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Psi 2
 

Psi 2

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  • This slide shows the different site of action of protein synthesis inhibitors
  • Buy AT 30, CELLS at 50 Protein Synthesis Inhibitors 30 S INHIBITORS Aminoglycoside Tetracyclines 50 S INHIBITORS Chloramphenicol Macrolides Clindamycin Streptogramins Oxazoladinones
  • I. Older Aminoglycosides: Is a large group of bactericidal drug Streptomycin Kanamycin Newer Aminoglycosides: Gentamicin Sisomicin Neomycin Paromomycin Amikacin Netilmicin Tobramycin
  • Antimicrobial Spectrum: Gram (-) Aerobic Bacilli Beta-lactamase producers: Staph. aureus N. gonorrhea Mycobacteria
  • Mechanism of action The initial event is passive diffusion via porin across the outer membrane. Drug is then actively transported across the cell membrane into the cytoplasm by an oxygen dependent process. The transmembrane electrochemical gradients supplies the energy for this process and transport is coupled by proton pump. Low extracellular pH and anaerobic conditions inhibit the transport by reducing the gradient. The transport may be enhanced by cell wall active drugs, such as penicillin and vancomycin. This enhancement may the basis of the synergism. Once inside the cell it binds the 30S subunit. Protein synthesis is inhibited by atleast 3 ways: Interferes with the intiation complex of peptide formation They induce misreading of mRNA, causing incorporation of incorrect amino acids into the peptide resulting in a non-functional or toxic protein They cause a breakup of polysomes into non-functional monosomes These activities occurs more or less simultaneously, and the overall effect is irreversible and lethal for the cells
  • Three principal mechanism of resistance. Microorganism develops by: The microorganism produces a transferase enzyme or enzyme that inactivate the aminoglycoside by adenylation, acetylation, or phosphorylation. This the principal type of resistance encountered. Impaired entry of the drug into the cell through cell surface alteration. This may be genotypic. Resulting from mutation or deletion of porin proteins. Or phenotypic, resulting from condition under which the oxygen dependent transport process is not functional The receptor protein on the 30S ribosome may be deleted or altered as a result of mutation
  • Kinetics Absorbed very poorly from intact gastrointestinal tract They are highly polar compounds that do not enter the cells readily. They are largely excluded from the CNS and the eye. Not significantly metabolize Primarilly excreted unchanged through glumerular filtration dosage adjustment must be observed to avoid accumulation of drug and toxicity in patient with renal insufficiency
  • Clinical Uses: severe gram (-) enteric bacteria especially when there is suspicion of sepsis Almost always used in combination with a beta-lactam antibiotic to extend coverage to include potential gram (+) pathogens and to take advatage of the synergism between the two classes of drugs. Penicillin aminoglycoside combinations also are used to achieve bactericidal activity in treatment of enterococcal endocarditis and to shorten duration of therapy for viridans streptococcal and staphylococcal endocarditis Mycobacterial infections Which aminoglycoside and what dose should be used depend upon the infection being treated and susceptibility of the isolate
  • Toxicity All aminoglycoside are ototoxic and nephrotoxic Ototoxicity and nephrotoxicity are more likely encountered when therapy is continued for more than five days Concurrent use with loop diuretics like ethcrynic acid can potentiate ototoxicity and should be avoided Ototoxicity can manifest itself as auditory damage resulting in tinnitus and high frequency hearing, loss. Neomycin, Kanamycin and amikacin are most ototoxic Or it can also manifest as vestibular damage evident by vertigo ataxia and loss of balance. Streptomycin, Gentamicin are most vestibulotoxic Concurrent used of nephrotoxic agent can potentiate nephrotoxicity and should be avoided Neomycin, Tobramycin, Gentamicin are the most nephrotoxic
  • Streptomycin Ribosomal resistance to this agent develops readily, limiting its role as a single agent mainly used as a second line agent for treatment of tuberculosis given at 0.5-1 g/d , IM or IV. usually given in drug combination to prevent emergence of resistance. In plague, tularemia and sometimes brucellosis, 1 g/d (15 mg/kg/d for children) IM or IV + oral tetracycline + Penicillin; effective for enterococcal endocarditis and 2 week therapy of viridans streptococcal endocarditis. can cause fever, skin rashes and other allergic reactions, pain at the injection site, vestibular dysfunction-most serious toxic effect if given during pregnancy, can cause deafness in the newborn
  • Gentamicin At present gentamicin is employed mainly in severe infections (sepsis and pneumonia) caused by gram negative bacteria that are likely resistant to other drugs especially pseudomonas, enterobacter, serratia, proteus, and klebsiella. Used in combination with cephalosporin or a penicillin Given at 5-6 mg/kg/d I300V in three equal doses Concurrently used with Penicillin G for bactericidal activity in endocarditis due to viridans streptococci or enterococci and in combn with Nafcillin in selected cases of staphylococcal endocarditis Neither gentamicin nor any other aminoglycosides should be used for single agent therapy of pneumonia because penetration of infected lung tissue is poor and local condition of low pH and low oxygen contribute to poor activity
  • Gentamicin sulfate 0.1% - 0.3% cream, ointment – for the treatment of infected burns, wounds, or skin lesions and the prevention of intravenous catheter infections. Topical gentamicin is partly inactivated by purulent exudates Ten milligrams can be injected subconjunctivally for treatment of ocular infections Nephrotoxicity is reversible and usually mild Irreversible ototoxicity manifested as vestibular dysfunction hypersensitivity reactions are uncommon
  • Tobramycin antimicrobrial spectrum and pharmacokinetic properties virtually identical to gentamicin given at 5-6 mg/kg IM or IV into three equal amounts q 8 hours. Blood levels should be monitored in renal insufficiency Slightly more active against pseudomonas but not to E. faecium Ototoxic and nephrotoxic
