereby resulting in increased morbidity, mortality and costs [3].
∗ Corresponding author. Tel.: +86 29 8532 3243; fax: +86 29 8532 3241. E-mail addresses: [email protected], [email protected] (Y. Dong). 1 These two authors contributed equally to this work.
Linezolid is a synthetic antimicrobial agent of the oxazolidinone class of antibiotics used for the treatment of serious infections caused by Gram-positive bacteria that are resistant to several other antibiotics. As the first US Food and Drug Administration (FDA)approved oxazolidinone, linezolid has a broad spectrum of activity against Gram-positive bacteria, including meticillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant pneumococci and vancomycin-resistant Enterococcus faecalis and Enterococcus faecium [4–7]. Recent studies have indicated that linezolid treatment for high-incidence ICU infections, including pneumonia and catheter-related bacteraemia, resulted in favourable clinical and microbiological responses [8–10]. However, organisms resistant to linezolid have emerged [11,12], which could result in an increase in attributable mortality and morbidity in ICU patients. Increased knowledge of the pharmacokinetic/pharmacodynamic (PK/PD) properties of antibiotics is useful for optimising dosage. In particular, the ratio of the area under the serum concentration–time curve over 24 h divided by the minimum inhibitory concentration (AUC0–24 /MIC) as well as the percentage
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H. Dong et al. / International Journal of Antimicrobial Agents 38 (2011) 296–300
of time that the drug concentration exceeds the MIC (T > MIC) are considered predictive parameters for the antimicrobial effect of linezolid. Previous studies in animal models suggest that linezolid has an increased antimicrobial effect against Streptococcus pneumoniae when linezolid free-fraction PD parameters (fT > MIC and fAUC0–24 /MIC) reach >40% and range from 48 to 147, respectively [13]. However, in the case of severely ill patients, multiple pathophysiological factors could interfere with the PK/PD properties of drugs. For instance, patients with major thermal injuries had increased non-renal clearance, which may result in PK alteration [14]. In addition, previous work has shown that clearance of linezolid was increased and that there was larger individual variability in dialysis patients [15]. Indeed, studies performed in severely ill patients indicate that the probability of eradication and clinical cure at specific infection sites was correlated with AUC0–24 /MIC and T > MIC values [16,17]. Specifically, higher success rates for linezolid treatment may occur at AUC0–24 /MIC values of 80–120 and T > MIC values >85% [16]. Therefore, the aim of this study was to evaluate the PK/PD profile of linezolid in severely ill Chinese ICU patients. 2. Materials and methods 2.1. Patients and experimental design Patients in the ICU of The First Affiliated Hospital of Xi’an Jiaotong University (Xi’an, China) were included in this study and were selected according to the following criteria: (i) males or nonpregnant females aged ≥18 years with suspected or documented Gram-positive infections, including meticillin-sensitive S. aureus, MRSA, enterococci and coagulase-negative staphylococci; (ii) no allergies to linezolid; (iii) not currently exposed to other drugs that may interfere with the analysis of linezolid; and (iv) simultaneous use of antimicrobials against Gram-negative strains and/or fungi was not considered as an exclusion criterion. Prior to the study, and after all patients were informed of the study details, written informed consent was obtained from all patients. When the subject was unable to provide legally effective consent, written informed consent was obtained from a close relative. The study protocol was approved by the Hospital Ethics Committee. All patients enrolled in the study were given an intermittent intravenous (i.v.) 600 mg dose of linezolid twice daily. Clinical diagnosis and laboratory analysis were performed daily to monitor hepatic and renal function and haemograms. The severity of the patient’s condition was determined using the Acute Physiology and Chronic Health Evaluation (APACHE) II score. To assess renal function, serum creatinine concentrations were determined and the creatinine clearance (CLCr ) rate was estimated by the Cockcroft–Gault equation [18]. Although the Cockcroft–Gault equation has some limitations, such as the requirement of a stable body state and lack of a body surface area correction, it is still widely used for calculating CLCr . Patients were considered to have normal renal function when the CLCr was >50 mL/min, moderately impaired renal function when the CLCr was 20–50 mL/min and total renal failure when the CLCr was <20 mL/min.
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was performed according to the manufacturer’s guidelines, and all required quality control tests were included. Bacterial eradication was evaluated by comparing the microbiological culture of samples from the same patient prior to and after treatment. Relief from symptoms was considered to be clinical cure, whilst patients with sustained or reoccurring infections were considered as failing to respond. 2.3. Measurement of serum linezolid concentrations Venous blood samples were collected prior to the first administration (0 h) and at 0.5, 1, 2, 3, 6, 10 and 12 h after the first administration of linezolid. In addition, 1 mL of venous blood was collected at each peak/trough for the remaining times for 72 h. Samples were centrifuged at 4000 rpm for 10 min and the supernatant was collected and stored at −80 ◦ C for further analysis. The total concentration of linezolid was detected using a highperformance liquid chromatography (HPLC) assay as previously described [19]. Briefly, samples were prepared by mixing the specimen with methanol (1:1) and allowing this mixture to rest at room temperature for 20 min, followed by centrifugation at 10 000 rpm for 10 min. Then, 50 L of supernatant was injected. The stationary phase was a Hypersil C18 column (150 mm × 4.6 mm, 5 m; Waters Corp., Milford, MA). The mobile phase consisted of a mixture of acetonitrile:water (23:77, v/v) adjusted to pH 5.0 by addition of phosphoric acid. The pump flow rate was 1.0 mL/min. Ultraviolet absorbance detection was used (max = 254 nm). Validation of the method yielded satisfactory results (r = 0.9996). The linear range of linezolid concentration was between 0.31 mg/L and 20 mg/L. The limit of linezolid quantification in serum was 0.31 mg/L. The intraday and interday coefficients of variation were less than 4% and 3.5%, respectively. Linezolid was stable after storage at room temperature for 24 h, freezing for 20 days or 40 days, or after three freeze–thaw cycles. 2.4. Statistical analysis Unless otherwise specified, data represent the mean ± standard deviation (S.D.). The concentration of linezolid in this study represents serum concentrations measured by HPLC. PK parameters were determined using DAS 2.0 software v2 (Mathematical Drug and Pharmacology Professional Committee of China, Shanghai, China), and a statistical moments analysis PK model was fitted. Numerical integration of the fitted functions was used to generate the area under the concentration–time curve over 12 h (AUC0–12 ), the AUC0–24 /MIC ratio and T > MIC. AUC0–24 was calculated as AUC0–24 = 2 × AUC0–12 [20]. 3. Results 3.1. Study population Characteristics of the eight critically ill patients with Grampositive bacterial infections included in the study are shown in Table 1.
