Tigecycline (Tygacil) is a first-in-class (a glycylcycline) intravenous antibiotic that was designed to circumvent many important bacterial resistance mechanisms. It is not affected by resistance mechanisms such as ribosomal protection, efflux pumps, target site modifications, S-lactamases, or DNA gyrase mutations. Tigecycline binds to the 30S ribosomal subunit and blocks peptide synthesis. The glycylcyclines bind to the ribosome with five times the affinity of common tetracyclines. Tigecycline also possesses a novel mechanism of action, interfering with the mechanism of ribosomal protection proteins. Tigecycline, unlike common tetracyclines, is not expelled from the bacterial cell by efflux pumping processes.
Tigecycline is recommended for the treatment of complicated skin and skin structure infections caused by E. coli, E. faecalis (vancomycin-susceptible isolates), S. aureus (methicillin-susceptible and methicillin-resistant isolates), S. pyogenes, and B. fragilis among others. Tigecycline is also indicated for complicated intra-abdominal infections caused by strains of Clostridium, Enterobacter, Klebsiella, and Bacteroides. To reduce the development of resistance to tigecycline, it is recommended that this antibiotic be used only for those infections caused by proven susceptible bacteria.
Glycylcyclines are structurally similar to tetracyclines, and appear to have similar adverse effects. These may include photosensitivity, pancreatitis, and pseudotumor cerebri. Nausea and vomiting have been reported.
Azactam (aztreonam for injection, intravenous or intramas-cular) contains the active ingredient aztreonam, which is a member of the monobactam class of antibiotics. A true antibiotic, aztreonam was originally isolated from cultures of the bacterium Chromobacterium violaceum. Now, the antibiotic is prepared by total synthesis. Monobactams possess a unique monocyclic jS-lactam nucleus, and are structurally unlike other S-lactams like the penicillins, cephalosporins, carbapenems, and cephamycins. The jS-lactam arrangement of aztreonam is unique, possessing an ^-sulfonic acid functionality. This group activates the jS-lactam ring toward attack. The side chain (3-position) aminothiazolyl oxime moiety and the 4-methyl group specify the antibacterial spectrum and jS-lactamase resistance.
The mechanism of action of aztreonam is essentially identical to that of other jS-lactam antibiotics. The action of aztreonam is inhibition of cell wall biosynthesis resulting from a high affinity of the antibiotic for penicillin binding protein 3 (PBP-3). Unlike other jS-lactam antibiotics, aztreonam does not induce bacterial synthesis of jS-lactamases. The structure of aztreonam confers resistance to hydrolysis by penicillinases and cephalosporinases synthesized by most Gramnegative and Gram-positive pathogens. Because of these properties, aztreonam is typically active against Gram-negative aerobic microorganisms that resist antibiotics hydrolyzed by jS-lactamases. Aztreonam is active against strains that are multiply-resistant to antibiotics such as cephalosporins, penicillins, and aminoglycosides. The antibacterial activity is maintained over a broad pH range (6-8) in vitro, as well as in the presence of human serum and under anaerobic conditions.
Aztreonam for injection is indicated for the treatment of infections caused by susceptible Gram-negative microorganism, such as urinary tract infections (complicated and uncomplicated), including pyelonephritis and cystitis (initial and recurrent) caused by E. coli, K. pneumoniae, P. mirabilis, P. aeruginosa, E. cloacae, K. oxytoca, Citrobacter sp., and S. marcescens. Aztreonam is also indicated for lower respiratory tract infections, including pneumonia and bronchitis caused by E. coli, K. pneumoniae, P. aeruginosa, H. influenzae, P. mirabilis, S. marcescens, and Enterobacter species. Aztreonam is also indicated for septicemia caused by E. coli, K. pneumoniae, P. aeruginosa, P. mirabilis, S. marcescens, and Enterobacter spp. Other infections responding to aztreonam include skin and skin structure infections, including those associated with postoperative wounds and ulcers and burns. These may be caused by E. coli, P. mirabilis, S. marcescens, Enterobacter species, P. aeruginosa, K. pneumoniae, and Citrobacter species. Intra-abdominal infections, including peritonitis caused by E. coli, Klebsiella species including K. pneumoniae, Enterobacter species including E. cloacae, P. aeruginosa, Citrobacter species including C. freundii, and Serratia species including S. marcescens. Some gynecologic infections, including endometritis and pelvic cellulitis caused by E. coli, K. pneumoniae, Enterobacter species including E. cloacae, and P. mirabilis also respond to aztreonam.
Ertapenem (Invanz, for injection) is a synthetic 1-ß-methyl carbapenem that is structurally related to ß-lactam antibiotics, particularly the thienamycin group. Its mechanism of action is the same as that of other ß-lactam antibiotics. The structure resists ß-lactamases and dehydropeptidases.
Ertapenem is indicated for the treatment of moderate to severe infections caused by susceptible strains causing complicated intra-abdominal infections such as Escherichia, Clostridium, Peptostreptococcus, and Bacteroides. The antibiotic is also indicated for complicated skin and skin structure infections including diabetic foot infections (without osteomyelitis). Treatable strains include Staphylococcus (MSSA), Streptococcus, Escherichia, Klebsiella, Proteus, and Bacteroides. Ertapenem is also indicated for community-acquired pneumonia caused by S. pneumoniae, Haemophilus infljuenzae, and M. catarrhalis. Complicated urinary tract infections and acute pelvic infections round out the indications for ertapenem.
Telithromycin (Ketek) is an orally bioavailable macrolide. The antibiotic is semisynthetic. Telithromycin is classified as a ketolide, and it differs chemically from the macrolide group of antibacterials by the lack of a-l-cladinose at 3-position of the erythronolide A ring, resulting in a 3-keto function. It is further characterized by imidazolyl and pyridyl rings inked to the macrolide nucleus through a butyl chain. The mechanism of action of telithromycin is the same as that of the macrolide class.
Telithromycin causes a blockade of protein synthesis by binding to domains II and V of 23S rRNA of the 50S ribo-somal subunit. Because telithromycin binds at domain II, activity against Gram-positive cocci is retained in the presence of resistance mediated by methylases that alter the domain V binding site. The antibiotic is also believed to inhibit the assembly of ribosomes. Resistance to telithromycin occurs because of riboprotein mutations.
Telithromycin is active against aerobic Gram-positive microorganisms such as S. pneumoniae (including mul-tidrug-resistant isolates), aerobic Gram-negative organisms such as H. influenzae and M. catarrhalis, and M. pneumoniae. Ketek is recommended for use in patients 18 years of age or older.
Telithromycin is metabolized by cytochrome P450. It therefore possesses several drug-drug interactions because of its ability to interact with various P450 isoforms. CYP3A4 inhibitors such as itraconazole caused the Cmax of telithromycin to increase by 22% and the area under the curve (AUC) to increase by 54%. Ketoconazole and grapefruit juice demonstrated similar patterns. CYP3A4 substrates such as cisapride caused a dramatic increase in
telithromycin plasma concentration. Simvastatin and midazolam also demonstrated increases in AUC when telithromycin was added. CYP2D6 substrates showed no effect on drug kinetics when administered with telithromycin. Other drug-drug interactions with telithromycin include digoxin (plasma peak and trough levels increased by 73% and 21%, respectively), theophylline (16% and 17% in steady-state Cmax and AUC, respectively), and some oral contraceptives.
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