Aminoglycosides and Nephrotoxicity
Medications that contain aminoglycosides are traditional Gram-negative antibacterial agents. They inhibit protein synthesis. They are also used to treat diarrhea and gout. Some of the common aminoglycosides are naftifine, aztreonam, tetracyclines, and sulfonamides. They are used to treat a wide variety of infections including urinary tract infections, pneumonia, and gonorrhea.
Resistance to b-lactam and fluoroquinolones
Despite the use of fluoroquinolones and beta-lactam antibiotics in the treatment of gonorrhea, resistance to these two antibiotics has increased. There is a need to identify mutations that contribute to resistance so that the antimicrobials can be used effectively.
Resistance to beta-lactam antibiotics occurs due to the alteration of the target enzymes that control drug entry. For example, mutations in gyrA increase resistance. In addition, mutations in marR inactivate the genes that decrease the translation of the ompF and tolC enzymes. Alternatively, bacteria may evade antibiotics by producing beta-lactamases. The production of ESBL is considered the main mechanism of resistance to b-lactams.
The presence of a plasmid, called Qnr, contributes to the alarming increase in resistance to quinolones. The plasmids have been found in Europe and East Asia. These plasmids contain genes that encode the enzymes that modify the fluoroquinolones.
Resistance mutations in the quinolone-resistance-determining region involve amino acid substitutions that alter the target enzymes. Several genes are involved, and mutations are usually selected first in the most susceptible target. The mutations affect the drug affinity. They also affect drug accumulation. The most common mutations are in gyrA, which decreases the activity of DNA gyrase in gram-negative organisms. Likewise, mutations in marR, which inactivate the acrAB enzyme, increase the activity of the pump.
Resistance to fluoroquinolones is often associated with clinical failure. However, a combination of antibiotics may be beneficial in patients with gram-negative bacilli. These antibiotics are associated with a decreased 28-day mortality in patients with bacteremia due to gram-negative bacteria.
These results suggest that the combination of fluoroquinolones and b-lactams may provide better outcomes in patients with gram-negative bacilli. However, further studies are necessary before combination therapy can be used routinely.
Nephrotoxicity
During the last decade, aminoglycosides have attracted considerable attention for their potential to cause nephrotoxicity. The aim of this minireview is to identify strategies for the safer use of these agents.
A number of clinical trials have been conducted to determine the safety of single daily dose aminoglycosides. However, most of these studies have failed to show real benefits. This review will focus on methods for prospective assessment of nephrotoxicity and will also consider some of the factors that contribute to risk.
The major risk factors for nephrotoxicity of aminoglycosides are patients with pre-existing renal disease and older patients. In addition, patients with severe obesity, hypokalemia, and dehydration are at high risk for nephrotoxicity.
The main cause of nephrotoxicity of aminoglycosides is the presence of cell necrosis. The underlying mechanism is not well understood. It has been suggested that lysosomal alterations lead to cell death. However, it is also possible that cell death is caused by lipid peroxidation.
The rate-limiting binding of polycationic antibiotics occurs at phosphoinositol-binding sites on the brush border of proximal tubular cells. Once a phosphoinositol binding site is found, an additional fraction of the drug enters proximal tubular cells through the basolateral cell transport system.
However, once the concentration reaches a clinically relevant range, saturation occurs. In addition, a small fraction of the drug is reabsorbed in the proximal tubule. This process is thought to contribute to the decline in the glomerular filtration rate.
A single daily dosing of aminoglycosides has been shown to reduce nephrotoxicity. Several randomized comparative clinical studies have been conducted to examine the effectiveness of single daily aminoglycosides. However, the role of individual aminoglycoside selection has not been clearly assessed during once-daily regimens.
Ototoxicity
During treatment for tuberculosis, aminoglycoside antibiotics can cause ototoxicity. This is a severe side effect. It can result in permanent hearing loss.
Aminoglycoside antibiotics are widely used in the world. They are effective against gram-negative bacterial infections. They are also used for chemotherapy. They are considered reversible but they have the potential to cause irreversible ototoxicity.
Aminoglycosides penetrate all cell types of the inner ear. They affect the hair cells in the base of the cochlea. They also affect the mesenchymal cells beneath the basilar membrane. They may also affect the balance system. They may also cause tooth discoloration.
Aminoglycosides are excreted through the kidneys. The rate of excretion of aminoglycosides is inversely proportional to renal function. Therefore, it is important to adjust dosages to compensate for delayed excretion.
