ANTIBACTERIAL AGENTS A. Defnit Def nitio ions ns I. Antibiotics Antibiotics II. Bacteriostatic III. Narrow-spectrum spectrum
: Antibacterial : Bactericidal : Broad-
Antibiotic : substance produced by a microorganisms that, in minute quantities is able to inhibit other microorganisms.
compound- natural, Antibacterial : any compoundsynthetic, or semi-synthetic, semi-synthetic, that is clinically useful in the treatment of bacterial infection. Bacteriostatic : agents that inhibit bacterial growth (e. !ulfonamide, !ulfonamide, chloramphenicol" Bactericidal only growing
: agents that generally generally #ill #ill
organisms. ( $%N, streptomycin " Narrow-spectr! : preferentially acti&e against either 'ram(-" or 'ram (" bacteria. Broad-spectr! : acti&e against both 'ram(" ) (-" bacteria. B. General Criteria "or e#ecti$e antibiotic action
*. %icroor&anis!s : unique and &ital target. ( speci+c proteins or nucleic acid" . Antibacterial a&ent : a. must be able to penetrate bacterial surface ) reach target in acti&e form. b. reach the infected tissue ( cross bloodbrain barrier" c. intracellular intracellul ar organisms (c" (c"
. 'ost : a. intact immune system b. &asculari/ation &asculari/ation and drainage 0Bacterial infections are di1cult to treat in neutropenic patirnts ) those with primary or secondary immunodef. Bacterial endocarditis, osteomyelitis ) abscesses are assoc. with minimal &asculari/ation &asculari/ation of the infected tissue Bronchiectasia, Bronchiectasia, #idney stones ) gall stones impair drainage- can gi&e origin to bact. Infectn- surgical remo&al of obstruction
C. General (rinciples o" e#ecti$e antibacterial t)erap*
*. +se Selecti$el* Selecti$el *. a. choice of antibacterial based on susceptibility susceptibility test. (empirical use, increases pre&alence of bacterial resistance 2 epidemiological data in the locality" b. life 2threatening 2threatening infection, collect samples prior for organism I3 before start of empiric treatment. c. use of potent, broad spectrum antibiotic &s. more common antibacterials. antibacteri als. . Institte pro!ptl* a. early treatment targets growing bacteria- low bact. $opulation. b. early treatment shorten therapyreduces possibility of superinfection. ,. Special sitations a. infection of poorly &asculari/ed tissue, treat with bactericidal agents. b. abscess or foreign bodies obstruction 2 surgery . ollow t)ro&)
0 In immunocompromised $s, the choice, dosages ) route of admin. Need to be chosen carefully to inc. t success.
0All anti&iral act intracellularly4 while many antibacterial are not e5ecti&e intracellularly. ( c, %hloram ) 6ouroquinolones" 07atch out for presence of superinfection ( antibiotic asso with colitis " ollow t)ro&). inadequate use of antibacterials ( dosing, premature termination"--- 8esistant strain.
a. In immunocompromised patients : choice, dosages, ) route of administration.. b. Infections with I% bacteria usually requires prolonged administration of antibiotics all anti&iral agents act intracellularly, bec this is essential for interference with &iral replication. in contrast many antibact. Agents are not e5ecti&e I% organisms. ( c, chloramphenicol ) 6ouroquinolones" in infected macrophages •
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c. In all patients recei&ing broadspectrum antibacterial agents, watch out for !! .suggesti&e of superinfection. (antibioticassoc colitis" CLASSIICATI/N I . Antibacterial agents that inhibit cell wall synthesis II. Antibacterial agents that inhibit nucleotide synthesis III. Antibacterial agents that inhibit nucleicacid synthesis I9. Antibacterial agents that inhibits protein synthesis
I. Antibacterial a&ents t)at in)ibit cell wall s*nt)esis 0-LACTA% ANTIBACTERIAL AGENTS : all are bactericidal a. (enicillins . 3isco&ered by leming in the *;<=s - rue antibiotic-antibacterial compounds from molds genus (enicilli! (*". %hemistry : all $%N=s are deri&ed from >-
aminopenicillamic acid in which the ?- lactam group is lin#ed to a thia/olidine ring. he antibacterial and pharmacologic properties of the di5erent $%N=s depend on the side chains attached to the basic nucleus. (". @ech. of action : (a". he bacterial targets for $%N=s are #nown as (enicillin-bindin& proteins1(B(s "4 - transpeptidase 4 carboypeptidase 4 autolytic en/ymes 0he maor antibacterial agents can be classi+ed acc to their mechanisms of action. ( *." structurally , the most impy feature of $%N, cephalosporins, carbapenems, ) monabactams is the ?-lactam ring. (B(s 2se&eral, as many as in C. coli. Inhibit $3' cross-lin#ing 2bacterial lysis (." Bacterial resistance. D some bacteria produce ?lactamase, an en/yme that inacti&ates ?lactams ( E." !pectrum of acti&ity : (a". Natural $%N=s are narrow spectrum antibiotics. ( &s. 'ram ) most anaerobes " Cception: . pallidum ,a grm(-" !usceptible to $%N, 4 Bacteroides fragilis , (anaerobe,beta-lactamase producer" is 8 to $%N (b". !emi-synthetic ?-lactamase resistant $%N=s (@ethicillin, oacillin, cloacillin, peninafcicillin and dicloacillin ". $enicillanase-resistant $%N=s !. aureus infection, penicillinase-resistant $%N are preferred bec. Ff high freq of ?-lactamase isolates.
