Therapeutic Drug Monitoring of Amikacin in Septic Patients
Therapeutic Drug Monitoring of Amikacin in Septic Patients
Introduction: Use of higher than standard doses of amikacin (AMK) has been proposed during sepsis, especially to treat less susceptible bacterial strains. However, few data are available on drug concentrations during prolonged therapy and on potential adverse events related to this strategy.
Methods: Sixty-three critically ill patients who required AMK administration for the treatment of severe infection were included in this study. After a loading dose (LD, 18 to 30 mg/kg), the daily regimen was adapted using therapeutic drug monitoring (TDM) of both peak (Cpeak) and trough (Cmin) concentrations. Target concentrations had to give a ratio of at least 8 between Cpeak and the minimal inhibitory concentration (MIC) of the isolated pathogen. A Cmin >5 mg/L was considered as potentially nephrotoxic. We recorded clinical and microbiological responses, the development of acute kidney injury (AKI) during therapy and ICU mortality.
Results: The median AMK LD was 1500 (750 to 2400) mg, which resulted in a Cpeak/MIC ≥8 in 40 (63%) patients. Increasing the dose in the 23 patients with a Cpeak/MIC <8 resulted in optimal Cpeak/MIC in 15 of these patients (79%). In 23 patients (37%), Cmin was >5mg/L after the LD, notably in the presence of altered renal function at the onset of therapy, needing prolongation of drug administration. Overall, only 11 patients (17%) required no dose or interval adjustment during AMK therapy. Clinical cure (32/37 (86%) vs. 16/23 (70%), P = 0.18)) and microbiological eradication (29/35 (83%) vs. 14/23 (61%), P = 0.07) were higher in patients with an initial optimal Cpeak/MIC than in the other patients. The proportion of patients with clinical cure significantly improved as the Cpeak/MIC increased (P = 0.006). Also, increased time to optimal Cpeak was associated with worse microbiological and clinical results. AKI was identified in 15 patients (24%) during AMK therapy; 12 of these patients already had altered renal function before drug administration. Survivors (n = 47) had similar initial Cpeak/MIC ratios but lower Cmin values compared to nonsurvivors.
Conclusions: TDM resulted in adjustment of AMK therapy in most of our septic patients. Early achievement of an optimal Cpeak/MIC ratio may have an impact on clinical and microbiological responses, but not on outcome. In patients with impaired renal function prior to treatment, AMK therapy may be associated with a further decline in renal function.
Aminoglycosides are an important therapeutic option for the treatment of life-threatening infections in critically ill patients. These drugs are usually used in combination with β- lactams in infections cause by Gram-negative bacteria to extend the spectrum of antimicrobial activity, and remain one of the few available therapies against multidrug-resistant pathogens, such as those producing extended-spectrum β-lactamases. Recent guidelines on the treatment of sepsis have recommended using combination therapy, especially in patients with septic shock or if Pseudomonas aeruginosa is suspected. In a meta-analysis, Kumar et al. also suggested that combination therapy including aminoglycosides increased survival rates among patients suffering from septic shock of various etiologies and with an expected mortality exceeding 25%.
The antibacterial activity of aminoglycosides is related to the peak concentration (Cpeak) obtained after drug injection. In particular, a ratio between Cpeak and the minimal inhibitory concentration (MIC) of the pathogen of greater than eight has been associated with increased clinical cure in uncomplicated infections. Nevertheless, sepsis may significantly alter the pharmacokinetic (PK) properties of these drugs, with increased distribution volume (Vd) and altered clearance, resulting in insufficient drug concentrations for the empiric treatment of P. aeruginosa. In this respect, a higher than recommended loading dose (LD) of amikacin (AMK) was necessary to rapidly achieve therapeutic drug concentrations in patients with severe sepsis and septic shock. However, the clinical impact of this strategy has not yet been studied among critically ill patients. Moreover, as these patients often suffer from acute kidney injury (AKI), which contributes to drug accumulation, the use of higher than recommended dose regimens may result in elevated trough concentrations (Cmin), which are associated with an increased risk of toxicity.
Galvez et al. showed that a daily dose of at least 30 mg/kg of AMK was necessary to achieve optimal drug concentrations; no increase in renal toxicity was reported compared to lower dose regimens, including 15 and 25 mg/kg. However, overall mortality in this study was only 9% and one may argue that these patients did not really represent a critically ill population with different organ dysfunctions and poor outcomes. Moreover, in such patients, the use of large amounts of fluid, of vasopressors and/or of renal replacement therapy may significantly impact on PK drug changes over time, which would be unpredictable if therapeutic drug monitoring (TDM) is not routinely performed.
The aim of this study was, therefore, to evaluate the impact of an AMK regimen based on dose adjustment using daily TDM in an ICU population with severe sepsis and septic shock.
