IMPROVE TIME TO BROAD-SPECTRUM ANTIBIOTICS
Corresponding Bundle Item
From the time of presentation, broad-spectrum antibiotics administered within 3 hours for ED admissions and 1 hour for non-ED ICU admissions.
Related Measures
Timing of Antibiotics
Background
Once severe sepsis is identified, antibiotics must be started rapidly to treat the underlying infection. Although early antibiotic administration seems to be an intuitive approach, administration of effective therapies is often delayed. Recent evidence supports that for patients with septic shock, the duration of hypotension prior the administration of antibiotics is a critical determinant in the survival of septic shock. [1]
The balance of evidence unwaveringly suggests that early administration of appropriate antibiotics reduces mortality in patients with Gram-positive and Gram-negative bacteremias. Some of the evidence supporting early administration is based upon the assumption that patients who fail to receive appropriate antibiotics essentially represent a set of patients for whom delay has occurred in antibiotic delivery. Several studies have confirmed the mortality benefit associated with appropriate antimicrobials in patients with severe infections due to Gram-negative and Gram-positive bacteria. [2-4]
In addition, the major sources of infection in severe sepsis or shock are pneumonia and intra-abdominal infections [5,6] and other sources generally account for < 5 percent of cases. The prevalence of pneumonia as a cause of sepsis lends support to the case for treating severe sepsis with early antibiotic administration. In a recent study of ventilator-acquired pneumonia, patients with significant organ dysfunction (required criteria for severe sepsis) who received antibiotics later had far greater ICU mortality: 37 percent vs. 7 percent, P=0.006; hospital mortality: 44 percent vs. 15 percent, P=0.01. [7]
Choice of Antibiotics
The choice of antibiotics should be guided by the susceptibility of likely pathogens in the community and the hospital, as well as any specific knowledge about the patient, including drug intolerance, underlying disease, the clinical syndrome. The regimen should cover all likely pathogens since there is little margin for error in critically ill patients. There is ample evidence that failure to initiate appropriate therapy promptly (i.e., therapy that is active against the causative pathogen) has adverse consequences on outcome. [2-4]
Although restricting the use of antibiotics, and particularly broad-spectrum antibiotics, is important for limiting superinfection and for decreasing the development of antibiotic resistant pathogens, patients with severe sepsis or septic shock warrant broad-spectrum therapy until the causative organism and its antibiotic susceptibilities are defined.
Availability
Establishing a supply of premixed antibiotics in an emergency department or critical care unit for such urgent situations is an appropriate strategy for enhancing the likelihood that antimicrobial agents will be infused promptly. Staff should be cognizant that some agents require more lengthy infusion time, whereas others can be rapidly infused or even administered as a bolus.
48- to 72-Hour Re-evaluation
Once the causative agent and antibiotic susceptibilities have been identified, restriction of the number of antibiotics and narrowing the spectrum of antimicrobial therapy is an important and responsible strategy for minimizing the development of resistant pathogens and for containing costs.
The antimicrobial regimen should always be reassessed after 48–72 hours on the basis of microbiological and clinical data with the aim of using a narrow-spectrum antibiotic to prevent the development of resistance, to reduce toxicity, and to reduce costs. Once a causative pathogen is identified, there is no evidence that combination therapy is more effective than monotherapy. The duration of therapy should typically be 7–10 days and guided by clinical response.
Dosing
All patients should receive a full loading dose of each antimicrobial. However, patients with sepsis or septic shock often have abnormal renal or hepatic function and may have abnormal volumes of distribution due to aggressive fluid resuscitation. The ICU pharmacist should be consulted to ensure that serum concentrations are attained that maximize efficacy and minimize toxicity. [8-11]
Grading the Evidence
The Surviving Sepsis Campaign recommends that intravenous antibiotic therapy be started as early as possible and within the first hour of recognition of septic shock (GRADE 1B) and severe sepsis without septic shock (1D). Appropriate cultures should be obtained before initiating antibiotic therapy, but should not prevent prompt administration of antimicrobial therapy (1D). The Surviving Sepsis Campaign also recommends that initial empirical anti-infective therapy include one or more drugs that have activity against all likely pathogens (bacterial and/or fungal) and that penetrate in adequate concentrations into the presumed source of sepsis (Grade 1B). Additional recommendations include reassessing the antimicrobial regimen daily to optimize efficacy, prevent resistance, avoid toxicity, and minimize costs (1C). The typical duration of therapy is limited to 7–10 days; longer if response is slow or there are undrainable foci of infection or host immunologic deficiencies (1D). Antimicrobial therapy should be stopped if the cause of apparent sepsis is found to be noninfectious (1D).
