Anitmicrobial General considerations

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Anitmicrobial General considerations

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Antimicrobial Agents (General Considerations):

Antimicrobial Agents (General Considerations) Prof. R. K. Dixit Pharmacology and Therapeutics K.G.M.U. Lucknow [email protected]

Objectives:

Objectives After this lecture students will be able to answer What are antimicrobials, antibiotics, chemotherapeutic agents (Terminologies used in antimicrobial treatment) Classification of antimicrobials (chemicals, mechanism, spectrum) Mechanisms of action of antimicrobials Resistance development in antimicrobials General adverse effects of antimicrobials General drug interactions related to antimicrobials Uses of antimicrobials (Therapeutic and Prophylaxis) Selection of appropriate antimicrobials Precautions while prescribing antimicrobials and failure

Slide 3:

A naturopath tells “ One should never take antibiotics Except in Pneumonia, a kidney infection, boils, meningitis, encephalitis, osteomyelitis, occular infections, or other serious illness………………………………………………….”

Allopath is Lucky to have the help of Antimicrobials :

Allopath is Lucky to have the help of Antimicrobials But This Luck may not last long due to reasons…… Inappropriate use,… Overuse….. Antimicrobial resistance Reduced immunity Worsening of environment Co morbid illnesses like diabetes, malnutrition…… Less interest of pharmaceuticals in this field Costly new antimicrobials

Antimicrobials , Antimicrobials , Antimicrobials , Antimicrobials, Antimicrobials , Antimicrobials Antimicrobials!!!:

Antimicrobials , Antimicrobials , Antimicrobials , Antimicrobials, Antimicrobials , Antimicrobials Antimicrobials !!! Penicillin, ampicillin, amoxycillin , ticarcillin , piperacillin , flucloxacillin , dicloxacillin , oxacillin , methicillin , nafcillin , carbenicillin , eryhtromycin , clindamycin , roxythromycin clarithromycin , tetracycline, doxycycline , minocycline , vancomycin , teicoplanin , augmentin , gentamicin , tobramycin , amikacin , streptomycin, azithromycin , aztreonam , cephalexin , cefotaxime , cephamandole , cefepime , ceftriaxone , ceftazidime , cefpirome , imipenem , chloramphenicol , cotrimoxazole , ciprofloxacin, norfloxacin , trimethoprim ,……. ………………………………………………………………………………………………………………………………………………….. hundreds of different antimicrobial agents on the market.

Terminology:

Terminology 6 Chemotherapy – U se of drugs to treat infections and malignancy Antimicrobials and Antineoplastic agents (Beware of using this) Pharmacodynamic agents- D rugs regulating physiological process of body and act on the body cells. Chemotherapeutic agents- S electively acting against microbes or malignant cells. (Don’t touch body cells) Antimicrobials – U sed in treating infectious microbial diseases. Antibiotics – P roduced from microbes to inhibit or kill other microbes in low concentration (Antimicrobials from microbes) All antibiotics are antimicrobials but all antimicrobials are not antibiotics

Slide 7:

Bacteriostatic - Stop the growth of bacteria Bactericidal- Kill the bacteria PAE- Post antibiotic effect Minimum Inhibitory Concentration (MIC)- Which stops the growth Minimum Bactericidal Concentration (MBC)- Which kills by 99.99% What about MBC-MIC value regarding cidal or static activity MBC – MIC if Less = Bactericidal MBC – MIC if More = Bacteristatic

Slide 8:

MBC – MIC is More MBC – MIC is Less What about MBC – MIC in this

Slide 9:

Prebiotics - Chemicals which stimulate the growth of intestinal commensals and prevent multiplication and establishment of pathogenic bacteria Inulin , Lactulose , Lactitol Probiotics - Live microbials used as supplements to maintain the intestinal bacterial flora. Lactobacilli and Bifidobacteria

Terminology Summary:

Terminology Summary Chemotherapy – Pharmacodynamic agents- Chemotherapeutic agents- Antimicrobials – Antibiotics – Bacteriostatic - Bactericidal- PAE- Minimum Inhibitory Concentration (MIC)- Minimum Bactericidal Concentration (MBC)- Prebiotics - Probiotics - Prophylaxis-

Beware of term Chemotherapy:

Beware of term Chemotherapy Presently it is used only for Antineoplastic agents

History of Antimicrobials:

History of Antimicrobials

Historical Perspectives:

Historical Perspectives Chenopodium - ( बथुआ ) for intestinal worms Mouldy curd – for boils Chaulmoogra oil ( कालमोगरा ) for Leprosy Mercury – for Syphilis Cinchona Bark- ( कुनैन ) for Malaria

Historical perspectives:

Historical perspectives Pasteur- (1877) Phenomenon of antibiosis Paul Ehrlich- (1906) Father of Chemotherapy, Coined term chemotherapy Domagk- (1935) Discovery of sulfonamides ( Prontosil to sulphanilamide ) Fleming, Chain, Florey- Penicillin (1929, 39, 41) from penicillium Waksman- Streptomycin, from actinomycetes , Coined term antibiotic

Introduction of Class of antimicrobial agents :

Introduction of Class of antimicrobial agents 1935 - Sulphonamides 1941 - Penicillins 1944 - Aminoglycosides 1945 - Cephalosporins 1949 - Chloramphenicol 1950 - Tetracyclines 1952 - Macrolides 1956 - Glycopeptides 1957 - Rifamycins 1959 - Nitroimidazoles 1962 - Quinolones 1968 - Trimethoprim 2000 - Oxazolidinones 2003 - Lipopeptides

Discovery is lagging behind the strength of Invaders (Not a Good Sign):

Discovery is lagging behind the strength of Invaders (Not a Good Sign)

Historical events Summary:

Historical events Summary Pasteur- Phenomenon of antibiosis Paul Ehrlich- Father of Chemotherapy & term chemotherapy Domagk- Discovery of sulfonamides Fleming, Chain, Florey- Penicillin (1929, 39, 41) Waksman- Streptomycin, from actinomycetes & term antibiotic 1935 – Sulphonamides 1941 – Penicillins 1944 – Aminoglycosides

Invaders And Agents Acting Against :

Invaders And Agents Acting Against Viruses Bacteria Gram Positive Gram Negative Acid fast Fungi Protozoa infections Amoeba Malarial parasite Others Helminthes Neoplastic cells Antiviral Antibacterial Against gram positive Against gram negative Antitubercular / Leprotic Antifungal Antiprotozoal Antiamoebic Antimalarial Other antiprotozoals Anthelmintics Antineoplastic / Chemotherapeutic agents

What are the most important factors to be good Antimicrobial agent or Chemotherapeutic Agent?????:

What are the most important factors to be good Antimicrobial agent or Chemotherapeutic Agent????? Selectivity and Specificity (Don’t Touch Human Cells) Efficacy Safety Stability

Human Vs Bacteria:

Human Vs Bacteria Human Cells are more lazy than Bacterial Cells Who’s Cells are more Lazy??? Exploring Selectivity and Specificity

Human Cell Vs Bacterial Cell:

Human Cell Vs Bacterial Cell Use Preformed folic acid for synthesis of DNA Use precursor of folic acid and synthesize Folic acid by themselves to be used for synthesis of DNA Topoisomerase II during DNA replication Topoisomerase IV and DNA Gyrase during DNA replication Sterols Hypnoids Different DNA dependent RNA Polymerase

Differences between human cells Vs Bacterial Cells (Makes the antibacterial selective):

Differences between human cells Vs Bacterial Cells (Makes the antibacterial selective) Human cells don’t posses wall ( Peptidoglycans = peptides + sugar) Human cell membrane is different ( Bacteria Contain Hypanoids in place of Sterol) Human cells take preformed dihydrofolic acid (no need of PABA in human) Dihydrofolic acid reducatase enzyme is different Topoisomerases are different (in bacteria topoisomerase IV, DNA Gyrase ) DNA dependent RNA polymerase is different Ribosome 60S subunit (in bacteria 50S) Ribosome 40S subunit (in bacteria 30S) Human Cells are more lazy than Bacterial Cells

Bacteria :

Bacteria ???????

