ANTIMIKROBA PENGGOLONGAN ANTIMIKROBA Berdasarkan mekanisme kerja obat : • Penghambat sintesis dinding sel. (Beta-laktam, Penisilin, Sefalosporin). • Mempengaruhi transpor aktif membran sel. ( Amfoterisin B, Azoles, Polimiksin, Polien). • Penghambat sintesis protein. (Aminoglikosida, Tetrasiklin, Makrolide, Kloramfenicol, Klindamisin). • Penghambat sintesis As. Nuklea. (Kuinolon, Sulfonamid, Pirimetamin, Sulfonamid, Trimetropin). Berdasarkan sumber / asal dari anti mikroba : I. Berasal dari alam: 1. Penisilin. 2. Tetrasiklin. 3. Kloramfenikol. 4. Streptomisin. 5. Polimiksin. 6. Sefalosporin. II. Berasal dari kimia sintetik : 1. Sulfonamida. 2. Isoniazid. 3. Kinolon. III. Berasal dari semi sintetik : 1. Nafsilin. Secara kimia maka anti mikroba dibagi atas 2 golongan: I. Golongan beta laktam. Anti mikroba beta laktam adalah: 1. Penisilin. 2. Sefalosporin. 3. Karbapenem. 4. Karbasepem. 5. Monobaktam. II. Golongan non-beta laktam. Berdasarkan aktivitas anti mikrobanya, maka penisilin diabagi atas: I. Aktivitas tinggi terhadap kuman Gram tetapi tidak tahan terhadap enzim penisilinase dan beta laktamase seperti: 1. Benzil penisilin 2. Fenoksi metil Pnc 3. Fenetisillin AB berdasar mekanisme kerja • Bakteriostatik a. Menahan pertumbuhan dan replikasi bakteri pada kadar serum yang dapat dicapai oleh tubuh manusia. b. Membatasi penyebaran infeksi saat sistem imun tubuh bekerja memobilsasi dan mengeliminasi bakteri patogen. misal: sulfanamid, kloramfenikol, tetrasiklin • Bakterisidal a. Membunuh bakteri serta jumlah total organisme hidup yang dapat diturunkan b. Dibagi 1. Bekerja pada fase tumbuh kuman misal: penisilin, sefalosporin, kuinolon 2. Bekerja pada fase istirahat misal: aminoglikosida, INH, kotrimoksazol II. Golongan Penisilin yang mempunyai aktivitavitas lemah terhadap kuman Gram tetapi tahan terhadap penisilinase. 1. Metisilin 2. Nafsilin 3. Oksasilin 4. Dikloksasilin 5. Kloksasilin 6. Floksasilin III. Golongan Penisilin yg mempunyai aktivitas yg kuat terhadap kuman Gram dan Gram , tetapi tidak tahan terhadap penisilinase dan beta laktamase. 1. 2 Ampisilin Amoksisilin 5 6 Bakampisilin Karbenisilin 9 Talampisilin 10 Piperasilin 3 4 Hetasilin Pivampisilin 7 8 Tikarsilin Episilin 11 Meziosilin 12 Aziosilin RESISTENSI • Mikroorganisme menghasilkan enzim yang merusak aktivitas obat. • Mikroorganisme mengubah permeabilitasnya terhadap obat. • Mikroorganisme mengubah struktur sasaran obat. • Mikroorganisme mengubah jalur metabolisme. • Mikroorganisme mengubah enzim. Beta-Laktam Antibiotics Bacterial Cell Wall Inhibitors Penicilins Cephalosporins Miscellaneus Narrow Spectrum Wider Spectrum Narrow Spectrum Narrow Spectrum Carbapenems Penicilinase Susceptible Penicilinase Resistant 1st Generation Aztreonam 2nd 3rd 4th Generation Vancomycin PENICILIN • 1929. A. Fleming jamur Penisilium. • All penicilin are derivat of 6-aminopenicillanic acid and contain a beta-lactam ring structure. • Inactivation with enzim Beta-lataktamase bacterial. Farmakologi. • Vary in resistence to gastric acid, vary in their oral bioavailability. • Ekskresi dengan cara glomerular filtrasi dan tubular sekresi. Mechanism of action. • Bactericidal drugs. • Inhibitor with following steps : – Binding to spesific reseptor. – Inhibition of transpeptidase enzyms.activation of autolytic enzims. Toxicity. • Allergy. • Gastrointestinal disturbances. Clinical use. • Narrow spectrum penicilinase susceptible agent : Penicilin G : infection cause by common streptococci, meningococci, gram positive bacilli, and spirachetes. • Narrow spectrum penicilinase resistant : Methicillin, nafcillin, oxacillin : primary use in the treatment of known or suspected staphylococcal infection. • Wider spectrum : – Ampicillin and amoxicillin : similar to penicillin use. – Piperacillin and ticarcillin : against several gram negative ( Pseudomonas, Enterobacter, and some case Kleibsiella species. SEFALOSPORIN Pertama sekali didapat Brotzu tahun 1948 dari Cephalosporium