  • Amikacin Semisynthetic derivative of kanamycin Resistant to many inactivating enzymes. Therefore can be employed against some organism resistant to gentamicin and tobramycin Strains of multi-drug M. tuberculosis including streptomycin-resistant strains are usually susceptible. Given at 7.5 – 15 mg/kg/day as once daily or 2-3x weekly Serum concentrations should be monitored Nephrotoxic and ototoxic (auditory portion of CN VIII)
  • Netilmicin shares many characteristics with gentamicin and tobramycin dosage and the routes of administration are the same , completely therapeutically interchangeable with gentamicin or tobramycin and has similar toxicities
  • Kanamycin & Neomycin Paromomycin also a member of this group. Used for bowel preparation for elective surgery There is complete cross-resistance between kanamycin and neomycin Not significantly absorbed from the GIT; excretion of any absorbed drug is mainly through GF into the urine Too toxic for parenteral use, now limited to topical and oral use Solutions 1-5 mg/ml- used on infected surfaces or injected into joints, pleural cavity, tissue spaces or abscess cavities where infection is present. ( 15 mg/kg/d) Ointments (Neomycin-Polymyxin-Bacitracin combination); applied to infected skin lesions or in the nares for suppression of staphylococci
  • In preparation for elective bowel surgery, 1 g of Neomycin given orally q 6-8 hours + 1 g of erythromycin base; Paromomycin, 1 g q 6 hours orally for 2 weeks; effective in intestinal amebiasis Nephrotoxic and ototoxic ( Auditory dysfunction) Sudden absorption of postoperatively instilled kanamycin from the peritoneal cavity (3-5 g) has resulted in curare-like neuromuscular blockade and respiratory arrest (Calcium gluconate and neostigmine can act as antidotes) Prolonged application to skin and eyes has resulted to severe allergic reactions
  • Spectinomycin Chemically related to the aminoglycosides Binds at the 30 S subunit (bacteriostatic) Dispensed as the dihydrochloride pentahydrate for IM injection Used almost solely as an alternative treatment for gonorrhea in patients who are allergic to penicillin or whose gonococci are resistant to other drugs Single dose of 2 g (40 mg/kg) Can cause pain at the injection site , occasionally fever and nausea Nephrotoxicity and anemia – rare
  • II.TETRACYCLINES: Short Acting: Tetracyline, Oxytetracycline, Chlortetracycline Intermediate Acting: Demeclocycline, Methacycline Long Acting: Doxycycline, Minocycline
  • Antimicrobial Spectrum: Rickettsia, V. cholera, M. pneumonia, Chlamydia, Shigella, H. pylori, P.tularensis, P.pseudomallei, Brucella, Psittacosis, Borrelia Minocycline – carrier state of Meningococcal infections, N. asteroides, N. gonnorhea
  • Mechanism of Action: Enter microorganisms in part by passive diffusion and in part by an energy-dependent process of active transport Binds to 30 S, blocking the binding of amino-acyl trna to the acceptor site and prevents the addition of amino acids to the growing peptide Bacteriostatic
  • There are three mechanism of resistance decreased intracellular accumulation due to impaired influx or increased efflux by an active transport protein pump ribosome protection due to production of proteins that interfere with tetracycline binding to the ribosome enzymatic inactivation
  • Kinetics Distributed widely to tissue and body fluids except for CSF Absorption occurs mainly in the upper small intestine and is impaired by food (except Doxycyline and Minocycline) Must not be taken with dairy products or antacids Cross placenta, excreted in milk As result of chelation with Ca, they are bound to and damage growing bones and teeth Carbamazepine, phenytoin, barbiturates, and chronic alcohol ingestion may shorten the half-life of doxycycline Excreted mainly in bile and urine (Doxycycline fecally eliminated; can be used in renal failure)
  • Clinical Uses: DOC in infection with M. pneumoniae, chlamidiae,ricketsiae,and spirochetes. No longer recommended for gonococcal disease due to resistance. Usually use in combination aminoglycosides Can also be used in Borrelia burgdorfi (Lyme disease), Chlamydia, Ureaplasma, M. pneumonia, Acne, Tularemia, Cholera, Leptospirosis, Protozoal infections Minocycline, 200 mg orally daily for 5 days – can eradicate the meningococcal carrier state Demeclocycline – inhibits the action of ADH in the renal tubule and has been used in the treatment of inappropriate secretion of ADH or similar peptides by certain tumors
  • Clinical Uses: Tetracyclines – 250-500 mg 4x/day adults; 20-40 mg/kg/d-children above 8 y/o Demeclocycline and Methacycline -> 600 mg daily Doxycyline and Minocycline -> 100 mg 1-2x/d Toxicity: Renal toxicity, local tissue toxicity, photosensitization, GI distress, discolors teeth, inhibits bone growth in children, potentially teratogenic, hepatotoxicity, vestibular toxicity
  • THE 50 S INHIBITORS: CHLORAMPHENICOL MACROLIDES CLINDAMYCIN/LINCOMYCIN STREPTOGRAMINS OXAZOLADINONES
  • I. CHLORAMPHENICOL Bactericidal – H. influenze, N. meningitides, B. fragilis Bacteriostatic – S. epidermidis, S. aureus, , M. pneumonia, L. monocytogenes, C.diphtheria, L. multocida, Salmonella sp., Shigella sp., E. coli, Rickettsia, Anaerobes
  • MECHANISM OF ACTION: attaches at P sites of 50 S subunit of microbial ribosomes and inhibits functional attachment of amino-acyl end of AA-t-RNA to 50 S subunit inhibits peptidyl transferase step
  • SPECTRUM: broad spectrum antibiotic more effective than Tetracyclines against Typhoid Fever and other Salmonella infections
  • KINETICS: well absorbed after oral administration; usual dosage is 50-100 mg/kg/d Chloramphenicol succinate used for parenteral administration is highly water soluble distributed into total body water excellent penetration into CSF, ocular and joint fluids rapidly excreted in urine, 10% as chloramphenicol; 90% as glucuronide conjugate; small amount of active drug is excreted into bile or feces systemic dosage need not be altered in renal insufficiency but must be reduced markedly in hepatic failure Newborns less than a week old and premature infants also clear Chloramphenicol less well, dosage should be reduced at 25 mg/kg/d.
  • CLINICAL USES: Meningitis, Rickettsia, Salmonella and anaerobic infections; ineffective against chlamydial infections occasionally used topically in the treatment of eye infections for its well penetration to ocular tissues and the aqueous humor ADVERSE EFFECTS: GIT, oral or vaginal candidiasis, irreversible aplastic anemia, reversible bone marrow depression, Gray Baby Syndrome New born infants lack an effective glucoronic acid conjugation mechanism for degradation and detoxification of chloramphenicol.
