DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 1 ANTIBIOTICS: By: Prof Avijit Mazumder

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 2 Objectives: What are antibiotics? What are the various classes and their mode of action? Why is resistance developing to antibiotics? Is this a problem? What role can the pharmaceutical scientists play in regard to this problem?

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9 Penicillins  First antibiotic to be used in 1941  Originally isolated from Pc notatum Low toxicity  Effective derivatives created from manipulating drug’s basic molecular structure  Kills bacteria by preventing them from forming the rigid cell wall  Because human cells do not have cell walls, they are not affected

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 10 MODE OF ACTION: NAM NAG L-Ala D-Glu L-Lys D-Ala L-Ala L-Lys D-Glu D-Ala GLY 5 D-Ala

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 11 Penicillins  amoxicillin (Amoxil, Trimox)  amoxicillin-clavulanate (Augmentin)  ampicillin (Principen)  ampicillin-sulbactam (Unasyn)  carbenicillin (Geocillin) Drug List

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 12  dicloxacillin  oxacillin  penicillin G (various)  penicillin V (Veetids)  piperacillin Penicillins Drug List

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 13  piperacillin-tazobactam (Zosyn)  ticarcillin (Ticar)  ticarcillin-clavulanate (Timentin) Penicillins Drug List

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 14 Therapeutic Uses of Penicillins  Beta-hemolytic streptococcus  Meningitis  Otitis media  Pneumonia  Respiratory infections  Tooth and gum infections  Venereal diseases (syphilis and gonorrhea)  Endocarditis due to streptococci

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 15 Penicillins’ Side Effects  Diarrhea  Allergies in 7% to 10% of population

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 16 Penicillins’ Dispensing Issues  Take on an empty stomach  Food slows absorption  Acids in fruit juices or colas could deactivate the drug

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 17 Penicillin Resistance  Penicillinase-resistant penicillins work against gram-positive aerobes  Extended-spectrum penicillins are more resistant to gram-negative bacteria  Penicillin combinations improve effect

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DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 23 Classification of newer penicillins  Acid Resistant Penicillins: Phenoxymethyl Pc.  Penicillinase resistant Penicillins: Methicillin, Cloxacillin  Extended Spectrum Penicillins: Ampicillin, Mezlocillin, Ticarcillin, Piperacillin  Β lactamase inhibitors: Clavulanic acid Salbactum

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 24 BETA LACTAMASE INHIBITORS  Clavulanic acid : Obtained from Streptomyces clavuligerus, it has a beta lactum ring but no antibacterial activity.  Addition of clavulanic acid reestablishes the activity of amoxicillin against beta lactamase producing acid resistant S.aureus, E.coli, Proteus, Salmonella that are not responsive to amoxicillin alone.

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 25 Cephalosporins  Have a mechanism of action similar to penicillins  A person allergic to penicillin, about 10% chance of being allergic

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 26 Cephalosporins Alert the Pharmacist if a patient allergic to penicillins is receiving a cephalosporin prescription. Warning!

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 27 Cephalosporins  First-generation  Similar to penicillinase-resistant penicillins with greater gram-negative coverage  Used for  community-acquired infections  mild to moderate infections

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 28 Cephalosporins  Second-generation  Increased activity, especially against Haemophilus influenzae  Used for Respiratory infections  UTIs

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 29 Cephalosporins  Third-generation  Active against a wide spectrum of gram- negative organisms  Long half-life, so once-a-day dosing for some  Used for  Ambulatory patients  Children

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 30 Cephalosporins  Fourth-generation  Active against a wide spectrum of gram- negative organisms  Long half-life, so once-a-day dosing for some.  Highly resistant to beta lactamases and so widely used against hospital acquired serious infections  Eg: Cefepime

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DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 32 Cephalosporins Side Effects  Share side effects of penicillin  Few may initiate unique toxic reactions  Lower frequency of toxicity than many other antibiotics

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 33 Cephalosporins All of the cephalosporins look alike when written in the generic form. Watch for dosing and indications for use. Warning!