Acremonium. Bakterisid. Farmakologi. • Sefalosporin dapat diberikan secara suntikan dan secara oral. • Sefalosporin mudah menembus barier plasenta, cairan Synovial, cairan pericardial, cairan pleura. • Ekskresi dengan cara glomerular filtrasi dan tubular sekresi. • Ekskresi sebagian melalui ginjal, sebagian melalui empedu, dan sebagian utuh. PEMBAGIAN • Generasi pertama : cefadroksil, sefazolin, sefaleksin, sefalotin, sefapirin, sefadrin. • Generasi kedua : sefamandol naftat, seforanid, sefonisid, sefoksitin, sefaklor, sefuroksim. • Generasi ketiga : natrium cefotazime, natrium cefotetan, natriumceftizicime, natrium ceftriaxone, ceftazidime, cefixime, natrium cefoperazone, cefodoxime proxetil • Indikasi klinik: 1. Bakteremia. 2. Infeksi campuran. 3. Meningitis. • Efek samping: Urtikaria/reaksi alergi, superinfeksi, demam, granulositopenia, anemia hemolitik, nefritis, SGOT meninggi. Other Beta-lactam Drugs • Aztreonam. • Karbapenem : Imipenem, Meropenem, Ertapenam. • Lorakarbef. • Beta-laktamase inhibitors : Asam Klavulonat, Sulbaktam, Tozabaktam. Other Inhibitors Of Cell Wall Syntetis • Vancomycin. • Fosfomycin. • Bacitracin. Bacterial Protein Synthesis Inhibitors Broad Spectrum Moderate Spectrum Narrow Spectrum Chloramphenicol Tetracyclines Lincosamides Streptogamins Macrolides Linezolid Ketolides CHLORAMFENICOL • Antibiotika sintetik pertama. • Diisolasi pertama kali dari pembenihan Streptomyces venezuelae. • Has a simple and distinctive structure. • Usually bacteriostatic and bactericidal. • Effective orally as well as parenterally. • Crosses the placental and blood-brain barrier. • Undergoes enterohepatic cycling, small fraction excreted in the urine unchanged. • Most of the drug is inactivated by hepatic glucoronosyltransferase. Clinical use. • Drug for severe infections caused by salmonella and for treatment of pneumococcal and meningococcal meningitis. Toxicity. • Git disturbances. • Inhibition of red cell maturation lead to a decrease in circulating erytrocytes (bone marrow). • Aplastic anemia. • Gray baby syndrom. TETRACYCLINES • • • • Oral absorbtion is variable. Have a wide tissue distribution and cross placental barrier. Undergoes enterohepatic cycling. Doxycycline is excreted mainly in feces, but the ather drugs are eliminated primarily in the urine. • Broad spectrum antibiotics (gram-positive and gramnegative). Clinical use. • Primary use : treatment for infected by Mycoplasma pneumoniae(in adult), Chlamidya, Rickettsia, and Vibrio. • Secondary use : alternative in the treatment of syphilis. • Selective use : GIT ulcus by Helicobacter Pilory(Tetracyclin), Lyme disease (Doxixyclin), Meningococcal carrier state (Minocyclin). Toxicity. • • • • GIT disturbances. Bone structure and teeth. Hepatic toxicity, Renal toxicity, Vestibular toxicity. Photosesitivities. MACROLIDES • Include : Erytromycin, Azithromycin, and Chlaritromycin. • Have good oraly bioavailability, but azithromycin absorbtion is impeded by food. • Elemination : erithromycin via biliary excretion, chlaritromycin via hepatic metabolism and urinary excretion. Clinical use. • Erythromycin : M. pneumoniae, Corynebacterium, Campylobacter jejuni, Chlamidya trachomatis, Legionella pneumophyla, Ureaplasma urealyticum, and Bordetella pertusis. • Azithromycin : H. influenza, Moraxela cataralis, and Neisseria. • Clarithromycin : M. avium, ulcer by H. pilory. Toxicity. • GIT irritation, Hypersensitivity (acute cholestatic hepatitis), increase risk hepatic hepatitis on children. CLINDAMYCIN • Good tissue penetration occurs after oral absorbtion. • Eleminated partly by metabolism and partly by biliary and renal excretion. • Clinical use : treatment of severe infection caused by certain anaerob such as Bacteroides, also Pneumocytsis carini, and Toxoplasma gondii. • Toxocity : GIT irritation, skin rash, neutropenia, hepatic dysfunction, and posible superinfections such as C. difficile pseudomembranous colitis. AMINOGLYCOSIDES SULFONAMID