Version May 2024
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 serum drug levels are closely monitored [5]. Animal models suggest that damage to tubular 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].
Aminoglycosides binding to the anionic phospholipids of the PTC may be transferred to the transmembrane protein megalin or bind directly to megalin by electrostatic interactions, and are subsequently endocytosed [13,14,20-35]. Megalin is a 600 kD cell surface scavenger receptor and has an affinity for positively charged proteins and other molecules like aminoglycosides [36]. Megalin binds to cubilin; both proteins are abundantly expressed in the renal proximal tubules and many other tissues, including glomerular podocytes and ciliary and inner ear epithelium [13,26,37].
Once megalin/cubilin-mediated endocytosis has occurred, endosomes containing the aminoglycosides are transported through the endocytic system, where they can either localize to lysosomes or be trafficked, in a retrograde fashion, first to the Golgi complex [33,38-41], then to the endoplasmic reticulum, and finally to the cytosol [42-45]. In the cytosol, aminoglycoside molecules accumulate in subcellular organelles such as the mitochondria and the nucleus, where they inhibit mitochondrial function and cause increased production of reactive oxygen species [44].
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 [46].
●Pharmacokinetically monitoring aminoglycoside therapy, serum creatinine, and utilizing a once-daily dosing regimen in selected patients have also demonstrated benefit [7-9,46-49]. (See "Dosing and administration of parenteral aminoglycosides".)
Agents — Several agents have emerged in preclinical studies as potential compounds to prevent aminoglycoside nephrotoxicity. Despite their potential, none have been adopted clinically for the prevention of aminoglycoside nephrotoxicity [50].
One class of compounds, the anionic polyamino acids (PAAs), which include polyaspartic acid and polyglutamic acid, has been extensively evaluated [14,45,51-57]. Early studies showed that PAA interferes with the binding of the aminoglycoside to the PTC plasma membrane [55-57]. Subsequent work showed that PAA binds directly to aminoglycosides and can displace them from negatively charged lysosomes [58]. This led researchers to postulate that PAA affords kidney protection by directly binding to the aminoglycoside or by displacing it from the lysosome and thus preventing its trafficking through the PTC [58].
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 [45,59,60]. 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 [59,61-67]. Cilastatin competes with megalin for binding to gentamicin and may inhibit toxicity [68]. In an animal model, inhibiting megalin-mediated endocytosis with the reversible ligand Lrpap1, also known as receptor-associated protein (RAP), prevented both clathrin-mediated and clathrin-independent proximal tubule endocytosis and minimized gentamicin nephrotoxicity [69].
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 [70]. The C2 compound was the specific congener shown to be bactericidal with less nephrotoxicity [70]. 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 [70].
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 [71-76]. Research to develop designer aminoglycosides for this purpose has led to the discovery of aminoglycoside derivatives with less cellular toxicity [71-74]. However, such compounds also have decreased bactericidal activity and thus would not be effective antibiotics [71,74]. 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 [77,78]. 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 [79]. In a later report on 25 patients, most were found to have no residual hearing loss [77].
Gentamicin and tobramycin are primarily vestibulotoxic, whereas neomycin, kanamycin, and amikacin are more ototoxic [78]. 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 aminoglycoside 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 [80]. 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 [81].
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 [78], and experimental evidence in animals showing ototoxicity prevention with antioxidant agents [82,83].
There appears to be a genetic predisposition to the development of ototoxicity with aminoglycosides. Point mutations in the small mitochondrial (12S) ribosomal RNA gene (eg, a nucleotide 1555 A to G substitution) have been described in a number of families with inherited susceptibility to ototoxicity [50,78,84,85]. The mutant mitochondrial human ribosomal RNA binds aminoglycosides with high affinity; in comparison, the wild-type human ribosomal RNA does not bind aminoglycosides at all [86]. Aminoglycoside binding presumably exacerbates the inherent mitochondrial defect induced by the mutation, resulting in a reduction in the overall translation rate below the minimum level required for normal mitochondrial function and increasing the generation of reactive oxygen species [87]. The prevalence of point mutations among individuals of European ancestry is approximately 1 in 500 [88,89].
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 [7,79]. (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 [79,90].
Genetic screening of patients prior to administering of aminoglycosides would be a valuable tool to aid in the prevention of ototoxicity [88,89]. A rapid screening test has been used in neonates to detect the m.1555A>G variant in a clinically relevant timeframe [91]. The patient and family history also remain valuable tools available to prevent aminoglycoside-induced ototoxicity.
Given the relative rarity of the 12S ribosomal point-mutations that confer susceptibility to aminoglycoside-induced hearing loss, it may not 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 [92]. 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 [93].
We believe that further study in a larger number of patients and in other clinical settings is required before NAC is routinely used to prevent ototoxicity. However, given the safety of NAC, some experts suggest that NAC should be administered to all patients with end-stage kidney disease receiving an aminoglycoside [94,95].
Limited evidence in nondialysis patients suggests that aspirin may provide some protection against ototoxicity [96-98]. 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 [99]. Similar results were found with gentamicin C1a, a congener of commercial gentamicin, and apramycin, an aminoglycoside used in veterinarian medicine [100].
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
●Prevalence of nephrotoxicity – 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.)
●Varying degrees of nephrotoxicity – Since aminoglycoside molecules readily bind to anionic phospholipids and megalin 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. Neomycin, which has the highest affinity for the PTC binding site, has the greatest nephrotoxicity of the aminoglycosides. Streptomycin, which has the least affinity for the PTC binding site, has the least nephrotoxicity. (See 'Proximal tubule cell transport and charge' above.)
●Prevention of nephrotoxicity
•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. (See 'Agents' above.)
●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. The pathogenesis of aminoglycoside-induced ototoxicity with hearing loss is less understood. (See 'Ototoxicity' above and 'Pathogenesis' above.)
●Prevention of ototoxicity
•The main strategies to prevent the development of ototoxicity due to aminoglycosides are once-daily dosing and careful monitoring of serum drug concentrations. However, some experts also administer N-acetylcysteine (NAC) to patients with end-stage kidney disease receiving an aminoglycoside. (See 'Prevention of ototoxicity' above.)
•Rapid tests for mitochondrial RNA mutations that confer increased sensitivity to aminoglycoside ototoxicity have been developed and may play a role in the future.
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Brian S Decker, MD, PharmD (deceased), who contributed to an earlier version of this topic review.
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