Tetra, Makrolid, Aminoglikosid

8/14/2019 Tetra, Makrolid, Aminoglikosid

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Tetrasiklin, makrolid,aminoglikosid,

kloramfenikol


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Tetrasiklin

Manfaat klinis:

antibiotik pilihanpertama utk infeksi

riketsia, mikoplasma,

& klamidia,

bruselosis, kolera,plague & Lyme

disease

utk infeksi campuran

pd sal nafas dan akne

Menghambat sintesisprotein

Bakteriostatik, tdk

bakterisidal

Mek Aksi

Luas, grm pos & neg

Mikoplasma, riketsia,klamidia, sproketa &protosoa (mis. amuba)

Spektrum

Minoksiklin jg efektifmelawan N. meningitidis

Ttp byk strain organisme ygresisten

Spektrum(lanjt)


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TetrasiklinESO:

yg paling sering:

gangguan GIT krn iritasilangsung & modifikasi

flora usus

Krn mengkhelat Ca2+,

tetrasiklin dideposit dlm

tulang & gigi yg sedangtumbuh, menyebabkan

pewarnaan gigi, kadang

hipoplasia gigi &

deformitas tulang tdk

diberikan pd anak2, wanita

hamil & menyusui

Biasanya diberikan peroral, tpdpt diberikan scr parenteral

Absorbsi dr usus inkomplit &ireguler, lbh baik bila tdk

bersama dg makanan

Farmako-kinetik

Tetrasiklin mengkhelat ionlogam (kalsium, magnesium,besi, aluminium) membentuk

komplek yg tdk terabsorbsiAbsorbsi berkurang bila ada

susu, antasid, dan sediaan besi

Farmakokinetik

Minosiklin & doksisiklindiabsorbsi scr komplit

Farmako-kinetik


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ChloramphenicolCrystalline

chloramphenicol is a

neutral, stable compound

with the following

structure:

It is soluble in alcohol but

poorly soluble in water.

Chloramphenicol

succinate, which is usedfor parenteral

administration, is highly

water-soluble. It is

hydrolyzed in vivo with

liberation of freechloramphenicol.

Antimicrobial Activity

Chloramphenicol is a potent inhibitor ofmicrobial protein synthesis. It binds reversiblyto the 50S subunit of the bacterial ribosome(Figure 441). It inhibits the peptidyltransferase step of protein synthesis.

Chloramphenicol is a bacteriostatic broad-spectrumantibiotic that is active against both aerobic andanaerobic gram-positive and gram-negativeorganisms. It is active also against rickettsiae but notchlamydiae. Haemophilus influenzae, Neisseriameningitidis, and some strains of bacteroides are highlysusceptible, and for them chloramphenicol may be

bactericidal.

Low-level resistance may emerge from largepopulations of chloramphenicol-susceptible cells byselection of mutants that are less permeable to thedrug. Clinically significant resistance is due toproduction of chloramphenicol acetyltransferase, a

plasmid-encoded enzyme that inactivates the drug.


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The systemic dosage of

chloramphenicol need not

be altered in renalinsufficiency, but it must

be reduced markedly in in

hepatic failure. Newborns

less than a week old and

premature infants alsoclear chloramphenicol less

well, and the dosage

should be reduced to 25

mg/kg/d. Excretion of activechloramphenicol (about 10%

of the total doseadministered) and of inactivedegradation products (about

90% of the total) occurs byway of the urine.

A small amount of activedrug is excreted into bile or

feces.

After absorption, chloramphenicolis widely distributed to virtually alltissues and body fluids, including

the central nervous system andcerebrospinal fluid such that the

concentration of chloramphenicolin brain tissue may be equal to that

in serum.

The drug penetrates cellmembranes readily. Most ofthe drug is inactivated either

by conjugation withglucuronic acid (principally in

the liver) or by reduction toinactive aryl amines.

PharmacokineticsAfter oral administration,

crystallinechloramphenicol is rapidly

and completely absorbed.

Chloramphenicol palmitateis a prodrug that is

hydrolyzed in the intestineto yield free

chloramphenicol.


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Chloramphenicol is

occasionally used

topically in the

treatment of eyeinfections because of

its

wide antibacterial

spectrum and itspenetration of ocular

tissues and the

aqueous humor. It is

ineffective forchlamydial infections.

Clinical Uses

It may be consideredfor treatment of

serious rickettsial

infections, such astyphus or RockyMountain spotted

fever, in

children for whomtetracyclines are

contraindicated, ie,those under 8 years of

age

It is an alternative to a-lactam antibiotic for

treatment of

meningococcalmeningitis occurringin patients who have

major hypersensitivityreactions to penicillinor bacterial meningitis

caused by penicillinresistant strains ofpneumococci.


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Adverse ReactionsGastrointestinal Disturbances Adults occasionally develop nausea,

vomiting, and diarrhea. This is rare inchildren. Oral or vaginal candidiasis

may occur as a result of alteration ofnormal microbial flora.

