Elimination and penetration of amikacin into urine in patients with decreased glomerular filtration rate

Abstract

Background: Amikacin monotherapy is recommended for urinary tract infection (UTI) treatment with multi-resistant pathogens. Even though amikacin efficacy in the treatment of UTIs is dependent on its urinary concentration, there are no robust data proving that sufficiently high urinary concentration is reached in patients with reduced glomerular filtration rate (GFR).

Methods: A prospective study to monitor amikacin penetration into urine of 70 patients [40 males, median (interquartile range) age 70 (65-79) years] with different levels of glomerular filtration decline, including patients treated by dialysis, was conducted. The bactericidal efficacy of amikacin in urine samples has been evaluated.

Results: Patients with estimated GFR (eGFR) <30 mL/min had significantly lower median amikacin urinary concentration than patients with eGFR >30 mL/min (89.75 vs 186.0 mg/L, P < .0001; 200.5 vs 830.0 mg/L, P < .0001; and 126.0 vs 408.0 mg/L, P < .0001 for minimal, maximal and minimal together with maximal concentrations, respectively). The amount of amikacin eliminated in the first 10-13 h after dose administration was dependent on eGFR (r² = 0.6144, P < .0001). The urinary concentration of amikacin in patients treated by dialysis was indirectly proportional to pH of urine. The plasma concentrations of amikacin did not correlate with urinary levels in patients in either of the GFR categories. Microbiological evaluation showed that the critical urinary concentration for efficacy of amikacin during UTI monotherapy in patients treated by dialysis is 100 mg/L. We found that 4 out of 11 patients treated by dialysis did not reach this level during the treatment.

Conclusion: Systemic administration of amikacin monotherapy in patients treated by dialysis is questionable as the concentrations of amikacin in their urine are often below the threshold of effectivity. Amikacin plasma concentrations are not a major determinant of amikacin concentration in urine, therefore pulse dosing is neither necessary nor safe in patients treated by dialysis, and may cause undesirable toxicity.

Keywords: UTI; aminoglycosides; dialysis; kidney impairment; pharmacokinetics.

Figure 1:

Scheme of plasma and urine sampling. (A) Patient with normal GFR with 24-h dosing interval; (B) patient with severely decreased GFR with 48-h dosing interval; (C) patient with moderately reduced GFR with 36-h dosing interval. The urine sampling was irregular due to the clinical issues. AM: infusion of amikacin.

Figure 2:

Calibration curve of AM in urine.

Figure 3:

AM urinary concentration (median, 1st and 3rd quartile and IQR) of in patients with various eGFRs.

Figure 4:

Elimination of AM (as % of administered dose) in the first urine collection sample (10–13 h after dosing).

Figure 5:

Linear regression of AM concentration in urine of patients treated by dialysis and urinary pH.

Figure 6:

All measured urine levels of AM and calculated peak plasma levels of AM. Circles: measured AM urinary concentration; crosses: calculated peak AM plasma concentrations; red line: minimum concentration for reliable efficacy against E. coli (100 mg/L). Patients with all measured urinary concentrations below target concentration are colored in red. 0: patients treated by dialysis.