Aminoglycosides in Septic Shock

Abstract

Aminoglycoside nephrotoxicity has been reported in patients with sepsis, and several risk factors have been described. Once-daily dosing and shorter treatment have reduced nephrotoxicity risk, and simplified aminoglycoside monitoring. This review focuses on nephrotoxicity associated with aminoglycosides in the subset of patients with septic shock or severe sepsis. These patients are radically different from those with less severe sepsis. They may have, for instance, renal impairment due to the shock per se, sepsis-related acute kidney injury, frequent association with pre-existing risk factors for renal failure such as diabetes, dehydration and other nephrotoxic treatments. In this category of patients, these risk factors might modify substantially the benefit-risk ratio of aminoglycosides. In addition, aminoglycoside administration in critically ill patients with sepsis is complicated by an extreme inter- and intra-individual variability in drug pharmacokinetic/pharmacodynamic characteristics: the volume of distribution (Vd) is frequently increased while the elimination constant can be either increased or decreased. Consequently, and although its effect on nephrotoxicity has not been explored, a different administration schedule, i.e. a high-dose once daily (HDOD), and several therapeutic drug monitoring (TDM) options have been proposed in these patients. This review describes the historical perspective of these different options, including those applying to subsets of patients in which aminoglycoside administration is even more complex (obese intensive care unit [ICU] patients, patients needing continuous or discontinuous renal replacement therapy [CRRT/DRRT]). A simple linear dose adjustment according to aminoglycoside serum concentration can be classified as low-intensity TDM. Nomograms have also been proposed, based on the maximum (peak) plasma concentration (Cmax) objectives, weight and creatinine clearance. The Sawchuk and Zaske method (based on the determination of Cmax and an intermediate aminoglycoside assay before minimum plasma concentration) and the Bayesian method were both classified as high-intensity TDM programmes. Given the mean cost of aminoglycoside nephrotoxicity, these programmes may be cost-effective if its prevalence is above 10 %. However, none of these high-intensity TDM programmes have demonstrated a reduction of aminoglycoside-associated nephrotoxicity in patients with septic shock. Therefore, the questions remain as to, first, whether a TDM programme is relevant and, second, what intensity of TDM is achievable in the ICU, i.e. how it can be practically applied in the ICU setting where urgent care and high workload are substantial obstacles to a sophisticated, optimized aminoglycoside administration.

Impact of a high loading dose of amikacin in patients with severe sepsis or septic shock

“…The present study was not designed to analyse and evaluate the association between acute kidney injury and trough concentration or aminoglycoside C max , in that trough concentrations were not measured in all patients, as suggested by French guidelines [4]. Furthermore, previous studies suggest that aminoglycoside-associated acute kidney injury cannot be solely attributed to aminoglycosides, because other factors are frequently associated with acute kidney injury in the ICU, including sepsis, septic shock or nephrotoxic drugs [25, 26]. …”

Propensity-Based Study of Aminoglycoside Nephrotoxicity in Patients with Severe Sepsis or Septic Shock

“…It allowed a better assessment of the causal link between the administration of AGs and AKI occurrence. It would therefore make sense to abandon the assessment of AG nephrotoxicity by the rate of acute renal failure occurring after the administration of AGs and to prefer a better methodological assessment of AG-associated AKI (19). No AG-associated AKI risk was found in this study (adjusted OR, 0.75; 95% confidence interval [CI],0.32 to 1.76), and there might even be a slight trend toward a reduced renal risk in AG patients, considering that the study population did not include patients with early acute renal failure.…”

“…These controversial data suggest that AG-associated AKI might not be attributable solely to AGs because of the frequent confounding factors associated with AKI (17)(18)(19), such as septic shock per se, other nephrotoxic drugs (20), direct effect of bacterial toxins, and comorbidities, such as diabetes or altered baseline renal function. The aim of this study was to assess the AG-attributed AKI (the real AG nephrotoxicity) in patients with septic shock or severe sepsis.…”

Susceptibility of Imipenem-Susceptible but Meropenem-Resistant bla IMP-6 -Carrying Enterobacteriaceae to Various Antibacterials, Including the Siderophore Cephalosporin Cefiderocol

“…The reports that cefiderocol and aztreonam have quite low k cat /K m or relative V max /K m values for IMP-1 suggest that one reason for the good antimicrobial activities of both compounds is the low level of hydrolysis by IMP-6 as well as IMP-1 (5,11,12). Although colistin and amikacin showed potent activity against ISMR Enterobacteriaceae in this study, safety issues such as nephrotoxicity remain concerns in clinical settings (13,14). Alternative treatment options for CPE infections, including those caused by IMP-6-producing strains, are needed.…”