Tetrasiklin, Tetrasiklin, makrolid, makrolid, aminoglikosid, aminoglikosid, kloramfenikolkloramfenikol

TetrasiklinTetrasiklin

Manfaat klinis:Manfaat klinis:antibiotik pilihan antibiotik pilihan pertama utk pertama utk infeksi riketsia, infeksi riketsia, mikoplasma, & mikoplasma, & klamidia, klamidia, bruselosis, kolera, bruselosis, kolera, plague & Lyme plague & Lyme diseasediseaseutk infeksi utk infeksi campuran pd sal campuran pd sal nafas dan aknenafas dan akne

TetrasiklinTetrasiklinESO:ESO:yg paling sering: yg paling sering: gangguan GIT krn gangguan GIT krn iritasi langsung & iritasi langsung & modifikasi flora ususmodifikasi flora ususKrn mengkhelat Krn mengkhelat Ca2+, tetrasiklin Ca2+, tetrasiklin dideposit dlm tulang dideposit dlm tulang & gigi yg sedang & gigi yg sedang tumbuh, tumbuh, menyebabkan menyebabkan pewarnaan gigi, pewarnaan gigi, kadang hipoplasia kadang hipoplasia gigi & deformitas gigi & deformitas tulangtulang→ tdk diberikan → tdk diberikan pd anak2, wanita hamil & pd anak2, wanita hamil & menyusuimenyusui

ChloramphenicolChloramphenicolCrystalline Crystalline chloramphenicol is a chloramphenicol is a neutral, stable neutral, stable compound with the compound with the following structure:following structure:It is soluble in alcohol It is soluble in alcohol but poorly soluble in but poorly soluble in water. water. Chloramphenicol Chloramphenicol succinate, which is succinate, which is used for parenteral used for parenteral administration, is administration, is highly water-soluble. highly water-soluble. It is hydrolyzed in vivo It is hydrolyzed in vivo with liberation of free with liberation of free chloramphenicolchloramphenicol..

The systemic dosage The systemic dosage of chloramphenicol of chloramphenicol need not be altered in need not be altered in renal insufficiency, but renal insufficiency, but it must be reduced it must be reduced markedly in in hepatic markedly in in hepatic failure. Newborns less failure. Newborns less than a week old and than a week old and premature infants also premature infants also clear chloramphenicol clear chloramphenicol less well, and the less well, and the dosage should be dosage should be reduced to 25 reduced to 25 mg/kg/d.mg/kg/d.

Chloramphenicol Chloramphenicol is occasionally is occasionally used topically in used topically in the treatment of the treatment of eye infections eye infections because of itsbecause of itswide antibacterial wide antibacterial spectrum and its spectrum and its penetration of penetration of ocular tissues and ocular tissues and the aqueous the aqueous humor. It ishumor. It isineffective for ineffective for chlamydial chlamydial infections.infections.

Adverse Adverse ReactionsReactions

Gastrointestinal DisturbancesGastrointestinal Disturbances• Adults occasionally develop Adults occasionally develop

nausea, vomiting, and diarrhea. nausea, vomiting, and diarrhea. This is rare in children. Oral or This is rare in children. Oral or vaginal candidiasis may occur as vaginal candidiasis may occur as a result of alteration of normal a result of alteration of normal microbial flora.microbial flora.

Bone Marrow DisturbancesBone Marrow Disturbances• Chloramphenicol commonly Chloramphenicol commonly

causes a dose-related reversible causes a dose-related reversible suppression of red cell suppression of red cell production at dosages exceeding production at dosages exceeding 50 mg/kg/d after 1–2 weeks. 50 mg/kg/d after 1–2 weeks. Aplastic anemia is a rare Aplastic anemia is a rare consequence of chloramphenicol consequence of chloramphenicol administration by any route. It is administration by any route. It is an idiosyncratic reaction an idiosyncratic reaction unrelated to dose, though it unrelated to dose, though it occurs more frequently with occurs more frequently with prolonged use. It tends to be prolonged use. It tends to be irreversible and can be fatal.irreversible and can be fatal.

Toxicity for Newborn InfantsToxicity for Newborn Infants• Newborn infants lack an Newborn infants lack an

effective glucuronic acid effective glucuronic acid conjugation mechanism for the conjugation mechanism for the degradation and detoxification degradation and detoxification of chloramphenicol. of chloramphenicol.

