Aminoglycoside

Streptomycin

Streptomycin is an antibiotic drug, the first of a class of drugs called aminoglycosides to be discovered, and was the first antibiotic remedy for tuberculosis. It is derived from the actinobacterium Streptomyces griseus. Streptomycin stops bacterial growth by damaging cell membranes and inhibiting protein synthesis. Specifically, it binds to the 23S rRNA molecule of the bacterial ribosome, which prevents the release of the growing protein (polypeptide chain). Humans have structurally different ribosomes than bacteria, thereby allowing the selectivity of this antibiotic for bacteria. Streptomycin cannot be given orally, but must be administered by regular intramuscular injection. An adverse effect of this medicine is ototoxicity. It can result in permanent hearing loss.

History

It was first isolated on October 19, 1943 in the laboratory of Selman Abraham Waksman at Rutgers University by Albert Schatz, a graduate student in his laboratory. Waksman and his laboratory discovered several antibiotics, including actinomycin, clavacin, streptothricin, streptomycin, grisein, neomycin, fradicin, candicidin, candidin, and others. Two of these, streptomycin and neomycin, found extensive application in the treatment of numerous infectious diseases. Streptomycin was the first antibiotic that could be used to cure the disease tuberculosis. Waksman is credited with having coined the term antibiotics.

The details and credit for the discovery of streptomycin were strongly contested by Albert Schatz and resulted in litigation. The contention arose because Schatz was the graduate student in charge of performing the lab work on streptomycin; however, it was argued that he was using techniques, equipment and lab space of Waksman's while under Waksman's direction. There is contention as to whether or not Schatz should have been included in the Nobel Prize awarded in 1952. However, the committee stated that the Nobel Prize was awarded not only for the discovery of streptomycin but also for the development of the methods and techniques that led up to its discovery and the discovery of many other antibiotics. The litigation ended with a settlement for Schatz and the official decision that Waksman and Schatz would be considered co-discoverers of streptomycin. Schatz was awarded the Rutgers medal in 1994, at the age of 74. The controversy ultimately had a negative impact on the careers of both Waksman and Schatz and the controversy continues today.

Uses : Tuberculosis in combination with other anti-TB drugs

Overview

Aminoglycosides are a group of antibiotics that are effective against certain types of bacteria. They include amikacin, gentamicin, kanamycin, neomycin, netilmicin, paromomycin, streptomycin, tobramycin and apramycin. Those which are derived from Streptomyces species are named with the suffix -mycin, while those which are derived from micromonospora are named with the suffix -micin.

Mechanism of action

Aminoglycosides work by binding to the bacterial 30S ribosomal subunit (some work by binding to the 50s subunit), inhibiting the translocation of the peptidyl-tRNA from the A-site to the P-site and also causing misreading of mRNA, leaving the bacterium unable to synthesize proteins vital to its growth. But their exact mechanism of action is not fully known.Aminoglycosides are potent bactericidal antibiotics that act by creating fissures in the outer membrane of the bacterial cell. They are particularly active against aerobic, gram-negative bacteria and act synergistically against certain gram-positive organisms. Gentamicin is the most commonly used aminoglycoside, but amikacin may be particularly effective against resistant organisms. Aminoglycosides are used in the treatment of severe infections of the abdomen and urinary tract, as well as bacteremia and endocarditis. They are also used for prophylaxis, especially against endocarditis. Resistance is rare but increasing in frequency. Avoiding prolonged use, volume depletion and concomitant administration of other potentially nephrotoxic agents decreases the risk of toxicity. Single daily dosing of aminoglycosides is possible because of their rapid concentration-dependent killing and post-antibiotic effect and has the potential for decreased toxicity. Single daily dosing of aminoglycosides appears to be safe, efficacious and cost effective. In certain clinical situations, such as patients with endocarditis or pediatric patients, traditional multiple dosing is still usually recommended.

Spectrum of activity

Aminoglycosides are useful primarily in infections involving aerobic, Gram-negative bacteria, such as Pseudomonas, Acinetobacter, and Enterobacter. In addition, some mycobacteria, including the bacteria that cause tuberculosis, are susceptible to aminoglycosides. The most frequent use of aminoglycosides is empiric therapy for serious infections such as septicemia, complicated intraabdominal infections, complicated urinary tract infections, and nosocomial respiratory tract infections. Usually, once cultures of the causal organism are grown and their susceptibilities tested, aminoglycosides are discontinued in favor of less toxic antibiotics.

Streptomycin was the first effective drug in the treatment of tuberculosis, though the role of aminoglycosides such as streptomycin and amikacin has been eclipsed (because of their toxicity and inconvenient route of administration) except for multiple drug resistant strains.

