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Beta lactams, protein sythesis inhibitors, other antibiotics 1-suman nizam.iiuc .pharmacy.b.pharm.

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IIUC(International Islamic University Chittagong)
Dept.Of Pharmacy.
Suman Nizam
B.Pharm

Published in: Health & Medicine, Technology
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Beta lactams, protein sythesis inhibitors, other antibiotics 1-suman nizam.iiuc .pharmacy.b.pharm.

  1. 1. BETA LACTAM ANTIBIOTICS AND OTHER CELL WALL SYNTHESIS INHIBITORS Ma. Shiela Cano-Guiking, M.D.
  2. 2. ♦PENICILLINS ♦ I. CLASSIFICATION ♦ A. PenicillinaseResistant ( Antistaphylococcal Penicillins) ♦ 1. Methicillin ( Staphcillin) 2. Nafcillin (Unipen, Nafcil, Nallpen) 3. Isoxazolyl penicillins ♦ a. Oxacillin b. Cloxacillin c. Dicloxacillin d. Flucloxacillin
  3. 3. ♦ B. Penicillinase-Susceptible ♦ 1. Narrow-Spectrum ♦ a. Benzylpenicillin – Penicillin G b. Phenoxymethyl penicillin – ♦ Penicillin V ♦ 2. Extended Spectrum ♦ A. Aminopenicillins ♦ a.1 Ampicillin a.2 Esters a.2.1. Bacampicillin a.2.2. Pivampicillin a.2.3. Talampicillin a.3. Amoxicillin
  4. 4. ♦ B. Carboxypenicillins ♦ a.1 Carbenicillin ♦ a.1.1. Indanyl carbenicillin e.g Geopen a.1.2. Disodium carbenicillin e.g. Pyopen a.2. Ticarcillin a.3. Temocillin ♦ C. Ureido-penicillins c.1. Mezlocillin c.2. Azlocillin c.3. Piperacillin c.4. Apalcillin
  5. 5. ♦ II. GENERAL PROPERTIES ♦ A. Chemical Properties ♦ Penicillins are derivatives of benzylpenicillin, from which the methyl benzene radical is split off by amidase producing 6-aminopenicillanic acid, the parent compound of all semisynthetic penicillins
  6. 6. ♦ The compound consists of 2 basic structures: ♦ 1 Thiazolidine Ring (A) ♦ 2.Beta-Lactam Ring (B) ♦ - Site of action of Beta-lactamase ♦ - Site of action of Amidase ♦ - Site of attachment of side chain ®, which determines many of the antibacterial and pharmacologic characteristics of a derivative ( spectrum and penicillin-resistance)
  7. 7. ♦ Mechanisms of Action: ♦ Specific: ♦ inhibit the last step in the ♦ peptidoglycan synthesis of the cell wall ♦ Underlying: ♦ 1. inhibition of transpeptidase ♦ enzymes 2. activation of penicillin binding ♦ proteins (PBPs) 3. activation of autolysins ♦ (murein hydrolases)
  8. 8. • ♦ C. Mechanisms of Resistance ♦ 1. inactivation of antibiotic by Beta lactamases ♦ 2. modification of PBPs ♦ 3. impaired penetration of drug to target PBPs ♦ 4. presence of an efflux pump ♦ Kinetics: ♦ - absorption vary with the preparation depending on their acid stability and protein binding ♦ - absorption of most oral penicillins (except amoxicillin) impaired by food and drugs should be given 1-2 hours before or after meal; parenteral – complete and rapid
  9. 9. ♦ - cannot penetrate the blood-brain barrier; but 50% of the plasma concentration can pass through in the presence of inflammation: ♦ Probenecid and certain organic acids can inhibit transfer from cerebrospinal fluid (CSF) to blood stream; may lead to increase CSF level. ♦ - Metabolized by the liver to penicillanic/penicillenic acid; penicillamine, penicilloic acid and other penicilloyl derivatives (allergenic metabolites) ♦ - Excreted primarily by the kidneys (90% tubular secretion, 10% glomerular filtration) small amount through bile and feces, sputum and milk; renal excretion inhibited by probenecid
  10. 10. ♦ E. Adverse Effects: ♦ 1. Hypersensitivity reactions ♦ most common adverse effects - cause the highest incidence of antibiotic allergy ♦ a. major antigenic determinant- penicilloyl metabolite skin testing( penicilloyl polylysine (PPL) ) ♦ b. Signs and symptoms: - varied skin rashes and purpuric reactions - angioedema and anyaphylactic reactions - fever - eosinophilia - interstitial nephritis
  11. 11. ♦ 2.Gastrointestinal disturbances after oral administration ♦ 3.Convulsions following rapid IV administration ♦ 4. Accidental injection into the sciatic nerve – severe pain and nerve dysfunction persisting for weeks 5. Chronic use may cause: hepatitis overgrowth of minor/atypical organisms following use of broad spectrum preparations
  12. 12. ♦6. Specific toxicities: ♦a. Procaine Penicillin G after accidental IV injection: pulmonary embolism acute psychotic reactions ♦b. Oxacillin and Nafcillin hepatitis granulocytopenia, bone marrow depression ♦c. Disodium Carbenicillin and high dose Penicillin G Na -hypernatermia ♦d. Penicillin G Potassium hyperkalemia with high doses
  13. 13. ♦ e. Penicillin G Sodium Jarisch_herxheimer reaction with high doses in secondary syphilis ♦ f. Carbenicillin and Ticarcillin bleeding diathesis ♦ g. Methicillin interstitial nephritis ♦ h. Ampicillin associated with pseudomembranous colitis
  14. 14. ♦ III. INDIVIDUAL AGENTS ♦ A. Penicillin G ♦ 1. Antimicrobial Spectrum - Streptococci, meningococci, enterococci, pen. susceptible pneumococci, non-B lactamase producing staph, Treponema, spirochetes, B. anthracis, Clostridium, Actinomyces, G(+) rods and non B lactamase producing G (-)anaerobic organisms ♦ 2.Kinetics - 1/3 of oral dose absorbed from intestinal tract rapidly; food impair absorption - maximal concentration: 30-60 min.
