Pharmacokinetic-pharmacodynamic Target Research Articles

Pharmacodynamics of a New Cephalosporin, PPI-0903 (TAK-599), Active against Methicillin-Resistant Staphylococcus aureus in Murine Thigh and Lung Infection Models: Identification of an In Vivo Pharmacokinetic-Pharmacodynamic Target

Pharmacodynamics of a New Cephalosporin, PPI-0903 (TAK-599), Active against Methicillin-Resistant Staphylococcus aureus in Murine Thigh and Lung Infection Models: Identification of an In Vivo Pharmacokinetic-Pharmacodynamic Target

Personalized therapeutics for levofloxacin: a focus on pharmacokinetic concerns

BackgroundPersonalized medicine should be encouraged because patients are complex, and this complexity results from biological, medical (eg, demographics, genetics, polypharmacy, and multimorbidities), socioeconomic, and cultural factors. Levofloxacin (LVX) is a broad-spectrum fluoroquinolone antibiotic. Awareness of personalized therapeutics for LVX seems to be poor in clinical practice, and is reflected in prescribing patterns. Pharmacokinetic–pharmacodynamic studies have raised concerns about suboptimal patient outcomes with the use of LVX for some Gram-negative infections. Meanwhile, new findings in LVX therapeutics have only been sporadically reported in recent years. Therefore, an updated review on personalized LVX treatment with a focus on pharmacokinetic concerns is necessary.MethodsRelevant literature was identified by performing a PubMed search covering the period from January 1993 to December 2013. We included studies describing dosage adjustment and factors determining LVX pharmacokinetics, or pharmacokinetic–pharmacodynamic studies exploring how best to prevent the emergence of resistance to LVX. The full text of each included article was critically reviewed, and data interpretation was performed.ResultsIn addition to limiting the use of fluoroquinolones, measures such as reducing the breakpoints for antimicrobial susceptibility testing, choice of high-dose short-course of once-daily LVX regimen, and tailoring LVX dose in special patient populations help to achieve the validated pharmacokinetic–pharmacodynamic target and combat the increasing LVX resistance. Obese individuals with normal renal function cleared LVX more efficiently than normal-weight individuals. Compared with the scenario in healthy subjects, standard 2-hour spacing of calcium formulations and oral LVX was insufficient to prevent a chelation interaction in cystic fibrosis patients. Inconsistent conclusions were derived from studies of the influence of sex on the pharmacokinetics of LVX, which might be associated with sample size and administration route. Children younger than 5 years cleared LVX nearly twice as fast as adults. Patients in intensive care receiving LVX therapy showed significant pharmacokinetic differences compared with healthy subjects. Creatinine clearance explained most of the population variance in the plasma clearance of LVX. Switching from intravenous to oral delivery of LVX had economic benefits. Addition of tamsulosin to the LVX regimen was beneficial for patients with bacterial prostatitis because tamsulosin could increase the maximal concentration of LVX in prostatic tissue. Coadministration of multivalent cation-containing drugs and LVX should be avoided. For patients receiving warfarin and LVX concomitantly, caution is needed regarding potential changes in the international normalized ratio; however, it is unnecessary to seek alternatives to LVX for the sake of avoiding drug interaction with warfarin. It is unnecessary to proactively reduce the dose of cyclosporin or tacrolimus when comedicated with LVX. Transporters such as organic anion-transporting polypeptide 1A2, P-glycoprotein, human organic cation transporter 1, and multidrug and toxin extrusion protein 1 are involved in the pharmacokinetics of LVX.ConclusionPersonalized LVX therapeutics are necessary for the sake of better safety, clinical success, and avoidance of resistance. New findings regarding individual dosing of LVX in special patient populations and active transport mechanisms in vivo are opening up new horizons in clinical practice.

Pharmacokinetic-Pharmacodynamic Target Attainment Analyses To EvaluateIn VitroSusceptibility Test Interpretive Criteria for Ceftaroline against Staphylococcus aureus and Streptococcus pneumoniae

