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Aminoglycosides & Spectinomycin Part A Aminoglycosides Overview • History and Source : the research made by Waksman and coworks within 19391943 • Clinical Applications: for the treatment of aerobic G- bacterial infections and tuberculosis • Two classes: crude product and semisynthetic derivative General properties 1. Antimicrobial activity: i) rapidly bactericidal to resting bacterium ii) broad-spectrum: G- bacilli and cocci,G+ organisms,TB iii) more active at alkaline iv) concentration-dependent activity v) the duration of post antibiotic effect (PAE) is concentration- dependent (10 hours). vi) first exposure effect (FEE) Peak Concentration Blood Concentration Bacterial growth is inhibited long after concentration below the MIC MIC Time (h) General properties 2. Mechanism of action: • inhibit protein synthesis • act as Ionic-absorbent, act directly on permeability of the cell membrane of bacterium. Inhibiting protein synthesis: P A Aminoglycosides 2.Mechanism of action - inhibit protein synthesis i) Interfering with the initiation complex of peptide formation. ii) Inducing misreading of mRNA, which causes the incorporation of incorrect amino acid into peptide, resulting nonfunctional or toxic protein. iii) causing breakup of polysomes into nonfunctional monosomes. iv) disrupt the normal cycle of ribosomal, make the ribosomal exhausted. 3. Mechanism of resistance produces enzymes Changes of Porins Altered ribosomal subunit Mechanism of Resistance i) The microorganism produces a transferase enzyme or enzymes that inactivate the aminoglycoside by adenylyation, acetylation, or phosphorylation. ii) Impaired entry of aminoglycoside into the cell. iii) The receptor protein on the 30S ribosomal subunit may be deleted or altered as a result of mutation. General properties ADME i) Absorption: not absorbed after po, but rapidly absorbed after IM. ii) Distribution: Binding to plasma protein is minimal, do not enter cell, nor do they cross BBB,but they cross the placenta, reach high concentrations in secretions and body fluids. Tissue level is low expect in the cortex of kidney. iii) Elimination: excreted mainly by glomerular filtration. If renal function is impaired, accumulation occurs with a increase in those toxic effects which are dose related. General properties Clinical Uses • be mostly used against aerobic G- bacteria (bacilli, enteric) and in sepsis, be almost always used in combination with b-lactam antibiotic and fluoroqunolones • Tuberculosis General properties Adverse reactions i) Ototoxicity • involves progressive damage to and destruction of the sensory cells in the cochlea and vestibular organ in the ear (irreversible!! Auditory and vestibular damage). ii) Nephrotoxicity • consists of damage to the kidney tubules and be reversed if stop using. General properties Adverse reactions iii) Neuromuscular blockade (paralysis) • generally occurred after intra-pleural or intraperitoneal instillation of large doses of an aminoglycosides • Calcium salt or inhibitor of cholinesterase (neostigmine) is the preferred treatment for this toxicity. iv) Allergic reaction • skin rashes fever, eosinophiliay , anaphylactic shock, etc. Aminoglycosides • • • • • • • Streptomycin Gentamicin Tobramycin Amikacin Netilmicin Neomycin Kanamycin • • • • • • • Arbekacin Dibekacin Micronomicin Sisomicin Etilmicin Isepamicin Astromicin Streptomycin 1. ADME i) Absorption: IM ii) Distribution: mainly at extracellular fluid, crosses the BBB and achieves therapeutic concentrations with inflamed meninges. iii) Excretion: 90%, kidney 2.Clinical uses i) plague and tularemia: combination with an oral tetracycline. ii) tuberculosis: as first-line agent iii) bacterial endocarditis: (enterococcal, viridans streptococcal, etc.), streptomycin and penicillin produce a synergistic bactericidal. 