Introduction

Aminoglycosides are a class of antibiotics that are used to treat serious infections caused by bacteria that are difficult to treat. Aminoglycosides are referred to as bactericidal antibiotics since they directly exterminate bacteria. They accomplish this by stopping bacteria from producing proteins needed for their survival.

Aminoglycosides are significant in medical treatment because they are effective against many types of bacteria that are resistant to other antibiotics, such as penicillins, cephalosporins, and tetracyclines. Aminoglycosides are often used in combination with other antibiotics to enhance their activity and prevent resistance. Aminoglycosides are particularly active against aerobic, gram-negative bacteria and some gram-positive bacteria, such as Staphylococcus aureus and Enterococcus faecalis. Aminoglycosides are also used to treat tuberculosis, plague, and brucellosis.

Types of Aminoglycosides

There are many types of aminoglycosides that differ in their chemical structure, spectrum of activity, pharmacokinetics, and toxicity. Aminoglycosides are composed of amino sugars linked by glycosidic bonds. The number, position, and configuration of the amino sugars determine the properties and functions of each aminoglycoside.

Some of the common aminoglycoside drugs are:

• Streptomycin: Streptomycin is the first aminoglycoside discovered in 1943. t originates from Streptomyces griseus and is the oldest contemporary substance employed to combat tuberculosis. Streptomycin is also used to treat plague, tularemia, and brucellosis. Streptomycin has a narrow spectrum of activity and is mainly effective against Mycobacterium tuberculosis, Yersinia pestis, Francisella tularensis, and Brucella spp. Streptomycin is administered by injection and can cause serious side effects, such as hearing loss, kidney damage, and allergic reactions.
• Gentamicin: Gentamicin is a broad-spectrum aminoglycoside that is derived from Micromonospora purpurea. It is used to treat severe infections caused by gram-negative bacteria, such as Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. Gentamicin is also effective against some gram-positive bacteria, such as Staphylococcus aureus and Enterococcus faecalis. Gentamicin is administered by injection or topical application and can cause side effects, such as hearing loss, kidney damage, and neuromuscular blockade.
• Tobramycin: Tobramycin is a semi-synthetic derivative of kanamycin that is derived from Streptomyces tenebrarius. It has a similar spectrum of activity as gentamicin but is more active against Pseudomonas aeruginosa and less active against Enterococcus faecalis. Tobramycin is used to treat infections caused by gram-negative bacteria, especially in cystic fibrosis patients. Tobramycin is administered by injection, inhalation, or topical application and can cause side effects, such as hearing loss, kidney damage, and neuromuscular blockade.
• Amikacin: Amikacin is a semi-synthetic derivative of kanamycin that is derived from Streptomyces kanamyceticus. It has a broader spectrum of activity than gentamicin and tobramycin, and is more resistant to bacterial enzymes that inactivate aminoglycosides. Amikacin is used to treat infections caused by gram-negative bacteria, especially those that are resistant to other aminoglycosides, such as Pseudomonas aeruginosa, Acinetobacter baumannii, and Mycobacterium avium complex. Amikacin is administered by injection and can cause side effects, such as hearing loss, kidney damage, and neuromuscular blockade.
• Neomycin: Neomycin is a complex mixture of three aminoglycosides that are derived from Streptomyces fradiae. It has a broad spectrum of activity against gram-negative and gram-positive bacteria, but is too toxic for systemic use. Neomycin is used topically to treat skin infections, such as impetigo, or orally to reduce the intestinal flora before surgery. Neomycin can cause side effects, such as hearing loss, kidney damage, and allergic reactions.

Aminoglycosides can be classified into different classes based on their chemical structure and characteristics, such as:

• Class I: These are the oldest and most diverse group of aminoglycosides, which include streptomycin, kanamycin, neomycin, and paromomycin. They have two or three amino sugars and a variable number of glycosidic bonds. They have a low affinity for the bacterial ribosome and are easily inactivated by bacterial enzymes.
• Class II: These are the most widely used group of aminoglycosides, which include gentamicin, tobramycin, amikacin, and netilmicin. They have two amino sugars and two glycosidic bonds. They have a high affinity for the bacterial ribosome and are less susceptible to bacterial enzymes.
• Class III: These are the newest and most potent group of aminoglycosides, which include plazomicin and sisomicin. They have one amino sugar and one glycosidic bond. They have a higher affinity for the bacterial ribosome and are more resistant to bacterial enzymes. They also have a lower toxicity and a longer half-life than other aminoglycosides.

Mechanism of Action of Aminoglycosides

Aminoglycosides are a class of antibiotics that are used to treat serious infections caused by bacteria that are difficult to treat. Aminoglycosides are termed bactericidal antibiotics because they directly eliminate bacteria. They accomplish this by stopping bacteria from producing proteins needed for their survival.

Interaction with Bacterial Ribosomes

The primary target of aminoglycosides is the bacterial ribosome, which is the molecular machine that synthesizes proteins from messenger RNA (mRNA). The bacterial ribosome consists of two subunits: the 30S and the 50S. The 30S subunit comprises 16S ribosomal RNA (rRNA) and 21 proteins, whereas the 50S subunit includes 23S and 5S rRNA along with 34 proteins. The 30S and 50S subunits join together to form the 70S ribosome, which has three sites for transfer RNA (tRNA) binding: the aminoacyl (A) site, the peptidyl (P) site, and the exit (E) site'

Aminoglycosides bind to the aminoacyl site of 16S rRNA within the 30S subunit, leading to misreading of the genetic code and inhibition of translocation. Aminoglycosides are pseudo-polysaccharides containing amino sugars and are polycationic. They interact with the negatively charged phosphate groups of the rRNA through electrostatic forces and hydrogen bonds. The binding of aminoglycosides to the 30S subunit induces conformational changes that affect the decoding center and the A site

Inhibition of Protein Synthesis in Bacteria

The binding of aminoglycosides to the 30S subunit interferes with the accuracy and efficiency of protein synthesis in bacteria. Aminoglycosides cause two major effects: promotion of mistranslation and elimination of proofreading.