  15. 15. ♦ - intravenous a. Aqueous Penicillin G - peak in 15-30 min -T ½ - 0.5-2 hrs. ♦ - intramuscular ♦ B. Procaine Penicillin G peak in 1-3 hrs. T1/2 – 12 hrs. ♦ C. Benzathine Penicillin G ♦ mean duration of antimicrobial activity - 26 days - 60% albumin bound ♦ - widely distributed to the tissues and body fluids - does not readily enter the cerebrospinal fluid when meninges are not inflamed ♦ - probenecid and uremia inhibits active transport secretion into the blood stream
  16. 16. ♦ Preparations: ♦ “ International Units “ – measure of strength ♦ Oral Preparations: ♦ Penicillin G Sodium Penicillin G Potassium ♦ Parenteral Preparations ♦ 1.short acting a. aqueous Penicillin G Potassium – 1.7 meq K/1M “u” b. aqueous Penicillin G Sodium – 2.4. meq Na/1M “u” ♦ 2. long acting a. Procaine Penicillin G – 300,000 – 600,000 “u” 120 mg procaine/vial b. Benzathine Penicillin G – 600,000 “u” 1.2 M “u”/vial
  17. 17. ♦ 4. Doses and Therapeutic Uses ♦ a. Aqueous Penicillin G ♦ Child: mild infections – 50,000 “u” – 100,000 “u”/kg/day in equally divided Doses every 4-6 hrs. for 7 days ♦ Severe infections – 200,000 “u” – 600,000 “u”/kg/day in equally divided Doses every 2-6 hrs. for 14 days.
  18. 18. ♦ a. Procaine Penicillin G – 300,000 – 600,000 “u” IM OD or BID for 7 days for Adults ♦ b. Benzathine Penicillin G – 1.2 million – 2.4 “u” IM monthly ♦ Syphilis – less than 1 year duration – 2.4 M “u” IM + Probenicid 1 gm/day for 10 days or 2.4 M “u” Benzathine Penicillin G IM single dose ♦ late latent, complicated – 20 M “u” aqueous Penicillin G/day for 10 days ♦ congenital syphilis – 50,000 “u”/kg/day aqueous Penicillin G for 10 days
  19. 19. ♦ Staphylococcal infections Gram (+) anaerobes Meningococcal infections Gonococcal infections Carrier state diphtheria ♦ Other unusual infections – actinomycosis, Anthrax, rat bite fever, listeria, pasteurella, lyme disease, erysipeloid ♦ Prophylaxis – recurrences of streptococcal, rheumatic fever, gonorrhea, syphilis, bacterial endocarditis
  20. 20. ♦ D . Penicillin V ♦ Oral form indicated only in minor infections Relative poor bioavailability; need for dosing 4x a day ♦ Gram (+) aerobic activities similar to Penicillin G 5-10x less active against gram(-) microbes, esp. Neisseria and certain anaerobes better absorbed from the gastrointestinal
  21. 21. ♦ D. Ampicillin ♦ 1. Microbial Spectrum Somewhat less active than Penicillin G against gram (+) cocci Enterococcal grp. D and viridans grp. Of streptococci - Listeria monocytogenes - H. influenza ♦ Effective for Shigellosis ♦ Should not be used for uncomplicated salmonella gastroenteritis – may prolong the carrier state
  22. 22. ♦ 2. Kinetics: ♦ Gastric acid stable and well absorbed from the gastrointestinal tract Orally absorbed drug peaks in 2 hrs. ♦ Intramuscular administered drug peaks in 1 hour Mainly excreted by the kidneys; also thru the bile and feces ♦ Undergoes enterohepatic circulation ♦ Other kinetic properties similar to Penicillin G Sodium
  23. 23. ♦ 3. Adverse Effects: ♦ “Ampicillin skin rash” – occurs in 7-8% others similar to Pen G ♦ 4. Preparations ♦ a. Oral ♦ Capsules – 250-500 mg Suspension – 125 mg, 250 mg/5 ml Drops – 100 mg/ml ♦ b. parenteral 250 mg; 500 mg/ml vial
  24. 24. ♦ 5. Doses ♦ a. mild infections Newborn – 25-50 mg every 12 hrs. Child – 50-100 mg/kg/d in 4-6 divided doses Adult – 1-4 gm/day ♦ b. severe infections Child – 200-600 mg/kg/day Adult – 6-12 gm/day ♦ E. Esters of Ampicillin ♦ No inherent antimicrobial activity as esters, but pharmacologically active following hydrolysis to Ampicillin 50% higher blood concentration than Ampicillin and Amoxicillin
  25. 25. ♦ F. Amoxicillin ♦ Closely related to Ampicillin in chemical and pharmacologic properties ♦ More rapidly and completely absorbed from gastrointestinal tract Attains higher serum levels than ampicillin
  26. 26. ♦ G. CARBOXYPENICILLINS AND UREIDOPENICILLINS ♦ 1. Antimicrobial Spectrum Gram (-) aerobes Pseudomonas aeroginosa Bacteroides fragilis; but in higher amount/dose ♦ Carboxypenicillins – certain indole (-) Proteus Ureidopenicillins – Klebsiella Azlocillin – 10x more active than carbenicillin against Pseudomonas