  • MACROLIDES:Are a group of closely related compound characterized by macrocyclic lactone ring ( usually containing 14 to 16 atoms) to which deoxy sugar are attached. The prototyped drug is erythromycin Old Generation: Erythromycin, Oleandomycin, Troleandomycin, Spiramycin, Josamycin New Generation: Rosaramycin, Roxithromycin, Clarithromycin, Azithromycin, Dirithromycin
  • MECHANISM OF ACTION: binds to the P site of the 50 S bacterial ribosomal subunit. Aminoacyl translocation and formation of initiation complex are blocked Inhibitory or bactericidal Activity is enhanced at alkaline pH.
  • Resistance: is usually plasmid-encoded Reduced permeability of the cell membrane or active efflux production (by Enterobacteriaceae) of esterases that hydrolyze macrolides modification of the ribosomal binding site by chromosomal mutation Efflux and methylase production account for the vast majority of cases of resistance in gram-positive organism Cross resistance is complete between rythromycin and other macrolides
  • SPECTRUM: Erythromycin has a narrow Gram (+) spectrum similar to Pen. G. Also active against Chlamydia and Legionella organisms
  • Erythromycin prototype distributed into total body water poor CSF penetration food interferes with absorption serum half life is app. 1.5 h normally and 5 hours in patients with anuria not removed by dialysis metabolized in the liver traverses the placenta and reaches the fetus COMMERCIAL PREPARATIONS: Oral-stearate, ethyl succinate, estolate salts: 250-500 mg q 6 h . Esterates are acid resistant and better absorbed. Estolate best obsorbed. Parenteral- lactobionate, gluceptate : 0.5-0.1. g q 6 hours
  • ADVERSE EFFECTS: GIT dysfunction, intrahepatic cholestatic jaundice (particularly the estolate preparation) erythromycin metabolites can inhibit cytochrome p450 enzymes & thus increase the serum concentrations of theophylline, oral anticoagulants, cyclosporine and methylprednisolone; also oral digoxin by increasing its bioavailability
  • Clarithromycin Derive from erythromycin by addition of methyl group and has improved acid stability and oral absorption more active against Gram (+) pathogens, Legionella and Chlamydia than Erythromycin lower frequency of GIT effects, less frequent dosing advantage over Erythromycin half life of 6 hours given at 250-500 mg twice daily
  • Azithromycin 15 atom lactone macrolide Derived from erythromycin by addition of a methylated nitrogen into the lactone ring Active against M. avium and T.gondii Less active than erythromycin and chlarithromycin against staph. and strep. More active against H. influenzae and chlamydia Penetrates into most tissues (except CSF) and phagocytic cells extremely well maintains high concentrations for prolonged periods into a number of tissues (lungs, tonsils, cervix) tissue half life – 2-4 days long half-life allows once daily oral administration and shortening of treatment in many cases ( 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 – 500 mg loading dose, followed by a 250 mg single daily dose for the next 4 days should be administered 1 hour before or 2 hours after meals; aluminum and magnesium delay absorption and reduce peak serum concentrations does not inactivate cytochrome p450 enzymes and free of the drug interactions that occur with erythromycin and clarithromycin
  • CLINDAMYCIN / LINCOMYCIN MECHANISM OF ACTION: attach to 50 S ribosomal subunit, inhibits protein synthesis by interfering with the formation of initiation complexes and translocation reaction SPECTRUM: Has a Narrow Gram (+) spectrum, excellent activity against anaerobic bacteria; strep, pneumococci, staphylococci
  • RESISTANCE: mutation of the ribosomal receptor site modification of the receptor by a constitutively expressed methylase enzymatic inactivation
  • Clindamycin is more clinically used than Lincomycin given at 150-300 mg q 6 hrs adults ;10-20 mg/kg/d for children low concentration in CSF well bone penetration excreted mainly via the liver, bile and urine half life is 2.5 hours normally and 6 hours in patients with anuria more toxic than erythromycin
  • Clinical uses: prophylaxis of endocarditis in patients with valvular heart disease for dental procedures most important indication is the treatment of severe anaerobic infection caused by bacteroides and other anaerobes that often participate in mixed infections + aminoglycoside or cephalosporin- used to treat penetrating wounds of the abdomen & gut, septic abortion, pelvic abscesses, aspiration pneumonia
  • septic abortion, pelvic abscesses, aspiration pneumonia + primaquine – effective alternative to trimethoprim sulfamethoxazole for moderate to moderately severe Pneumocystis carinii pneumonia in AIDS patients + pyrimethamine for AIDS – related toxoplasmosis of the brain. ADVERSE EFFECTS: Diarrhea, nausea , skin rashes, impaired liver function and neutropenia Antibiotic associated colitis caused by toxigenic C. difficile.
  • Quinuprisitn-Dalfopristin (Synercid) action is similar to macrolides except bactericidal for staph and most organisms except Enterococcus faecium prolonged postantibiotic effect up to 10 h for Staph. aureus administered IV at 7.5 mg/kg q 8 -12 h eliminated through fecal route, < 20% urine Patients with hepatic insufficiency may not tolerate the drug at usual doses inhibits CYP 3A4, which metabolizes warfarin, diazepam, astemizole, terfenadine, cisapride, nonnucleoside reverse transcriptase inhibitors and cyclosporine.
  • Clinical Uses: infections caused by Vancomycin resistant strains of E faecium but not E. faecalis, bacteremia or respiratory tract infections caused by methicillin-resistant staphylococci and penicillin susceptible and resistant strains of S. pneumonia Toxicities: infusion related events, pain at the injection site, arthralgia, myalgia
  • OXAZOLADINONES: Linezolid (Zyvox) inhibits protein synthesis by preventing formation of the ribosome complex that initiated protein synthesis. Its unique binding site located on 23 S ribosomal RNA of the 50 S subunit, results in no cross resistance with other drug classes Has high oral bioavailability, half life of 4-6 h Uses : staph, strep, enterococci, G(+) anaerobic cocci, G (+) rods, Corynebacterium, L. monocytogenes - treatment of infections caused by vancomycin resistant E. faecium and other infections caused by multiple drug resistant organisms.
