By: Angela Basir, PharmD Candidate c/o 2023 and Muatasem Jaser, PharmD Candidate c/o 2023

                 Sepsis is a clinical syndrome defined as a life-threatening organ dysfunction caused by a dysregulated host response to an infection.¹ Septic shock is a subset of sepsis in which underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially increase mortality.² Being that sepsis is a medical emergency, early identification for treatment is essential. Signs and symptoms of sepsis are generally nonspecific and include confusion, disorientation, tachycardia, fever, chills, and diaphoresis.² It is crucial to administer antibiotics in a timely manner and utilize antimicrobial stewardship efforts in order to avoid progression to septic shock and increased mortality rates. 

The underlying pathophysiology of sepsis is very complex and not completely understood. The host response to infection results in the release of excess pro-inflammatory mediators which spread throughout the entire body and cause systemic inflammation, organ dysfunction, and tissue damage. Cellular injury occurs through tissue ischemia, cytopathic injury, and alterations in the rate of apoptosis. Almost all organ systems are impacted, including the circulatory, pulmonary, gastrointestinal, hepatic, renal and central nervous systems. The circulatory system responds with diffuse vasodilation and increased endothelial permeability secondary to inflammation. These alterations can ultimately lead to hypotension, intravascular hypovolemia, and hypoperfusion.³ An array of clinical screening tools, including the quick Sequential Organ Failure Score, Sequential Organ Failure Assessment, Systemic Inflammatory Response Syndrome Criteria, and National Early Warning Score (or Modified Early Warning Score), are important for initiating empiric treatment.¹ 

In October of 2021, revisions were made to the Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock.¹ Multiple recommendations were discussed in comparison to the previous guidelines published in 2016. Major changes were made regarding the recommended optimal time for antimicrobial administration. For definite or probable sepsis, with or without shock, the initiation of antimicrobials should be within 1 hour of recognition. For adults with possible septic shock, or a high likelihood for sepsis, antimicrobials should be administered within 1 hour of recognition. Additionally, the current recommendation for adults with possible sepsis, in the absence of shock, is to administer antimicrobials within 3 hours from the time of sepsis recognition.¹  

The rationale for the timing of antimicrobial administration comes from a retrospective cohort study conducted by Kumar et al. which analyzed adults aged 18 years and older with septic shock.⁴ This study took place in 14 intensive care units across the United States and Canada, involving 2,154 patients with septic shock and similar acute physiology and chronic health evaluation (APACHE II) scores. APACHE II uses a point score based upon initial values of 12 routine physiologic measurements, age, and previous health status to provide a general measure of severity of disease.⁵ The average score was 26 (range 0 to 71), with an increasing score ultimately depicting an increase in the risk of hospital mortality.⁵ The average age of participants was 63 years old with an approximately equal distribution between males and females. Roughly 66.5% of the infections occurred within the respiratory system, gastrointestinal tract, or intra-abdominal area.⁴ 

Kumar et al. sought to see if there was any association between early effective antimicrobial therapy and increased survival rates in patients with septic shock. In order to evaluate this, the time of antimicrobial therapy initiation following an onset or recurrence of hypotension was recorded. The study defined hypotension as one of the following: a mean arterial blood pressure of 65 mmHg or less, a systolic blood pressure of 90 mmHg or less, or a decrease of 40 mmHg from baseline. According to figure 1, antimicrobial therapy administered within 30 minutes of the initial signs of hypotension was associated with an 82.7% survival rate. When antibiotics were administered within the first hour of hypotension, the associated survival rate was 77.2%. Of note, over the first 6 hours after the onset of hypotension, each hour of delayed antimicrobial therapy was associated with a reduction in survival rates by 7.6% (range 3.6 to 9.9%). Furthermore, figure 2 represents the time of hypotension onset and mortality rates, expressed as an odds ratio. Within the first 2 hours of delayed antimicrobial therapy, the odds ratio for mortality was approximately 1.7 (95% CI 1.12 to 2.48), and showed a statistically significant increase to a maximum odds ratio of 93 when therapy is delayed for more than 36 hours.⁴  

The above data suggests that early administration of antimicrobial therapy in patients with septic shock is associated with a decrease in hospital mortality, length of stay, and organ dysfunction.⁴ Therefore, it would be of best practice for the medical team to make a maximum effort in ordering, delivering, and administering effective antibiotics as quickly as possible for patients with presumed sepsis or septic shock.  

