S. Ibrahim

Pharmacodynamic parameters and toxicity of netilmicin (6 milligrams/kilogram/day) given once daily or in three divided doses to cancer patients with urinary tract infection.

The pharmacologic parameters and toxicity of netilmicin (6 mg/kg/day) given once daily (qd) or thrice daily (tid) for the treatment of urinary tract infections were studied in a randomized prospective study of 60 cancer patients. The overall efficacy was 96%. Nephrotoxicity, assessed by the measure of urinary excretion of phospholipids, was lower for the patients receiving the qd regimen than for those receiving the tid regimen. Elevation of serum creatinine (20% over baseline) occurred in one patient receiving the qd regimen and in three receiving the tid regimen. Cochleotoxicity, assessed by pure-tone audiometry (250 to 18,000 Hz) occurred in one patient receiving the qd regimen and none receiving the tid regimen. Concentrations in sera were measured on days 1 and 5. No significant accumulation was observed in either group. Median serum bactericidal titers, expressed as reciprocal values (percentage of the sera with a titer greater than or equal to 8), were measured against 25 test organisms in samples collected 6 h after the administration of netilmicin and were, for the qd group, 16 (82%) against members of the family Enterobacteriaceae and less than 2 (8%) against Pseudomonas aeruginosa, and for the tid group, 4 (57%) against members of the Enterobacteriaceae and less than 2 (0%) against P. aeruginosa. The rate of killing in serum was rapid (2 to 3 log in 2 h against P. aeruginosa; 3 to 5 log in 2 h against members of the Enterobacteriaceae) and correlated with the sampling time and hence the concentration in serum of netilmicin. The duration of the postantibiotic effect in serum depended also on the strain and the sampling time of the serum.

Once-a-day Administration of Amikacin in Neonates - Assessment of Nephrotoxicity and Ototoxicity

Neonates, especially preterms, are known to have low glomerular filtration rates (GFR). This may result in elevated trough concentrations during multiple administration of aminoglycosides (AGs), potentially leading to nephro- and ototoxic reactions. The once-daily administration (q.d.) of AGs has been shown to be equally or better tolerated in adults and children than the conventional schedules (twice daily, b.i.d.; thrice daily, t.i.d.), while offering potential pharmacodynamic and nursing advantages. No data, however, are available for neonates. As a consequence, this pilot study was conducted in order to assess the tolerance of the once-a-day administration of amikacin in comparison with the twice daily dose regimen, in relation to the pharmacokinetics of the drug under these two schedules. 22 Male neonates (gestational age > or = 34 weeks; postnatal age < or = 2 days) were randomized to receive amikacin (AK) (15 mg/kg/day) q.d. (n = 10) or b.i.d. (n = 12) together with ampicillin (50 mg/kg/12 h). AK plasma levels were measured at days 1, 3, 5 and 7 of treatment just before the next dose (trough level) and 1 h after completion of infusion (peak level) and after 3 and 6 h only at day 1. Due to the small size of the samples, no difference in efficacy could be assessed and was not the aim per se. Glomerular dysfunction was assessed by creatinine clearance, and tubular injuries by the urinary excretion of proteins (retinol binding protein, beta 2-microglobulin, clara cell protein (P1) and microalbumin), enzymes (N-acetyl-beta-D-glucosaminidase, alkaline phosphatase, alanine aminopeptidase, and gamma-glutamyltransferase), and total phospholipids (TPL) in urine. Ototoxicity was assessed by brainstem auditory evoked potentials (BAEPs) at days 0, 3 and 9 of therapy. Eight healthy neonates served as controls. All patients showed a normal and similar increase of GFR during the first postnatal days. Proteinuria did not increase, but enzymuria and TPL increased significantly during the treatment in both AK groups without significant difference between groups. BAEPs at day 9 were not significantly different between treated and untreated patients. We conclude from this pilot study that, in the absence of more toxicity, the q.d. administration of AK in neonates of > or = 34 weeks of gestational age may be recommended over its bid schedule in view of its potential advantages.

