INTRODUCTION — The main concerns with the use of aminoglycoside antibiotics are nephrotoxicity and ototoxicity. This topic will review what is known about the pathogenesis of these complications and how the nephrotoxicity might be prevented. The manifestations of and risk factors for aminoglycoside nephrotoxicity are discussed separately. (See "Manifestations of and risk factors for aminoglycoside nephrotoxicity".)
NEPHROTOXICITY — Acute kidney injury (AKI) due to acute tubular necrosis is a relatively common complication of aminoglycoside therapy, with a rise in the serum creatinine concentration of more than 0.5 to 1 mg/dL (44 to 88 micromol/L) or a 50 percent increase in serum creatinine concentration from baseline occurring in 10 to 20 percent of adult patients [1,2]. A rise in serum creatinine occurs in 20 to 33 percent of pediatric patients, in whom the use of gentamicin is high, especially in neonates in the intensive care unit [3]. Aminoglycosides are freely filtered across the glomerulus; almost all of the drug is then excreted, with 5 to 10 percent of a parenteral intravenous dose being taken up and sequestered by the proximal tubule cells (PTCs), where the aminoglycoside can achieve concentrations vastly exceeding the concurrent serum concentration [4].
The intracellular accumulation of aminoglycosides is confined primarily to the S1 and S2 segments of the proximal tubule. However, following kidney ischemia, the S3 portion is also a site of intracellular aminoglycoside concentrations. AKI can develop even if drug levels are closely monitored [5]. Animal models suggest that damage to collecting duct cells also occurs [6].
Dose frequency also may be important as multiple human studies suggest that giving a large dose of aminoglycoside once a day is as effective an antimicrobial regimen and less nephrotoxic than giving aminoglycosides in the conventional, divided-dose regimen [7-11] (see "Dosing and administration of parenteral aminoglycosides"). Aminoglycosides may also have a deleterious effect on the developing kidney in preterm and small for gestational age infants [12].
Renal transport of aminoglycosides
Proximal tubule cell transport and charge — Multiple amine groups on the aminoglycoside molecule confer a cationic charge at physiologic pH [13,14]. As a result, aminoglycoside molecules readily bind to anion phospholipids within the plasma membrane of the PTC in a saturable, electrostatic manner [13-16]. The relative affinity of an aminoglycoside for the PTC plasma membrane correlates with the nephrotoxicity observed in clinical practice [5,17-19]:
●Neomycin, which has the highest affinity for the PTC binding site, has the greatest nephrotoxicity of the aminoglycosides.
●Tobramycin and gentamicin have lower binding affinity, conferring less nephrotoxicity.
●Amikacin has even less binding affinity and, likewise, has less nephrotoxic potential than tobramycin and gentamicin.
●Streptomycin, which has the least affinity for the PTC binding site, has the least nephrotoxicity [5,17,18].
After the aminoglycoside binds to the anionic phospholipid of the PTC, it is rapidly transferred to the transmembrane protein megalin and endocytosed [13,14,20-35]. Megalin is a 600 kD cell surface scavenger receptor and has a high affinity for proteins, with regions of positively charged amino acids. It is abundantly expressed in the renal proximal tubules and many other tissues, including glomerular podocytes and ciliary and inner ear epithelium [13,26,36].
Once megalin-mediated endocytosis has occurred, endosomes containing the aminoglycosides are transported through the endocytic system, where they co-localize to lysosomes and, in a retrograde fashion, to the Golgi complex [33,37-40]. From the Golgi complex, aminoglycosides traffic in a retrograde fashion to the endoplasmic reticulum and then to the cytosol [41-44]. In the cytosol, aminoglycoside molecules accumulate in subcellular organelles such as the mitochondria and the nucleus where they inhibit mitochondrial function [43].
This pathway of the aminoglycosides to the Golgi complex and subcellular organelles is consistent with the disruption in both protein sorting and synthesis and mitochondrial function observed in aminoglycoside nephrotoxicity.
Prevention
Clinical strategies — Clinical strategies that may minimize the potential for nephrotoxicity include:
●Selection of the least toxic aminoglycoside, when possible. Gentamicin is considered the most nephrotoxic, followed in decreasing order of nephrotoxicity by tobramycin, amikacin, netilmicin, and streptomycin [1].
