Aminoglycosides
Commonly used aminoglycosides include gentamicin, tobramycin, and amikacin. Aminoglycosides are bactericidal drugs especially useful against many gram-negative rods. Certain aminoglycosides are used against other organisms (e.g., streptomycin is used in the therapy of MDR tuberculosis, and gentamicin is used in combination with penicillin G against enterococci). Aminoglycosides are named for the amino sugar component of the molecule, which is connected by a glycosidic linkage to other sugar derivatives (Figure 1).
Fig1. Aminoglycosides. Aminoglycosides consist of amino sugars joined by a glycosidic linkage. The structure of gentamicin is shown.
The two important modes of action of aminoglycosides have been documented best for streptomycin; other aminoglycosides probably act similarly. Both inhibition of the initiation com plex and misreading of messenger RNA (mRNA) occur; the former is likely more important for the bactericidal activity of the drug. An initiation complex composed of a streptomycin treated 30S subunit, a 50S subunit, and mRNA will not function; that is, no peptide bonds are formed, no polysomes are made, and a frozen “streptomycin monosome” results. Misreading of the triplet codon of mRNA so that the wrong amino acid is inserted into the protein also occurs in streptomycin-treated bacteria. The site of action on the 30S subunit includes both a ribosomal protein and the ribosomal RNA (rRNA). As a result of inhibition of initiation and misreading, membrane damage occurs and the bacterium dies. Aminoglycosides also inhibit ribozyme-mediated self-splicing of rRNA, which may contribute to its inhibitory activity.
Aminoglycosides have certain limitations in their use: (1) They have a toxic effect both on the kidneys and on the auditory and vestibular portions of the eighth cranial nerve. To avoid toxicity, serum levels of the drug, blood urea nitrogen, and creatinine should be measured. (2) They are poorly absorbed from the gastrointestinal tract and cannot be given orally. (3) They penetrate the spinal fluid poorly and must be given intrathecally in the treatment of meningitis. (4) They are ineffective against anaerobes because their transport into the bacterial cell requires oxygen.
Tetracyclines
Tetracyclines are a family of antibiotics with bacteriostatic activity against a variety of gram-positive and gram-negative bacteria, Mycoplasma, Chlamydiae, and Rickettsiae. They inhibit protein synthesis by blocking the aminoacyl transfer RNA (tRNA) from entering the acceptor site on the 30S ribosomal subunit. However, the selective action of tetracycline on bacteria is not at the level of the ribosome, because tetracycline in vitro will inhibit protein synthesis equally well in purified ribosomes from both bacterial and human cells. Selectivity is based on its greatly increased uptake into susceptible bacterial cells compared with human cells.
Tetracyclines, as the name indicates, have four cyclic rings with different substituents at the three R groups (Figure 2). The various tetracyclines (e.g., doxycycline, minocycline, and oxytetracycline) have similar antimicrobial activity but different pharmacologic properties. In general, tetracyclines have low toxicity but are associated with some important side effects.
(1) They can lead to brown staining of the teeth of fetuses and young children as a result of deposition of the drug in developing teeth; tetracyclines are avid calcium chelators. For this reason, tetracyclines are contraindicated for use in pregnant patients and in children younger than 8 years of age.
(2) Photosensitivity (rash upon exposure to sunlight) is a common side effect.
(3) Esophageal irritation can occur, so it is advised to drink fluid and not lay down immediately after taking these medications.
(4) Tetracyclines also chelate iron, and so products containing iron, such as iron-containing vitamins, should not be taken during therapy with tetracyclines.
(5) Like other antibiotics, they can suppress the normal flora of the intestinal tract, which can lead to diarrhea and over growth by drug-resistant bacteria and fungi. Second is that sup pression of Lactobacillus in the vaginal normal flora results in a rise in pH, which allows Candida albicans to grow and cause vaginitis.
Fig2. Tetracycline structure. The four-ring structure is depicted with its three R sites. Chlortetracycline, for example, has R = Cl, R1 = CH3, and R2 = H.
Tigecycline (Tygacil) is the first clinically available member of the glycylcycline class of antibiotics. They have a structure similar to tetracyclines and have the same mechanism of action as tetracyclines and have a similar range of adverse effects. Tigecycline is used to treat skin and skin structure infections caused by S. aureus, group A and group B streptococci, VRE, E. coli, and Bacteroides fragilis. It is also used to treat complicated intraabdominal infections caused by a variety of facultative and anaerobic bacteria. In 2018, the FDA approved eravacycline, a drug closely related to tigecycline, for the treatment of complicated intraabdominal infections.
Also in 2018, the FDA approved omadacycline for the treatment of acute bacterial skin and soft tissue infections and community-acquired bacterial pneumonia. Omadacycline is a new-generation tetracycline that is effective against gram positive cocci, for example, S. aureus, enterococci, as well as S. pneumoniae. It is also effective against Haemophilus influenzae, E. coli, Legionella, and Mycoplasma. It is less prone to various bacterial resistance mechanisms than many other tetracyclines.