To provide support for in vitro susceptibility test interpretive criteria decisions for ceftaroline against Staphylococcus aureus and Streptococcus pneumoniae, as well as dose adjustment recommendations for renal impairment, pharmacokinetic-pharmacodynamic (PK-PD) target attainment was evaluated for simulated patients administered intravenous (i.v.) ceftaroline fosamil at 600 mg twice daily (q12h) and simulated patients with renal impairment administered various dosing regimens. Using a previously developed population PK model, Monte Carlo simulation was used to generate ceftaroline plasma concentration profiles for simulated patients with normal renal function or mild, moderate, or severe renal impairment. Using these profiles, the percentage of time during the dosing interval that free-drug concentrations remained above the MIC (f%T>MIC) for ceftaroline at steady state was calculated. Percentages of simulated patients achieving f %T>MIC targets for S. aureus and S. pneumoniae based on murine infection models were calculated by MIC. At MICs of 2 mg/liter for S. aureus and 1 mg/liter for S. pneumoniae, the percentages of simulated patients with normal renal function and mild renal impairment following administration of ceftaroline fosamil at 600 mg q12h, moderate renal impairment following administration of ceftaroline fosamil at 400 mg q12h, and severe renal impairment following administration of ceftaroline fosamil at 300 mg q12h achieving f %T>MIC targets (≥26 for S. aureus and ≥44 for S. pneumoniae) exceeded 90%. The results of these analyses, which suggested that in vitro susceptibility test interpretive criteria defining susceptible could be as high as MICs of ≤2 and ≤1 mg/liter for ceftaroline against S. aureus and S. pneumoniae, respectively, provide support for current FDA and CLSI criteria, which define susceptible as MICs of 1 and 0.5 mg/liter, respectively. Recommendations for dose adjustments for patients with renal impairment were also supported by the results of these analyses.

Pharmacokinetics of Oseltamivir and Oseltamivir Carboxylate in Critically Ill Patients Receiving Continuous Venovenous Hemodialysis and/or Extracorporeal Membrane Oxygenation

To investigate oseltamivir and oseltamivir carboxylate pharmacokinetics in critically ill patients who were receiving continuous venovenous hemodialysis (CVVHD) and/or extracorporeal membrane oxygenation (ECMO). Prospective, open-label, pharmacokinetic study. Intensive care units of an academic medical center. Thirteen critically ill patients aged 13years or older with suspected or confirmed H1N1 influenza who had a prescription for oseltamivir and were concurrently receiving CVVHD and/or ECMO between October 2009 and January 2010. Oseltamivir 150mg was administered nasogastrically or nasoenterically every 12hours. Blood samples were collected at baseline and at 1, 2, 4, 6, 8, 10, and 12hours after administration of the fourth oseltamivir dose or subsequent doses. In patients receiving CVVHD, effluent also was collected at the same time points. Urine was collected throughout the 12-hour dosing interval. Eight patients received CVVHD only, four patients received both CVVHD and ECMO, and one patient received ECMO only. Pharmacokinetic parameters for the patient who received only ECMO were not reported. The median maximum plasma concentration and area under the plasma concentration-time curve for the 12-hour dosing interval (AUC(0-12) ) for the remaining 12 patients were 83.4ng/ml and 216ng•hour/ml, respectively, for oseltamivir and 2000ng/ml and 21,500ng•hour/ml, respectively, for oseltamivir carboxylate. Mean clearance due to CVVHD was 33.8ml/minute for oseltamivir and 50.2ml/minute for oseltamivir carboxylate. For patients who received ECMO, no substantial differences between pre- and post-ECMO oxygenator plasma concentrations were found for oseltamivir or oseltamivir carboxylate. Although the optimal pharmacokinetic-pharmacodynamic targets for oseltamivir carboxylate remain unclear, in the patients receiving CVVHD with or without ECMO, a regimen of oseltamivir 150mg every 12hours yielded a median oseltamivir carboxylate AUC(0-12) considerably higher than would be expected in non-critically ill patients receiving the same dosage regimen.

Declining susceptibilities of gram-negative bacteria to the fluoroquinolones: Effects on pharmacokinetics, pharmacodynamics, and clinical outcomes

Published evidence of rising gram-negative bacterial resistance to fluoroquinolone therapy is reviewed, with a focus on the potential need for revising pharmacokinetic-pharmacodynamic (PK-PD) targets in order to maintain acceptable clinical outcomes. With a more than threefold increase in fluoroquinolone use among U.S. adults since the introduction of second- and third-generation (i.e., "respiratory") fluoroquinolones 15 years ago, surveillance data indicate a decline in some gram-negative organisms' susceptibility to this antimicrobial class. These trends have raised concerns that the need to attain higher organism-specific minimum inhibitory concentrations (MICs) may lead to worse patient outcomes, even when MIC values are below current established "clinical breakpoints" for fluoroquinolone susceptibility. A growing body of evidence from PK-PD studies suggests that current fluoroquinolone dosing regimens are no longer adequate to achieve validated PK-PD targets. For example, a Monte Carlo simulation using PK data from U.S. hospitals showed decreasing rates of response to standard ciprofloxacin and levofloxacin i.v. dosing regimens among patients treated for infections with Escherichia coli and Klebsiella species. These findings suggest that currently accepted PK-PD targets may need to be revised for certain patient populations, including patients with bloodstream infections (BSIs). More research is needed to confirm the appropriateness of adjusting clinical breakpoints and other strategies to combat rising fluoroquinolone resistance. The use of the fluoroquinolones has markedly increased since the introduction of the respiratory fluoroquinolones. Surveillance data and PK-PD studies have raised concerns about suboptimal patient outcomes with the use of fluoroquinolones for some gram-negative infections, particularly BSIs. PK-PD goals and clinical breakpoints may need to be revised for these infections.