●Correcting hypokalemia and hypomagnesemia prior to administering an aminoglycoside.
●Other effective clinical strategies include avoiding aminoglycosides in patients with reduced effective arterial volume (or optimizing volume status prior to giving aminoglycosides), adjusting the dose for kidney function, limiting the duration of therapy to 7 to 10 days, and minimizing concomitant nephrotoxic medications [45].
●Pharmacokinetically monitoring aminoglycoside therapy and utilizing a once-daily dosing regimen in selected patients have also demonstrated benefit [7-9,45-48]. (See "Dosing and administration of parenteral aminoglycosides".)
Agents — Several agents have emerged as potential compounds to prevent aminoglycoside nephrotoxicity. Despite their potential, none have been adopted clinically for the prevention of aminoglycoside nephrotoxicity.
One class of compounds, the anionic polyamino acids (PAAs), which include polyaspartic acid and polyglutamic acid, has been extensively evaluated [14,44,49-55]. Early studies showed that PAA interferes with the binding of the aminoglycoside to the PTC plasma membrane [53-55]. Subsequent work showed that PAA binds directly to aminoglycosides and can displace them from negatively charged lysosomes [56]. This led researchers to postulate that PAA affords renal protection by directly binding to the aminoglycoside or by displacing it from the lysosome and thus preventing its trafficking through the PTC [56].
Other compounds evaluated for their potential role in preventing aminoglycoside nephrotoxicity include antioxidants. As examples, desferrioxamine, methimazole, vitamin E, vitamin C, and selenium have been effective in preventing gentamicin nephrotoxicity [44,57,58]. Superoxide dismutase, lipoic acid, dimethyl-sulfoxide (DMSO), N-acetylcysteine (NAC), melatonin, and the peroxisome proliferator-activated receptor gamma agonist pioglitazone have also demonstrated utility in preventing aminoglycoside nephrotoxicity in preclinical models [57,59-65].
A gentamicin congener that retains its antimicrobial efficacy with a lower potential for aminoglycoside nephrotoxicity has been isolated. Commercially available gentamicin is not a homogeneous compound; rather, it is a mixture of C1, C1a, C2, and C2a congeners that differ in their nephrotoxic potential [66]. The C2 compound was the specific congener shown to be bactericidal with less nephrotoxicity [66]. Via immunofluorescent techniques, the C2 congener is transported intracellularly to the Golgi complex in reduced quantities. This is likely the reason for its lack of nephrotoxicity [66].
Independent of their antimicrobial activity, aminoglycosides are characterized by their ability to induce read-through of premature termination codons, making them potential therapies in the treatment of inherited diseases such as cystic fibrosis [67-72]. Research to develop designer aminoglycosides for this purpose has led to the discovery of aminoglycoside derivatives with less cellular toxicity [67-70]. However, such compounds also have decreased bactericidal activity and thus would not be effective antibiotics [67,70]. Ongoing research in this area may lead to the discovery of other aminoglycoside derivatives that maintain antibacterial efficacy while minimizing cellular toxicity.
OTOTOXICITY — Aminoglycosides are associated with cochlear and vestibular toxicity in a substantial proportion of patients receiving the drug for prolonged periods, leading to hearing loss and disequilibrium, respectively [73,74]. The relative frequency with which these occur is uncertain, and both may not be clinically evident in the same patient. In one series of 33 patients presenting to a neurology clinic with vestibular symptoms, formal audiology testing revealed that 10 of 27 tested patients did not have associated hearing loss greater than expected for age [75]. In a later report on 25 patients, most were found to have no residual hearing loss [73].
Gentamicin and tobramycin are primarily vestibulotoxic, whereas neomycin, kanamycin, and amikacin are more ototoxic [74]. The clinical findings and diagnosis of individuals with aminoglycoside vestibulotoxicity are presented separately. (See "Causes of vertigo", section on 'Aminoglycoside toxicity'.)
