Mechanisms and Impact of Aminoglycoside

What Are Aminoglycosides?

Aminoglycoside (AG) is a kind of antibiotics with amino sugar and amino cyclic alcohol structure. It is mainly used in clinical treatment of gram-negative bacteria, Pseudomonas aeruginosa and other infections. It was widely used from 1960s to 1970s.

The first aminoglycoside antibiotic in human history was streptomycin discovered in 1940. This structure was isolated from the secretion of Streptomyces and was mainly used in the treatment of tuberculosis, but it has a serious problem of drug resistance and can damage the eighth pair of brain nerves and cause deafness. In 1957, kanamycin was extracted from Streptomyces kanamycin and used in the treatment of gram-negative bacteria. To solve the problem of drug-resistant strains, structural modification was carried out based on kanamycin. New drugs such as amikacin and tobramycin were developed. In 1963, gentamicin was isolated from the fermentation broth of Micromonospora. It is a mixture of aminoglycosides, which has good resistance to gram-negative bacteria and relatively low toxicity. In the 1970s, new aminoglycoside antibiotics, such as neomycin and ribostamycin, were extracted from Streptomyces, and these new drugs, while not as highly active in antimicrobial activity as the previously discovered drugs, had greatly reduced side effects and were safer than the earlier aminoglycosides.

Figure 1. Structures of natural AGs and of semisynthetic analog
(Source: Jospe-Kaufman M, et al. 2020)

They are potent broad-spectrum antibiotics; unlike penicillin, they are effective against aerobic gram-negative pathogens, including Enterobacteriaceae and Pseudomonas spp. In addition, they have bactericidal potential, and synergistic bactericidal effect with other drugs (especially ampicillin and other beta lactams) is also significant. Aminoglycosides are also hypoallergenic, making them particularly suitable for emergency situations.

Aminoglycoside Toxicity

The improved prognosis of patients is overshadowed by the frequent toxic side effects of AGs. The side effects of aminoglycosides act mainly on the kidneys (nephrotoxicity), vestibular and auditory organs (ototoxicity), and neuromuscular junctions.

Figure 3. Mechanisms of cytotoxic effects of aminoglycosides and cell signaling pathways (example: gentamicin)
(Source: Lopez-Novoa JM, et al. 2011)

Aminoglycoside Nephrotoxicity

Adverse nephrotoxicity has been estimated to occur in up to 25% of all patients treated with aminoglycoside. AG generally exerts its nephrotoxic effects through three mechanisms: renal tubular toxicity, decreased glomerular filtration, and decreased renal blood flow.

Renal tubular toxicity is the primary mechanism by which aminoglycosides cause nephrotoxicity. In the proximal renal tubule, these substances undergo endocytosis and are concentrated in lysosomes, Golgi apparatus and endoplasmic reticulum. Once the threshold is reached, aminoglycosides are excreted into the cytoplasm and act on mitochondria to induce apoptosis and necrosis. In addition, they inhibit a number of transporters in the proximal renal tubule, thereby affecting tubular reabsorption and impairing cell viability. Symptoms in patients in the early stages of injury are characterized by increased urinary excretion of calcium, magnesium, protein, and other organic anions, sometimes leading to hypocalcemia, hypomagnesemia, and proteinuria, and, as the extent of the damage increases, increased excretion of potassium, sodium, and serum creatinine.

Patient-specific risk factors for the development of aminoglycoside-associated nephrotoxicity include older age, decreased baseline renal function, pregnancy, dehydration, decreased kidney mass, hypothyroidism, hepatic dysfunction, metabolic acidosis, and sodium deficiency. Drug-related risk factors include non-steroidal anti-inflammatory drugs, diuretics, amphotericin B, cisplatin, cyclosporine, iodine-containing contrast media, vancomycin, and cephalosporins. Limiting risk factors also reduces the likelihood of nephrotoxicity from aminoglycosides. A study evaluating the effect of individualized pharmacokinetic monitoring on the incidence of aminoglycoside nephrotoxicity demonstrated that the incidence of nephrotoxicity was significantly higher in patients who did not receive pharmacokinetic monitoring than in those who had their pharmacokinetic levels monitored. In addition, the study identified risk factors for the development of nephrotoxicity including initial concentration troughs, duration of treatment, concomitant administration of piperacillin, clindamycin, or vancomycin, age greater than 50 years, and pneumonia. Thankfully, nephrotoxicity is reversible and can be treated clinically with hydration therapy, so that once treatment with aminoglycosides is discontinued, patients can usually regain normal kidney function.

Streptomycin ELISA Kits

Streptomycin Antibodies

Streptomycin Antigens

Kanamycin ELISA Kits

Kanamycin Antibodies

Kanamycin Antigens

Amikacin ELISA Kits

Amikacin Antibodies

Amikacin Antigens

Tobramycin Antibodies

Tobramycin Antigens