Appropriate Antibiotic Dosage Levels in the Treatment of Severe Sepsis and Septic Shock

Abstract

Antibiotic treatment of critically ill patients remains a significant challenge. Optimal antibacterial strategy should achieve therapeutic drug concentration in the blood as well as the infected site. Achieving therapeutic drug concentrations is particularly difficult when infections are caused by some pathogens, such as Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus (MRSA) and Gram-negative rods, because of their low susceptibility to antimicrobials. In sepsis, pharmacokinetics (PKs) of antibiotics are profoundly altered and may result in inadequate drug concentrations, even when recommended regimens are used, which potentially contribute to increased mortality and spread of resistance. The wide inter-individual PK variability observed in septic patients strongly limits the a priori prediction of the optimal dose that should be administered. Higher than standard dosages are necessary for the drugs, such as β-lactams, aminoglycosides, and glycopeptides, that are commonly used as first-line therapy in these patients to maximize their antibacterial activity. However, the benefit of reaching adequate drug concentrations on clinical outcome needs to be further determined.

Population Pharmacokinetics and Pharmacodynamics Modeling To Optimize Dosage Regimens of Sulbactam in Critically Ill Patients with Severe Sepsis Caused by Acinetobacter baumannii

“…Although pathophysiological conditions are relatively stable in most patients, in critically ill patients with sepsis, changes in these conditions can occur, resulting in changes in V and CL for antimicrobial agents (17). An extravasation of a large volume of fluid into the interstitial space and tissue edema, associated with increased capillary leakage and the use of inotropes during the treatment of septic shock, can lead to a larger V than the values obtained from healthy subjects.…”

“…An extravasation of a large volume of fluid into the interstitial space and tissue edema, associated with increased capillary leakage and the use of inotropes during the treatment of septic shock, can lead to a larger V than the values obtained from healthy subjects. Increased renal clearance resulting from increased cardiac output during the initial hyperdynamic state of severe sepsis and, on the other hand, decreased renal clearance with end-organ dysfunction can be observed with severe sepsis and septic shock (12,17,18). Our population PK studies of sulbactam were performed during the steady state on the 4th day of sulbactam administration, and the two-compartment model was the best model for describing the concentration-time profile of sulbactam, which was consistent with the results of previous population PK studies (11,19,20).…”

Population Pharmacokinetics and Monte Carlo Dosing Simulations of Meropenem during the Early Phase of Severe Sepsis and Septic Shock in Critically Ill Patients in Intensive Care Units

“…In critically ill patients with severe sepsis and septic shock, PK changes, including changes in V and CL, for antimicrobial agents can occur as a result of the patients' altered pathophysiological condition (15). The presence of extensive fluid extravasation and tissue edema, associated with increased capillary leakage and the use of inotropes during septic shock, can yield a larger V than the values obtained from healthy subjects.…”

“…The presence of extensive fluid extravasation and tissue edema, associated with increased capillary leakage and the use of inotropes during septic shock, can yield a larger V than the values obtained from healthy subjects. Moreover, increased cardiac output during the initial hyperdynamic state of severe sepsis, leading to increased renal blood flow and increased free fraction of antibiotics, as observed with hypoalbuminemia, can result in increased renal clearance, particularly for highly protein-bound hydrophilic antimicrobial agents; on the other hand, the renal clearance may be decreased with end-organ dysfunctions that can occur with severe sepsis and septic shock (12,15,16). As a consequence of these alterations in V and CL, the half-life (t 1/2 ) of antimicrobial agents can be affected, leading to undesirable therapeutic outcomes.…”

Consideraciones farmacocinéticas en el paciente crítico

“…La farmacocinética no entrega información de efectividad, y la farmacodinamia sobre la disposición de los antibióticos 27 . Según eso, los antibióticos se clasifi can como concentración-dependiente o tiempo-dependiente (concentración independiente) dado por el gráfi co de concentración plasmática/tiempo (Figura 1), que ha permitido hacer la terapia antimicrobiana más segura y efectiva 4,[27][28][29] . Es la cantidad total administrada la que determina su efi cacia 27 .…”