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1、Assoc.Prof.Ivan Lambeve-mail:NONBETA-LACTAMANTIBIOTICSMedical University of Sofia,Faculty of MedicineDepartment of Pharmacology and Toxicology-lactamsGlycopeptidesAminoglycosidesTetracyclinesChloramphenicolMacrolidesLincosamidesRifampicinPolymyxinsANTIBIOTICS mechanism of actionAminoglycosides have
2、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.AMINOGLYCOSIDESStreptomycinGentamicinTobramycinMecha
3、nisms of actionAminoglycosides are irreversible inhibitors of proteinsynthesis,but the precise mechanism for bactericidalactivity is not known.The initial event is passive diffusionvia porin channels across the cell wall.Drug isthen actively transported across the cell membrane intothe cytoplasm.The
4、 transmembrane electrochemical gradient supplies the energy for this process.Low extracellular pH and anaerobic conditions inhibit 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 synergis
5、m of these antibiotics with aminoglycosides.Inside the cell,aminoglycosides bind to specific 30S-subunit ribosomal proteins.Protein synthesisis inhibited by aminoglycosides in at least three ways:(1)interference with the initiation complex(2)of peptide formation;(3)(2)misreading of mRNA,which causes
6、 incorporation(4)of incorrect amino acids into the peptide,resulting(5)in a nonfunctional or toxic protein;(6)(3)breakup of polysomes into nonfunctional(7)monosomes.These activities occur more or less(8)simultaneously,and the overall effect is irrever-(9)sible and lethal for the cell.Aminoglycosides
7、 act bactericidal on dividing and no dividing microorganisms.They are in general active against staphylococci and aerobic Gram-negative organisms including P.aeruginosa and almost all the Enterobacteriaceae.Clinical usesAminoglycosides are mostly used against Gram-negative enteric bacteria,especiall
8、y when the isolate may be drug-resistant and when there is suspicion of sepsis.They are almost always used in combination with a-lactam antibiotic to extend coverage to include potential Gram-positive pathogens and to take advantage of the synergism between these two classes of drugs.Penicillin-amin
9、oglycoside combinations also areused to achieve bactericidal activity in treatment of enterococcal endocarditis and to shorten duration of therapy for viridans streptococcal and staphy-lococcal endocarditis.Spectinomycin is structurally relatedto aminoglycosides.It lacks amino sugars and glycosides
10、bonds.Spectinomycin is active against many Gram-positiveand Gram-negative organisms,but it is used as analternative treatment for drug-resistant gonorrhea orgonorrhea in penicillin-allergic patients.Strains of gonococci may be resistant to spectinomycin,but there is no cross-resistance with other dr
11、ugs.Spectinomycin is rapidly absorbed after i.m.injection.A single dose of 40 mg/kg up to a maximum of 2 g isgiven.There is pain at the injection site.Nephrotoxicityand anemia have been observed rarely.Streptomycin and gentamicin are the most vestibulotoxic.Nephrotoxicity results in rising serum cre
12、atininelevels or reduced creatinine clearance.Neomycin,kanamycin,and amikacin are the most ototoxic agents.Neomycin,tobramycin,and gentamicin are the most nephrotoxic.In very high doses,aminoglycosides canproduce a curare-like effect with neuromuscularblockade that results in respiratory paralysis.T
13、his paralysis is usually reversible by calcium gluconate(given promptly)or neostigmine.Hypersensitivity occurs infrequently.II.TETRACYCLINESTetracyclines enter microorganisms in part by passivediffusion and in part by an energy-dependent processof active transport.Susceptible cells concentrate the d
14、rug intracellularly.Once inside the cell,tetracyclinesbind reversibly to the 30S subunit of the bacterialribosome,blocking the binding of aminoacyl-tRNAto the acceptor site on the mRNA-ribosome complexThis prevents addition of amino acids to the growingpeptide.Tetracyclines are broad-spectrum bacter
15、iostaticantibiotics that inhibit protein synthesis.Tetracyclines are active against many Gram-positiveand Gram-negative bacteria,including anaerobes,rickettsiae,chlamydiae,mycoplasmas,and L-forms;and against some protozoa,eg,amebas.The antibacterial activities of most tetracyclines aresimilar except
16、 that tetracycline-resistant strains maybe susceptible to doxycycline and minocycline,all of which are poor substrates for the efflux pump that mediates resistance.Differences inclinical efficacy for susceptible organisms are minorand attributable largely to features of absorption,distribution,and e
17、xcretion of individual drugs.Antimicrobial Activity PharmacokineticsTetracyclines mainly differ in their absorption after oraladministration and their elimination.Absorption after oral administration is approximately 6070%for tetracycline,oxytetracycline,andmethacycline;and 95100%for doxycycline and
