Application of Antimicrobial Pharmacodynamic Concepts into Clinical Practice: Focus on β‐Lactam Antibiotics

  title={Application of Antimicrobial Pharmacodynamic Concepts into Clinical Practice: Focus on $\beta$‐Lactam Antibiotics},
  author={Thomas P. Lodise and Ben M. Lomaestro and George L. Drusano},
  journal={Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy},
In recent years there have been tremendous strides in understanding the relationship between the pharmacodynamics of β‐lactams and microbiologic response. For β‐lactams, in vitro and animal studies suggest that the amount of time in which free or non–protein‐bound antimicrobial concentration exceeds the minimum inhibitory concentration (MIC) of the organism (fT>MIC) is the best predictor of bacterial killing and microbiologic response. Using population pharmacokinetic modeling and Monte Carlo… 

Pharmacodynamic Thresholds for Beta-Lactam Antibiotics: A Story of Mouse Versus Man

Murine based targets specific to each antibiotic are most useful during dosage regimen development and susceptibility breakpoint assessment, while a range of exposures between 50 and 100% fT > MIC are reasonable to define the beta-lactam TDM therapeutic window for most infections.

Use of pharmacodynamic principles to inform β-lactam dosing: "S" does not always mean success.

Prolonged infusions of intravenous β-lactams are not only associated with improved probability of target attainment (PTA) profiles but offer possible cost savings and greater potential for reducing emergence of resistance relative to intermittent infusions.

Pharmacokinetic and pharmacodynamic properties of meropenem.

  • D. Nicolau
  • Biology, Medicine
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
  • 2008
Pharmacokinetic and pharmacodynamic modeling can identify regimens with the greatest probability of attaining this target, and probabilities can be compared with clinical and microbiological responses in patients.

Application of Pharmacodynamic Profiling for the Selection of Optimal β-lactam Regimens in a Large University Hospital.

Towards precision medicine: Therapeutic drug monitoring-guided dosing of vancomycin and β-lactam antibiotics to maximize effectiveness and minimize toxicity.

Precision dosing through TDM is expanding and is especially important in populations with altered PK/PD, including critically ill, obese, and older adults, where it is vital to maximize antimicrobial effectiveness and decrease adverse event rates.

In Vivo Pharmacodynamic Profiling of Doripenem against Pseudomonas aeruginosa by Simulating Human Exposures

Doripenem is a new broad-spectrum carbapenem with activity against a range of gram-negative pathogens, including nonfermenting bacteria such as Pseudomonas aeruginosa, which resulted in the most pronounced bactericidal effects, while killing was variable for 20 to 30% fT>MIC.

Extended infusion of beta-lactam antibiotics: optimizing therapy in critically-ill patients in the era of antimicrobial resistance

It is concluded that EI/CI is probably beneficial in the treatment of critically-ill patients in whom an organism has been identified, particularly those with respiratory infections.

Integration of pharmacokinetic/pharmacodynamic modeling and simulation in the development of new anti-infective agents – minimum inhibitory concentration versus time-kill curves

An overview of the present PK/PD approaches used in anti-infective therapy is provided and their role in improving drug therapy is discussed.

Pharmacokinetic and Pharmacodynamic Analysis of Ceftazidime/Avibactam in Critically Ill Patients.

The study results suggest that the current dosing regimens of CZA can provide effective antimicrobial activity in ICU patients against CZA-susceptible (MIC ≤8 mg/L) isolates against multi-drug-resistant Enterobacteriaceae susceptible to CZA.



Optimizing Pharmacodynamic Target Attainment Using the MYSTIC Antibiogram: Data Collected in North America in 2002

Given the lack of agreement between percent susceptibility and probability of target attainment for certain antimicrobial regimens, a methodology employing stochastic pharmacodynamic analyses may be a more useful tool for differentiating the most-optimal compounds and dosing regimens in the clinical setting of initial empirical therapy.

Pharmacokinetics and Pharmacodynamics of Meropenem in Febrile Neutropenic Patients with Bacteremia

Based on the first published report of a relationship between a pharmacodynamic index and clinical outcome in a febrile neutropenic population, dosing with intravenous meropenem 500 mg every 6 hours is predicted to be comparable to the currently recommended 1 g every 8 hours for serious infections.

Pharmacodynamics of levofloxacin: a new paradigm for early clinical trials.

Exposure to levofloxacin was significantly associated with successful clinical and microbiological outcomes and occurrence of adverse events in infected patients and could be used to determine optimal treatment dose in clinical trials in a shorter time frame with fewer patients.

Use of Monte Carlo Simulation to Design an Optimized Pharmacodynamic Dosing Strategy for Meropenem

Monte Carlo simulation was employed to determine pharmacodynamic target attainment rates for several prolonged infusion meropenem dosage regimens as compared with the traditional 30‐minute infusion against Enterobacteriaceae, Acinetobacter species, and Pseudomonas aeruginosa populations.

Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men.

  • W. Craig
  • Biology, Medicine
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
  • 1998
The potential value of using pharmacokinetic/pharmacodynamic parameters as guides for establishing optimal dosing regimens for new and old drugs and for new emerging pathogens and resistant organisms should make the continuing search for the therapeutic rationale of antibacterial dosing of mice and men worthwhile.

Antimicrobial pharmacodynamics: critical interactions of 'bug and drug'

  • G. Drusano
  • Biology, Medicine
    Nature Reviews Microbiology
  • 2004
The goal of any anti-infective therapy is to administer a dose of drug that has an acceptably high probability of achieving the desired therapeutic effect balanced with an acceptable low probability of toxicity.

Comparative dose-effect relations at several dosing intervals for beta-lactam, aminoglycoside and quinolone antibiotics against gram-negative bacilli in murine thigh-infection and pneumonitis models.

This paper evaluated the impact of dosing interval on the relative efficacy and potency of beta-lactams, aminoglycosides, and ciprofloxacin against Pseudomonas aeruginosa in murine pneumonitis and thigh-infection models.

Comparative antibiotic dose-effect relations at several dosing intervals in murine pneumonitis and thigh-infection models.

Compared the relative efficacy and potency of three beta-lactams and two aminoglycosides in lung and thigh-infection models in neutropenic mice by defining the maximum attainable antimicrobial effect at 24 h (Emax) and the total dose required to reach 50% of maximum effect (P50) at several dosing intervals.