Pathogenesis — The pathogenesis of aminoglycoside-induced ototoxicity with hearing loss is less understood. Sustained or excessive peak serum concentrations are thought to be a risk factor.
One hypothesis is related to receptors for N-methyl-D-aspartate (NMDA), which are present at the synapse between cochlear hair cells and neural afferents [76]. Aminoglycosides can mimic the positive modulation of polyamines at these receptors, possibly producing excitotoxic damage. The observation that the administration of NMDA antagonists markedly attenuates hearing loss in animals is consistent with this hypothesis. Furthermore, there is a high correlation between in vitro activation of the receptor and relative cochlear toxicity in humans (gentamicin > tobramycin > amikacin > neomycin). In addition to these functional changes, aminoglycosides also may induce structural changes, such as loss of target innervation and degeneration of spiral ganglion neurons [77].
Aminoglycosides create reactive oxygen species that damage the inner ear. Support for this hypothesis includes the findings of aminoglycoside-induced reactive oxygen species in vitro [74], and experimental evidence in animals showing ototoxicity prevention with antioxidant agents [78,79].
There appears to be a genetic predisposition to the development of ototoxicity with aminoglycosides. Point mutations in the small (12S) ribosomal RNA gene have been described in a number of families with inherited susceptibility to ototoxicity [74,80,81]. The mutant human RNA binds aminoglycosides with high affinity; in comparison, the wild-type human RNA does not bind aminoglycosides at all [82]. The presumed mechanism is that aminoglycoside binding exacerbates the inherent defect induced by the mutation, resulting in a reduction in the overall translation rate below the minimum level required for normal cellular function [83]. The prevalence of such point mutations among individuals of European ancestry is approximately 1 in 500 [84,85].
Prevention of ototoxicity — Traditionally, a number of the strategies used to help prevent the development of ototoxicity due to aminoglycosides are the same as those used to prevent nephrotoxicity. These strategies include once-daily dosing and careful monitoring of serum drug concentrations. However, ototoxicity has been reported even in those with target serum levels and once-daily dosing [7,75]. (See "Dosing and administration of parenteral aminoglycosides", section on 'Ototoxicity'.)
Another approach is to use audiometric testing among patients receiving aminoglycoside therapy. However, hearing loss may occur even after the termination of antibiotic therapy [75,86].
Genetic screening of patients prior to administering of aminoglycosides would be a valuable tool to aid in the prevention of ototoxicity [84,85]. However, there are no rapid screening tests commercially available that provide results in a clinically relevant timeframe. The patient and family history remain our most valuable tools available to prevent aminoglycoside-induced ototoxicity.
In addition, given the relative rarity of the 12S ribosomal point-mutations that confer susceptibility to aminoglycoside-induced hearing loss, it is unlikely that it would be economically feasible to perform general screening or for most laboratories to carry these diagnostic tests. Although aminoglycosides remain powerful tools in our antibiotic armamentarium, there are reasonable alternatives that provide similar spectrums of bacterial coverage. For patients that require gram-negative bacterial coverage and whose personal or family history suggests a risk for ototoxicity, considering these antibiotic alternatives may be a more prudent approach.
Based upon the observations that oxidative stress may cause ototoxicity, the efficacy of N-acetylcysteine (NAC), a thiol-containing antioxidant, was evaluated in hemodialysis patients receiving gentamicin [87]. In this study, 53 hemodialysis patients with catheter-induced bacteremia were randomly assigned to gentamicin plus NAC (600 mg twice daily) or gentamicin alone. Pure-tone audiograms were performed at baseline, one week, and at six weeks after gentamicin therapy was stopped. NAC was given until the first otologic examination, which was approximately one week after completion of antibiotic therapy. Compared with the control group, NAC therapy significantly lowered the incidence of audiologic toxicity (25 versus 60 percent). Protection primarily occurred in the high-frequency range, and NAC was not associated with any adverse effects.
Another study that included 60 patients on continuous ambulatory peritoneal dialysis (CAPD) suggested that oral administration of NAC prevented ototoxicity related to intraperitoneal amikacin and vancomycin and may have improved high-frequency function at four weeks [88].
