Optimizing Antimicrobial Therapy of Sepsis and Septic Shock: Focus on Antibiotic Combination Therapy

Abstract

Severe sepsis and septic shock with sepsis-associated multiple organ failure represent the major causes of infection-associated mortality and remain the most common cause of death in intensive care units (ICUs) of developed countries. They account for 10 to 15% of all ICU admissions and 25% of sepsis cases 1 ; up to 50 to 75% of severe sepsis cases progress to septic shock. 2 Septic shock alone represents 5 to 8% of all ICU admissions. 3 Historically, the mortality associated with sepsis and septic shock has been 50 to 75%. [4][5][6] This decreased after the development of modern antimicrobial therapies, starting with penicillin in the early 1940s. Since then sepsis-associated mortality has fallen to the 30 to 50% range. 4,5 Since the development of modern antimicrobials, bacterial pathogens have continuously evolved under their selective pressure. There has also been a gradual increase in the incidence of sepsis over the intervening decades. 7 Current estimates suggest a doubling of total cases of severe sepsis in United States by 2050 (from the actual 800,000 cases per year AbstractThere has been little improvement in septic shock mortality in the past 70 years, despite ever more broad-spectrum and potent antimicrobials. In the past, resuscitative elements have been the primary area of clinical septic shock management and research. The question of the optimal use of antimicrobial therapy was relatively ignored in recent decades. This review explores the pathophysiology of sepsis in an attempt to produce a better understanding and define key determinants of antimicrobial therapy response in septic shock. Optimizing existing antimicrobials delivery can drive significant improvements in the outcome of sepsis and septic shock. Inappropriate antimicrobial selection and dosing or delays in the administration substantially increase mortality and morbidity in life-threatening infections. Definitive combination therapy (where a pathogen known to be susceptible to a given agent is additionally covered by another agent) remains controversial. Although some in vitro studies, animal models, and clinical studies of infection including endocarditis, gram-negative bacteremia, and neutropenic infections have supported combination therapy, the potential clinical benefit in other severe infections has been questioned. Several meta-analyses have failed to demonstrate improvement of outcome with combination therapy in immunocompetent patients with sepsis and/or gram-negative bacteremia. These meta-analyses did not undertake subgroup analyses of the septic shock population. This article reviews the existing evidence supporting combination therapy for severe infections, sepsis, and septic shock.

Optimization of Synergistic Combination Regimens against Carbapenem- and Aminoglycoside-Resistant Clinical Pseudomonas aeruginosa Isolates via Mechanism-Based Pharmacokinetic/Pharmacodynamic Modeling

“…Studies by Kumar et al (39,40) found that rapid and early antibiotic treatment significantly increases survival in an immunocompetent murine infection model of septic shock. These studies and our simulations suggest that a continuous infusion of imipenem at 5 g/day (with a loading dose) plus tobramycin at 7 mg/kg every 24 h may provide a beneficial effect in reducing the bacterial burden to an extent where the immune system in immunocompetent patients can achieve bacterial clearance.…”

In vitro diagnosis of sepsis: a review

“…7 It remains controversial if combination antimicrobial therapy produces a better outcome than adequate single-agent antibiotic therapy in patients with sepsis. [53][54][55] One major retrospective analysis of sepsis showed an increased mortality of 7.6% for each hour of delay in the administration of appropriate antibiotic. 6 Despite extensive research in the last few decades to define sepsis and to improve the outcome of patients, it remains a challenge to identify the better therapeutic approach for clinical management and for survival of subjects.…”

Right first time!

“…However, the timeliness of appropriate therapeutic management influences the prognosis in sepsis (3). Early recognition of infectious source and early initiation of appropriate empiric antimicrobial therapy with source control is crucial for decreasing the risk of organ failure (5). The Surviving Sepsis Campaign suggested two "bundles" of care to improve outcome in sepsis and septic shock; initial management bundle in emergency department within 6 hours and accomplished management bundle in intensive care units (ICU) (6).…”

“…For these antibiotics, the key PK parameter for maximum efficacy is the time that serum levels above the minimal inhibitory concentration (MIC) of the pathogen. Continuous or prolonged infusion is suggested to have the optimal efficacy (improved clinical cure, shorter hospitalization and lower mortality) from beta lactams, carbapenems and linezolid (5,30). Whereas, fluoroquinolones, aminoglycosides, colistin and vancomycin are concentrationdependent antibiotics and high peak drug concentrations are needed for maximal efficacy (5,30).…”

“…Continuous or prolonged infusion is suggested to have the optimal efficacy (improved clinical cure, shorter hospitalization and lower mortality) from beta lactams, carbapenems and linezolid (5,30). Whereas, fluoroquinolones, aminoglycosides, colistin and vancomycin are concentrationdependent antibiotics and high peak drug concentrations are needed for maximal efficacy (5,30). For PF/PD optimization of antibiotics and improved outcome in septic shock patients, therapeutic drug monitoring is suggested for many antibiotics (vancomycin, beta lactams, etc.)…”