  27. 27. 2.Preparations a. Carbenicillin Disodium salt – contains approximately 5 meq sodium/gm for parenteral administration Indanyl esters – 500 mg tablets b.Ureidopenicillins Parenteral preparations
  28. 28. ♦ H. Penicillinase-Resistant ♦ 1. Methicillin -15-80x more active against penicillinase producing microbes than Penicillin G; only parenterally available; currently many resistant strains of Staph. Aureus have emerged, no longer used because of nephrotoxicity ♦ 2. Nafcillin – slightly more active than Cloxacillin against penicillinase producing Staph. Aureus, available in oral and parenteral preparations: GIT absorption is erratic ♦ 3. Isoxazolyl Penicillins Stable in gastric acid and adequately absorbed after oral administration Dicloxacillin is most active against penicillinase
  29. 29. ♦ CEPHALOSPORINS ♦ I. CLASSIFICATION ♦ A. First Generation ♦ 1. Cephaloridine-Loridine, Ceporan ♦ 2. Cephalothin-Keflin ♦ 3. Cephalexin-Keflex, Ceporex ♦ 4. Cefazolin-Cefacidal ♦ 5. Cephradine-Velosef ♦ 6. Cepharpirin-Cefadyl ♦ 7. Cephadroxil-Doricef, Cefamox
  30. 30. – B. Second Generation ♦ 1. Cefaclor-Ceclor ♦ 2. Cefoxitin – Mefoxin ♦ 3. Cefuroxime – Zinacef, Zinnat ♦ 4. Cefonicid – Monocid ♦ 5. Cefotetan - Cefotan ♦ 6. Cefamdandole – Mandol ♦ 7. Cefprozil – Cefzil ♦ 8. Loracarbef – Lorabid ♦ 9. Cefmetazole – Zefazone ♦ 10. Ceforanide
  31. 31. ♦ C. Third Generation ♦ 1. Cefotaxime – Claforan ♦ 2. Cefoperazone – Cefobid ♦ 3. Moxolactam – Moxam ♦ 4. Ceftizoxime – Cefizox ♦ 5. Ceftriaxone – Rocephin ♦ 6. Ceftazidime – Fortum ♦ 7. Cefotiam – Ceradolan ♦ 8. Cefixime – Suprax ♦ 9. Cefetamet – Globocef ♦ 10. Cefpodoxime – Vantin ♦ 11. Ceftibuten – Cedax ♦ 12. Cefdinir –Omnicef ♦ 13. Cefditoren
  32. 32. ♦ D. Fourth Generation 1. Cefepime – Maxipime 2. Cefpirome – Cefrom ♦ II. BASIS FOR CLASSIFICATION A. Antimicrobial Spectrum B. Pharmacokinetic Properties
  33. 33. ♦ III. GENERAL PROPERTIES ♦ A. Chemistry ♦ 7-amino cephalosporanic acid – parent compound ♦ contains an R2 that makes the compound stable in dilute acid and highly penicillinase resistant * MW – 400-450 *Soluble to water and relatively stable to ph and temperature changes
  34. 34. ♦ C7 modifications alter antibacterial activity ♦ C3 substitutes change metabolism and kinetic properties ♦ B. MECHANISM OF ACTION AND RESISTANCE Similar to penicillins ♦ C. Antimicrobial Spectrum Generally broader spectrum than Penicillins Generally more effective than Penicillins against B- lactamase-producing microbes (except enterococci, Methicillin-resistant Staph. aureus and Staph. epidermis)
  35. 35. ♦ D. SPECIFIC GROUPS/INDIVIDUAL AGENTS ♦ 1. FIRST GENERATION ♦ Good activity against gram (+) and modest against gram (-) microbes ♦ Penetration of the cerebrospinal fluid (CSF) is inadequate ♦ UTI, minor staph lesions, minor polymicrobial infections – cellulitis, soft tissue abscess
  36. 36. ♦ 2. SECOND GENERATION ♦ Better activity against anaerobes and gram (-) aerobes ♦ Only Cefuroxime can produce sufficient CSF level ♦ Sinusitis, otitis, LRTI, mixed anaerobic infections such as peritonitis/diverticulitis
  37. 37. ♦ 3. THIRD GENERATION ♦ Generally less active than the first generation against gram (+) cocci but most active against gram (-) including B-lactamase- producing strains ♦ Cefoperazone, Ceftazidime – (more active) against Pseudomonas
  38. 38. ♦ Active against anaerobes – Cefoperazone, Cefotaxime ♦ Ceftizoxime, Moxolactam – B. fragilis ♦ Cefoperazone & Ceftriaxone ♦ -excreted primarily in the bile; ♦ Probenecid does not affect renal excretion ♦ Cross BBB except Cefoperazone, Cefixime, Ceftibuten and Cefpodoxime proxetil
  39. 39. ♦ Ceftriaxone, 125 mg inj., ♦ Cefixime, single 400 mg oral dose -N. gonorrhea ♦ Cefoperazone –(T1/2 – 2 hrs. ) 25-100 mg/kg/d injected q 8-12 hrs ♦ Cefixime 200 mg orally twice a day or 400 mg OD Cefpodoxime proxetil & Ceftibuten – 200 mg 2x/day Meningitis caused by pneumococci, meningococci, H. influenza & susceptible enteric gram (-) rods but not by L. monocytogenes; ♦ should be used in combination with aminoglycoside for the treatment of meningitis caused by P. aeruginosa.