(c". Ctended-spectrum $enicillins : e5ecti&e &s. a &ariety of 'ram(" ) 'ram(-" bacteria. -----
also be allergic to %ephalosporins. @ildly nephrotoic esp. later generations.
aminopenicillins (ampicillins, amoycillins" carboypenicillins ( carbenicillin, ticarcillin" ureidopenicillins ( a/locillin"4 pipera/ine (piperacillin" ?-lactamase inhibitors (cla&ulanic acid, sulbactam *Via manipulation of 6-aminopenicillamic molecule.
Fther ?-lactam antibacterial agents: (*". Carbapene!s 1 i!ipene!2 : &ery broadspectrum acti&ity
G. oicity : allergic reactions
0@onobactams : e5ecti&e &s. pseudomonas
CE('AL/S(/RINS:
/t)er in)ibitors o" bacterial cell wall s*nt)esis:
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(*". %hemistry : semisynthetic ?-lactam antibacterial agents from >-aminopenicillamic acid, howe&er, the thia/olidine ring is replaced by a dihydrothia/ine ring. (". %lassi+cation : three(" generations2 chronological 3e&elopment (a". *st 2gen : oral ) inectable forms %efa/olin, %ephalein , %ephalothin (b". nd 2gen. : mostly inectables %efamandole, %efaclor, %efoitin , %efuroime
0%arbapenems : only Histeria4 grp. 3 strep, $seudomonas, ) pasteurella multicida. 3 Resistant (". %onobacta!s 1 a4treona!2 : e5ecti&e &s. some 'ram(-", aerobic bacteria
a. C*closerine : rarely used, nd line antimycobacterial drug. Ftotoic (when adm parenterally"
b. 5anco!*cin : antibiotic of choice for infections caused by methicillin 3R staphylococci and penicillanseproducing enterococci. : poorly absorbed by the intestinal mucosa
(c". rd2 gen : mostly inectables. %efotaime , %eftriaone
: can be adm orally for local treatment of intestinal infections (e.g. pseudomembranous colitis due to %lostridium di1cile"
(". !pectrum of acti&ity : broad-spectrum ntibacterials
: more toic than $%N, main target of toicity is the #idney
(a". @ost cephalosporins are R to staphylococcal penicillanases (b". nd ) rd gen. cephalosporins are R to most ?Hactamases produced by gramnegati&e org
(E". oicity : *< -*G of patients allergic to $%N might
c. Bacitracin : mainly used in topical ointments, due to nephrotoicity ) Ftotoicity when adm parenterally. Antibacterial a&ents t)at in)ibit ncleotide s*nt)esis
*. Sl"ona!ides : sulfadia/ine (s" sulfamethoa/ole ) sul+soa/ole (m"
sulfamethoydia/ine (H" @ech. : bacteriostatic J broad spectrumJ well absorbed orally -- bloc#s synthesis of tetrahydrofolate ) folate -- wea# inhibitors of dihydrofolate reductase oicity : K$! reaction ( nd to $%N" -- high doses may cause hematologic d/ ) crystal formation in the urinary tract. 0!ulfonamised are structurally similar to $ABA ( para amino ben/oic acid" . Tri!et)opri! : structurally similar to dihydrofolic acid, is bound by dihydro folate reductase. . Sl"a!et)o6a4ole-tri!et)opri!: strong synergistic combi. ( bacteriostatic combi Lbactericidal" : useful in 'M infections , bacterial gastroenteritis 4 ) long-term prophylais of bacterial infections in immuno-compromised patients. (KI9" Antibiotic t)at in)ibit ncleic acid s*nt)esis
*. DNA s*nt)esis in)ibitors a. No$obiocin :3NA gyrase inhibitors replaced by quinolones ( same @ech action"
(". loro8inolones :deri&ati&es of Nalidiic acid eg o6oacin , cipro6oacin, lome6oacin "
c. Nitroi!ida4oles9 %etronida4oles : anti6agellates ) &s. obligate anaerobic bacteria. . RNA transcription in)ibitors : inacti&ate 3NA-dependent 8NA polymerase.