Infections caused by Gram-positive bacteria can also be treated with aminoglycosides, but other types of antibiotics are more potent and less damaging to the host. In the past the aminoglycosides have been used in conjunction with beta-lactam antibiotics in streptococcal infections for their synergistic effects, particularly in endocarditis. One of the most frequent combinations is Ampicillin (a beta-lactam, or penicillin-related antibiotic) and Gentamicin. Often, hospital staff refer to this combination as "amp and gent" or more recently called "pen and gent" for penicillin and gentamycin.

Aminoglycosides are mostly ineffective against anaerobic bacteria, fungi and viruses.

Toxicity

Because of their potential for Ototoxicity and Nephrotoxicity (kidney toxicity), aminoglycosides are administered in doses based on body weight. Blood drug levels and Creatinine are monitored during the course of therapy. Serum creatinine measurements are used to estimate how well the kidneys are functioning and as a marker for kidney damage caused by these drugs.

Routes of administration

Since they are not absorbed from the gut, they are administered intravenously and intramuscularly. Some are used in topical preparations for wounds. Oral administration can be used for gut decontamination (e.g. in hepatic encephalopathy).

Specific Agents

 Amikacin (Amikin®), Gentamicin (Garamycin®), Kanamycin (Kantrex®), Neomycin, Netilmicin (Netromycin®), Streptomycin, Tobramycin (Nebcin®)

The first aminoglycoside, streptomycin, was isolated from Streptomyces griseus in 1943. Neomycin, isolated from Streptomyces fradiae, had better activity than streptomycin against aerobic gram-negative bacilli but, because of its formidable toxicity, could not safely be used systemically. Gentamicin, isolated from Micromonospora in 1963, was a breakthrough in the treatment of gram-negative bacillary infections, including those caused by Pseudomonas aeruginosa. Other aminoglycosides were subsequently developed, including amikacin (Amikin), netilmicin (Netromycin) and tobramycin (Nebcin), which are all currently available for systemic use


Amikacin

Amikacin is an aminoglycoside antibiotic used to treat different types of bacterial infections. Amikacin works by binding to the bacterial 30S ribosomal subunit, causing misreading of mRNA and leaving the bacterium unable to synthesize proteins vital to its growth.Amikacin may be administered once or twice a day but must be given by the intravenous or intramuscular route. There is no oral form available. Dosage must be adjusted in people with kidney failure.Amikacin is most often used for treating severe, hospital-acquired infections with multidrug resistant Gram negative bacteria such as Pseudomonas aeruginosa, Acinetobacter, and Enterobacter. Amikacin may be combined with a beta-lactam antibiotic for empiric therapy for people with neutropenia and fever.Side effects of amikacin are similar to other aminoglycosides. Kidney damage and hearing loss are the most important effects. Because of this potential, blood levels of the drug and markers of kidney function (creatinine) may be monitored.

Gentamicin

Gentamicin (also gentamycin) is an aminoglycoside antibiotic, and can treat many different types of bacterial infections, particularly Gram-negative infection. However, gentamicin is not used for Neisseria gonorrheae, Neisseria meningitidis or Legionella pneumophila infections.Gentamicin works by binding to a site on the bacterial ribosome, causing the genetic code to be misread.Like all aminoglycosides, when gentamicin is given orally, it is not effective. This is because it is absorbed from the small intestine, and then travels through the portal vein to the liver, where it is inactivated. Therefore, it can only be given intravenously, intramuscularly or topically.E. Coli has shown some resistance to gentamicin, despite being Gram-negative.

Side effects

Gentamicin can cause deafness or a loss of equilibrioception in genetically susceptible individuals. These individuals have a normally harmless mutation in their DNA, that allows the gentamicin to affect their cells. The cells of the ear are particularly sensitive to this. It is sometimes used intentionally for this purpose in severe Ménière’s disease, to disable the vestibular apparatus.Gentamicin can also be highly nephrotoxic, particularly if multiple doses accumulate over a course of treatment. For this reason gentamicin is usually dosed by body weight. Various formulae exist for calculating gentamicin dosage. Also serum levels of gentamicin are monitored during treatment.

Kanamycin

Kanamycin (marketed under the brand name Kantrex®) is an aminoglycoside antibiotic, available in both oral and intravenous forms, and used to treat a wide variety of infections.

Pharmacology

Kanamycin works by affecting an unknown aspect of translocation (part of the translation process in which the mRNA is shifted one codon in relation to the ribosome), and by causing messenger RNA (mRNA) to be misread by the ribosome, causing a lethal level of translational errors.

Side effects

Common side effects include changes in hearing (either hearing loss or ringing in the ears), toxicity to kidneys, and allergic reactions to the drug.

Neomycin

Neomycin is an aminoglycoside antibiotic that is found in many topical medications such as creams, ointments and eyedrops.