• Consequently, when infants are Consequently, when infants are given dosages above 50 given dosages above 50 mg/kg/d, the drug may mg/kg/d, the drug may accumulate, resulting in the accumulate, resulting in the gray baby syndrome, gray baby syndrome, with with vomiting, flaccidity, vomiting, flaccidity, hypothermia, gray color, shock, hypothermia, gray color, shock, and collapse. and collapse.

• To avoid this toxic effect, To avoid this toxic effect, chloramphenicol should be used chloramphenicol should be used with caution in infants and the with caution in infants and the dosage limited to 50 mg/kg/d or dosage limited to 50 mg/kg/d or less (during the first week of less (during the first week of life) in full-term infants and 25 life) in full-term infants and 25 mg/kg/d in premature infants.mg/kg/d in premature infants.

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Interaction with Interaction with Other DrugsOther Drugs

• Chloramphenicol inhibits Chloramphenicol inhibits hepatic microsomal hepatic microsomal enzymes that metabolize enzymes that metabolize several drugs. Half-lives several drugs. Half-lives are prolonged, and the are prolonged, and the serum concentrations of serum concentrations of phenytoin, tolbutamide, phenytoin, tolbutamide, chlorpropamide, and chlorpropamide, and warfarin are increased. warfarin are increased. Like other bacteriostatic Like other bacteriostatic inhibitors of microbial inhibitors of microbial protein synthesis, protein synthesis, chloramphenicol can chloramphenicol can antagonize bactericidal antagonize bactericidal drugs such as penicillins drugs such as penicillins or aminoglycosides.or aminoglycosides.  

MacrolidesMacrolides • The macrolides are a The macrolides are a group of closely related group of closely related compounds characterized compounds characterized by a macrocyclic lactoneby a macrocyclic lactonering (usually containing ring (usually containing 14 or 16 atoms) to which 14 or 16 atoms) to which deoxy sugars are deoxy sugars are attached. The prototype attached. The prototype drug,drug,erythromycin, waserythromycin, wasobtained from obtained from Streptomyces erythreus. Streptomyces erythreus. Clarithromycin and Clarithromycin and azithromycin are azithromycin are semisynthetic derivatives semisynthetic derivatives of erythromycin.of erythromycin.

ErythromycinErythromycin

• Antimicrobial ActivityAntimicrobial Activity• Erythromycin is effective Erythromycin is effective

against gram-positive against gram-positive organisms, especially organisms, especially pneumococci, streptococci, pneumococci, streptococci, staphylococci, are and staphylococci, are and corynebacteria, in plasma corynebacteria, in plasma concentrations of 0.02–2 concentrations of 0.02–2 g/mL. Gramnegative g/mL. Gramnegative organisms such as organisms such as neisseria species, neisseria species, Bordetella pertussis, Bordetella pertussis, Bartonella henselae, Bartonella henselae, and and Bquintana Bquintana (etiologic agents (etiologic agents of cat-scratch disease and of cat-scratch disease and bacillary angiomatosis), bacillary angiomatosis), some rickettsia species, some rickettsia species, Treponema pallidum, Treponema pallidum, and and campylobacter species are campylobacter species are susceptible. susceptible.

• The antibacterial action The antibacterial action of erythromycin may be of erythromycin may be inhibitory or bactericidal, inhibitory or bactericidal, particularly at higher particularly at higher concentrations, for concentrations, for susceptible organisms. susceptible organisms. Activity is enhanced at Activity is enhanced at alkaline pH. Inhibition of alkaline pH. Inhibition of protein synthesis occurs protein synthesis occurs via binding to the 50S via binding to the 50S ribosomal RNA. Protein ribosomal RNA. Protein synthesis is inhibited synthesis is inhibited because aminoacyl because aminoacyl translocation reactions translocation reactions and the formation of and the formation of initiation complexes are initiation complexes are blocked (Figure 44– 1).blocked (Figure 44– 1).

ResistanceResistance• Resistance to erythromycin is Resistance to erythromycin is

usually plasmid-encoded. Three usually plasmid-encoded. Three mechanisms have been identified: mechanisms have been identified: (1) reduced permeability of the cell (1) reduced permeability of the cell membrane or active efflux; (2) membrane or active efflux; (2) production (by production (by Enterobacteriaceae) of esterases Enterobacteriaceae) of esterases that hydrolyze macrolides; and (3) that hydrolyze macrolides; and (3) modification of the ribosomal modification of the ribosomal binding site (so-called ribosomal binding site (so-called ribosomal protection) by chromosomal protection) by chromosomal mutation or by a macrolide-mutation or by a macrolide-inducible or constitutive inducible or constitutive methylase. Efflux and methylase methylase. Efflux and methylase production account for the vast production account for the vast majority of cases of resistance in majority of cases of resistance in gram-positive organisms. gram-positive organisms.