Gram Positive Gram Negative:

Gram Positive Gram Negative

Gram positive & Gram Negative:

Gram positive & Gram Negative Gram positive bacteria have Thick cell wall Peptidoglycan directly accessible from environment Gram negative bacteria have Thin cell wall Surrounded by inner and outer membrane Of lipopolysaccharide , phospholipids, and proteins Outer membrane is a barrier to diffusion of antibiotics Limited antibiotics may diffuse through porins

Cell Wall Structure in Gram Positive :

Cell Wall Structure in Gram Positive Dipeptidase bond

Summary of Invaders:

Summary of Invaders Viruses Bacteria Gram Positive- Thick cell wall of peptidoglycan and accessible from outside Gram Negative- Thin cell wall embedded in between outer and inner membrane (Difficult to get access) Fungus Protozoa Helminthes Neoplastic cells

Relax and Revise:

Relax and Revise

Antimicrobial Classification:

Antimicrobial Classification Chemical structure Mechanism of Action Organism type Spectrum of activity Static or Cidal Origin of antimicrobials

Slide 31:

Organism affected Anti-viral Anti-bacterial Anti-fungal Anti- protozoal Anthelmintic Antitubercular Antileprotic Sources Fungi- Penicillin Cephalosporins Griseofulvin Bacteria- Polymyxin B Colistin Bacitracin Actinomycetes - Most common Aminoglycosides Tetracyclines Chloramphenicol Macrolides

Here onwards we will focus on Antibacterials only during this lecture:

Here onwards we will focus on Antibacterials only during this lecture

Slide 33:

Spectrum Narrow Penicillin G Streptomycin Isoniazide Broad Tetracycline Chloramphenicol Extended Ampicillin Amoxicillin Sulphonamides Fluoroquinolones Most…….. Bacteristatic Sulfonamides and Trimethoprim (alone ) Tetracyclines Macrolides (Erythromycin) Chloramphenicol Ethambutol Nitrofurantoin Bactericidal Cotrimoxazol Penicillins Cephalosporins Aminoglycosides Vancomycin , Daptomycin Fluroquinolones (ciprofloxacin) INH, Rifampicin , Pyrazinamide Polymixins , Bacitracin Metronidazole

Differences Between Human Cells Vs Bacterial Cells To Use As Selective Targets For The Antibacterial Agents:

Differences Between Human Cells Vs Bacterial Cells To Use As Selective Targets For The Antibacterial Agents

Differences between human cells Vs Bacterial Cells (Makes the antibacterial selective):

Differences between human cells Vs Bacterial Cells (Makes the antibacterial selective) Human cells don’t posses wall ( Peptidoglycans = peptides + sugar) Human cell membrane is different ( Bacteria Contain Hypanoids in place of Sterol) Human cells take preformed dihydrofolic acid (no need of PABA in human) Dihydrofolic acid reducatase enzyme is different (thousand time affinity) Topoisomerase II are different (in bacteria topoisomerase IV, DNA Gyrase ) DNA dependent RNA polymerase is different Ribosome 60S subunit (in bacteria 50S) Ribosome 40S subunit (in bacteria 30S) 1 2 3 4 5 6 7 8 Human Cells are more lazy than Bacterial Cells

Mechanism of action (Targets):

Mechanism of action (Targets) Cell Wall synthesis inhibition- Beta- lactams , Vancomycin , Cycloserines Cell membrane Leakage- Polypeptides, Polyenes Folate Synthesis inhibition- Sulfonamides Pyrimethamine DNA gyrase and Topoisomerase inhibition- Fluroquinolones RNA polymerase inhibition- Rifampicin ,, Protein Synthesis Inhibition- (ATT) Inhibition of 50S ribosome-Chloramphenicol, Macrolides , Clindamycin, Linezolid Inhibition of 30S ribosome -Aminoglycosides, tetracyclines 7 8 1 2 3 4 5 6 Human Cells are more lazy than Bacterial Cells

Slide 37:

1 2 3 4 5 6 7 8 Human Cells are more lazy than Bacterial Cells

Summary Of Selective Targets Against Bactria:

Summary Of Selective Targets Against Bactria Cell wall made of Peptidoglycans Cell membrane Containing Hypanoids in place of Sterol Synthesis of dihydrofolic acid from the precurosor PABA Different Dihydrofolic acid reducatase enzyme Different Topoisomerase ( topoisomerase IV, DNA Gyrase ) Different DNA dependent RNA polymerase Ribosomal 50S subunit Ribosomal 30S subunit Human Cells are more lazy than Bacterial Cells 7 8 1 2 3 4 5 6

Bacterial Cell Wall Structure:

Bacterial Cell Wall Structure Beta Lactams

Slide 41:

Protein Synthesis

Protein Synthesis:

Protein Synthesis Chloramphenicol - Macrolides - Erythromycin, Azithromycin etc. Aminoglycosides. Gentamicin , Amikacin , etc.

Folate Metabolism and sequence of Protein synthesis in bacteria:

Folate Metabolism and sequence of Protein synthesis in bacteria

Slide 44:

PABA Dihydrofolic acid Tetrahydrofolic acid Purines and Pyrimidines DNA And RNA DNA unwinding (DNA gyrase ) Threads sepeartion (Topoisomerase IV) DNA dependent RNA Polymerase tRNA + Amino Acids Ribosome unit (50S) Ribosome unit (30S) Protein Synthesis Dihydro -folic acid Synthetase Dihydro -folic acid reductase DNA multiplication mRNA Sulphonamides (PABA analogue and inhibitor of DHFAS) Trimethoprim and Pyrimethamine (inhibitor of DHFAR) Quinolones (Inhibitor of DNA gyrase and Topoisomerase IV) Rifampicin (inhibitor of DNA dependant RNA Polymerase) Chloramphenicol, Macrolides (50S) Aminoglycosides, Tetracyclines (30S)

Slide 45:

DNA unwinding (DNA gyrase ) Threads sepeartion (Topoisomerase IV) PABA Dihydrofolic acid Tetrahydrofolic acid Purines and Pyrimidines DNA And RNA Dihydro -folic acid Synthetase Dihydro -folic acid reductase RNA Polymerase tRNA + Amino Acids Ribosome unit (50S) Ribosome unit (30S) Protein Synthesis mRNA Sulphonamides (PABA analogue and inhibitor of DHFAS) Trimethoprim and Pyrimethamine (inhibitor of DHFAR) Quinolones (Inhibitor of DNA gyrase and Topoisomerase IV) Rifampicin (inhibitor of DNA dependant RNA Polymerase) Chloramphenicol, Macrolides (50S) Aminoglycosides, Tetracyclines (30S) 3 4 5 6 7 8

Slide 46:

Cell Wall synthesis inhibition- Beta- lactams , Vancomycin , Cycloserines Cell membrane Leakage- Polypeptides, Polyenes PABA Dihydrofolic acid Tetrahydrofolic acid Purines and Pyrimidines DNA And RNA DNA unwinding (DNA gyrase ) Threads sepeartion (Topoisomerase IV) RNA Polymerase mRNA tRNA + Amino Acids Ribosome unit (50S) Ribosome unit (30S) Protein Synthesis Dihydro -folic acid Synthetase Dihydro -folic acid reductase DNA multiplication Sulphonamides (PABA analogue and inhibitor of DHFAS) Trimethoprim and Pyrimethamine (inhibitor of DHFAR) Quinolones (Inhibitor of DNA gyrase and Topoisomerase IV) Rifampicin (inhibitor of RNA Polymerase) Chloramphenicol, Macrolides (50S) Aminoglycosides, Tetracyclines (30S) 1 2 3 4 5 6 7 8

Slide 47:

1 2 3 4 5 6 7 8

Slide 48:

Cell mebrane Polypeptides and Polyenes Polymyxin , Colistin , Bacitracin , Nystatin , Amphotericin -B, Hamycin Cell Wall synthesis by acting on cross linking Penicillins , Cephalosporins, Monobactams , Carbapenems , Vancomycin , Teicoplanin , Cell wall synthesis by acting on inhibition of mycolic acid (Long Fatty acid present in mycobacterial family) Isoniazide , Pyrizinamide , Ethambutol Interfering with folic acid metabolism Sulphonamides - Sulfamethoxazole , Sulfadoxine , Diaminopyrimidines - Trimethoprim , Pyrimethamine DNA gyrase and topoisomerase IV inhibitors Quinolones - Nalidixic acid, ciprofloxacin, Ofloxacin , Pfloxacin , Gatifloxacin , Sparfloxacin Inhibition of DNA dependeant RNA Polymerase Rifampicin , Acting on 50S ribosome Macrolides - Erythromycin, Clarithromycin , Azithromycin , Roxithromycin , Chloramphenicol, Lincomycin , Clindamycin , Linezolid Acting on 30 S ribosome Aminoglycosides - Streptomycin, Gentamycin , Kanamycin , Amikacin , Tobramycin Tetracyclines - Oxytetracycline , Doxycycline Antibacterial - Co- trimoxazole Antimalarial - Co- trimazine 1 2 3 4 5 6 7 8 2

Relax and Revise:

Relax and Revise

Slide 50:

Which of the following will have effect for longer time on the control of notorious activities of baby Post Pityai Effect (Post Antibiotic effect)

Post-Antibiotic Effect:

Post-Antibiotic Effect Capacity to inhibit the growth of bacteria after removal of the drug from the culture (body) Provides additional time for the immune system to remove bacteria that might have survived Post Pityai Effect

Slide 52:

ANT IMICROBIALS Dose-dependent (With PAE) Time-dependent Antibacterial effect directly depends on their concentrations in the locus of in fection (high doses 1-2 times/24h) Aminoglycosides F lu or oq inolones Metronidazol Amphoter i cin B Effectiveness depends on a period of time, during which concentration in blood overwhelms MIC for a particular causative agent (constant i.v . infusion or 3-6 times/24h) Beta-lactames Glycopeptides Macrolides Tetracyclines Vancomycin Post Pityai Effect

Antimicrobial Classification According to the Chemical Classes:

Antimicrobial Classification According to the Chemical Classes ( P ublic L oves GOOD Q uality BATSMAN )

Chemical Classification (Public Loves GOOD Quality BATSMAN):

Chemical Classification ( P ublic L oves GOOD Q uality BATSMAN ) P olypeptides - Polymyxin , Colistin , Bacitracin P oyene antibiotics- Nystatin , Amphotericin -B, Hamycin L incosamide - Lincomycin , Clindamycin G lycopeptides - Vancomycin , Teicoplanin O xazolidinone - Linezolid O thers----------------- Riampicin , Griseofulvin , etc Di aminopyrimidines - Trimethoprim , Pyrimethamine Q uinolones - Nalidixic acid, ciprofloxacin B eta- lactam - Penicillins , Cephalosporins, Monobactams , Carbapenems A minoglycosides - Streptomycin, Gentamycin T etracyclines - Oxytetracycline , Doxycycline S ulphonamides - Sulfadiazine, Sulfamethoxazole , M acrolides - Erythromycin, Clarithromycin A zoles- Fluconazole , Clotrimazole N itroimidazoles - Metronidazole , Tinidazole N icotinic acid derivatives- Isoniazide , Pyrizinamide , Ethionamide N itrobenzene derivaties - Chloramphenicol N itrofuran derivatives- Nitrofurantoin , Furazolidone

Chemical Classification (Public Loves GOOD Quality BATSMAN):

Chemical Classification ( P ublic L oves GOOD Q uality BATSMAN ) P olypeptides - Polymyxin , Colistin , Bacitracin P oyene antibiotics- Nystatin , Amphotericin -B, Hamycin L incosamide - Lincomycin , Clindamycin G lycopeptides - Vancomycin , Teicoplanin O xazolidinone - Linezolid O thers----------------- Riampicin , Griseofulvin , etc Di aminopyrimidines - Trimethoprim , Pyrimethamine Q uinolones - Nalidixic acid, ciprofloxacin B eta- lactam - Penicillins , Cephalosporins, Monobactams , Carbapenems A minoglycosides - Streptomycin, Gentamycin T etracyclines - Oxytetracycline , Doxycycline S ulphonamides - Sulfadiazine, Sulfamethoxazole , M acrolides - Erythromycin, Clarithromycin A zoles- Fluconazole , Clotrimazole , Itroconazole N itroimidazoles - Metronidazole , Tinidazole N icotinic acid derivatives- Isoniazide , Pyrizinamide , Ethionamide N itrobenzene derivaties - Chloramphenicol N itrofuran derivatives- Nitrofurantoin , Furazolidone Bactericidal Cotrimoxazole

Chemical Classification (Public Loves GOOD Quality BATSMAN):

Chemical Classification ( P ublic L oves GOOD Q uality BATSMAN ) P olypeptides - Polymyxin , Colistin , Bacitracin P oyene antibiotics- Nystatin , Amphotericin -B, Hamycin L incosamide - Lincomycin , Clindamycin G lycopeptides - Vancomycin , Teicoplanin O xazolidinone - Linezolid O thers----------------- Riampicin , Griseofulvin , etc Di aminopyrimidines - Trimethoprim , Pyrimethamine Q uinolones - Nalidixic acid, ciprofloxacin B eta- lactam - Penicillins , Cephalosporins, Monobactams , Carbapenems A minoglycosides - Streptomycin, Gentamycin T etracyclines - Oxytetracycline , Doxycycline S ulphonamides - Sulfadiazine, Sulfamethoxazole , M acrolides - Erythromycin, Clarithromycin A zoles- Fluconazole , Clotrimazole , Itroconazole N itroimidazoles - Metronidazole , Tinidazole N icotinic acid derivatives- Isoniazide , Pyrizinamide , Ethionamide N itrobenzene derivaties - Chloramphenicol N itrofuran derivatives- Nitrofurantoin , Furazolidone Bacteriostatic

Chemical Classification (Public Loves GOOD Quality BATSMAN):

Chemical Classification ( P ublic L oves GOOD Q uality BATSMAN ) P olypeptides - Polymyxin , Colistin , Bacitracin P oyene antibiotics- Nystatin , Amphotericin -B, Hamycin L incosamide - Lincomycin , Clindamycin G lycopeptides - Vancomycin , Teicoplanin O xazolidinone - Linezolid O thers----------------- Riampicin , Griseofulvin , Isoniazide etc Di aminopyrimidines - Trimethoprim , Pyrimethamine Q uinolones - Nalidixic acid, ciprofloxacin B eta- lactam - Penicillin G, Cephalosporins, Monobactams , Carbapenems A minoglycosides - Gentamycin , Amikacin T etracyclines - Oxytetracycline , Doxycycline S ulphonamides - Sulfadiazine, Sulfamethoxazole , M acrolides - Erythromycin, Clarithromycin A zoles- Fluconazole , Clotrimazole , Itroconazole N itroimidazoles - Metronidazole , Tinidazole N icotinic acid derivatives- Isoniazide , Pyrizinamide , Ethionamide N itrobenzene derivaties - Chloramphenicol N itrofuran derivatives- Nitrofurantoin , Furazolidone Narrow Spectrum

Chemical Classification (Public Loves GOOD Quality BATSMAN):

Chemical Classification ( P ublic L oves GOOD Q uality BATSMAN ) P olypeptides - Polymyxin , Colistin , Bacitracin P oyene antibiotics- Nystatin , Amphotericin -B, Hamycin L incosamide - Lincomycin , Clindamycin G lycopeptides - Vancomycin , Teicoplanin O xazolidinone - Linezolid O thers----------------- Riampicin , Griseofulvin , Isoniazide etc Di aminopyrimidines - Trimethoprim , Pyrimethamine Q uinolones - Nalidixic acid, ciprofloxacin B eta- lactam - Penicillins , Cephalosporins, Monobactams , Carbapenems A minoglycosides - Streptomycin, Gentamycin T etracyclines - Oxytetracycline , Doxycycline S ulphonamides - Sulfadiazine, Sulfamethoxazole , M acrolides - Erythromycin, Clarithromycin A zoles- Fluconazole , Clotrimazole , Itroconazole N itroimidazoles - Metronidazole , Tinidazole N icotinic acid derivatives- Isoniazide , Pyrizinamide , Ethionamide N itrobenzene derivaties - Chloramphenicol N itrofuran derivatives- Nitrofurantoin , Furazolidone Borad Spectrum