• Promotion of mistranslation: Aminoglycosides alter the fidelity of the codon-anticodon recognition, resulting in the incorporation of incorrect amino acids into the growing polypeptide chain. This leads to the production of defective proteins that may have altered functions or may be degraded by the cell. Mistranslation can also affect the expression of genes that are regulated by riboswitches, which are mRNA sequences that change their conformation in response to the binding of specific metabolites. Aminoglycosides can induce or inhibit the expression of these genes by altering the riboswitch structure.
• Elimination of proofreading: Aminoglycosides block the translocation of the tRNA from the A site to the P site of the ribosome, preventing the elongation of the polypeptide chain. Aminoglycosides also inhibit the function of the ribosome recycling factor (RRF) and the elongation factor G (EF-G), which are involved in the termination and dissociation of the ribosome from the mRNA. These effects lead to the accumulation of stalled ribosomes on the mRNA, preventing the initiation of new rounds of protein synthesis.

The inhibition of protein synthesis by aminoglycosides leads to the death of bacteria, as they are unable to perform essential functions or adapt to environmental changes. Aminoglycosides are particularly effective against rapidly growing bacteria, as they require more protein synthesis and are more susceptible to the toxic effects of mistranslation.

Aminoglycosides Examples

Aminoglycosides are a class of antibiotics that kill bacteria by stopping their production of proteins. They are used to treat serious infections in a clinical setting, such as ear, eye, or intravenous (IV) infections. Aminoglycosides are derived from various species of soil bacteria, such as Streptomyces and Micromonospora. Some of the common aminoglycosides are:

• Gentamicin: Gentamicin is a broad-spectrum aminoglycoside that is effective against many types of gram-negative bacteria, such as Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. It is also active against some gram-positive bacteria, such as Staphylococcus aureus and Enterococcus faecalis. Gentamicin is administered by injection or topical application and can cause side effects, such as hearing loss, kidney damage, and neuromuscular blockade.
• Tobramycin: Tobramycin is a semi-synthetic derivative of kanamycin that has a similar spectrum of activity as gentamicin, but is more potent against Pseudomonas aeruginosa and less potent against Enterococcus faecalis. Tobramycin is used to treat infections caused by gram-negative bacteria, especially in cystic fibrosis patients. Tobramycin is administered by injection, inhalation, or topical application and can cause side effects, such as hearing loss, kidney damage, and neuromuscular blockade.
• Amikacin: Amikacin is a semi-synthetic derivative of kanamycin that has a broader spectrum of activity than gentamicin and tobramycin, and is more resistant to bacterial enzymes that inactivate aminoglycosides. Amikacin is used to treat infections caused by gram-negative bacteria, especially those that are resistant to other aminoglycosides, such as Pseudomonas aeruginosa, Acinetobacter baumannii, and Mycobacterium avium complex. Amikacin is administered by injection and can cause side effects, such as hearing loss, kidney damage, and neuromuscular blockade.
• Streptomycin: Streptomycin is the first aminoglycoside discovered in 1943. It originates from Streptomyces griseus and is the first modern substance employed against tuberculosis. Streptomycin is also used to treat plague, tularemia, and brucellosis. Streptomycin has a narrow spectrum of activity and is mainly effective against Mycobacterium tuberculosis, Yersinia pestis, Francisella tularensis, and Brucella spp. Streptomycin is administered by injection and can cause serious side effects, such as hearing loss, kidney damage, and allergic reactions.

Aminoglycosides Classification

Aminoglycosides can be classified into different classes based on their chemical structure and characteristics, such as:

• Class I: These are the oldest and most diverse group of aminoglycosides, which include streptomycin, kanamycin, neomycin, and paromomycin. They have two or three amino sugars and a variable number of glycosidic bonds. They have a low affinity for the bacterial ribosome and are easily inactivated by bacterial enzymes.
• Class II: These are the most widely used group of aminoglycosides, which include gentamicin, tobramycin, amikacin, and netilmicin. They have two amino sugars and two glycosidic bonds. They have a high affinity for the bacterial ribosome and are less susceptible to bacterial enzymes.
• Class III: These are the newest and most potent group of aminoglycosides, which include plazomicin and sisomicin. They have one amino sugar and one glycosidic bond. They have a higher affinity for the bacterial ribosome and are more resistant to bacterial enzymes. They also have a lower toxicity and a longer half-life than other aminoglycosides.

The different classes of aminoglycosides have different advantages and disadvantages in terms of their activity, resistance, and toxicity. For example, class I aminoglycosides have a wider spectrum of activity than class II and III, but they are also more prone to resistance and toxicity. Class II aminoglycosides have a balanced profile of activity, resistance, and toxicity, but they are less effective against some resistant bacteria. Class III aminoglycosides have a superior profile of activity, resistance, and toxicity, but they are also more expensive and less available than other classes.

