Tetrasiklin, makrolid, aminoglikosid, kloramfenikol

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

Mek Aksi

Menghambat sintesis protein Bakteriostatik, tdk bakterisidal

Spektrum

Luas, grm pos & neg Mikoplasma, riketsia, klamidia, sproketa & protosoa (mis. amuba)

Spektrum (lanjt)

Minoksiklin jg efektif melawan N. meningitidis Ttp byk strain organisme yg resisten

Tetrasiklin
ESO: yg paling sering: gangguan GIT krn iritasi langsung & modifikasi flora usus Krn mengkhelat Ca2+, tetrasiklin dideposit dlm tulang & gigi yg sedang tumbuh, menyebabkan pewarnaan gigi, kadang hipoplasia gigi & deformitas tulang tdk diberikan pd anak2, wanita hamil & menyusui
Farmakokinetik

Biasanya diberikan peroral, tp dpt diberikan scr parenteral Absorbsi dr usus inkomplit & ireguler, lbh baik bila tdk bersama dg makanan

Farmakokinetik

Tetrasiklin mengkhelat ion logam (kalsium, magnesium, besi, aluminium) membentuk komplek yg tdk terabsorbsi Absorbsi berkurang bila ada susu, antasid, dan sediaan besi

Farmakokinetik

Minosiklin & doksisiklin diabsorbsi scr komplit

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

Antimicrobial Activity
Chloramphenicol is a potent inhibitor of microbial protein synthesis. It binds reversibly to the 50S subunit of the bacterial ribosome (Figure 441). It inhibits the peptidyl transferase step of protein synthesis.
Chloramphenicol is a bacteriostatic broad-spectrum antibiotic that is active against both aerobic and anaerobic gram-positive and gram-negative organisms. It is active also against rickettsiae but not chlamydiae. Haemophilus influenzae, Neisseria meningitidis, and some strains of bacteroides are highly susceptible, and for them chloramphenicol may be bactericidal. Low-level resistance may emerge from large populations of chloramphenicol-susceptible cells by selection of mutants that are less permeable to the drug. Clinically significant resistance is due to production of chloramphenicol acetyltransferase, a plasmid-encoded enzyme that inactivates the drug.

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

Chloramphenicol palmitate is a prodrug that is hydrolyzed in the intestine to yield free chloramphenicol.

After absorption, chloramphenicol is widely distributed to virtually all tissues and body fluids, including the central nervous system and cerebrospinal fluid such that the concentration of chloramphenicol in brain tissue may be equal to that in serum.

The drug penetrates cell membranes readily. Most of the drug is inactivated either by conjugation with glucuronic acid (principally in the liver) or by reduction to inactive aryl amines.

Excretion of active chloramphenicol (about 10% of the total dose administered) and of inactive degradation products (about 90% of the total) occurs by way of the urine.

A small amount of active drug is excreted into bile or feces.

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

Clinical Uses
It is an alternative to a -lactam antibiotic for treatment of meningococcal meningitis occurring in patients who have major hypersensitivity reactions to penicillin children for whom or bacterial meningitis tetracyclines are caused by penicillin contraindicated, ie, resistant strains of those under 8 years of pneumococci. age
It may be considered for treatment of serious rickettsial infections, such as typhus or Rocky Mountain spotted fever, in

Adverse Reactions

Gastrointestinal Disturbances Adults 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. Bone Marrow Disturbances Chloramphenicol commonly causes a dose-related reversible suppression of red cell production at dosages exceeding 50 mg/kg/d after 12 weeks. Aplastic anemia is a rare consequence of chloramphenicol administration by any route. It is an idiosyncratic reaction unrelated to dose, though it occurs more frequently with prolonged use. It tends to be irreversible and can be fatal.

Toxicity for Newborn Infants Newborn infants lack an effective glucuronic acid conjugation mechanism for 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 should be used 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 and 25 mg/kg/d in premature infants.

Interaction with Other Drugs

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

Macrolides

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

Erythromycin

Antimicrobial Activity Erythromycin is effective against gram-positive organisms, especially pneumococci, streptococci, staphylococci, are and corynebacteria, in plasma concentrations of 0.022 g/mL. Gramnegative organisms such as neisseria species, Bordetella pertussis, Bartonella henselae, and Bquintana (etiologic agents of cat-scratch disease and bacillary angiomatosis), some rickettsia species, Treponema pallidum, and campylobacter species are susceptible.

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

Resistance

Resistance to erythromycin is usually plasmid-encoded. Three mechanisms have been identified: (1) reduced permeability of the cell membrane or active efflux; (2) production (by Enterobacteriaceae) of esterases that hydrolyze macrolides; and (3) modification of the ribosomal binding site (so-called ribosomal protection) by chromosomal mutation or by a macrolide-inducible or constitutive methylase. Efflux and methylase production account for the vast majority of cases of resistance in gram-positive organisms. Cross-resistance is complete between erythromycin and the other macrolides. Also clindamycin and streptogramin B (so-called macrolidelincosamide-streptogramin, or MLS-type B, resistance), which share the same ribosomal binding site.

