Nephrotoxicity, high frequency ototoxicity, efficacy and serum kinetics of once versus thrice daily dosing of netilmicin in patients with serious infections

Abstract

The effect of dosing regimen on nephrotoxicity, high frequency ototoxicity, efficacy and serum kinetics was studied in a prospective, randomised clinical study. Therapy was started with total daily doses of 6 mg/kg given once (od) or thrice (tid) daily to 56 and 57 patients, respectively. Subsequent doses were adjusted according to serum levels. No major differences in toxicity or efficacy were noticed between od and tid regimens: clinical failures occurred in two and two patients, four and five patients suffered from a decrease of ^ 20 dB at least unilaterally at one frequency between 8 and 18 kHz, six and seven patients had a >25 /jmol/L or >25% increase in serum creatinine, respectively. Serum creatinine or creatinine clearance did not change significantly during either therapy. Major differences between the two study groups were limited to pharmacokinetic parameters. Od dosing resulted in higher peak (mean of 21.6 vs 7.2 mg/L) and lower trough levels (0.5 vs 1.4mg/L).

A Meta-Analysis of the Relative Efficacy and Toxicity of Single Daily Dosing Versus Multiple Daily Dosing of Aminoglycosides

“…The treatment allocation was blinded in only two studies [38,57]. Studies represented both single-center [33-35, 37, 39, 42-48, 51-53,56-58] and multicenter investigations [36,38,40,41,49,50,54,55].…”

“…We considered patients documented to have superinfections [43] and postoperative wound infections [35,38] to have been treated successfully and patients for whom clinical outcomes were "indeterminant" [54][55][56] to have been treated unsuccessfully. Otherwise, we accepted the original criteria for clinical success used in each study.…”

“…age, < I Y Creatinine level, > 2.0 mg/dL; PMNs, < 1.0 X 10 9/L; aminoglycoside therapy within the prior 2 w; aminoglycoside allergy; "critically ill patients" Creatinine level, > 12.0 mg/dL; preexisting hearing loss (;" 50 dB); "severe unrelated pathology"; aminoglycoside therapy within the prior 15 d; concurrent therapy with nephrotoxic or ototoxic drugs; active UTI or middle ear infection Creatinine level, > 3.4 mg/dL; estimated creatinine clearance, < 30 mLimin; prior auditory or vestibular disease; PMNs, < 1.0 X 10 9 /L; pregnancy; aminoglycoside allergy; age, < 16 y Creatinine clearance, < 25 mLimin; prior auditory disease; aminoglycoside therapy within prior mo; PMNs, < 1.0 X 10 8/L; life expectancy, < 1 mo Creatinine level, > 3.4 mg/dL; dialysis; parenteral antibiotic therapy within the preceding 4 d; pregnancy; nursing; obvious noninfectious cause of fever; aminoglycoside or ,B-Iactam allergy Creatinine level, > 2.0 mg/dL; PMNs, < 1.0 X 109/L;prior hearing loss or vestibular disease; aminoglycoside therapy within the prior 2 w; pregnancy; aminoglycoside allergy; life expectancy, < 2 w Creatinine level, > 1.5 mg/dL; known renal disease; diabetes mellitus; severe immunosuppressive disease; diuretic use Creatinine level, > 1.4 mg/dL; known otologic disease; receipt of aminoglycoside or other nephrotoxic drugs within the preceding 4 w; aminoglycoside allergy; age, <18 y or >75 y Creatinine clearance, < 30 mL/min; penicillin allergy; age,~18 Y Creatinine level, > 1.5 mg/dL; known auditory disease; aminoglycoside treatment within the preceding 4 w; pregnancy; aminoglycoside allergy; age, < 16 y Creatinine level, > 1.5 mg/dL; known auditory disease; PMLs, < 0. We did not observe any statistically significant differences in clinical outcomes when we excluded all studies in which intramuscular therapy was given [35,37,38,40,42], adjunctive antimicrobial therapy was uncontrolled [36,40,42,45,46,48,49,[51][52][53]55,56,58], or all or most patients had urinary tract infections [49] or surgically treated intra-abdominal infections [35,38,40,41]. All comparative analyses of the clinical response to therapy by the fixed effects model yielded results that were similar to those based on the random effects model.…”

Population Pharmacokinetic Study of Amikacin Administered Once or Twice Daily to Febrile, Severely Neutropenic Adults

“…Indeed, the terminal half-life might have been underestimated in most studies because they were based on a two-sample (a peak and a trough) design, with the values of the pharmacokinetic parameters for amikacin being estimated by the method of Sawchuk and Zaske (31), i.e., with the implicit assumption of a one-compartment model. The study by Hary et al (14) was based on a two-compartment model, but the samples were only taken during the 8 h following the administration of the first dose, so that it is difficult to estimate a half-life longer than 3 or 4 h. Blaser et al (5), in a study of netilmicin administered t.i.d. or o.d.…”

Efficacy and Tolerability of Extended-Interval Aminoglycoside Administration in Pediatric Patients

“…In addition, high concentrations of aminoglycosides may prevent the expected emergence of resistance by targeting resistant subpopulations. Blaser [37] demonstrated a reduction in the emergence of resistant subpopulations of P. aeruginosa when netilmicin concentrations were ≥8 times the MIC. EIAA rather than CAA would more likely achieve these concentrations and, therefore, decrease the emergence of resistance.…”