Intrapatient Variability of Aminoglycoside Pharmacokinetic Parameters in Simulated Extended-Interval Aminoglycoside Dosing

Extended-Interval Dosing of Aminoglycoside Antibiotics in Critically Ill Patients

“…53 Studies also concluded that use of the Hartford Nomogram did not reliably result in targeted C max :MIC ratios and was associated with exceedingly long drug-free periods at the end of the dosing interval. 44,47,51,53 During the initial development and validation of the Hartford Nomogram, patients with highly variable or altered aminoglycoside pharmacokinetics were excluded from evaluation. These included patients with such conditions as pregnancy, burns > 20% of total body surface area, ascites, and renal failure requiring hemodialysis; children were also excluded.…”

“…[26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43] In consideration of known pharmacokinetic changes among the critically ill, it is surely no surprise that a large number of studies and case reports have now documented difficulties with the use of EIAD regimens in critically ill patients (Table 1). 41,[44][45][46][47][48][49][50][51][52][53] As would be predicted based on changes in V d , studies have reported extreme variations in C max and half-life following administration of doses ranging from 5 mg/kg to 7 mg/kg of gentamicin or tobramycin. Studies have typically used a target C max of 20 mg/L based on commonly utilized EIAD protocols such as that developed by Nicolau and colleagues at Hartford Hospital in Hartford, Connecticut (commonly referred to as the "Hartford Nomogram").…”

“…In 1 study, 30% of patients had undetectable concentrations for 8 hours or more with the use of EIAD; 51 other studies have reported the mean drug-free period to range from 6 to 9 hours. [44][45][46][47]53 The significance of this long drug-free period at the end of the dosing interval is in respect to the expected PAE of aminoglycosides for gram-negative organisms. Since the PAE for aminoglycosides lasts no longer than approximately 7 to 8 hours under the best of circumstances in in vitro models, undetectable concentrations for more than this period of time in the clinical setting would be expected to allow regrowth of surviving organisms.…”

“…1 However, several studies specifically evaluated the use of the Hartford Nomogram during EIAD in critically ill patients and generally concluded that the nomogram did not perform accurately in this population. 44,47,49,51,53 One study found that the nomogram accurately predicted the drug dosing interval in 100% of 9 surgical ICU patients 49 ; however, a second study reported that the nomogram was accurate in only 42% of 31 medical ICU patients. 53 Studies also concluded that use of the Hartford Nomogram did not reliably result in targeted C max :MIC ratios and was associated with exceedingly long drug-free periods at the end of the dosing interval.…”

“…Since the Hartford Nomogram does not appear to be the most optimal method of monitoring EIAD in critically ill patients, use of more traditional therapeutic drug monitoring methods involving 2 or more serum drug levels has been advocated. 44,47,51,53 There are also difficulties with this approach to drug monitoring during EIAD, namely, selecting the appropriate number and timing of serum concentrations and choosing appropriate goals to use in interpreting these concentrations. Based on theoretical principles of EIAD as well as commonly accepted protocols such as the Hartford Nomogram, which are apparently effective in other populations, a C max of 20 mg/L and a drug-free (< 0.5 mg/L) period of at least 4 hours at the end of the dosing interval are reasonable goals to use for monitoring purposes.…”