2.2. Evaluation of therapeutic efficacy
3.2. Pharmacokinetics
Before the start of treatment, patient specimens were collected from suspected or documented infection sites and were examined to identify the causative organisms and to perform sensitivity testing. For patients with pathogens sensitive to linezolid, the MIC was measured. A VITEK 2 automated system (bioMérieux, Lyon, France) was used for rapid microbial identification, followed by determination of MIC values by Etest (AB BIODISK, Solna, Sweden). Testing
First, the dynamic serum concentration of linezolid was monitored at baseline and at 0.5, 1, 2, 3, 6, 10 and 12 h after the first administration (Fig. 1). As shown in Fig. 1, the linezolid concentration reached a peak serum concentration (Cmax ) at 1.4 h following administration. The average Cmax of all the patients tested was 15.70 ± 6.58 mg/L. Thereafter, the concentration gradually declined until the trough serum concentration (Cmin ) (4.10 ± 4.99 mg/L) was
H. Dong et al. / International Journal of Antimicrobial Agents 38 (2011) 296–300
Table 1 Characteristics of eight critically ill patients with Gram-positive bacterial infections enrolled in the study. Characteristic
N
Gendera Age (years)b Entry diagnosisa Pulmonary infection Chest infection Intra-abdominal infection Urinary tract infection Pathogena Staphylococcus Enterococcus faecium Enterococcus faecalis Other Gram-positive strains CLCr (mL/min)b ALB (g/L)b APACHE II scoreb Treatment (days)b No. of TDM measurementsa
7 M/1 F 50.5 ± 17.6 (33–77) 3 1 1 3 1 3 1 3 45.3 ± 32.1 30.7 ± 8.4 16.4 ± 6.1 10 (3–16) 152
Concentration (mg/L)
10 5 0 10
5
12
24
36
48
60
72
84
3.3. Pharmacokinetic/pharmacodynamic analysis and evaluation of therapeutic efficacy
15
8
10
Fig. 2. Average patient serum concentrations at indicated time points during treatment. All patients were given an intravenous drip of 600 mg of linezolid twice daily. Patients’ blood samples were collected at the indicated time points and until 72 h after administration. Serum linezolid was detected using high-performance liquid chromatography (HPLC).
20
6
15
Time (h)
25
4
20
0
30
2
25
0
CLCr , creatinine clearance; ALB, albumin; APACHE, Acute Physiology and Chronic Health Evaluation; TDM, therapeutic drug monitoring. a Data represent absolute numbers. b Data represent mean ± standard deviation (range).
0
30 Concentration (mg/L)
298
12
14
Time (h) Fig. 1. Average patient serum concentrations of linezolid following the first administration. All patients were given an intravenous drip of 600 mg of linezolid twice daily. Patients’ blood samples were collected at the indicated time point within the first 12 h and serum linezolid was detected using high-performance liquid chromatography (HPLC).
reached at 12 h after the first administration. As treatment continued, measurement was carried out every 12 h until 72 h after the onset of treatment (Fig. 2). The PK parameters, including Cmax , elimination half-life, AUC0–12 , clearance rate and volume of distribution, of each individual patient were as given in Table 2. All of the major PK parameters mentioned above varied considerably amongst patients. By contrast, the average Cmin at various time points remained relatively similar between different patients, exhibiting no more than a 2.3-fold difference (between 3.23 mg/L and 7.26 mg/L).
The probability of cure amongst these treated patients was further analysed by evaluating both clinical and microbiological responses (Table 3). In addition, two major PK/PD parameters predictive of linezolid efficacy (AUC0–24 /MIC and T > MIC) were evaluated [16,17]. Consistent with other PK parameters measured in this study, PK/PD parameters were highly variable amongst the patients. Furthermore, a divergence between AUC0–24 /MIC and T > MIC values and probability of clinical cure was observed in this study. According to our observations, although four patients with an AUC0–24 /MIC ranging from 80 to 120 and T > MIC of >85% were clinically and microbiologically cured, another patient with markedly higher AUC0–24 /MIC and T > MIC values (>200 and >85%, respectively) failed to respond to treatment. This likely indicates that the peculiar pathophysiological conditions of this patient, which included pulmonary fibrosis and infections, might have a considerable impact on the therapeutic effect of linezolid, even when PK/PD parameters fall in the favourable range. On the other hand, although two patients with AUC0–24 /MIC values <80 and T > MIC values of <85% failed to show good clinical and microbiological response as predicted, one patient with intra-abdominal infection was completely cured (T > MIC at 59.7% and AUC0–24 /MIC at 46.80). 4. Discussion The pharmacokinetics/pharmacodynamics of linezolid have been investigated extensively in laboratory models, healthy volunteers and stable patients. However, very limited information exists regarding PK/PD parameters for linezolid in the most critically ill patients [21]. However, in China this drug has been used for clinical patients since 2007 and there have been no studies of Chinese critically ill patients since its implementation. In this study, the
Table 2 Pharmacokinetic parameters of individual patients. Patient No.