Abstract and Introduction
Abstract
Introduction: Use of higher than standard doses of amikacin (AMK) has been proposed during sepsis, especially to treat less susceptible bacterial strains. However, few data are available on drug concentrations during prolonged therapy and on potential adverse events related to this strategy.
Methods: Sixty-three critically ill patients who required AMK administration for the treatment of severe infection were included in this study. After a loading dose (LD, 18 to 30 mg/kg), the daily regimen was adapted using therapeutic drug monitoring (TDM) of both peak (Cpeak) and trough (Cmin) concentrations. Target concentrations had to give a ratio of at least 8 between Cpeak and the minimal inhibitory concentration (MIC) of the isolated pathogen. A Cmin >5 mg/L was considered as potentially nephrotoxic. We recorded clinical and microbiological responses, the development of acute kidney injury (AKI) during therapy and ICU mortality.
Results: The median AMK LD was 1500 (750 to 2400) mg, which resulted in a Cpeak/MIC ≥8 in 40 (63%) patients. Increasing the dose in the 23 patients with a Cpeak/MIC <8 resulted in optimal Cpeak/MIC in 15 of these patients (79%). In 23 patients (37%), Cmin was >5mg/L after the LD, notably in the presence of altered renal function at the onset of therapy, needing prolongation of drug administration. Overall, only 11 patients (17%) required no dose or interval adjustment during AMK therapy. Clinical cure (32/37 (86%) vs. 16/23 (70%), P = 0.18)) and microbiological eradication (29/35 (83%) vs. 14/23 (61%), P = 0.07) were higher in patients with an initial optimal Cpeak/MIC than in the other patients. The proportion of patients with clinical cure significantly improved as the Cpeak/MIC increased (P = 0.006). Also, increased time to optimal Cpeak was associated with worse microbiological and clinical results. AKI was identified in 15 patients (24%) during AMK therapy; 12 of these patients already had altered renal function before drug administration. Survivors (n = 47) had similar initial Cpeak/MIC ratios but lower Cmin values compared to nonsurvivors.
Conclusions: TDM resulted in adjustment of AMK therapy in most of our septic patients. Early achievement of an optimal Cpeak/MIC ratio may have an impact on clinical and microbiological responses, but not on outcome. In patients with impaired renal function prior to treatment, AMK therapy may be associated with a further decline in renal function.
Introduction
Aminoglycosides are an important therapeutic option for the treatment of life-threatening infections in critically ill patients. These drugs are usually used in combination with β- lactams in infections cause by Gram-negative bacteria to extend the spectrum of antimicrobial activity, and remain one of the few available therapies against multidrug-resistant pathogens, such as those producing extended-spectrum β-lactamases. Recent guidelines on the treatment of sepsis have recommended using combination therapy, especially in patients with septic shock or if Pseudomonas aeruginosa is suspected. In a meta-analysis, Kumar et al. also suggested that combination therapy including aminoglycosides increased survival rates among patients suffering from septic shock of various etiologies and with an expected mortality exceeding 25%.
The antibacterial activity of aminoglycosides is related to the peak concentration (Cpeak) obtained after drug injection. In particular, a ratio between Cpeak and the minimal inhibitory concentration (MIC) of the pathogen of greater than eight has been associated with increased clinical cure in uncomplicated infections. Nevertheless, sepsis may significantly alter the pharmacokinetic (PK) properties of these drugs, with increased distribution volume (Vd) and altered clearance, resulting in insufficient drug concentrations for the empiric treatment of P. aeruginosa. In this respect, a higher than recommended loading dose (LD) of amikacin (AMK) was necessary to rapidly achieve therapeutic drug concentrations in patients with severe sepsis and septic shock. However, the clinical impact of this strategy has not yet been studied among critically ill patients. Moreover, as these patients often suffer from acute kidney injury (AKI), which contributes to drug accumulation, the use of higher than recommended dose regimens may result in elevated trough concentrations (Cmin), which are associated with an increased risk of toxicity.
Galvez et al. showed that a daily dose of at least 30 mg/kg of AMK was necessary to achieve optimal drug concentrations; no increase in renal toxicity was reported compared to lower dose regimens, including 15 and 25 mg/kg. However, overall mortality in this study was only 9% and one may argue that these patients did not really represent a critically ill population with different organ dysfunctions and poor outcomes. Moreover, in such patients, the use of large amounts of fluid, of vasopressors and/or of renal replacement therapy may significantly impact on PK drug changes over time, which would be unpredictable if therapeutic drug monitoring (TDM) is not routinely performed.
The aim of this study was, therefore, to evaluate the impact of an AMK regimen based on dose adjustment using daily TDM in an ICU population with severe sepsis and septic shock.