  • METABOLIC INHIBITORS Sulfonamides structural analogs of PABA competitively inhibit dihydropteroate synthase inhibits growth by reversibly blocking folic acid synthesis bacteriostatic
  • Spectrum of activity: Inhibit the growth both Gm (+) and Gm (-) bacteria, Nocardia, Chlamydia trachomatis & some protozoa Enteric bacteria such as E.coli,klebsiella, salmonella,shigella, and enterobacter are also inhibited Rickettsia – not inhibited but growth stimulated by sulfas
  • Resistance Mutation that cause overproduction of PABA Enzyme inactivation Loss of permeability to sulfonamides Resistant cells may be present in susceptible bacteria    
  • Divided into Three Major Group Oral, absorbable a. Short acting – Sulfacytine, Sulfisoxazole, Sulfamethizole b. Intermediate acting – Sulfadiazine, Sulfamethoxazole, Sulfapyridine c. Long acting – Sulfadoxine   Oral, non absorbable – Sulfasalazine Topical – Sulfacetamide, Mafenide, Silver Sulfadiazine (burn victims)  
  • topical a.Sodium sulfacetamide ophthalmic sol’n or ointment – for bacterial conjunctivitis b. Mafenide acetate- prevent bacterial colonization and infection of burn wounds c. Silver sulfadiazine –prevent of infection in burn wounds
  • Pharmacokinetics Well absorbed from the GIT Widely distributed in the body including the CNS Highly bound to albumin Penetrate the CNS well Cross the placenta & secreted thru breast milk Acetylated ..retains toxic potential urine
  • SPECTRUM: gram (+) & gram (-) Simple urinary tract infection - used short to medium acting agents like sulfisoxazole and sulfmethoxazole Ocular infection Burn infections Ulcerative colitis With pyrimethamine: Toxoplasmosis Malaria
  • Adverse Reaction Hypersensitivity Reaction Photosensitivity Nausea & vomiting Hemolytic anemia Crysralluria & nephrotoxicity ( tx alkalinize the urine by NaHCO 3) sulfonamides ppt. at neutral or acid pH Kernicterus CI: Pregnancy & newborn DI: Compete with wafarin, tolbutamide, methotrexate for PPB
  • TRIMETOPRIM SULFAMETHOXAZOLE ( CO-TRIMOXAZOLE ) COMBINATION CAUSES: 1. INCREASE POTENCY 2. INCREASE SPECTRUM 3. DECREASE INCIDENCE OF RESISTANCE MOA: blocks the sequential steps in the obligate enzymatic reaction in bacteria preventing formation of nucleotide
  • Pharmacokinetcs Trimetoprim: more lipid soluble, greater Vd Given in 1: 5 ratio Uses UTI Pneumocystis carinii pneumonia (drug of choice) Shigellosis Systemic salmonella infection caused by ampicillin and chloramphenicol resistant-organism Some nontuberculous mycobacterial infection  
  • Megaloblastic anemia Leucopenia Prevented by administration of folinic acid 6-8mg/day Granulocytopenia  
  • NUCLEIC ACID SYNTHESIS INHIBITORS First Generation: Nalidixic acid Second Generation: Ofloxacin, Ciprofloxacin, Norfloxacin, Levofloxacin Third Generation: Gatifloxin, Sparfloxacin Clinafloxacin, Fourth Generation: Trovafloxacin, Moxifloxacin The newer generation has greater activity against gram positive organism
  • Bactericidal Inhibits DNA Gyrase or Topoisomerase II - Block the relaxation of supercoiled DNA that is catalyzed by DNA gyrase Inhibits Topoisomerase IV – interferes with the separation of replicated chromosomal DNA during cell division
  • Resistance Modification of DNA Gyrase Decreased accumulation in the bacterial cell due to : reduction of the porin proteins in the outer membrane energy dependent efflux system of the inner membrane
  • Clinical Uses SPECTRUM: broad ; aerobic gm (+) & gm (-) but not anaerobes UTI Sexually transmitted diseases : Gonorrhea, Chlamydia, chacroid Prostatitis Respiratory infection due to H. influenza, M. catarrhalis, Strep pneumoniae, M. pneumoniae Norfloxacin is the least active against both gram + and gram – organism Second generation – ciprofloxacin, levofloxacin, = excellent gram – and moderate to good gram + activity
  • CIPROFLOXACIN Most widely used DOC for anthrax Most potent for Ps, aeroginosa Synergististic with beta lactams M. tuberculosis NORfLOXACIN Not effective in systemic infection (fail to achieve systemic antibacterial level and least active agent for gram+ as well as Gram-
  • LEVOFLOXACIN Prostatitis ,E. coli Sexually transmitted diseases, gonorrhea Skin & lower infections S. pneumoniae TROVA & MOXIFLOXACIN Anaerobes, P. AEROGINOSA GATIFLOXACIN Resp infection , S. pneuomoniae
  • Side Effects Nausea & diarrhea Headache, dizziness, light headedness Arthralgia & joint swelling Rashes & photophobia
  • CI: PREGNANT WOMEN, NEONATES ARRYTHMIAS: SPARFLOXACIN & MOXIFLOXACIN: prolong QT intervals DI: ↓ ABSORPTION WITH ANTACID , FeSo4 Cimetidine interferes elimination Ciprofloxacin & ofloxacin: ↑ theophylline levels

Psi 2 Psi 2 Presentation Transcript

  • Protein Synthesis Inhibitors Claro M. Isidro M.D.
  • Protein Synthesis
    • Stages of Protein Synthesis
    • 1. Initiation - involves formation of an initiation complex that contains mRNA, both subunits of ribosomes and the first aminoacyl-tRNA (formyl-methionyl tRNA)
    • 2. Elongation - includes synthesis of the first peptide bond to addition of the last amino acid. Also involved
      • Peptide bond formation - polypeptide is transferred from peptidyl-tRNA in the P site to aminoacyl-tRNA in the A site
      • Translocation - moves ribosome one codon; places peptidyl-tRNA in the P site; deacylated tRNA leaves via the E site; A site is empty for next aa-tRNA
  • Summary
    • 3. Termination – encompasses the release of the completed polypeptide chain and dissociation of the ribosome from the mRNA.
  •  
  • Protein Synthesis Inhibitors
    • 30 S INHIBITORS
    • A minoglycoside
    • T etracyclines
    • Buy AT 30 , CELLS at 50
    • 50 S INHIBITORS
    • C hloramphenicol
    • Macrolides ( E rythromycin)
    • C l indamycin
    • Oxazoladinones ( l inozelid)
    • S treptogramins
  • I. AMINOGLYCOSIDES
    • Older Aminoglycosides:
    • Streptomycin
    • Kanamycin
    • Newer Aminoglycosides:
    • Gentamicin
    • Netilmicin
    • Tobramycin
    • Sisomicin
    • Neomycin
    • Paromomycin
    • Amikacin
  • I. AMINOGLYCOSIDES
    • Antimicrobial Spectrum:
    • Gram (-) Aerobic Bacilli
    • Beta-lactamase producers:
    • Staph. aureus
    • N. gonorrhea
    • Mycobacteria
  • I. AMINOGLYCOSIDES
    • Mechanism of Action:
    • interferes with initiation complex of peptide formation
    • induces misreading of mRNA causing incorporation of incorrect AA
    • causes breakup of polysomes into nonfunctional monosomes
    • Require oxygen uptake, therefore ineffective against anaerobes.