3. Adverse reactions i) Allergic reaction skin rashes, fever, anaphylactic shock ii) Ototoxicity: disturbance of vestibular function, deafness of newborn iii) Nephrotoxicity iv) Neuromuscular blockade (paralysis):Myasthenia Gravis, anesthetics, scoline Gentamicin 1. ADME Gentamicin can accumulate in cortex of the kidney . 2.Clinical use : i) serious G- bacillary infections (sepsis, pneumonia, etc.). ii) infection induced by enterococcal, viridans streptococcal, staphylococcal etc. (in combination with other antibiotics, e.g. b-lactams) iii) prevent the infection induced by operation (e.g., gastrointestinal operation ) iv) local application or intrathecal administration (rarely use) 3. Adverse reactions i) Nephrotoxicity (reversible and mild) ii) Ototoxicity (irreversible!) iii) Nausea and vomiting etc. Tobramycin 1. antimicrobial activity & pharmacokinetics: very similar to those of gentamicin; has crossresistance to gentamicin. 2. Adverse reactions: Ototoxicity and Nephrotoxicity (may be less than dose gentamicin). Netilmicin 1. similar to gentamicin & tobramycin in its pharmacokinetic properties. 2. broad spectrum, against aerobic G- bacilli. 3. tolerance to many aminoglycosides (gentamicin, tobramycin) - inactivating enzymes. 4. less toxic Amikacin 1.Antibacterial activity: the broadest in the group. 2.Clinical uses : • Treatment of G-bacillary infections which resistance to gentamicin and tobramycin. • Most strains resistance to amikacin found is also resistance to other aminoglycosides. • combination with b-lactams, produce a synergistic bactericidal. 3. Adverse reactions i) Ototoxicity ii) Nephrotoxicity iii) Neuromuscular blockade (paralysis) iv) skin rashes, fever, nausea and vomiting etc. Macrolides and lincomycin Structure Representative drugs First generation Erythromycin Dirithromycin Meleumycin Josamycin Acetylspiramycin Midecamycin Rokitamycin Roxithromycin Second Clarithromycin generation Azithromycin Acetylmidecamycin flurithromycin Penicillin-resistant Staphylococcus Penicillin-allergic patients Penicillin-resistant Staphylococcus Penicillin-allergic patients 1. Antibacterial spectrum board bactericidal or bacteriostatic drugs G+ and G- bacteria, cocci, Neisseria gonorrhea, gram-positive bacilli, and spirochetes, mycoplasma, rickettsiosis 2. Mechanisms Inhibition of protein synthesis (1) reversible binding to 50S subunit of ribosome (23S rRNA) (2) L22 protein binding in 50S subunit, lead to disruption of ribosome 3. Clinical Usage (1) Streptococci infection (2) Legionella pneumophila (3) infection from spirochetes, mycoplasma, rickettsiosis 4. Adverse reaction (1) GI (2) hepatic damage (3) superinfection: infection that occurs while treating another infection. e.g. oral fungal infection (4) Ototoxicity (5) allergic reaction Lincomycin & Clindamycin • Antibacterial spectrum (1) board bactericidal or bacteriostatic drugs, similar to the macrolides (2) Anaerobic G+ and G- bacteria 2. Mechanisms Inhibition of protein synthesis L16 protein binding in 50S subunit, lead to disruption of ribosome. Avoid to using with erythromycin (same binding sites), antagonistic effects. 3. Clinical Usage (1) Aerobic bacteria (2) anaerobic bactreria (3) infection from staphylcoccus in bone tissues (osteomyelitis ) 4. Adverse reaction (1) GI (2) hepatic damage (3) allergic reaction Tetracyclins and chloramphenicol Natural products Semisynthesis Chlortetracycline Oxytetracycline tetracycline Doxycycline Methacycline minocycline 1. Antibacterial spectrum board bacteriostatic drugs G+ and G- bacteria, cocci, spirochetes, mycoplasma, rickettsiosis, chlamydia. 