Optimisation of imipenem regimens in patients with impaired renal function by pharmacokinetic-pharmacodynamic target attainment analysis of plasma and urinary concentration data

In this study, a pharmacokinetic-pharmacodynamic (PK-PD) target attainment analysis of imipenem (IPM) in patients with impaired renal function was conducted. IPM (500mg) was administered via a 0.5-h or 1-h infusion to 27 patients with varying renal function. A population PK model was developed by simultaneously fitting plasma and urinary concentration data. A two-compartment model adequately described IPM pharmacokinetics, and creatinine clearance (CLCr) was identified as the most significant covariate. A PK-PD simulation predicted the probabilities of attaining the target in plasma [40% of the time above the minimum inhibitory concentration (MIC)] and defined the PK-PD breakpoints (the highest MICs at which the probabilities were ≥90%). In a patient with a CLCr of 90mL/min, prolongation of infusion time (from 0.5h to 1.5h) increased the PK-PD breakpoint from 1μg/mL to 2μg/mL with a 500mg dose every 8h (q8h) and from 2μg/mL to 4μg/mL with a 500mg dose every 6h (q6h). Meanwhile, in a patient with a CLCr of 20mL/min, the PK-PD breakpoints for both 0.5-h and 1.5-h infusions were 1μg/mL with a 250mg dose every 12h (q12h), 2μg/mL with a 250mg dose q8h and a 500mg dose q12h, and 4μg/mL with a 250mg dose q6h. These results indicate that a shorter dosing interval is beneficial in patients with impaired renal function as it results in greater PK-PD breakpoints and a reduction in excessive maximum plasma concentrations. These results help to optimise IPM regimens, particularly in patients with impaired renal function.

Ciprofloxacin pharmacokinetics and oral absorption of generic ciprofloxacin tablets in dogs

To determine the pharmacokinetics of ciprofloxacin in dogs, including oral absorption following administration of generic ciprofloxacin tablets. 6 healthy Beagles. In a crossover study design, ciprofloxacin was administered as a generic tablet (250 mg, PO; mean dose, 23 mg/kg) and solution (10 mg/kg, IV) to 6 dogs. In a separate experiment, 4 of the dogs received ciprofloxacin solution (10 mg/mL) PO via stomach tube (total dose, 250 mg). Blood samples were collected before (time 0) and for 24 hours after each dose. Plasma concentrations were analyzed with high-pressure liquid chromatography. Pharmacokinetic analysis was performed by means of compartmental modeling. When ciprofloxacin was administered as tablets PO, peak plasma concentration was 4.4 μg/mL (coefficient of variation [CV], 55.9%), terminal half-life (t(1/2)) was 2.6 hours (CV, 10.8%), area under the time-concentration curve was 22.5 μg•h/mL (CV, 62.3%), and systemic absorption was 58.4% (CV, 45.4%). For the dose administered IV, t(1/2) was 3.7 hours (CV, 52.3%), clearance was 0.588 L/kg/h (CV, 33.9%), and volume of distribution was 2.39 L/kg (CV, 23.7%). After PO administration as a solution versus IV administration, plasma concentrations were more uniform and consistent among dogs, with absorption of 71% (CV, 7.3%), t(1/2) of 3.1 hours (CV, 18.6%), and peak plasma concentration of 4.67 μg/mL (CV, 17.6%). Inconsistent oral absorption of ciprofloxacin in some dogs may be formulation dependent and affected by tablet dissolution in the small intestine. Because of the wide range in oral absorption of tablets, the dose needed to reach the pharmacokinetic-pharmacodynamic target concentration in this study ranged from 12 to 52 mg/kg (CV, 102%), with a mean dose of 25 mg/kg, once daily, for bacteria with a minimum inhibitory concentration ≤ 0.25 μg/mL.

