What does aminoglycoside do to a cell?
Aminoglycosides can cause the cell to overcome the stop codons, insert a random amino acid, and express a full-length protein. The aminoglycoside gentamicin has been used to treat cystic fibrosis (CF) cells in the laboratory to induce them to grow full-length proteins.
How are aminoglycosides administered?
They are typically administered intravenously, while some can be taken orally. Aminoglycosides act through inhibition of protein synthesis. Once inside the bacterial cell, they bind to the A- site in ribosomal RNA of the 30S subunit and cause a misreading of transfer RNA codons.
What is the mechanism of action of aminoglycosides in protein synthesis?
The inhibition of protein synthesis is mediated through aminoglycosides' energy-dependent, sometimes irreversible binding, to the cytosolic, membrane-associated bacterial ribosome (image at right).
How are aminoglycosides used to treat Gram positive infections?
While less common, aminoglycosides ( in combination with other drugs) have also been used for select gram-positive infections. They are typically administered intravenously, while some can be taken orally. Aminoglycosides act through inhibition of protein synthesis.
What is the mechanism of action of aminoglycosides?
The aminoglycosides primarily act by binding to the aminoacyl site of 16S ribosomal RNA within the 30S ribosomal subunit, leading to misreading of the genetic code and inhibition of translocation [3,4].
How do aminoglycosides work in the body?
Aminoglycosides inhibit protein synthesis by binding, with high affinity, to the A-site on the 16S ribosomal RNA of the 30S ribosome (Kotra et al. 2000). Although aminoglycoside class members have a different specificity for different regions on the A-site, all alter its conformation.
How do aminoglycosides get into bacteria?
Since aminoglycosides require an active electron transport chain to enter a bacterium, anaerobic bacteria are intrinsically resistant.
What do aminoglycosides target?
Aminoglycosides are a class of clinically important antibiotics used in the treatment of infections caused by Gram-positive and Gram-negative organisms. They are bactericidal, targeting the bacterial ribosome, where they bind to the A-site and disrupt protein synthesis.
Why do aminoglycosides cause ototoxicity?
Aminoglycosides appear to generate free radicals within the inner ear, with subsequent permanent damage to sensory cells and neurons, resulting in permanent hearing loss. Two mutations in the mitochondrial 12S ribosomal RNA gene have been previously reported to predispose carriers to aminoglycoside-induced ototoxicity.
Which of the following is a mechanism of aminoglycosides?
There are three mechanisms of aminoglycoside resistance: reduced uptake or decreased cell permeability, alterations at the ribosomal binding sites, or production of aminoglycoside modifying enzymes.
Why do aminoglycosides have post antibiotics?
Aminoglycosides demonstrate rapid, concentration-dependent killing as well as an important postantibiotic effect, probably due to their irreversible binding to the ribosomes. Simultaneously, toxicity (renal and auditory) is delayed as uptake of the drug into the target tissues is saturable.
Is aminoglycosides time dependent or concentration?
The aminoglycosides and fluoroquinolones exhibit concentration-dependent killing. Thus, the main PK-PD parameters that correlate with their efficacy are the ratio of peak serum drug concentration to MIC and the ratio of the area under the concentration versus time curve to MIC.
How do aminoglycosides cause nephrotoxicity?
GENERAL FEATURES OF AMINOGLYCOSIDE NEPHROTOXICITY Aminoglycosides are nephrotoxic because a small but sizable proportion of the administered dose (≈5%) is retained in the epithelial cells lining the S1 and S2 segments of the proximal tubules (135) after glomerular filtration (30).
What bacteria do aminoglycosides treat?
Aminoglycosides are a class of antibiotics used mainly in the treatment of aerobic gram-negative bacilli infections, although they are also effective against other bacteria including Staphylococci and Mycobacterium tuberculosis. They are often used in combination with other antibiotics.
What are the two major side effects of aminoglycosides?
The major side effects of aminoglycosides are kidney injury, hearing impairment and vestibular toxicity.
What are the main indications of aminoglycosides?
Since this drug class has demonstrated effectiveness in multi-drug resistant Gram-negative pathogens, aminoglycosides are indicated for empiric therapy in patients with severe illness; this includes empiric treatment for patients with infective endocarditis, sepsis, complicated intraabdominal infections, and ...
Which part of the body may be damaged by aminoglycosides?