Cmax (mg/L)
t1/2 (h)
AUC0–12 (mg h/L)
CL (L/h/kg)
Vd (L/kg)
1 2 3 4 5 6 7 8 Mean ± S.D.
13.00 27.08 5.57 17.09 12.75 12.72 22.30 15.10 15.70 ± 6.58
4.72 13.31 3.42 2.89 2.70 8.08 3.25 5.80 5.52 ± 3.63
96.16 216.82 31.66 100.55 46.80 113.60 67.68 100.57 96.73 ± 56.45
0.09 0.02 0.28 0.10 0.20 0.06 0.14 0.07 0.12 ± 0.08
0.59 0.38 1.37 0.40 0.80 0.64 0.65 0.62 0.68 ± 0.31
Cmax , peak serum concentration; t1/2 , elimination half-life; AUC0–12 , 12-h area under the serum concentration–time curve; CL, clearance rate; Vd , volume of distribution; S.D., standard deviation.
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Table 3 Pharmacokinetic/pharmacodynamic parameters of individual patients. Patient No.
T > MIC
AUC0–24 /MICa
1 2 3 4 5 6 7 8
100 100 53.4 100 59.7 100 80.1 100
96.16 216.82 31.66 100.55 46.80 113.60 67.68 100.58
Cmin,ss (mg/L) 2.19 11.40 5.34 3.78 3.37 7.59 1.20 9.00
± ± ± ± ± ± ± ±
0.99 2.40 0.14 1.74 0.60 1.73 0.26 4.61
MIC (g/mL)
Bacteriological response
Clinical responseb
2 2 2 2 2 2 2 2
E R R E E E R E
+ − − + + + − +
MIC, minimum inhibitory concentration; T > MIC, percentage of time that the drug concentration exceeded the MIC; AUC0–24, 24-h area under the serum concentration–time curve; Cmin,ss , average trough serum steady-state concentration; E, bacterial eradication; R, bacterial recurrence. a AUC0–24 was calculated as AUC0–24 = AUC0–12 × 2. b Symptom relief was considered to be clinical cure (+), whilst patients with sustained or reoccurring infections were considered as having failed to respond (−).
PK/PD properties of linezolid in severely ill patients in the ICU were examined in order to reduce the risk for these patients of developing multiresistant Gram-positive infections. According to the data, patients admitted to the ICU exhibited highly variable PK/PD properties, likely due to the peculiar pathophysiological conditions known to affect the disposition of antibiotics [20,22]. In contrast, the MIC of the pathogens from all of the patients included in this study were similar. These observations raise concerns that using standard linezolid dosage regimens could result in subtherapeutic concentrations in some patients, which could further lead to clinical failure or microbiological resistance. Therefore, it is critical to monitor individual PK/PD properties when administering linezolid to critically ill patients. Better individual knowledge of PK/PD properties will help to individualise the dosage regimen and improve therapeutic efficacy. This study also highlights the impact of the patient’s pathophysiological condition on the probability of cure. Despite the fact that AUC0–24 /MIC values between 80 and 120 and T > MIC values of >85% can be generalised to predict the efficacy of linezolid in most ICU patients [16,17], in this study a discrepancy between treatment outcome and PK/PD values was observed in certain cases. For example, one patient with an AUC0–24 /MIC value of 46.80 and a T > MIC value of 59.7% still exhibited favourable clinical and bacterial responses. This is likely due to the causative organisms and infection site particular to this case. Efficient drainage post surgery may help with the local elimination of E. faecalis caused by intra-abdominal infections. Indeed, Rayner et al. [16] also reported that patients with intra-abdominal infections had a higher cure rate when treated with linezolid. On the other hand, a patient with pulmonary fibrosis and infections failed to respond to treatment although AUC0–24 /MIC and T > MIC values were remarkably higher in this patient than in the others. Honeybourne et al. [23] previously reported that linezolid exhibited extraordinary penetration into pulmonary tissues, especially the epithelial lining fluid. However, PK/PD parameters and antimicrobial effects were not evaluated in that study. Therefore, the pathophysiological changes of the patient, such as injury of pulmonary alveolar epithelial cells and vascular endothelial cells, as well as collagen proliferation might affect the local efficacy of linezolid. Follow-up studies with a larger number of patients are needed to determine more appropriate ranges for AUC0–24 /MIC and T > MIC values for patients with pulmonary disorders. Taken together, whilst the role of AUC0–24 /MIC and T > MIC values in predicting the therapeutic effect of linezolid treatment in ICU patients was confirmed for most subjects, the appropriate range for patients with certain pathophysiological changes remains debatable. The current results indicate that five patients with varying degrees of renal dysfunction, four of which exhibited AUC0–24 in the range 80–120 and T > MIC of >85%, ended in clinical cure. One of the five patients exhibited AUC0–24 values <80 and a T > MIC of <85% and was considered a clinical treatment failure. Although
the pathophysiological conditions of critically ill patients and some clinical interventions (e.g. vascular tone, fluid status, cardiac output, vasoactive agents, etc.) will cause dramatic changes in organ function and result in enhanced renal clearance, this study does not adequately reflect the consequences of these changes because the sample size is small. This may be related to the fact that renal clearance of linezolid is reduced as renal function is decreased, whilst non-renal clearance is increased [24]. The failure of treatment due to enhanced excretory organ function, which results in unexpectedly low linezolid serum concentrations and corresponding changes of pharmacokinetics/pharmacodynamics, should be studied further in critically ill patients. So far, several approaches have been undertaken to reduce the emergence of multiresistant bacteria, including knowledge of local ecology, de-escalation following culture results, and shortening the duration of treatment [3]. The present results suggest that in the case of severely ill patients, basing the dose of antibiotics on individual PK/PD properties could be an important strategy for optimum linezolid therapy. Previous work also indicated that the management of critically ill patients should include therapeutic approaches such as the ‘de-escalating strategy’, which includes the administration of empirical antibacterials active against multiresistant pathogens followed by directed treatment based on unequivocal data from antibacterial susceptibility testing. Optimisation of antibacterial treatment should be viewed in the context of the need to determine plasma drug concentrations, pharmacoeconomic considerations and control of drug-related adverse events [20]. Moreover, previous studies [25,26] also recommend increasing the frequency of linezolid administration in critically ill