    • Bactericidal
  • I. AMINOGLYCOSIDES
    • Microbial Resistance:
    • enzyme inactivation
    • Cell surface alteration
    • receptor protein alteration
    • oxygen requirement related
  • I. AMINOGLYCOSIDES
    • Kinetics:
    • Very poorly absorbed from intact GIT, well absorbed thru IM, IV
    • They are highly polar compounds that do not enter the cells readilly, poorly penetrate the BBB
    • not significantly metabolized
    • primarily excreted unchanged through GF
  • I. AMINOGLYCOSIDES
    • Clinical Uses:
    • severe gram (-) enteric bacteria especially when there is suspicion of sepsis
    • always used in combination with a beta-lactam antibiotic to extend coverage to include potential gram (+) pathogens
    • Penicillin aminoglycoside combinations also are used to achieve bactericidal activity in treatment of enterococcal endocarditis and to shorten duration of therapy for viridans streptococcal and staphylococcal endocarditis
    • Mycobacterial infections
  • I. AMINOGLYCOSIDES
    • Toxicity:
    • Ototoxicity (esp. with loop diuretics)
      • Auditory damage – Neomycin, Kanamycin and Amikacin
      • Vestibular damage- Streptomycin, Gentamicin
    • Nephrotoxicity (esp. with vancomycin & amphotericin)
    • Neomycin, Tobramycin, Gentamicin - most nephrotoxic
  • STREPTOMYCIN
    • ribosomal resistance to this agent develops readily, limiting its role as a single agent
    • Mainly used as 2 nd line agent for the treatment of tuberculosis given at 0.5-1 g/d , IM or IV.
    • usually given in drug combination to prevent emergence of resistance.
    • In plague, tularemia and sometimes brucellosis, 1 g/d (15 mg/kg/d for children) IM or IV + oral tetracycline is used
    • + Penicillin; effective for enterococcal endocarditis and 2 week therapy of viridans streptococcal endocarditis.
    • can cause pain at the injection site, fever, skin rashes and other allergic reactions
    • most serious toxic effect is vestibular dysfunction
    • if given during pregnancy, can cause deafness in the newborn
  • GENTAMICIN
    • in severe infections (sepsis and pneumonia) caused by gram (-) bacteria that are likely resistant to other drug, used in combination with a cephalosporin or a penicillin
    • given at 5-6 mg/kg/d IV in three equal doses
    • + Penicillin G for bactericidal activity in endocarditis due to viridans streptococci or enterococci and in combination with Nafcillin in selected cases of staphylococcal endocarditis
  • Gentamicin
    • Nei ther gentamicin nor any other aminoglycosides should be used for single agent therapy of pneumonia because penetration of infected lung tissue is poor and local condition of low pH and low oxygen contribute to poor activity
    • Serum concentrations and renal function should be monitored if administration for more than a few days or if renal function is changing
  • GENTAMICIN
    • Gentamicin sulfate 0.1% - 0.3% cream, ointment – for the treatment of infected burns, wounds, or skin lesions and the prevention of intravenous catheter infections.
    • Topical gentamicin is partly inactivated by purulent exudates
    • Ten milligrams can be injected subconjunctivally for treatment of ocular infections
    • Nephrotoxicity is reversible and usually mild
    • Ototoxicity is Irreversible manifested as vestibular dysfunction
    • hypersensitivity reactions are uncommon
  • TOBRAMYCIN
    • Antimicrobrial spectrum and pharmacokinetic properties is identical to gentamicin
    • Given at 5-6 mg/kg IM or IV into three equal amounts q 8 hours.
    • Blood levels should be monitored in renal insufficiency
    • Slightly more active against pseudomonas but not to E. faecium
    • Ototoxic and nephrotoxic
  • AMIKACIN
    • semisynthetic derivative of kanamycin
    • resistant to many inactivating enzymes
    • Strains of multiple drug resistant tuberculosis, including Streptomycin resistant are usually susceptible
    • given at 7.5 -15mg/kg/d as a once-daily or 2-3x weekly
    • Serum concentrations should be monitored
    • Nephrotoxic and ototoxic (auditory portion of CN VIII)
  • NETILMICIN
    • shares many characteristics with gentamicin and tobramycin
    • dosage and the routes of administration are the same
    • completely therapeutically interchangeable with gentamicin or tobramycin and has similar toxicities
  • KANAMYCIN & NEOMYCIN
    • Paromomycin
    • Used for bowel preparation for elective surgery
    • Complete cross-resistance between kanamycin and neomycin
    • Not significantly absorbed from the GIT; excretion of any absorbed drug is mainly through GF into the urine
    • Too toxic for parenteral use, now limited to topical and oral use
    • Solutions 1-5 mg/ml- used applied on infected surfaces or injected into joints, pleural cavity, tissue spaces or abscess cavities where infection is present. ( 15 mg/kg/d)
    • Ointments (Neomycin-Polymyxin-Bacitracin combination); applied to infected skin lesions or in the nares for suppression of staphylococci
  • KANAMYCIN & NEOMYCIN
    • In preparation for elective bowel surgery, 1 g of Neomycin given orally q 6-8 hours + 1 g of erythromycin base
    • Paromomycin, 1 g q 6 hours orally for 2 weeks is effective in intestinal amebiasis
    • Nephrotoxic and ototoxic ( Auditory dysfunction)
    • Sudden absorption of postoperatively instilled kanamycin from the peritoneal cavity (3-5 g) has resulted in curare-like neuromuscular blockade and respiratory arrest (Calcium gluconate and neostigmine can act as antidotes)
    • Prolonged application to skin and eyes-severe allergic reactions
  • SPECTINOMYCIN
    • chemically related to the aminoglycosides
    • binds at the 30 S subunit (bacteriostatic)
    • dispensed as the dihydrochloride pentahydrate for IM injection