Further study in a larger number of patients and other clinical settings is required to better understand the role of NAC in preventing ototoxicity [89]. However, given the proven safety of NAC and the severity and irreversibility of aminoglycoside-induced ototoxicity, a reasonable argument can be made that NAC should be administered to all end-stage kidney disease patients receiving an aminoglycoside. Such therapy can be particularly considered in hemodialysis patients with existing hearing loss due to previous exposure to aminoglycosides.
Limited evidence in nondialysis patients suggests that aspirin may provide some protection against ototoxicity [90-92]. Whether this finding extends to dialysis patients without causing significant adverse effects is unclear.
Less ototoxic forms of aminoglycosides may also be useful in preventing ototoxicity. An animal study of an aminoglycoside congener (N1MS) has demonstrated excellent activity against Escherichia coli, Klebsiella pneumoniae, and extended-spectrum B-lactamases while preserving hair cells and hearing relative to its parent compound [93]. Similar results were found with gentamicin C1a, a congener of commercial gentamicin, and apramycin, an aminoglycoside used in veterinarian medicine [94].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic kidney disease in adults".)
SUMMARY AND RECOMMENDATIONS
●Acute kidney injury (AKI) due to acute tubular necrosis is a relatively common complication of aminoglycoside therapy, affecting 10 to 20 percent of patients. (See 'Nephrotoxicity' above.)
●Since aminoglycoside molecules readily bind to anionic phospholipids within the plasma membrane of the proximal tubule cell (PTC) in a saturable, electrostatic manner, the relative affinity of an aminoglycoside for the PTC plasma membrane correlates with the nephrotoxicity observed in clinical practice. (See 'Proximal tubule cell transport and charge' above.)
●For prevention, clinical strategies are primarily utilized to minimize the potential for nephrotoxicity. These include selection of the least toxic aminoglycoside when possible, correcting hypokalemia and hypomagnesemia prior to administering an aminoglycoside, avoiding aminoglycosides in patients with reduced effective arterial volume, adjusting the dose for kidney function, limiting the duration of therapy to 7 to 10 days, and minimizing concomitant nephrotoxic medications. We suggest utilizing a once-daily dosing regimen in selected patients. (Grade 2B). (See 'Clinical strategies' above.)
●Although several agents have emerged as potential compounds to prevent aminoglycoside nephrotoxicity, none have been adopted clinically for the prevention of aminoglycoside nephrotoxicity. (See 'Agents' above.)
●Aminoglycosides are associated with cochlear and vestibular toxicity in a substantial proportion of patients receiving the drug for prolonged periods, leading to hearing loss and disequilibrium, respectively. The pathogenesis of aminoglycoside-induced ototoxicity with hearing loss is less understood. (See 'Ototoxicity' above and 'Pathogenesis' above.)
●To prevent the development of ototoxicity due to aminoglycosides, strategies include once-daily dosing and careful monitoring of serum drug concentrations. N-acetylcysteine (NAC) can also be considered among patients with end-stage kidney disease receiving an aminoglycoside. (See 'Prevention of ototoxicity' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Brian S Decker, MD, PharmD (deceased), who contributed to an earlier version of this topic review.
1 : Aminoglycoside nephrotoxicity.
2 : Risk factors for nephrotoxicity in patients treated with aminoglycosides.
3 : Aminoglycoside-induced nephrotoxicity in children.
4 : Aminoglycosides: single or multiple daily dosing? A meta-analysis on efficacy and safety.
5 : Double-blind comparison of the nephrotoxicity and auditory toxicity of gentamicin and tobramycin.
6 : Gentamicin-Induced Acute Kidney Injury in an Animal Model Involves Programmed Necrosis of the Collecting Duct.
7 : A meta-analysis of studies on the safety and efficacy of aminoglycosides given either once daily or as divided doses.
8 : Once-daily aminoglycoside dosing in immunocompetent adults: a meta-analysis.
9 : Effectiveness and safety of once-daily aminoglycosides: a meta-analysis.
10 : Single or multiple daily doses of aminoglycosides: a meta-analysis.
11 : Once versus thrice daily gentamicin in patients with serious infections.