• Cross-resistance is complete Cross-resistance is complete between erythromycin and the between erythromycin and the other macrolides. Also clindamycin other macrolides. Also clindamycin and streptogramin B (so-called and streptogramin B (so-called macrolidelincosamide-macrolidelincosamide-streptogramin, or MLS-type B, streptogramin, or MLS-type B, resistance), which share the same resistance), which share the same ribosomal binding site. ribosomal binding site.

PharmacokinetiPharmacokineticscs

• Erythromycin base is destroyed by Erythromycin base is destroyed by stomach acid and must be stomach acid and must be administered with enteric coating. administered with enteric coating. Food interferes with absorption. Food interferes with absorption.

• Adjustment for renal failure is not Adjustment for renal failure is not necessary. Erythromycin is not necessary. Erythromycin is not removed by dialysis. Large removed by dialysis. Large amounts of an administered dose amounts of an administered dose are excreted in the bile and lost in are excreted in the bile and lost in feces, and only 5% is excreted in feces, and only 5% is excreted in the urine.the urine.

• Absorbed drug is distributed widely Absorbed drug is distributed widely except to the brain and except to the brain and cerebrospinal fluid. Erythromycin is cerebrospinal fluid. Erythromycin is taken up by polymorphonuclear taken up by polymorphonuclear leukocytes and macrophages. It leukocytes and macrophages. It traverses the placenta and reaches traverses the placenta and reaches the fetus.the fetus.

Clinical UsesClinical UsesEmergence of Emergence of erythromycin erythromycin resistance in strains resistance in strains of group A of group A streptococci and streptococci and pneumococci pneumococci (penicillin-resistant (penicillin-resistant pneumococci in pneumococci in particular) has made particular) has made macrolides less macrolides less attractive as first-attractive as first-line agents for line agents for treatment of treatment of pharyngitis, skin pharyngitis, skin and soft tissue and soft tissue infections, and infections, and pneumonia. pneumonia.

• An erythromycin is the drug of An erythromycin is the drug of choice in corynebacterial choice in corynebacterial infections (diphtheria, infections (diphtheria, corynebacterial sepsis, corynebacterial sepsis, erythrasma); in respiratory, erythrasma); in respiratory, neonatal, ocular, or genital neonatal, ocular, or genital chlamydial infections; and in chlamydial infections; and in treatment of community-treatment of community-acquired pneumonia because acquired pneumonia because its spectrum of activity its spectrum of activity includes the pneumococcus, includes the pneumococcus, mycoplasma, and legionella. mycoplasma, and legionella.

• Erythromycin is also useful as Erythromycin is also useful as a penicillin substitute in a penicillin substitute in penicillin-allergic individuals penicillin-allergic individuals with infections caused by with infections caused by staphylococci (assuming that staphylococci (assuming that the isolate is susceptible), the isolate is susceptible), streptococci, or pneumococci. streptococci, or pneumococci.

Adverse Adverse ReactionsReactions

Gastrointestinal EffectsGastrointestinal Effects• Anorexia, nausea, Anorexia, nausea,

vomiting, and diarrhea vomiting, and diarrhea occasionally accompany occasionally accompany oral administration.oral administration.

Liver ToxicityLiver Toxicity• Erythromycins can Erythromycins can

produce acute cholestatic produce acute cholestatic hepatitis (fever, jaundice, hepatitis (fever, jaundice, impaired liver function), impaired liver function), probably as a probably as a hypersensitivity reaction. hypersensitivity reaction. Most patients recover Most patients recover from this, but hepatitis from this, but hepatitis recurs if the drug is recurs if the drug is readministered. Other readministered. Other allergic reactions include allergic reactions include fever, eosinophilia, and fever, eosinophilia, and rashes.rashes.

Drug Drug InteractionsInteractions

• Erythromycin Erythromycin metabolites can inhibit metabolites can inhibit cytochrome P450 cytochrome P450 enzymes and thus enzymes and thus increase the serum increase the serum concentrations of concentrations of numerous drugs, numerous drugs, including theophylline, including theophylline, oral anticoagulants, oral anticoagulants, cyclosporine, and cyclosporine, and methylprednisolone.methylprednisolone.