Uses

Neomycin is overwhelmingly used as a topical preparation. It can also be given orally, where it is usually combined with other antibiotics. Neomycin is not absorbed from the gastrointestinal tract, and has been used as a preventative measure for hepatic encephalopathy and hypercholesterolemia. By killing bacteria in the intestinal tract, it keeps ammonia levels low and prevents hepatic encephalopathy, especially prior to GI surgery. It is not given intravenously, as neomycin is extremely nephrotoxic (causes kidney damage), especially compared to other aminoglycosides. The exception to this, is when it is included in some vaccines as a preservative, but in very small quantities -typically 0.025 mg per dose

Spectrum

Similar to other aminoglycosides, neomycin has excellent activity against Gram negative bacteria, and has partial activity against Gram positive bacteria. It is relatively toxic to humans, and some people have allergic reactions to it. See: Hypersensitivity.Neomycin is used in the laboratory on agar plates to grow mutant forms of bacteria that carry genes for resistance to neomycin. The resistant genes to neomycin are found within the plasmid of the bacteria; which may or may not be incorporated into the bacteria's circular chromosome.

History

Neomycin was discovered in 1949 by the microbiologist Selman Waksman and his student Hubert Lechevalier. It is produced naturally by the bacterium Streptomyces fradiae

Netilmicin

Netilmicin is an aminoglycoside antibiotic.An aminoglycoside antibiotic active against most Gram-negative and some Gram-positive bacteria, including many gentamycin-resistant strains. The antibiotic enters the cell through a porin channel and binds to the 30S ribosomal subunit, causing misreading of mRNA.

The use of Netilmicin

Twenty patients with a variety of serious or difficult infections and 5 additional orthopaedic patients with clinical evidence of post-operative wound infection were treated with netilmicin. The results indicate that twice daily dosage with 150 mg intramuscularly, either alone or in combination with other antibiotic therapy, was highly effective. Overall, 25 (96%) infections responded clinically and 19 (73%) were improved bacteriologically. There was no evidence of ototoxicity: a number of patients had impaired renal function which developed during therapy, but all returned to normal or pre-treatment levels by the time that treatment was completed, despite the fact that 15 patients were receiving diuretics. It is suggested in view of its effectiveness, more predictable serum levels after standard dosage and apparent lack of toxicity, that netilmicin should be considered as the first choice aminoglycoside antibiotic instead of gentamicin.


Tobramycin

Tobramycin sulfate is an aminoglycoside antibiotic used to treat various types of bacterial infections, particularly Gram-negative infections.

Mechanism of action

Tobramycin works by binding to a site on the bacterial ribosome, causing the genetic code to be misread.

Administration

Like all aminoglycosides, tobramycin does not pass the gastro-intestinal tract, so for systemic use it can only be given intravenously or intramuscularly. This formulation for injection is branded Nebcin®. Patients with cystic fibrosis will often take an inhalational form (Tobi®) for suppression of Pseudomonas aeruginosa infections. Tobramycin is also combined with dexamethasone as an ophthalmic solution (TobraDex®).Bausch & Lomb Pharmaceuticals, Inc. makes a sterile Tobramycin Ophthalmic Solution (eye-drops) with a tobramycin concentration of 0.3%, which is available by prescription only in the United States. Though in some countries such as Italy it is over the counter. It is mixed with 0.01% benzalkonium chloride as a preservative. These concentrations result in 3 mg per ml and 0.1 mg per ml, respectively.

Side effects

Like other aminoglycosides, tobramycin can cause deafness or a loss of equilibrioception in genetically susceptible individuals. These individuals have a normally harmless mutation in their DNA, that allows the tobramycin to affect their cells. The cells of the ear are particularly sensitive to this.Tobramycin can also be highly toxic to the kidneys, particularly if multiple doses accumulate over a course of treatment.For these reasons, when tobramycin is given parenterally, it is usually dosed by body weight. Various formulae exist for calculating tobramycin dosage. Also serum levels of tobramycin are monitored during treatment.

Apramycin

The novel aminoglycoside antibiotic apramycin is shown to be a potent inhibitor of protein synthesis in bacteria both in vivo and in vitro. In cell-free systems from Escherichia coli programmed with poly(U), apramycin induces translation errors, as assayed by incorporation of leucine, isoleucine and serine, although this effect occurs only to a limited extent. Apramycin inhibits the translocation step of protein synthesis both in vivo, in protoplasts of Bacillus megaterium, and in vitro, in cell-free systems from E. coli. It is proposed that this is the primary inhibitory effect of the drug.

Paromomycin

Paromomycin sulfate (brand name Humatin) is a drug that fights intestinal amoeba infection, or amebiasis and a drug being developed to cure visceral leishmaniasis in India. Paromomycin was granted orphan drug status in 2005. It inhibits protein synthesis by binding to 16S ribosomal RNA. It is approved by the Drug Controller General of India against visceral leishmaniasis.
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