Evaluation of fluoroquinolone reduced dosage regimens in elderly patients by using pharmacokinetic modelling and Monte Carlo simulations

Fluoroquinolones are widely used in geriatric patients, but elderly patients are known to be at increased risk of decline in renal function. As fluoroquinolones usually exhibit a dominant renal elimination pathway, reduced dosage regimens are often used in geriatric patients. Our objective was to assess the capability to reach a pharmacokinetic-pharmacodynamic target of efficacy with such reduced dosage regimens of ofloxacin, levofloxacin and ciprofloxacin in elderly patients. Using Monte Carlo simulations, 1000 simulated elderly patients were created, based on published pharmacokinetic and pharmacodynamic data, and measured demographic data. Three usually proposed drug regimens taking renal function into account were evaluated using compartmental models. The probability of reaching an fAUC/MIC >100 was calculated for each regimen. For MICs <1 mg/L, all simulated patients reach the efficacy target. However, with higher values of MIC, the proposed regimens were inefficient for patients with moderate or severe renal impairment: 3.4% and 30.2% of patients with moderate renal impairment reached the efficacy target for ciprofloxacin and ofloxacin, respectively, for an MIC of 2 mg/L. For ciprofloxacin, more than 80% of patients with severe renal impairment were unable to reach the target fAUC/MIC with an MIC as low as 1 mg/L, whereas for levofloxacin, all simulated patients reached the efficacy target until an MIC of 4 mg/L. This suggests that the proposed dosage reduction does not allow the same exposure to be achieved in elderly patients with renal impairment, eventually leading to treatment failure or development of resistant strains.

Modeling Approach To Characterize Intraocular Doripenem Pharmacokinetics after Intravenous Administration to Rabbits, with Tentative Extrapolation to Humans

The aim of this study was to determine the penetration of doripenem administered intravenously into the rabbit aqueous and vitreous humors. Nineteen New Zealand White rabbits received a 20-mg dose of doripenem intravenously over 60 min. Specimens of aqueous humor, vitreous humor, and blood were obtained 30 min (n = 5), 1 h (n = 5), 2 h (n = 5), and 3 h (n = 4) after the beginning of the infusion and analyzed by high-performance liquid chromatography (HPLC). A pharmacokinetic (PK) model was developed to fit the experimental data. Doripenem concentrations in aqueous humor were lower than those in plasma ultrafiltrates at all sampling times, with an average aqueous humor-to-plasma ultrafiltrate area under the concentration-time curve ratio estimated as 8.3%. A pharmacokinetic model with peripheral elimination described the data adequately and was tentatively used to predict concentration-versus-time profiles and pharmacokinetic-pharmacodynamic (PK-PD) target attainment in patients under various dosing regimens. In conclusion, systematically administered doripenem does not seem to be a promising approach for the treatment of intraocular infections, especially since it could not be detected in the vitreous humor. However, this study has provided an opportunity to develop a new PK modeling approach to characterize the intraocular distribution of doripenem administered intravenously to rabbits, with tentative extrapolation to humans.

Validation of the Effectiveness of a Vancomycin Nomogram in Achieving Target Trough Concentrations of 15–20 mg/L Suggested by the Vancomycin Consensus Guidelines

To assess and validate the effectiveness of a newly constructed vancomycin dosing nomogram in achieving target trough serum concentrations of 15-20 mg/L. Prospective multicenter study. Five tertiary care teaching hospitals. A total of 200 adults who required vancomycin dosages targeted to attain recommended trough vancomycin serum concentrations of 15-20 mg/L. The new nomogram, which based dosing on weight and renal function, was used to calculate patients' initial vancomycin dosages. Serum trough concentrations were measured before the fourth or fifth dose, and dosages were adjusted as needed. Median patient age was 56 years (interquartile range [IQR] 49-65 yrs), median weight was 71.2 kg (IQR 63-85 kg), and median creatinine clearance was 66.5 ml/minute (IQR 52-82 ml/min). The median initial vancomycin trough concentration achieved was 17.5 mg/L (IQR 15.0-20.0 mg/L), with 116 patients (58%) achieving the initial target trough of 15-20 mg/L. The median percent error was 13.6%, and the mean ± SD error for predicted versus actual serum trough concentrations was -0.50 ± 0.021 mg/L. One hundred fifty-four patients (77%) eventually achieved the trough target concentration within a median of 2 days. One hundred forty patients (70%) achieved initial troughs of 14-21 mg/L and 160 (80%) achieved troughs of 13-22 mg/L. Nine patients (4.5%) experienced nephrotoxicity while receiving vancomycin, which occurred after a median of 8 days of therapy. The median initial vancomycin trough concentration for these patients was 18.5 mg/L (IQR 15.3-19.3 mg/L), with eight of the nine patients having trough concentrations of 15 mg/L or greater. Fifty-eight percent of patients achieved the target trough of 15-20 mg/L (median 17.5 mg/L). The performance of the nomogram improved to 80% when the trough range was adjusted to 13-22 mg/L. Caution should be applied when using this nomogram. The nomogram should not replace clinical judgment, and dosage adjustments should be based on pharmacokinetic-pharmacodynamic targets and clinical response.