patients to prevent subtherapeutic concentrations. Although these questions were not specifically addressed in this study, we believe that an integrative strategy including all of these approaches might result in a reduced incidence of multiresistant bacteria. It should not be overlooked that the number of cases enrolled in this study was relatively limited. A previous study compared the PK/PD profiles of linezolid administered by intermittent or continuous infusion in critically ill septic patients and concluded that continuous infusion had theoretical advantages over intermittent infusion in terms of achieving optimal AUC0–24 /MIC values [27]. In the current study, 600 mg i.v. drip twice daily resulted in favourable AUC0–24 /MIC values. Whether continuous i.v. drip could further improve therapeutic efficiency will be addressed in further studies involving larger numbers of patients. In addition, most patients included in this study were simultaneously treated with other drugs, which might interfere with the clinical response observed. In conclusion, the standard fixed dosage of 600 mg twice daily may ensure adequate PD exposure to linezolid in ca. 60–70% of cases, but the remaining 30–40% of cases require therapeutic drug monitoring [28]. This study also showed that pathophysiological conditions of critically ill patients may severely affect
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therapeutic efficacy. Therefore, we have discovered an important role for the determination of each individual patient’s PK/PD properties in ensuring that dosage is optimised to achieve therapeutically relevant concentrations and to prevent the occurrence of multiresistance. Acknowledgments The authors would like to thank the doctors and nurses of the ICU of The First Affiliated Hospital of Xi’an Jiaotong University (Xi’an, China) for their essential contributions to this study. Funding: This study was supported by Research Funding, The First Affiliated Hospital of Medical College, Xi’an Jiaotong University (Xi’an, China) (No. 2008YK28). Competing interests: None declared. Ethical approval: The study protocol was approved by the Hospital Ethics Committee. References [1] Cortés JA, Garzón DC, Navarrete JA, Contreras KM. Impact of inappropriate antimicrobial therapy on patients with bacteremia in intensive care units and resistance patterns in Latin America. Rev Argent Microbiol 2010;42: 230–4. [2] Maviglia R, Nestorini R, Pennisi M. Role of old antibiotics in multidrug resistant bacterial infections. Curr Drug Targets 2009;10:895–905. [3] Leone M, Martin C. How to break the vicious circle of antibiotic resistances? Curr Opin Crit Care 2008;14:587–92. [4] Ashtekar DR, Costa-Periera R, Shrinivasan T, Iyyer R, Vishvanathan N, Rittel W. Oxazolidinones, a new class of synthetic antituberculosis agent. In vitro and in vivo activities of DuP-721 against Mycobacterium tuberculosis. Diagn Microbiol Infect Dis 1991;14:465–71. [5] Eliopoulos GM, Wennersten CB, Gold HS, Moellering Jr RC. In vitro activities in new oxazolidinone antimicrobial agents against enterococci. Antimicrob Agents Chemother 1996;40:1745–7. [6] Jorgensen JH, McElmeel ML, Trippy CW. In vitro activities of the oxazolidinone antibiotics U-100592 and U-100766 against Staphylococcus aureus and coagulase-negative Staphylococcus species. Antimicrob Agents Chemother 1997;41:465–7. [7] Noskin GA, Siddiqui F, Stosor V, Kruzynski J, Peterson LR. Successful treatment of persistent vancomycin-resistant Enterococcus faecium bacteremia with linezolid and gentamicin. Clin Infect Dis 1999;28:689– 90. [8] Ament PW, Jamshed N, Horne JP, Linezolid:. its role in the treatment of Gram-positive, drug-resistant bacterial infections. Am Fam Physician 2002;65:663–70. [9] Bain KT, Wittbrodt ET. Linezolid for the treatment of resistant Gram-positive cocci. Ann Pharmacother 2001;35:566–75.
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International Journal of Antimicrobial Agents journal homepage: http://www.elsevier.com/locate/ijantimicag
Clinical pharmacokinetic/pharmacodynamic profile of linezolid in severely ill Intensive Care Unit patients Haiyan Dong a,1 , Xue Wang b,1 , Yalin Dong a,∗ , Jin’e Lei c , Hao Li b , Haisheng You a , Maoyi Wang a , Jianfeng Xing d , Jinyao Sun a , Huifang Zhu a a
Department of Pharmacy, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China Central Intensive Care Unit, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China c Department of Laboratory, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China d Department of Pharmacy, Medical School of Xi’an Jiaotong University, Xi’an 710061, China b
a r t i c l e
i n f o
Article history: Received 3 March 2011 Accepted 5 May 2011 Keywords: Pharmacokinetic/pharmacodynamic (PK/PD) Linezolid Severely ill patients Gram-positive bacteria Intensive Care Unit (ICU)
a b s t r a c t Severely ill Intensive Care Unit (ICU) patients have an increased risk of developing multiresistant Gram-positive infections, largely due to the inappropriate use of antimicrobials. In this study, the pharmacokinetic/pharmacodynamic (PK/PD) profile of linezolid, an antibiotic against Gram-positive infections, was characterised in eight critically ill patients admitted to the ICU. Remarkable variation amongst patients in the PK parameters of linezolid was observed, including a 5–7-fold difference in peak serum concentration (Cmax ) (mean ± standard deviation 15.70 ± 6.58 mg/L) and 12-h area under the serum concentration–time curve (AUC0–12 ) (96.73 ± 56.45 mg h/L), although the minimum inhibitory concentration (MIC) was similar amongst patients. In particular, variation amongst patients was found in the ratio of AUC0–24 /MIC (range 31.66–216.82, mean 96.73) and the percentage of time that the serum concentration exceeded the MIC (T > MIC) (range 53.4–100%), two parameters used to predict linezolid efficacy. These variations highlight the importance of individual monitoring of linezolid PK/PD properties in critically ill patients. Furthermore, it was observed that regardless of AUC0–24 /MIC and T > MIC values, the clinical and microbiological responses of patients were primarily affected by the individual’s pathophysiological condition. In summary, these findings point to highly variable PK/PD properties of linezolid in severely ill patients, providing the rationale for targeting linezolid dosage to each individual patient’s specific properties. An optimal dosage regimen based on individual PK/PD properties and pathophysiological conditions will help reduce the occurrence of resistance in Gram-positive bacteria. © 2011 Published by Elsevier B.V. and the International Society of Chemotherapy.