Chemical Classification (Public Loves GOOD Quality BATSMAN):

Chemical Classification ( P ublic L oves GOOD Q uality BATSMAN ) P olypeptides - Polymyxin , Colistin , Bacitracin P oyene antibiotics- Nystatin , Amphotericin -B, Hamycin L incosamide - Lincomycin , Clindamycin G lycopeptides - Vancomycin , Teicoplanin O xazolidinone - Linezolid O thers----------------- Riampicin , Griseofulvin , Isoniazide etc Di aminopyrimidines - Trimethoprim , Pyrimethamine Q uinolones - Nalidixic acid, ciprofloxacin B eta- lactam - Penicillins , Cephalosporins, Monobactams , Carbapenems A minoglycosides - Streptomycin, Gentamycin T etracyclines - Oxytetracycline , Doxycycline S ulphonamides - Sulfadiazine, Sulfamethoxazole , M acrolides - Erythromycin, Clarithromycin A zoles- Fluconazole , Clotrimazole , Itroconazole N itroimidazoles - Metronidazole , Tinidazole N icotinic acid derivatives- Isoniazide , Pyrizinamide , Ethionamide N itrobenzene derivaties - Chloramphenicol N itrofuran derivatives- Nitrofurantoin , Furazolidone Most are Extended Spectrum

Chemical Classification (Public Loves GOOD Quality BATSMAN):

Chemical Classification ( P ublic L oves GOOD Q uality BATSMAN ) P olypeptides - Polymyxin , Colistin , Bacitracin P oyene antibiotics- Nystatin , Amphotericin -B, Hamycin L incosamide - Lincomycin , Clindamycin G lycopeptides - Vancomycin , Teicoplanin O xazolidinone - Linezolid O thers----------------- Riampicin , Griseofulvin , etc Di aminopyrimidines - Trimethoprim , Pyrimethamine Q uinolones - Nalidixic acid, ciprofloxacin B eta- lactam - Penicillins , Cephalosporins, Monobactams , Carbapenems A minoglycosides - Streptomycin, Gentamycin T etracyclines - Oxytetracycline , Doxycycline S ulphonamides - Sulfadiazine, Sulfamethoxazole , M acrolides - Erythromycin, Clarithromycin A zoles- Fluconazole , Clotrimazole N itroimidazoles - Metronidazole , Tinidazole N icotinic acid derivatives- Isoniazide , Pyrizinamide , Ethionamide N itrobenzene derivaties - Chloramphenicol N itrofuran derivatives- Nitrofurantoin , Furazolidone Cell membrane Inhibition 1

Chemical Classification (Public Loves GOOD Quality BATSMAN):

Chemical Classification ( P ublic L oves GOOD Q uality BATSMAN ) P olypeptides - Polymyxin , Colistin , Bacitracin P oyene antibiotics- Nystatin , Amphotericin -B, Hamycin L incosamide - Lincomycin , Clindamycin G lycopeptides - Vancomycin , Teicoplanin O xazolidinone - Linezolid O thers----------------- Riampicin , Griseofulvin , etc Di aminopyrimidines - Trimethoprim , Pyrimethamine Q uinolones - Nalidixic acid, ciprofloxacin B eta- lactam - Penicillins , Cephalosporins, Monobactams , Carbapenems A minoglycosides - Streptomycin, Gentamycin T etracyclines - Oxytetracycline , Doxycycline S ulphonamides - Sulfadiazine, Sulfamethoxazole , M acrolides - Erythromycin, Clarithromycin A zoles- Fluconazole , Clotrimazole N itroimidazoles - Metronidazole , Tinidazole N icotinic acid derivatives- Isoniazide , Pyrizinamide , Ethionamide N itrobenzene derivaties - Chloramphenicol N itrofuran derivatives- Nitrofurantoin , Furazolidone Cell wall Inhibition by acting on cross linking Cell wall synthesis inhibition by acting on inhibition of mycolic acid (Long Fatty acid present in mycobacteria ) 2

Chemical Classification (Public Loves GOOD Quality BATSMAN):

Chemical Classification ( P ublic L oves GOOD Q uality BATSMAN ) P olypeptides - Polymyxin , Colistin , Bacitracin P oyene antibiotics- Nystatin , Amphotericin -B, Hamycin L incosamide - Lincomycin , Clindamycin G lycopeptides - Vancomycin , Teicoplanin O xazolidinone - Linezolid O thers----------------- Riampicin , Griseofulvin , etc Di aminopyrimidines - Trimethoprim , Pyrimethamine Q uinolones - Nalidixic acid, ciprofloxacin B eta- lactam - Penicillins , Cephalosporins, Monobactams , Carbapenems A minoglycosides - Streptomycin, Gentamycin T etracyclines - Oxytetracycline , Doxycycline S ulphonamides - Sulfadiazine, Sulfamethoxazole , M acrolides - Erythromycin, Clarithromycin A zoles- Fluconazole , Clotrimazole , Itroconazole N itroimidazoles - Metronidazole , Tinidazole N icotinic acid derivatives- Isoniazide , Pyrizinamide , Ethionamide N itrobenzene derivaties - Chloramphenicol N itrofuran derivatives- Nitrofurantoin , Furazolidone Interfering with folic acid metabolism 3 & 4

Chemical Classification (Public Loves GOOD Quality BATSMAN):

Chemical Classification ( P ublic L oves GOOD Q uality BATSMAN ) P olypeptides - Polymyxin , Colistin , Bacitracin P oyene antibiotics- Nystatin , Amphotericin -B, Hamycin L incosamide - Lincomycin , Clindamycin G lycopeptides - Vancomycin , Teicoplanin O xazolidinone - Linezolid O thers----------------- Riampicin , Griseofulvin , etc Di aminopyrimidines - Trimethoprim , Pyrimethamine Q uinolones - Nalidixic acid, ciprofloxacin B eta- lactam - Penicillins , Cephalosporins, Monobactams , Carbapenems A minoglycosides - Streptomycin, Gentamycin T etracyclines - Oxytetracycline , Doxycycline S ulphonamides - Sulfadiazine, Sulfamethoxazole , M acrolides - Erythromycin, Clarithromycin A zoles- Fluconazole , Clotrimazole , Itroconazole N itroimidazoles - Metronidazole , Tinidazole N icotinic acid derivatives- Isoniazide , Pyrizinamide , Ethionamide N itrobenzene derivaties - Chloramphenicol N itrofuran derivatives- Nitrofurantoin , Furazolidone Interfering with folic acid metabolism Analogue of PABA and defective folic acid is formed 3

Chemical Classification (Public Loves GOOD Quality BATSMAN):

Chemical Classification ( P ublic L oves GOOD Q uality BATSMAN ) P olypeptides - Polymyxin , Colistin , Bacitracin P oyene antibiotics- Nystatin , Amphotericin -B, Hamycin L incosamide - Lincomycin , Clindamycin G lycopeptides - Vancomycin , Teicoplanin O xazolidinone - Linezolid O thers----------------- Riampicin , Griseofulvin , etc Di aminopyrimidines - Trimethoprim , Pyrimethamine Q uinolones - Nalidixic acid, ciprofloxacin B eta- lactam - Penicillins , Cephalosporins, Monobactams , Carbapenems A minoglycosides - Streptomycin, Gentamycin T etracyclines - Oxytetracycline , Doxycycline S ulphonamides - Sulfadiazine, Sulfamethoxazole , M acrolides - Erythromycin, Clarithromycin A zoles- Fluconazole , Clotrimazole , Itroconazole N itroimidazoles - Metronidazole , Tinidazole N icotinic acid derivatives- Isoniazide , Pyrizinamide , Ethionamide N itrobenzene derivaties - Chloramphenicol N itrofuran derivatives- Nitrofurantoin , Furazolidone Interfering with folic acid metabolism Inhibition of Dihydrofolate Reductase (Thousand Times more affinity for bacterial than for human) 4

Chemical Classification (Public Loves GOOD Quality BATSMAN):

