Aminoglycosides

1. Filtration

1. Filtration

2. Binding

2. Binding

Lysosomal phospholipidosis

ABOVE thœshold: lysosomal swelling, ddsmptlon or leakage

Lysosomal phospholipidosis

Cell necrosis regeneration

FIGURE 11-3

Renal handling of aminoglycosides: 1) glomerular filtration; 2) binding to the brush border membranes of the proximal tubule; 3) pinocytosis; and 4) storage in the lysosomes [3].

Nephrotoxicity and otovestibular toxicity remain frequent side effects that seriously limit the use of aminoglycosides, a still important class of antibiotics. Aminoglycosides are highly charged, poly-cationic, hydrophilic drugs that cross biologic membranes little, if at all [4,5]. They are not metabolized but are eliminated unchanged almost entirely by the kidneys. Aminoglycosides are filtered by the glomerulus at a rate almost equal to that of water. After entering the luminal fluid of proximal renal tubule, a small but toxicologi-cally important portion of the filtered drug is reabsorbed and stored in the proximal tubule cells. The major transport of amino-glycosides into proximal tubule cells involves interaction with acidic, negatively charged phospholipid-binding sites at the level of the brush border membrane.

After charge-mediated binding, the drug is taken up into the cell in small invaginations of the cell membrane, a process in which megalin seems to play a role [6]. Within 1 hour of injection, the drug is located at the apical cytoplasmic vacuoles, called endocy-totic vesicles. These vesicles fuse with lysosomes, sequestering the unchanged aminoglycosides inside those organelles.

Once trapped in the lysosomes of proximal tubule cells, amino-glycosides electrostatically attached to anionic membrane phospho-lipids interfere with the normal action of some enzymes (ie, phos-pholipases and sphingomyelinase). In parallel with enzyme inhibition, undigested phospholipids originating from the turnover of cell membranes accumulate in lysosomes, where they are normally digested. The overall result is lysosomal phospholipidosis due to nonspecific accumulation of polar phospholipids as "myeloid bodies," so called for their typical electron microscopic appearance. (Adapted from De Broe [3].)

Ultrastructural appearance of proximal tubule cells in aminoglycoside-treated patients (4 days of therapeutic doses). Lysosomes (large arrow) contain dense lamellar and concentric structures. Brush border, mitochondria (small arrows) and peroxisomes are unaltered. At higher magnification the structures in lysosomes show a periodic pattern. The bar in A represents 1 ^m, in part B, 0.1 ^m [7].

RtjP

FIGURE 11-5 (see Color Plate)

Administration of aminoglycosides for days induces progression of lysosomal phospholipidosis. The overloaded lysosomes continue to swell, even if the drug is then withdrawn. In vivo this overload may result in loss of integrity of the membranes of lysosomes and release of large amounts of lysosomal enzymes, phospholipids, and aminoglycosides into the cytosol, but this has not been proven. Thus, these aminoglycosides can gain access to and injure other organelles, such as mitochondria, and disturb their functional integrity, which leads rapidly to cell death. As a consequence of cell necrosis, A, intratubular obstruction by cell debris increased intratubule pressure, a decrease in the glomerular filtration rate and cellular infiltration, B, may ensue. In parallel with these lethal processes in the kidney, a striking regeneration process is observed that is characterized by a dramatic increase in tubule cell turnover and proliferation, C, in the cortical interstitial compartment.

200-

150-

100-

5 10

Serum gentamicin concentration, ßg/ml

5 10

Serum gentamicin concentration, ßg/ml

80 90 100

Serum gentamicin concentration, ßg/ml

FIGURE 11-6

A, Relationship between constant serum levels and concomitant renal cortical accumulation of gentamicin after a 6 hour intravenous infusion in rats. The rate of accumulation is expressed in micrograms of aminoglycoside per gram of wet kidney cortex per hour, due to the linear accumulation in function of time. Each point represents one rat whose aminoglycosides were measured in both kidneys at the end of the infusion and the serum levels assayed twice during the infusion [8].

(Continued on next page)

1000

I I One injection a day H Three injections a day I I Continuous infusion

Days of administration

FIGURE 11-6 (Continued)

B, Kidney cortical concentrations of gentamicin in rats given equal daily amounts of aminoglycoside in single injections, three injections, or by continuous infusion over 8 days. Each block represents the mean of seven rats ±SD. Significance is shown only between cortical levels achieved after continuous infusion and single injections (aster-isk—P < 0.05; double asterisk—P < 0.01) [9].

