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.

Pharmacokinetic-pharmacodynamic target attainment analyses to evaluate in vitro susceptibility 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.

Use of pharmacokinetic-pharmacodynamic analyses to optimize therapy with the systemic antifungal micafungin for invasive candidiasis or candidemia.

Echinocandins have become a first-line therapy for invasive candidiasis (IC). Using phase 3 trial data for patients with IC, pharmacokinetic-pharmacodynamic (PK-PD) relationships for efficacy for micafungin were examined. Micafungin exposures were estimated using a population pharmacokinetic model, and univariable and multivariable logistic regressions were used to identify factors associated with outcome, including the micafungin area under the concentration-time curve (AUC)/MIC ratio. Monte Carlo simulation was used to evaluate the probability of achieving AUC/MIC ratios associated with efficacy. Mycological and clinical success rates for evaluable cases were 89.4 and 90.9, respectively. MIC50s and MIC90s for Candida species inhibition were 0.008 and 0.5 mg/liter, respectively. The median AUC/MIC ratio was 15,511 (range, 41.28 to 98,716). Univariable analyses revealed a significant relationship between the AUC/MIC ratio and mycological response, with the worst response being among patients with lower (≤3,000) AUC/MIC ratios (P=0.005). For patients with Candida parapsilosis, AUC/MIC ratios of ≥285 were predictive of a higher mycological response (P=0.11). Multivariable logistic regression demonstrated the AUC/MIC ratio, APACHE II score, and history of corticosteroid use to be significant independent predictors of a favorable response. PK-PD target attainment analyses suggested that 76.7% and 100% of patients would achieve an AUC/MIC ratio of ≥3,000 for an MIC of 0.03 mg/liter and an AUC/MIC ratio of ≥285 for an MIC of <0.5 mg/liter, respectively. The identification of a lower AUC/MIC ratio target for C. parapsilosis than other Candida species suggests consideration of species-specific echinocandin susceptibility breakpoints and values that are lower than those currently approved by regulatory agencies.

Application of patient population-derived pharmacokinetic-pharmacodynamic relationships to tigecycline breakpoint determination for staphylococci and streptococci.

Correctly determined susceptibility breakpoints are important to both the individual patient and to society at large. A previously derived patient population pharmacokinetic model and Monte Carlo simulation (9999 patients) were used to create a likelihood distribution of tigecycline exposure, as measured by the area under the concentration-time curve at 24 h (AUC(24)). Each resultant AUC(24) value was paired with a clinically relevant fixed MIC value ranging from 0.12 to 2 mg/L. For each AUC(24)-MIC pair, the probability of microbiologic response was calculated using an exposure-response relationship, which was derived from patients with complicated skin and skin structure infections that involved Staphylococcus aureus or streptococci or both. The median probability of microbiologic success was 94% or greater for MIC values up to and including 0.25 mg/L. The median probability of microbiologic success was 66% or less for MIC values of 0.5 mg/L or greater. These data support a susceptibility breakpoint of 0.25 mg/L for S. aureus and streptococci.

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.