  40. 40. ♦ 4. FOURTH GENERATION ♦ More resistant to hydrolysis by chromosomal beta lactamases (eg. Those produced by enterobacter) ♦ Good activity against P. aeruginosa, enterobacteriaceae, staph. aureus, S. pneumoniae Highly active against Haemophilus & Neisseria ♦ Penetrates well into CSF Cleared by kidneys T1/2 – 2 hrs Good activity against most penicillin resistant strains of streptococci Useful in the treatment of enterobacter infections
  41. 41. ♦ E. ADVERSE EFFECTS 1. Allergy 2. Toxicity: 3. Renal toxicity – interstitial nephritis and even tubular necrosis ♦ Cephalosporin that contains a methyl thiotetrazole group ( Cefamandole, Cefmetazole, Cefotetan, Cefoperazone) ♦ – cause disulfiram like reactions, hypoprothrombinemia and bleeding disorders- ♦ Antidote: Vit K, 10 mg 2x/week ♦ Moxolactam – interferes with platelet
  42. 42. MONOBACTAMS Monocyclic beta lactam ring Resistant to B-lactamase Active against gram (-) rods including Pseudomonas and Serratia Aztreonam – resembles aminoglycosides in spectrum of activity Given 1-2 g IV q 8 hrs.; T1/2 – 1-2 hrs
  43. 43. ♦ BETA LACTAMASE INHIBITORS ( CLAVULANIC ACID, SULBACTAM & TAZOBACTAM) ♦ Resemble B- lactam molecules Bind to Beta-lactamase, inactivate them and prevent the destruction ♦ Synergistic with other beta-lactams ♦ A. Clavulanic Acid – produced by S. Clavuligerul potentnt inhibitor of beta-lactamases (plasmid encoded) weak antibacterial action combined with Amoxicillin (Augmentin) or Ticarcillin( Timentin): the combination widens the antimicrobial spectrum B. Sulbactam Pivoxil and Ampicillin ( Unasyn)
  44. 44. ♦ CARBAPENEMS ♦ - structurally related to Beta lactam antibiotics ♦ 1. Imipenem – gram (-) rods, gram (+) org. & anaerobes inactivated by dehydropeptidases in renal tubules resulting in low urinary concentration combined with Cilastatin ( dehydropeptidase inhibitor ) to reduce inactivation ♦ penetrates body tissues and fluids well including the CSF .25-0.5 g IV q 6-8 hrs Adverse effects include nausea, vomiting, diarrhea, reactions to infusion site; excessive in renal failure – seizures ♦ 2. Meropenem – slightly greater activity against gram (-) aerobes does not require an inhibitor
  45. 45. ♦ ERTAPENEM -Less active than meropenem or imipenem against Pseudomonas aeruginosa and acinetobacter species - It is not degraded by renal dehydropeptidase
  46. 46. ♦ OTHER CELL WALL SYNTHESIS INHIBITORS ♦ 1. VANCOMYCIN ♦ Gram (+) staph Water soluble and quite stable ♦ MOA - Inhibits cell wall synthesis by binding firmly to D-Ala-D-Ala terminus of nascent peptidoglycan pentapeptide ♦ Resistance – modification of the D-Ala-D-Ala binding site of the peptidoglycan building block in which the terminal D-Ala is replaced by D- lactate resulting to loss of a critical H bond that facilitates high affinity binding of vancomycin to its target and loss of activity
  47. 47. ♦ Synergistic with gentamicin and Streptomycin against E. faecium and E. faecalis strains that do not exhibit high levels of aminoglycoside resistance ♦ Poorly abosorbed from the GIT Administered orally for the treatment of antibiotic associated enterocolitis caused by C. difficile; 0.125 – 0.25 g q 6 hrs ♦ 99% excreted by glomerular filtration T1/2 6-10 days – not removed by dialysis
  48. 48. ♦ - Sepsis or endocarditits caused by Methicillin resistant staph Combined with Cefotaxime, Ceftriaxone or Rifampicin for the treatment of meningitis suspected or known to be caused by a highly penicillin resistant strain of pneumococcus. ♦ - Recommended dosage is 30 mg/kg/day in two or three divided doses - Adults with normal renal function – 1 g every 12 hrs Children – 40 mg/kg/d in 3 to 4 divided dose - ♦ Causes phlebitis, chills and fever, ototoxicity, nephrotoxicity, red man or red neck syndrome
  49. 49. ♦ 2. FOSFOMYCIN ♦ - inhibits a very early stage of bacterial cell wall synthesis - inhibits cytoplasmic enzyme enol pyruvate transferase by covalently binding to the cysteine residue of the active site and blocking the phosphoenolpyruvate to UDP-N- acetylglucosamine – 1st step in the formation of UDP-N- acetylmuramic acid, the precursor of acetylmuramic acid – found only in bacterial cell walls. ♦
  50. 50. ♦ - Drug is transported into the cell by glycerophosphate or glucose 6 phosphate transport systems - Resistance is due to inadequate transport of drug into the cell ♦ - Active against both Gram (+) and Gram (-) - In vitro synergism with beta lactams, aminoglycosides or fluoroquinolones - Available orally ( 2-4 g, single dose in uncomplicated UTI) and parenterally - Excreted through the kidneys - Safe in pregnancy
  51. 51. 4. BACITRACIN - cyclic peptide mixture - active against Gram (+) organisms - inhibits cell wall formation by interfering with dephosphorylation - in cycling of the lipid carrier that transfers peptidoclycan subunits to the growing cell wall nephrotoxic - poorly absorbed; limited to topical use 500 units/g ointment + Polymyxin B or Neomycin
  52. 52. ♦ 5. CYCLOSERINE ♦ - water soluble; very unstable at acid ph treat tuberculosis caused by M. tuberculosis resistant to first line agents - structural analogs of D-alanine and inhibits incorporation of D-alanine into peptidoglycan pentapeptide by inhibiting alanine racemase which converts L alanine to D alanine and D- alanyl- D-alanine ligase ♦ - widely distributed into tissues - excreted through the urine - 0.5 – 1 g /d in 2 – 3 divided doses - causes dose related CNS toxicity, headaches, tremors, acute psychocis, convulsions
  53. 53. THANK YOU VERY MUCH AND STUDY WELL!
  54. 54. PROTEIN SYNTHESIS INHIBITORS Ma. Shiela Cano-Guiking, M.D.