Extending the time frame for the administration of antimicrobials in possible sepsis to 3 hours allows for a time-sensitive course of rapid investigation to rule out other causes of illness, which may be beneficial in the management of antimicrobial stewardship.¹ Antimicrobial stewardship is a coordinated set of interventions which are designed to improve and to measure the appropriateness of antimicrobials.⁶ Antimicrobial stewardship promotes the selection of optimal drug regimens, doses, duration of therapies, and routes of administration to prevent the overuse of broad-spectrum antibiotics. Limiting therapy to the shortest duration prevents resistance and improves patient outcomes. 

Sepsis diagnoses are subjective in nature, and signs and symptoms are overall nonspecific. Questions may arise as to how to pick an appropriate empiric antibiotic regimen in such a limited timeframe. This is where antimicrobial stewardship efforts play a vital role, especially when broad spectrum antimicrobial coverage, or empiric therapy, is needed. Empiric therapy refers to antibiotics that are administered during the period prior to the receipt of blood cultures and antibiotic susceptibility test results.⁷ Once more information is known about the infection, several antimicrobial stewardship efforts can be made by clinical pharmacists to optimize treatment and minimize the risk of resistance. For example, once the pathogen is identified and susceptibility results are known, antibiotic de-escalation should be implemented, and definitive therapy should be used. Definitive therapy is defined as using the narrowest spectrum antibiotic that a bacteria is susceptible towards.⁸ The use of de-escalation protocols and susceptibility reports are major advancements in improving resistance. Examples include switching from double coverage combination therapy to monotherapy or discontinuing empiric antibiotics for bacteria found not to be isolated in cultures.⁹ 

Rapid diagnosis and administration of appropriate antibiotics is essential for the improvement of mortality in patients with sepsis. Strategies including de-escalation and discontinuation should be implemented as well, especially in situations where illnesses are due to noninfectious causes or when susceptibility test results are available. The allowance of a 3-hour interval prior to starting antimicrobial therapy in patients with possible sepsis in the absence of shock will more than likely have a positive impact on the rates of resistance patterns as this prevents the overuse of broad-spectrum antibiotics in situations where use may not be warranted. Additionally, it is essential to understand the importance of implementing a multidisciplinary approach to patient care which adheres to the standards of antimicrobial stewardship programs. This is where the role of pharmacists becomes vital in the treatment of infections requiring multiple courses of antimicrobial therapy. 

References

1. Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Critical Care Medicine. https://journals.lww.com/ccmjournal/Fulltext/2021/11000/Surviving_Sepsis_Campaign__International.21.aspx. Published 10/04/2021. 
2. Singer M, Deutschman C, et al. The Third International Consensus Definitions for Sepsis and Septic Shock – Sepsis-3. JAMA Network. https://jamanetwork.com/journals/jama/fullarticle/2492881. Published 02/23/2016. 
3. Jacobi J. Pathophysiology of Sepsis. Am J Health Syst Pharm. 2002;59 Suppl 1:S3-S8. doi:10.1093/ajhp/59.suppl_1.S3 
4. Kumar A, Roberts D, Wood K, et al. Duration of Hypotension Before Initiation of Effective Antimicrobial Therapy is the Critical Determinant of Survival in Human Septic Shock. D. Samuel Gottesman Library. https://ovidsp-dc2-ovid-com.elibrary.einsteinmed.edu. Published 06/01/2006.
5. Knaus WA, Draper EA. APACHE II: A severity of disease classification system. Crit Care Med 1985; 13:818 – 829.
6. Antimicrobial Stewardship. Association for Professionals in Infection Control and Epidemiology. https://apic.org/professional-practice/practice-resources/antimicrobial-stewardship/. Published 01/2013.
7. McGregor J, Rich S, Harris A, et al. A Systematic Review of the Methods Used to Assess the Association between Appropriate Antibiotic Therapy and Mortality in Bacteremic Patients. Clinical Infectious Diseases. https://academic.oup.com/cid/article/45/3/329/358789. Published 08/01/2007.
8. Leekha S, Terrell CL, Edson RS. General Principles of Antimicrobial Therapy. Mayo Clin Proc. 2011;86(2):156-167. doi:10.4065/mcp.2010.0639
9. Seok H, Jeon JH, Park DW. Antimicrobial Therapy and Antimicrobial Stewardship in Sepsis. Infect Chemother. 2020;52(1):19-30. doi: 10.3947/ic.2020.52.1.19

Published by Rho Chi Post