Chemical Classification ( P ublic L oves GOOD Q uality BATSMAN ) P olypeptides - Polymyxin , Colistin , Bacitracin P oyene antibiotics- Nystatin , Amphotericin -B, Hamycin L incosamide - Lincomycin , Clindamycin G lycopeptides - Vancomycin , Teicoplanin O xazolidinone - Linezolid O thers----------------- Riampicin , Griseofulvin , etc Di aminopyrimidines - Trimethoprim , Pyrimethamine Q uinolones - Nalidixic acid, ciprofloxacin B eta- lactam - Penicillins , Cephalosporins, Monobactams , Carbapenems A minoglycosides - Streptomycin, Gentamycin T etracyclines - Oxytetracycline , Doxycycline S ulphonamides - Sulfadiazine, Sulfamethoxazole , M acrolides - Erythromycin, Clarithromycin A zoles- Fluconazole , Clotrimazole , Itroconazole N itroimidazoles - Metronidazole , Tinidazole N icotinic acid derivatives- Isoniazide , Pyrizinamide , Ethionamide N itrobenzene derivaties - Chloramphenicol N itrofuran derivatives- Nitrofurantoin , Furazolidone Inhibition of DNA gyrase or Topoisomerase IV 5

Chemical Classification (Public Loves GOOD Quality BATSMAN):

Chemical Classification ( P ublic L oves GOOD Q uality BATSMAN ) P olypeptides - Polymyxin , Colistin , Bacitracin P oyene antibiotics- Nystatin , Amphotericin -B, Hamycin L incosamide - Lincomycin , Clindamycin G lycopeptides - Vancomycin , Teicoplanin O xazolidinone - Linezolid O thers----------------- Riampicin , Griseofulvin , etc Di aminopyrimidines - Trimethoprim , Pyrimethamine Q uinolones - Nalidixic acid, ciprofloxacin B eta- lactam - Penicillins , Cephalosporins, Monobactams , Carbapenems A minoglycosides - Streptomycin, Gentamycin T etracyclines - Oxytetracycline , Doxycycline S ulphonamides - Sulfadiazine, Sulfamethoxazole , M acrolides - Erythromycin, Clarithromycin A zoles- Fluconazole , Clotrimazole , Itroconazole N itroimidazoles - Metronidazole , Tinidazole N icotinic acid derivatives- Isoniazide , Pyrizinamide , Ethionamide N itrobenzene derivaties - Chloramphenicol N itrofuran derivatives- Nitrofurantoin , Furazolidone Inhibition of DNA dependent RNA polymerase 6

Chemical Classification (Public Loves GOOD Quality BATSMAN):

Chemical Classification ( P ublic L oves GOOD Q uality BATSMAN ) P olypeptides - Polymyxin , Colistin , Bacitracin P oyene antibiotics- Nystatin , Amphotericin -B, Hamycin L incosamide - Lincomycin , Clindamycin G lycopeptides - Vancomycin , Teicoplanin O xazolidinone - Linezolid O thers----------------- Riampicin , Griseofulvin , etc Di aminopyrimidines - Trimethoprim , Pyrimethamine Q uinolones - Nalidixic acid, ciprofloxacin B eta- lactam - Penicillins , Cephalosporins, Monobactams , Carbapenems A minoglycosides - Streptomycin, Gentamycin T etracyclines - Oxytetracycline , Doxycycline S ulphonamides - Sulfadiazine, Sulfamethoxazole , M acrolides - Erythromycin, Clarithromycin A zoles- Fluconazole , Clotrimazole , Itroconazole N itroimidazoles - Metronidazole , Tinidazole N icotinic acid derivatives- Isoniazide , Pyrizinamide , Ethionamide N itrobenzene derivaties - Chloramphenicol N itrofuran derivatives- Nitrofurantoin , Furazolidone Act by binding with 50S ribosome 7

Chemical Classification (Public Loves GOOD Quality BATSMAN):

Chemical Classification ( P ublic L oves GOOD Q uality BATSMAN ) P olypeptides - Polymyxin , Colistin , Bacitracin P oyene antibiotics- Nystatin , Amphotericin -B, Hamycin L incosamide - Lincomycin , Clindamycin G lycopeptides - Vancomycin , Teicoplanin O xazolidinone - Linezolid O thers----------------- Riampicin , Griseofulvin , etc Di aminopyrimidines - Trimethoprim , Pyrimethamine Q uinolones - Nalidixic acid, ciprofloxacin B eta- lactam - Penicillins , Cephalosporins, Monobactams , Carbapenems A minoglycosides - Streptomycin, Gentamycin T etracyclines - Oxytetracycline , Doxycycline S ulphonamides - Sulfadiazine, Sulfamethoxazole , M acrolides - Erythromycin, Clarithromycin A zoles- Fluconazole , Clotrimazole , Itroconazole N itroimidazoles - Metronidazole , Tinidazole N icotinic acid derivatives- Isoniazide , Pyrizinamide , Ethionamide N itrobenzene derivaties - Chloramphenicol N itrofuran derivatives- Nitrofurantoin , Furazolidone Act by binding with 30S ribosome 8

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1 2 3 4 5 6 7 8

Chemical Classification (Public Loves GOOD Quality BATSMAN):

Chemical Classification ( P ublic L oves GOOD Q uality BATSMAN ) P olypeptides - Polymyxin , Colistin , Bacitracin P oyene antibiotics- Nystatin , Amphotericin -B, Hamycin L incosamide - Lincomycin , Clindamycin G lycopeptides - Vancomycin , Teicoplanin O xazolidinone - Linezolid O thers----------------- Riampicin , Griseofulvin , etc Di aminopyrimidines - Trimethoprim , Pyrimethamine Q uinolones - Nalidixic acid, ciprofloxacin B eta- lactam - Penicillins , Cephalosporins, Monobactams , Carbapenems A minoglycosides - Streptomycin, Gentamycin T etracyclines - Oxytetracycline , Doxycycline S ulphonamides - Sulfadiazine, Sulfamethoxazole , M acrolides - Erythromycin, Clarithromycin A zoles- Fluconazole , Clotrimazole N itroimidazoles - Metronidazole , Tinidazole N icotinic acid derivatives- Isoniazide , Pyrizinamide , Ethionamide N itrobenzene derivaties - Chloramphenicol N itrofuran derivatives- Nitrofurantoin , Furazolidone Cotrimoxazole

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Relax and Revise

What is this?????:

What is this?????

Antimicrobial Resistance:

Antimicrobial Resistance Resistance Intrinsic Acquired Mutation Conjugation Transformation Transduction Not Dangerous/ less clinical importance Transmitted vertically only Dangerous/ clinical importance Can be transferred Horizontally and Vertically

Inherent Resistance (Not Much of clinical importance):

Inherent Resistance (Not Much of clinical importance) Bacteria naturally resistant e.g ., Gram-negative bacteria resistant to penicillins Genes transferred to the bacterial progeny Bacteria may be resistant because No mechanism to transport the drug into the cell Do not contain antibiotic’s target process or protein

Acquired Resistance:

Acquired Resistance Due to exposure of antimicrobials Horizontal evolution: Resistance genes pass from resistant to nonresistant strain, Antibiotics- a selective pressure. Gene transfer mechanisms: C onjugation. T ransduction. T ransformation.