  55. 55. The 30 S Inhibitors: I. AMINOGLYCOSIDES Older Aminoglycosides: Streptomycin Kanamycin Newer Aminoglycosides: Gentamicin Tobramycin Neomycin Amikacin Netilmicin Sisomicin
  56. 56. Antimicrobial Spectrum: 1. Gram (-) Aerobic Bacilli 2. Beta-lactamase producers: Staph. aureus N. gonorrhea 3. Mycobacteria 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 - Requires oxygen uptake, therefore ineffective against anaerobes. - Bactericidal
  57. 57. Microbial Resistance: 1. enzyme inactivation 2. Cell surface alteration 3. receptor protein alteration 4. oxygen requirement related Kinetics: minimally absorbed from the GIT, well absorbed thru IM, IV poorly penetrate the BBB not significantly metabolized primarily executed unchanged through GF Clinical Uses: severe gram (-) rod infections Mycobacterial infections
  58. 58. Toxicity: Ototoxicity (esp. with loop diuretics) Auditory damage – Neomycin, Kanamycin and Amikacin Vestibular Damage – Streptomycin, Gentamicin Nephrotoxicity (esp. with cephalosporins) Neomycin, Tobramycin, Gentamicin- most nephrotoxic
  59. 59. 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 (7.5-15 mg/kg/day for children) IM or IV should be used only in combination with other agents to prevent emergence of resistance - In plague, tularemia and sometimes brucellosis, 1 g/d (15 mg/kg/day 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 injection site, vestibular dysfunction – most serious toxic effect If given during pregnancy, can cause deafness in the newborn
  60. 60. GENTAMICIN employed mainly in severe infections (sepsis and pneumonia) caused by gram (-) bacteria in combination with a cephalosporin or a penicillin may be life saving given at 5-6 mg/kg/day 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 Serum concentrations and renal function should be monitored if administered for more than a few days or if renal function is changing (eg. Sepsis; often complicated by acute renal failure)
  61. 61. 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
  62. 62. TOBRAMYCIN Antimicrobial 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 E. faecium Ototoxic and nephrotoxic
  63. 63. AMIKACIN semisynthetic derivative of kanamycin resistant to many inactivating enzymes for tuberculosis; given at 7.5 – 15 mg/kg/d as a once daily or 2- 3x weekly Serum concentrations should be monitored Nephrotoxic and ototoxic
  64. 64. 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
  65. 65. KANAMYCIN AND NEOMYCIN Paromomycin is also a member of this group and all have similar properties 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/day)
  66. 66. 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 amoebiasis 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
  67. 67. 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 )
  68. 68. 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. gonorrhea
  69. 69. 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 and prevents attachment of aminoacyl tRNA, prevents the addition of amino acids to the growing peptide Bacteriostatic 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
  70. 70. Kinetics: limited CNS penetration absorption occurs mainly in the upper small intestine and is impaired by food ( except Doxycycline and Minocycline) Must not be taken with milk or antacids Cross placenta, excreted in milk 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
  71. 71. Clinical Uses: Borrelia burgdorfi (Lyme disease), Chlamydia, Ureaplasma, M. pneumonia, Rickettsia, 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 Tetracycline – 250-500 mg 4x/day adults 20-40 mg/kg/d – children above 8 y/0 600 mg daily dose for Demeclocycline and Methacycline 100 mg 1-2x/d for Doxycycline and Minocycline Toxicity: Renal toxicity, local tissue toxicity, photosensitization, GI distress, discolors teeth, inhibits bone growth in children, potentially teratogencic, hepatotoxicity, vestibular toxicity
  72. 72. THE 50 S INHIBITORS: CHLORAMPHENICOL MACROLIDES CLINDAMYCIN/LINCOMYCIN STREPTOGRAMINS OXAZOLADINONES
  73. 73. I CHLORAMPHENICOL Bactericidal – H. influenzae, N. meningitides, B. fragilis Bacteriostatic – S. epidermidis, S. aureus, , M. pneumonia, L. monocytogenes, diphtheria, L. multocida, Salmonella sp., Shigella sp., E. coli, Rickettsia, Anaerobes,ineffective for chlamydial infections 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
  74. 74. Spectrum: broad spectrum antibiotic more effective than Tetracyclines against Typhoid Fever and other Salmonella infections Kinetics: well absorbed after oral administration 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 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
  75. 75. 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 aqeous humor Adverse Effects: GIT, oral or vaginal candidiasis, irreversible aplastic anemia, reversible bone marrow depression, Gray Baby Syndrome
  76. 76. II. MACROLIDES: 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 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
  77. 77. Spectrum: Erythromycin has a narrow Gram (+) spectrum similar to Pen. G. Also active against Chlamydia and Legionella organisms 1. 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
  78. 78. Commercial Preparations: Oral-stearate, ethyl succinate, estolate salts – 250-500 mg q 6 h adults 40 mg/kg/d - children Parenteral- lactobionate, gluceptate – 0.5-1 g q 6 hours for adults 20-40 mg/kg/d for children Adverse Effects: GIT dysfunction, intrahepatic cholestatic jaundice - Erythromycin metabolites can inhibit cytochrome p450 enzymes and thus increase the serum concentrations of theophylline, oral anticoagulants, cyclosporine and methylprednisolone;also oral digoxin by increasing its bioavailability
  79. 79. 2. Clarithromycin - hydroxylated derivative of erythromycin - 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