1. Introduction Severely ill patients in the Intensive Care Unit (ICU) are often at risk of developing multiresistant Gram-positive bacterial infections. In fact, the growing incidence of the appearance and spread of multiresistant Gram-positive infections in the ICU constitutes a significant health problem in many countries [1,2]. In developed countries, up to 52% of ICU patients with bacteraemia have attributable mortality, more than two-fold that of the general population (23%) [1]. Incorrect use of antimicrobials is a major risk factor contributing to the generation of multidrug-resistant microorganisms, thereby resulting in increased morbidity, mortality and costs [3].
∗ Corresponding author. Tel.: +86 29 8532 3243; fax: +86 29 8532 3241. E-mail addresses: [email protected], [email protected] (Y. Dong). 1 These two authors contributed equally to this work.
Linezolid is a synthetic antimicrobial agent of the oxazolidinone class of antibiotics used for the treatment of serious infections caused by Gram-positive bacteria that are resistant to several other antibiotics. As the first US Food and Drug Administration (FDA)approved oxazolidinone, linezolid has a broad spectrum of activity against Gram-positive bacteria, including meticillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant pneumococci and vancomycin-resistant Enterococcus faecalis and Enterococcus faecium [4–7]. Recent studies have indicated that linezolid treatment for high-incidence ICU infections, including pneumonia and catheter-related bacteraemia, resulted in favourable clinical and microbiological responses [8–10]. However, organisms resistant to linezolid have emerged [11,12], which could result in an increase in attributable mortality and morbidity in ICU patients. Increased knowledge of the pharmacokinetic/pharmacodynamic (PK/PD) properties of antibiotics is useful for optimising dosage. In particular, the ratio of the area under the serum concentration–time curve over 24 h divided by the minimum inhibitory concentration (AUC0–24 /MIC) as well as the percentage
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of time that the drug concentration exceeds the MIC (T > MIC) are considered predictive parameters for the antimicrobial effect of linezolid. Previous studies in animal models suggest that linezolid has an increased antimicrobial effect against Streptococcus pneumoniae when linezolid free-fraction PD parameters (fT > MIC and fAUC0–24 /MIC) reach >40% and range from 48 to 147, respectively [13]. However, in the case of severely ill patients, multiple pathophysiological factors could interfere with the PK/PD properties of drugs. For instance, patients with major thermal injuries had increased non-renal clearance, which may result in PK alteration [14]. In addition, previous work has shown that clearance of linezolid was increased and that there was larger individual variability in dialysis patients [15]. Indeed, studies performed in severely ill patients indicate that the probability of eradication and clinical cure at specific infection sites was correlated with AUC0–24 /MIC and T > MIC values [16,17]. Specifically, higher success rates for linezolid treatment may occur at AUC0–24 /MIC values of 80–120 and T > MIC values >85% [16]. Therefore, the aim of this study was to evaluate the PK/PD profile of linezolid in severely ill Chinese ICU patients. 2. Materials and methods 2.1. Patients and experimental design Patients in the ICU of The First Affiliated Hospital of Xi’an Jiaotong University (Xi’an, China) were included in this study and were selected according to the following criteria: (i) males or nonpregnant females aged ≥18 years with suspected or documented Gram-positive infections, including meticillin-sensitive S. aureus, MRSA, enterococci and coagulase-negative staphylococci; (ii) no allergies to linezolid; (iii) not currently exposed to other drugs that may interfere with the analysis of linezolid; and (iv) simultaneous use of antimicrobials against Gram-negative strains and/or fungi was not considered as an exclusion criterion. Prior to the study, and after all patients were informed of the study details, written informed consent was obtained from all patients. When the subject was unable to provide legally effective consent, written informed consent was obtained from a close relative. The study protocol was approved by the Hospital Ethics Committee. All patients enrolled in the study were given an intermittent intravenous (i.v.) 600 mg dose of linezolid twice daily. Clinical diagnosis and laboratory analysis were performed daily to monitor hepatic and renal function and haemograms. The severity of the patient’s condition was determined using the Acute Physiology and Chronic Health Evaluation (APACHE) II score. To assess renal function, serum creatinine concentrations were determined and the creatinine clearance (CLCr ) rate was estimated by the Cockcroft–Gault equation [18]. Although the Cockcroft–Gault equation has some limitations, such as the requirement of a stable body state and lack of a body surface area correction, it is still widely used for calculating CLCr . Patients were considered to have normal renal function when the CLCr was >50 mL/min, moderately impaired renal function when the CLCr was 20–50 mL/min and total renal failure when the CLCr was <20 mL/min.