Resistance Transfer Horizontal:

Resistance Transfer Horizontal

Antibiotics put selection pressure on development of resistant strain:

Antibiotics put selection pressure on development of resistant strain Bunch of bacteria including a resistant variety When antimicrobial given most of the normal bacteria die The resistant Bactria multiply and start dominating Eventually entire infection evolves into a resistant strain Non resistant Bacteria R esistant Bacteria Dead Bacteria To save your future generations Please don't use antibiotics inadvertently and inappropriately

Resistance to Antibiotics:

Resistance to Antibiotics 5. Adaptation of alternate metabolic pathway

Factors favoring Resistance:

Factors favoring Resistance Prescription related factors: Overuse and Underuse Early discontinuation Over continuation Less dose, duration Livestock doping : Animals exposure

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Relax and Revise

Adverse Drug Reactions of Antimicrobials:

Adverse Drug Reactions of Antimicrobials General Hypersensitivity reactions CNS GIT Injectable S/E Vitamin Deficiency Super infections Teratogenic Masking of infections Intolerance Drug induced fever Specific

General-Adverse effects of antimicrobials :

General-Adverse effects of antimicrobials Hypersensitivity reaction- Penicllins , Sulphonamides Skin rashes , Angioedema , Bronchospasm Anaphylaxis, Management with OASIS O xygen, A drenaline {Physiological antagonist of histamine} A ntihistaminics S teroid , I V fluid S upportive ,

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Gastrointestinal symptoms- Nausea, Anorexia, Gastric irritation , Flatulence , indigestion, Altered GI motility, Mouth ulcers, Glossititis , Stomatitis , Chelitis Esophagitis , Mal-absorption syndrome Tetracyclines, Chloramphenicol, Quinolones , Ampicilline , Metronidazole

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Injectable Side effects- Pain, Abscess formation, Thrombo -phlebitis Flushing, redness in case of rapid IV

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Deficiency of Vitamins- V itamin B complex and Vitamin K ,

Reduced Efficacy of other drugs:

Reduced Efficacy of other drugs Drugs which need entero -hepatic recirculation for their effect like Oral contraceptives

Super infections :

Super infections New infection Most common organisms Pseudomonas, Candida, Proteus Clostridium difficle - Pseudomembranous Colitis Due to removal of inhibitory mechanisms ( Bacteriocins and competition for nutrition) Common in immunocompromised, Diabetic, Surgical patients Common drugs causing super infections (CAT) C lindamycin , C otrimoxazole , C hloramphenicol A mpicillin T etracyclines Treated by Metronidazole , Vancomycin , Bacitracin

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CNS- Headache, Irritability , Sedation , Tinnitus , Ataxia, Forgetfulness Slurred speech, Blurring of vision Convulsions in high dose of cephalosporins

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Masking of infections- eg . Tt Gonorrhea mask Syphilis Idiosyncratic and Intolerance- Drug Fever-

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Teratogenic effects- No antimicrobial is absolutely safe during pregnancy No one is Category A Category B, C and D can be given under special situation Category X absolutely contraindicated to pregnant

FDA Categorization of Drugs in Pregnancy:

FDA Categorization of Drugs in Pregnancy Category A (Most safe But No antibiotic is under this) Controlled studies in women fail to demonstrate a risk Category B (Safe Usually prescribed ) Either animal have not demonstrated or not confirmed in controlled studies in women Category C (Under special circumstance) Either studies in animals are positive or studies in women and animals are not available. Category D (Special circumstance with consent) P ositive evidence of human fetal risk, but the benefits may be acceptable despite the risk Category X ( Never prescribed during pregnancy) Studies in animals or human beings have demonstrated fetal abnormalities

Antibiotics in Pregnancy:

Antibiotics in Pregnancy FDA Category Antibiotics in Category A B Penicillins , Cephalosporins, Carbapenems (except Imipenem ), Daptomycin , Vancomycin (oral), Clindamycin, Erythromycin, Azithromycin , Metronidazole (avoid first trimester), Nitrofurantoin , Acyclovir, Amphoterocin B, Ethambutol C Quinolones , Chloramphenicol, Clarithromycin , Imipenem , Linezolid , Trimethoprim /Sulfa (D if used near term), Vancomycin (IV), Rifampin , INH, PZA, PAS, Fluconazole , Caspofungin D Tetracyclines (Doxy, Tige , Mino), Voriconazole , Aminoglycosides (some put gentamicin as a category C) X Ribavarin Betalactam ( Penicillins and Cephalosporins) Macrolides Quinolones Sulphonamides Tertracylines Aminoglycosides

Relax and Revise General Side Effects of Antimicrobials:

Relax and Revise General Side Effects of Antimicrobials

Specific Side effects of antimicrobials :

Specific Side effects of antimicrobials Bone marrow suppression- Chloramphenicol ( Aplastic Anaemia ) Thrombocytopenia- Sulphonamides Cephalosporins Cefamandole Cefoperazone Cefotetan Same which produce Disulfiram like reaction

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Renal toxicity- Aminoglycosides Tetracyclines EXCEPT Doxycycline , Cephalothin, Cephaloridine Vancomycin Nitrofurantoin , Nalidixic acid Talampicillin Amphotericin B Flucytosine Methacillin

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Hepatotoxicity - Rifampicin , Isoniazide (in fast acetylators due to accumulation of Acetyl – isoniazide and acetyl – hydrazine) Pyrazinamide Tetracycline , Erythromycin estolate , Talampicillin , Nalidixic acid, Trovafloxacin Oxacillin , Isoniazide Produce Hepatotoxicity in Fast Acetylators Peripheral Neuropathy in Slow Acetylators

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Photo allergic & Photoxicity - Tetracyclines Demeclocycline Doxycycline Quinolones Sparfloxacin UV A rays  age skin cells and linked to long-term skin damage UV B rays are the main rays that cause sunburns (B are Bad) UV C rays   don’t get through our atmosphere Time of day:  UV rays are strongest between 10 am and 4 pm.

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Ototoxicty - Aminoglycosides, Vancomycin Diabetes insipidus - Demeclocycline Drugs producing Diabetes inspidus - Lithium, Demeclocycline Drug used in treatment of Lithium induced Diabetes inspidus - Amiloride

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Neuromuscular block- Amino-glycosides Polymyxin - B Colistin Gaping of wound Respiratory paralysis in Myasthenia gravis

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Retinal damage- Chloroquine Neuropathy- Polypeptides Amphotericin B Nitrofurantoin Carbenicillin Dapsone Chloroquine Isoniazid- in slow acetylators Due to increased excretion of pyridoxine Accumulated INH hydrazone inhibits pyridoxine-kinase ( Pyridoxine Kinase converts pyridoxine to active form) Isoniazide Produce Hepatotoxicity in Fast Acetylators Peripheral Neuropathy in Slow Acetylators

Isoniazid Side effect depends on Acetylation status of Patient:

Isoniazid Side effect depends on Acetylation status of Patient North Indians are 40% Fast 45% Intermediate 15% Slow Acetylators Neurotoxicity Hepatotoxicity Hydrazonation Acetylation

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Haemolysis (G-6-PD deficiency), - X-Linked recessive. G-6-P-D is required for regeneration of NADPH. NADPH is required for reduction of oxidized glutathione Reduced glutathione protects –against oxidative injury Precipitating pro-oxidants Naphthalene, Methylene Blue, Beans ( Favism ) S ulfa drugs, P rimaquine , I soniazide , N itrofurantoin , N alidixic acid, D apsone , Furazolidione , Quinolones , Chloramphenicol, Chloroquine , Haemolysis occurs during oxidative stress G-6-P-D Glutathion reductase Glutathione Glutathione disulphide NADP NADPH S P I N D elivery Protects

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Discolouration of Teeth and bone damage- Tetracyclines Redman (Red neck) Syndrome- Vancomycin , Teicoplanin , Discolouration of secretions (saliva, sweat, urine )- Rifampicin , Clofazimine , Nitrofurantoin

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Kernicterus - Sulphonamides Flu-like syndrome- Rifampicin Antitestosterone effect- Ketoconazole ( ↓ testosterone leading to gynaecomastia )

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Crystaluria - Sulphonamides Cholestatic jaundice- Erythromycin estolate , Nitrofurantoin Fosfomycin ,

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Optic neuritis- Ethambutol Tendon rupture- Fluroquinolones

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Jarisch Herxheimer Reaction- Penicillin in syphilis Inflammatory reaction against endotoxins released by the death of spirochetes Increased inflammatory cytokines Manifest as fever, Chills, hypotension, headache, flushing, myalgia and skin lesions Treatment by NSAIDS, Steroids, and general care Other causes Relapsing fever (louse or tick born) Leptosporiosis Q Fever Brucellosis

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Alopecia- All anti-cancer drugs Fanconi’s Syndrome- (Renal toxicity)- Expiry date tetracyclines - D ue to toxic metabolites epitetracycline

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Pseudotumor cerebri - and bulging fontanelles - Tetracyclines Hyperuricemia - Pyrazinamide (Gout) Pulmonary eosonophilic syndrome- Tetracylines

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Disulfiram like reaction – ( G ood C hief M inister) G riseofulvin , C efoperazone C efotetan C efamandole , M etronidazole , Ethyl Alcohol – (Alcohol dehydrogenase or Acetaldehyde synthetase) Acetaldehyde- (Acetaldehyde dehydrogenase) Acetic Acid- Kreb’s cycle- ATP + CO2+ H2O (Blocked by Disulfiram )- Accumulation of Acetaldehyde and precipitations of syndrome consisting of Headache, Vomiting, Flushing etc.

