By David R. Ha, PharmD, BCIDP
Infectious Diseases and Antimicrobial Stewardship Pharmacist; Manager, Stanford Antimicrobial Safety and Sustainability Program, Stanford Health Care; Lecturer, Stanford University School of Medicine, Division of Infectious Diseases and Geographic Medicine; Program Coordinator, PGY2 Infectious Diseases Pharmacy Residency Program, Stanford Healthcare
SYNOPSIS: This multicenter, observational study provides the first focused comparison of short vs. prolonged antibiotic courses for carbapenem-resistant Enterobacterales bloodstream infections, suggesting that short courses (eight to 10 days) have similar outcomes to prolonged courses.
SOURCE: Soto CL, Hsu AJ, Lee JH, et al. Identifying effective durations of antibiotic therapy for the treatment of carbapenem-resistant Enterobacterales bloodstream infections: A multicenter observational study. Clin Infect Dis 2023; Aug 16. doi: https://doi-org.laneproxy.stan..... [Online ahead of print].
Soto and colleagues, in this multicenter retrospective observational study, sought to compare shorter with longer courses of antibiotic therapy for carbapenem-resistance Enterobacterales (CRE) bloodstream infections (BSI).
They included consecutive adult inpatients with monomicrobial CRE BSI admitted to one of 24 hospitals in 2019. CRE was defined as a bacterium in the Enterobacterales order with documented resistance to any carbapenem antibiotic. Patients were excluded if they had complicated BSI (e.g., osteoarticular infection, endocarditis, endovascular infection, or central nervous system [CNS] infection), receipt of 72 hours or more of empiric antibiotic therapy without activity against the CRE pathogen, receipt of agents other than novel beta-lactams (e.g., ceftazidime/avibactam) unless receiving an anti-pseudomonal carbapenem for an ertapenem-monoresistant CRE, receipt of monotherapy with aminoglycosides, fluoroquinolones, polymyxins, or tetracycline-derivatives, receipt of 21 days or longer of antibiotic therapy, or patients in whom antibiotics were prematurely terminated due to care withdrawal (patients needed to be alive at least one day after completing antibiotic therapy for inclusion).
The primary outcome measure was a composite of all-cause mortality or recurrent BSI with the same bacterial species within 30 days of completing antibiotic therapy. Short-course antibiotic therapy was defined as seven to 10 days, and prolonged courses were defined as 14-21 days. Inverse probability of treatment weighting (IPTW) was used to account for selection bias.
In total, 183 patients met eligibility criteria, with 66 (36%) and 117 (64%) in the short- and prolonged-course groups, respectively. Klebsiella pneumoniae (52%) and Enterobacter cloacae complex (36%) were the predominant CRE organisms identified. Among all CRE isolates, 35% had a carbapenemase gene identified (all were Klebsiella pneumoniae carbapenemase [KPC]), and 20% were ertapenem-monoresistant. The most common treatment regimen included ceftazidime/avibactam (41%) or meropenem/vaborbactam (11%), and 15% of patients treated with a beta-lactam/beta-lactamase inhibitor received concomitant therapy with an aminoglycoside, fluoroquinolone, or polymyxin. Notably, 90% of patients overall had adequate source control interventions.
There were some differences in baseline characteristics between groups. Patients in the short-course group tended to have a greater proportion of urinary infections, and patients 65 years of age or older and were less likely to have source control. IPTW balanced these differences.
There was no difference in the primary outcome between the short- and prolonged-course groups in the IPTW cohort (13.6% vs. 11.9%; odds ratio [OR], 1.21; 95% confidence interval [CI], 0.55-2.31). There were no differences in the components of the primary composite outcome for mortality (3.4% vs. 4.6%) or recurrent bacteremia (6.1% vs. 5.7%).
The authors concluded that seven to 10 days of antibiotic therapy may be sufficient for patients with CRE BSI provided adequate source control was achieved, when necessary.
COMMENTARY
Over the past five years, there has been increasing focus on shorter courses of therapy (generally seven days) for gram-negative bacteremia largely due to the publication of three randomized trials.1 A major limitation of these data, however, has been the exclusion of certain drug-resistant organisms like Pseudomonas aeruginosa and multi-drug-resistant Enterbacterales (including CRE). While some retrospective data on duration of therapy exist for BSI due to certain organisms like Pseudomonas aeruginosa, data on resistant Enterobacterales, especially CRE, are lacking. Hence, the question of “How long can we treat?” for CRE BSI remains.
Numerous studies have demonstrated high mortality (up to 50%) associated with CRE infections.2 A systematic review and meta-analysis of CRE infections previously found that a duration shorter than 10 days was associated with mortality; however, this finding may have been confounded, since patients who expired during therapy were included and more often would be associated with shorter course therapy because patients would not have survived long enough to receive longer courses.3
This observational study conducted by Soto et al provides a focused comparison of short vs. prolonged antibiotic courses for CRE BSI and suggests that short courses (median nine days; interquartile range [IQR], eight to 10 days) have similar outcomes to prolonged courses. However, there are several aspects to this study that are worth noting when considering which patients and pathogens these findings may be applicable to.
First, “active” therapy was largely a beta-lactam +/- beta-lactamase inhibitor in this study, and a fairly low (15%) proportion of patients had concomitant therapy with other agents. Appropriately, polymyxin monotherapy, well-known to be associated with worse outcomes (i.e., mortality, toxicity) relative to beta-lactams, was excluded, alongside monotherapy with aminoglycosides, fluoroquinolones, and tetracycline derivatives. Thus, these outcomes may not apply to monotherapy with these excluded agents.
Second, patients who were on inactive empiric therapy for more than 72 hours initially were excluded. While this was a reasonable exclusion criterion for the study’s intended purpose, in practice, patients with CRE infections frequently may be on inactive empiric therapy while organism identification and susceptibility testing are awaited, and CRE-active therapy seldom is used empirically. The majority of participating hospitals (22 of 24) employed some type of rapid genotypic resistance testing on blood cultures, and it is well known that time to effective therapy for gram-negative infections is a major predictor of ultimate outcome.4 Additionally, the majority of patients (90%) received adequate source control interventions, when necessary, so these findings should not be applied to patients with inadequate source control. Similar to existing randomized trials on gram-negative bacteremia durations, the majority of patients had urinary infections (63% to 65% in the IPTW cohort).
The diversity of carbapenem resistance among pathogens should be noted. Carbapenemase production among pathogens was fairly low (35%) and, accordingly, while K. pneumoniae was the predominant pathogen, E. coli was uncommon (< 12%). The second most common pathogen was E. cloacae (36%), not commonly associated with “CRE” organisms; however, this likely was due to the fact that the CRE definition used was in accordance with the Centers for Disease Control and Prevention (CDC): resistance to any carbapenem. This resulted in the inclusion of ertapenem-resistant but antipseudomonal carbapenem (e.g., meropenem)-susceptible organisms, whose resistance mechanism is distinct from antipseudomonal carbapenem-resistant organisms, where carbapenemase predominates. However, it is not clear that these differences between pathogens would translate into any meaningful differences in duration-associated outcomes. Existing randomized trials on gram-negative bacteremia, while predominated by E. coli, also include various other Enterobacterales, and application of these data generally is not restricted by organism.1
Taken together, it seems reasonable that an eight- to 10-day course of active therapy with a beta-lactam +/- beta-lactamase inhibitor is sufficient for CRE BSI, provided that source control, if applicable, is adequate, the patient received active therapy within 72 hours of initial positive blood cultures, and no complicating factors exist (e.g., endocarditis/endovascular infection, osteoarticular infection, or CNS infection).
This study by Soto et al is a welcome addition to the literature and shines light on a previously unassessed question: “How long do I treat CRE BSI?” A powered, prospective trial on duration of therapy for CRE BSI is unlikely to exist for some time; thus, such retrospective analyses are likely to be informative for many years ahead.
REFERENCES
- Turjeman A, von Dach E, Molina J, et al. Duration of antibiotic treatment for Gram-negative bacteremia — Systematic review and individual participant data (IPD) meta-analysis. EClinicalMedicine 2023;55:101750.
- Centers for Disease Control and Prevention. Healthcare Facilities: Information about CRE. Last reviewed Nov. 4, 2019. https://www.cdc.gov/hai/organisms/cre/cre-facilities.html.
- Zhou R, Fang X, Zhang J, et al. Impact of carbapenem resistance on mortality in patients infected with Enterobacteriaceae: A systematic review and meta-analysis. BMJ Open 2021;11:e054971.
- Timbrook TT, Morton JB, McConeghy KW, et al. The effect of molecular rapid diagnostic testing on clinical outcomes in bloodstream infections: A systematic review and meta-analysis. Clin Infect Dis 2017;64:15-23.
This multicenter, observational study provides the first focused comparison of short vs. prolonged antibiotic courses for carbapenem-resistant Enterobacterales bloodstream infections, suggesting that short courses (eight to 10 days) have similar outcomes to prolonged courses.
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