Principles of antiobic therapy
Bactericidal Bacteristatic Additive Synergistic(penicillins plus aminoglycosides) Antagonistic(antagonistic plus tetracyclines)
Antibiotics- Mehanism of action
Antibiotics- Mehanism of action
-Lactam antibiotics (beta-lactam antibiotics)
he Penicillins
Antistaphylococcal penicillins
!afcillin (parenteral,very narrow spectrum:know or suspected staphylococci :not MRSA) "#acillin(parenteral,same with nafcillin) $iclo#acillin(Oral) Methicillin(parenteral%same &ith nafcillin) 'lo#acillin (both) (luclo#acillin (both)
Aminopenicillins(Broad spectrum%)ram *ve bacteria (not staph+(,-,coli%.,influen/a%Listeria monocytogenes(ambicillin)%Borellia borgdorferi (amo#icillin)%.,pylori(amo#icillin)%&ith aminoglycosides against enteroccal 0
Amo#icillin(oral) Ampicillin( oth) Aminopenicillins -lactamase inhibitors Amo#icillin-clavulanate(oral) Ampicillin-sulbactam (parenteral)
Aminopenicillins(Broad spectrum%)ram *ve bacteria (not staph+(,-,coli%.,influen/a%Listeria monocytogenes(ambicillin)%Borellia borgdorferi (amo#icillin)%.,pylori(amo#icillin)%&ith aminoglycosides against enteroccal 0
Amo#icillin(oral) Ampicillin( oth) Aminopenicillins -lactamase inhibitors Amo#icillin-clavulanate(oral) Ampicillin-sulbactam (parenteral)
Extended-spectrum penicillins(antipseudomonal%gram negative rods) Piperacillin% ticarcillin%a/locillin
(Natural penicillins 1very narro& spectrum1steptococci%pneumonococci%meni ngococci reponema pallidum) Penicillin ) Penicillin 2
Toxicity
Adverse reactions to the penicillins are relatively common3 an estimated 45 to 675 of people are allergic to these agents, Li8e most antibiotics% penicillins can cause nausea% vomiting% and diarrhea, hey also have been associated &ith drug fever% rash% serum sic8ness% interstitial nephritis% hepatoto#icity% neurologic to#icity% and hematologic abnormalities, 9rticaria% angioedema% and anaphyla#is occur and are referred to as immediate hypersensitivity reactions, "f these% the most feared is anaphylaxis% &hich is rare but life threatening, Persons allergic to one penicillin should be considered allergic to all penicillins% and cross-allergenicity may e#tend to other -lactam antibiotics,
Second )eneration 'ephalosporins
!o drugs enter the '!S apart of cefuro#ime
Most enter the '!S,:mportant in the empiric management of meningitis and sepsis
hird )eneration 'ephalosporins
(ourth )eneration 'ephasporins
;esistant to most -lactamases ,-nter '!S< ;enal clearance similar to penicillins,$ose modification in renal dysfunction 'ephopera/one and 'eftra#ione are largely eliminated by the bile
o#icity-side effects
"ne of the attractions of the cephalosporins is their relatively favorable safety profile, ;arely% these agents cause immediate hypersensitivity reactions consisting of rash% urticaria% or anaphyla#is, :n this regard% appro#imately =5 to 675 of individuals allergic to penicillin &ill also have a reaction to cephalosporins, hus% it is usually recommended that individuals &ith a history of severe immediate hypersensitivity reactions% such as urticaria and anaphyla#is% to penicillin not be treated &ith cephalosporins, "ther rare adverse effects include reversible neutropenia% thrombocytosis% hemolysis% diarrhea% and elevated liver function tests, 'efotetan may cause hypoprothrombinemia and% &hen used &ith alcohol% a disulfi ram-li8e reaction, Both of these effects are associated &ith the methylthiotetra/ole moiety at ;> of this agent (see (ig, =-6>), Since
"ther Beta-Lactam $rugs A/treonam
A/treonam is a monobactam that is resistant to betalactamases produced by certain gram-negative rods% including !lebsiella, "seudomonas, and Serratia# he drug has no activity against gram-positive bacteria or anaerobes, :t is an inhibitor of cell &all synthesis% preferentially binding to a specific penicillin-binding protein (PBP4)% and is synergistic &ith aminoglycosides, A/treonam is administered intravenously and is eliminated via renal tubular secretion, :ts half-life is prolonged in renal failure, Adverse effects include gastrointestinal upset &ith possible superinfection% vertigo and headache% and rarely hepatoto#icity, Although s8in rash may occur% there is no cross-allergenicity &ith penicillins,