Differentiating Between Classes

The following table summarizes the main differences between the three classes of aminoglycosides:

Table

Aminoglycosides Uses and Benefits

Aminoglycosides are used to treat serious bacterial infections that are caused by aerobic, gram-negative bacteria and some gram-positive bacteria. Aminoglycosides have several benefits, such as:

• Treatment of bacterial infections: Aminoglycosides are effective against many types of bacteria that are resistant to other antibiotics, such as penicillins, cephalosporins, and tetracyclines. Aminoglycosides are particularly active against Pseudomonas aeruginosa, which is a common cause of hospital-acquired infections and infections in immunocompromised patients. Aminoglycosides are also used to treat tuberculosis, plague, and brucellosis, which are serious and potentially fatal diseases.
• Spectrum of activity: Aminoglycosides have a broad spectrum of activity against gram-negative bacteria and some gram-positive bacteria. They can kill bacteria directly by inhibiting their protein synthesis and causing membrane damage. They can also enhance the activity of other antibiotics by facilitating their penetration into the bacterial cell.
• Combination therapy with other antibiotics: Aminoglycosides are often used in combination with other antibiotics to increase their efficacy and prevent resistance. For example, aminoglycosides can be combined with beta-lactam antibiotics, such as penicillins and cephalosporins, to treat enterococcal and staphylococcal infections. Aminoglycosides can also be combined with glycopeptide antibiotics, such as vancomycin and teicoplanin, to treat methicillin-resistant Staphylococcus aureus (MRSA) infections. Aminoglycosides can also be combined with macrolide antibiotics, such as erythromycin and azithromycin, to treat Mycobacterium avium complex infections.

Aminoglycosides Drugs

Aminoglycosides are a class of antibiotics that kill bacteria by stopping their production of proteins. They are used to treat serious infections in a clinical setting, such as ear, eye, or intravenous (IV) infections. Aminoglycosides are derived from various species of soil bacteria, such as Streptomyces and Micromonospora. Some of the common aminoglycosides are:

• Gentamicin: Gentamicin is a broad-spectrum aminoglycoside that is effective against many types of gram-negative bacteria, such as Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. It is also active against some gram-positive bacteria, such as Staphylococcus aureus and Enterococcus faecalis. Gentamicin is administered by injection or topical application and can cause side effects, such as hearing loss, kidney damage, and neuromuscular blockade.

• Tobramycin: Tobramycin is a semi-synthetic derivative of kanamycin that has a similar spectrum of activity as gentamicin, but is more potent against Pseudomonas aeruginosa and less potent against Enterococcus faecalis. Tobramycin is used to treat infections caused by gram-negative bacteria, especially in cystic fibrosis patients. Tobramycin is administered by injection, inhalation, or topical application and can cause side effects, such as hearing loss, kidney damage, and neuromuscular blockade.

• Amikacin: Amikacin is a semi-synthetic derivative of kanamycin that has a broader spectrum of activity than gentamicin and tobramycin, and is more resistant to bacterial enzymes that inactivate aminoglycosides. Amikacin is used to treat infections caused by gram-negative bacteria, especially those that are resistant to other aminoglycosides, such as Pseudomonas aeruginosa, Acinetobacter baumannii, and Mycobacterium avium complex. Amikacin is administered by injection and can cause side effects, such as hearing loss, kidney damage, and neuromuscular blockade.

• Streptomycin: Streptomycin is the first aminoglycoside discovered in 1943. It comes from Streptomyces griseus and was the initial modern remedy employed against tuberculosis. Streptomycin is also used to treat plague, tularemia, and brucellosis. Streptomycin has a narrow spectrum of activity and is mainly effective against Mycobacterium tuberculosis, Yersinia pestis, Francisella tularensis, and Brucella spp. Streptomycin is administered by injection and can cause serious side effects, such as hearing loss, kidney damage, and allergic reactions.

Administration and Dosage Guidelines

Aminoglycosides are usually given by injection into a vein or a muscle, or by inhalation or topical application. The dosage and duration of treatment depend on the type and severity of the infection, the patient’s weight, age, kidney function, and response to the drug. Aminoglycosides have a narrow therapeutic window, meaning that there is a small difference between the effective and toxic doses. Therefore, careful monitoring of blood levels and kidney function is required to ensure safety and efficacy.

The following are some general guidelines for the administration and dosage of aminoglycosides:

• Injection: Aminoglycosides are usually given once or twice a day by injection into a vein or a muscle. The dose is calculated based on the patient’s weight and the desired peak and trough concentrations of the drug in the blood. Peak concentration is the highest level of the drug in the blood, which should be reached within 30 minutes after the injection. Trough concentration is the lowest level of the drug in the blood, which should be measured just before the next dose. The optimal peak and trough concentrations vary depending on the type of aminoglycoside and the type of infection. For example, for gentamicin, the recommended peak concentration is 5 to 10 micrograms per milliliter (mcg/mL) and the recommended trough concentration is less than 2 mcg/mL for most infections.

• Inhalation: Aminoglycosides can be given by inhalation using a nebulizer, which is a device that turns liquid medicine into a fine mist that can be breathed in. This method is mainly used for patients with cystic fibrosis who have chronic lung infections caused by Pseudomonas aeruginosa. The dose and frequency of inhalation depend on the type of aminoglycoside and the patient’s condition. For example, for tobramycin, the recommended dose is 300 milligrams (mg) twice a day for 28 days, followed by 28 days off.

• Topical: Aminoglycosides can be applied to the skin or the eyes as creams, ointments, drops, or sprays. This method is used for minor infections, such as skin infections, eye infections, or ear infections. The dose and frequency of topical application depend on the type and location of the infection and the patient’s response. For example, for gentamicin eye drops, the recommended dose is one or two drops every four hours for seven to 10 days.