A novel subcutaneous controlled‐release amoxicillin degradable implant for extended‐interval administration in veterinary medicine

Dosage forms of antimicrobials play a critical role in facilitating the attainment of pharmacokinetic-pharmacodynamic (PK-PD) targets as well as adherence in both veterinary and human medicine. The purpose of this study was to develop and evaluate a controlled-release subcutaneous amoxicillin implant for single-dose therapy of large ruminants such as goats, sheep, and deer. The degradable implant, designed to attain PK-PD targets following single administration, was evaluated for amoxicillin release rate and time-concentration profile. In vitro release studies demonstrated constant-rate release of approximately 40% of amoxicillin content within 96 h. In an in vivo study in goats, serving as a model for target animals, a serum concentration of approximately 0.4 mg/L was achieved within 8 h of implant insertion and maintained for >6 days. In comparison, in control goats given a standard single intramuscular amoxicillin dose of 15 mg/kg, amoxicillin peaked at 1.2 mg/L after 1 h, rapidly dropping to below detection level at 8 h. These results suggest that the proposed implant offers a unique modality for animal caregivers to conveniently administer a full antimicrobial course following a single dose of an efficient PK-PD-optimized dosage form. Furthermore, modifications of implant composition may allow for tailoring of its characteristics to various PK, PD, microbiological, and clinical requirements.

Flucloxacillin dosing in critically ill patients with hypoalbuminaemia: special emphasis on unbound pharmacokinetics

To describe the total and unbound plasma concentration-time profiles for highly protein-bound flucloxacillin (95%-97% protein binding) in critically ill patients with hypoalbuminaemia and without severe renal dysfunction, and to use population pharmacokinetic modelling and Monte Carlo simulations to assess the probability of target attainment against an MIC distribution. Ten patients with hypoalbuminaemia and receiving flucloxacillin as part of therapy were enrolled. Sixty-seven total, 67 unbound plasma and 10 urine samples were collected and analysed. Population pharmacokinetic modelling of unbound plasma data and Monte Carlo simulations were then undertaken with NONMEM. Non-compartmental pharmacokinetic analysis was performed for total plasma concentrations. Total flucloxacillin V was increased in critically ill patients with hypoalbuminaemia 2-fold compared with healthy volunteer data. Unbound flucloxacillin concentrations after 2 g bolus fell below 1 mg/L 4 h after the end of the infusion, providing evidence that standard dosing would be insufficient for the treatment of methicillin-susceptible Staphylococcus aureus (MSSA) (MIC = 2 mg/L). Monte Carlo simulations suggest that continuous infusion of 8 g/24 h flucloxacillin would enable 100% successful attainment of the pharmacodynamic target, 50% fT( > MIC). For more aggressive targets (4-5x MIC for 100% fT( > MIC)), continuous infusion of higher doses (i.e. 12 g/24 h) would be required. Administration of standard doses by intermittent bolus is likely to result in underdosing, and continuous infusion of higher doses is more likely to achieve pharmacokinetic-pharmacodynamic targets for the treatment of infections caused by the most common wild type of MSSA. Our data emphasize the importance of using unbound concentrations for determining dosage regimens for highly bound antibiotics.