TRIMETROPRIM FLUOROQUINOLONES AMINOGLYCOSIDES • Structurally related amino sugars attached by glycosidic linkage. • Hidrofilic, stabil dalam larutan, lebih aktif dalam keadaan pH alkalin daripada asam. • Not absorbed after oral administration and must be given intramuscularly, or intravenously for systemic effect. • Not readily cross the blood blood-brain barrier. • Excretion by glomerular filtration. Mechanism of Action. • Bactericidal with irreversible inhibitors of protein synthesis. • With 3 ways : – Block formation of the initiation complex. (menggangu komplex awal pembentukan peptida) – Misreading of the code on the mRNA templete.) (terjadi penggabungan asam amino yang salah dlm peptida) – Inhibit translocation.(polisom→monosom inaktif) Clinical use. • Gentamycin, Tobramycin, and Amikacin are important drug for treatment of serious infection caused by aerobic gram-negative bacteria. • Netilmicin is usually reseved for treatment of serious infections caused by organism resistant to the other aminoglycosides. • Streptomycin for treatment infection caused by micobacterium. • Kanamicin ototoxicitas tinggi, nephrotoxic.(penggunaan oral dibatasi) Toxicity. – – – – Ototoxicity. Nephrotoxicity. Neuromuscular blokade. Skin reaction. SULFONAMID TRIMETHOPRIM • Anti metabolites selectively. • Sulfonamid ihibit of folic acid synthesis, trimethoprim is a inhibitor of bacterial dihydrofolate reductase. • Sulfonamid-trimethoprin synergis of action. • Sulfonamid may be classified as : short acting (sulfisoxazole→6 jam), intermediate acting (sulfamethoxazole→10-12 jm), and long acting (sulfadoxine→7-9 hr). • Excretion with glomerular filtration (urine). • K.I untuk penyakit riketsia. Clinical use. • Sulfonamid : – Oral : simple urinary trac. infection, ulcerative colitis, rheumathoid arthritis, toxoplasmosis.infeksi sal.nafs,sinusitis,bronkhitis,pneumoni,otitis media,D.Basiler. – Topical : ocular infection, burn infection, dermatitis herpetiformis. • Trimethoprim : – Oral : acute urinary tract. infection. • Combination of Trimethoprim-Sulfametoxazole (TMP-SMX) : – Oral : respiratory and urinary tract. infection, prostatitis, etc. – Intravenous/drip with 125ml dextrose 5 % in 60-90mt : Pneumonia caused by P. carinii on the AIDS patient, sepsis gram-negative bacteria, shigellosis. Toxicity. • Sulfonamid : Hypersensitivity, GIT disturbances, Haematoxicity (granulocytopenia, thrombocytopenia, and aplastic anemia), Nephrotoxicity. • Trimethoprim : Megaloblastic anemia, Leukopenia, and Granulocytopenia. FLUOROQUINOLONES • Have good oral bioavailability and penetrate most body tissue. • Classified by generation based : – 1st Generation : Nalidixic acid, Norfloxacin, has activity against the common pathogens that cause urinary tract infection. – 2nd Generation : Ciprofloxacin, Ofloxacin, have greater activity against gram negatif bacteria, gonococcus, gram positif coccus, mycobacteria, mycoplasma pneumonia. – 3rd Generation : Levofloxacin, Gatifloxacin, Sparfloxacin, less active against gram negative bacteria, but have greater activity against gram positive cocci. – 4th Generation : Moxifloxacin, Trovafloxacin, the broadest spectrum fluoroquinolon, with enhanced activity against anaerobes. • Mechanism of action. Interfere with bacterial DNA synthesis by inhibiting topoisomerisase II and IV. • Clinical use : – Treatment of infections of urogenital and GI tract by gram negative organism. – Alternative in gonorrhea, administered in single oral dose (ciprofloxacin, ofloxacin). – Community-acquired pneumonia. – Anaerobic bacteria infection (moxifloxacin, trovafloxacin). Toxicity. • GI distress. • Skin rashes, headache, dizziness, insomnia, abnormal liver function test, phototoxicity. • Cartilage problems in developing animals not recommended for use in children and pragnancy. • Increase plasma levels of theophylline enhancing theophylline toxicity. • Cardiac arrhithmias (sparfloxacin). • Hepatotoxicity (trovafloxacin).