Monitoring and Adjustments

Aminoglycosides require close monitoring of blood levels and kidney function to prevent toxicity and ensure effectiveness. Blood levels of aminoglycosides are measured by taking blood samples at specific times after the injection. The peak and trough concentrations are then compared with the target ranges for the type of aminoglycoside and the type of infection. If the blood levels are too high or too low, the dose or the frequency of administration may need to be adjusted.

Kidney function is monitored by measuring the serum creatinine level, which is a waste product that is filtered by the kidneys. If the serum creatinine level increases, it means that the kidneys are not working well and the aminoglycoside dose may need to be reduced or stopped. Kidney function should be checked before starting aminoglycoside therapy and at regular intervals during the treatment.

Other factors that may affect the blood levels and kidney function of aminoglycosides include the patient’s age, weight, hydration status, other medications, and other medical conditions. These factors should be taken into account when prescribing and monitoring aminoglycoside therapy.

Aminoglycosides Side Effects

Aminoglycosides are powerful antibiotics, but they also have serious side effects that can affect the kidneys, the ears, and the nervous system. The risk and severity of side effects depend on the type, dose, and duration of aminoglycoside therapy, as well as the patient’s age, weight, kidney function, and other medical conditions. The most common and serious side effects of aminoglycosides are:

• Nephrotoxicity: Aminoglycosides can damage the kidneys by causing inflammation and cell death in the tubules, which are the structures that filter the blood and produce urine. This can lead to a decrease in kidney function and an increase in serum creatinine levels. Nephrotoxicity can be reversible if the aminoglycoside is stopped or the dose is reduced, but it can also be permanent and lead to chronic kidney disease or end-stage renal disease. The risk of nephrotoxicity is higher in patients who have pre-existing kidney problems, are elderly, are dehydrated, or are taking other nephrotoxic drugs, such as nonsteroidal anti-inflammatory drugs (NSAIDs), cisplatin, or vancomycin. Nephrotoxicity can be prevented or minimized by monitoring the blood levels and kidney function of aminoglycosides, adjusting the dose accordingly, and maintaining adequate hydration.

• Ototoxicity: Aminoglycosides can damage the ears by causing degeneration and death of the hair cells, which are the sensory cells that detect sound and motion in the inner ear. This can lead to hearing loss, tinnitus (ringing in the ears), and vestibular toxicity (loss of balance and dizziness). Ototoxicity can be irreversible and can occur even after the aminoglycoside is stopped. The risk of ototoxicity is higher in patients who have pre-existing hearing problems, are elderly, have a genetic predisposition, or are taking other ototoxic drugs, such as loop diuretics, aspirin, or quinine. Ototoxicity can be prevented or minimized by monitoring the blood levels and hearing function of aminoglycosides, adjusting the dose accordingly, and avoiding exposure to loud noises.

• Allergic reactions: Aminoglycosides can cause allergic reactions in some patients, such as rash, itching, hives, swelling, or anaphylaxis (a severe and potentially life-threatening reaction that involves difficulty breathing, low blood pressure, and shock). Allergic reactions can occur at any time during or after the aminoglycoside therapy. The risk of allergic reactions is higher in patients who have a history of allergy to aminoglycosides or other antibiotics, such as penicillins or cephalosporins. Allergic reactions can be prevented or treated by avoiding or discontinuing the aminoglycoside therapy, and administering antihistamines, corticosteroids, or epinephrine as needed.

Is Vancomycin an Aminoglycoside?

Vancomycin is a glycopeptide antibiotic that is often confused with aminoglycosides because of their similar names and uses. However, vancomycin is not an aminoglycoside and has a different chemical structure, mechanism of action, and spectrum of activity.

Clarifying the Distinction

Vancomycin is a glycopeptide antibiotic that is derived from Streptomyces orientalis. It has a complex structure that consists of a heptapeptide core with seven amino acids and a trisaccharide side chain with three sugars. Vancomycin is a large molecule that has a molecular weight of about 1,500 daltons.

Aminoglycosides are a class of antibiotics that are derived from various species of soil bacteria, such as Streptomyces and Micromonospora. They have a simpler structure that consists of two or three amino sugars linked by glycosidic bonds. Aminoglycosides are smaller molecules that have a molecular weight of about 300 to 600 daltons.

Differences in Mechanism of Action

Vancomycin and aminoglycosides have different mechanisms of action that target different aspects of bacterial cell wall and protein synthesis.

• Vancomycin: Vancomycin inhibits the synthesis of the bacterial cell wall by binding to the terminal D-alanyl-D-alanine residues of the peptidoglycan precursors, which are the building blocks of the cell wall. This prevents the cross-linking of the peptidoglycan chains by the enzyme transpeptidase, which is essential for the strength and integrity of the cell wall. As a result, the bacterial cell wall becomes weak and susceptible to osmotic lysis and cell death.
• Aminoglycosides: Aminoglycosides inhibit the synthesis of bacterial proteins by binding to the 30S subunit of the ribosome, which is the molecular machine that synthesizes proteins from mRNA. This interferes with the accuracy and efficiency of protein synthesis by causing mistranslation and blocking translocation. As a result, the bacterial proteins become defective and toxic, and the bacterial cell dies.

Vancomycin and aminoglycosides have different spectra of activity that cover different types of bacteria.