Monobactams
'arbapenems
'arbapenem use is associated &ith several adverse events% including nausea and vomiting% diarrhea% rash% and drug fever, A more &orrisome complication associated &ith carbapenems is sei/ures, Patients &ith pree#isting central nervous system disease and &ith renal insufficiency are most at ris8 for this complication and should be given these drugs &ith caution, :nitially% meropenem &as felt to be less li8ely to cause sei/ures than imipenem% but this is no& controversial, ;esults of animal e#periments suggest that doripenem is less li8ely to cause sei/ures than the other carbapenems, :n summary% carbapenems have e#cellent activity against a broad spectrum of bacteria% including many aerobic gram-positive bacteria% most aerobic gram-negative bacteria% and most anaerobes, As a result% these compounds are among the most po&erful antibacterial agents in use today,
Vancomycin has a narro& spectrum of activity and is used for serious infections caused by drug-resistant gram-positive organisms% including methicillin-resistant staphylococci (M;SA)% and in combination &ith a third-generation cephalosporin such as ceftria#one for treatment of infections due to penicillin-resistant pneumococci (P;SP), 2ancomycin is also a bac8up drug for treatment of infections caused by $lostridium difficile#Teicoplanin, another glycopeptide% has similar characteristics 2ancomycin-resistant enterococci are increasing and pose a potentially serious clinical problem because such organisms usually e#hibit multiple-drug resistance, , 2ancomycin is not absorbed from the gastrointestinal tract and may be given orally for bacterial enterocolitis, ?hen given parenterally% vancomycin penetrates most tissues(but not '!S) and is eliminated unchanged in the urine, $osage modification is mandatory in patients &ith renal impairment
)lycopeptides
)lycopeptides
o#icity-Side effects
2ancomycin may cause hearing loss% especially &hen administered along &ith an aminoglycoside, ;apid infusion has been associated &ith @red manA syndrome% in &hich patients develop pruritus and an erythematous rash on the face% nec8% and upper torso, ;ed man syndrome is not a true allergy and can often be avoided by infusing vancomycin at a slo&er rate, ;arely% neutropenia may occur &ith use of this agent, elavancin has been associated &ith effects involving the central nervous system (insomnia% psychiatric disorders% and headache)% gastrointestinal system (metallic<soapy taste% nausea% vomiting)% and the urinary tract (foamy urine), :n summary% glycopeptides antibiotics have e#cellent activity against most aerobic and anaerobic gram-positive bacteria, $espite increasing resistance% they should continue to be &or8horses in the treatment
Aminoglycosides
6>
67
I JKFLM 6 JKFLM > JKFLM 4
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7 BCDEEF 6 BCDEEF > BCDEEF 4 BCDEEF G
he main differences among the individual aminoglycosides lie in their activities against specific organisms% particularly gramnegative rods, Gentamicin, tobramycin, and amikacin are important drugs for the treatment of serious infections caused by aerobic gram-negative bacteria% including %scherichia coli and %nterobacter, !lebsiella, "roteus, "rovidencia, "seudomonas, and Serratia species, hese aminoglycosides also have activity against strains of &aemophilus influen'ae, Mora(ella catarrhalis, and Shi)ella species% although they are not drugs of choice for infections caused by these organisms, :n most cases% aminoglycosides are used in combination &ith a beta-lactam antibiotic, ?hen used alone% aminoglycosides are not reliably effective in the treatment of infections caused by gram-positive cocci, Antibacterial synergy may occur &hen aminoglycosides are used in combination &ith cell &all synthesis inhibitors, -#amples include their combined use &ith penicillins in the treatment of pseudomonal% listerial% and enterococcal infections,
o#icity