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was performed according to the manufacturer’s guidelines, and all required quality control tests were included. Bacterial eradication was evaluated by comparing the microbiological culture of samples from the same patient prior to and after treatment. Relief from symptoms was considered to be clinical cure, whilst patients with sustained or reoccurring infections were considered as failing to respond. 2.3. Measurement of serum linezolid concentrations Venous blood samples were collected prior to the first administration (0 h) and at 0.5, 1, 2, 3, 6, 10 and 12 h after the first administration of linezolid. In addition, 1 mL of venous blood was collected at each peak/trough for the remaining times for 72 h. Samples were centrifuged at 4000 rpm for 10 min and the supernatant was collected and stored at −80 ◦ C for further analysis. The total concentration of linezolid was detected using a highperformance liquid chromatography (HPLC) assay as previously described [19]. Briefly, samples were prepared by mixing the specimen with methanol (1:1) and allowing this mixture to rest at room temperature for 20 min, followed by centrifugation at 10 000 rpm for 10 min. Then, 50 L of supernatant was injected. The stationary phase was a Hypersil C18 column (150 mm × 4.6 mm, 5 m; Waters Corp., Milford, MA). The mobile phase consisted of a mixture of acetonitrile:water (23:77, v/v) adjusted to pH 5.0 by addition of phosphoric acid. The pump flow rate was 1.0 mL/min. Ultraviolet absorbance detection was used (max = 254 nm). Validation of the method yielded satisfactory results (r = 0.9996). The linear range of linezolid concentration was between 0.31 mg/L and 20 mg/L. The limit of linezolid quantification in serum was 0.31 mg/L. The intraday and interday coefficients of variation were less than 4% and 3.5%, respectively. Linezolid was stable after storage at room temperature for 24 h, freezing for 20 days or 40 days, or after three freeze–thaw cycles. 2.4. Statistical analysis Unless otherwise specified, data represent the mean ± standard deviation (S.D.). The concentration of linezolid in this study represents serum concentrations measured by HPLC. PK parameters were determined using DAS 2.0 software v2 (Mathematical Drug and Pharmacology Professional Committee of China, Shanghai, China), and a statistical moments analysis PK model was fitted. Numerical integration of the fitted functions was used to generate the area under the concentration–time curve over 12 h (AUC0–12 ), the AUC0–24 /MIC ratio and T > MIC. AUC0–24 was calculated as AUC0–24 = 2 × AUC0–12 [20]. 3. Results 3.1. Study population Characteristics of the eight critically ill patients with Grampositive bacterial infections included in the study are shown in Table 1.
2.2. Evaluation of therapeutic efficacy
3.2. Pharmacokinetics
Before the start of treatment, patient specimens were collected from suspected or documented infection sites and were examined to identify the causative organisms and to perform sensitivity testing. For patients with pathogens sensitive to linezolid, the MIC was measured. A VITEK 2 automated system (bioMérieux, Lyon, France) was used for rapid microbial identification, followed by determination of MIC values by Etest (AB BIODISK, Solna, Sweden). Testing
First, the dynamic serum concentration of linezolid was monitored at baseline and at 0.5, 1, 2, 3, 6, 10 and 12 h after the first administration (Fig. 1). As shown in Fig. 1, the linezolid concentration reached a peak serum concentration (Cmax ) at 1.4 h following administration. The average Cmax of all the patients tested was 15.70 ± 6.58 mg/L. Thereafter, the concentration gradually declined until the trough serum concentration (Cmin ) (4.10 ± 4.99 mg/L) was
H. Dong et al. / International Journal of Antimicrobial Agents 38 (2011) 296–300
Table 1 Characteristics of eight critically ill patients with Gram-positive bacterial infections enrolled in the study. Characteristic
N
Gendera Age (years)b Entry diagnosisa Pulmonary infection Chest infection Intra-abdominal infection Urinary tract infection Pathogena Staphylococcus Enterococcus faecium Enterococcus faecalis Other Gram-positive strains CLCr (mL/min)b ALB (g/L)b APACHE II scoreb Treatment (days)b No. of TDM measurementsa
7 M/1 F 50.5 ± 17.6 (33–77) 3 1 1 3 1 3 1 3 45.3 ± 32.1 30.7 ± 8.4 16.4 ± 6.1 10 (3–16) 152
Concentration (mg/L)
10 5 0 10
5
12
24
36
48
60
72
84
3.3. Pharmacokinetic/pharmacodynamic analysis and evaluation of therapeutic efficacy
15
8
10
Fig. 2. Average patient serum concentrations at indicated time points during treatment. All patients were given an intravenous drip of 600 mg of linezolid twice daily. Patients’ blood samples were collected at the indicated time points and until 72 h after administration. Serum linezolid was detected using high-performance liquid chromatography (HPLC).
20
6
15
Time (h)
25
4
20
0
30
2
25
0
CLCr , creatinine clearance; ALB, albumin; APACHE, Acute Physiology and Chronic Health Evaluation; TDM, therapeutic drug monitoring. a Data represent absolute numbers. b Data represent mean ± standard deviation (range).
0
30 Concentration (mg/L)
298
12
14
Time (h) Fig. 1. Average patient serum concentrations of linezolid following the first administration. All patients were given an intravenous drip of 600 mg of linezolid twice daily. Patients’ blood samples were collected at the indicated time point within the first 12 h and serum linezolid was detected using high-performance liquid chromatography (HPLC).
reached at 12 h after the first administration. As treatment continued, measurement was carried out every 12 h until 72 h after the onset of treatment (Fig. 2). The PK parameters, including Cmax , elimination half-life, AUC0–12 , clearance rate and volume of distribution, of each individual patient were as given in Table 2. All of the major PK parameters mentioned above varied considerably amongst patients. By contrast, the average Cmin at various time points remained relatively similar between different patients, exhibiting no more than a 2.3-fold difference (between 3.23 mg/L and 7.26 mg/L).
