Clinical study

Effect of schedule of administration on the therapeutic efficacy of penicillin: Importance of the aggregate time penicillin remains at effectively bactericidal levels

Optimal antibiotic therapy for critically ill patients can be complicated by the altered physiology associated with critical illness. Antibiotic pharmacokinetics and exposures can be altered driven by the underlying critical illness and medical interventions that critically ill patients receive in the intensive care unit. Furthermore, pathogens that are usually isolated in the intensive care unit are commonly less susceptible and “resistant” to common antibiotics. Indeed, antibiotic dosing that does not consider these unique differences will likely fail leading to poor clinical outcomes and the emergence of antibiotic resistance in the intensive care unit. The aims of this narrative review were to describe the pharmacokinetics of beta-lactam antibiotics in critically ill patients, to highlight pharmacokinetic/pharmacodynamic targets for both non-critically ill and critically ill patients, and to discuss important strategies that can be undertaken to optimize beta-lactam antibiotic dosing for critically ill patients in the intensive care unit.

La terapia antibiótica óptima en los pacientes en estado crítico puede complicarse por la alteración de la fisiología asociada a esta etapa de la enfermedad. La farmacocinética y la exposición a los antibióticos pueden verse alteradas por la enfermedad crítica subyacente y las intervenciones médicas que reciben estos pacientes en la unidad de cuidados intensivos. Además, las cepas que suelen encontrarse en la unidad de cuidados intensivos suelen ser menos susceptibles y “resistentes” a los antibióticos más habituales. De hecho, una dosificación de antibióticos que no tenga en cuenta estas diferencias únicas, probablemente fracasará y dará lugar a resultados clínicos deficientes y a la aparición de resistencia a los antibióticos en la unidad de cuidados intensivos. Los objetivos de esta revisión son describir la farmacocinética de los antibióticos betalactámicos en pacientes críticos, destacar los objetivos farmacocinéticos/farmacodinámicos para los pacientes y exponer algunas estrategias importantes que pueden optimizar la dosificación de los antibióticos betalactámicos en pacientes críticos en la unidad de cuidados intensivos.

Methicillin-resistant Staphylococcus aureus (MRSA) is an important pathogen with multiple antibiotic resistance that causes morbidity and mortality worldwide. Multidrug-resistant (MDR) MRSA with increased resistance to currently available antibiotics has challenged the world to develop new therapeutic agents. Stigmasterol and lupeol, from the plant Phyllanthus columnaris, exhibit antibacterial activities against MRSA. The aim of this study was to utilise next-generation sequencing (NGS) to provide further insight into the novel transcriptional response of MRSA exposed to stigmasterol and lupeol.

Time–kill analysis of one MRSA reference strain (ATCC 43300) and three clinical isolates (WM3, BM1 and KJ7) for both compounds was first performed to provide the bacteriostatic/bactericidal profile. Then, MRSA ATCC 43300 strain treated with both compounds was interrogated by NGS.

Both stigmasterol and lupeol possessed bacteriostatic properties against all MRSA tested; however, lupeol exhibited both bacteriostatic and bactericidal properties within the same minimum inhibitory concentration and minimum bactericidal concentration values against BM1 (12.5 mg/mL). Transcriptome profiling of MRSA ATCC 43300 revealed significant modulation of gene expression with multiple desirable targets by both compounds, which caused a reduction in the translation processes leading to inhibition of protein synthesis and prevention of bacterial growth.

This study highlights the potential of both stigmasterol and lupeol as new promising anti-MRSA agents.

An understanding of the pharmacokinetic (PK) and pharmacodynamic (PD) principles that determine response to antimicrobial therapy can provide the clinician with better-informed dosing regimens. Factors influential on antibiotic disposition and clinical outcome are presented, with a focus on the primary site of infection. Techniques to better understand antibiotic PK and optimize PD are acknowledged.

PubMed (inception–April 2016) was reviewed for relevant publications assessing antimicrobial exposures within different anatomic locations and clinical outcomes for various infection sites.

A limited literature base indicates variable penetration of antibiotics to different target sites of infection, with drug solubility and extent of protein binding providing significant PK influences in addition to the major clearing pathway of the agent. PD indices derived from in vitro studies and animal models determine the optimal magnitude and frequency of dosing regimens for patients. PK/PD modeling and simulation has been shown an efficient means of assessing these PD endpoints against a variety of PK determinants, clarifying the unique effects of infection site and patient characteristics to inform the adequacy of a given antibiotic regimen.

Appreciation of the PK properties of an antibiotic and its PD measure of efficacy can maximize the utility of these life-saving drugs. Unfortunately, clinical data remain limited for a number of infection site–antibiotic exposure relationships. Modeling and simulation can bridge preclinical and patient data for the prescription of optimal antibiotic dosing regimens, consistent with the tenets of personalized medicine.

El desarrollo de regímenes de dosificación de antibióticos que se adhieren a los principios farmacocinéticos/farmacodinámicos puede prolongar la vida útil clínica de nuestros antibióticos existentes, reduciendo al mínimo la aparición de resistencia. Este artículo resume la relevancia de las características farmacocinéticas/farmacodinámicas de las diferentes clases de antibióticos en el desarrollo de resistencia. Con base en los datos disponibles, proponemos dar unas recomendaciones de dosificación que se pueden adoptar en el ámbito clínico, para maximizar el éxito terapéutico y limitar la aparición de resistencia en las unidades de cuidados intensivos.

The development of antibiotic dosing regimens that adhere to the PK/PD principles may prolong the clinical lifespan of our existing antibiotics by reducing the emergence of resistance. This article presents a summary of the relevance of PK/PD characteristics of different antibiotic classes on the development of antibiotic resistance. On the basis of the available data, dosing recommendations are proposed that can be adopted in the clinical setting, in order to maximise therapeutic success and limit the emergence of resistance in intensive care units.