Aminoglycosides have been reported to cause ototoxicity in utero. The mechanism is not yet clear, but it may be associated with selective tissue penetration. It is thought that the loss of balance or hearing can be explained by an effect on the brain.
The effect of aminoglycosides on hearing may be permanent and affect the patient’s quality of life. This can be prevented by using antioxidants. It is also important to understand that the ototoxic effects of aminoglycosides are due to free radicals. The role of antioxidants is to counteract the effects of free radicals. They can also delay cell death.
Several studies have shown that the ototoxic effects of aminoglycosides can be prevented by using anti-free radical agents. These agents can block ROS as cell signaling molecules. However, they can also cause problems in long-term treatment. These effects can also be prevented by using chelators.
Neuromuscular blockade and hypersensitivity reactions
Several clinical conditions require the neuromuscular blocking effects of aminoglycosides, but certain agents have been associated with harmful side effects. These include ototoxicity, exacerbation of muscle weakness, and nephrotoxicity. These reactions can lead to death.
The neuromuscular junction is a synapse that allows the transfer of nerve impulses. In a normal neuromuscular junction, the neuron stores the neurotransmitter acetylcholine (ACh). This neurotransmitter is released by the presynaptic neuron to stimulate the muscle fiber. The neuromuscular junction is also the site where the motor neuron communicates with the skeletal muscle fiber.
There are two types of neuromuscular blocking agents: depolarizing and non-depolarizing. Depolarizing agents act directly on the NMJ, causing paralysis of the muscle. Nondepolarizing agents block the acetylcholine response to the NMJ.
The effects of aminoglycosides on the ear include ototoxicity and hearing loss. Aminoglycosides enter the inner ear rapidly and dissipate slowly. Some patients may have genetic mutations that predispose them to ototoxicity.
Pregnancy is an important risk factor for fetal harm. It is important to inform pregnant patients about the risk of fetal harm from aminoglycosides. It is also recommended that they not be given ZEMDRI during pregnancy.
Aminoglycosides are associated with nephrotoxicity, renal disease, and hypersensitivity reactions. The renal effects of aminoglycosides are usually reversible. However, the risk of nephrotoxicity may increase with the use of concomitant nephrotoxic agents. Other risk factors include old age, renal impairment, and the presence of concomitant neuromuscular blocking agents.
Patients should be educated about the potential for interactions between aminoglycosides and neuromuscular blocking agents. Combined pre and postoperative testing should be performed to detect hypersensitivity reactions. In addition, it is important to monitor for signs of toxicity, including dizziness, nausea, stridor, flushing, and low blood pressure.
Pharmacokinetics
Several studies have focused on the pharmacokinetics of aminoglycosides. These studies have aimed to identify the most effective dosing regimens and the pharmacokinetics of aminoglycosides in patients with varying body sizes. In addition, they have also studied the interaction of aminoglycosides with the plasma membrane and the effect of acidic conditions on the bactericidal activity of aminoglycosides.
Several studies have shown that the distribution of aminoglycosides in the human body is highly variable. The distribution of aminoglycosides is highly dependent on a number of factors, including age, gender, and body water content. Moreover, there is also a nonlinear relationship between cumulative exposure and toxicity.
Aminoglycosides are highly polar cationic molecules. They are highly effective antimicrobial agents against gram-negative bacilli. Their activity is pH-dependent, and the optimum pH for antibacterial activity is between six and eight. They disrupt the outer membrane of bacteria, causing its collapse and destabilizing cell wall integrity.
The interaction of aminoglycosides with plasma membranes also affects electrolyte balance and the permeability of the membrane. Moreover, the bactericidal action of aminoglycosides is enhanced at low pH, and the bactericidal activity of aminoglycosides is less effective at high pH.
The pharmacokinetics of aminoglycosides is mainly determined by the serum half-life, volume of distribution, and clearance. These parameters are critical to the successful treatment of gram-negative bacterial infections. They should be monitored in order to minimize the risks of aminoglycoside therapy.
The pharmacokinetics of aminoglycosides vary significantly in neonates. This phenomenon is related to the high occurrence of bacterial infections in this population. Moreover, a high incidence of neonatal sepsis necessitates antibiotic therapy early in life. Several studies have suggested that the pharmacokinetics of aminoglycosides may be altered by sepsis.
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