The major side effects of aminoglycosides are kidney injury, hearing impairment and vestibular toxicity.
How do aminoglycosides cause nephrotoxicity?
GENERAL FEATURES OF AMINOGLYCOSIDE NEPHROTOXICITY Aminoglycosides are nephrotoxic because a small but sizable proportion of the administered dose (≈5%) is retained in the epithelial cells lining the S1 and S2 segments of the proximal tubules (135) after glomerular filtration (30).
Why aminoglycosides are not absorbed orally?
Because it is poorly absorbed orally, neomycin causes a decrease in intestinal bacteria, thereby decreasing ammonia production and absorption from the colon. The aminoglycosides all have serious toxicities which often limit their applicability and the dose and duration of therapy.
Why do aminoglycosides have post antibiotics?
Aminoglycosides demonstrate rapid, concentration-dependent killing as well as an important postantibiotic effect, probably due to their irreversible binding to the ribosomes. Simultaneously, toxicity (renal and auditory) is delayed as uptake of the drug into the target tissues is saturable.
What are the aminoglycosides used for?
Aminoglycosides are also an important component of combination therapy for multidrug-resistant tuberculosis (MDR-TB) and certain non-tuberculous mycobacterial (NTM) infections. Current MDR-TB treatment guidelines recommend inclusion of one of the following agents during the intensive phase of therapy: amikacin, kanamycin, streptomycin, or capreomycin, a cyclic peptide antibiotic that is often considered as an aminoglycoside because of its mechanism of action. Each of these agents possesses potent bactericidal activity against M. tuberculosis(Ho et al. 1997) and the choice of agent depends on previous injectable use (if any) and the likelihood of resistance. A meta-analysis including 32 studies with >9000 treatment episodes did not reveal any clear differences in efficacy among the available agents (World Health Organization 2011). Similar to treatment of MDR-TB, combination therapy for patients with fibrocavitary, severe nodular/bronchiectatic or macrolide-resistant lung disease because of the M. aviumcomplex generally includes amikacin or streptomycin (Griffith et al. 2007). Among the rapidly growing mycobacteria, amikacin is the preferred agent for infections because of M. fortuitumor M. abscessus, whereas tobramycin is the most active agent against M. chelonae(Griffith et al. 2007).
How does aminoglycoside enter the cell?
Aminoglycoside entry into bacterial cells is comprised of three distinct stages, the first of which increases permeability of the bacterial membrane, whereas the second and third are energy-dependent. The first stage involves electrostatic binding of the polycationic aminoglycoside to the negatively charged components of the bacterial membrane, such as the phospholipids and teichoic acids of Gram-positive organisms and the phospholipids and lipopolysaccharide (LPS) of Gram-negative organisms, followed by displacement of magnesium ions (Davis 1987; Taber et al. 1987; Ramirez and Tolmasky 2010). These cations are responsible for cross bridging and stabilization of the lipid components of the bacterial membrane and their removal leads to disruption of the outer membrane, enhanced permeability, and initiation of aminoglycoside uptake (Hancock et al. 1981, 1991; Hancock 1984; Ramirez and Tolmasky 2010). This phenomenon facilitates entry into the cytoplasm via a slow, energy-dependent, electron-transport-mediated process (Kislak 1972; Martin et al. 1972; Davis 1987; Taber et al. 1987; Ramirez and Tolmasky 2010). Inhibition of protein synthesis and mistranslation of proteins occurs once aminoglycoside molecules access the cytoplasm. These mistranslated proteins insert into and cause damage to the cytoplasmic membrane itself and facilitate subsequent aminoglycoside entry (Nichols and Young 1985; Davis et al. 1986). This then leads to rapid uptake of additional aminoglycoside molecules into the cytoplasm, increased inhibition of protein synthesis, mistranslation, and accelerated cell death (Davis et al. 1986; Davis 1987; Taber et al. 1987; Ramirez and Tolmasky 2010).
What is the relationship between aminoglycosides and pharmacodynamics?