• Erythromycin increases Erythromycin increases serum concentrations of serum concentrations of oral digoxin by oral digoxin by increasing its increasing its bioavailability.bioavailability.

ClarithromycinClarithromycin• Clarithromycin is derived from Clarithromycin is derived from

erythromycin by addition of a erythromycin by addition of a methyl group and has methyl group and has improved acid stability and improved acid stability and oral absorption compared with oral absorption compared with erythromycin. erythromycin.

• Its mechanism of action is the Its mechanism of action is the same as that of erythromycin.same as that of erythromycin.

• Clarithromycin and Clarithromycin and erythromycin are virtually erythromycin are virtually identical with respect to identical with respect to antibacterial activity except antibacterial activity except that clarithromycin is more that clarithromycin is more active against active against Mycobacterium Mycobacterium avium avium complex. complex. Clarithromycin also has Clarithromycin also has activity against activity against M leprae M leprae and and Toxoplasma gondii. Toxoplasma gondii. Erythromycin-resistant Erythromycin-resistant streptococci and staphylococci streptococci and staphylococci are also resistant to are also resistant to clarithromycin.clarithromycin.

• Except for the specific Except for the specific organisms noted above, the organisms noted above, the two drugs are otherwise two drugs are otherwise therapeutically very similar, therapeutically very similar, and the choice of one over the and the choice of one over the other usually turns on issues of other usually turns on issues of cost & tolerability.cost & tolerability.

• The advantages of The advantages of clarithromycin compared clarithromycin compared with erythromycin are lower with erythromycin are lower frequency offrequency ofgastrointestinal intolerance gastrointestinal intolerance and less frequent dosing. and less frequent dosing.

Clarithromycin Clarithromycin is metabolized is metabolized in the liver.in the liver.

• The major metabolite is The major metabolite is 14-hydroxyclarithromycin, 14-hydroxyclarithromycin, which also has which also has antibacterial activity. antibacterial activity.

• A portion of active drug A portion of active drug and this major metabolite and this major metabolite is eliminated in the urine, is eliminated in the urine, and dosage reduction (eg, and dosage reduction (eg, a 500 mg loading dose, a 500 mg loading dose, then 250 mg once or then 250 mg once or twice daily) is twice daily) is recommended for patients recommended for patients with creatinine clearances with creatinine clearances less than 30 mL/min.less than 30 mL/min.

• Clarithromycin has drug Clarithromycin has drug interactions similar to interactions similar to those described for those described for erythromycin.erythromycin.

AzithromycinAzithromycin • Azithromycin is derived Azithromycin is derived from erythromycin by from erythromycin by addition of a methylated addition of a methylated nitrogen into the lactone nitrogen into the lactone ring of erythromycin.ring of erythromycin.

• Its spectrum of activity Its spectrum of activity and clinical uses are and clinical uses are virtually identical to those virtually identical to those of clarithromycin. of clarithromycin.

• Azithromycin is active Azithromycin is active against against M avium M avium complex complex and and T gondii. T gondii. Azithromycin Azithromycin is slightly less active than is slightly less active than erythromycin and erythromycin and clarithromycin against clarithromycin against staphylococci and staphylococci and streptococci and slightly streptococci and slightly more active against more active against H H influenzae.influenzae.

• azithromycin penetrates into most azithromycin penetrates into most tissues (except cerebrospinal fluid) tissues (except cerebrospinal fluid) and phagocytic cells extremely and phagocytic cells extremely well, with tissue concentrations well, with tissue concentrations exceeding serum concentrations exceeding serum concentrations by 10-to 100-fold. by 10-to 100-fold.

• The drug is slowly released from The drug is slowly released from tissues (tissue half-life of 2–4 days) tissues (tissue half-life of 2–4 days) to produce an elimination half-life to produce an elimination half-life approaching 3 days. approaching 3 days.

• These unique properties permit These unique properties permit once-daily dosing and shortening once-daily dosing and shortening of the duration of treatment in of the duration of treatment in many cases. For example, a single many cases. For example, a single 1 g dose of azithromycin is as 1 g dose of azithromycin is as effective as a 7-day course of effective as a 7-day course of doxycycline for chlamydial doxycycline for chlamydial cervicitis and urethritis. cervicitis and urethritis.

