Determining β-lactam exposure threshold to suppress resistance development in Gram-negative bacteria

Tam, Vincent H.; Chang, Kai-Tai; Zhou, Jian; Ledesma, Kimberly R.; Phe, Kady; Gao, Song; Bambeke, Françoise Van; Sánchez-Díaz, Ana Maria; Zamorano, Laura; Oliver, Antonio; Cantón, Rafael

doi:10.1093/jac/dkx001

Cited by 73 publications

(57 citation statements)

References 33 publications

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“…In pneumonia, a PK/PD target at the site of the infection of fT>MIC of 50% in ELF has been associated with bacterial killing and suppression of resistant subpopulation amplification in a murine model of pneumonia [14]. Unlike other PK/PD targets calculated in the plasma [45,46], this has been more precisely defined at the site of the infection. This was the pharmacodynamic target used in this analysis and is higher than that often cited for the efficacy of the carbapenem class.…”

Section: Discussionmentioning

confidence: 99%

Intrapulmonary concentrations of meropenem administered by continuous infusion in critically ill patients with nosocomial pneumonia: a randomized pharmacokinetic trial

et al. 2020

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Background: Optimal antimicrobial drug exposure in the lung is required for successful treatment outcomes for nosocomial pneumonia. Little is known about the intrapulmonary pharmacokinetics (PK) of meropenem when administered by continuous infusion (CI). The aim of this study was to evaluate the PK of two dosages of meropenem (3 g vs 6 g/day by CI) in the plasma and epithelial lining fluid (ELF) in critically ill patients with nosocomial pneumonia.Methods: Thirty-one patients (81% male, median (IQR) age 72 (22) years) were enrolled in a prospective, randomized, clinical trial. Sixteen patients received 1 g/8 h and 15 2 g/8 h by CI (8 h infusion). Plasma and ELF meropenem concentrations were modeled using a population methodology, and Monte Carlo simulations were performed to estimate the probability of attaining (PTA) a free ELF concentration of 50% of time above MIC (50% fT>MIC), which results in logarithmic killing and the suppression of resistance in experimental models of pneumonia. Results: The median (IQR) of meropenem AUC 0-24 h in the plasma and ELF was 287.6 (190.2) and 84.1 (78.8) mg h/ L in the 1 g/8 h group vs 448.1 (231.8) and 163.0 (201.8) mg h/L in the 2 g/8 h group, respectively. The penetration ratio was approximately 30% and was comparable between the dosage groups. In the Monte Carlo simulations, only the highest approved dose of meropenem of 2 g/8 h by CI allowed to achieve an optimal PTA for all isolates with a MIC < 4 mg/L.

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Section: Discussionmentioning

confidence: 99%

Intrapulmonary concentrations of meropenem administered by continuous infusion in critically ill patients with nosocomial pneumonia: a randomized pharmacokinetic trial

et al. 2020

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“…In addition, measuring an MIC is no sinecure and significant variability within and between methods exists [29]. Not everything will be solved by simple adherence to guidelines, and there is a need for further studies into optimized dosing as a consequence of regional prevalence of antibiotic resistance [30].…”

Section: Optimized Dosing For Reducing Selection Of Resistancementioning

confidence: 99%

Diagnostic and medical needs for therapeutic drug monitoring of antibiotics

Mabilat

Gros

Nicolau

et al. 2019

Eur J Clin Microbiol Infect Dis

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Therapeutic drug monitoring (TDM) of antibiotics has been practiced for more than half a century, but it is still not widely applied for infected patients. It has a traditional focus on limiting toxicity of specific classes of antibiotics such as aminoglycosides and vancomycin. With more patients in critical care with higher levels of sickness severity and immunosuppression as well as an increasingly obese and ageing population, an increasing risk of suboptimal antibiotic exposure continues to escalate. As such, the value of TDM continues to expand, especially for beta-lactams which constitute the most frequently used antibiotic class. To date, the minimum inhibitory concentration (MIC) of infectious microbes rather than classification in terms of susceptible and resistant can be reported. In parallel, increasingly sophisticated TDM technology is becoming available ensuring that TDM is feasible and can deliver personalized antibiotic dosing schemes. There is an obvious need for extensive studies that will quantify the improvements in clinical outcome of individual TDM-guided dosing. We suggest that a broad diagnostic and medical investigation of the TDM arena, including market analyses and analytical technology assessment, is a current priority.

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“…8,11 Exposure to antibiotics has been shown to upregulate several of these efflux pump systems while downregulating membrane porins (e.g., OprD), often leading to overt antibiotic resistance across multiple classes. 8,10,15 P. aeruginosa may express an array of b-lactamases. The most common system for classifying b-lactamases is the Amber classification system, which uses enzyme structure.…”

mentioning

confidence: 99%

Approach to the Treatment of Patients with Serious Multidrug‐Resistant Pseudomonas aeruginosa Infections

2020

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Multidrug resistance(MDR) among Pseudomonas aeruginosa (PSA) isolates presents a significant clinical challenge and can substantially complicate the approach to selection of optimal antibiotic therapy. This review addresses major considerations in antibiotic selection for patients with suspected or documented serious MDR‐PSA infections. Common mechanisms contributing to MDR among clinical PSA isolates are summarized. Empiric and definitive therapy considerations are addressed including the potential role of combination therapy. Newer agents with in vitro activity against MDR‐PSA (e.g., ceftolozane‐tazobactam, ceftazidime‐avibactam, imipenem‐relebactam, and cefiderocol) and their potential roles in clinical settings are discussed. Although these newer agents are promising options for the treatment of MDR‐PSA, clinical data remain generally limited. Future studies are needed to determine optimal agents for the empiric and definitive treatment of MDR‐PSA.

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Determining β-lactam exposure threshold to suppress resistance development in Gram-negative bacteria

Abstract: The development of β-lactam resistance during therapy could be suppressed by an optimized dosing exposure. Validation of the proposed target in a well-designed clinical study is warranted.

Cited by 73 publications

References 33 publications

Intrapulmonary concentrations of meropenem administered by continuous infusion in critically ill patients with nosocomial pneumonia: a randomized pharmacokinetic trial

Intrapulmonary concentrations of meropenem administered by continuous infusion in critically ill patients with nosocomial pneumonia: a randomized pharmacokinetic trial

Diagnostic and medical needs for therapeutic drug monitoring of antibiotics

Approach to the Treatment of Patients with Serious Multidrug‐Resistant Pseudomonas aeruginosa Infections

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