Pharmacokinetics

Erythromycin base is destroyed by stomach acid and must be administered with enteric coating. Food interferes with absorption. Adjustment for renal failure is not necessary. Erythromycin is not removed by dialysis. Large amounts of an administered dose are excreted in the bile and lost in feces, and only 5% is excreted in the urine. Absorbed drug is distributed widely except to the brain and cerebrospinal fluid. Erythromycin is taken up by polymorphonuclear leukocytes and macrophages. It traverses the placenta and reaches the fetus.

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

An erythromycin is the drug of choice in corynebacterial infections (diphtheria, corynebacterial sepsis, erythrasma); in respiratory, neonatal, ocular, or genital chlamydial infections; and in treatment of community-acquired pneumonia because its spectrum of activity includes the pneumococcus, mycoplasma, and legionella. Erythromycin is also useful as a penicillin substitute in penicillinallergic individuals with infections caused by staphylococci (assuming that the isolate is susceptible), streptococci, or pneumococci.

Adverse Reactions

Gastrointestinal Effects Anorexia, nausea, vomiting, and diarrhea occasionally accompany oral administration. Liver Toxicity Erythromycins can produce acute cholestatic hepatitis (fever, jaundice, impaired liver function), probably as a hypersensitivity reaction. Most patients recover from this, but hepatitis recurs if the drug is readministered. Other allergic reactions include fever, eosinophilia, and rashes.

Drug Interactions

Erythromycin metabolites can inhibit cytochrome P450 enzymes and thus increase the serum concentrations of numerous drugs, including theophylline, oral anticoagulants, cyclosporine, and methylprednisolone. Erythromycin increases serum concentrations of oral digoxin by increasing its bioavailability.

Clarithromycin

Clarithromycin is derived from erythromycin by addition of a methyl group and has improved acid stability and oral absorption compared 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 that clarithromycin is more active against Mycobacterium avium complex. Clarithromycin also has activity against M leprae and Toxoplasma gondii. Erythromycinresistant streptococci and staphylococci are also resistant to clarithromycin.

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

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

Clarithromycin is metabolized in the liver.

The major metabolite is 14hydroxyclarithromycin, which also has antibacterial activity. A portion of active drug and this major metabolite is eliminated in the urine, and dosage reduction (eg, a 500 mg loading dose, then 250 mg once or twice daily) is recommended for patients with creatinine clearances less than 30 mL/min. Clarithromycin has drug interactions similar to those described for erythromycin.

Azithromycin

Azithromycin is derived from erythromycin by addition of a methylated nitrogen into the lactone ring of erythromycin. Its spectrum of activity and clinical uses are 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 staphylococci and streptococci and slightly more active against H influenzae.

 azithromycin penetrates into most tissues (except cerebrospinal fluid) and phagocytic cells extremely well, with tissue concentrations exceeding serum concentrations by 10-to 100fold. The drug is slowly released from tissues (tissue half-life of 24 days) to produce an elimination half-life approaching 3 days. These unique properties permit oncedaily dosing and shortening of the duration of treatment in many cases. For example, a single 1 g dose of azithromycin is as effective as a 7-day course of doxycycline for chlamydial cervicitis and urethritis. Community-acquired pneumonia can be treated with azithromycin given as a 500 mg loading dose, followed by a 250 mg single daily dose for the next 4 days.

 Azithromycin is highly active against chlamydia. Azithromycin differs from erythromycin and clarithromycin mainly in pharmacokinetic properties.

 Aluminum and magnesium antacids do not alter bioavailability but delay absorption and reduce peak serum concentrations. Because it has a 15-member (not 14-member) lactone ring, azithromycin does not inactivate cytochrome P450 enzymes and therefore is free of the drug interactions that occur with erythromycin and clarithromycin. Azithromycin is rapidly absorbed and well tolerated orally. It should be administered 1 hour before or 2 hours after meals.

Aminoglycosides

Aminoglycosides are a group of bactericidal antibiotics originally obtained from various streptomyces species and sharing chemical, antimicrobial, pharmacologic, and toxic characteristics. The group includes streptomycin, neomycin, kanamycin, amikacin, gentamicin, tobramycin, sisomicin, netilmicin, and others.

General Properties of Aminoglycosides

Aminoglycosides are used most widely against gramnegative enteric bacteria, especially in bacteremia and sepsis, in combination with vancomycin or a penicillin for endocarditis, and for treatment of tuberculosis. Streptomycin is the oldest and best-studied of the aminoglycosides. Gentamicin, tobramycin, and amikacin are the most widely employed aminoglycosides at present. Neomycin and kanamycin are now largely limited to topical or oral use.

 Aminoglycosides are not absorbed orally & must be given by injection. Has narrow therapeutic index & are potentially toxic. The most important sideeffec: damage to VIIIth cranial nerve (ototoxicity) & damage to the kidney

Gentamicin is the most important aminoglycosides

Its main use being in the empirical treatment of acute lifethreatening Gram negative infection (e.g. Pseudomonas aeroginosa) in hospital, until antibiotic sensitivities are known.

Amikasin is less affected by aminoglycosideinactivating enzyme & is used in serious Gram-negative infections that are gentamicin resistant

Netilmicin is claimed to be less toxic than gentamicin Neomycin: too toxic for parenteral use, used topically in skin infections and orally to sterilize the bowel prior to surgery Streptomycin is active against M. tuberculosis.