COMMENTARY

Broad-Spectrum Antibiotics Reduce Hospital Mortality

Andrew Shorr, MD, MPH

Disclosures

October 20, 2017

This is Andy Shorr from Washington, DC, with the pulmonary and critical care update. At the American Thoracic Society (ATS) 2017 conference [in May], a number of important papers were presented and simultaneously published online in major medical journals. I'd like to discuss one of those manuscripts right now. It's an article by Seymour and colleagues, published online in the New England Journal of Medicine,[1] that deals with outcomes in severe sepsis and septic shock.

These authors were interested in investigating how the bundles that are recommended as part of the Surviving Sepsis campaign correlate with improved outcomes. There's been substantial work that suggests that as we've applied the bundle of care, in terms of issues related to antibiotic administration and fluid resuscitation, we have improved outcomes in severe sepsis and septic shock. These authors took advantage of some regulations that recently went into effect in New York State that required the completion of both a 3-hour and 6-hour bundle in the care of patients who present in the emergency department with severe sepsis or septic shock. The 3-hour bundle focuses on issues related to identifying sepsis, such as measuring lactate; issues related to antibiotics and infection in terms of drawing blood cultures before the initiation of antibiotic therapy; and then the initiation of timely, or rather broad-spectrum, initial appropriate antibiotic therapy. The 6-hour bundle deals with issues related to fluid resuscitation and that initial crystalloid bolus.

These authors went back and looked, retrospectively, at the observational data that were reported to the State of New York. They had the advantage of examining 49,000 cases of severe sepsis and septic shock presented in the emergency department. It nicely showed that for each hour delay in completion of important aspects of the bundle—and for the 3-hour bundle, that important aspect would be initiation of broad-spectrum antibiotic therapy—there was a stepwise increased risk for mortality. More specifically, they noted that there was about a 4% chance of increased risk for death, or an odds ratio of 1.04 per hour in terms of hospital mortality related to timeliness of that initial broad-spectrum antibiotic therapy.

The other thing that's important to realize is that they saw that the median time to completion of that initial 3-hour bundle was only 1.3 hours. That's rather impressive. That means that most places are getting the bundle done in less than 90 minutes.

When it came to issues related to fluid administration, they realized that they only looked at this in patients who either had initial lactate above 4 mEq/L, or who had hypotension when presenting with their severe sepsis or septic shock. When they looked at the fluid bolus part, they did not see a significant relationship between the hitting of that target, the administration of that initial bolus of fluid, and improved hospital mortality.

When you look at the data, it's important to realize several substantial limitations with this analysis. First of all, it is essentially retrospective observational data. Second, they are limiting their analysis only to community-onset infection. They don't provide any data about how many of these patients have healthcare-associated infection, or pure community-associated infection; it's only looking at things from the perspective of the emergency department. In addition, it's not clear how sick these patients were. The median lactate across the cord was about 2.5 mEq/L. There's no question that these are sick people, but they aren't substantially very sick. That suggests that perhaps this study may not have had the power when it came particularly to the issue of the fluid resuscitation piece, to identify patients who were going to benefit from fluid resuscitation as aggressively as recommended for septic shock.

The other thing that's important to note is that there's a lot of potential here for what's called confounding by indication. For example, sicker people with higher lactates are more likely to get more aggressive initial fluids. Conversely, if you have your lactate checked because you met the 3-hour bundle, you're more likely to have fluids given. There's some confounding by how the patients are treated. It's the same thing when it comes to looking at the patients who had the bundle completed at 3 hours, as opposed to looking at the fluid resuscitation or 6-hour piece. If you look at the patients in this cohort, the patients who had the bundle completed at 3 hours, there were more respiratory infections in that population. That's a sicker group of patients—patients with, say, urosepsis. There is certainly some potential for confounding by indication.

Despite these limitations, which the authors are very transparent about, the data suggest that this approach to being broad initially with our antibiotic therapy is crucial. Now, realize that this is not a new theme. This has been in the literature, predominantly the pneumonia literature, for a decade and a half. Now it's finally made its way to the sepsis literature, but it clearly suggests that initial appropriate antibiotic therapy saves lives.

Unfortunately, in the current study by Seymour and colleagues, all they could look at was broad-spectrum therapy. They couldn't really assess whether that therapy was appropriate. Overly broad therapy raises the risk of promoting resistance and wasting a scarce resource. We need to get better at figuring out how to use our antibiotics, and we hope that with better risk-stratification tools, better patient identification tools, more rapid diagnostics that not only tell us what the pathogen is but what it's susceptible to, we're going to improve outcomes even further.

The take-home message is that these data, in a huge dataset representative of an entire state, indicate that the broad-spectrum antibiotic approach is crucial and pays dividends in terms of reducing hospital mortality.

This is Andy Shorr from Washington, DC.

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