The above category 1 recommendations are strong recommendations for care based on a number of qualitative considerations. “B” level evidence generally derives from randomized control trials with certain limitations or very well-done observational or cohort studies. “C” level evidence reflects well-done observational or cohort studies with controls. “D” level evidence generally reflects case series data or expert opinion.
The Surviving Sepsis Campaign also suggests clinicians consider combination therapy in Pseudomonas infections (2D) and consider combination empiric therapy in neutropenic patients (2D). Combination therapies should last 3–5 days and be de-escalated following determination of microbial susceptibilities (2D). These category 2 suggestions are weaker recommendations for care based on a number of qualitative considerations. “D” level evidence generally reflects case series data or expert opinion.
Tips
1. Establish a standardized clinical protocol that includes the empiric administration of antibiotics in severe sepsis within 3 hours of presentation for ED admissions and 1 hour for ICU admissions.
2. Do establish a pre-mixed quantity of broad-spectrum antibiotics available in the emergency department and ICU, in order to avoid delays involving pharmacy acquisition of the antibiotic.
3. Do infuse antibiotics through multiple lines as available in order to speed delivery of agents.
4. Do cover both Gram-positive and Gram-negative organisms.
5. Do consider specific knowledge about the patient’s past organism burden if available (including fungal infection), the setting from which the patient arrived in the emergency department (for example, another institution that may harbor resistant organisms), and community and hospital resistance patterns in making choices.
6. Consider double antibiotic coverage for Pseudomonas if clinical suspicion warrants, although there is no evidence-based definitive answer on this issue.
References
1. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension prior to initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006; 34:1589-1596
2. Leibovici L, Shraga I, Drucker M, et al. The benefit of appropriate empirical antibiotic treatment in patients with bloodstream infection. J Intern Med. 1998;244:379–386.
3. Kollef MH, Sherman G, Ward S, et al. Inadequate antimicrobial treatment of infections: A risk factor for hospital mortality among critically ill patients. Chest. 1999;115:462–474.
4. Ibrahim EH, Sherman G, Ward S, et al. The influence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting. Chest. 2000;118:146–155.
5. Brun-Buisson C, Doyon F, Carlet J. Bacteremia and severe sepsis in adults: A multicenter prospective survey in ICUs and wards of 24 hospitals. Am J Respir Crit Care Med. 1996;154:617–624.
6. Opal SM, Garber GE, LaRosa SP, et al. Systemic host responses in severe sepsis analyzed by causative microorganism and treatment effects of drotrecogin alfa (activated). Clin Infect Dis. 2003;37:50–58.
7. Clec'h C, Timsit JF, De Lassence A. Efficacy of adequate early antibiotic therapy in ventilator-associated pneumonia: influence of disease severity. Intensive Care Med. 2004;30(7):1327-1333.
8. Hatala R, Dinh T, Cook DJ. Once-daily aminoglycoside dosing in immunocompetent adults: A meta-analysis. Ann Intern Med. 1996;124:717–725.
9. Ali MZ, Goetz MB. A meta-analysis of the relative efficacy and toxicity of single daily dosing versus multiple daily dosing of aminoglycosides. Clin Infect Dis. 1997;24:796–809.
10. Amsden GW, Ballow CH, Bertino JS. Pharmacokinetics and pharmacodynamics of anti-infective agents. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 5th ed. Philadelphia, PA: Churchill Livingstone; 2000:253–261.
11. Hyatt JM, McKinnon PS, Zimmer GS, et al. The importance of pharmacokinetic/ pharmacodynamic surrogate markers to outcomes. Focus on antibacterial agents. Clin Pharmacokinet. 1995;28:143–160.
Content adapted extensively from:
• Dellinger, RP, Levy, MM, Carlet, JM, et al. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008; [published correction appears in Crit Care Med. 2008; 36:1394-1396] 36:296-327
• Bochud PY, Bonten M, Marchetti O, et al. Antimicrobial therapy for patients with severe sepsis and septic shock: An evidence-based review. Crit Care Med. 2004;32(Suppl.):S495–S512.