The probability of cure amongst these treated patients was further analysed by evaluating both clinical and microbiological responses (Table 3). In addition, two major PK/PD parameters predictive of linezolid efficacy (AUC0–24 /MIC and T > MIC) were evaluated [16,17]. Consistent with other PK parameters measured in this study, PK/PD parameters were highly variable amongst the patients. Furthermore, a divergence between AUC0–24 /MIC and T > MIC values and probability of clinical cure was observed in this study. According to our observations, although four patients with an AUC0–24 /MIC ranging from 80 to 120 and T > MIC of >85% were clinically and microbiologically cured, another patient with markedly higher AUC0–24 /MIC and T > MIC values (>200 and >85%, respectively) failed to respond to treatment. This likely indicates that the peculiar pathophysiological conditions of this patient, which included pulmonary fibrosis and infections, might have a considerable impact on the therapeutic effect of linezolid, even when PK/PD parameters fall in the favourable range. On the other hand, although two patients with AUC0–24 /MIC values <80 and T > MIC values of <85% failed to show good clinical and microbiological response as predicted, one patient with intra-abdominal infection was completely cured (T > MIC at 59.7% and AUC0–24 /MIC at 46.80). 4. Discussion The pharmacokinetics/pharmacodynamics of linezolid have been investigated extensively in laboratory models, healthy volunteers and stable patients. However, very limited information exists regarding PK/PD parameters for linezolid in the most critically ill patients [21]. However, in China this drug has been used for clinical patients since 2007 and there have been no studies of Chinese critically ill patients since its implementation. In this study, the
Table 2 Pharmacokinetic parameters of individual patients. Patient No.
Cmax (mg/L)
t1/2 (h)
AUC0–12 (mg h/L)
CL (L/h/kg)
Vd (L/kg)
1 2 3 4 5 6 7 8 Mean ± S.D.
13.00 27.08 5.57 17.09 12.75 12.72 22.30 15.10 15.70 ± 6.58
4.72 13.31 3.42 2.89 2.70 8.08 3.25 5.80 5.52 ± 3.63
96.16 216.82 31.66 100.55 46.80 113.60 67.68 100.57 96.73 ± 56.45
0.09 0.02 0.28 0.10 0.20 0.06 0.14 0.07 0.12 ± 0.08
0.59 0.38 1.37 0.40 0.80 0.64 0.65 0.62 0.68 ± 0.31
Cmax , peak serum concentration; t1/2 , elimination half-life; AUC0–12 , 12-h area under the serum concentration–time curve; CL, clearance rate; Vd , volume of distribution; S.D., standard deviation.
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Table 3 Pharmacokinetic/pharmacodynamic parameters of individual patients. Patient No.
T > MIC
AUC0–24 /MICa
1 2 3 4 5 6 7 8
100 100 53.4 100 59.7 100 80.1 100
96.16 216.82 31.66 100.55 46.80 113.60 67.68 100.58
Cmin,ss (mg/L) 2.19 11.40 5.34 3.78 3.37 7.59 1.20 9.00
± ± ± ± ± ± ± ±
0.99 2.40 0.14 1.74 0.60 1.73 0.26 4.61
MIC (g/mL)
Bacteriological response
Clinical responseb
2 2 2 2 2 2 2 2
E R R E E E R E
+ − − + + + − +
MIC, minimum inhibitory concentration; T > MIC, percentage of time that the drug concentration exceeded the MIC; AUC0–24, 24-h area under the serum concentration–time curve; Cmin,ss , average trough serum steady-state concentration; E, bacterial eradication; R, bacterial recurrence. a AUC0–24 was calculated as AUC0–24 = AUC0–12 × 2. b Symptom relief was considered to be clinical cure (+), whilst patients with sustained or reoccurring infections were considered as having failed to respond (−).
PK/PD properties of linezolid in severely ill patients in the ICU were examined in order to reduce the risk for these patients of developing multiresistant Gram-positive infections. According to the data, patients admitted to the ICU exhibited highly variable PK/PD properties, likely due to the peculiar pathophysiological conditions known to affect the disposition of antibiotics [20,22]. In contrast, the MIC of the pathogens from all of the patients included in this study were similar. These observations raise concerns that using standard linezolid dosage regimens could result in subtherapeutic concentrations in some patients, which could further lead to clinical failure or microbiological resistance. Therefore, it is critical to monitor individual PK/PD properties when administering linezolid to critically ill patients. Better individual knowledge of PK/PD properties will help to individualise the dosage regimen and improve therapeutic efficacy. This study also highlights the impact of the patient’s pathophysiological condition on the probability of cure. Despite the fact that AUC0–24 /MIC values between 80 and 120 and T > MIC values of >85% can be generalised to predict the efficacy of linezolid in most ICU patients [16,17], in this study a discrepancy between treatment outcome and PK/PD values was observed in certain cases. For example, one patient with an AUC0–24 /MIC value of 46.80 and a T > MIC value of 59.7% still exhibited favourable clinical and bacterial responses. This is likely due to the causative organisms and infection site particular to this case. Efficient drainage post surgery may help with the local elimination of E. faecalis caused by intra-abdominal infections. Indeed, Rayner et al. [16] also reported that patients with intra-abdominal infections had a higher cure rate when treated with linezolid. On the other hand, a patient with pulmonary fibrosis and infections failed to respond to treatment although AUC0–24 /MIC and T > MIC values were remarkably higher in this patient than in the others. Honeybourne et al. [23] previously reported that linezolid exhibited extraordinary penetration into pulmonary tissues, especially the epithelial lining fluid. However, PK/PD parameters and antimicrobial effects were not evaluated in that study. Therefore, the pathophysiological changes of the patient, such as injury of pulmonary alveolar epithelial cells and vascular endothelial cells, as well as collagen proliferation might affect the local efficacy of linezolid. Follow-up studies with a larger number of patients are needed to determine more appropriate ranges for AUC0–24 /MIC and T > MIC values for patients with pulmonary disorders. Taken together, whilst the role of AUC0–24 /MIC and T > MIC values in predicting the therapeutic effect of linezolid treatment in ICU patients was confirmed for most subjects, the appropriate range for patients with certain pathophysiological changes remains debatable. The current results indicate that five patients with varying degrees of renal dysfunction, four of which exhibited AUC0–24 in the range 80–120 and T > MIC of >85%, ended in clinical cure. One of the five patients exhibited AUC0–24 values <80 and a T > MIC of <85% and was considered a clinical treatment failure. Although