    • used solely as an alternative treatment for gonorrhea in patients who are allergic to penicillin or whose gonococci are resistant to other drugs
    • single dose of 2 g (40 mg/kg)
    • Can cause pain at the injection site , occasionally fever and nausea
    • Nephrotoxicity and anemia – rare
  • II.TETRACYCLINES :
    • Short Acting:
    • Tetracyline, Oxytetracycline, Chlortetracycline
    • Intermediate Acting: Demeclocycline, Methacycline
    • Long Acting:
    • Doxycycline, Minocycline
  • II. TETRACYCLINES
    • Antimicrobial Spectrum:
    • Rickettsia, V. cholera, M. pneumonia, Chlamydia, Shigella, H. pylori, P.tularensis, P.pseudomallei, Brucella, Psittacosis, Borrelia
    • Minocycline – carrier state of Meningococcal infections, N. asteroides, N. gonnorhea
  • II. TETRACYCLINES
    • Mechanism of Action:
    • enter microorganisms in part by passive diffusion and in part by an energy-dependent process of active transport
    • binds to 30S subunit, blocking the binding of amino-acyl t-rna to the acceptor site and prevents the addition of amino acids to the growing peptide
    • Bacteriostatic
  • II. TETRACYCLINES
    • Resistance:
    • decreased intracellular accumulation due to impaired influx or increased efflux by an active transport protein pump
    • ribosome protection due to production of proteins that interfere with tetracycline binding to the ribosome
    • enzymatic inactivation
  • II. TETRACYCLINES
    • Kinetics
    • Distributed widely to tissue and body fluids except for CSF
    • Absorption occurs mainly in the upper small intestine and is impaired by food (except Doxycyline and Minocycline)
    • Must not be taken with dairy products or antacids
    • Cross placenta, excreted in milk
    • As result of chelation with Ca, they are bound to and damage growing bones and teeth
    • Carbamazepine, phenytoin, barbiturates, and chronic alcohol ingestion may shorten the half-life of doxycycline
    • Excreted mainly in bile and urine (Doxycycline fecally eliminated; can be used in renal failure)
  • II. TETRACYCLINES
    • Clinical Uses:
    • DOC in infection with M. pneumoniae, chlamidiae,ricketsiae,and spirochetes.
    • No longer recommended for gonococcal disease due to resistance. Usually use in combination aminoglycosides
    • Borrelia burgdorfi (Lyme disease), Chlamydia, Ureaplasma, Acne, Tularemia, Cholera, Leptospirosis, Protozoal infections
    • Minocycline, 200 mg orally daily for 5 days – can eradicate the meningococcal carrier state
    • Demeclocycline – inhibits the action of ADH in the renal tubule and has been used in the treatment of inappropriate secretion of ADH or similar peptides by certain tumors
  • II. TETRACYCLINES
    • Clinical Uses:
    • Tetracyclines – 250-500 mg 4x/day adults; 20-40 mg/kg/d-children above 8 y/o
    • Demeclocycline and Methacycline -> 600 mg daily
    • Doxycyline and Minocycline -> 100 mg 1-2x/d
    • Toxicity:
    • Renal toxicity, local tissue toxicity, photosensitization, GI distress, discolors teeth, inhibits bone growth in children, potentially teratogenic, hepatotoxicity, vestibular toxicity
  • THE 50 S INHIBITORS:
    • CHLORAMPHENICOL
    • MACROLIDES
    • CLINDAMYCIN/LINCOMYCIN
    • STREPTOGRAMINS
    • OXAZOLADINONES
  • I. CHLORAMPHENICOL
    • Bactericidal – H. influenzae, N. meningitides, B. fragilis
    • Bacteriostatic – S. epidermidis, S. aureus, , M. pneumonia, L. monocytogenes, C.diphtheria, L. multocida, Salmonella sp., Shigella sp., E. coli, Rickettsia, Anaerobes
  • I. CHLORAMPHENICOL
    • MECHANISM OF ACTION:
    • Bind to the 50 S subunit of microbial ribosomes and blocks the functional attachment of amino-acyl-tRNA to the acceptor site
    • inhibits peptidyl transferase step
  • I. CHLORAMPHENICOL
    • SPECTRUM:
    • broad spectrum antibiotic
    • more effective than Tetracyclines against Typhoid Fever and other Salmonella infections
  • I. CHLORAMPHENICOL
    • KINETICS:
    • well absorbed after oral administration; usual dosage is 50-100 mg/kg/d
    • Chloramphenicol succinate used for parenteral administration is highly water soluble
    • Well distributed to all tissues & body fluids, including the CSF, ocular and joint fluids
    • rapidly excreted in urine, 10% as chloramphenicol; 90% as glucuronide conjugate; small amount of active drug is excreted into bile or feces
    • systemic dosage need not be altered in renal insufficiency but must be reduced markedly in hepatic failure
    • Newborns less than a week old and premature infants also clear Chloramphenicol less well, dosage should be reduced at 25 mg/kg/d.
  • I. CHLORAMPHENICOL
    • CLINICAL USES:
    • Meningitis, Rickettsia, Salmonella and anaerobic infections;
    • ineffective against chlamydial infections
    • occasionally used topically in the treatment of eye infections for its well penetration to ocular tissues and the aqueous humor
    • ADVERSE EFFECTS:
    • GIT, oral or vaginal candidiasis, irreversible aplastic anemia, reversible bone marrow depression, Gray Baby Syndrome
  • II. MACROLIDES:
    • Old Generation:
    • Erythromycin, Oleandomycin, Troleandomycin, Spiramycin, Josamycin
    • New Generation:
    • Rosaramycin, Roxithromycin, Clarithromycin, Azithromycin, Dirithromycin
  • II. MACROLIDES
    • MECHANISM OF ACTION:
    • binds to the P site of the 50 S bacterial ribosomal subunit.
    • Aminoacyl translocation and formation of initiation complex are blocked
    • Inhibitory or bactericidal
  • II. MACROLIDES
    • RESISTANCE:
    • reduced permeability of the cell membrane or active efflux
    • production (by Enterobacteriaceae) of esterases that hydrolyze macrolides
    • modification of the ribosomal binding site by chromosomal mutation
  • II. MACROLIDES
    • SPECTRUM:
    • Erythromycin has a narrow Gram (+) spectrum similar to Pen. G.