12 : Nephrotoxic effects of the aminoglycosides on the developing kidney
13 : Molecular aspects of renal handling of aminoglycosides and strategies for preventing the nephrotoxicity.
14 : Identification of the aminoglycoside binding site in rat renal brush border membranes.
15 : In vivo uptake kinetics of aminoglycosides in the kidney cortex of rats.
16 : Aminoglycosides: nephrotoxicity.
17 : Controlled comparison of amikacin and gentamicin.
18 : Randomised, controlled trial of the comparative efficacy, auditory toxicity, and nephrotoxicity of tobramycin and netilmicin.
19 : Correlation between renal membrane binding and nephrotoxicity of aminoglycosides.
20 : Evidence that epithelial glycoprotein 330/megalin mediates uptake of polybasic drugs.
21 : Gentamicin inhibits rat renal cortical homotypic endosomal fusion: role of megalin.
22 : Megalin and cubilin: multifunctional endocytic receptors.
23 : Megalin and cubilin: synergistic endocytic receptors in renal proximal tubule.
24 : Essential role of megalin in renal proximal tubule for vitamin homeostasis.
25 : The pathogenic antigen of Heymann nephritis is a membrane glycoprotein of the renal proximal tubule brush border.
26 : Tissue distribution of human gp330/megalin, a putative Ca(2+)-sensing protein.
27 : Megalin deficiency offers protection from renal aminoglycoside accumulation.
28 : Megalin/gp330 mediates uptake of albumin in renal proximal tubule.
29 : Role of megalin in renal handling of aminoglycosides.
30 : Membrane receptors for endocytosis in the renal proximal tubule.
31 : Mechanisms of aminoglycoside nephrotoxicity.
32 : Alterations in lysosomal enzymes of the proximal tubule in gentamicin nephrotoxicity.
33 : Apically and basolaterally internalized aminoglycosides colocalize in LLC-PK1 lysosomes and alter cell function.
34 : Transport of gentamicin and fluid-phase endocytosis markers in the LLC-PK1 kidney epithelial cell line.
35 : Surface binding and intracellular uptake of gentamicin in the cultured kidney epithelial cell line (LLC-PK1).
36 : Mild ischemia predisposes the S3 segment to gentamicin toxicity.
37 : Transport of gentamicin in rat proximal tubule.
38 : Autoradiography of gentamicin uptake by the rat proximal tubule cell.
39 : Gentamicin-induced apoptosis in LLC-PK1 cells: involvement of lysosomes and mitochondria.
40 : Aminoglycoside antibiotics traffic to the Golgi complex in LLC-PK1 cells.
41 : Retrograde transport from the Golgi complex to the ER of both Shiga toxin and the nontoxic Shiga B-fragment is regulated by butyric acid and cAMP.
42 : Toxin entry: retrograde transport through the secretory pathway.
43 : Gentamicin traffics retrograde through the secretory pathway and is released in the cytosol via the endoplasmic reticulum.
44 : Importance of glycolipid synthesis for butyric acid-induced sensitization to shiga toxin and intracellular sorting of toxin in A431 cells.
45 : How to prevent, recognize, and treat drug-induced nephrotoxicity.
46 : Aminoglycoside-associated nephrotoxicity in the elderly.
47 : A meta-analysis of extended-interval dosing versus multiple daily dosing of aminoglycosides.
48 : A study of once-daily amikacin with low peak target concentrations in intensive care unit patients: pharmacokinetics and associated outcomes.
49 : Agents ameliorating or augmenting experimental gentamicin nephrotoxicity: some recent research.
50 : Protection against gentamicin-induced early renal alterations (phospholipidosis and increased DNA synthesis) by coadministration of poly-L-aspartic acid.
51 : Mechanism of protection afforded by polyaspartic acid against gentamicin-induced phospholipidosis. II. Comparative in vitro and in vivo studies with poly-L-aspartic, poly-L-glutamic and poly-D-glutamic acids.
52 : Polyaspartic acid protects against gentamicin nephrotoxicity in the rat.
53 : Inhibition of renal membrane binding and nephrotoxicity of aminoglycosides.