the pathophysiological conditions of critically ill patients and some clinical interventions (e.g. vascular tone, fluid status, cardiac output, vasoactive agents, etc.) will cause dramatic changes in organ function and result in enhanced renal clearance, this study does not adequately reflect the consequences of these changes because the sample size is small. This may be related to the fact that renal clearance of linezolid is reduced as renal function is decreased, whilst non-renal clearance is increased [24]. The failure of treatment due to enhanced excretory organ function, which results in unexpectedly low linezolid serum concentrations and corresponding changes of pharmacokinetics/pharmacodynamics, should be studied further in critically ill patients. So far, several approaches have been undertaken to reduce the emergence of multiresistant bacteria, including knowledge of local ecology, de-escalation following culture results, and shortening the duration of treatment [3]. The present results suggest that in the case of severely ill patients, basing the dose of antibiotics on individual PK/PD properties could be an important strategy for optimum linezolid therapy. Previous work also indicated that the management of critically ill patients should include therapeutic approaches such as the ‘de-escalating strategy’, which includes the administration of empirical antibacterials active against multiresistant pathogens followed by directed treatment based on unequivocal data from antibacterial susceptibility testing. Optimisation of antibacterial treatment should be viewed in the context of the need to determine plasma drug concentrations, pharmacoeconomic considerations and control of drug-related adverse events [20]. Moreover, previous studies [25,26] also recommend increasing the frequency of linezolid administration in critically ill patients to prevent subtherapeutic concentrations. Although these questions were not specifically addressed in this study, we believe that an integrative strategy including all of these approaches might result in a reduced incidence of multiresistant bacteria. It should not be overlooked that the number of cases enrolled in this study was relatively limited. A previous study compared the PK/PD profiles of linezolid administered by intermittent or continuous infusion in critically ill septic patients and concluded that continuous infusion had theoretical advantages over intermittent infusion in terms of achieving optimal AUC0–24 /MIC values [27]. In the current study, 600 mg i.v. drip twice daily resulted in favourable AUC0–24 /MIC values. Whether continuous i.v. drip could further improve therapeutic efficiency will be addressed in further studies involving larger numbers of patients. In addition, most patients included in this study were simultaneously treated with other drugs, which might interfere with the clinical response observed. In conclusion, the standard fixed dosage of 600 mg twice daily may ensure adequate PD exposure to linezolid in ca. 60–70% of cases, but the remaining 30–40% of cases require therapeutic drug monitoring [28]. This study also showed that pathophysiological conditions of critically ill patients may severely affect
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therapeutic efficacy. Therefore, we have discovered an important role for the determination of each individual patient’s PK/PD properties in ensuring that dosage is optimised to achieve therapeutically relevant concentrations and to prevent the occurrence of multiresistance. Acknowledgments The authors would like to thank the doctors and nurses of the ICU of The First Affiliated Hospital of Xi’an Jiaotong University (Xi’an, China) for their essential contributions to this study. Funding: This study was supported by Research Funding, The First Affiliated Hospital of Medical College, Xi’an Jiaotong University (Xi’an, China) (No. 2008YK28). Competing interests: None declared. Ethical approval: The study protocol was approved by the Hospital Ethics Committee. References [1] Cortés JA, Garzón DC, Navarrete JA, Contreras KM. Impact of inappropriate antimicrobial therapy on patients with bacteremia in intensive care units and resistance patterns in Latin America. Rev Argent Microbiol 2010;42: 230–4. [2] Maviglia R, Nestorini R, Pennisi M. Role of old antibiotics in multidrug resistant bacterial infections. Curr Drug Targets 2009;10:895–905. [3] Leone M, Martin C. How to break the vicious circle of antibiotic resistances? Curr Opin Crit Care 2008;14:587–92. [4] Ashtekar DR, Costa-Periera R, Shrinivasan T, Iyyer R, Vishvanathan N, Rittel W. Oxazolidinones, a new class of synthetic antituberculosis agent. In vitro and in vivo activities of DuP-721 against Mycobacterium tuberculosis. Diagn Microbiol Infect Dis 1991;14:465–71. [5] Eliopoulos GM, Wennersten CB, Gold HS, Moellering Jr RC. In vitro activities in new oxazolidinone antimicrobial agents against enterococci. Antimicrob Agents Chemother 1996;40:1745–7. [6] Jorgensen JH, McElmeel ML, Trippy CW. In vitro activities of the oxazolidinone antibiotics U-100592 and U-100766 against Staphylococcus aureus and coagulase-negative Staphylococcus species. Antimicrob Agents Chemother 1997;41:465–7. [7] Noskin GA, Siddiqui F, Stosor V, Kruzynski J, Peterson LR. Successful treatment of persistent vancomycin-resistant Enterococcus faecium bacteremia with linezolid and gentamicin. Clin Infect Dis 1999;28:689– 90. [8] Ament PW, Jamshed N, Horne JP, Linezolid:. its role in the treatment of Gram-positive, drug-resistant bacterial infections. Am Fam Physician 2002;65:663–70. [9] Bain KT, Wittbrodt ET. Linezolid for the treatment of resistant Gram-positive cocci. Ann Pharmacother 2001;35:566–75.
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