De-Escalation in Under 48 Hours Reduces 90-Day C difficile Infection Incidence 3-Fold


A novel study from Seddon and colleagues adds to the body of evidence that supports what antimicrobial stewardship programs are so often challenged to do, early de-escalation.

A novel study from Seddon and colleagues adds to the body of evidence that supports what antimicrobial stewardship programs are so often challenged to do, early de-escalation.1 The study’s investigators looked at the independent risk factors of empiric antipseudomonal β-lactam (APBL) therapy for patients with Enterobacteriaceae bloodstream infections who received more than 48 hours of therapy compared with those who received less and found a 3-fold lower incidence of Clostridium difficile infection in patients who received less than 48 hours of APBL therapy.

With each hour that passes after receiving noneffective therapy, patients with sepsis are at increased risk of mortality.2,3 As a result, empiric treatment for the condition often includes APBL therapy. With the increased threat of antimicrobial resistance, however, clinicians are growing concerned over the development of difficult-to-treat gram-negative bacteremia, and so the initial selection of the appropriate, targeted antibiotic is imperative.4,5 Furthermore, excessive antimicrobial coverage brings additional risks, such as C difficile infection.

Seddon and colleagues challenged the practice of broad-spectrum antipseudomonal coverage up front for those patients without risk factors, referencing another recent study completed at their center. The results from that study demonstrated only 1% prevalence of Pseudomonas aeruginosa bloodstream infections in community-onset, immunocompetent patients who have not received prior antimicrobial use within 3 months.6 In addition, the investigators assessed the risk of antimicrobial exposure and early de-escalation of APBL therapy at 48 hours on the rate of C difficile infection.7,8

The retrospective cohort study included 951 adult patients with gram-negative bloodstream infections. Data were collected for 54 months. Not all non-Enterobacteriaceae bloodstream cases (n = 78) were included, as the authors stated they lacked the possibility of de-escalation. Those patients who were discharged, transferred, or died were also excluded from the results (n = 56). Additionally, the investigators excluded those patients with recent (within a year) or concurrent C difficile infection (developed within 24 hours of blood culture collection).

A total of 808 patients with a first episode monomicrobial Enterobacteriaceae bloodstream infection who received an APBL were included in the study. Nearly half of the patients (n = 414) received more than 48 hours of APBL versus the patients (n = 394) who received less than 48 hours of similar therapy. (An APBL-antimicrobial agent was described as the following: piperacillin/tazobactam, ceftazidime, cefepime, imipenem/cilastatin, meropenem, and aztreonam.)

C difficile infection was determined by positive C difficile toxin B polymerase chain reaction. To overcome the highly sensitive test and account for clinical C difficile infection incidence, the 2 institutions in the study were consistent with their hospital policies related to the diagnosis and testing of C difficile infection. Stool samples must have conformed to container in order to be assessed or otherwise were rejected. Patients who received laxatives within 48 hours of stool collection were excluded. Patients were not routinely screened for C difficile infection.

The investigators looked at therapy from the index visit to any subsequent admissions within 90 days of bloodstream infection. Baseline characteristics of those who received more than 48 hours of APBL were that they were slightly younger, more likely male, and more likely to have received antimicrobials within of bloodstream infections (time frame not defined); a higher Charlson Comorbidity Index score; a longer hospital length of stay (HLOS) prior to bloodstream infection; a higher Pitt Bacteremia Score; and higher incidence of intra-abdominal source.

Of interest, the isolates were reported to be Escherichia coli (56%), Klebsiella species (21%), Proteus mirabilis (7%), Enterobacter species (7%), Serratia species (4%), Citrobacter species (1%), Salmonella species (1%), and other Enterobacteriaceae (2%). Most infections were from the urinary tract (56%).

The investigators also found that HLOS following bloodstream infection and total exposure to antimicrobials was longer in those who received more than 48 hours of APBL (11 days vs 7 days; P <.001).

Of the 808 patients, 463 had complete follow-up within 90 days of bloodstream infection. Of those 463, 29 developed a C difficile infection. The overall incidence of C difficile infection was 4.4% for the study group, and most cases were hospital-acquired (83%; n = 24). The remaining patients (17%; n = 5) required hospital readmissions. Ultimately, the results showed the incidence of C difficile infection was higher in patients who received more than 48 hours of APBL than those who received 48 hours or less of APBL (7.0% vs. 1.8%; log-rank P = .002).

After adjustments for the propensity to receive more than 48 hours of APBL (and other variables that were of an univariable association with receiving APBL for less than 48 hours and had an associated P value of <.05), the higher risk for C difficile infection remained consistent with the previously defined independent risk of those with end-stage renal disease.9

Ultimately, this study provides evidence that early de-escalation of broad-spectrum antibiotics has clinical benefits. Antimicrobial de-escalation is often the stewardship intervention performed most and is also met with the least clinician acceptance. Perhaps this study could serve as an education tool and assist in modifying prescriber behavior for those clinicians who are reluctant to de-escalate, especially in patients with severe illness.

Microbiology results are the pillar of definitive antimicrobial selection. A question remains, however, regarding whether the use of rapid diagnostic testing for gram-negative identification and susceptibility, paired with real-time antimicrobial stewardship to the narrowest antimicrobial within 48 hours, has a role in further reducing the incidence of C difficile infection in hospitalized adults with Enterobacteriaceae bloodstream infections.10

Dr. Zappas received her PharmD from Wingate University School of Pharmacy and completed a PGY-1 pharmacy residency at Bayfront Health in St Petersburg, Florida. She received a teaching certificate from the University of Florida. Dr. Zappas joined Florida Hospital Orlando in 2010 as an antimicrobial stewardship pharmacist. She led many clinical programs as the clinical pharmacy coordinator as well as the director of the PGY-1 Pharmacy Residency Program. Dr. Zappas is also board certified in pharmacotherapy, with advanced qualification in infectious diseases. She joined Accelerate Diagnostics in 2018 as director of clinical development and optimization.


  1. Seddon MM, Bookstaver PB, Justo JA, et al. Role of early de-escalation of antimicrobial therapy on risk of Clostridioides difficile infection following Enterobacteriaceae bloodstream infections [published online October 12, 2018]. Clin Infect Dis. doi: 10.1093/cid/ciy863.
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