Pharmacokinetic–pharmacodynamic target attainment analysis of meropenem in Japanese adult patients

This study was a pharmacokinetic (PK)-pharmacodynamic (PD) target attainment analysis of meropenem in Japanese adult patients. Plasma drug concentration data (265 samples from 42 patients) were used for population PK modeling and Monte Carlo simulation to assess the probability of attaining the PK-PD target (40% of the time above the MIC for the bacterium). The final population PK model identified creatinine clearance (Cl(cr), ml/min) and body weight (BW, kg) as the most significant covariates: Cl (l/h) = 0.0905 × Cl(cr) + 2.03, V(c)(l) = 0.199 9 BW, Q (l/h) = 4.02, and V(p) (l) = 4.55, where Cl is the clearance, Vc and Vp are the volumes of distribution of the central and peripheral compartments, respectively, and Q is the intercompartmental clearance. The Monte Carlo simulation developed the PK-PD breakpoints (the highest MIC values at which the probabilities of target attainment in plasma are 80% or more) for meropenem regimens, the values of which varied with the Cl(cr) and BW of the patient. The simulation also demonstrated that 0.25 g every 12 h (0.5-h infusion) achieved a target attainment probability of 82.4-100% against Escherichia coli, methicillin-susceptible Staphylococcus aureus, Haemophilus influenzae, and Streptococcus pneumoniae isolates. However, against Pseudomonas aeruginosa isolates, 0.5 g every 8 h or 1 g every 8 h was required to achieve 80% or more probability in most typical patients. These results provide a PK-PD-based strategy for tailoring a meropenem regimen according to Clcr and BW of a Japanese adult patient and susceptibility of the causative bacteria.

Curbing resistance development: maximizing the utility of available agents.

Ventilator-associated pneumonia (VAP) in hospital intensive care units (ICUs) is associated with high morbidity and mortality. Effective treatment of VAP can be challenging due to a high prevalence of Pseudomonas aeruginosa and multidrug-resistant (MDR) pathogens as causative organisms. To present the etiology of VAP in the United States (including national resistance trends of common nosocomial pathogens) and review dosing strategies aimed to optimize pharmacokinetic-pharmacodynamic parameters of antimicrobial agents. The majority of nosocomial pneumonia cases are caused by gram-negative pathogens, most commonly P. aeruginosa, Enterobacter spp., A. baumannii, and K. pneumoniae. S. aureus is the most common gram-positive pathogen, with 55% of VAP isolates exhibiting methicillin resistance. Combination therapy is recommended when MDR pathogens and P. aeruginosa are suspected, although short-course therapy and deescalation should be considered when appropriate to reduce the risk of resistance. Optimized dosing strategies are important in increasing the probability of achieving successful outcomes. For example, when administering intravenous -lactam therapy, prolonged infusion can be effective in increasing the T > MIC. Clinicians need to be familiar with local antibiograms as well as regional resistance trends in order to choose appropriate therapy for VAP. Optimized dosing strategies can be effective in increasing the probability of attaining pharmacokinetic-pharmacodynamic targets predictive of successful clinical outcomes.