a. Ri"a!pin : *st line anti B drug. 4 Heprosy ) Hegionella : %hemoprophylais of patient=s contact during outbrea#s due to Neisseria meningitides ) K. in6uen/ae Antibacterial a&ents t)at in)ibits protein s*nt)esis *. In)ibitors o" ,;S riboso!al nit a. A!ino&l*cosides < L binds irre&ersibly to
@ech. : BactericidalJ broad spectrum &s. 'ram(-" organism. $arenteral adm. Not absorbed in 'I
b. 7inolones :3NA gyrase inhibitors
(*". Nalidi6ic acid :*st quinolone, broadspectrum, mainly used in 'M 4 relati&ely toic causing 'I ) neurologic s. (&isual"
Aminoglycosides preparations4 *. Strepto!*cin :*st aminoglycoside. Ftotoic. nd- line anti B . Neo!*cin : for local ) topical admin . =ana!*cin E. Genta!icin 9 Tobra!*cin 9 A!i>acin 9 Netil!icin
*Aminoglycosides & β-lactams are synergistic when used in combination. ( both are bactericidal)
oicity : 8enal and Ner&ous system toicity b. Tetrac*clines< - produced by !8C$F@%C! species
b.*. short-acting : etracycline 4 Fytetracycline 4 chlortetracycline4 3emeclocycline, @ethacycline b.. long-acting : 3oycycline 4 @inocycline - broad-spectrum bacteriostatic agents. - e5ecti&e &s. intracellular bacteria - alternati&e to $%N in syphilis ) gonorrhea - metaboli/ed by the li&er , not ecreted in the urine % toicity : *. 'I upset . ( antibiotic-assoc colitis" . !uperinfection (loss of normal 6ora " . ellowish discoloration of teeth (contraindicated in pregnant women and children." E. Increased photosensiti&ity . In)ibitors o" ?;S riboso!al nit a. C)lora!p)enicol : *st antimicrobial compound synthesi/ed in the laboratory: : broad spectrum, e5ecti&e &s anaerobes : penetrate blood-brain barrier
0hloramphenicol ! "# in $yphoid fe%er 'ocy ountain spotted fe%er . in+uen,a meningitis %hloramphenicol oicity : (a". 'ray baby syndrome (b". Blood dyscrasias .
- anemia, leu#openia, ) thrombocytopenia, which may progress to aplastic anemia. b. %acrolide antibiotics : L binds to G
Dr& Resistance
@echanisms of 3rug 8esistance : (strategy" *. $athogen pre&ents entry of the drug . $resence of membrane translocases that pumps drug out of the cell.OePu pumpsO . 3rug inacti&ation through chemical modi+cation. e. Kydrolysis of ?-lactam ring by penicillanase /ri&in and trans!ission o" dr& resistance<
A. 'enes for drug resistance are present on both4 a. bacterial chromosome (spont. mutation" b. plasmids ( small etra chromosomal 3NA" L R plas!ids B. Ctensi&e drug treatment fa&ors de&elopment ) spread of antibiotic-resistant strains. L sperin"ection pseudomembranous enterocolitis : %. di1cile
Strate&ies to co!bat dr& resistance: *. drugs gi&en at a conc. high enough to destroy susceptible bacteria ) most spontaneous mutants L drug combinations ( anti-B"
. chemotherapeutic drugs should be used only when necessary, pathogen should be identi+ed, drug sensiti&ity done. . search for new antimicrobials