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 34  cefaclor (Ceclor)  cefadroxil (Duricef)  cefazolin (Ancef)  cefdinir (Omnicef)  cefditoren (Spectracef)  cefepime (Maxipime) Cephalosporins Drug List

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 35  cefotaxime (Claforan)  cefotetan (Cefotan)  cefoxitin (Mefoxin)  cefpodoxime (Vantin)  cefprozil (Cefzil)  ceftazidime (Fortaz)  ceftibuten (Cedax) Cephalosporins Drug List

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 36  ceftizoxime (Cefizox)  ceftriaxone (Rocephin)  cefuroxime (Ceftin, Zinacef)  cephalexin (Keflex)  cephradine (Velosef) Cephalosporins Drug List

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 37 USES OF CEPHALOSPORINS  Alternative to Pc G particularly in allergic patients  Respiratory tract infections caused by gram negetive spp  Penicillinase resistant staphylococal infection  Septicaemias caused by gram negetive organism: aminoglycosides+ cephalosporins  Surgical prophylaxis: First generation cephalosporins eg cefazolin(im) is employed in all surgery.  Meningitis: Pyogenic meningitis require bactericidal activity in CSF pref with Ab at sev times higher conc than MBC  Hospital acquired infection

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DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 41 Aminoglycosides  Treat serious infections  Inhibits bacterial protein synthesis by binding to ribosomal subunits

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 42 Aminoglycosides  Less frequent dosing may help reduce toxicity  Less drug accumulates in the kidney and ear  Simplified drug monitoring  Levels should be checked prior to administration of second dose to confirm drug elimination

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 43 Aminoglycosides’ Side Effects  Nephrotoxicity, destructive to kidney  Ototoxicity  Permanent deafness  Equilibrium problems

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 44  amikacin  gentamicin (Garamycin, Genoptic)  kanamycin (Kantrex)  neomycin (Myciguent, Neo-Fradin)  streptomycin (none)  tobramycin (Nebcin) Aminoglycosides Drug List

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 45 Tetracyclines  Broad-spectrum bacteriostatic antibiotics  Inhibit protein synthesis in bacteria by binding to ribosomes  Suppress the infection and require phagocytes to complete the eradication of the bacteria

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 46 Therapeutic Uses of Tetracyclines  Acne  Chronic bronchitis Pneumoniae infection Pneumoniae infection  Rickettsia infection  Chlamydia infection  Traveler’s diarrhea

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 47 Tetracyclines’ Side Effects  Gastrointestinal upset with nausea and vomiting

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 48 Tetracyclines’ Dispensing Issues  Avoid antacids to avoid chelation with minerals  Photosensitization  To be avoided by pregnant women and children  Expired drugs are dangerous

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 49  doxycycline (Vibramycin)  minocycline (Minocin)  tetracycline (Sumycin) Tetracyclines Drug List

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DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 51 Macrolides  Inhibit protein synthesis by combining with ribosomes  Used primarily to treat pulmonary infections

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 52 Macrolides Drugs of choice for the following illnesses and specific bacteria:  Chlamydia  Group A beta-hemolytic streptococcus  H. influenzae  S. pneumoniae

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 53 Macrolides’ Dispensing Issues Although most antibiotics should be taken on an empty stomach, erythromycins usually cause severe GI distress, so should be taken with food

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 54  azithromycin (Zithromax, Z-PAK)  clarithromycin (Biaxin)  dirithromycin (Dynabac)  erythromycin base (Eryc, Ery-Tab)  erythromycin ethylsuccinate (E.E.S., EryPed)  erythromycin lactobionate (Erythrocin)  erythromycin stearate (Erythrocin)  erythromycin-sulfisoxazole (Pediazole) Macrolides Drug List

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 55 Ketolides  Block protein synthesis by binding to ribosomal subunits  May inhibit the formation of newly forming ribosomes  Used to treat bacterial infections in the lungs and sinuses

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 56  telithromycin (Ketek) Ketolides Drug List

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DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 58 Quinolones  Synthetic antimicrobials having a quinolone structure that are primarily against gram negative bacteria.  First member was nalidixic acid used for UTI and GIT infections only due to low potency  Strong, rapid bactericidal action against most gram-negative and many gram-positive bacteria  Antagonize the enzyme responsible for coiling and replicating DNA, causing DNA breakage and cell death

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 59 FLUROQUINOLONES  First generation fluroquinolones:  Norfloxacin, Ciprofloxacin  Second generation fluroquinolones:  Levofloxacin, Sparfloxacin, Gatifloxacin

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 60 MODE OF ACTION OF FLUROQUINOLONES  The FQ inhibits DNA gyrase which nicks double starnded DNA  Mechanism of resistance development:  Due to chromosomal mutation producing a DNA Gyrase with reduced affinity for FQ  Reduced permeability of these drugs across bacterial cell membranes  FQ resistance are slow to develop

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 61 Therapeutic Uses of Quinolones  Bone and joint infections caused by gram-negative organisms  Infectious diarrhea  Ophthalmic infections  Some sexually transmitted diseases  Upper respiratory infections  UTIs

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 62 Quinolones’ Side Effects  Primarily gastrointestinal, with nausea and vomiting  Dizziness  Unpleasant taste  Can cause joint problems such as swelling and malformations  Patients taking them have a tendency to injure tendons

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 63 Quinolones’ Dispensing Issues  Not to be given with theophylline  Antacids interfere with absorption  Avoid exposure to sun

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 64  ciprofloxacin (Ciloxan, Cipro)  gatifloxacin (Tequin)  gemifloxacin (Factive)  levofloxacin (Levaquin)  moxifloxacin (Avelox, Vigamox)  norfloxacin (Noroxin)  ofloxacin (Floxin, Ocuflox) Quinolones Drug List

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 65 Streptogramins  Inhibit protein synthesis within the bacterial ribosomes  Alternative to vancomycin  Side effects similar to quinolones nausea and vomiting joint swelling dizziness

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 66 Cyclic Lipopetides  Bind bacterial membranes and cause the cell membrane to depolarize  Leads to  Inhibition of DNA and RNA synthesis  Bacterial death

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 67  daptomycin (Cubicin) Do not take with statins. Warning! Cyclic Lipopetides Drug List

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 68 Antibiotics Independent of Classes These antibiotics are independent of other classes and each other due to structural differences.

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 69  chloramphenicol (Chloromycetin)  clindamycin (Cleocin)  linezolid (Zyvox)  metronidazole (Flagyl)  pentamidine (NebuPent, Pentam)  vancomycin (Vancocin) Antibiotics Independent of Classes Drug List

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 70 Antibiotics Independent of Classes Vancomycin (Vancocin): Glycopeptide antibiotic; acting by inhibition of bacterial CW Synthesis. It binds to terminal dipeptide d-ala-d-ala sequence of peptidoglycan chain and prevent its release from cell wall and thereby preventing its cross linking. Bacterial resistance is increasing due to overuse. Warning!

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 71 Antibiotics Independent of Classes Uses of clindamycin (Cleocin)  Acne  Alternative to penicillin in dental prophylaxis  Anaerobic pneumonia  Bone infections  Bowel infections  Female genital infections  Intra-abdominal infections

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 72 Antibiotics Independent of Classes clindamycin (Cleocin) If patient develops diarrhea, the drug must be discontinued. Warning!

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 73 Antibiotics Independent of Classes metronidazole (Flagyl) Place a do not drink alcohol warning sticker on this medication.

DR AVIJIT MAZUMDER, SPTM,NMIMS UNIVERSITY, MUMBAI 74 Adjunct in Treating Sepsis  Sepsis is a life-threatening result of serious infections.  Properties of drotrecogin alfa (Xigris)  Anticoagulant  Anti-inflammatory

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