Ototoxicity Auditory or vestibular damage (or both) may occur &ith any aminoglycoside and may b irreversible, Auditory impairment is more li8ely &ith ami8acin and 8anamycin3 vestibular dysfunction is more li8ely &ith gentamicin and tobramycin, "toto#icity ris8 is proportion to the plasma levels and thus is especially high if dosage is not appropriately modified a patient &ith renal dysfunction, "toto#icity may be increased by the use of loop diuretics, Because ototo#icity has been reported after fetal e#posure% the aminoglycosides are contraindicated in pregnancy unless their potential benefits are Nudged to out&eigh ris8, Nephrotoxicity ;enal to#icity usually ta8es the form of acute tubular necrosis, his adverse effect% &hich is often reversible% is more common in elderly patients and in those concurrently receiving amphotericin B% cephalosporins% or vancomycin, )entamicin and tobramycin are the most nephroto#ic, Neuromuscular Blockade hough rare% a curare-li8e bloc8 may occur at high doses of aminoglycosides and may result in respiratory paralysis, :t is usually reversible by treatment &ith calcium and neostigmine% but ventilatory support may be reOuired, S8in ;eactions Allergic s8in reactions may occur in patients% and contact dermatitis may occur in
o#icity
Ototoxicity Auditory or vestibular damage (or both) may occur &ith any aminoglycoside and may b irreversible, Auditory impairment is more li8ely &ith ami8acin and 8anamycin3 vestibular dysfunction is more li8ely &ith gentamicin and tobramycin, "toto#icity ris8 is proportion to the plasma levels and thus is especially high if dosage is not appropriately modified a patient &ith renal dysfunction, "toto#icity may be increased by the use of loop diuretics, Because ototo#icity has been reported after fetal e#posure% the aminoglycosides are contraindicated in pregnancy unless their potential benefits are Nudged to out&eigh ris8, Nephrotoxicity ;enal to#icity usually ta8es the form of acute tubular necrosis, his adverse effect% &hich is often reversible% is more common in elderly patients and in those concurrently receiving amphotericin B% cephalosporins% or vancomycin, )entamicin and tobramycin are the most nephroto#ic, Neuromuscular Blockade hough rare% a curare-li8e bloc8 may occur at high doses of aminoglycosides and may result in respiratory paralysis, :t is usually reversible by treatment &ith calcium and neostigmine% but ventilatory support may be reOuired, S8in ;eactions Allergic s8in reactions may occur in patients% and contact dermatitis may occur in
o#icity
Ototoxicity Auditory or vestibular damage (or both) may occur &ith any aminoglycoside and may b irreversible, Auditory impairment is more li8ely &ith ami8acin and 8anamycin3 vestibular dysfunction is more li8ely &ith gentamicin and tobramycin, "toto#icity ris8 is proportion to the plasma levels and thus is especially high if dosage is not appropriately modified a patient &ith renal dysfunction, "toto#icity may be increased by the use of loop diuretics, Because ototo#icity has been reported after fetal e#posure% the aminoglycosides are contraindicated in pregnancy unless their potential benefits are Nudged to out&eigh ris8, Nephrotoxicity ;enal to#icity usually ta8es the form of acute tubular necrosis, his adverse effect% &hich is often reversible% is more common in elderly patients and in those concurrently receiving amphotericin B% cephalosporins% or vancomycin, )entamicin and tobramycin are the most nephroto#ic, Neuromuscular Blockade hough rare% a curare-li8e bloc8 may occur at high doses of aminoglycosides and may result in respiratory paralysis, :t is usually reversible by treatment &ith calcium and neostigmine% but ventilatory support may be reOuired, S8in ;eactions Allergic s8in reactions may occur in patients% and contact dermatitis may occur in
:nhibitors of Microbial Protein Synthesis