54 : Comparative assessment of poly-L-aspartic and poly-L-glutamic acids as protectants against gentamicin-induced renal lysosomal phospholipidosis, phospholipiduria and cell proliferation in rats.
55 : Inhibition of gentamicin uptake in rat renal cortex in vivo by aminoglycosides and organic polycations.
56 : Mechanism of protection afforded by polyaspartic acid against gentamicin-induced phospholipidosis. I. Polyaspartic acid binds gentamicin and displaces it from negatively charged phospholipid layers in vitro.
57 : Gentamicin nephrotoxicity in humans and animals: some recent research.
58 : Influence of iron, deferoxamine and ascorbic acid on gentamicin-induced nephrotoxicity in rats.
59 : Effect of superoxide dismutase treatment on gentamicin nephrotoxicity in rats.
60 : Effect of dimethyl sulfoxide on gentamicin-induced nephrotoxicity in rats.
61 : Role of DL alpha-lipoic acid in gentamicin induced nephrotoxicity.
62 : Effect of N-acetylcysteine on gentamicin-mediated nephropathy in rats.
63 : Melatonin: reducing the toxicity and increasing the efficacy of drugs.
64 : Melatonin administration prevents the nephrotoxicity induced by gentamicin.
65 : Pioglitazone attenuates kidney injury in an experimental model of gentamicin-induced nephrotoxicity in rats.
66 : A non-nephrotoxic gentamicin congener that retains antimicrobial efficacy.
67 : Repairing faulty genes by aminoglycosides: development of new derivatives of geneticin (G418) with enhanced suppression of diseases-causing nonsense mutations.
68 : The designer aminoglycoside NB84 significantly reduces glycosaminoglycan accumulation associated with MPS I-H in the Idua-W392X mouse.
69 : Suppression of CFTR premature termination codons and rescue of CFTR protein and function by the synthetic aminoglycoside NB54.
70 : Development of novel aminoglycoside (NB54) with reduced toxicity and enhanced suppression of disease-causing premature stop mutations.
71 : Mechanism and evidence of nonsense suppression therapy for genetic eye disorders.
72 : Gentamicin B1 is a minor gentamicin component with major nonsense mutation suppression activity.
73 : Hearing loss in patients with vestibulotoxic reactions to gentamicin therapy.
74 : Mechanisms of aminoglycoside ototoxicity and targets of hair cell protection.
75 : Permanent gentamicin vestibulotoxicity.
76 : N-methyl-D-aspartate antagonists limit aminoglycoside antibiotic-induced hearing loss.
77 : Protection of auditory neurons from aminoglycoside toxicity by neurotrophin-3.
78 : Recent advances in understanding aminoglycoside ototoxicity and its prevention.
79 : Protection from ototoxicity of intraperitoneal gentamicin in guinea pig.
80 : Mitochondrial ribosomal RNA mutation associated with both antibiotic-induced and non-syndromic deafness.
81 : Inherited susceptibility to aminoglycoside ototoxicity: genetic heterogeneity and clinical implications.
82 : Specific binding of aminoglycosides to a human rRNA construct based on a DNA polymorphism which causes aminoglycoside-induced deafness.
83 : A biochemical basis for the inherited susceptibility to aminoglycoside ototoxicity.
84 : Prevalence of mitochondrial 1555A-->G mutation in European children.
85 : Prevalence of mitochondrial 1555A-->G mutation in adults of European descent.
86 : Current perspectives on inner ear toxicity.
87 : Gentamicin-induced ototoxicity in hemodialysis patients is ameliorated by N-acetylcysteine.
88 : Protective effect of N-acetylcysteine from drug-induced ototoxicity in uraemic patients with CAPD peritonitis.
89 : N-Acetylcysteine in the prevention of ototoxicity.
90 : Aspirin attenuates gentamicin ototoxicity: from the laboratory to the clinic.
91 : Aspirin to prevent gentamicin-induced hearing loss.
92 : Ototoxicity.
93 : Designer aminoglycosides prevent cochlear hair cell loss and hearing loss.
94 : Lower ototoxicity and absence of hidden hearing loss point to gentamicin C1a and apramycin as promising antibiotics for clinical use.