Antibiotics in Sepsis: Is Early Always Better?

Timely administration of broad-spectrum antibiotics in septic patients saves lives.  Though this has been demonstrated in hundreds of clinical investigations over the last few decades, antibiotics remain the most controversial topic in the management of severe sepsis and septic shock.  In October, 2015 The Center for Medicare and Medicaid Services (CMS) introduced a new core measure entitled SEP-1:  Early Management Bundle, Severe Sepsis/Septic Shock.  A central element of the core measure holds hospitals responsible for administering antibiotics within three hours of the diagnosis of severe sepsis and septic shock.  In 2018, The Surviving Sepsis Committee, largely considered the worldwide authority on the management of sepsis, revised it’s regularly published guidelines to recommend antibiotic infusion within one hour for patients diagnosed with sepsis.  Early administration of antibiotics is one component of the sepsis bundle in addition to a 30 ml/kg crystalloid bolus and serial lactic acid checks. If the patient remains hypotensive despite the initial crystalloid bolus, a clinician should assess whether the patient is fluid responsive and should initiate norepinephrine to maintain a MAP>65 mmHg. If the required norepinephrine dose reaches a moderate-high rate, you should consider placement of an arterial line and a central line. In this post, we will briefly review the evidence supporting early antibiotic use, review newer evidence pointing to potential harm from unnecessary antibiotics and propose a more nuanced, less reflexive approach to timing of antibiotic infusion.

In 2006, Kumar et al. published in Critical Care Medicine that each hour delay in antibiotic infusion for patients in septic shock increases hospital mortality by 7%.1  In 2019, Peltan et al. reconfirmed the importance of early antibiotics, showing that in this population of patients with severe sepsis and septic shock, each hour delay in antibiotic infusion was associated with a 10% increase in one year mortality. 2  These two studies, oft cited by sepsis committees around the globe, serve as tools to convince providers of the urgency of antibiotics in patients with sepsis.  These and dozens of similar studies, all retrospective comparisons, serve as the basis for guidelines that mandate early antibiotic infusion.

No double blinded trial randomizing patients to early vs late antibiotics has been or will be conducted.  To do so would be unethical.   However, we must acknowledge that with pressure for early antibiotics we risk treating some patients who do not have infection.  Sepsis is an elusive diagnosis.  No CT pulmonary angiogram with arterial occlusion or electrocardiogram with ST elevation exists for sepsis.  As an emergency department physician, I must admit that at the time of admission, I sometimes don’t know whether a patient truly has an infection as the cause of her SIRS physiology and organ dysfunction.  In 2015, Klouwenberg et al. demonstrated that only 58% of patients admitted to the ICU were determined by a panel of experts to definitely or probably have infection.3  A survey conducted to gain insight into the now retired Pneumonia Core Measure, showed that greater than 50% of emergency physicians believed they had given antibiotic to patients that did not have pneumonia. 4  The certainty of infection comes retrospectively.  In the studies demonstrating efficacy of antibiotics, sepsis is determined from chart review after culture results are available.   Those given antibiotics and later determined to have a noninfectious diagnosis are not usually included in these studies.

So what of these patients?  Is it possible that they are harmed by the antibiotics they receive unnecessarily?  In addition to early antibiotics, CMS requires acute care hospitals to actively participate in antimicrobial stewardship.  Evidence shows that to avoid antibiotics when infection is not present and to use the narrowest spectrum of antibiotics for the shortest duration possible when infection is present, reduces antibiotic resistance.  Antimicrobial stewardship has potential to reduce disease caused by resistant organisms, not just for an individual patient but for hospitals and communities in general.  Early antibiotics and antimicrobial stewardship can be at odds, as evidenced by the Infectious Disease Society of America’s tepid support for SSG.

In addition to bringing superbugs to our ICUs, antibiotics may cause harm for individual patients.  In Intensive Care Medicine in 2020, Alrukumaran, et al. review the current understanding of potential antimicrobial harms. 5  Patients exposed to broad spectrum antibiotics experience a disruption of the microbiome in the lung, gut and skin.  This dysbiosis has been shown to lead to more frequent infections with Clostridium Dificile and other opportunistic pathogens but also more frequent hospitalizations.  The direct effects of antibiotics on organ function are also well studied, vancomycin and renal toxicity being a common example.   In addition, some antibiotics are known to have direct toxicity on the cellular level.  For example, amoxicillin and fluoroquinolones have been shown in vitro to interfere with the electron transport chain, inhibiting cellular energy production.  Theorized but less well studies is the effect antibiotics may have on the mitochondria on leukocytes and other immune cells, which paradoxically may lead to host immune system collapse.  Finally, early antibiotics may interfere with our ability to accurately diagnose the offending pathogen, and this can lead to prolonged courses of broader than needed therapy.  For example, the patient with diabetic foot infection who looks great but has a lactate of 2.1 requires antibiotics within three hours, but those antibiotics may prevent the surgeon from obtaining positive intraoperative cultures which would allow a narrower course of antibiotics.  Operative and bedside procedures for source control and tissue/fluid sampling would ideally be performed prior to starting antibiotics in stable patients.

How do we avoid the potentially harmful effects of antibiotics while not withholding antibiotics from those who will truly benefit? Clinical acumen matters.  We must always strive to take in all the data available, avoid dangerous biases and make evidence-based decisions with the information available.  Related is the functionality of the health care system.  Hospitals that actively participate in sepsis care performance improvement realize significant reductions in sepsis mortality.  The ability to get labs and radiologic results quickly matters.  High performance centers have protocols in place to care for the sickest patients, that include bringing ancillary services to bedside, obtaining bundle compliance quickly and placing central lines and arterial lines early to support resuscitation.

Regarding antibiotics, the rapidity of treatment ought to weigh the severity of illness and certainty of diagnosis. Sepsis guidelines reflect the best care for cohorts of patients, not the patient in front of you. If an individual patient clearly has a bacterial infection, prompt treatment is indicated regardless of illness severity. If there is diagnostic uncertainty, however, clinicians should calibrate their response to severity of illness and probability of infection. Immediate antibiotics are warranted if the patient has shock or rapid deterioration, even if there is only a small possibility that their condition is due to infection.   Antibiotics can be delayed in stable patients in whom there is a great deal of diagnostic uncertainty.  A more nuanced approach to antibiotics will allow us to continue the treat the sickest patients rapidly and aggressively while not exposing others to potential harm.

REFERENCES

  1. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006;34(6):1589-96.
  2. Peltan, et al. ED Door-to-Antibiotic Time in ED and Long-Term Mortality. 2019.02.08. 938-946.
  3. Pulia, et al. Emerg Med Clin N Am 35 (2017) 199–217
  4. Klein Klouwenberg PM, Cremer OL, van Vught LA, et al. Likelihood of infection in patients with presumed sepsis at the time of intensive care unit admission: a cohort study. Crit Care 2015; 19:319.
  5. Damiani et al. Effecto of performance improvement programs on compliance with sepsis bundles and mortality:  a systematic review and meta-analysis of observational studies.  PLoS One.  2015; 10(5).
Read all articles in antibiotic stewardship, antibiotics, antimicrobial stewardship, Arterial Line, Arterial line insertion, Arterial line placement, Arterial Lines, Central Line, Central line insertion, central line placement, central lines, Central Venous Catheter, central venous catheters, Featured, Sepsis, Septic Shock, severe sepsis, shock, Systemic inflammatory response syndrome
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