PK-PD Compass: bringing infectious diseases pharmacometrics to the patient's bedside.

Antimicrobial stewardship programs face many challenges, one of which is a lack of guidance regarding antimicrobial dose, interval, and duration. There is no tool that considers patient demographic, pathogen susceptibility, and pharmacokinetic-pharmacodynamic (PK-PD) targets for efficacy in order to evaluate appropriate antimicrobial dosing regimens. The PK-PD Compass, an educational mobile application, was developed to address this unmet need. The application consists of a Monte Carlo simulation algorithm which integrates pharmacokinetic (PK) and PK-PD data, patient-specific characteristics, and pathogen susceptibility data. Through the integration of these data, the application allows practitioners to assess the percent probability of PK-PD target attainment for 35 intravenous antimicrobial agents across 29 infection categories. Population PK models for each drug were identified, evaluated, and refined as needed. Susceptibility breakpoints were based upon FDA and CLSI criteria. By incorporating these data into one interface, clinicians can select the infection, pathogen, and antimicrobial agents of interest and obtain the percent probability of PK-PD target attainment for each regimen based upon patient-specific characteristics. The antimicrobial dosing regimens provided include those recommended by standard guidelines and reference texts. However, unlike these references, potential choices are prioritized based on percent probabilities of PK-PD target attainment. Such data will educate clinicians on selecting optimized antibiotic regimens through the lens of PK-PD.

Pharmacodynamic modeling of intravenous antibiotics against gram-negative bacteria collected in the United States.

BACKGROUND: In the era of escalating antimicrobial resistance, the choice of effective empiric antimicrobial therapy has become considerably more difficult. In an attempt to improve antimicrobial selection, pharmacodynamic modeling that considers the drug, dose, dosing interval, and duration of infusion is increasingly used as a tool to assist in the clinical decision-making process. OBJECTIVE: The aim of the PASSPORT (Probability of target attainment of Antibacterial agents Studied for Susceptibility and Pharmacodynamic Optimization in Regional Trials) study was to compare the probabilities of achieving requisite pharmacodynamic exposure (eg, T>MIC, AUC/MIC) of common intravenous antibiotics against Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa. METHODS: Using a 5000-patient Monte Carlo simulation, pharmacodynamic analyses were conducted for standard and high-dose, prolonged (ie, 3-to 4-hour) infusions of cefepime, ceftazidime, ceftriaxone, ciprofloxacin, doripenem, ertapenem, imipenem, levofloxacin, meropenem, and piperacillin/tazobactam in adult patients with normal renal function (>or=50 mL/min). MIC data were incorporated from the 2008 TRUST (Tracking Resistance in the United States Today)-12 surveillance program, a long-running resistance study in 56 participating US hospitals. The cumulative fraction of response (CFR) was determined for each regimen against each population of E coli, K pneumoniae, A baumannii, and P aeruginosa. Optimal CFR was defined a priori as >or=90%. RESULTS: All of the beta-lactam regimens had optimal CFRs against E coli, and all but piperacillin/tazobactam 3.375 g q6h had optimal CFRs against K pneumoniae. The fluoroquinolones had the lowest CFRs against all of the pathogen populations tested (73.2%-88.9% against E coli and K pneumortfae; 44.5 %-61.9 % against A baumannii and P aeruginosa). Optimal CFR against A baumannii was not achieved with any of the regimens. Against P aeruginosa, high-dose, prolonged-infusion doripenem and meropenem had CFRs of 97.2% to 98.8%, followed by high-dose, prolonged-infusion ceftazidime (93.3%) and cefepime (93.2%). High-dose, prolonged-infusion regimens were associated with increased CFRs for all (beta-lactams by approximately 10% over that of standard 0.5-hour infusion regimens against the nonfermenting gram-negative bacilli. CONCLUSIONS: Based on this model, standard doses of most intravenous (beta-lactam regimens had high probabilities of achieving optimal exposure against Enterobacteriaceae. For nonfermenting gram-negative bacilli such as A baumannii and P aeruginosa, high-dose, prolonged infusions of cefepime, ceftazidime, doripenem, and meropenem had the highest probabilities of achieving bactericidal exposure.

Clinical pharmacodynamics of cefepime in patients infected with Pseudomonas aeruginosa.

We evaluated cefepime exposures in patients infected with Pseudomonas aeruginosa to identify the pharmacodynamic relationship predictive of microbiological response. Patients with non-urinary tract P. aeruginosa infections and treated with cefepime were included. Free cefepime exposures were estimated by using a validated population pharmacokinetic model. P. aeruginosa MICs were determined by Etest and pharmacodynamic indices (the percentage of the dosing interval that the free drug concentration remains above the MIC of the infecting organism [fT > MIC], the ratio of the minimum concentration of free drug to the MIC [fC(min)/MIC], and the ratio of the area under the concentration-time curve for free drug to the MIC [fAUC/MIC]) were calculated for each patient. Classification and regression tree analysis was used to partition the pharmacodynamic parameters for prediction of the microbiological response. Monte Carlo simulation was utilized to determine the optimal dosing regimens needed to achieve the pharmacodynamic target. Fifty-six patients with pneumonia (66.1%), skin and skin structure infections (SSSIs) (25%), and bacteremia (8.9%) were included. Twenty-four (42.9%) patients failed cefepime therapy. The MICs ranged from 0.75 to 96 microg/ml, resulting in median fT > MIC, fC(m)(in)/MIC, and fAUC/MIC exposures of 100% (range, 0.8 to 100%), 4.3 (range, 0.1 to 27.3), and 206.2 (range, 4.2 to 1,028.7), respectively. Microbiological failure was associated with an fT > MIC of < or =60% (77.8% failed cefepime therapy when fT > MIC was < or =60%, whereas 36.2% failed cefepime therapy when fT > MIC was >60%; P = 0.013). A similar fT > MIC target of < or =63.9% (P = 0.009) was identified when skin and skin structure infections were excluded. While controlling for the SSSI source (odds ratio [OR], 0.18 [95% confidence interval, 0.03 to 1.19]; P = 0.07) and combination therapy (OR, 2.15 [95% confidence interval, 0.59 to 7.88]; P = 0.25), patients with fT > MIC values of < or =60% were 8.1 times (95% confidence interval, 1.2 to 55.6 times) more likely to experience a poor microbiological response. Cefepime doses of at least 2 g every 8 h are required to achieve this target against CLSI-defined susceptible P. aeruginosa organisms in patients with normal renal function. In patients with non-urinary tract infections caused by P. aeruginosa, achievement of cefepime exposures of >60% fT > MIC will minimize the possibility of a poor microbiological response.