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Grey Baby Syndrome- (Ashen Grey Cyanosis)- Chloramphenicol Pulmonary Fibrosis- Bleomycin , Nitrofurantoin Vomiting Ashen gray color of the skin Hypotension Cyanosis Hypothermia Cardiovascular collapse Hypotonia Abdominal distension Irregular respiration Increased blood lactate

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Very Special- Gatifloxacin Prolongs QT interval and arrhythmia Hypo or hyperglycemia in patients of diabetes. Aminoglcosides have NOT side effects- N euromuscular block (more with Neomycin and Streptomycin), N ephrotoxicity least with Streptomycin O totoxicity (Vestibular by Streptomycin, Gentamicin while Cochlear by Neomycin, Amikacin ) T eratogenic) High dose of Ceftriaxone Pseudo- lithiasis (Gall bladder sludge)

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Mafenide Has carbonic anhydrase inhibitor activity May alkalinize urine and cause acidosis Hyperventilation 8-Hydroxy-quinoines ( Iodochloro-hydroxyquinol ,) SMON ( Subacute myelo -optic neuropathy ) Antianabolic effect (reduce protein synthesis)- Tetracyclines

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Drug Interactions:

Drug Interactions

Important Drug Interactions of Antimicrobials:

Important Drug Interactions of Antimicrobials Synergism/Addition/ Antagonism Combinations of more than one antimicrobial Combination of antimicrobial with other agents Pharmacodynamic Pharmacokinetic (ADME) Chlelation /(Antacids, Milk)- Tetracyclines Alteration of pH/ Ionization of drug- Penicillins Alteration with Enterohepatic recirculation- (OCP) Inducer (Barbiturates, Rifampicin, Griseofulvin, Carbamazepine) Inhibitor (Cimetidine, Chlolramphenicol, Erythromycin, Quinolones) Protein biding displacement of drug (Important with high protein binding drugs)- Sulphonamides Pharmaceutical During manufacture, packaging, Storage During drug administration During Mixing and injecting drug Mixing in oral solutions Mixing in solvent, In bottle, No drug in Blood, Plasma and Electrolyte solutions

Important Drug Interactions of Antimicrobials:

Important Drug Interactions of Antimicrobials Pharmaceutical During Manufacture, Packaging, Storage During drug administration During Mixing and injecting drug (If precipitate Reject) Mixing in oral solutions (Not advisable) Mixing in solvent (According to instructions) No drug in Blood, Plasma Albumin Ringer lactate

Important Drug Interactions of Antimicrobials:

Important Drug Interactions of Antimicrobials Synergism/Addition( Cidal + Cidal , Static + Static) Antagonism ( Cidal + Static) When more sensitive to Cidal Combination of antimicrobial with other agents Best combo is Cidal + Cidal ( Betalactam + Aminoglycoside ) Pharmacodynamic

Important Drug Interactions of Antimicrobials:

Important Drug Interactions of Antimicrobials Pharmacokinetic (ADME) Chelation /(Antacids, Milk)- Tetracyclines, Quinolones Alteration with Enterohepatic recirculation- OCP with antimicrobials Inducers- Rifampicin , Griseofulvin Inhibitors- Erythromycin , Chlolramphenicol , Quinolones (Grape fruit ( Furanocoumarins ) Protein biding displacement of drug- Sulphonamides

List of Important Interactions Related to Antimicrobials:

List of Important Interactions Related to Antimicrobials Sulphonamides Oral hypoglycaemics (Especially Sulphonylureas ) Increased hypoglycemia Oral anticoagulants Increased anticoagulation (Protein binding displacement) Methotrexate (Inhibitor of Dihydrofolate Reducatase) Increased methotrexate toxicity ( Folate deficiency) Protein binding displacement Folic acid depletion

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Fluoroquinolone Antacids (Al, Mg, Ca), Zinc, Iron, Sucralfate, Milk Reduced absorption of Fluoroquinolone Theophylline Increased concentration due to decreased metabolism. (Least with Lome , Levo , Spar) Warfarin (Oral anti-coagulant) Enhanced effect due to decreased metabolism (least with Levo , Spar) Drugs prolonging Q-T interval Quinidine Amidarone Procainamide Erythromycin Cisapride Astemizole Terfenadine Enhance Q-T interval leading to dangerous arrhythmia Chelation Enzyme inhibitor Q-T prolongation

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Ampicillin (Penicillin), (Cephalosporin) Contraceptive pills Failure of contraception (Inhibition of enterohepatic recirculation) Tetracycline, Chloramphenicol, Erythromycin Antagonism of bactericidal action (Cidal with Static) Aminoglycoside in same syringe Inactivation of both (Pharmaceutical) Hydrocortisone Inactivation of penicillin (Pharmaceutical) Allopurinol Increased incidence of non- urticarial maculo-papular rashes Probenecid Decreases tubular secretion of penicillin and increases action ( Pk ) Clavulanic acid, Sulbactam Inhibition of Betalactamase leading to better effect (Synergism) Intestinal flora damage Pharmaceutical incompatibility Idiosyncratic Secretion in renal tubule

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Cephaloridine Furosemide Increased nephrotoxicity Rifampicin Warfarin and OCP Failure of anti-coagulation and contraception Griseofulvin Cefoperazone, Cefotetan, Cefamandole Metronidazole ( G ood C hief M inister ) Alcohol Disulfiram like syndrome (Aldehyde Syndrome) Ethyl Alcohol – (Alcohol dehydrogenase or Acetaldehyde synthetase) Acetaldehyde- (Acetaldehyde dehydrogenase) Acetic Acid- Kreb’s cycle- ATP + CO2+ H2O (Blocked by Disulfiram )- Accumulation of Acetaldehyde and precipitations of syndrome consisting of Headache, Vomiting, Flushing etc. Enzyme Inducer Nephrotoxic Aldehyde dehydrogenase inhibitor

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Nalidixic acid Oral anticoagulants Enhanced anticoagulation Nitrofurantoin Nalidixic acid Antagonises action of nalidixic acid (Never give NaNi ) Probenecid Reduced tubular secretion leading to decreased concentration in urine Amphotericin -B Digitalis Amphotericin induced hypokalemia increases digitalis toxicity

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Erythromycin Theophylline, Carbamazepine, Statins , Warfarin, Terfenadine, Inhibition of metabolism (Inhibit CYP3A4) Terfenadine Q-T prolongation leading to life threatening ventricular arrhythmias Linezolid MAO inhibitors Increased toxicity of MAO inhibitors (Linezolid is reversible inhibitor of MAO and may lead to cheese reaction with food containing tyramine and can precipitate Serotonin syndrome (confusion, hypertension, seizures, tachycardia and muscle rigidity) Enzyme inhibitor Q-T prolongation MAO inhibitor property

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Aminoglycosides Furosemide, Ethacrynic acid Increased Ototoxicity Skeletal muscle relaxants (curare like drugs) Enhanced and persistent neuromuscular blockade Gaping of suture Delay wound healing Tetracyclines Contraceptive pills Failure of contraception Antacids, Iron Milk , Food Decreased absorption due to Chelation NOT Damage of intestinal flora Chelation

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Chloramphenicol Oral hypoglycemic Increased hypoglycemic effect (due to enzyme inhibition by Chloramphenicol) Oral anti-coagulant Enhanced anticoagulant Enzyme inhibitor

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Ketoconazole Cisapride, Terfenadine, Astemizole , Quinidine , Warfarin, Cyclosporine Tacrolimus Statins Ketoconazole inhibits CYP3A4 leading to decreased metabolism and accumulation of other drug (Least with Fluconazole ) H2 blockers, PPI, Antacids Decreased absorption of Ketoconazole due to decreased gastric acidity Amphotericin B Ketoconazole inhibits the synthesis of ergosterol and produces depletion of membrane ergosterol reducing the binding sites for Amphotericin B Griseofulvin Other drug Inducer of microsomal enzymes Enzyme inhibitor Absorption in acidic pH Inhibitor of ergosterol Enzyme inducer