2. Mechanisms (1) Cell membrane transportation (2) Inhibition of protein synthesis 30S subunit of ribosome (3) permeability 3. Clinical Usage (1) spirochetes (2) mycoplasma (3) rickettsiosis, (4) chlamydia (5) bacteria 4. Adverse reaction (1) GI (2) hepatic damage (3) superinfection: infection that occurs while treating another infection. e.g. oral fungal infection (4) teeth and bone (5) renal toxicity (6) photosensitized reaction (7) ototoxicity chloramphenicol 1. Antibacterial spectrum board bacteriostatic bactericidal drugs G+ and G- bacteria, spirochetes, mycoplasma, rickettsiosis, 2. Mechanisms Inhibition of protein synthesis 70S ribosome complex, 50S hematopoietic stromal cell in bone marrow, mammary 70S is similar to baterial 70S, lead to bone marrow suppression 3. Clinical Usage (1) bacterial meningitis, purulent Meningitis in Children (2) Corynebacterium diphtheriae infection (3) eye infection (bacteria) (4) anaerobic infection 4. Adverse reaction (1) GI (2) Gray baby syndrome: disturb the ribosome function in mitochondria ability of detoxication via glucuronic acid conjugation ability of renal excretion (3) bone marrow suppresion: AA, anemia, granulocytopenia, thrombopenia Vancomycins • Antibacterial Mechanism Inhibiting cell wall synthesis by binding to the D-Ala-D-Ala terminus of nascent peptidoglycan pentapeptide. • Resistance occurred because of the alteration of D-Ala-D-Ala to the D-Ala-D-Ser. Fig. Antibacterial Mechanism of Vancomycins Vancomycins • ADME • Oral administration (poorly absorbed). • Intravenous administration, is excreted by glomerular filtration (accumulates when renal function is impaired). • Widely distributed in the body, including CSF when the meninges is inflamed. Vancomycins • Clinical Uses 1) severe infection caused by MRSA etc. 2) alternative for b-lactam 3) enterococcal or staphyococcal endocarditis (combination with gentamicin). 4) pseudomembranous colitis ***Overuse should be avoided, in view of limited options for treatment of resistant gram positive infections. Vancomycins • Adverse Reactions 1) Hypersensitive reaction (e.g. red man syndrome) 2) Ototoxicity 3) Nephrotoxicity 4) Gl effects, Phlebitis etc. Part B Synthetic antimicrobial agents Synthetic antimicrobial agents • Quinolones Generation Example 1 Nalidixic acid 2 Pipemidic acid 3 Norfloxacin 4 Clinfloxacin time 1962 1973 1980’s 1990’s • Sulfonamides • Other Synthetic antimicrobial Trimethoprim, Nitrofurans From chloroquine to nalidixic acid First generation fluoroquinolones R 6 5 8 R 4 1 7 R 3 2 From ofloxacin to levofloxacin Fluoroquinolones General properties of Quinolones Antimicrobial activity & spectrum: (1) bactericidal and have significant PAE. (2) aerobic G- bacteria, Pesudomonas, aerobic G+ bacteria, Chlamydia spp., Legionella pneumophila , anaerobic bacteria, mycobacteria, multipleresistance strains. Mechanism of action DNA gyrase Topoisomerase Key enzymes in DNA replication: bacterial DNA is supercoiled. Mechanism of action porin DNA gyrase Gram (-) Topo isomerase Gram (+) Mechanism of action DNA gyrase Catalytic subunite Fluoroquinolones: 4 stacked molecules DNA gyrase ATP binding subunite Mechanism of resistance decreased permeability active efflux system porin DNA gyrase Gram (-) Topo isomerase mutation of the enzymes Gram (+) ADME of fluoroquinolones • Absorption: well absorbed; bound by divalent cations – Do not administer with iron, magnesium, calcium • Distribution: all distribute widely (even in CSF), and most concentrate in urine • Metabolism: – hepatic metabolism diminishes the activity of norfloxacin and ciprofloxacin – Several have predominately hepatic clearance (Grepafloxacin, Sparfloxacin, Trovafloxacin) • Excretion: urinary excretion predominates for the first generation fluoroquinolones Clinical Uses • • • • • • Urinary tract infections. GI and abdominal infections. Respiratory tract infections. Bone, joint and soft tissues infections, Osteomyelitis. Meningitis STD: Neisseria gonorrhea and Chlamydia (Quinolone resistance in gonorrhea increasing) Adverse reactions • Gastrointestinal effects. • CNS side effects. • Allergic reaction. • Hepatotoxicity, nephrotoxicity. • Joint/cartilage toxicity, Tendinopathy – Achilles tendon rupture – Limited FDA approval for children (under 18) Fluoroquinolones agents • • • • • • • • • Norfloxacin Ciprofloxacin Ofloxacin Levofloxacin Lomefloxacin Fleroxacin Sparfloxacin Clinafloxacin Gatifloxacin Sulfonamides : Inhibitors of Folate Synthesis 2,4-Diaminoazobenzen-4’-sulfonamide Prontosil Gerhard Domagk Nobel Laureate 1939 Antimicrobial activity: •A wide antimicrobial spectrum. •Exerting only bacteriostatic effect. Mechanism of action Pteridine+PABA Dihydropteroate synthase Blocked by sulfonamides Dihydropteroic acid glutamate Dihydrofolic acid Dihydrofolate reductase NADPH Blocked by trimethoprim NADPH Tetrahydrofolic acid Mechanism of Resistance • A lower affinity for sulfonamides by the dihydropteroate synthase • Decreased cell permeability or active efflux of the drug • An alternative pathway to synthesis the essential metabolites • An increased production of essential metabolites Classification & Clinical uses : • Oral absorbable agents (Systemic infections) ─ Short-acting agents: Sulfafurazole (SIZ) ─ Medium-acting agents: Sulfadiazine (SD) [Co: pyrimethamine → toxoplasmosis] best in the CSF and brain → → meningitis Sulfamethoxazole (SMZ) [Co: trimethoprim, named trimoxazole / TMP-SMZ ─ Long-acting agents: Sulfadoxine (SDM) [Co: pyrimethamine → malaria] • Oral nonabsorbable agents (Intestinal infections) Sulfasalazine • Topical agents (Infections of burn and wound) Mafenide (SML) Sulfadiazine sliver Sulfacetamide (SA) ADME of sulfonamides • Approximately 70%-100% of an oral dose is absorbed. • Distributing throughout all tissues of the body, even in CSF ( sulfadiazine and sulfisoxazole, may be effective in meningeal infections) ;readily passing through the placenta. • Metabolized in the liver by acetylation. • Eliminated mainly in the urine as the unchanged drug and metabolic product. In acid urine, the eliminated may precipitate, thus induced renal disturbance. Adverse reactions • Hypersensitivity reaction • Urinary tract disturbances: Sulfonamide crystalluria • • • • Hematopoietic system disturbances Kernicterus Hepatitis GI effects Drugs interactions • All sulfonamides are bound in varying degree to plasma protein. Combination agents: Co-trimoxazole 1) Features • Trimethoprim in combination with Sulfamethoxazole (1:5,eg,160mg:800mg for p.o.) exerts a synergistic effects (bacteriocidal effect ). • Co-block essential enzymes of folate metabolism. • The ADME of the two agents is similar. Pteridine+PABA Dihydropteroate synthase Blocked by sulfonamides Dihydropteroic acid glutamate Dihydrofolic acid Dihydrofolate reductase NADPH Blocked by trimethoprim NADPH Tetrahydrofolic acid 2)Clinical Uses • • • • Chronic and recurrent infections in the urinary tract Bacterial respiratory infections GI infections (e.g. induced by Salmonella) pneumocystis carinii pneumonia 3)Adverse reactions • There is no evidence that co-trimoxazole, when given in recommended dose, induced folate deficiency in normal persons. • Trimethoprim(TMP): megaloblastic anemia • Sulfamethoxazole (SMZ): all adverse reactions mentioned • HIV patients (fever, rashes, leukopenia, diarrhea, hyperkalemia) • Drug interactions: warfarin, phenytoin, etc.