  80. 80. 3.Azithromycin - more active than erythromycin against several Gram (-) pathogens - maintains high concentrations for prolonged periods into a number of tissues (lungs, tonsil, 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
  81. 81. AZITHROMYCIN
  82. 82. KETOLIDES ♦ - semisynthetic 14 membered ring macrolides ♦ Telithromycin – ♦ active in vitro against S pyogenes, S. penumoniae, S. aureus, H. influenzae, Moraxella catarrhalis, mycopasmas, legionella sp, chlamydia sp, Helicobacter pylori, N. gonorrhoaea, B. fragilis, T gondii and nontuberculosis mycobacteria
  83. 83. -Oral bioavailability – 57% - good tissue and intracellular penetration - metabolized in the liver - eliminated by a combination of biliary and urinary routes of excretion - administered as a once daily dose of 800 mg - indicated for treatment of respiratory tract infections, including community acquired bacterial pneumonia, acute exacerbations of chronic bronchitis, sinusitis and streptococcal pharyngitis - a reversible inhibitor of the CYP3A4 enzyme system
  84. 84. TELITHROMYCIN
  85. 85. 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 Resistance: mutation of the ribosomal receptor site modification of the receptor by a constitutively expressed methylase enzymatic inactivation
  86. 86. Clindamycin is more clinically used than Lincomycin: excellent absorption 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 prophylaxis of endocarditis in patients with valvular heart disease for dental procedures
  87. 87. 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 and the gut 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
  88. 88. ADVERSE EFFECTS: Diarrhea, nausea, skin rashes, impaired liver function and neutropenia; Antibiotic associated colitis caused by toxigenic C. difficile
  89. 89. NEWER AGENTS: STREPTOGRAMINS: 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 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, bacteremis or respiratory tract infections caused by methicillin-resistant staphylococci and penicllin susceptibe and resistant strains of S. pheumonia Toxicities: infusion related events, pain at the injection site, arthralgia, myalgia synd
  90. 90. STREPTOGRAMIN A
  91. 91. STREPTOGRAMIN B
  92. 92. 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
  93. 93. METABOLIC INHIBITORS: SULFONAMIDES - structurally similar to p-aminobenzoic acid (PABA) that competitively inhibits dihydropteroate synthase - inhibits growth by reversibly blocking folic acid synthesis - mammalian cells do not make folic acid and are not affected - cross the placenta and secreted in breast milk and should not be given to pregnant Women - highly bound to plasma proteins esp, albumin - penetrates CNS well
  94. 94. SPECTRUM: - Gram (+) & Gram (-) Bacteria - Nocardia - C. trachomatis - Enteric bacteria (E. coli, Klebsiella, Salmonella, Shigella Enterobacter) Ricketssia – sulfonamides do not inhibit these organisms but stimulate its growth Resistance: - occurs as a result of mutations that: 1. cause overproduction of PABA 2. cause production of a folic acid synthesizing enzyme that has a low affinity for Sulfonamides 3. cause a loss of permeability to the sulfonamides
  95. 95. Pharmacokinetics: - 3 MAJOR GROUPS: 1. ORAL, ABSORBABLE 2. ORAL, NON-ABSORBABLE 3. TOPICAL Intravenous Preparation: - Na salts of sulfonamides in D5W Oral, absorbable sulfonamides:
  96. 96. DRUGS HALF LIFE ORAL ABS 1.short acting Sulfacytine Sulfisoxazole Sulfamethizole Short Short (6 h) Short (9 h) Prompt (peaks in 1-4h) Prompt Prompt 2. Medium acting Sulfadiazine Sulfamethoxazole Sulfapyridine Intermediate(10-17h) Intermediate (10-12h) No data Slow (peak in 4-8h) Slow Slow Long Acting Sulfadoxine Long (7-9 days) Intermediate
  97. 97. absorbed from stomach and small intestine - distributed widely to tissues and body fluids (CSF), placenta and fetus - protein binding 20% to over 90% - therapeutic concentration – 40-100 ug/ml of blood - peak blood levels – 2h to 6 h after oral ingestion - metabolism: glucoronidation or acetylation in liver - eliminated in urine-mainly by glomerular filtration
  98. 98. CLINICAL USES: 1. Urinary tract infection Sulfisoxazole – 1 gm 4x daily }combined with PHENAZOPYRIDINE Sulfamethoxazole – 1 g 2-3 x daily } (U.T. anesthetic) 2. Respiratory infections 3. Sinusitis, bronchitis, pneumonia 4. Otitis media 5. Dysentery 6. Acute Toxoplasmosis Sulfadiazine + Pyrimethamine – Synergistic Block sequential steps in folate synthesis: Sulfadizine- inhibits dihydropteroate synthase Pyrimethamine – inhibits dihydrofolate reductase Dosage – Sulfadiazine – 1 g 4x daily Sulfadiazine + pyrimethamine – 75 mg loading dose ffd by 25 mg OD Folinic Acid – administered to minimize bone marrow suppression 7. Malaria - sulfadoxine + pyrimethamine – 2nd line agent in the treatment for malaria
  99. 99. ORAL, NONABSORBABLE AGENTS Sulfasalazine (Salicylazosulfapyridine) more effective than soluble sulfonamides or other antimicrobials taken orally in inflammatory bowel disease ulcerative colitis enteritis other inflammatory bowel disease split by intestinal microflora to yield: Sulfapyridine – absorbed and may lead to toxic symptoms If more than 4 g of sulfasalazine is taken per day esp. in persons who are slow acetylators 5-aminosalicylate (5-ASA) – released in the colon in high concentrations and is responsible for an anti-inflammatory effect
  100. 100. TOPICAL AGENTS: Sodium Sulfacetamide ophthalmic solution or ointment effective for bacterial conjunctivitis adjunct therapy for trachoma Mafenide acetate used topically to prevent bacterial colonization and infection of burn wounds inhibits also carbonic anhydrase – cause metabolic acidosis Silver Sulfadiazine less toxic topical sulfonamide preferred to mafenide for prevention of infection of burn woulds ADVERSE REACTIONS: Cross allergy with the ffg. carbonic anhydrase inhibitors, thiazides, furosemide, bumetanide, furosemide, diazoxide, sulfonylureas, hypoglycemics Most common adverse effects: Fever, skin rashes, exfoliative dermatitis, nausea, vomiting, urticaria, photosensitivity
