Abstract
The aim of this study was to reveal population pharmacokinetics and assess the efficacies of various dosage regimens of sulbactam in terms of the probability of target attainment with this agent over a range of MICs. Monte Carlo simulations were performed to determine the probability of attaining specific pharmacodynamic targets. The results indicated that a regimen consisting of a 4-h infusion of 3 g of sulbactam every 8 h would be an alternative treatment option for less-susceptible pathogens.
TEXT
During the past 2 decades, various Acinetobacter species, in particular Acinetobacter baumannii, have emerged as agents of serious nosocomial infections in critically ill patients in intensive-care units. These species are resistant to most common antimicrobial agents, and only a few antibiotics provide effective treatment for infections caused by these multidrug-resistant (MDR) pathogens (1, 2). Sulbactam, a β-lactamase inhibitor, is commercially available mainly in combination with β-lactam antibiotics (as in ampicillin-sulbactam or cefoperazone-sulbactam), and its major role in formulation is to bind irreversibly to active sites of enzymes produced by bacteria in order to block the activity of β-lactamases against β-lactam antibiotics. The antimicrobial property that distinguishes sulbactam from other β-lactamase inhibitors is its activity against Acinetobacter spp. (3). Therefore, due to the worldwide spread of MDR A. baumannii, for which only a few effective antimicrobial agents are currently available, sulbactam is being considered as an alternative treatment option. This agent is characterized by time-dependent antimicrobial activity, and the percentage of the exposure time during which the free-drug concentration remains above the MIC (%T>MIC) is the pharmacokinetic/pharmacodynamic (PK/PD) index that best correlates with efficacy (4). A previous study showed that sulbactam remained 93% stable for 24 h at 37°C (5). Thus, the preferred method of administration to maximize this parameter would be continuous or prolonged infusion. However, to date, there have been no pharmacodynamic modeling studies of this agent. To our knowledge, the current study is the first PK/PD modeling study of sulbactam using a Monte Carlo simulation (MCS) with healthy volunteers. The aims of the study were (i) to reveal a population PK model to describe the disposition of sulbactam in humans and (ii) to assess the efficacies of various dosage regimens of sulbactam in terms of the probability of target attainment (PTA) over a range of MICs.
The study was conducted with 12 nonsmoking, nonalcoholic, nonobese healthy volunteers, 6 males and 6 females, with a mean age of 27.58 ± 5.23 years (range, 19 to 37 years), a mean weight of 58.29 ± 7.03 kg (range, 47 to 69 kg), and a mean body mass index of 21.59 ± 1.66 kg/m2 (range, 18.65 to 23.87 kg/m2). The protocol for the study was approved by the Ethics Committee of Songklanagarind Hospital, and written informed consent was obtained from each subject prior to the beginning of the study. All subjects underwent a prestudy evaluation to ensure that they had no underlying illness and were not currently taking or had not recently taken any medications. All subjects had a creatinine clearance rate of ≥80 ml/min and no known history of intolerance to sulbactam or any β-lactam. All subjects had normal biochemical and hematological laboratory profiles. Sulbactam (Sibatam) was generously donated by the Siam Pharmaceutical Co., Ltd., Bangkok, Thailand. The subjects were randomized into two groups. Group I received a 1-h infusion of a single 1-g dose of sulbactam diluted in 100 ml of normal saline solution via an infusion pump at a constant flow, and group II received a 4-h infusion of a single 1-g dose of sulbactam diluted in 100 ml of normal saline solution via an infusion pump at a constant flow. The sulbactam PK studies were carried out after the administration of sulbactam. Blood samples (∼3 ml) were obtained through a peripheral venous catheter at the following times: shortly before the administration of sulbactam (time zero) and then at 0.5, 1, 1.5, 2, 3, 4, 4.5, 5, 6, 8, and 12 h after the start of the infusion. All blood samples were added to a heparinized tube, centrifuged within 5 min at 1,000 × g and 4°C for 10 min, and stored at −80°C until analysis (within 1 week). The concentrations of sulbactam were determined by the method of Bawdon and Madsen (6). The method of PK analysis is described in detail elsewhere (7). In brief, differential equations describing a three-compartment infusion model were solved numerically using Taylor series expansion (8), using the Visual Basic programming language in Microsoft Excel, and PK parameters were obtained by minimizing the objective functions of the sum of squared errors (SSE) of logarithmically transformed data using random heuristic optimization (9, 10). The Monte Carlo simulation of concentration-time profiles was performed using the Box-Muller transform to simulate the log-normal distribution of PK parameters (11), and the generated PK parameters were selected numerically to ensure the same statistical behavior. Twenty-five thousand iterations were performed to calculate the probabilities of attaining 20%, 30%, and 40% T>MIC.