18、 minocycline.A portion of an orally administered doseof tetracycline remains in the gut lumen,modifies intestinal flora,and is excreted in the feces.Absorption occurs mainly in the upper small intestineand is impaired by food(except doxycycline and minocycline);by divalent cations(Ca2+,Mg2+,Fe2+)or
19、Al3+;by dairy products and antacids,which containmultivalent cations;and by alkaline pH.Tetracyclines are excreted mainly in bile and urine.Concentrations in bile exceed those in serum tenfold.Some of the drug excreted in bile is reabsorbed fromthe intestine(enterohepatic circulation)and may contrib
20、ute to maintenance of serum levels.From 10 to 50%of various tetracyclines is excreted into the urine,mainly by glomerular filtration.Ten to 40%of the drug is excreted in feces.Doxycycline,in contrast to othertetracyclines,is eliminated by nonrenal mechanisms,do not accumulate significantly and requi
21、re no dosage adjustment in renal failure.Tetracyclines are classified as:(1)short-acting(chlortetracycline,tetracycline,(2)oxytetracycline)based on plasma t1/2 of 68 h;(3)(2)intermediate acting(demeclocycline and(4)methacycline)t1/2 12 h;(5)(3)long-acting(doxycycline and minocycline)(6)with plasma t
22、1/2 1618 h.(7)The almost complete absorption and slow(8)excretion of doxycycline and minocycline(9)allow for once-daily dosing.Clinical UsesA tetracycline is the drug of choice in infections withM.pneumoniae,chlamydiae,rickettsiae,and some spirochetes.They are used in combination regimens to treat g
23、astric and duodenal ulcer disease caused byH.pylori.They may be used in various Gram-positiveand Gram-negative bacterial infections,including Vibrio infections.In cholera,tetracycline resistance has appearedduring epidemics.A newly approved tetracycline analog,tigecycline,is a semisynthetic derivati
24、ve of minocycline.It is poorly absorbed orally and must be administeredintravenously(t1/2 36 h).Many tetracycline-resistant strains are susceptible totigecycline.Its spectrum is very broad.Coagulase-negative staphylococci and S.aureus,including MRS,vancomycin-intermediate,and vancomycin-resistant st
25、rains;streptococci,penicillin-susceptible and resistant;enterococci,including vancomycin-resistant strains;Gram-positiverods;Enterobacteriaceae;multidrug-resistant strainsof Acinetobacter spp.;anaerobes,both Gram-positiveand Gram-negative;atypical agents,rickettsiae,chlamydia,and legionella;and rapi
26、dly growing mycobacteria all are susceptible.Proteus and P.aeruginosa,however,are resistant.Tetracyclines modify the normal flora,with suppression of susceptible coliform organisms andovergrowth of pseudomonas,proteus,staphylococci,resistant coliforms,clostridia,and candida.This canresult in intesti
27、nal functional disturbances,anal pruritus,vaginal or oral candidiasis,or enterocolitiswith shock and death.Tetracyclines are readily bound to calcium depositedin newly formed bone or teeth in young children.When a tetracycline is given during pregnancy,it canbe deposited in the fetal teeth,leading t
28、o fluorescence,discoloration,and enamel dysplasia;it can be depositedin bone,where it may cause deformity or growthinhibition.If the drug is given for long periods to childrenunder 8 years of age,similar changes can result.Tetracyclines can probably impair hepatic function,especially during pregnanc
29、y,in patients with preexisting hepatic insufficiency and when high dosesare given intravenously.Hepatic necrosis has been reported with daily doses of 4 g i.v.Renal tubular acidosis and other renal injury resul-ting in nitrogen retention is a conraindication to the administration of outdated tetracy
30、cline preparations.Tetracyclines given with diuretics may produce nitrogen retention.Tetracyclines other thandoxycycline may accumulate to toxic levels in patientswith impaired kidney function.Intravenous injection can lead to venous thrombosis.Intramuscular injection produces painful localirritatio
31、n and should be avoided.Systemically administered tetracycline,especially demeclocycline,can induce sensitivity tosunlight or ultraviolet light,particularly infair-skinned persons.Dizziness,vertigo,nausea,and vomiting havebeen noted particularly with doxycycline andMinocycline at high doses.The main
32、 mechanisms of resistance to tetracycline and its analogues are:(1)impaired influx or increased efflux by an(2)active transport protein pump;(3)(2)ribosome protection due to production of proteins that interfere with tetracycline binding to the ribosome;3)enzymatic inactivation.III.CHLORAMPHENICOLCh
33、loramphenicol and macrolides bind to the 50S subunit and blocktranspeptidation and protein synthesis.It has bacteriostatic action.Because of potential toxicity,bacterial resistance,and the availability of many other effective alternatives,chloramphenicol is rarely used.It may be consideredfor treatm