The relationship between aminoglycoside pharmacokinetics (PKs) and pharmacodynamics (PDs) has been studied extensively in mice. The PK/PD variable that is most often correlated with efficacy of aminoglycosides is the ratio of area under the concentration–time curve (AUC) to MIC, although peak concentration also appears to play a role. The magnitude of the PK/PD target for aminoglycosides is not as well defined as it is for other antibiotic classes because of, until recently, the lack of development of new aminoglycosides. Available data suggests that significant variations in the PK/PD target exist between species and body site of infection. For example, an AUC/MIC target of 100 was reportedly associated with a 1- to 2-log10kill in the mouse neutropenic thigh infection model with amikacin and K. pneumoniae(Craig 2011), whereas this same group reported better efficacy at the same dose level and with the same strain in the mouse lung infection model (Craig et al. 1991). These results were potentially a result of a longer measured PAE in the lung compared with the thigh (Craig et al. 1991).
What is a plazomicin?
Plazomicin is a new aminoglycoside that was specifically engineered to be resistant to the action of the AMEs that are prevalent in key Gram-negative pathogens (Armstrong and Miller 2010). It is synthesized from a sisomicin scaffold that is intrinsically refractory to modification by APH(3′)-III, -VI, and -VII and ANT(4′), which confer amikacin resistance because of an absence of the 3′- and 4′-OH groups. Modification at the N-1 position via addition of a hydroxylaminobutyric acid substituent sterically hinders the action of the AAC(3), ANT(2″), and APH(2″) enzymes, which confer resistance to gentamicin and tobramycin. Finally, addition of a hydroxyethyl substituent at the 6′ position inhibits the action of the AAC(6′) enzymes, which confer resistance to a broad range of agents, including amikacin, tobramycin, and gentamicin (Fig. 4). Importantly, these modifications to sisomicin do not reduce intrinsic potency as has been associated with previous efforts to protect the 6′ position and, as predicted, lead to improved activity against Enterobacteriaceae (MIC90≤2 mg/L) that are resistant to currently available aminoglycosides (Nagabhushan et al. 1982; Aggen et al. 2010). Plazomicin retains vulnerability to modification by AAC(2′)-I, a chromosomal AME found in P. stuartiiand some mycobacterial species. However, this enzyme is rare, has not been found on a mobile element and has not been shown to have clinical relevance in Mycobacteriumspp. In addition, plazomicin, like all 4,6-linked aminoglycosides, is inactive against isolates that produce RMTs. As described above, this mechanism of resistance frequently travels on mobile genetic elements with NDM-positive Enterobacteriaceae, and, thus, plazomicin is not active against many isolates harboring this enzyme (Berçot et al. 2011; Livermore et al. 2011; Mushtaq et al. 2011; Poirel et al. 2014).
How does rRNA methyltransferase modify aminoglycosides?
Target site modification leading to aminoglycoside resistance occurs via the action of 16S rRNA methyltransferases (RMTs). These enzymes modify specific rRNA nucleotide residues in a manner that blocks aminoglycosides from effectively binding to their target (Beauclerk and Cundliffe 1987; Cundliffe 1989; Wachino and Arakawa 2012). There are two general classes of RMTs that are characterized by the specific nucleotide residues that they modify. These include enzymes that render bacteria resistant to 4,6-di-substituted aminoglycosides via methylation of the N7 position of nucleotide G1405(Thompson et al. 1985; Beauclerk and Cundliffe 1987) and those that affect both 4,6- and 4,5-di-substituted aminoglycosides through methylation of the N1 position of nucleotide A1408(Skeggs et al. 1985; Beauclerk and Cundliffe 1987; Mingeot-Leclercq et al. 1999).
How does resistance to aminoglycosides work?
Aminoglycoside resistance takes many different forms including enzymatic modification, target site modification via an enzyme or chromosomal mutation, and efflux. Each of these mechanisms has varying effects on different members of the class and often multiple mechanisms are involved in any given resistant isolate. Resistance to aminoglycosides via target site mutations has not been observed because nearly all prokaryotes, with the exception of Mycobacteriumspp. (Bercovier et al. 1986) and Borreliaspp. (Schwartz et al. 1992), encode multiple copies of rRNA. Although contemporary large-scale surveillance programs provide an understanding of phenotypic aminoglycoside resistance among important pathogens, these studies have generally not focused on the epidemiology of specific resistance mechanisms (Jones et al. 2014; Sader et al. 2015).
How do aminoglycosides inhibit protein synthesis?
Aminoglycosides inhibit protein synthesis by binding, with high affinity, to the A-site on the 16S ribosomal RNA of the 30S ribosome (Kotra et al. 2000). Although aminoglycoside class members have a different specificity for different regions on the A-site, all alter its conformation. As a result of this interaction, the antibiotic promotes mistranslation by inducing codon misreading on delivery of the aminoacyl transfer RNA. This results in error prone protein synthesis, allowing for incorrect amino acids to assemble into a polypeptide that is subsequently released to cause damage to the cell membrane and elsewhere (Davis et al. 1986; Mingeot-Leclercq et al. 1999; Ramirez and Tolmasky 2010; Wilson 2014). Some aminoglycosides can also impact protein synthesis by blocking elongation or by directly inhibiting initiation (Davis 1987; Kotra et al. 2000; Wilson 2014). The exact mechanism of binding and the subsequent downstream effects varies by chemical structure, but all aminoglycosides are rapidly bactericidal (Davis 1987; Mingeot-Leclercq et al. 1999) and typically produce a prolonged postantibiotic effect (PAE) (Zhanel et al. 1991) The PAE has been shown to be directly related to the length of time that the bacteria take to recover from the inhibition of protein synthesis (Stubbings et al. 2006). It is hypothesized that this is dependent on the eventual disassociation of the antibiotic from its target and exit from the cell.
Why is it important to monitor aminoglycosides?
Therapeutic drug monitoring is necessary with aminoglycosides to optimize patient outcomes and limit toxicity. However, there is no universal agreement on the method of monitoring. Therapeutic drug monitoring has been shown to reduce hospital stay duration and toxicities. Studies also suggest that therapeutic drug monitoring reduces mortality. It is important to note that monitoring clearance should be considered in critically ill, burn, and obese patients due to their abnormal distribution volume. [15]
What subunit does aminoglycoside bind to?
Aminoglycosides have bactericidal activity in which they bind to the bacteria ribosomal 30S subunit. Specifically, they are believed to bind to the A-site (aminoacyl) on the 16S rRNA, a component of the ribosomal 30S subunit. Through this binding, the genetic code gets misread, and the translation is disrupted, leading to the bacteria being unable to carry out protein synthesis. [3][4]
What are the adverse effects of aminoglycosides?
The main noted adverse effects of aminoglycosides are ototoxicity, nephrotoxicity, and neuromuscular blockade. Therefore, patients should be educated to look out for warning signs of these adverse effects before the initiation of aminoglycoside therapy. [1]
How long can you use aminoglycosides?
For directed treatment, aminoglycoside use for longer than 48 hours is acceptable. They are part of directed combination treatment for brucellosis, listeriosis, CNS nocardiosis, and Pseudomonas aeruginosainfection. Aminoglycosides monotherapy is for tularemia, resistant mycobacteria, bacteremia caused by Campylobacterspp.and Yersinia spp., and drug-resistant gram-negative pathogens. The Infectious Diseases Society of America Guidelines should be referenced to see if an aminoglycoside is the correct agent to use for a particular patient. [1][2]
Is amikacin an aminoglycoside?
Aminoglycosides have a broad spectrum of activity covering aerobic organisms, including gram-negative bacteria and mycobacteria. There are several drugs within the aminoglycoside class, including gentamicin, tobramycin, amikacin, neomycin, plazomicin, and streptomycin, and FDA-approved indications vary between the for these individual aminoglycosides. This activity reviews the indications, contraindications, mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent to members of the interprofessional team who wish to prescribe aminoglycosides.
Can aminoglycosides be used for genitourinary infections?
Typically, in these settings, aminoglycosides should not be used for more than two days, due to toxic ity to the patient .
Is aminoglycoside a new class of antimicrobials?
Although not a new class of antimicrobials, aminoglycosides have continued to prove their clinical value in fighting infections. Aminoglycosides have a broad spectrum of activity covering aerobic organisms, including gram-negative bacteria and mycobacteria. Because there are several drugs within the aminoglycoside class, including gentamicin, tobramycin, amikacin, neomycin, plazomicin, paromomycin, and streptomycin, FDA approved indications vary between the different individual aminoglycosides.
What is the purpose of aminoglycosides?
Aminoglycosides are a group of antibiotics used to treat infections caused by Gram-negative bacteria and mycobacteria. Clinically used aminoglycosides can be primarily cochleotoxic (amikacin and kanamycin) or primarily vestibulotoxic (gentamicin, streptomycin, and tobramycin) ( Selimoglu, 2007 ).
What is the AADA gene?
Aminoglycoside adenylyltransferase (aadA) genes mediate resistance to streptomycin and spectinomycin. In a pathogenic porcine Escherichia coli, the novel aaA5 has now been described integrated with a trimethoprim resistance gene (6). The aadA6 gene has been sequenced from Pseudomonas aeruginosa and can confer high-level resistance to spectinomycin in E. coli (7). All strains of multidrug resistant Vibrio cholerae O1 El Tor isolated in Albania were resistant to spectinomycin, and resistance to this antibiotic was mediated by the aadA1 gene cassette located in the bacterial chromosome within a class 1 integron (8). Another class 1 integron that contained aadA2 was found in pathogenic Salmonella typhimurium isolates from France and was also chromosomally located (9). An aadA gene has also been described in Enterococcus faecalis (10).
Is aminoglycoside a polar cation?
Aminoglycosides are polar cations and as a result have very poor oral bioavailability. Only a mere 0.3%–1.5% of an orally or rectally administered dose of aminoglycoside appears in the urine. However, there are case reports of aminoglycoside toxicity in patients with chronic kidney disease (CKD) on long-term oral or rectal aminoglycoside treatment (Ali, 1995; Burton et al., 2006; Chambers, 2006 ). In the pleural and synovial fluid, the transport of aminoglycosides is slow. This poor absorption can be overcome with repeated administrations, though, resulting in aminoglycoside concentrations in the pleural and synovial fluid that approximate the plasma concentration. Interruptions in the continuity of mucous membranes and intact skin facilitate aminoglycoside absorption. Patients with gastric ulcers and inflammatory bowel disease have increased gastrointestinal absorption of aminoglycosides. Similarly, skin lesions such as ulcers, burn injuries, and large wounds have led to aminoglycoside toxicity when transdermal aminoglycoside therapy is used for protracted periods of time. The well-perfused peritoneal membrane permits rapid and complete absorption of intraperitoneally administered aminoglycosides.
What is the mechanism of aminoglycosides?from sciencedirect.com
Aminoglycosides are usually bactericidal in action. Although the exact mechanism has not been fully elucidated, these drugs appear to inhibit protein synthesis in susceptible bacteria by irreversibly binding to 30S ribosomal subunits. The aminoglycosides consist of amikacin, gentamicin, kanamycin, neomycin, netilmicin, paromycin, and tobramycin.
What are aminoglycosides used for?from sciencedirect.com
Aminoglycosides (Fig. 3; 25) were among the first antibiotics to be developed as antibacterial drugs with the discovery of streptomycin by Waksman in the early 1940s. 68 This class of drugs has been widely utilized for decades due to broad-spectrum activity encompassing staphylococci and Gram-negative bacteria, 69 but also mycobacteria. 70 Aminoglycosides act by binding to the aminoacyl tRNA site (A-site) of the bacterial ribosome, 71 resulting in the cessation of protein synthesis. They are generally considered to be bactericidal agents, 72 although cidality is often enhanced in the presence of β-lactam antibiotics. 73 The most frequently used agents are gentamicin ( 26 ), tobramycin ( 27 ), and amikacin ( 28 ). They have been utilized for treatment of a variety of bacterial infections including sepsis, skin and soft tissue infections (SSTIs), serious infections of the respiratory tract, serious bone and joint infections, intraabdominal infections (IAIs) (including peritonitis), postoperative infections (including postvascular surgery), ophthalmic disease, the management of cystic fibrosis (CF) with inhaled tobramycin, and tuberculosis (TB) (streptomycin [ 29 ]) ( https://dailymed.nlm.nih.gov/dailymed/search.cfm?startswith=amikacin&x=14&y=12 ). Because of the potential for ototoxicity 74 and nephrotoxicity, 75 as well as the increasing resistance seen for all antibiotics, aminoglycosides are currently not utilized as frequently as other drugs such as the β-lactams, unless the appearance of aminoglycoside susceptibility in highly resistant Gram-negative bacteria suggests that an aminoglycoside may be a reasonable therapeutic option. Encouraging results have recently been reported for the investigational aminoglycoside plazomicin ( 30 ), a semisynthetic aminoglycoside based on sisomicin ( 31 ), designed to avoid common aminoglycoside resistance mechanisms, particularly those related to aminoglycoside-modifying enzymes (AMEs). 76 This novel aminoglycoside is currently under development for the treatment of serious antibiotic-resistant infections caused by enteric bacteria. 77
What is the most common antibiotic used to treat Gram negative bacteria?from sciencedirect.com
Aminoglycosides are potent bactericidal antibiotics that act by inhibiting bacterial protein synthesis, thereby binding bacterial 30S or 50S ribosomal subunit, inhibiting the translocation of the peptidyl-tRNA from the A-site to the P-site, and also causing misreading of mRNA. They are broad-spectrum antibiotics, effective against many Gram-negative and Gram-positive bacteria. Gentamicin is the most commonly used aminoglycoside. In addition to gentamicin, kanamycin, tobramycin, amikacin, streptomycin, and neomycin are the examples of aminoglycosides (Mingeot-Leclercq et al., 1999; Schwalbe et al., 2007 ).
What causes aminoglycoside resistance?from sciencedirect.com
Aminoglycoside resistance can be caused by three major mechanisms. Production of AMEs is the most common, occurring in both staphylococci and Gram-negative bacteria. Enzymes that modify specific drugs either by N-acetylation, O-adenylation, or O-phosphorylation can cause aminoglycoside inactivation. 78 Multiple AMEs may exist in a single bacterial strain, with two or three AMEs frequently appearing in aminoglycoside-resistant Enterobacteriaceae or Acinetobacter spp. 78 Plazomicin evades most AMEs, except for an uncommon chromosomal acetylase that inactivates plazomicin and gentamicin, 76 and has been identified only in Providencia stuartii. 78 In staphylococci, a limited number of AMEs may be produced alone or in combination 76,79,80 resulting in resistance to amikacin and tobramycin, but generally showing lower MICs for gentamicin and plazomicin. A second common aminoglycoside resistance mechanism is alteration of the ribosomal binding, often through 16S rRNA methyl transferases (RMTs) in the Enterobacteriaceae. 78,81 Both AMEs and RMTs can be found on transferable elements that may be circulated among species, thus increasing the proliferation of resistance. Dissemination may be due to both clonal spread and plasmidic transfer of mobile resistance determinants. RMTs may travel on the same plasmids as ESBL-encoding genes 82 or quinolone resistance proteins 83 and are often associated with insertion sequences. 83 One of the most disconcerting appearances of these methylases has been the identification of RMTs in highly antibiotic-resistant Gram-negative pathogens that produce the NDM-1. 84 A third aminoglycoside mechanism, primarily in Gram-negative bacteria, involves decreased penetration and/or increased efflux. Membrane alterations that affect aminoglycoside permeability are infrequently encountered in most enteric bacteria with the exception of the Proteae, which typically have an outer membrane that impedes the aminoglycoside entry 85 (including plazomicin 78 ). In P. aeruginosa, aminoglycosides often exhibit higher MICs as a result of hyperproduction of the MexXY efflux pump, 86 whereas in Acinetobacter baumannii, increased expression of the AdeB efflux system may contribute to reduced sensitivity to plazomicin. 87
What is the function of aminoglycosides in the ribosome?from sciencedirect.com
Aminoglycosides bind irreversibly to the 30S ribosome to interfere with the reading of the microbial genetic code and to inhibit protein synthesis. Aminoglycosides are generally bactericidal, and their efficacy in several cases can be greatly enhanced by the concomitant use of cell wall–inhibiting β-lactams and glycopeptides.
What is aerosolized aminoglycoside used for?from sciencedirect.com
Aerosolized aminoglycosides, initially used to treat cystic fibrosis exacerbations , 203-207,208 have recently shown promise in chronic bronchiectatic infections 460,461 and ventilator-associated pneumonias. Most of the infections studied have involved P. aeruginosa, and the inhaled aminoglycoside used in conjunction with a systemic β-lactam. Aerosolized aminoglycosides were associated with improved clinical and microbiologic cure rates, with less nephrotoxicity. 462-464 A large, randomized placebo-controlled trial is currently underway. 463
What are the risk factors for aminoglycoside nephrotoxicity?from sciencedirect.com
Risk factors for aminoglycoside nephrotoxicity include the type of AG, high peak serum levels, cumulative dose, the duration and frequency of administration, and patient-related factors such as age, preexisting renal dysfunction, hypoalbuminemia, liver dysfunction, decreased renal perfusion, and the concomitant use of nephrotoxic drugs. 132
How do aminoglycosides inhibit protein synthesis?
