Circadian variations in serum levels and the renal toxicity of aminoglycosides in patients

Abstract

Animals show a faster clearance and a lower incidence of nephrotoxicity and ototoxicity when aminoglycosides are administered during the activity period. Human data on a circadian rhythm in pharmacokinetics are conflicting, and there are no data on a circadian rhythm in toxicity. When aminoglycosides are administered once daily, as is often done, a circadian rhythm in pharmacokinetics or toxicity could have clinical implications. In a prospective study we investigated the influence of drug administration time on serum drug levels and the incidence of nephrotoxicity in 221 patients with serious infections treated with gentamicin or tobramycin once daily. We did not find statistically significant differences in trough or peak levels for the three time periods (midnight to 7:30 AM, 8 AM to 3:30 PM, and 4 to 11:30 PM). Nephrotoxicity occurred significantly more frequently when the aminoglycosides were administered during the rest period (midnight to 7:30 AM; p = 0.004). In addition to the coadministration of high-dose furosemide or other nephrotoxic antibiotics and the duration of treatment, the time of administration was still an independent risk factor in a multivariate analysis.

<![CDATA[<B>Aminoglycoside nephrotoxicity</B>]]>

“…This was proven in a study involving 179 patients with severe infections treated with gentamicin or tobramicin. The nephrotoxicity was 34.6% during periods of resting (midnight to 7:30 a.m.) against 12.5% (8:00 a.m. to 3:30 p.m.) and 9.3% (4:00 p.m. to 11:30 p.m.) during active periods [50]. This variation is related to alterations in urinary pH, as there is greater interaction of aminoglycosides and anionic phospholipids when the pH is low [78].…”

“…Among the factors related to patients are advanced age [46], preexistent renal disease [47], hypotension, volume depletion and hepatic dysfunction [48,49]. Factors related to aminoglycoside are high doses [2], the use of the drug for more than three days [2], reduction in the interval between doses [2], recent use of aminoglycosides and the administration of the drug between midnight and 7 o'clock a.m. [50]. The concomitant use of vancomycin, amphotericin B, furosemid, clindamycin, piperacilin, cephalosporin, foscarnet and the use of iodine contrast are also clinically associated with greater nephrotoxicity [2].…”

Insuficiência renal aguda nefrotóxica: prevalência, evolução clínica e desfecho

“…17,18 Com relação às características clínicas, a maioria dos casos de IRA nefrotóxica isolada é não oligúrica (42%), porém, quando relacionada a outras causas, a prevalência de oligúria aumenta. 19,20 Em nosso estudo, 35,8% do total de pacientes com IRA nefrotóxica isolada eram oligúricos, comparados a 40,2% daquela relacionada a outras causas. A indicação dialítica mais frequente foi hipervolemia, em consonância com a maioria dos estudos.…”

“…25 Alguns fatores aumentam a ocorrência de nefrotoxicidade por aminoglicosídeos, como uso de doses elevadas, uso da droga por mais de três dias, diminuição do intervalo das doses, uso recente de aminoglicosídeos e administração da droga no período das 24h às 7h. 19,20 Em nosso estudo, 12% apresentaram IRA nefrotóxica isolada.…”

Nonstationary disposition of valproic acid during prolonged intravenous infusion: contributions of unbound clearance and protein binding

“…Numerous studies have suggested that the disposition and biologic effects of drugs can vary depending on the time of day [1][2][3]. Diurnal variations in steady-state concentrations have been observed for aminoglycosides [4], chemotherapeutic agents [5], and several anticonvulsants including carbamazepine [6], phenytoin [7], and ethosuximide [8].…”