1、,Assoc. Prof. Ivan Lambev e-mail: itlambevmail.bg,NONBETA-LACTAM ANTIBIOTICS,Medical University of Sofia, Faculty of Medicine Department of Pharmacology and Toxicology,-lactams Glycopeptides,Aminoglycosides Tetracyclines Chloramphenicol Macrolides Lincosamides,Rifampicin,Polymyxins,ANTIBIOTICS mecha
2、nism of action,Aminoglycosides have a hexose ring, either streptidine (in streptomycin) or 2-deoxystreptamine (other aminoglycosides), to which various amino sugars are attached by glycosidic linkages. They are water-soluble, stable in solution, and more active at alkaline than at acid pH.,I. AMINOG
3、LYCOSIDES,Streptomycin,Streptomycin is an aminoglycoside antibiotic. Its antibacterial activity is due to it binding to the 30S subunit of the bacterial ribosome and inhibiting of protein synthesis. It has a wide spectrum of anti- bacterial activity but is primarily use to treat mycobacterial infect
4、ions (i.m.). The main problems are eighth nerve toxi-city (vestibulotoxicity more than deaf-ness), nephrotoxicity, allergic reactions.,Gentamicin,Tobramycin,Mechanisms of action,Aminoglycosides are irreversible inhibitors of protein synthesis, but the precise mechanism for bactericidal activity is n
5、ot known. The initial event is passive diffusion via porin channels across the cell wall. Drug is then actively transported across the cell membrane into the cytoplasm. The transmembrane electrochemical gradient supplies the energy for this process. Low extracellular pH and anaerobic conditions inhi
6、bit transport by reducing the gradient. Transport may be enhanced by cell wall-active drugs such as penicillin or vancomycin; this enhancement may be the basis of the synergism of these antibiotics with aminoglycosides.,Inside the cell, aminoglycosides bind to specific 30S-subunit ribosomal proteins
7、. Protein synthesis is inhibited by aminoglycosides in at least three ways:interference with the initiation complex of peptide formation; (2) misreading of mRNA, which causes incorporationof incorrect amino acids into the peptide, resultingin a nonfunctional or toxic protein; (3) breakup of polysome
8、s into nonfunctional monosomes. These activities occur more or less simultaneously, and the overall effect is irrever-sible and lethal for the cell.,Aminoglycosides act bactericidal on dividing and no dividing microorganisms.They are in general activeagainst staphylococciand aerobic Gram-negativeorg
9、anisms including P. aeruginosaand almost all the Enterobacteriaceae.,Clinical uses Aminoglycosides are mostly used against Gram- negative enteric bacteria, especially when the isolate may be drug-resistant and when there is suspicion of sepsis. They are almost always used in combination with a -lact
10、am antibiotic to extend coverage to include potential Gram- positive pathogens and to take advantage of the synergism between these two classes of drugs. Penicillin-aminoglycoside combinations also are used to achieve bactericidal activity in treatment of enterococcal endocarditis and to shorten dur
11、ation of therapy for viridans streptococcal and staphy- lococcal endocarditis.,Amikacin Gentamicin sol. 80 mg/2 ml (80 mg/8 h i.m.) Kanamycin Neomycin - Bivacin spray derm. fl 150 ml(neomycin/bacitracin) - Nemybacin ung. ophth. 2,5 g(neomycin/bacitracin) Streptomycin Tobramycin,Spectinomycin is stru
12、cturally related to aminoglycosides. It lacks amino sugars and glycosides bonds.,Spectinomycin is active against many Gram-positive and Gram-negative organisms, but it is used as an alternative treatment for drug-resistant gonorrhea or gonorrhea in penicillin-allergic patients. Strains of gonococci
13、may be resistant to spectinomycin, but there is no cross-resistance with other drugs. Spectinomycin is rapidly absorbed after i.m. injection. A single dose of 40 mg/kg up to a maximum of 2 g is given. There is pain at the injection site. Nephrotoxicity and anemia have been observed rarely.,Adverse e
14、ffects All aminoglycosides are ototoxic and nephrotoxic. Ototoxicity and nephrotoxicity are more likely to be encountered when therapy is continued for more than 5 days, at higher doses, in the elderly, and in the setting of renal insufficiency. Concurrent use with loop diuretics (eg, furosemide, et
15、hacrynic acid) or other nephrotoxic antimicrobial agents (vancomycin, amphotericin) can potentiate nephro- toxicity and should be avoided. Ototoxicity can manifest as auditory damage, resulting in tinnitus and high-frequency hearing loss initially, or as vestibular damage, evident by vertigo, ataxia
16、, and loss of balance.,Streptomycin and gentamicin are the most vestibulotoxic. Nephrotoxicity results in rising serum creatinine levels or reduced creatinine clearance. Neomycin, kanamycin, and amikacin are the most ototoxic agents. Neomycin, tobramycin, and gentamicin are the most nephrotoxic. In
17、very high doses, aminoglycosides can produce a curare-like effect with neuromuscular blockade that results in respiratory paralysis. This paralysis is usually reversible by calcium gluconate (given promptly) or neostigmine. Hypersensitivity occurs infrequently.,Mechanisms of resistance1. Production
18、of a transferase enzyme or enzymesinactivates the aminoglycoside by adenylylation,acetylation, or phosphorylation. This is the prin-cipal type of resistance encountered clinically. 2. Impaired entry of aminoglycoside into the cell. This may be genotypic, resulting from mutationor phenotypic, resulti
19、ng from growth conditions. 3. The receptor protein on the 30S ribosomal subunit may be deleted or altered as a resultof a mutation.,II. TETRACYCLINES,Tetracyclines enter microorganisms in part by passive diffusion and in part by an energy-dependent process of active transport. Susceptible cells conc
20、entrate the drug intracellularly. Once inside the cell, tetracyclines bind reversibly to the 30S subunit of the bacterial ribosome, blocking the binding of aminoacyl-tRNA to the acceptor site on the mRNA-ribosome complex This prevents addition of amino acids to the growing peptide. Tetracyclines are
21、 broad-spectrum bacteriostatic antibiotics that inhibit protein synthesis.,Tetracyclines are active against many Gram-positive and Gram-negative bacteria, including anaerobes, rickettsiae, chlamydiae, mycoplasmas, and L-forms; and against some protozoa, eg, amebas. The antibacterial activities of mo
22、st tetracyclines are similar except that tetracycline-resistant strains may be susceptible to doxycycline and minocycline, all of which are poor substrates for the efflux pump that mediates resistance. Differences in clinical efficacy for susceptible organisms are minor and attributable largely to f
23、eatures of absorption, distribution, and excretion of individual drugs.,Antimicrobial Activity,Pharmacokinetics Tetracyclines mainly differ in their absorption after oral administration and their elimination. Absorption after oral administration is approximately 6070% for tetracycline, oxytetracycli
24、ne, and methacycline; and 95100% for doxycycline and minocycline. A portion of an orally administered dose of tetracycline remains in the gut lumen, modifies intestinal flora, and is excreted in the feces. Absorption occurs mainly in the upper small intestine and is impaired by food (except doxycycl
25、ine and minocycline); by divalent cations (Ca2+, Mg2+, Fe2+) or Al3+; by dairy products and antacids, which contain multivalent cations; and by alkaline pH.,Tetracyclines are 4080% bound by serum proteins. Tetracyclines are distributed widely to tissues and body fluids except for CSF, where concentr
26、ations are 1025% of those in serum. Minocycline reaches very high concentrations in tears and saliva, which makes it useful for eradication of the meningococcal carrier state. Tetracyclines cross the placenta to reach the fetus and are also excreted in milk. As a result of chelation with calcium, te
27、tracyclines are bound to and damage growing bones and teeth. Carbamazepine, phenytoin, barbiturates, and chronic alcohol ingestion may shorten the half-life of doxycycline 50% by induction of hepatic enzymes that metabolize the drug.,Tetracyclines are excreted mainly in bile and urine. Concentration
28、s in bile exceed those in serum tenfold. Some of the drug excreted in bile is reabsorbed from the intestine (enterohepatic circulation) and may contribute to maintenance of serum levels. From 10 to 50% of various tetracyclines is excreted into the urine, mainly by glomerular filtration. Ten to 40% o
29、f the drug is excreted in feces. Doxycycline, in contrast to other tetracyclines, is eliminated by nonrenal mechanisms, do not accumulate significantly and require no dosage adjustment in renal failure.,Tetracyclines are classified as:short-acting (chlortetracycline, tetracycline, oxytetracycline) b
30、ased on plasma t1/2 of 68 h; (2) intermediate acting (demeclocycline and methacycline) t1/2 12 h; (3) long-acting (doxycycline and minocycline) with plasma t1/2 1618 h.The almost complete absorption and slow excretion of doxycycline and minocycline allow for once-daily dosing.,Clinical UsesA tetracy
31、cline is the drug of choice in infections with M. pneumoniae, chlamydiae, rickettsiae, and some spirochetes. They are used in combination regimens to treat gastric and duodenal ulcer disease caused by H. pylori. They may be used in various Gram-positive and Gram-negative bacterial infections, includ
32、ing Vibrio infections. In cholera, tetracycline resistance has appeared during epidemics.,Tetracyclines remain effective in most chlamydial infections, including sexually transmitted diseases. Tetracyclines are no longer recommended in gonococcal disease because of resistance. A tetracycline usually
33、 in combination with an aminog- lycoside is indicated for plague, tularemia, and bru- cellosis. Tetracyclines are sometimes used in the treatment of protozoal infections, eg, those due to E. histolytica or P. falciparum. Other uses include treatment of acne, exacerbations of bronchitis, community-ac
34、quired pneumonia, Lyme disease, relapsing fever, leptospirosis, and some nontuber- culous mycobacterial infections (eg, M. marinum).,A newly approved tetracycline analog, tigecycline, is a semisynthetic derivative of minocycline. It is poorly absorbed orally and must be administered intravenously (t
35、1/2 36 h).,Many tetracycline-resistant strains are susceptible to tigecycline. Its spectrum is very broad. Coagulase-negative staphylococci and S. aureus, including MRS, vancomycin-intermediate, and vancomycin-resistant strains; streptococci, penicillin-susceptible and resistant; enterococci, includ
36、ing vancomycin-resistant strains; Gram-positive rods; Enterobacteriaceae; multidrug-resistant strains of Acinetobacter spp.; anaerobes, both Gram-positive and Gram-negative; atypical agents, rickettsiae, chlamydia, and legionella; and rapidly growing mycobacteria all are susceptible. Proteus and P.
37、aeruginosa, however, are resistant.,Adverse Reactions Hypersensitivity reactions (drug fever, skin rashes) to tetracyclines are uncommon. Nausea, vomiting, and diarrhea are the most common reasons for disconti- nuing tetracycline medication. These effects are attri- butable to direct local irritatio
38、n of the intestinal tract. Nausea, anorexia, and diarrhea can usually be con- trolled by administering the drug with food or carboxy- methylcellulose, reducing drug dosage, or discont- inuing the drug.,Tetracyclines modify the normal flora, with suppression of susceptible coliform organisms and over
39、growth of pseudomonas, proteus, staphylococci, resistant coliforms, clostridia, and candida. This can result in intestinal functional disturbances, anal pruritus, vaginal or oral candidiasis, or enterocolitis with shock and death. Tetracyclines are readily bound to calcium deposited in newly formed
40、bone or teeth in young children. When a tetracycline is given during pregnancy, it can be deposited in the fetal teeth, leading to fluorescence, discoloration, and enamel dysplasia; it can be deposited in bone, where it may cause deformity or growth inhibition. If the drug is given for long periods
41、to children under 8 years of age, similar changes can result.,Tetracyclines can probably impair hepatic function, especially during pregnancy, in patients with preexisting hepatic insufficiency and when high doses are given intravenously. Hepatic necrosis has been reported with daily doses of 4 g i.
42、v. Renal tubular acidosis and other renal injury resul- ting in nitrogen retention is a conraindication to the administration of outdated tetracycline preparations. Tetracyclines given with diuretics may produce nitrogen retention. Tetracyclines other than doxycycline may accumulate to toxic levels
43、in patients with impaired kidney function.,Intravenous injection can lead to venous thrombosis. Intramuscular injection produces painful local irritation and should be avoided. Systemically administered tetracycline, especially demeclocycline, can induce sensitivity to sunlight or ultraviolet light,
44、 particularly in fair-skinned persons. Dizziness, vertigo, nausea, and vomiting have been noted particularly with doxycycline and Minocycline at high doses.,The main mechanisms of resistance to tetracycline and its analogues are: impaired influx or increased efflux by anactive transport protein pump
45、; (2) ribosome protection due to production of proteins that interfere with tetracycline binding to the ribosome; 3) enzymatic inactivation.,III. CHLORAMPHENICOL,Chloramphenicol and macrolides bind to the 50S subunit and block transpeptidation and protein synthesis. It has bacteriostatic action.,Bec
46、ause of potential toxicity, bacterial resistance, and the availability of many other effective alternatives, chloramphenicol is rarely used. It may be considered for treatment of serious rickettsial infections such as typhus and Rocky Mountain spotted fever. It is an alternative to a beta-lactams fo
47、r treatment of meningococcal meningitis occurring in patients who have major hypersensitivity reactions to penicillin or bacterial meningitis caused by penicillin-resistant strains of pneumococci.,Adverse Reactions of Chloramphenicol Adults occasionally develop nausea, vomiting, and diarrhea. This i
48、s rare in children. Oral or vaginal candidiasis may occur as a result of alteration of normal microbial flora. Chloramphenicol causes a dose-related reversible suppression of red cell production at dosages exceeding 50 mg/kg/d after 12 weeks. Aplastic anaemia, a rare consequence (1 in 24 000 to 40 0
49、00 courses of therapy) of chloramphenicol administration by any route. It tends to be irreversible and can be fatal.,Newborn infants lack an effective glucuronic acid conjugation mechanism for the degradation and detoxification of chloramphenicol. Consequently, when infants are given dosages above 5
50、0 mg/kg/d, the drug may accumulate, resulting in the gray baby syndrome, with vomiting, flaccidity, hypothermia, gray color, shock, and collapse. To avoid this toxic effect, chloramphenicol should be used with caution in infants and the dosage limited to 50 mg/kg/d or less (during the first week of life) in full-term infants. Chloramphenicol inhibits hepatic microsomal enzymes that metabolize phenytoin and warfarin.,