The inhibition of protein synthesis is mediated through aminoglycosides' energy-dependent, sometimes irreversible binding, to the cytosolic, membrane-associated bacterial ribosome (image at right). (Aminoglycosides first cross bacterial cell walls— lipopolysaccharide in gram-negative bacteria—and cell membranes, where they are actively transported.) While specific steps in protein synthesis affected may vary somewhat between specific aminoglycoside agents, as can their affinity and degree of binding, aminoglycoside presence in the cytosol generally disturbs peptide elongation at the 30S ribosomal subunit, giving rise to inaccurate mRNA translation and therefore biosynthesis of proteins that are truncated, or bear altered amino acid compositions at particular points. Specifically, binding impairs translational proofreading leading to misreading of the RNA message, premature termination, or both, and so to inaccuracy of the translated protein product. The subset of aberrant proteins that are incorporated into the bacterial cell membrane may then lead to changes in its permeability and then to "further stimulation of aminoglycoside transport". The amino sugar portion of this class of molecules (e.g., the 2-deoxystreptamine in kanamycins, gentamicins, and tobramycin, see above) are implicated in the association of the small molecule with ribosomal structures that lead to the infidelities in translation (ibid.). Inhibition of ribosomal translocation —i.e., movement of the peptidyl-tRNA from the A- to the P-site—has also been suggested. Recent single-molecule tracking experiments in live E. coli showed an ongoing but slower protein synthesis upon treatment with different aminoglycoside drugs. ( Spectinomycin, a related but distinct chemical structure class often discussed with aminoglycosides, does not induce mRNA misreading and is generally not bactericidal.)
What is the suffix for aminoglycosides?
Nomenclature. Aminoglycosides that are derived from bacteria of the Streptomyces genus are named with the suffix -mycin , whereas those that are derived from Micromonospora are named with the suffix -micin.
What is gentamicin used for?
The aminoglycoside gentamicin has been used to treat cystic fibrosis (CF) cells in the laboratory to induce them to grow full-length proteins. CF is caused by a mutation in the gene coding for the cystic fibrosis transmembrane conductance regulator ( CFTR) protein.
What is the name of the molecule that inhibits protein synthesis?
Aminoglycoside. Streptomycin. 2D line-angle representation. Aminoglycoside is a medicinal and bacteriologic category of traditional Gram-negative antibacterial medications that inhibit protein synthesis and contain as a portion of the molecule an amino-modified glycoside ( sugar ).
Which antibiotics are bactericidal against Gram-negative bacteria?
Aminoglycoside antibiotics display bactericidal activity against Gram-negative aerobes and some anaerobic bacilli where resistance has not yet arisen but generally not against Gram-positive and anaerobic Gram-negative bacteria. Streptomycin is the first-in-class aminoglycoside antibiotic.
Is aminoglycoside a pregnancy drug?
Aminoglycosides are in pregnancy category D, that is, there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.
Is aminoglycoside a bactericidal agent?
Aminoglycosides display concentration-dependent bactericidal activity against "most gram-negative aerobic and facultative anaerobic bacilli" but not against gram-negative anaerobes and most gram-positive bacteria. They require only short contact time, and are most effective against susceptible bacterial populations that are rapidly multiplying.
Pharmacology
Traditionally, the antibacterial properties of aminoglycosides were believed to result from inhibition of bacterial protein synthesis through irreversible binding to the 30S bacterial ribosome.
Clinical Uses
Aminoglycosides display bactericidal, concentration-dependent killing action and are active against a wide range of aerobic gram-negative bacilli. They are also active against staphylococci and certain mycobacteria.
Drug Resistance
Most resistance to aminoglycosides is caused by bacterial inactivation by intracellular enzymes. Because of structural differences, amikacin is not inactivated by the common enzymes that inactivate gentamicin and tobramycin.
Drug Interactions and Adverse Effects
Because the body does not metabolize aminoglycosides, aminoglycoside activity is unchanged by induction or inhibition of metabolic enzymes, such as those in the cytochrome P450 system. Certain medications may increase the risk of renal toxicity with aminoglycoside use ( Table 3 ).
Single vs. Multiple Daily Doses
Aminoglycoside antibiotics exhibit rapid concentration-dependent killing action. 5, 11 Increasing concentrations with higher dosages increases both the rate and the extent of bacterial cell death.
Cost
A comparison of the costs of single daily dosing and traditional multiple dosing should include not only the cost of the antibiotic but also the costs of labor, laboratory monitoring and drug toxicity.
