Antimicrobial stewardship

Appropriate antimicrobial selection

Appropriate antibiotic therapy is the cornerstone of management in septic shock and in any serious infection requiring intensive care unit (ICU) care and has a great influence on hospital mortality. Appropriate antibiotic therapy is defined as an initial antimicrobial regimen that demonstrates in vitro activity against the isolated organisms responsible for the infection, whereas inappropriate antibiotic therapy is defined as an initial regimen demonstrating a lack of in vitro activity against the causative pathogens. The administration of inappropriate initial antibiotic therapy can lead to treatment failures and adverse outcomes. Similar associations between the administration of inappropriate initial antimicrobial therapy and greater mortality have been shown for bloodstream infections by Candida . Moreover, the importance of treating all pathogens associated with serious infection is further emphasized by a retrospective analysis of patients with severe sepsis and septic shock. For the entire cohort, the number needed to treat with appropriate antimicrobial therapy to prevent one patient death was 4.0 (95% confidence interval [CI], 3.7–4.3). The importance of early appropriate antibiotic selection was also demonstrated in a recent randomized trial among patients with Escherichia coli or Klebsiella pneumonia bloodstream infection and ceftriaxone resistance demonstrating that definitive treatment with piperacillin-tazobactam compared with meropenem resulted in greater 30-day mortality. This study also highlights the importance of early identification of antibiotic resistance to optimize antimicrobial prescription in order to improve patient outcomes.

The importance of selecting appropriate initial antimicrobial therapy has been emphasized in the most recent Surviving Sepsis Guidelines. The guidelines recommend that initial empiric antiinfective therapy include one or more drugs that have activity against all likely pathogens (bacterial and/or fungal or viral) and that the antibiotics penetrate, in adequate concentrations, into the tissues presumed to be the source of sepsis (grade 1B). This guideline urges clinicians to use the patient’s history (including drug intolerances), recent receipt of antibiotics, underlying disease, clinical syndrome, and susceptibility patterns of pathogens in the community and hospital and that have been previously documented to colonize or infect the patient when making decisions regarding initial antimicrobial regimen selection.

Timing of antibiotic administration

In addition to selecting an appropriate antimicrobial regimen, the timing of antibiotic delivery is an essential element in determining the outcome of critically ill patients with infection. Several studies have found strong relationships between delays in effective antimicrobial initiation and in-hospital mortality for serious infections, including ventilator-associated pneumonia (VAP) and septic shock. ^, A meta-analysis of randomized and observational studies evaluating the impact of goal-directed bundles on the outcomes of patients with septic shock found that timely antibiotic administration was statistically more common among patients receiving protocolized management of septic shock. Members of the Surviving Sepsis Campaign subsequently performed a retrospective analysis of a large data set collected prospectively from 165 ICUs in Europe, the United States, and South America. In-hospital mortality was 29.7% for the cohort as a whole, and there was a statistically significant increase in the probability of death associated with the number of hours of delay for the first antibiotic administration.

Timely administration of effective antibiotics seems to be an important element in determining the outcome of critically ill patients. As discussed later, prediction tools for the presence of antibiotic resistance and rapid diagnostics may allow for a more rapid administration of appropriate therapy. However, emergency departments and ICUs should also ensure that they have processes in place to obtain and deliver antibiotic therapy expeditiously once the order for such therapy is received from the treating physicians.

The use of treatment bundles for the management of patients with sepsis and septic shock has been associated with lower hospital mortality thought to be caused primarily by the earlier administration of antibiotics. ^, However, these treatment bundles fail to examine important clinical issues, including whether antibiotic therapy is necessary in all patients with presumed sepsis, the dosing strategies and duration of antibiotics, and whether the administered antibiotic regimen is active against the offending pathogens. The success of sepsis treatment bundles has now been used, in part, by the authors of the Surviving Sepsis Campaign Guidelines to recommend the use of broad-spectrum antibiotics within 1 hour of presentation in all patients with clinically suspected sepsis. However, a recent editorial has attempted to focus attention on the problems associated with the overuse of antibiotics in patients with possible sepsis. This editorial highlights the difficulties in establishing an accurate diagnosis of sepsis attributed to underlying infection, the adverse consequences associated with routine administration of antibiotics in critically ill patients, and the problem of equating sepsis with the more severe condition of septic shock. Recent pleas have emerged from the Infectious Diseases Society of America, emergency medicine thought leaders, and critical care thought leaders urging for more rational approaches for directing antibiotic therapy in complex patients and eliminating the 1-hour sepsis bundle.

Adequate dosing of antimicrobials and pharmacokinetic/pharmacodynamic considerations

In addition to delivering timely appropriate antibiotic regimens, adequate drug concentrations at the site of infection are needed to optimize clinical outcomes. Beta-lactam and carbapenem antibiotics are time-dependent antimicrobials whose activities are primarily related to the duration the free drug concentration exceeds the pathogen minimum inhibitory concentration (T _FREE /MIC). Many factors influence the pharmacokinetics of antimicrobials in critically ill patients. Hypoalbuminemia, large-volume crystalloid administration, large pleural effusions or abdominal ascites, catecholamines, augmented renal clearance (ARC), and renal replacement therapies can all significantly alter infection site concentrations of administered antibiotics.

In VAP treatment, particularly for gram-negative bacteria (GNB), dose and duration of treatment might need to be augmented despite having selected an appropriate initial regimen. For instance, meta-analyses of tigecycline showed an increased mortality in nosocomial pneumonia, particularly VAP driven by GNB infections. A randomized trial of patients with hospital-acquired pneumonia (HAP) found that tigecycline with or without ceftazidime had inferior cure rates to imipenem-cilastatin with or without vancomycin across all pathogens. The hypothesis that the tigecycline dose (75 mg every 12 hours) was too low to achieve high enough concentrations above the MICs of pathogens prompted a higher-dose study (100 mg every 12 hours) compared with imipenem-cilastatin. Similarly, ceftobiprole, a cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA) and an extended GNB spectrum equivalent to ceftazidime or cefepime, was compared with linezolid and ceftazidime in patients with HAP/VAP. Even though it achieved similar cure rates in patients with HAP, ceftobiprole was inferior to linezolid and ceftazidime in patients with VAP, in large part thought to be a result of the underdosing of ceftobiprole in critically ill patients. This concern has led to a doubling of the dose of ceftolozane/tazobactam for the treatment of HAP/VAP.

Critically ill patients display different pharmacokinetics; therefore newer drug administration strategies for beta-lactams and carbapenems have been investigated to include the use of prolonged infusions in order to optimize antibiotic delivery to infection sites. Several recent meta-analyses suggest that prolonged infusions of beta-lactam and carbapenem antibiotics may be associated with improved outcomes in critically ill patients. However, the results from the largest multicenter trial performed to date of prolonged antibiotic infusion in critically ill patients failed to demonstrate any mortality benefit.

One of the best examples of the need for proper antibiotic dosing and drug exposure at the site of infection was recently demonstrated in a multicenter trial. These investigators aimed to determine whether beta-lactam antibiotic dosing in critically ill patients achieves concentrations associated with maximal activity and whether antibiotic concentrations affect patient outcome. Of the 248 patients treated for infection, 16% did not achieve a T _FREE /MIC ratio greater than 1 at 50% of the dosing interval, and these patients were 32% less likely to have a positive clinical outcome. Positive clinical outcome was associated with a T _FREE /MIC ratio greater than 1 at both 50% and 100% of the dosing intervals. These data suggest that many critically ill patients experience adverse outcomes as a result of inadequate antibiotic exposure.