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Combating bacterial resistance to antimicrobials in severe septic ICU patients: importance of meropenem, piperacillin serum monitoring as a dose adjustment and duration of infusion strategies

Pharmacy & Pharmacology International Journal
Silvia R C J Santos,1 Thais Vieira de Camargo,1 Claudia Garcia Messiano,1 Leonard de Vinci Kanda Kupa,1 Vanessa Kazubeck de Souza,1 Ronaldo Morales Jr,1 Débora C Sanches Pinto,2 Elson Mendes da Silva Junior,2 João Manoel da Silva Junior,2 David de Souza Gomez2


Introduction: In view of the growing challenge to the use of antimicrobials for adequate and effective therapy of nosocomial infections, international health agencies have reinforced that combating bacterial resistance and preventing the development of multidrug-resistant (MDR) strains are urgent, since hospital infection control committees have reported a significant increase in the minimum inhibitory concentration (MIC) for therapeutic agents against nosocomial pathogens. Meropenem and piperacillin-tazobactam are largely prescribed in the therapy of septic shock caused by susceptible Gram-negative bacteria. Usually the 0.5 hr.-intermittent infusion that was widely used at the last 30 years in these patients, providing coverage only against susceptible Gram-negative pathogens up to MIC 2 mg/L according to Clinical Standard Laboratory Institute (CSLI database). New strategies have been recommended to combat the development of resistance to pathogens isolated from cultures to increase the coverage of these antimicrobials.
Subject: A systematic review was carried out to evaluate pharmacodynamics based on pharmacokinetics that could affect the coverage of beta-lactams agents (meropenem or piperacillin-tazobactam) after intermittent or extended infusion in septic patients with preserved or augmented renal clearance by applying pharmacokinetic-pharmacodynamics (PK/PD) tools.
Methods: Criteria considered was based on the PICO strategy: Patient, Intervention, Comparison, and Outcome. Several prospective controlled clinical studies were considered in this review, mostly published in the last decade, including clinical protocols conducted in septic patients with Pharmacy & Pharmacology International Journal Research Article Open Access preserved or augmented renal clearance. The primary endpoint was the pharmacodynamics based on microbiology of the isolates obtained from cultures, and antimicrobial coverage considering drug infusion and the percentage of patients achieving the therapeutic target (100% f?T>MIC) recommended. The primary outcome was to compare the intermittent infusion (0.5 hr.) with extended (2 to 4 hrs.) infusion related to antimicrobial efficacy done by the pharmacokinetic-pharmacodynamics (PK/PD) tools based on drug serum levels. It was considered also the impact of pharmacokinetic changes that may affect the coverage of beta-lactams in ICU septic patients on the isolated gram-negative strains. As a secondary outcome, the change in pharmacokinetics as a function of the duration of drug infusion reported in septic patients, also considering its comparison with the reference data reported in healthy volunteers.
Results: In the review of studies, the coverage strategy was based on the prediction index (%f?T>MIC) of drug effectiveness. Superiority of the 3hrs.-extended infusion by comparison with the 0.5hr.-intermittent infusion was evidenced in the most part of studies which had an increase on drug effectiveness in critically ill patients for both antimicrobials. It was demonstrated that different changes might occur in the pharmacokinetics of these beta-lactams as a function of the duration of drug infusion. It is important to highlight that PK-data selected from clinical studies occurred mainly in the early phase of septic shock in those critically ill patients with preserved renal function and receiving vasopressors.
Conclusion: Drug serum levels of these beta-lactams should be implemented in the routine of tertiary hospitals always associated with the PK/PD approach to know the antimicrobial coverage. Therefore, the clinical and microbiological cures by eradicating soon the susceptible pathogens will contribute to the reduction of deaths, combating the mutant´s selection, and preventing consequently the development of bacterial resistance.


septic patients, meropenem, piperacillin-tazobactam, pharmacokinetics-pharmacodynamics approach, coverage dependent of drug infusion