Redefining Success for VAP: 360-Degree Approach

BACKGROUND: Ventilator-associated pneumonia (VAP) in hospital intensive care units (ICUs) is associated with high morbidity and mortality. Effective treatment of VAP can be challenging due to a high prevalence of Pseudomonas aeruginosa and multidrug-resistant (MDR) pathogens as causative organisms. OBJECTIVE: To present the etiology of VAP in the United States (including national resistance trends of common nosocomial pathogens) and review dosing strategies aimed to optimize pharmacokinetic-pharmacodynamic parameters of antimicrobial agents. SUMMARY: The majority of nosocomial pneumonia cases are caused by gram-negative pathogens, most commonly P. aeruginosa, Enterobacter spp., A. baumannii, and K. pneumoniae. S. aureus is the most common gram-positive pathogen, with 55% of VAP isolates exhibiting methicillin resistance. Combination therapy is recommended when MDR pathogens and P. aeruginosa are suspected, although short-course therapy and deescalation should be considered when appropriate to reduce the risk of resistance. Optimized dosing strategies are important in increasing the probability of achieving successful outcomes. For example, when administering intravenous β-lactam therapy, prolonged infusion can be effective in increasing the T > MIC. CONCLUSION: Clinicians need to be familiar with local antibiograms as well as regional resistance trends in order to choose appropriate therapy for VAP. Optimized dosing strategies can be effective in increasing the probability of attaining pharmacokinetic-pharmacodynamic targets predictive of successful clinical outcomes. J Manag Care Pharm. 2009;15(5)(Suppl):S5-S9 Copyright © 2009, Academy of Managed Care Pharmacy. All rights reserved. DAVID S. BURGESS, PharmD, FCCP, is Clinical Professor of Pharmacy and Medicine, University of Texas at Austin, Austin, Texas, and the University of Texas Health Science Center at San Antonio, San Antonio, Texas. CORRESPONDENCE: David S. Burgess, PharmD, FCCP, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, MSC 6220, San Antonio, TX 78229-3900. Tel.: 210.567.8329; Fax: 210.567.8328; E-mail: burgessd@uthscsa.edu Author Introduction Ventilator-associated pneumonia (VAP) is among the most common nosocomial infections originating in the intensive care unit (ICU), affecting 9% to 27% of all intubated patients.1,2 The attributable mortality can be as high as 33% to 50%.1,2 The risk of VAP is correlated to the length of stay (LOS) in the hospital or ICU as well as to the duration of mechanical ventilation.2 Pseudomonas aeruginosa and multidrug-resistant (MDR) organisms account for over 20% of VAP infections, with higher rates observed in those with prolonged hospitalization.3 Infection by these problematic pathogens is associated with increased mortality, duration of mechanical ventilation, and hospital LOS.3 Therefore, when managing patients at high risk for VAP, it is important to recognize the local epidemiology and resistance trends in order to select the most appropriate initial antimicrobial therapy. Etiology of Hospital-Acquired Pneumonia Surveillance data from the National Healthcare Safety Network (NHSN, formerly the National Nosocomial Infections Surveillance System) have shown that gram-negative pathogens are the predominant cause of nosocomial pneumonia, accounting for approximately 70% of infections.4 Among the infections caused by gram-negative pathogens, P. aeruginosa is the leading cause (accounting for approximately 20%) followed by Enterobacter spp., Klebsiella pneumoniae, and Acinetobacter baumannii.4 The proportion of infections due to Acinetobacter has nearly doubled over the past 2 decades (from 4% in 1986 to 7% in 2003). However, there has been a gradual trend of increasing infections due to grampositive pathogens, mainly Staphylococcus aureus. The etiology of VAP can vary based on (a) local epidemiological trends as well as (b) the timing of onset of infection. According to the 2006–2007 NHSN data, the most common pathogen associated with VAP is S. aureus (24.4%) followed by P. aeruginosa (16.3%), Enterobacter spp. (8.4%), A. baumannii (8.4%), and K. pneumoniae (7.5%) (Table 1).5 The time of onset is also an important predictor of causative pathogens. Early-onset VAP, defined as VAP occurring within the first 5 days of hospitalization, is caused by enteric gram-negative bacteria (including Escherichia coli, K. pneumoniae, and Enterobacter spp.), Haemophilus influenzae, Streptococcus pneumoniae, and methicillin-susceptible S. aureus (MSSA).2,6 Late-onset VAP, defined as VAP occurring after 5 days of hospitalization, is more likely to be caused by MDR pathogens,2,6 including those associated with early-onset VAP as well as P. aeruginosa and A. baumannii. The variety and complexity of pathogens associated with VAP make choosing an appropriate initial therapy challenging. Appropriate Antimicrobial Therapy for VAP The American Thoracic Society (ATS) and the Infectious Diseases

START Stewardship Tactics for Antimicrobial Resistance Trends

START Stewardship Tactics for Antimicrobial Resistance Trends

Containing costs and containing bugs: are they mutually exclusive?

The overall health care costs for managing patients with community-acquired pneumonia (CAP) in U.S. hospitals is burdensome. While pharmacy costs comprise only a minor proportion of these costs, hospital length of stay (LOS) is the greatest contributor. Infections due to antimicrobial-resistant pathogens are also associated with increased overall health care cost. Therefore, strategies that aim to minimize antimicrobial resistance and reduce hospital LOS may have the greatest impact in reducing overall health care costs in managing patients with CAP. To evaluate how antimicrobial resistance can impact health care costs associated with CAP and review strategies to minimize the risk of resistance development while promoting appropriate antimicrobial therapy (including optimized dosing) and decreasing hospital LOS. Antimicrobial resistance can increase the risk of clinical failure and result in higher overall health care costs. Further development of antimicrobial resistance during therapy should, therefore, be minimized. This can be achieved through optimized antimicrobial dosing strategies- using a higher dose of concentration-dependent agents or prolonged infusion of time-dependent agents - that increase the probability of attaining pharmacokinetic-pharmacodynamic targets for eradication of the pathogen and hence successful clinical outcomes. Decreasing LOS must be a priority when attempting to reduce hospital costs. Active intravenous-to-oral switch therapy has been shown to effectively reduce LOS. Appropriate short-course regimens may also offer the opportunity for effective treatment while reducing or eliminating unnecessary antimicrobial exposure that not only reduces the potential for drug-related adverse events, but may also minimize the selection of resistant organisms. Clinical failure and antimicrobial resistance can significantly increase the cost of managing patients with CAP, primarily by increasing LOS. Therefore, strategies should be employed to minimize the risk of resistance development and reduce LOS. These include early appropriate therapy, optimized dosing based on pharmacodynamic principles, and efficient IV-to-PO switch therapy when appropriate.