    • DOC in corynebacterial infection (diptheria and corynebacterial sepsis)
    • Also active against Chlamydia and Legionella organisms
  • Erythromycin
    • prototype
    • distributed widely to the body fluids except CSF
    • Base form easily destroyed by stomach acid & must be administered with enteric coating
    • food interferes with absorption
    • serum half life is app. 1.5 h normally and 5 hours in patients with anuria
    • is not removed by dialysis
    • metabolized in the liver excreted in the bile & feces
    • traverses the placenta and reaches the fetus
    • COMMERCIAL PREPARATIONS:
    • Oral-stearate, ethyl succinate, estolate salts: 250-500 mg q 6 h
    • Parenteral- lactobionate, gluceptate : 0.5-0.1. g q 6 hours
  • Erythromycin
    • ADVERSE EFFECTS:
    • GIT dysfunction, intrahepatic cholestatic jaundice (particularly with estolate prep)
    • erythromycin metabolites can inhibit cytochrome p450 enzymes & thus increase the serum concentrations of theophylline, oral anticoagulants, cyclosporine, methylprednisolone and digoxin by increasing its bioavailability
  • Clarithromycin
    • Derive from erythromycin by addition of methyl group
    • more active against Gram (+) pathogens, Legionella and Chlamydia than Erythromycin
    • lower frequency of GIT effects, less frequent dosing
    • half life of 6 hours
    • given at 250-500 mg twice daily
  • Azithromycin
    • Active against M. avium and T.gondii
    • Less active than erythromycin and chlarithromycin against staph. and strep.
    • More active against H. influenzae and chlamydia
    • Penetrates into most tissues (except CSF) and phagocytic cells extremely well
    • maintains high concentrations for prolonged periods into a number of tissues (lungs, tonsils, cervix)
    • tissue half life – 2-4 days
    • long half-life allows once daily oral administration and shortening of treatment in many cases ( a single 1 g dose of azithromycin is as effective as a 7 day course of doxycycline for chlamydial cervicitis and urethritis )
  • Azithromycin
    • Community acquired pneumonia – 500 mg loading dose, followed by a 250 mg single daily dose for the next 4 days
    • should be administered 1 hour before or 2 hours after meals; aluminum and magnesium delay absorption and reduce peak serum concentrations
    • does not inactivate cytochrome p450 enzymes and free of the drug interactions that occur with erythromycin and clarithromycin
  • III. CLINDAMYCIN / LINCOMYCIN
    • MECHANISM OF ACTION:
    • attach to 50 S ribosomal subunit, inhibits protein synthesis by interfering with the formation of initiation complexes and translocation reaction
    • SPECTRUM:
    • Narrow Gram (+) spectrum, excellent activity against anaerobic bacteria; strep, pneumococci, staphylococci
  • III. CLINDAMYCIN / LINCOMYCIN
    • RESISTANCE:
    • mutation of the ribosomal receptor site
    • modification of the receptor by a constitutively expressed methylase
    • enzymatic inactivation
  • III. CLINDAMYCIN / LINCOMYCIN
    • Clindamycin is more clinically used than Lincomycin
    • Penetrates well into most tissue except brain and CSF
    • given at 150-300 mg q 6 hrs adults ;10-20 mg/kg/d for children
    • well bone penetration
    • Metabolized in the liver, excreted in the bile and urine
    • half life is 2.5 hours normally and 6 hours in patients with anuria
    • more toxic than erythromycin
  • CLINDAMYCIN
    • Clinical uses:
    • prophylaxis of endocarditis in patients with valvular heart disease for dental procedures
    • most important indication is the treatment of severe anaerobic infection caused by bacteroides and other anaerobes that often participate in mixed infections
    • + aminoglycoside or cephalosporin- used to treat penetrating wounds of the abdomen & gut, septic abortion, pelvic abscesses, aspiration pneumonia
  • CLINDAMYCIN
    • + primaquine – effective alternative to trimethoprim sulfamethoxazole for moderate to moderately severe Pneumocystis carinii pneumonia in AIDS patients
    • + pyrimethamine – in AIDS related toxoplasmosis of the brain.
    • ADVERSE EFFECTS:
    • Diarrhea, nausea , skin rashes, impaired liver function and neutropenia
    • Antibiotic associated colitis caused by toxigenic C. difficile.
  • STREPTOGRAMINS
    • Quinupristin-Dalfopristin (Synercid)
    • action is similar to macrolides
    • bactericidal for staph and most organisms except Enterococcus faecium
    • prolonged postantibiotic effect up to 10 h for Staph. aureus
    • administered IV at 7.5 mg/kg q 8 -12 h
    • eliminated through fecal route, < 20% urine
    • Patients with hepatic insufficiency may not tolerate the drug at usual doses
    • inhibits CYP 3A4 P450, which metabolizes warfarin, diazepam, astemizole, terfenadine, cisapride, nonnucleoside reverse transcriptase inhibitors and cyclosporine.
  • STREPTOGRAMINS
    • Clinical Uses:
    • infections caused by Vancomycin resistant strains of E faecium but not E. faecalis,
    • bacteremia or respiratory tract infections caused by methicillin-resistant staphylococci and penicillin susceptible and resistant strains of S. pneumonia
    • Toxicities:
    • infusion related events like pain at the injection site, arthralgia, myalgia
  • OXAZOLADINONES: Linezolid (Zyvox)
    • inhibits protein synthesis by preventing formation of the ribosome complex that initiated protein synthesis.
    • Its unique binding site located on the 23 S ribosomal RNA of the 50 S subunit, results in no cross resistance with other drug classes
    • Has high oral bioavailability, half life of 4-6 h
    • Uses : staph, strep, enterococci, G(+) anaerobic cocci, G (+) rods, Corynebacterium, and L. monocytogenes
    • treatment of infections caused by vancomycin resistant E. faecium and other infections caused by multiple drug resistant organisms.
  • METABOLIC INHIBITORS Claro M. Isidro M.D.