In rats, nephrotoxicity of gentamicin is more pronounced when the total daily dose is administered by continuous infusion rather than as a single injection. Thus, a given daily drug does not produce the same degree of toxicity when it is given by different routes. Indeed, renal cortical uptake is "less efficient" at high serum concentration than at low ones. A single injection results in high peak serum levels that overcome the saturation limits of the renal uptake mechanism. The high plasma concentrations are followed by fast elimination and, finally, absence of the drug for a while. This contrasts with the continuous low serum levels obtained with more frequent dosing when the uptake at the level of the renal cortex is not only more efficient but remains available throughout the treatment period. Vm —maximum velocity.

FIGURE 11-7

Time, hrs

Time, hrs

250-

100-

250-

100-

Gentamicin Netilmicin Tobramycin Amikacin

Gentamicin Netilmicin Tobramycin Amikacin

FIGURE 11-7

Course of serum concentrations, A, and of renal cortical concentrations, B, of gentamicin, netilmicin, tobramycin, and amikacin after dosing by a 30-minute intravenous injection or continuous infusion over 24 hours [10,11].

Two trials in humans found that the dosage schedule had a critical effect on renal uptake of gentamicin, netilmicin [10], amikacin, and tobramycin [11]. Subjects were patients with normal renal function (serum creatinine concentration between 0.9 and 1.2 mg/dL, proteinuria lower than 300 mg/24 h) who had renal cancer and submitted to nephrectomy. Before surgery, patients received gentamicin (4.5 mg/kg/d), netilmicin (5 mg/kg/d), amikacin (15 mg/kg/d), or tobramycin (4.5 mg/kg/d) as a single injection or as a continuous intravenous infusion over 24 hours. The single-injection schedule resulted in 30% to 50% lower cortical drug concentrations of netilmicin, gentamicin, and amikacin as compared with continuous infusion. For tobramycin, no difference in renal accumulation could be found, indicating the linear cortical uptake of this particular aminoglycoside [8]. These data, which supported decreased nephrotoxic potential of single-dose regimens, coincided with new insights in the antibacterial action of aminoglycosides (concentration-dependent killing of gram-negative bacteria and prolonged postantibiotic effect) [12]. N.S.—not significant.

FIGURE 11-8

RISK FACTORS FOR AMINOGLYCOSIDE NEPHROTOXICITY I Risk factors for aminoglycoside nephro-

toxicity. Several risk factors have been identified and classified as patient related, aminoglycoside related, or related to concurrent administration of certain drugs.

The usual recommended aminoglycoside dose may be excessive for older patients because of decreased renal function and decreased regenerative capacity of a damaged kidney. Preexisting renal disease clearly can expose patients to inadvertent overdosing if careful dose adjustment is not performed. Hypomagnesemia, hypokalemia, and calcium deficiency may be predisposing risk factors for consequences of aminoglycoside-induced damage [13]. Liver disease is an important clinical risk factor for aminoglycoside nephrotoxicity, particularly in patients with cholestasis [13]. Acute or chronic endotoxemia amplifies the nephrotoxic potential of the aminoglycosides [14].

FIGURE 11-9

Prevention of aminoglycoside nephrotoxicity. Coadministration of other potentially nephrotoxic drugs enhances or accelerates the nephrotoxicity of aminoglycosides. Comprehension of the phar-macokinetics and renal cell biologic effects of aminoglycosides, allows identification of aminoglycoside-related nephrotoxicity risk factors and makes possible secondary prevention of this important clinical nephrotoxicity.

Patient-Related Factors

Aminoglycoside-Related Factors

Other Drugs

Older age*

Recent aminoglycoside therapy

Amphotericin B

Preexisting renal disease

Cephalosporins

Female gender

Larger doses*

Cisplatin

Magnesium, potassium, or

Treatment for 3 days or more*

Clindamycin

calcium deficiency*

Intravascular volume depletion*

Cyclosporine

Hypotension*

Dose regimen*

Foscarnet

Hepatorenal syndrome

Furosemide

Sepsis syndrome

Piperacillin Radiocontrast agents Thyroid hormone

* Similar to experimental data.

* Similar to experimental data.

PREVENTION OF AMINOGLYCOSIDE NEPHROTOXICITY

Identify risk factor Patient related Drug related Other drugs

Give single daily dose of gentamicin, netilmicin, or amikacin

Reduce the treatment course as much as possible

Avoid giving nephrotoxic drugs concurrently

Make interval between aminoglycoside courses as long as possible

Calculate glomerular filtration rate out of serum creatinine concentration

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