• Community-acquired pneumonia Community-acquired pneumonia can be treated with azithromycin can be treated with azithromycin given as a 500 mg loading dose, given as a 500 mg loading dose, followed by a 250 mg single daily followed by a 250 mg single daily dose for the next 4 days.dose for the next 4 days.

• Azithromycin is Azithromycin is highly active against highly active against chlamydia.chlamydia.

• Azithromycin differs Azithromycin differs from erythromycin from erythromycin and clarithromycin and clarithromycin mainly in mainly in pharmacokinetic pharmacokinetic properties. properties.

• Aluminum and magnesium Aluminum and magnesium antacids do not alter antacids do not alter bioavailability but delay bioavailability but delay absorption and reduce peak absorption and reduce peak serum concentrations.serum concentrations.

• Because it has a 15-Because it has a 15-member (not 14-member) member (not 14-member) lactone ring, azithromycin lactone ring, azithromycin does not inactivate does not inactivate cytochrome P450 enzymes cytochrome P450 enzymes and therefore is free of the and therefore is free of the drug interactions that occur drug interactions that occur with erythromycin and with erythromycin and clarithromycin.clarithromycin.

• Azithromycin is rapidly Azithromycin is rapidly absorbed and well tolerated absorbed and well tolerated orally. It should be orally. It should be administered 1 hour before administered 1 hour before or 2 hours after meals. or 2 hours after meals.

AminoglycosideAminoglycosidess

• Aminoglycosides are a Aminoglycosides are a group of bactericidal group of bactericidal antibiotics originally antibiotics originally obtained from variousobtained from various

• streptomyces species streptomyces species and sharing chemical, and sharing chemical, antimicrobial, antimicrobial, pharmacologic, and toxic pharmacologic, and toxic characteristics.characteristics.

• The group includes The group includes streptomycin, streptomycin, neomycin, kanamycin, neomycin, kanamycin, amikacin, gentamicin, amikacin, gentamicin, tobramycin,tobramycin,

• sisomicin, netilmicin, sisomicin, netilmicin, and others.and others.

General General Properties of Properties of AminoglycosidesAminoglycosides

• Aminoglycosides are used Aminoglycosides are used most widely against gram-most widely against gram-negative enteric bacteria, negative enteric bacteria, especially in bacteremia and especially in bacteremia and sepsis, in combination with sepsis, in combination with vancomycin or a penicillin vancomycin or a penicillin for endocarditis, and for for endocarditis, and for treatment of tuberculosis.treatment of tuberculosis.

• Streptomycin is the oldest Streptomycin is the oldest and best-studied of the and best-studied of the aminoglycosides.aminoglycosides.

• Gentamicin, tobramycin, Gentamicin, tobramycin, and amikacin are the most and amikacin are the most widely employed widely employed aminoglycosides at present.aminoglycosides at present.

• Neomycin and kanamycin Neomycin and kanamycin are now largely limited to are now largely limited to topical or oral use.topical or oral use.

• Aminoglycosides are Aminoglycosides are not absorbed orally & not absorbed orally & must be given by must be given by injection.injection.

• Has narrow therapeutic Has narrow therapeutic index & are potentially index & are potentially toxic.toxic.

• The most important The most important side-effec: damage to side-effec: damage to VIIIth cranial nerve VIIIth cranial nerve (ototoxicity) & damage (ototoxicity) & damage to the kidneyto the kidney

Gentamicin is the Gentamicin is the most important most important aminoglycosidesaminoglycosides

• Its main use being in Its main use being in the ‘empirical’ the ‘empirical’ treatment of acute treatment of acute life-threatening life-threatening Gram negative Gram negative infection (e.g. infection (e.g. Pseudomonas Pseudomonas aeroginosa) in aeroginosa) in hospital, until hospital, until antibiotic antibiotic sensitivities are sensitivities are known.known.

Amikasin is less Amikasin is less affected by affected by aminoglycoside-aminoglycoside-inactivating inactivating enzyme & is used enzyme & is used in serious Gram-in serious Gram-negative negative infections that are infections that are gentamicin gentamicin resistantresistant

• Netilmicin is claimed Netilmicin is claimed to be less toxic than to be less toxic than gentamicingentamicin

• Neomycin: too toxic Neomycin: too toxic for parenteral use, for parenteral use, used topically in skin used topically in skin infections and orally infections and orally to sterilize the bowel to sterilize the bowel prior to surgeryprior to surgery

• Streptomycin is Streptomycin is active against M. active against M. tuberculosis. tuberculosis.