$rugs that inhibit protein synthesis vary considerably in terms of chemical structures and their spectrum of antimicrobial activity, 'hloramphenicol% tetracyclines% and the aminoglycosides &ere the first inhibitors of bacterial protein synthesis to be discovered, Because they had a broad spectrum of antibacterial activity and &ere thought to have o& to#icities% they &ere overused, Many once highly susceptible bacterial species have become resistant% and most of these drugs are no& used for more selected targets, -rythromycin% an older macrolide antibiotic% has a narro&er spectrum of action but continues to be active against several important pathogens, A/ithromycin and clarithromycin% semisynthetic macrolides% have some distinctive properties compared &ith erythromycin% as does clindamycin, !e&er inhibitors of microbial protein synthesis% &hich include streptogramins% line/olid% telithromycin% and tigecycline (a tetracycline analog) have activity against certain bacteria that have developed resistance to older antibiotics,
$o#ycycline is particulary useful in prostatitis because it reaches high levels in prostatic fluid Minocycline1in saliva and tears at high concentration%used in menigoccal carrier state
o#icity
he tetracyclines are relatively safe drugs% but several contraindications must be 8ept in mind, "ne of the core rings of these agents is a potent chelator of metal ions such as calcium, his may result in the gray to yello& discoloration of actively forming teeth and deposition in gro&ing bone, (or these reasons% the tetracyclines should not be given to pregnant &omen and given cautiously to children younger than the age of I years, .ypersensitivity reactions such as rashes and anaphyla#is occur but are not common, An e#ception is the blue-blac8 hyperpigmentation of s8in and mucous membranes observed relatively freOuently &ith minocycline use, he tetracyclines are also associated &ith phototo#icity, )astrointestinal side effects such as nausea% vomiting% and esophageal ulceration are also seen% as is hepatoto#icity,
o#icity
o#icity
:t is not possible to summari/e chloramphenicol &ithout discussing its to#icity profile% &hich has had a maNor impact on the usefulness of this agent, he most serious of thes effects involves the bone marro&, 'hloramphenicol commonly causes reversible dosedependent bone marro& suppression during the course of therapy,More feared but mu more are is the development of irreversible aplastic anemia% &hich typically occurs
after completion of a course of therapy, As might be e#pected% both these to#icities have dramatically limited the use of chloramphenicol, his agent can also lead to a fatal condition in neonates called gray baby syndromeand to neurologic abnormalities such as optic neuritis,:n summary% chloramphenicol ha a broad spectrum of activity that includes many aerobic gram-positive% aerobic gram-negative% anaerobic% and atypical bacteria, :ts use% ho&ever% has been severely limited by its to#icity profile,
Macrolides
he macrolide antibiotics ( erythromycin, a ithromycin, and clarithromycin ) are large cyclic lactone ring structures &ith attached sugars, he drugs have good oral bioavailability% but a/ithromycin absorption is impeded by food, Macrolides distribute to most body tissues% but a/ithromycin is uniOue in that the levels achieved in tissues and in phagocytes are considerably higher than those in the plasma,(bone concetration important in ostiomyelitis) he elimination of erythromycin (via biliary e#cretion) and clarithromycin (via hepatic metabolism and urinary e#cretion of intact drug) is fairly rapid (half-lives of > and H h% respectively), hey inhibit pG=7 A/ithromycin is eliminated slo&ly (half-life >PG days)% mainly in the urine ,:t doesnQt inhibit pG=7 Antibacterial Activity -rythromycin has activity against many species of $ampylobacter, $hlamydia, Mycoplasma, *e)ionella, gram-positive cocci% and some gram-negative organisms, he spectra of activity of a/ithromycin and clarithromycin are similar but include greater activity against species of $hlamydia,Mycobacterium avium comple#% and +o(oplasma# A/ithromycin is also effective in gonorrhea% as an alternative to ceftria#one and in syphilis% as an alternative to penicillin ), ;esistance to the macrolides in gram-positive organisms involves efflu# pump mechanisms and the production of a methylase that adds a methyl group to the ribosomal binding site,