  • SULFONAMIDES
    • METABOLIC INHIBITORS
    • Sulfonamides
    • structural analogs of PABA
    • competitively inhibit dihydropteroate synthase (catalyzed the synthesis dihydropteroic acid)
    • inhibits growth by reversibly blocking folic acid synthesis
    • bacteriostatic
  •  
  • SULFONAMIDES
    • Spectrum of activity:
    • Inhibit the growth both Gm (+) and Gm (-) bacteria, Nocardia, Chlamydia trachomatis & some protozoa
    • Enteric bacteria such as E.coli,klebsiella, salmonella,shigella, and enterobacter are also inhibited
    • Rickettsia – not inhibited but growth stimulated by sulfas
  • SULFONAMIDES
    • RESISTANCE
    • occur as a result of mutations that:
      • cause overproduction of PABA
      • cause production of a folic acid synthesizing enzyme that has a low affinity for sulfonamides
      • cause a loss of permeability to sulfonamides
  • SULFONAMINDES
    • Pharmacokinetics: three major groups
    • oral, absorbable
    • a. short-acting: sulfacytine, sulfisoxazole, sulfamethizole
    • b. medium- acting: sulfadiazine, sulfamethoxazole, sulfapyridine
    • c. long- acting: sulfadoxine
    • oral, nonabsorbable
    • a. Sulfasalazine
    • b. Olsalazine
  • SULFONAMIDES
    • topical
    • a.Sodium sulfacetamide ophthalmic sol’n or ointment – for bacterial conjunctivitis
    • b. Mafenide acetate- prevent bacterial colonization and infection of burn wounds
    • c. Silver sulfadiazine –prevent of infection in burn wounds
  • SULFONAMIDES
    • Pharmacokinetics
    • Well absorbed from the GIT
    • Widely distributed in the body including the CNS, placenta & fetus
    • Highly bound to albumin
    • Acetylated or glucorinated in the liver
    • Excreted into the urine – mainly by glomerular filtration
  • SULFONAMIDE
    • SPECTRUM: gram (+) & gram (-)
    • Simple urinary tract infection
    • Ocular infection
    • Burn infections
    • Ulcerative colitis
    • With pyrimethamine: Toxoplasmosis
    • Malaria
  • SULFONAMIDES
    • Adverse Reaction
    • Hypersensitivity Reaction
    • Photosensitivity
    • Nausea & vomiting
    • Hemolytic anemia
    • Crystalluria & nephrotoxicity ( tx alkalinize the urine by NaHCO 3
    • Kernicterus in the newborn
    • CI: Pregnancy & newborn
    • DI: Compete with wafarin, tolbutamide, methotrexate for PPB
  • TRIMETOPRIM SULFAMETHOXAZOLE (CO-TRIMOXAZOLE)
    • COMBINATION CAUSES:
    • 1. INCREASE POTENCY
    • 2. INCREASE SPECTRUM
    • 3. DECREASE INCIDENCE OF RESISTANCE
    • MOA: blocks the sequential steps in the obligate enzymatic reaction in bacteria preventing formation of nucleotide
  • CO-TRIMOXAZOLE
    • Pharmacokinetcs
    • Trimetoprim: more lipid soluble, greater Vd
    • Given in 1: 5 ratio
    • CLINICAL USES
    • SPECTRUM: broad gm + & gm –
    • UTI, pneumonia, gonorrhea & prostatitis, Acute chronic bronchitis, acute otitis media, chancroid, shigellosis, typhoid fever, nocardiosis
  • CO-TRIMOXAZOLE
    • HYPERSENSITIVITY REACTIONS
    • PHOTOSENSITIVITY
    • NAUSEA & VOMITING
    • HEMOLYTIC ANEMIA
    • CRYSTALLURIA & NEPHROTOXCITY
    • KERNICTERUS
    • CI: PREGNANCY & NEWBORN
    • DI: COMPETE WITH WARFARIN, METHOTREXATE FOR PPB
    • Other drug combinations
    • Sulfadiazine + pyrimethamine
    • for leishmaniasis & toxoplasmosis
    • 2. Sulfadoxime + pyrimethamine
    • for Falciparum malaria
  • NUCLEIC ACID SYNTHESIS INHIBITORS
    • First Generation: Nalidixic acid
    • Second Generation: Ofloxacin, Ciprofloxacin, Norfloxacin, Levofloxacin
    • Third Generation: Gatifloxin, Sparfloxacin Clinafloxacin,
    • Fourth Generation: Trovafloxacin, Moxifloxacin
  • Fluoroquinolones
    • Bactericidal
    • Inhibits DNA Gyrase or Topoisomerase II - Block the relaxation of supercoiled DNA that is catalyzed by DNA gyrase
    • Inhibits Topoisomerase IV – interferes with the separation of replicated chromosomal DNA during cell division
  • Fluoroquinolones
    • Resistance
    • Modification of DNA Gyrase
    • Decreased accumulation in the bacterial cell due to :
      • reduction of the porin proteins in the outer membrane
      • energy dependent efflux system of the inner membrane
  • Fluoroquinolones
    • Clinical Uses
    • SPECTRUM: broad ; aerobic gm (+) & gm (-) but not anaerobes
    • UTI
    • Sexually transmitted diseases : Gonorrhea, Chlamydia, chacroid, Prostatitis
    • Respiratory infection due to H. influenza, M. catarrhalis, Strep pneumoniae, M. pneumoniae
    • Nosocomial infection (P. aeroginosa)
    • GIT infections due to : E.coli, Shigella, & Salmonella
    • Chronic bone infection due to Pseudomonas & Staph. aereus
    • Diabetic foot infections
  • CIPROFLOXACIN
    • Most widely used
    • DOC for anthrax
    • Most potent for P. aeroginosa
    • Synergistic with beta lactams
    • M. tuberculosis
    • NORfLOXACIN
    • Not effective in systemic infection
  • LEVOFLOXACIN
    • Prostatitis ,E. coli
    • Sexually transmitted diseases, gonorrhea
    • Skin infections
    • S. pneumoniae
    • TROVA & MOXIFLOXACIN
      • Anaerobes, P. AEROGINOSA
        • GATIFLOXACIN
      • Resp infection , S. pneuomoniae
  • Fluoroquinolones
    • Side Effects
    • Nausea & diarrhea
    • Headache, dizziness, light headedness
    • Arthralgia & joint swelling
    • Rashes & photophobia
  • Fluoroquinolones
    • CI: PREGNANT WOMEN, NEONATES
    • ARRYTHMIAS: SPARFLOXACIN &
    • MOXIFLOXACIN: prolong QT intervals
    • DI: ↓ ABSORPTION WITH ANTACID , FeSo4
    • Cimetidine interferes elimination
    • Ciprofloxacin & ofloxacin: ↑ theophylline levels
  •  
    • 1-3. Three stages of protein synthesis
    • 4. Drugs that inhibit 30S subunit
    • 5. DOC for anthrax
    • 6 & 7. Drugs that inhibit 50S subunit
    • 8. Enzyme inhibited by sulfonamide
    • 9. Enzyme inhibited by flouroquinolone
    • 10. DOC for anaerobic infection