Bone Marrow Disturbances Chloramphenicol commonly causes a

dose-related reversible suppression ofred cell production at dosagesexceeding 50 mg/kg/d after 12weeks. Aplastic anemia is a rareconsequence of chloramphenicoladministration by any route. It is an

idiosyncratic reaction unrelated todose, though it occurs morefrequently with prolonged use. Ittends to be irreversible and can befatal.


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Toxicity for Newborn Infants Newborn infants lack an effective

glucuronic acid conjugationmechanism for the degradation and

detoxification of chloramphenicol. Consequently, when infants aregiven dosages above 50 mg/kg/d,the drug may accumulate, resultingin the gray baby syndrome, withvomiting, flaccidity, hypothermia,

gray color, shock, and collapse. To avoid this toxic effect,chloramphenicol should be usedwith caution in infants and thedosage limited to 50 mg/kg/d orless (during the first week of life) infull-term infants and 25 mg/kg/d inpremature infants.


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Interaction with

Other Drugs

Chloramphenicol inhibitshepatic microsomalenzymes that metabolizeseveral drugs. Half-lives areprolonged, and the serumconcentrations of phenytoin,tolbutamide,chlorpropamide, and

warfarin are increased.Like other bacteriostaticinhibitors of microbialprotein synthesis,chloramphenicol can

antagonize bactericidaldrugs such as penicillins oraminoglycosides.


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Macrolides The macrolides are a groupof closely relatedcompounds characterized

by a macrocyclic lactonering (usually containing 14or 16 atoms) to which deoxysugars are attached. The

prototype drug,erythromycin, wasobtained from Streptomyceserythreus. Clarithromycinand azithromycin are

semisynthetic derivatives oferythromycin.


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Erythromycin

Antimicrobial Activity Erythromycin is effective

against gram-positive

organisms, especiallypneumococci, streptococci,staphylococci, are andcorynebacteria, in plasmaconcentrations of 0.022

g/mL. Gramnegativeorganisms such as neisseriaspecies, Bordetella pertussis,Bartonella henselae, andBquintana (etiologic agents

of cat-scratch disease andbacillary angiomatosis),some rickettsia species,Treponema pallidum, andcampylobacter species are

susceptible.


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The antibacterial action oferythromycin may beinhibitory or bactericidal,particularly at higherconcentrations, forsusceptible organisms.Activity is enhanced atalkaline pH. Inhibition of

protein synthesis occurs viabinding to the 50S ribosomalRNA. Protein synthesis isinhibited because aminoacyltranslocation reactions and

the formation of initiationcomplexes are blocked(Figure 441).


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Resistance Resistance to erythromycin is usually

plasmid-encoded. Three mechanismshave been identified: (1) reducedpermeability of the cell membrane oractive efflux; (2) production (by

Enterobacteriaceae) of esterases thathydrolyze macrolides; and (3)modification of the ribosomal bindingsite (so-called ribosomal protection)by chromosomal mutation or by amacrolide-inducible or constitutivemethylase. Efflux and methylaseproduction account for the vastmajority of cases of resistance ingram-positive organisms.

Cross-resistance is complete betweenerythromycin and the othermacrolides. Also clindamycin and

streptogramin B (so-calledmacrolidelincosamide-streptogramin,or MLS-type B, resistance), whichshare the same ribosomal binding site.


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Pharmacokinetics Erythromycin base is destroyed bystomach acid and must beadministered with enteric coating.Food interferes with absorption.

Adjustment for renal failure is notnecessary. Erythromycin is notremoved by dialysis. Large amountsof an administered dose are excretedin the bile and lost in feces, and only

5% is excreted in the urine. Absorbed drug is distributed widely

except to the brain and cerebrospinalfluid. Erythromycin is taken up bypolymorphonuclear leukocytes and

macrophages. It traverses the placentaand reaches the fetus.


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Clinical UsesEmergence of

erythromycin resistance

in strains of group Astreptococci and

pneumococci (penicillin-

resistant pneumococci

in particular) has made

macrolides lessattractive as first-line

agents for treatment of

pharyngitis, skin and

soft tissue infections,

and pneumonia.

An erythromycin is the drug ofchoice in corynebacterial infections(diphtheria, corynebacterial sepsis,erythrasma); in respiratory,neonatal, ocular, or genitalchlamydial infections; and intreatment of community-acquiredpneumonia because its spectrumof activity includes thepneumococcus, mycoplasma, andlegionella.

Erythromycin is also useful as apenicillin substitute in penicillin-allergic individuals with infectionscaused by staphylococci (assumingthat the isolate is susceptible),

streptococci, or pneumococci.


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Adverse Reactions Gastrointestinal Effects Anorexia, nausea, vomiting,

and diarrhea occasionally

accompany oraladministration.

Liver Toxicity

Erythromycins can produceacute cholestatic hepatitis(fever, jaundice, impairedliver function), probably asa hypersensitivity reaction.

Most patients recover fromthis, but hepatitis recurs ifthe drug is readministered.Other allergic reactionsinclude fever, eosinophilia,

and rashes.