Figure 1 demonstrates the simulated plasma concentration-time profiles for an average subject in the population for different durations of infusion of 1-, 2-, 3-, and 4-g doses (Fig. 1A, B, C, and D, respectively) and for 3-, 6-, 9-, and 12-g doses administered every 24 h as a continuous infusion (Fig. 1E). The population PK parameters are shown in Table 1, and the PTAs for different sulbactam regimens at specific MICs, with targets of 20% T>MIC, 30% T>MIC, and 40% T>MIC, are shown in Table 2. Sulbactam has been found to be approximately 38% bound to protein (12), and only the remaining free drug is available for antimicrobial activity. Studies in animal infection models have shown that for most β-lactams, drug concentrations do not need to exceed the MIC for 100% of the dosing interval in order to achieve a significant antibacterial effect (13, 14), and for some β-lactams, the %T>MIC required for bactericidal activity is 40% of the dosing interval (15). A randomized, prospective study of critically ill patients with ventilator-associated pneumonia (VAP) was conducted to evaluate the efficacy and safety of two high-dosage regimens of ampicillin-sulbactam (daily doses of 18 and 9 g and of 24 and 12 g, respectively). The clinical and bacteriological results of the study indicated that high-dosage regimens of this agent could be an alternative treatment option for MDR A. baumannii infection in patients with VAP (16). Another previous prospective cohort study in critically ill patients with VAP also found that a high-dose of ampicillin-sulbactam (6 and 3 g, respectively, every 8 h [q8h]) and 3 million IU of colistin q8h were comparably effective and safe treatments for MDR A. baumannii infections in this patient population (17). The MIC90 of sulbactam against A. baumannii at our hospital was ≤8 mg/liter. In the current study, the probabilities of the prolonged-infusion regimens of sulbactam achieving targets of 20% T>MIC, 30% T>MIC, and 40% T>MIC were greater than those of the 1-h infusion regimens. In addition, prolongation of the infusion time was a more effective strategy than dose escalation for achieving a high PTA (≥90%) for pathogens with high MICs. A high PTA for a target of 40% T>MIC with MICs of 2 mg/liter was observed when sulbactam was administered by a 4-h infusion of 1 g q8h. For pathogens with MICs of 4 and 8 mg/liter, high PTAs were achieved when the dosages of sulbactam were increased to 4-h infusions of 2 g q8h and 3 g q8h, respectively. From these data, it appears that for the treatment of less-susceptible pathogens, the dosage regimen of sulbactam should be increased to a 4-h infusion of 3 g q8h. However, the prolonged infusion of 4 g of sulbactam q8h and the continuous infusion of 12 g sulbactam q24h did not achieve higher PTAs than a prolonged infusion of 3 g of sulbactam q8h.
Fig 1.
Simulated concentration-time profiles for 1-g (A), 2-g (B), 3-g (C), and 4-g (D) doses of sulbactam with various durations of infusion and for various doses of sulbactam administered over 24 h as a continuous infusion (E). The profiles shown are for an average subject in the population.
Table 1.
Pharmacokinetic parameters of sulbactam in 12 healthy volunteers after administration by 1-h and 4-h infusions
| Parametera | Geometric mean | Geometric SD | Median | 95% CIb |
|---|---|---|---|---|
| k12 (h−1) | 0.637 | 2.003 | 0.866 | 0.189–1.430 |
| k21 (h−1) | 0.663 | 1.736 | 0.658 | 0.242–1.464 |
| k13 (h−1) | 8.626 | 2.035 | 8.797 | 3.116–22.629 |
| k31 (h−1) | 5.424 | 2.058 | 5.464 | 1.819–18.781 |
| kel (h−1) | 3.223 | 1.380 | 3.391 | 2.006–4.865 |
| CL (liters/h) | 11.903 | 1.978 | 12.693 | 4.777–33.546 |
| V (liters) | 3.693 | 1.434 | 3.743 | 2.382–6.895 |
k12, intercompartmental transfer rate constant from compartment X1 to X2; k21, intercompartmental transfer rate constant from compartment X2 to X1; k13, intercompartmental transfer rate constant from compartment X1 to X3; k31, intercompartmental transfer rate constant from compartment X3 to X1; kel, elimination rate constant from compartment X1; CL, total clearance; V, volume of distribution.
CI, confidence interval.
Table 2.