Use of a clinically derived exposure–response relationship to evaluate potential tigecycline-Enterobacteriaceae susceptibility breakpoints

Potential tigecycline-Enterobacteriaceae susceptibility breakpoints were evaluated using 2 approaches, which differed in the nature of the probabilities assessed by MIC value. Using a previously derived tigecycline population pharmacokinetic model and Monte Carlo simulation, a probability density function of steady-state area under the concentration–time curve for 24 h (AUC SS(0-24)) values for 9999 patients was generated. AUC SS(0-24) values were divided by clinically relevant fixed MIC values to derive AUC SS(0-24)/MIC ratios, which were used to calculate the clinical response expectation by MIC value based upon a logistic regression model for efficacy (1st approach). For the 2nd approach, the probability of pharmacokinetic–pharmacodynamic (PK-PD) target attainment was calculated as the proportion of patients with AUC SS(0-24)/MIC ratios greater than the threshold value of 6.96, the PK-PD target associated with optimal clinical response. Probabilities of clinical response and PK-PD target attainment were poorly correlated at MIC values >0.25 mg/L. For instance, the median probability of clinical success was 0.76, whereas the probability of PK-PD target attainment was 0.27 at an MIC value of 1 mg/L, suggesting that the probability of PK-PD target attainment metrics underestimates the clinical performance of tigecycline at higher MIC values.

Pharmacokinetic-Pharmacodynamic Target Attainment Analysis of Biapenem in Adult Patients: A Dosing Strategy

Background: A pharmacokinetic-pharmacodynamic (PK-PD) target attainment analysis to build a dosing strategy for biapenem in adult patients has not been conducted. Methods: A total of 321 plasma concentration samples from 68 adult patients (1–6 samples per patient) were assayed biologically and chromatographically, and used for a population PK modeling and Monte Carlo simulation to assess the probability of attaining the PK-PD target (40% of the time above the minimum inhibitory concentration). Results: The population PK model was based on the standard two-compartment model, and creatinine clearance (Cl_cr) was the most significant covariate that affected the drug clearance. The Monte Carlo simulation demonstrated that the dosages up to 600 mg Q12H (0.5-h infusions) achieved a PK-PD target attainment probability of ≧90%, which varied with Cl_cr of the patient and susceptibility of the tested bacterium; however, higher dosage with prolonged infusion time (600 mg Q8H, 3 h infusion) was required for a high probability against Pseudomonas aeruginosa and Haemophilus influenzae isolates in the case of Cl_cr = 90 ml/min. Conclusion: These results provide guidance for constructing a PK-PD-based strategy for tailoring biapenem regimens in adult patients.

Meropenem Pharmacokinetics, Pharmacodynamics, and Monte Carlo Simulation in the Neonate

Hospitalized neonates are exposed to antibiotic-resistant bacterial pathogens and develop nosocomial infections. Limited data are available regarding the neonatal pharmacokinetics of meropenem, a broad spectrum carbapenem antibiotic. Neonates <2 months of age received a single dose of meropenem at 10 or 20 mg/kg. Meropenem serum concentrations were measured at specified times during the 24 hours postinfusion. Population pharmacokinetics (PPK) were evaluated using NONMEM. Using Monte Carlo simulation (MCS), the probability of pharmacokinetic-pharmacodynamic target attainment was evaluated by computer modeling from predictions extrapolated from PPK data, using "virtual" dosing regimens of 10, 20, and 40 mg/kg administered every 8 or 12 hours against community- and hospital-acquired pathogens. Thirty-seven neonates were enrolled, 22 were born at <36 weeks (range, 23-41 weeks) gestational age. Meropenem clearance was greater in neonates with older chronologic ages and in those born at later gestational ages. Serum creatinine and postconceptional age (PCA) were the best overall predictors of meropenem elimination: CL (L/h/kg) = 0.041 + 0.040/SCr + 0.003 x (PCA-35). MCS demonstrated that in infants during the first 2 weeks of life, a dosage of 20 mg/kg/dose every 8 hours achieved the desired PD target in 95% of preterm neonates and 91% of term neonates against Pseudomonas aeruginosa isolated from patients managed in adult and pediatric intensive care units in the United States. MCS based on PPK determinations demonstrated that a meropenem dose of 20 mg/kg every 8 hours should provide adequate therapy for most nosocomial Gram-negative pathogens.