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Drug Interactions Erythromycin metabolitescan inhibit cytochrome P450enzymes and thus increase

the serum concentrations ofnumerous drugs, includingtheophylline, oralanticoagulants,cyclosporine, andmethylprednisolone.

Erythromycin increasesserum concentrations of oraldigoxin by increasing itsbioavailability.


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Clarithromycin Clarithromycin is derived from

erythromycin by addition of amethyl group and has improved

acid stability and oral absorptioncompared with erythromycin. Its mechanism of action is the

same as that of erythromycin. Clarithromycin and erythromycin

are virtually identical with respect

to antibacterial activity except thatclarithromycin is more activeagainstMycobacterium aviumcomplex. Clarithromycin also hasactivity againstM leprae andToxoplasma gondii. Erythromycin-

resistant streptococci andstaphylococci are also resistant toclarithromycin.


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Except for the specific organismsnoted above, the two drugs areotherwise therapeutically verysimilar, and the choice of one overthe other usually turns on issues ofcost & tolerability.

The advantages ofclarithromycin compared witherythromycin are lowerfrequency ofgastrointestinal intolerance andless frequent dosing.


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Clarithromycin is

metabolized in the

liver.

The major metabolite is 14-hydroxyclarithromycin,which also has antibacterialactivity.

A portion of active drug andthis major metabolite iseliminated in the urine, anddosage reduction (eg, a 500

mg loading dose, then 250mg once or twice daily) isrecommended for patientswith creatinine clearancesless than 30 mL/min.

Clarithromycin has druginteractions similar to thosedescribed for erythromycin.


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Azithromycin Azithromycin is derived fromerythromycin by addition of amethylated nitrogen into the

lactone ring of erythromycin. Its spectrum of activity and

clinical uses are virtuallyidentical to those ofclarithromycin.

Azithromycin is active againstM avium complex and T gondii.Azithromycin is slightly lessactive than erythromycin andclarithromycin against

staphylococci and streptococciand slightly more activeagainst H influenzae.


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azithromycin penetrates into mosttissues (except cerebrospinal fluid)and phagocytic cells extremely well,with tissue concentrations exceedingserum concentrations by 10-to 100-

fold. The drug is slowly released from

tissues (tissue half-life of 24 days) toproduce an elimination half-lifeapproaching 3 days.

These unique properties permit once-

daily dosing and shortening of theduration of treatment in many cases.For example, a single 1 g dose ofazithromycin is as effective as a 7-daycourse of doxycycline for chlamydialcervicitis and urethritis.

Community-acquired pneumonia canbe treated with azithromycin given asa 500 mg loading dose, followed by a250 mg single daily dose for the next 4days.


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Azithromycin is highlyactive against

chlamydia. Azithromycin differs

from erythromycin and

clarithromycin mainlyin pharmacokineticproperties.


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Aluminum and magnesium

antacids do not alterbioavailability but delayabsorption and reduce peak

serum concentrations. Because it has a 15-member (not

14-member) lactone ring,azithromycin does notinactivate cytochrome P450

enzymes and therefore is free ofthe drug interactions that occurwith erythromycin andclarithromycin.

Azithromycin is rapidlyabsorbed and well toleratedorally. It should beadministered 1 hour before or 2hours after meals.


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Aminoglycosides Aminoglycosides are agroup of bactericidalantibiotics originally

obtained from various streptomyces species and

sharing chemical,antimicrobial,

pharmacologic, and toxiccharacteristics. The group includes

streptomycin, neomycin,kanamycin, amikacin,gentamicin, tobramycin,

sisomicin, netilmicin,and others.


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General Properties of

Aminoglycosides

Aminoglycosides are usedmost widely against gram-negative enteric bacteria,especially in bacteremia and

sepsis, in combination withvancomycin or a penicillin forendocarditis, and fortreatment of tuberculosis.

Streptomycin is the oldest and

best-studied of theaminoglycosides. Gentamicin, tobramycin, and

amikacin are the most widelyemployed aminoglycosides at

present. Neomycin and kanamycin are

now largely limited to topicalor oral use.


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Aminoglycosides are notabsorbed orally & must be

given by injection. Has narrow therapeutic

index & are potentially

toxic. The most important side-

effec: damage to VIIIthcranial nerve (ototoxicity)& damage to the kidney


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Gentamicin is the

most important

aminoglycosides

Its main use being inthe empirical

treatment of acute life-threatening Gramnegative infection (e.g.Pseudomonasaeroginosa) in hospital,until antibioticsensitivities are known.


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Amikasin is less

affected by

aminoglycoside-

inactivating enzyme& is used in serious

Gram-negative

infections that are

gentamicin resistant

Netilmicin is claimed tobe less toxic than

gentamicin Neomycin: too toxic for

parenteral use, used

topically in skininfections and orally tosterilize the bowel priorto surgery

Streptomycin is activeagainst M. tuberculosis.

Documents

Tetra, Makrolid, Aminoglikosid