  101. 101. Urinary tract disturbances: sulfas may ppt. in urine at neutral or acid ph- Crystalluria – treated with sod. Bicarbonate to alkalinize urine and fluids to maintain adequate hydration Hematuria Obstruction implicated in nephrosis and allergic nephritis OTHER SIDE EFFECTS: Stevens-Johnson Syndrome – uncommon but serious and potentially fatal type of skin & mucous membrane eruptions Hematopoietic disturbances: hemolytic or aplastic anemia, thrombocytopenia, granulocytopenia, leukemoid reaction, provoke hemolytic reactions in patients with deficient rbc glucose 6 phosphate dehydrogenase increased risk of kernicterus in newborns when sulfonamides were taken near the end of pregnancy Stomatitis, Conjunctivitis, Arthritis, Hepatitis Polyarteritis nodosa – rare Psychosis – rare
  102. 102. STEVENS JOHNSON SYNDROME
  103. 103. TOXIC EPIDERMAL NECROLYSIS
  104. 104. TRIMETHOPRIM well absorbed from the gut widely distributed in body fluids and tissues incldg. CSF found in high concentrations in prostatic & vaginal fluids Even if given orally alone or in combination with sulfonamides, it will have the same half-life More lipid soluble – larger volume of distribution than sulfonamides RESISTANCE TO TM: due to reduced cell permeability due to overproduction of dihydrofolate reductase due to production of an altered reductase & reduced drug binding CLINICAL USES: Oral TM: acute UTI 100 mg BID community acquired organisms – 200 ug to 600 ug/ml concentration of TM in urine ADVERSE EFFECTS: megaloblastic anemia, leucopenia, granulocytopenia Prevention of adverse effects: simultaneous administration of folinic acid 6 mg-8 mg/day
  105. 105. TRIMETHOPRIM-SULFAMETHOXAZOLE (CO- TRIMOXAZOLE) synergistically active antimicrobial agent which blocks two sequential steps in the obligate enzymatic reaction in bacteria preventing the formation of nucleotides: Sulfamethoxazole – competitively inhibits the incorporation of PABA into folic acid Trimethoprim inhibits dihydrofolate reductase preventing the reduction of dihydrofolate to tetrahydrofolate
  106. 106. ADVANTAGES OF THE COMBINATION: increased potency increases spectrum decreased incidence of resistance exhibits selective toxicity for bacteria which must synthesize their own folic acid Trimethoprim is more potent, more lipid soluble and has a greater volume of distribution than sulfa drugs Penetrates CSF well 65-70% of each drug is protein bound Eliminated in the urine within 24 h – reduce dose by half if creatinine clearance is 15-30 ml/min CLINICAL USES: Oral TMP-SMX urinary tract infection:
  107. 107. complicated UTI – 2 double strength tabs (TM-160 mg+SM 800 mg) q 12 hours Recurrent UTI prophylaxis – ½ of regular size (single strength) 3x weekly Prostatitis – 2 double strength tabs (TM 160 mg + SM 800 mg) q 12 h Susceptible strains of shigella and salmonella 2 double strength tabs q 12 h Children with shigellosis, UTI, otitis media-8mg/kg TM and 40 mg/kg SM q 12 hours P. carinii and other pathogens – orally 15-20 mg/kg in immunosuppressed patients – one double strength tab daily or 3x weekly Nontuberculous mycobacterial infection Respiratory tract pathogens – useful alternative to B lactamase for community acquired bacterial pneumonia
  108. 108. CLINICAL USES: Inravenous TMP-SMX: drug of choice for moderately severe to severe pneumocystis pneumonia esp. patients with AIDS TM 80 mgs + SM 400mg/5 ml diluted in 125 ml of D5W Folinic acid increases morbidity and treatment failures so not used Used for Gram (-) bacterial sepsis – incldg. Those caused by some multiple drug resistant species such as Enterobacter and Serratia Shigellosis Typhoid fever UTI caused by susceptible organisms if patient is unable to take drug orally Dosage- 10-20 mg/kg/day of TM component Oral Pyrimethamine + Sulfadiazine= used in the treatment of leishmaniasis and toxoplasmosis Pyrimethamine + Sulfadoxine = used in the treatment of Falciparum malaria
  109. 109. ADVERSE EFFECTS: mostly due to untoward reactions to SMX dermatological effects GI effects: glossitis, stomatitis, nausea and vomiting CNS disturbances: headache, depression, hallucinations Hematologic reactions- aplastic, hemolytic and macrocytic anemia, coagulation disorders Vasculitis Renal impairment or damage AIDS PATIENTS more sensitive to increased frequency of reactions toward TMP- SMX drug: -rashes, hemtologic effects-leukopenia, fever, diarrhea, elevated hepatic aminotransterases, hyperkalemia, hyponatremia
  110. 110. FLUOROQUINOLONES QUINOLONES synthetic fluorinated analogs of nalidixic acid block bacterial DNA synthesis by inhibiting bacterial topoisomerase II (DNA Gyrase) and topoisomerase IV INHIBITION OF DNA GYRASE prevents relaxation of positively supercoiled DNA that is required for normal transcription and replication INHIBITION OF TOPOISOMERASE IV interferes with separation of replicated chromosomal DNA into the respective daughter cells during cell division
  111. 111. EARLY QUINOLONES (Nalidixic Acid, Oxolinic acid, Cinoxacin) did not achieve systemic antibacterial levels useful only for treatment of lower UTI ANTIBACTERIAL ACTIVITY: Gram (-) aerobic bacteria- excellent activity Gram (+) organism – limited activity NORFLOXACIN – least active against gm (+) and Gm (-) SECOND GROUP excellent gm (-) activity, moderate gm (+) activity Ciprofloxacin (prototype), Enoxacin, Lomefloxacin, Levofloxacin, Ofloxacin, Pefloxacin Methicillin susceptible S. aureus – susceptible to fluoroquinolones Methicillin resistant S. aureus – resistant to fluoroquinolones Ciprofloxacin – most active against gm (-) expecially P. aeroginosa Levofloxacin – 2x more potent than ofloxacin superior activity against gm (+) org. incldg S. pneumoniae
