Pharmacokinetic/Pharmacodynamics-Optimized Antimicrobial Therapy in Patients with Hospital-Acquired Pneumonia/Ventilator-Associated Pneumonia

Abstract

Hospital-acquired pneumonia and ventilator-associated pneumonia continue to cause significant morbidity and mortality. With increasing rates of antimicrobial resistance, the importance of optimizing antibiotic treatment is key to maximize treatment outcomes. This is especially important in critically ill patients in intensive care units, in whom the infection is usually caused by less susceptible organisms. In addition, the marked physiological changes that can occur in these patients can cause serious changes in antibiotic pharmacokinetics which in turn alter the attainment of therapeutic drug exposures. This article reviews the various aspects of the pharmacokinetic changes that can occur in the critically ill patients, the barriers to achieving therapeutic drug exposures in pneumonia for systemically delivered antibiotics, the optimization for commonly used antibiotics in hospital- and ventilator-associated pneumonia, the agents that should be avoided in the treatment regimen, as well as the use of adjunctive therapy in the form of nebulized antibiotics.

Dose Fractionation of Moxifloxacin for Treatment of Tuberculosis: Impact of Dosing Interval and Elimination Half-Life on Microbial Kill and Resistance Suppression

“…Another important issue is the recognition that true between-patient variability exists in pharmacokinetic parameter values in a population. Such differences may lead to subpopulations of patients that do not respond to therapy in the expected way (14)(15)(16)). An example is the population of patients with ventilator-associated bacterial pneumonia who have higher glomerular filtration rates (14,15).…”

“…Such differences may lead to subpopulations of patients that do not respond to therapy in the expected way (14)(15)(16)). An example is the population of patients with ventilator-associated bacterial pneumonia who have higher glomerular filtration rates (14,15). In some instances, such a subpopulation may result in driver switching, leading to failure of therapy (8,9).…”

Model‐Informed Drug Development for Anti‐Infectives: State of the Art and Future

“…53 Where necessary, infection site-specific anti-infective doses may be needed; for example, in the treatment of meningitis/ventriculitis (e.g., meropenem and ceftriaxone) 54 and ventilator-associated pneumonia (e.g., ceftolozane and tazobactam). 55 Understanding the breadth of patient scenarios that will be encountered is of fundamental importance to provide sufficient data and guidance to enable clinicians to optimally use a drug after its licensed indication. The spectra of MIDD methods that can be applied to support established dosing in various subpopulations is extensive.…”

“…Although the systemic and infection‐site PK of many anti‐infectives can change in various patient groups (e.g., critically ill, burn, trauma, and patients wth obesity), changes in immune system function and severity of infection can also affect parameter estimates and these can be accounted for by MIDD 53 . Where necessary, infection site‐specific anti‐infective doses may be needed; for example, in the treatment of meningitis/ventriculitis (e.g., meropenem and ceftriaxone) 54 and ventilator‐associated pneumonia (e.g., ceftolozane and tazobactam) 55 . Understanding the breadth of patient scenarios that will be encountered is of fundamental importance to provide sufficient data and guidance to enable clinicians to optimally use a drug after its licensed indication.…”

Empirical Antibiotic Therapy for Gram-Negative Bacilli Ventilator-Associated Pneumonia: Observational Study and Pharmacodynamic Assessment

“…Concerning fluoroquinolones, both C max /MIC and area under the curve (AUC)/MIC ratios are related to the efficacy, with optimal values around 8–12 and 125–250 respectively [ 3 , 6 ]. Nevertheless, antibiotic therapy of VAP in ICU patients is challenging because of the wide pharmacokinetic variability combined to potentially high antibiotics MICs for Gram-negative bacilli (GNB) [ 7 , 8 ]. Previously published data pointed out that these PK/PD targets were not reached for ICU patients, highlighting the risk of “PD failure” [ 9 , 10 , 11 ].…”