Probabilities of target attainment for sulbactam regimens in 12 healthy volunteers
| Dosage regimen | Duration of infusion (h) | MIC (mg/liter) | Probability of attaining the following %T>MICa: |
||
|---|---|---|---|---|---|
| 20% | 30% | 40% | |||
| 1 g q8h | 1 | 1 | 0.17 | 0.00 | 0.00 |
| 2 | 0.04 | 0.00 | 0.00 | ||
| 4 | 0.06 | 0.00 | 0.00 | ||
| 2 | 1 | 0.99 | 0.21 | 0.00 | |
| 2 | 0.99 | 0.06 | 0.00 | ||
| 4 | 0.96 | 0.00 | 0.00 | ||
| 3 | 1 | 0.99 | 0.99 | 0.44 | |
| 2 | 0.99 | 0.99 | 0.20 | ||
| 4 | 0.88 | 0.87 | 0.02 | ||
| 4 | 1 | 0.99 | 0.99 | 0.99 | |
| 2 | 0.97 | 0.97 | 0.97 | ||
| 4 | 0.73 | 0.73 | 0.72 | ||
| 2 g q8h | 1 | 1 | 0.43 | 0.11 | 0.02 |
| 2 | 0.17 | 0.00 | 0.00 | ||
| 4 | 0.04 | 0.00 | 0.00 | ||
| 2 | 1 | 1.00 | 0.46 | 0.07 | |
| 2 | 0.99 | 0.21 | 0.00 | ||
| 4 | 0.99 | 0.06 | 0.00 | ||
| 3 | 1 | 0.99 | 0.99 | 0.66 | |
| 2 | 0.99 | 0.99 | 0.44 | ||
| 4 | 0.99 | 0.99 | 0.19 | ||
| 4 | 1 | 0.99 | 0.99 | 0.99 | |
| 2 | 0.99 | 0.99 | 0.99 | ||
| 4 | 0.97 | 0.97 | 0.97 | ||
| 3 g q8h | 1 | 4 | 0.09 | 0.00 | 0.00 |
| 8 | 0.02 | 0.00 | 0.00 | ||
| 16 | 0.06 | 0.00 | 0.00 | ||
| 2 | 4 | 0.99 | 0.14 | 0.00 | |
| 8 | 0.99 | 0.03 | 0.00 | ||
| 16 | 0.91 | 0.00 | 0.00 | ||
| 3 | 4 | 0.99 | 0.99 | 0.34 | |
| 8 | 0.97 | 0.97 | 0.10 | ||
| 16 | 0.73 | 0.72 | 0.00 | ||
| 4 | 4 | 0.99 | 0.99 | 0.99 | |
| 8 | 0.92 | 0.92 | 0.91 | ||
| 16 | 0.52 | 0.52 | 0.50 | ||
| 4 g q8h | 1 | 4 | 0.17 | 0.01 | 0.00 |
| 8 | 0.04 | 0.00 | 0.00 | ||
| 16 | 0.00 | 0.00 | 0.00 | ||
| 2 | 4 | 0.99 | 0.21 | 0.00 | |
| 8 | 0.99 | 0.06 | 0.00 | ||
| 16 | 0.97 | 0.00 | 0.00 | ||
| 3 | 4 | 0.99 | 0.99 | 0.43 | |
| 8 | 0.99 | 0.99 | 0.19 | ||
| 16 | 0.88 | 0.87 | 0.02 | ||
| 4 | 4 | 0.99 | 0.99 | 0.99 | |
| 8 | 0.97 | 0.97 | 0.97 | ||
| 16 | 0.73 | 0.72 | 0.72 | ||
| 3 g q24h | 24 | 4 | 0.23 | 0.23 | 0.23 |
| 6 g q24h | 24 | 4 | 0.74 | 0.74 | 0.74 |
| 9 g q24h | 24 | 4 | 0.92 | 0.92 | 0.92 |
| 12 g q24h | 24 | 4 | 0.97 | 0.97 | 0.97 |
%T>MIC, percentage of the dosing interval during which drug concentrations in tissue and serum are above the MIC.
This study had a few limitations that must be noted. First, the study was performed with healthy volunteers, and thus, it may be problematic to extrapolate the findings to critically ill patients with severe sepsis, because PK changes, including increased volume of distribution and clearance of hydrophilic antibiotics, may occur in this patient population compared with healthy subjects, resulting in fluctuations in the concentrations of the drug in plasma and in the PK/PD index. Second, the concentrations of both free and protein-bound sulbactam in plasma were measured in this study, whereas only free drug is used for calculating the PK/PD index to determine the antimicrobial activity of this agent.
In conclusion, a high PTA (≥90%) for a target of 40% T>MIC with a MIC of 8 mg/liter was observed when sulbactam was administered by a 4-h infusion of 3 g q8h, which indicated that this dosage regimen would be an alternative treatment option for less-susceptible pathogens. However, further pharmacodynamic studies of sulbactam in critically ill patients with severe sepsis should be conducted to assess the efficacies of various dosage regimens of this agent.
ACKNOWLEDGMENTS
This work was supported by a faculty grant from the Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkla, Thailand.
We thank David Patterson for checking the English of the manuscript.
Footnotes
Published ahead of print 6 May 2013
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