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Relax and Revise

Bacteriological Culture and Sensitivity Tests:

Bacteriological Culture and Sensitivity Tests

Bacteriological Culture and Sensitivity Testing:

Bacteriological Culture and Sensitivity Testing Plate – Kirby-Bauer test Strip- Epsilometer test Dilution – T est tubes

Culture and Sensitivity Results:

Culture and Sensitivity Results Minimum inhibitory concentration ( MIC ) The lowest concentration of drug that prevents visible bacterial growth after 24 hours of incubation Organism and antimicrobial specific Interpretation Drug’s activity versus the organism Site of infection Drug resistance Report organism(s) and susceptibilities Susceptible (S) or ++++ Intermediate (I) or + Resistant (R) or -

Combination Therapy: Uses:

Combination Therapy: Uses 1. Empirical therapy 2. Poly-microbial infections (Suspected mixed infection) 3. To prevent development of resistance Good combo is 2 bactericidal e.g. cell wall inhibitor & protein synthesis inhibitors e.g. Betalactam with Aminoglycosides Deadly Trio is 2 bactericidal with anti- anaerob Eg . Betalactam with Aminoglycoside with Metronidazole (BAM)

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Uses of Antimicrobials in General Treatment and Prophylaxis CNS – Meningitis, Brain abscess Eye - Conjunctivitis, Blepharitis, Stye, Mouth and Face - Stomatitis, Gingivitis, Pulpitis , Pyorrhoea , Sinusitis ENT - Otitis, Rhinitis, Tonsillitis, Pharyngitis, Laryngitis, RTI- Tracheitis, Bronchitis, Bronchiolitis , Pneumonia, Pleuritis , Effusion, GITI- Dysentery, Gastroenteritis, Cholecystitis , Cholangitis , Appendicitis, UTI - Urethritis, Cystitis, Ureteritis, Pyelonephritis , Prostatitis, Epidydimitis Pelvic organ infections , Pelvic Organ Infections (PID)- Vaginitis, Cervicitis , Endometritis, STDs- Chancroid, Syphilis, Gonorrhoea, Non-specific urethritis , (Chlamydia trachomatis), Granuloma inguinale, Donovanosis, Genital Herpes, Trichomonas Vaginitis Skin (and Soft tissue)- Boil, Carbuncles, Furuncles, Bone - Osteomyelitis, Special Infections- Typhoid, Tuberculosis, Leprosy,

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CNS Eye Mouth Sinuses ENT RTI GITI Skin Bones STD Special

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Selection of A Drug:

Selection of A Drug

Choice of antimicrobial agents:

Choice of antimicrobial agents Patient- Age- Pediatric -----------General---------------------Geriatric General condition (G.C)- Consciousness etc….. Hepatic , Renal functions- Other metabolic factors Pregnancy- Genetics- (G-6-PD deficiency) Immune status of patient- History of allergy Financial condition- Infection- Site Type (Microbe)- Guess, Confirm with C/S Intensity Presence of pus, clot, Hematoma Drug- Spectrum Sensitivity Dosage form availability Relative Toxicity (selection depends on patient) Acceptable pharmacokinetic profile Price

Antimicrobial therapy:

Antimicrobial therapy Empirical (Experience Based) Infecting organism(s) not yet identified Experience based on Site, Size, Season, Spectrum More “broad spectrum” Definitive (Organism Based) Organism(s) identified Specific therapy (“narrow” spectrum) Prophylactic or preventative Given in anticipation of infection

Empirical therapy:

Empirical therapy Know the common pathogens responsible for common infections Know the antimicrobial spectrum of activity Take sample before starting empirical therapy in complicated cases

Selecting a Therapeutic Regimen:

Selecting a Therapeutic Regimen Confirm presence of infection: History signs and symptoms Investigations Predisposing factors Before selecting Empirical therapy get material for c/s or for microscopy Consider the spectrum of activity; Narrow vs broad spectrum Special conditions like Sepsis or meningitis, Pt. with Diabetes, Immunosupression Pt. with other co morbid illnesses

Prophylactic use of antimicrobials in important conditions:

Prophylactic use of antimicrobials in important conditions Rheumatic fever- Benzathine Penicillin Tuberculosis - Isoniazid, Rifampicin Mycobacterium avium complex- Azithromycin , Clarithromycin Pneumocystis – Cotrimoxazole HIV exposed person- Zidovudine + Lamivudine + Indinavir HIV in foetus – Zidovudine to mother

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Meningococcal meningitis- Rifampicin / Sulfadiazine Gonorrhoea / Syphilis- Ampicillin or Ceftrioxone Genital herpes – Acyclovir Malaria- Chloroquine , Mefloquine Influenza A- Amantadine Cholera - Tetracyclines Whooping cough – Erythromycin Plaque - Doxycycline Bird flu- Oseltamivir ( Tamiflu )

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Dental extraction, Tonsillectomy, Endoscopies- Amoxicillin Catherization - Cotrimoxazole , Norfloxacin , Ampicillin, Gentamicin COPD- Ampicillin, Doxycycline Immunocompromised - Cephalosporins ± Aminoglycosides ± Fluroquinolones ± Metronidazole General Surgical prophylaxis- BAM or CAM or FAM

Monitoring Therapeutic Response:

Monitoring Therapeutic Response Clinical assessment Improvement in signs and symptoms Fever curve,  WBC  Erythema , pain, cough, drainage, etc. Laboratory tests

Antimicrobial Factors in Drug Selection:

Antimicrobial Factors in Drug Selection

The Criteria of the Ideal Antibiotic::

The Criteria of the Ideal Antibiotic: Maximum Selectivity against microbes R each at the desired site(BBB) Retention time l ong enough to be effective Shelf life good Least Toxic to the human cells Resistance development Expensive Allergic Suppression of normal flora

Causes of failure of antimicrobial therapy:

Causes of failure of antimicrobial therapy Improper selection of D company – D rug, D ose, D uration D osage form and Route D elay of treatment D rug quality questionable Failure to apply adjuvant measures Immune-compromised status Extra smart organism Resistant, Dormant

Summary :

Summary Antimicrobials are among the most important advances of modern medicine. The general concept regarding antimicrobials Antibacterial spectrum, Classification of antimicrobials Chemotherapeutic drugs Vs Pharmacodynamic drugs Bacteriostatic drugs, Vs Bactericidal drugs MIC Vs MBC Post antibiotic effect, General side effects of antimicrobials General Mechanisms of actions of antimicrobials (1-8) General Drug interactions of antimicrobials Antimicrobial Resistance- Selection of appropriate antimicrobial Causes of failure

Summary:

Summary Appropriate selection of antimicrobials is complicated . It is not only the matching a drug to a bug Antimicrobial selection depends on Clinical efficacy, Adverse effect profile, Pharmacokinetic disposition, and Cost ultimately guide therapy Once chosen, the dose, duration must be based on Age, Sex (pregnancy) and weight of the patient, Site, Severity of infection, Route of elimination, And other factors including co-morbid conditions Use antimicrobials Only when needed For optimum time period as needed to treat the infection Try to limit the emergence of bacterial resistance

Superbugs (Microorganisms with multiple resistance) :

Superbugs (Microorganisms with multiple resistance) MRSA - Methicillin - resistant Staphylococcus aureus VISA - V ancomycin intermediate resistant Staphylococc і VRE - Vancomycin - resistant enterococci ESBLs - Extended-spectrum beta- lactamases (microorganisms – resistant to cephalosporins and monobactams ) PRSP - Penicillin-resistant Streptococcus pneumoniae MRPA (MDR-PA)- Multidrug resistant Pseudomonas aeruginosa MRAB (MDR-AB) - Multidrug resistant Acinetobacter baumannii

Why worry?:

Why worry? MDRO are dangerous Difficult to treat More virulent Increase mortality and morbidity Resource-intensive More expensive and toxic antibiotics Increase length of hospitalization Increase demand for isolation-facilities

Why Worry???? