Study shows inadequate antibiotic use and prevalence of antibiotic-resistant pathogens with hospitalized patients with sepsis

April 23, 2020

A study, published in JAMA Network Open, looked at 17,430 adults with culture-positive sepsis admitted to 104 US hospitals and the outcomes of their antibiotic treatment.

The study found that 67.0% of the patients received empiric broad-spectrum antibiotics, but resistant gram-positive organisms were isolated in only 13.6% of patients and resistant gram-negative organisms in 13.2%. Both undertreatment (failure to cover organisms) and overtreatment (resistant organisms targeted but not isolated) were associated with higher mortality after detailed risk adjustment.

Broad-spectrum antibiotics are recommended for all patients with suspected sepsis to minimize the risk of undertreatment. However, little is known regarding the net prevalence of antibiotic-resistant pathogens across all patients with community-onset sepsis or the outcomes associated with unnecessarily broad empiric treatment.

Sepsis, the syndrome of life-threatening organ dysfunction complicating severe infection, is a leading cause of death in hospitalized patients. Early active antibiotic therapy is associated with better outcomes. Therefore, national quality measures and international guidelines recommend immediate empiric broad-spectrum antibiotics for all patients with suspected sepsis.

However, it is unclear how many patients presenting with sepsis require coverage for methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, and other potentially resistant pathogens. Most existing epidemiologic studies present rates of resistance to selected antimicrobials per pathogen rather than quantifying overall resistance rates across all patients and syndromes associated with sepsis. These data are needed to inform the rational use of antibiotics, given that overuse of broad-spectrum therapy may also confer harm by selecting for antibiotic-resistant bacteria, increasing the risk of adverse events, such as Clostridioides difficile infections, and raising costs.8-12 Overtreatment has also been associated with higher mortality rates in some populations.13-15 Therefore, we sought to elucidate the epidemiology of antibiotic-resistant pathogens in patients with culture-positive community-onset sepsis and the risks of both inadequate and unnecessarily broad antibiotic treatments in US hospitals.

The study showed that inadequate empiric antibiotic therapy (ie, ≥1 pathogen nonsusceptible to all antibiotics administered on the first or second day of treatment) and unnecessarily broad empiric therapy (ie, active against methicillin-resistant Staphylococcus aureus [MRSA]; vancomycin-resistant Enterococcus [VRE]; ceftriaxone-resistant gram-negative [CTX-RO] organisms, including Pseudomonas aeruginosa; or extended-spectrum β-lactamase [ESBL] gram-negative organisms when none of these were isolated).

The study concluded that most patients with community-onset sepsis did not have resistant pathogens, yet broad-spectrum antibiotics were frequently administered. Both inadequate and unnecessarily broad empiric antibiotics were associated with higher mortality. These findings underscore the need for better tests to rapidly identify patients with resistant pathogens and for more judicious use of broad-spectrum antibiotics for empiric sepsis treatment.

Vancomycin was the most commonly prescribed empiric antibiotic (7262 [41.7%]), followed by an anti-Pseudomonal fluoroquinolone (ciprofloxacin or levofloxacin, 6997 [40.1%]), piperacillin-tazobactam (5911 [33.9%]), ceftriaxone (5187 [29.8%]), and third- or fourth-generation cephalosporins (ceftazidime or cefepime, 2300 [13.2%]).

Prior studies have estimated the national and global burden of antimicrobial resistance, but this study is among the first to estimate the net prevalence of antibiotic resistance across all culture sites in patients with culture-positive community-onset sepsis. The researchers found that approximately 1 in 8 patients had resistant gram-positive organisms (primarily MRSA and rarely VRE) and 1 in 8 had resistant gram-negative organisms (primarily ceftriaxone-resistant gram-negative organisms and rarely ESBL or CRE).

More than two-thirds of patients received broad-spectrum therapy directed at resistant organisms, but MRSA was only isolated in 1 in 6 patients treated with vancomycin or linezolid, P aeruginosa or other ceftriaxone-resistant gram-negative organisms in 1 in 6 patients treated with anti-Pseudomonal agents, VRE in 1 in 16 patients treated with linezolid or daptomycin, and ESBLs in 1 in 70 patients treated with carbapenems. Both inadequate and unnecessarily broad empiric therapy were associated with higher mortality after detailed risk adjustment.

There are several other potential explanations for the association between overtreatment and higher mortality. As many as 20% of hospitalized patients who receive antibiotics experience adverse effects.45 Even a single dose of antibiotics can increase the risk of C difficile; this risk is higher with broad- vs narrow-spectrum antibiotics.46,47 We found unnecessarily broad empiric therapy was associated with a 26% increased risk of C difficile infection in our study. Unnecessary antibiotics may also increase the risk of acute kidney injury.48 We observed a trend toward more acute kidney injury in patients treated with unnecessarily broad antibiotics. In particular, the combination of vancomycin and piperacillin-tazobactam, a common regimen during the study period, is associated with renal toxicity.49 Broad-spectrum antibiotics also disrupt the gut microbiome, an increasingly recognized modulator of the immune system and outcomes in sepsis. Lastly, broad-spectrum antibiotics may increase the risk of resistant hospital-acquired infections.

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