Effect of Netilmicin and Amikacin on Urinary Phospholipids Excretion in Humans

Lysosomal phospholipidosis of proximal tubular cells is an early index of aminoglycoside-induced nephrotoxicity and has been documented both biochemically and morphometrically in animals and humans treated with therapeutic doses of these antibiotics (see Laurent and Tulkens 1987, for review). The various aminoglycosides differ in their capacity to induce this alteration (Laurent et al 1982; De Broe et al 1984) and amikacin, in particular, induces considerably less changes than netilmicin (Tulkens et al 1983; De Broe et al 1983). In animals, aminoglycoside administration is also associated with a marked increase of phospholipiduria (Ibrahim and Tulkens 1986; Josepovitz et al 1986). The purpose of present study was to examine phospholipiduria in humans and to compare the effect of amikacin and netilmicin in this respect.

Increased levels of protein- and lipid-bound sialic acids in the renal cortex of rats injected with low doses of gentamicin.

Administration of the aminoglycoside antibiotic, gentamicin, even at therapeutic doses, causes renal lysosomal phospholipidosis. We now report that protein- and lipid-bound sialic acid levels are increased significantly in a time-dependent fashion in the renal cortex of rats injected with gentamicin (10 mg/kg body wt. per day) for 4-10 days and a significant relationship could be observed between these two parameters. This elevation was not due to tissue regeneration, since it was not observed in cisplatin-treated animals.

Inhibition of aminoglycoside-induced nephrotoxicity in rats by polyanionic peptides.

In the present study, we compared poly-L-Asp with poly-L-Glu and poly-D-Glu in vitro and in vivo for their ability to inhibit the GM-induced nephrotoxicity. In vitro, all three polyanions (i) bound GM over a wide range of pH; (ii) displaced GM previously bound to negatively charged phospholipid bilayers at acid pH (i.e. under the conditions prevailing in lysosomes in vivo), and thereby (iii) decreased the inhibitory potency of GM towards lysosomal phospholipase A1. Thus, one was tempted to predict that all three polyanions would have the potential of protecting against AG-induced nephrotoxicity. However, when co-administered to rats with GM, poly-L-Asp and poly-D-Glu completely suppressed the development of lysosomal phospholipidosis, as assessed by biochemical criteria and increased drug accumulation, whereas poly-L-Glu did not offer such protection despite a relatively lower increase in drug accumulation levels. Histoautoradiography also confirmed that poly-L-Asp, but not poly-L-Glu, was a nephroprotectant against the tissue proliferative response induced by GM. Morphologically, poly-L-Asp almost completely and poly-D-Glu totally prevented the accumulation of myeloid bodies in lysosomes. In vitro incubation in the presence of purified lysosomal extracts revealed marked differences in the hydrolysis rate of these peptides (poly-D-Glu:poly-L-Asp:poly-L-Glu = 1:1.2:16.9). Assuming that all three polyanionic peptides are transported and accumulated in lysosomes to the same extent, these results not only suggest that their stability in lysosomes is an essential requisite for protection against lysosomal phospholipidosis, but also strengthen our hypothesis that the site of action of poly-L-Asp is inside the lysosomes but not at the level of the renal membranes. In addition, poly-D-Glu alone or combined with GM induced another type of morphological lesion, not related to AG-induced nephrotoxicity which, to our knowledge, has not yet been described.

Urinary Phospholipids Patterns After Treatment With Aminoglycoside Antibiotics and Cis-Platinum

Oto- and nephro-toxicity are the two main limiting factors in the clinical use of aminoglycoside antibiotics. The earliest renal alteration induced by aminoglycosides is the development of a phospholipidosis in proximal tubular cells related to the inhibition of the activities of lysosomal phospholipases and sphingomyelinase (see Tulkens, 1986 for review). Josepovitz et al. (1986) reported that large doses of aminoglycosides, the use of which is associated with the rapid onset of widespread tubular necrosis and kidney dysfunction, induce a marked urinary excretion of phospholipids in rats. We have observed that this excretion already occurs in animals treated at low, clinically relevant doses (Ibrahim & Tulkens, 1986), suggesting that it was not solely due to tubular necrosis and shedding of phospholipid-overloaded cell casts in the lumen. We have therefore examined the phospholipid excretion in humans treated with normal doses of an aminoglycoside, in the absence of significant alteration of the renal function. In parallels we have examined the phospholipid excretion in rats treated with another nephrotoxin acting on proximal tubular cells but which does not cause phospholipidosis, namely cis-platinum.