ANTIBIOTICS By Prof Avijit Mazumder DR AVIJIT MAZUMDER

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

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? DR AVIJIT MAZUMDER, SPTM, NMIMS UNIVERSITY, 2

DR AVIJIT MAZUMDER, SPTM, NMIMS UNIVERSITY, 3

DR AVIJIT MAZUMDER, SPTM, NMIMS UNIVERSITY, 4

DR AVIJIT MAZUMDER, SPTM, NMIMS UNIVERSITY, 5

DR AVIJIT MAZUMDER, SPTM, NMIMS UNIVERSITY, 6

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DR AVIJIT MAZUMDER, SPTM, NMIMS UNIVERSITY, 8

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, 9

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

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

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

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

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, 14

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

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, 16

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

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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, 23

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, 24

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, 25

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

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, 27

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

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

Cephalosporins § Fourth-generation § Active against a wide spectrum of gramnegative 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 DR AVIJIT MAZUMDER, SPTM, NMIMS UNIVERSITY, 30

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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, 32

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

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

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

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

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 DR AVIJIT MAZUMDER, SPTM, NMIMS UNIVERSITY, 37

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

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, 42

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

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

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, 45

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

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

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, 48

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

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

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, 52

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, 53

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

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, 55

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

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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, 58

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

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

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, 61

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, 62

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

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

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, 65

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, 66

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

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

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

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. Warning! Bacterial resistance is increasing due to overuse. DR AVIJIT MAZUMDER, SPTM, NMIMS UNIVERSITY, 70

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, 71

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

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

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