• Vancomycin: Vancomycin is mainly active against gram-positive bacteria, such as Staphylococcus aureus, Streptococcus pneumoniae, and Enterococcus faecium. Vancomycin is especially effective against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE), which are resistant to most other antibiotics. Vancomycin has a limited activity against gram-negative bacteria, such as Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa, because it cannot penetrate their outer membrane.
• Aminoglycosides: Aminoglycosides are mainly active against gram-negative bacteria, such as Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. Aminoglycosides are also effective against some gram-positive bacteria, such as Staphylococcus aureus and Enterococcus faecalis. Aminoglycosides have no activity against anaerobic bacteria, such as Clostridium difficile, because they require oxygen to enter the bacterial cell.

Aminoglycosides Contraindications

Aminoglycosides are a class of antibiotics that kill bacteria by stopping their production of proteins. They are used to treat serious infections caused by gram-negative bacteria and some gram-positive bacteria. However, aminoglycosides also have serious side effects that can affect the kidneys, the ears, and the nervous system. Therefore, aminoglycosides should be used with caution in certain populations and situations, and with close monitoring of blood levels and kidney function.

Precautions in Special Populations

Aminoglycosides should be used with caution in the following special populations:

• Pregnant women: Aminoglycosides can cross the placenta and cause fetal toxicity, such as hearing loss, kidney damage, and skeletal abnormalities. Aminoglycosides should be avoided during pregnancy unless the benefits outweigh the risks and no safer alternatives are available.
• Breastfeeding women: Aminoglycosides can pass into breast milk and cause adverse effects in the nursing infant, such as diarrhea, rash, and growth retardation. Aminoglycosides should be avoided during breastfeeding unless the benefits outweigh the risks and no safer alternatives are available.
• Children: Aminoglycosides can affect the growth and development of children, especially the bones and the ears. Aminoglycosides should be used with caution in children and only when indicated by the severity of the infection. The dose and duration of treatment should be adjusted according to the child’s weight, age, and kidney function.
• Elderly: Aminoglycosides can cause more severe and frequent side effects in elderly patients, such as hearing loss, kidney damage, and neuromuscular blockade. Aminoglycosides should be used with caution in elderly patients and only when indicated by the severity of the infection. The dose and duration of treatment should be adjusted according to the patient’s weight, age, and kidney function.
• Patients with kidney impairment: Aminoglycosides can worsen kidney function and increase the risk of nephrotoxicity in patients with kidney impairment. Aminoglycosides should be used with caution in patients with kidney impairment and only when indicated by the severity of the infection. The dose and frequency of administration should be reduced and the blood levels and kidney function should be monitored closely.
• Patients with hearing impairment: Aminoglycosides can worsen hearing function and increase the risk of ototoxicity in patients with hearing impairment. Aminoglycosides should be used with caution in patients with hearing impairment and only when indicated by the severity of the infection. The dose and duration of treatment should be minimized and the hearing function should be monitored closely.
• Patients with neuromuscular disorders: Aminoglycosides can interfere with the transmission of nerve impulses to the muscles and cause neuromuscular blockade, which can lead to respiratory paralysis and death. Aminoglycosides should be avoided in patients with neuromuscular disorders, such as myasthenia gravis, botulism, and Guillain-Barré syndrome. If aminoglycosides are unavoidable, the dose and duration of treatment should be minimized and the neuromuscular function should be monitored closely.

Drug Interactions and Cautions

Aminoglycosides can interact with other drugs and cause additive or antagonistic effects. The following are some of the common drug interactions and cautions involving aminoglycosides:

• Other nephrotoxic drugs: Aminoglycosides can increase the risk of nephrotoxicity when used with other drugs that can damage the kidneys, such as nonsteroidal anti-inflammatory drugs (NSAIDs), cisplatin, vancomycin, and amphotericin B. These drugs should be avoided or used with caution and with close monitoring of kidney function when combined with aminoglycosides.
• Other ototoxic drugs: Aminoglycosides can increase the risk of ototoxicity when used with other drugs that can damage the ears, such as loop diuretics, aspirin, and quinine. These drugs should be avoided or used with caution and with close monitoring of hearing function when combined with aminoglycosides.
• Other neuromuscular blocking agents: Aminoglycosides can enhance the effects of other drugs that can block the neuromuscular transmission, such as succinylcholine, tubocurarine, and botulinum toxin. These drugs should be avoided or used with caution and with close monitoring of neuromuscular function when combined with aminoglycosides.
• Other antibiotics: Aminoglycosides can have synergistic or antagonistic effects when used with other antibiotics. For example, aminoglycosides can have synergistic effects with beta-lactams, glycopeptides, and macrolides against certain gram-positive bacteria, such as enterococci and staphylococci. However, aminoglycosides can have antagonistic effects with tetracyclines, chloramphenicol, and clindamycin against certain gram-negative bacteria, such as Pseudomonas aeruginosa. The choice and combination of antibiotics should be based on the type and susceptibility of the bacteria causing the infection.

Future Developments and Alternatives

Aminoglycosides are facing the challenge of increasing bacterial resistance and decreasing clinical efficacy. Therefore, there is a need for the development of new aminoglycosides or alternatives that can overcome the resistance mechanisms and reduce the toxicity of these antibiotics.

Research on New Aminoglycosides

One of the main strategies for the development of new aminoglycosides is the chemical modification of the existing aminoglycosides to improve their activity, spectrum, and safety. For example, plazomicin is a semi-synthetic derivative of sisomicin that has enhanced activity against aminoglycoside-resistant gram-negative bacteria, such as carbapenem-resistant Enterobacteriaceae (CRE). Plazomicin was approved by the US Food and Drug Administration (FDA) in 2018 for the treatment of complicated urinary tract infections (cUTIs) caused by susceptible bacteria.

