Re: ‘The renal safety of a single dose of gentamicin in patients with sepsis in the emergency department’ - Author’s reply
Authors: Maarten Cobussen, Michiel B. Haeseker, Paul H.M. Savelkoul, Patricia M. Stassen
Journal: Clinical Microbiology and Infection (2020)

Lawandi and Lee have provided us with valuable comments [[1]Lawandi A. Lee T.C. Are empiric aminoglycosides really safe for the kidney?.Clin Microbiol Infect. 2020; (Online ahead of print.)Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar,[2]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]. 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. In the Netherlands, the susceptibility of the combination of amoxicillin/clavulanic acid plus gentamicin is comparable. In 2019 the World Health Organization (WHO) listed piperacillin/tazobactam as a ‘Watch’ antibiotic in the 2019 WHO AWaRe Classification Database [[3]World Health Organization-WHO) World Health Organization model list of essential medicines: 21st list, 2019. WHO, Geneva2019Google Scholar]. This means that it has a higher resistance potential and is at relatively high risk of selection of bacterial resistance. Therefore, according to the WHO, it should be prioritized as a key target of stewardship programmes to limit its use. Furthermore, the WHO recommends piperacillin/tazobactam only as an empiric treatment option for a limited number of specific infections (i.e. complicated intraabdominal infections, febrile neutropenia and hospital-acquired pneumonia) [[3]World Health Organization-WHO) World Health Organization model list of essential medicines: 21st list, 2019. WHO, Geneva2019Google Scholar]. The use of aminoglycosides as empiric antibiotic therapy meets the WHO guidelines because it could reduce the use of piperacillin/tazobactam. Regarding our colleagues' corrections: the correct numbers are indeed 64 (11.2%) of 571 for the gentamicin group and 82 (8.2%) of 1002 for the nongentamicin group. However, using the chi-square test for the univariate analysis, the significance of the found difference is still p 0.06, as is stated in Table 2 of the original manuscript [[2]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]. With respect to specific questions regarding the analysis of acute kidney injury (AKI) after admission, the highest serum creatinine in the first week of admission was used, relative to the serum creatinine at the emergency department (ED). We used the serum creatinine at the time of presentation at the ED as baseline for the analysis of AKI after admission because gentamicin was administered at that moment. With respect to the subgroups without AKI at presentation, 45 (11.5%) of 390 patients treated with gentamicin developed AKI after admission compared to 53 (6.8%) of 774 not treated with gentamicin (p 0.007). This difference is explained by the fact that patients in the gentamicin group were more severely ill compared to those in the nongentamicin group, as was illustrated by the higher presence of ≥2 quick Sequential Organ Failure Assessment (qSOFA) criteria (p 0.002), shock (p 0.04) and intensive care unit admissions (p 0.02). In addition to this, patients in the gentamicin group had a higher creatinine baseline (p <0.001). We performed a multivariate logistic regression analysis for risk factors of AKI after admission. The aforementioned patients without AKI at admission were also included in this analysis. Our multivariate analysis showed that the development of AKI after admission was independently associated with shock, diabetes mellitus and higher baseline creatinine, but not with a single dose of gentamicin. The hypothesis that a single dose of gentamicin is harmful to patients with sepsis in the ED is therefore not supported by our multivariate analysis, and our conclusion on the renal safety of a single dose of gentamicin still stands. We disagree with Lawandi and Lee on the use of a stratified analysis because a multivariable analysis relies on the same principles as stratification but does not have the limitations of stratification [[4]Kahlert J. Gribsholt S.B. Gammelager H. Dekkers O.M. Luta G. Control of confounding in the analysis phase—an overview for clinicians.Clin Epidemiol. 2017; 9: 195-204Crossref PubMed Scopus (41) Google Scholar]. The missing values are a combination of discharge of patients who recover from AKI and patients with a favourable course who are not followed up as rigorously as patients who are in a worse condition: median (range) length of stay was 5 (3–6) days for patients with missing creatinine values versus 11 (7–18) days in patients without persistent AKI versus 21 (10–27) days in patients with persistent AKI. Therefore, we assume that an overestimation of AKI is more likely than an underestimation. Furthermore, to our knowledge, there are no well-defined methods reported to compensate for these missing values [[5]Zeng X. McMahon G.M. Brunelli S.M. Bates D.W. Waikar S.S. Incidence, outcomes, and comparisons across definitions of AKI in hospitalized individuals.Clin J Am Soc Nephrol. 2014; 9: 12-20Crossref PubMed Scopus (247) Google Scholar]. In our study, overall mortality was indeed higher in the gentamicin group. However, as we stated in our article, these patients were more severely ill, as were the patients in the mentioned study of Deelen et al. [[6]Deelen J.W.T. Rottier W.C. Buiting A.G.M. Dorigo-Zetsma J.W. Kluytmans J. 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. 2020; (in press)Abstract Full Text Full Text PDF Scopus (9) Google Scholar]. No survival benefit for a combination therapy with gentamicin was found in our study; however, our study was not designed to investigate this matter. In their letter, Lawandi and Lee debate the empirical use of aminoglycosides in patients with sepsis. Two recent studies however support our findings [[7]Carlsen S. Boel J. Jarlov J.O. Gjorup I. Soborg C. Arpi M. The effect of short-course gentamicin therapy on kidney function in patients with bacteraemia—a retrospective cohort study.Eur J Clin Microbiol Infect Dis. 2018; 37: 2307-2312Crossref PubMed Scopus (9) Google Scholar,[8]Pitta R.D. Gasparetto J. De Moraes T.P. Telles J.P. Tuon F.F. Antimicrobial therapy with aminoglycoside or meropenem in the intensive care unit for hospital associated infections and risk factors for acute kidney injury.Eur J Clin Microbiol Infect Dis. 2020; 39: 723-728Crossref PubMed Scopus (6) Google Scholar], as does the mentioned study by Heffernan et al. [[9]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 metaanalysis.Int J Antimicrob Agents. 2020; 55: 105839Crossref PubMed Scopus (8) Google Scholar], that a single dose of gentamicin is safe with regard to renal function. In addition, the empirical use of gentamicin can reduce the use of reserve antibiotics, such as piperacillin/tazobactam, third- and fourth-generation cephalosporins and carbapenems and keep resistance levels for these antibiotics low. This is in our opinion a compelling argument. All authors report no conflicts of interest relevant to this letter. Re: ‘The renal safety of a single dose of gentamicin in patients with sepsis in the emergency department’ by Cobussen et al.Clinical Microbiology and InfectionVol. 27Issue 2PreviewSepsis 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. Full-Text PDF Open ArchiveRenal 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 Access