  112. 112. THIRD GROUP: improved activity against gm (+) organism particularly S. pneumoniae and some staph Clinafloxacin – best activity against gm (+) activity Gatifloxacin Sparfloxacin – some activity against anaerobes not as active as ciprofloxacin against gm (-) FOURTH GROUP enhanced gm (+) activity good activity against anaerobic bacteria Moxifloxacin, Trovafloxacin Other activities: Atypical pneumoniae ( Mycoplasma, Chlamydia Intracellular pathoges (Legionella, Mycobacteria tb, and M. avium complex) RESISTANCE: Due to one or more point mutations in the quinolone binding region of the target enzyme Due to a change in the permeability of the organism
  113. 113. DNA GYRASE – primary target in E. coli with single step mutants exhibiting amino acid substitution in the alpha subunit of the gyrase TOPOISOMERASE IV – secondary target in E. coli that is alerted in mutants expressing higher levels of resistance IN STAPH AND STREP Topoisomase IV – primary target DNA gyrase – secondary target cross resistance to other members
  114. 114. PHARMACOKINTEICS: well absorbed after oral intake bioavailability 80-95% distributed widely in body fluids and tissues Half life 3 hrs- norfloxacin and ciprofloxacin 10 hrs. – pefloxacin & Fleroxacin > 10 hrs. – sparfloxacin Long half life : Levofloxacin, moxifloxacin, sparfloxacin, trovafloxacin Ofloxacin and Levofloxacin – identical pharmacokinetics Oral absorption impaired by divalent cations including those antacinds Alatrovafloxacin – inactive prodrug of trovafloxacin for parenteral administration Concentration is higher in prostate, kidney, neutrophiles and macrophages than in serum
  115. 115. ELIMINATION: Renal – tubular secretion, Glomerular filtration - If creatinine clearance < 50%ml/min – adjust dosage Sparfloxacin – a50 % fecal, 50% renal If creatinine clearance <50 ml/min -400 mg LD followed by 200 mg q other day Non renal – trovafloxacin and moxifloxacin _ CI in patients with hepatic failure CLINICAL USES: UTI – even when caused by multi drug resistant bacteria like pseudomonas Norfloxacin 400 mg Bid Ciprofloxacin 500 mg BID Ofloxacin 400 mg BID Prostatitis – 4-6 wks Norfloxacin, Ciprofloxacin, Ofloxacin Bacterial Diarrhea
  116. 116. Shigella, Salmonella, toxigenic E. coli, campylobacter Infection of soft tissues, bones, joints, intraabdomina and respiratory tract infection even caused by Pseudomonas and Enterobacter Gonococcal infection, including disseminated disease Ciprofloxacin, ofloxacin oral single dose Chlamydia urethritis or cervicitis ofloxacin x 7 days Legionellosis Ciprobay – 2nd line agent TB and atypical mycobacteria infection Eradication of meningococci carrier Prophylaxis in neutropenic patient Upper and lower RTI Newer fluoroquinolones enhanced gm (+) activity and atypical pneumonia
  117. 117. ADVERSE EFFECTS: most common – nausea, vomiting and diarrhea Others – headache, dizziness, insomnia, skin rash, abn liver function test Trovafloxacin – associated rarely with acute hepatitis and hepatic failure Photosensitivity – lomefloxacin, pefloxacin CV toxicity – Grepafloxacin Damage growing cartilage and cause arthrpathy- not recommended < 18 y/o Tendinitis – may rupture DRUG INTERACTION: Theophylline – increase metabolism of theophylline – elevated concentration-seizures CONTRAINDICATIONS: Nursing mothers, children, pregnancy
  118. 118. NALIDIXIC ACID First antibacterial quinolone introduced in 1963 Not fluorinated Very rapid elimination, no systemic bacterial effects Used only for UTI Oxolinic Acid and Cinoxacin – similar structure NOVOBIOCIN: Acidic antibiotic prod. By Streptococcus niveius Inhibitor of B subunit of DNA gyrase Active mainly against gm (+) bacteria Rapid emergence of resistance; inc. incidence of adverse effects No clear indication
  119. 119. URINARY ANTISEPTICS: Methenamine Mandelate and Hippurate releases mandelic acid, hippuric acid or formaldehyde in sufficiently acidic urine bactericidal or bacteriostatic to most organisms causing UTI except Proteus Nalidixic Acid and Cinoxacin: interferes with DNA polymerization by binding to DNA gyrase causes nausea, vomiting, skin rashes and CNS effects
  120. 120. Nitrofurantoin well absorbed after ingestion excreted into the urine 100 mg q 6 h with food or milk contraindicated in severe renal insufficiency bactericidal or bacteriostatic for many gram (+) and gram (-) antagonizes the action of nalidixic acid causes hypersensitivity, nausea, vomiting, neuropathies and hemolytic anemia in G6PD Trimethoprim selective inhibition of bacterial dihydrofolate reductase may be bacteriostatic or bacteridial + Sulfamethoxazole – P. carinii, shigellosis, prostatitis, some nontuberculous mycobacterial infections, systemic salmonella infections, complicated UTI
  121. 121. MISCELLANEOUS ANTIBACTERIAL DRUGS: Metronidazole penetrates CSF, metabolism-liver treatment of amoebic infections, intraabdominal infections, vaginitis, antibiotic associate enterocolitis, brain abscess oral, IV, rectal suppository causes metallic taste, glossitis and anorexia
  122. 122. Polymyxin B group of basic peptides active against Gram (-), bactericidal treatment of serious enteric infections(Pathogenic E. coli, Shigella, Enterobacter, Klebsiella and Pseudomonas , not Proteus) poor tissue distribution attach to and disrupt bacterial cell membrane, bind and inactivate endotoxin toxicity includes neurological and renal effects topical (+Bacitracin+Neomycin)
  123. 123. Mupirocin ointment for topical application active against staph aureus; inh. Isoleucyl tRNA synthetase indicated for impetigo, intranasal application for elimination of methicillin resistant S. aureus carriage by patient or health care workers

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