Another strategy for the development of new aminoglycosides is the discovery of novel natural aminoglycosides from various sources, such as soil bacteria, marine organisms, and plants. For example, apramycin is a natural aminoglycoside isolated from Streptomyces tenebrarius that has activity against aminoglycoside-resistant gram-negative bacteria, such as Pseudomonas aeruginosa and Acinetobacter baumannii. Apramycin is currently under preclinical development for the treatment of respiratory infections caused by these bacteria.

Emerging Trends in Antibiotic Therapy

Besides the development of new aminoglycosides, there are also other emerging trends in antibiotic therapy that can offer alternatives or adjuncts to the use of aminoglycosides. Some of these trends are:

• Combination therapy with other agents: Aminoglycosides can be combined with other agents that can enhance their activity, reduce their resistance, or mitigate their toxicity. For example, aminoglycosides can be combined with inhibitors of aminoglycoside-modifying enzymes, such as arbekacin, which can restore the susceptibility of aminoglycoside-resistant bacteria. Aminoglycosides can also be combined with antioxidants, such as N-acetylcysteine, which can protect the kidneys and the ears from the oxidative damage caused by aminoglycosides.
• Nanoparticle delivery systems: Aminoglycosides can be encapsulated or conjugated with nanoparticles, such as liposomes, polymeric micelles, or gold nanoparticles, which can improve their solubility, stability, bioavailability, and targeting. Nanoparticle delivery systems can also reduce the dose and frequency of administration, and the systemic toxicity of aminoglycosides. For example, liposomal amikacin is a nanoparticle formulation of amikacin that can be delivered by inhalation to the lungs, where it can achieve high concentrations and prolonged retention, and treat pulmonary infections caused by resistant bacteria, such as Mycobacterium avium complex and Pseudomonas aeruginosa. Liposomal amikacin was approved by the European Medicines Agency (EMA) in 2018 for the treatment of nontuberculous mycobacterial lung infections.
• Non-antibiotic therapies: Aminoglycosides can be replaced or supplemented by non-antibiotic therapies that can modulate the host immune system, disrupt the bacterial virulence factors, or interfere with the bacterial communication and biofilm formation. For example, immunotherapy, such as vaccines, antibodies, or cytokines, can enhance the host defense against bacterial infections. Anti-virulence therapy, such as quorum sensing inhibitors, biofilm disruptors, or toxin neutralizers, can attenuate the bacterial pathogenicity and facilitate the clearance of the infection. Non-antibiotic therapies can also reduce the selective pressure and the emergence of antibiotic resistance.

Conclusion

• Aminoglycosides are a class of antibiotics that kill bacteria by stopping their production of proteins. They are used to treat serious infections caused by gram-negative bacteria and some gram-positive bacteria. However, aminoglycosides also have serious side effects that can affect the kidneys, the ears, and the nervous system. Therefore, aminoglycosides should be used with caution in certain populations and situations, and with close monitoring of blood levels and kidney function.

Aminoglycosides can be classified into different classes based on their chemical structure and characteristics, such as class I, class II, and class III. Aminoglycosides can also be combined with other agents or delivered by nanoparticles to improve their activity, spectrum, and safety. Aminoglycosides can also be replaced or supplemented by non-antibiotic therapies that can modulate the host immune system, disrupt the bacterial virulence factors, or interfere with the bacterial communication and biofilm formation.

Vancomycin is a glycopeptide antibiotic that is often confused with aminoglycosides because of their similar names and uses. However, vancomycin is not an aminoglycoside and has a different chemical structure, mechanism of action, and spectrum of activity. Vancomycin inhibits the synthesis of the bacterial cell wall by binding to the peptidoglycan precursors, while aminoglycosides inhibit the synthesis of bacterial proteins by binding to the ribosome. Vancomycin is mainly active against gram-positive bacteria, while aminoglycosides are mainly active against gram-negative bacteria.

In conclusion, aminoglycosides are powerful antibiotics that can treat serious infections, but they also have serious side effects that require careful monitoring and adjustment. Aminoglycosides should be used with caution and under proper medical supervision. Aminoglycosides are not the same as vancomycin, which is a different class of antibiotic with a different mechanism of action and spectrum of activity. 😊

FAQ

1. What are the different types of aminoglycosides?

Aminoglycosides can be classified into different classes based on their chemical structure and characteristics, such as class I, class II, and class III. Some of the common aminoglycosides are gentamicin, tobramycin, amikacin, and streptomycin.

2. What are the benefits of aminoglycosides?

Aminoglycosides are effective against many types of bacteria that are resistant to other antibiotics, such as penicillins, cephalosporins, and tetracyclines. Aminoglycosides are particularly active against gram-negative bacteria, such as Pseudomonas aeruginosa, which is a common cause of hospital-acquired infections and infections in immunocompromised patients. Aminoglycosides are also used to treat tuberculosis, plague, and brucellosis, which are serious and potentially fatal diseases.

3. What are side effects of aminoglycosides?

Aminoglycosides have serious side effects that can affect the kidneys, the ears, and the nervous system. The most common and serious side effects of aminoglycosides are nephrotoxicity (kidney damage), ototoxicity (hearing loss), and neuromuscular blockade (muscle weakness). These side effects can be irreversible and can occur even after the aminoglycoside is stopped. The risk and severity of side effects depend on the type, dose, and duration of aminoglycoside therapy, as well as the patient’s age, weight, kidney function, and other medical conditions.

4. What are aminoglycosides used for?

Aminoglycosides are used to treat serious bacterial infections that are caused by aerobic, gram-negative bacteria and some gram-positive bacteria. Aminoglycosides are usually given by injection into a vein or a muscle, or by inhalation or topical application. The dosage and duration of treatment depend on the type and severity of the infection, the patient’s weight, age, kidney function, and response to the drug. Aminoglycosides require close monitoring of blood levels and kidney function to prevent toxicity and ensure effectiveness

5. What type of drug is an aminoglycoside?

Aminoglycoside is a type of antibiotic, which is a drug that kills or inhibits the growth of bacteria. Antibiotics are classified into different groups based on their chemical structure, mechanism of action, and spectrum of activity. Aminoglycoside is a group of antibiotics that share a common structure of amino sugars linked by glycosidic bonds. Aminoglycoside is a bactericidal antibiotic, which means that it kills bacteria directly by inhibiting their protein synthesis.

6. Is aminoglycoside a drug class?

Yes, aminoglycoside is a drug class, which is a group of drugs that have similar chemical structures, mechanisms of action, or therapeutic effects. Aminoglycoside is a class of antibiotics that kill bacteria by stopping their production of proteins. Aminoglycoside is a subclass of a larger class of antibiotics called protein synthesis inhibitors, which are antibiotics that interfere with the process of making proteins in bacteria.

7. Which aminoglycoside is best?

There is no definitive answer to which aminoglycoside is best, as different aminoglycosides have different advantages and disadvantages in terms of their activity, resistance, and toxicity. The choice of aminoglycoside depends on the type and susceptibility of the bacteria causing the infection, the severity and location of the infection, the patient’s condition and preferences, and the availability and cost of the drug. Some of the factors that can influence the selection of aminoglycoside are:

• Activity: Aminoglycosides have a broad spectrum of activity against gram-negative bacteria and some gram-positive bacteria, but they have no activity against anaerobic bacteria. Aminoglycosides can be classified into different classes based on their chemical structure and characteristics, such as class I, class II, and class III. Class I aminoglycosides have a wider spectrum of activity than class II and III, but they are also more prone to resistance and toxicity. Class II aminoglycosides have a balanced profile of activity, resistance, and toxicity, but they are less effective against some resistant bacteria. Class III aminoglycosides have a superior profile of activity, resistance, and toxicity, but they are also more expensive and less available than other classes.
• Resistance: Aminoglycosides can be inactivated by bacterial enzymes that modify their structure and prevent their binding to the ribosome. These enzymes are called aminoglycoside-modifying enzymes (AMEs) and they can be produced by many types of bacteria, especially gram-negative bacteria. Aminoglycosides can also be resisted by mutations in the ribosomal genes or by efflux pumps that expel the drug from the bacterial cell. The resistance to aminoglycosides can be intrinsic (natural) or acquired (due to exposure to the drug). The resistance to aminoglycosides can be overcome by using higher doses, combining with other antibiotics, or using newer aminoglycosides that are more resistant to AMEs.
• Toxicity: Aminoglycosides have serious side effects that can affect the kidneys, the ears, and the nervous system. The most common and serious side effects of aminoglycosides are nephrotoxicity (kidney damage), ototoxicity (hearing loss), and neuromuscular blockade (muscle weakness). These side effects can be irreversible and can occur even after the aminoglycoside is stopped. The risk and severity of side effects depend on the type, dose, and duration of aminoglycoside therapy, as well as the patient’s age, weight, kidney function, and other medical conditions. The toxicity of aminoglycosides can be prevented or minimized by monitoring the blood levels and kidney function of aminoglycosides, adjusting the dose accordingly, and maintaining adequate hydration.

8. Why is it called aminoglycoside?

Aminoglycoside is called aminoglycoside because it is composed of amino sugars linked by glycosidic bonds. Amino sugars are sugars that have an amino group (NH2) attached to one of their carbon atoms, such as glucosamine or galactosamine. Glycosidic bonds are covalent bonds that link two sugar molecules or a sugar molecule and another molecule, such as an alcohol or an amine. Aminoglycoside is a pseudo-polysaccharide, which means that it is a molecule that resembles a polysaccharide (a long chain of sugar molecules) but is not a true polysaccharide.

9. What is the most commonly used aminoglycoside?

The most commonly used aminoglycoside is gentamicin, which is a broad-spectrum aminoglycoside that is effective against many types of gram-negative bacteria, such as Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. It is also active against some gram-positive bacteria, such as Staphylococcus aureus and Enterococcus faecalis. Gentamicin is administered by injection or topical application and can cause side effects, such as hearing loss, kidney damage, and neuromuscular blockade. Gentamicin is often used in combination with other antibiotics to enhance their activity and prevent resistance.

10. What are the most used aminoglycosides?

The most used aminoglycosides are gentamicin, tobramycin, amikacin, and streptomycin. These are the four aminoglycosides that are listed in the World Health Organization (WHO) Model List of Essential Medicines, which is a list of the most important medications needed in a basic health system.

12. What is gentamicin used for?

Gentamicin is a broad-spectrum aminoglycoside that is used to treat severe infections caused by gram-negative bacteria, such as Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. It is also effective against some gram-positive bacteria, such as Staphylococcus aureus and Enterococcus faecalis. Gentamicin is often used in combination with other antibiotics to enhance their activity and prevent resistance. Gentamicin is administered by injection or topical application and can cause side effects, such as hearing loss, kidney damage, and neuromuscular blockade.

13. What do aminoglycosides target?

Aminoglycosides target the bacterial ribosome, which is the molecular machine that synthesizes proteins from messenger RNA (mRNA). The bacterial ribosome consists of two subunits: the 30S and the 50S. The 30S subunit contains 16S ribosomal RNA (rRNA) and 21 proteins, while the 50S subunit contains 23S and 5S rRNA and 34 proteins. The 30S and 50S subunits join together to form the 70S ribosome, which has three sites for transfer RNA (tRNA) binding: the aminoacyl (A) site, the peptidyl (P) site, and the exit (E) site.

Aminoglycosides bind to the aminoacyl site of 16S rRNA within the 30S subunit, leading to misreading of the genetic code and inhibition of translocation. Aminoglycosides are synthetic polysaccharides comprising amino sugars and possess a positive charge due to multiple amino groups. They interact with the negatively charged phosphate groups of the rRNA through electrostatic forces and hydrogen bonds. The binding of aminoglycosides to the 30S subunit induces conformational changes that affect the decoding center and the A site.

14. What are the classification of antibiotics?

Antibiotics are classified into different groups based on their chemical structure, mechanism of action, and spectrum of activity. Some of the major classes of antibiotics are:

• Beta-lactams: These are antibiotics that have a four-membered ring called beta-lactam in their structure. They include penicillins, cephalosporins, carbapenems, and monobactams. They inhibit the synthesis of the bacterial cell wall by binding to the penicillin-binding proteins (PBPs), which are enzymes that cross-link the peptidoglycan chains of the cell wall. They are mainly active against gram-positive bacteria and some gram-negative bacteria. They are susceptible to beta-lactamases, which are bacterial enzymes that hydrolyze the beta-lactam ring and inactivate the antibiotic.
• Glycopeptides: These are antibiotics that have a peptide core with sugar moieties attached to it. They include vancomycin and teicoplanin. They inhibit the synthesis of the bacterial cell wall by binding to the terminal D-alanyl-D-alanine residues of the peptidoglycan precursors, which are the building blocks of the cell wall. They are mainly active against gram-positive bacteria, especially MRSA and VRE. They have a limited activity against gram-negative bacteria, because they cannot penetrate their outer membrane.
• Aminoglycosides: These are antibiotics that have amino sugars linked by glycosidic bonds. They include gentamicin, tobramycin, amikacin, and streptomycin. They inhibit the synthesis of bacterial proteins by binding to the 30S subunit of the ribosome, which is the molecular machine that synthesizes proteins from mRNA. They are mainly active against gram-negative bacteria and some gram-positive bacteria. They have no activity against anaerobic bacteria, because they require oxygen to enter the bacterial cell.
• Tetracyclines: These are antibiotics that have a four-ring structure with a central naphthacene ring. They include tetracycline, doxycycline, minocycline, and tigecycline. They inhibit the synthesis of bacterial proteins by binding to the 30S subunit of the ribosome, preventing the attachment of the tRNA to the A site. They have a broad spectrum of activity against gram-positive and gram-negative bacteria, as well as some atypical bacteria, such as Chlamydia, Mycoplasma, and Rickettsia. They are susceptible to efflux pumps, which are bacterial mechanisms that expel the drug from the cell.
• Macrolides: These are antibiotics that have a large lactone ring with one or more sugars attached to it. They include erythromycin, azithromycin, clarithromycin, and telithromycin. They inhibit the synthesis of bacterial proteins by binding to the 50S subunit of the ribosome, preventing the translocation of the tRNA from the A site to the P site. They have a narrow spectrum of activity against gram-positive bacteria and some atypical bacteria, such as Legionella, Mycoplasma, and Chlamydia. They are susceptible to macrolide-resistant enzymes, which are bacterial enzymes that modify the 50S subunit and prevent the binding of the antibiotic.

15. What is the medicinal chemistry of aminoglycosides?

Aminoglycosides are a class of antibiotics that have amino sugars linked by glycosidic bonds. Amino sugars are sugars that have an amino group (NH2) attached to one of their carbon atoms, such as glucosamine or galactosamine. Glycosidic bonds are covalent bonds that link two sugar molecules or a sugar molecule and another molecule, such as an alcohol or an amine. Aminoglycosides are pseudo-polysaccharides, which means that they are molecules that resemble polysaccharides (long chains of sugar molecules) but are not true polysaccharides.

Aminoglycosides can be classified into different classes based on their chemical structure and characteristics, such as class I, class II, and class III. Class I aminoglycosides have two or three amino sugars and a variable number of glycosidic bonds. Class II aminoglycosides have two amino sugars and two glycosidic bonds. Class III aminoglycosides have one amino sugar and one glycosidic bond. The number, position, and configuration of the amino sugars determine the properties and functions of each aminoglycoside.

Aminoglycosides are polycationic molecules that interact with the negatively charged phosphate groups of the rRNA through electrostatic forces and hydrogen bonds. The binding of aminoglycosides to the 30S subunit induces conformational changes that affect the decoding center and the A site. Aminoglycosides can be inactivated by bacterial enzymes that modify their structure and prevent their binding to the ribosome. These enzymes are called aminoglycoside-modifying enzymes (AMEs) and they include acetyltransferases, phosphotransferases, and nucleotidyltransferases.

16. Are aminoglycosides gram positive or negative?

Aminoglycosides are mainly active against gram-negative bacteria, such as Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. They are also effective against some gram-positive bacteria, such as Staphylococcus aureus and Enterococcus faecalis. Aminoglycosides have no activity against anaerobic bacteria, such as Clostridium difficile, because they require oxygen to enter the bacterial cell.

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