34、ent of serious rickettsial infections such astyphus and Rocky Mountain spotted fever.It is an alternative to a beta-lactams for treatment of meningococcal meningitis occurring in patients who have major hypersensitivity reactions to penicillin or bacterial meningitis caused by penicillin-resistant s
35、trains of pneumococci.Adverse Reactions of ChloramphenicolAdults occasionally develop nausea,vomiting,and diarrhea.This is rare in children.Oral or vaginal candidiasis may occur as a result of alteration of normal microbial flora.Chloramphenicol causes a dose-related reversiblesuppression of red cel
36、l production at dosages exceeding 50 mg/kg/d after 12 weeks.Aplasticanaemia,a rare consequence(1 in 24 000 to 40 000 courses of therapy)of chloramphenicol administration by any route.It tends to be irreversibleand can be fatal.Newborn infants lack an effective glucuronic acid conjugation mechanism f
37、or the degradation and detoxification of chloramphenicol.Consequently,when infants are given dosages above 50 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 shouldbe use
38、d 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 inhibitshepatic microsomal enzymes that metabolize phenytoin and warfarin.IV.MACROLIDES and KETOLIDESAzithromycin(t1/2 4068 h,tab.500 mg)ErythromycinClarithromyci
39、n(antihelicobacter activity)Josamycin(saliva excretion)MidecamycinOleandomycin(saliva excretion)RoxithromycinSpiramycin(saliva excretion)Rodogyl(spiramicin/metronidazole)with significant saliva excretion)Ketolides:Telithromycin Inhibition of bacterial protein synthesis by macrolideslisteria,and cert
40、ain mycobacteria,Gram-negative organisms such as Neisseria spp.,Bordetella pertussis,Bartonella henselae,and B.quintana(etiologic agentsof cat-scratch disease and bacillary angiomatosis),some rickettsia spp.,T.pallidum,and campylobacterspp.are susceptible.Erythromycin is effective againstGram-positi
41、ve microorganisms(pneumococci,streptococci,staphylococci,and coryne-bacteria),Mycoplasma,legionella,Chlamydia trachomatis,Adverse Reactions of Erythromycin Anorexia,nausea,vomiting,and diarrhea accompanyoral administration.GI intolerance,which is due to a direct stimulation of gut motility,is the mo
42、st common reason for discontinuing erythromycin and substitutinganother antibiotic.Erythromycin can produce acute cholestatic hepatitis(fever,jaundice,impaired liver function),probably asa hypersensitivity reaction.Most patients recover fromthis,but hepatitis recurs if the drug is readministered.Ery
43、thromycin metabolites can inhibit cytochrome P450 enzymes and thus increase the serum concen-trations of theophylline,oral anticoagulants,cyclos-porine,methylprednisolone,and digoxin.Resistance to erythromycin is usually plasmid-encoded.Three mechanisms have been identified:(1)reduced permeability o
44、f the cell membrane or active efflux;(2)production(by Enterobacteriaceae)of esterases that hydrolyze macrolides;(3)modification of the ribosomal binding site (so-called ribosomal protection)by chromosomal mutation or by a macrolide-inducible or constitutive methylase.Cross-resistance is complete bet
45、ween erythromycin and the other macrolides.Clarithromycin is derived from erythromycin by addition of a methyl group and has improved acid stability and oral absorption compared with erythromycin.Clarithromycin and erythromycin are virtually identical with respect to antibacterial activityexcept tha
46、t clarithromycin is more active against M.avium complex.Clarithromycin also has activityagainst M.leprae,T.gondii,and H.pylori.Erythromycin-resistant streptococci and staphylococci are also resistant to clarithromycin.The advantages of clarithromycin compared with erythromycin are lower incidence of
47、 gastrointestinalintolerance and less frequent dosing.Azithromycin has spectrum of activity and clinicaluses virtually identical to those of clarithromycin.Azithromycin is active against M.avium complex and T.gondii.Azithromycin is slightly less active than erythromycin and clarithromycin against st
48、aphylo-cocci and streptococci and slightly more active against H.influenzae.Azithromycin is highly activeagainst chlamydia.It plasma t1/2 is long.Telithromycin is active in vitro against S.pyogenes,S.pneumoniae,S.aureus,H.influenzae,Moraxellacatarrhalis,mycoplasmas,Legionella,Chlamydia,H.pylori,N.go
49、norrhoeae,B.fragilis,and T.gondii.Many macrolide-resistantstrains are susceptibleto ketolides.V.LINCOSAMIDESClindamycin is a chlorine-substituted derivativeof lincomycin,an antibiotic that is elaboratedby Streptomyces lincolnensis.Clindamycin is indicated for treatment of anaerobicinfection caused b
50、y bacteroides and other anaerobesthat often participate in mixed infections.Clindamycin,sometimes in combination with an aminoglycoside orcephalosporin,is used to treat penetrating wounds ofthe abdomen and the gut;infections originating in thefemale genital tract,eg,septic abortion and pelvicabscess