Re: ‘The renal safety of a single dose of gentamicin in patients with sepsis in the emergency department’ by Cobussen et al.
Authors: A. Lawandi, Todd C. Lee
Journal: Clinical Microbiology and Infection (2020)

Sepsis is associated with a high risk of mortality; hence, there is a desire to ensure that adequate antibiotics are administered as soon as possible. Faced with the possibility of antimicrobial resistance, many clinicians will turn towards double coverage of Gram-negative pathogens. One approach to double coverage is the addition of a single dose of an aminoglycoside to cover in case of β-lactam resistance while culture and susceptibility results are pending. Such an approach may have benefit if (a) the aminoglycoside adds a substantial amount of additional coverage to the paired second agent, (b) there is a compelling argument against the use of broader spectrum agents in emergency department patients with sepsis, and (c) the aminoglycoside does not harm the patient. The first depends on the local hospital epidemiology. For instance, at the McGill University Health Center emergency department, 96% of Gram-negatives in the blood are sensitive to piperacillin–tazobactam, and hence the added yield of an aminoglycoside would be minimal. The second is an issue of antibiotic stewardship philosophy which differs from centre to centre. However, the third is relevant to almost all settings: what is the potential for aminoglycoside-related harm? In their article, Cobussen et al. conclude that the addition of a single dose of gentamicin to the treatment of patients with suspected bacterial sepsis in the emergency department is safe with regard to renal function [[1]Cobussen M. Haeseker M.B. Stoffers J. Wanrooij V.H.M. Savelkoul P.H.M. Stassen P.M. The renal safety of a single dose of gentamicin in patients with sepsis in the emergency department.Clin Microbiol Infect. 2020; (in press)https://doi.org/10.1016/j.cmi.2020.06.030Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar]. Using a comparison of patients drawn from three hospital emergency departments—one which uses empirical gentamicin and two others which do not—they evaluated 571 and 1002 patients, respectively, and looked for acute kidney injury (AKI) within 1 week of admission and persisting into the second week. After admission, they reported that 64/571 patients (which is actually 11.2% and not the 12.0% reported) and 82/1001 patients (8.2% versus the reported 8.9%) developed AKI. Using the corrected numbers, there was a risk difference of 3.0% (95%CI 0–6.1%; p 0.046), suggesting harm in univariate analysis. Of these patients, 181 (31.6%) and 228 (22.8%) already had AKI on presentation, and it is unclear how the concept of AKI after admission was applied to them. It would be helpful to look at the incidence of AKI post admission in those without AKI at presentation (390 and 774 patients respectively) separately from the incidence of worsening AKI in those who presented with it. These groups can easily be differentiated in the emergency department before any medication is administered. Can the authors provide additional granularity for these subgroups? While the authors do include AKI on admission in the multivariable analysis, we think there is a clinical advantage to a stratified analysis. Persistent AKI was defined as KDIGO class 1 or greater during the second week of admission, and it was seen in 16/260 (6.2%) who did and 15/454 (3.3%) who did not receive gentamicin for a risk difference of 2.8% (95%CI –0.5% to 6.2%; p 0.07). However, there are 311 and 468 patients respectively who are unaccounted for. Some of these patients presumably died before 2 weeks; however, what happened to the rest? The authors state that they chose to classify patients as having no AKI when creatinine values were not available, but if this was done for survivors, why are there so many missing patients? Moreover, as compared to assuming that missing creatinine values were within the normal range, carrying forward the last creatine value may be a more conservative and applicable approach to this question. What would the rates of persistent AKI be if this were done for people who were alive beyond day 14? Overall, the authors should be commended for having provided more data on the approach of empirical single-dose gentamicin in the emergency department. Yet, even if a reanalysis as proposed does not conclusively demonstrate harm, the question remains as to whether double coverage is beneficial. In this study, overall mortality was higher in the aminoglycoside group. Three recent studies provide additional context. There was no survival benefit demonstrated from the addition of short courses of single daily dose aminoglycosides to a β-lactam in two prospective cohort studies (one in 535 critically ill immunocompromised patients [[2]René L. Rello J. Silvio T.F. Ben Hadj Salem O. Bauer P.R. Séguin A. et al.Aminoglycosides in immunocompromised critically ill patients with bacterial pneumonia and septic shock: a post-hoc analysis of a prospective multicenter multinational Cohort.2020https://doi.org/10.1097/SHK.0000000000001553Crossref Scopus (2) Google Scholar] and another in 626 patients with proven Gram-negative bacteraemia [[3]Deelen J.W.T. Rottier W.C. Buiting A.G.M. Dorigo-Zetsma J.W. Kluytmans J.a.JW. van der Linden P.D. et al.Short-course aminoglycosides as adjunctive empirical therapy in patients with Gram-negative bloodstream infection, a cohort study.Clin Microbiol Infect. 2021; 27: 269-275https://doi.org/10.1016/j.cmi.2020.04.041Abstract Full Text Full Text PDF Scopus (9) Google Scholar]), nor was a benefit demonstrated in a recent systematic review and meta-analysis involving 3686 patients [[4]Heffernan A.J. Sime F.B. Sun J. Lipman J. Kumar A. Andrews K. et al.β-Lactam antibiotic versus combined β-lactam antibiotics and single daily dosing regimens of aminoglycosides for treating serious infections: a meta-analysis.Int J Antimicrob Agents. 2020; 55: 105839https://doi.org/10.1016/j.ijantimicag.2019.10.020Crossref PubMed Scopus (8) Google Scholar]. Perhaps, as a way forward, proponents of empirical aminoglycoside therapy will need to demonstrate benefit as well as the absence of statistically significant harm. Conceptualization: AL and TCL; writing – original draft: TCL; writing – review & editing: AL and TCL. Dr Lee receives research salary support from the Fonds de Recherche du Québec - Santé . This research was supported (in part) by the Intramural Research Program of the NIH , Clinical Center. The findings and conclusions in this study are those of the authors and do not necessarily represent the official position of the National Institutes of Health. No additional external funding was used to fund this work. Renal safety of a single dose of gentamicin in patients with sepsis in the emergency departmentClinical Microbiology and InfectionVol. 27Issue 5PreviewTo determine the effect of a single dose of gentamicin on the incidence and persistence of acute kidney injury (AKI) in patients with sepsis in the emergency department (ED). Full-Text PDF Open AccessRe: 'The renal safety of a single dose of gentamicin in patients with sepsis in the emergency department' - Author's replyClinical Microbiology and InfectionVol. 27Issue 2PreviewLawandi and Lee have provided us with valuable comments [1,2]. As mentioned in our article, we agree that the combination of β-lactam antibiotics plus aminoglycosides is widely used in the empirical therapy of sepsis— however, not to double antibiotic coverage, as stated by Lawandi and Lee, but rather to broaden the Gram-negative spectrum. We also agree that empiric sepsis therapy should be locally adjusted to local resistance patterns; with a 96% susceptible coverage with piperacillin/tazobactam, there is only a small additional effect of aminoglycosides. Full-Text PDF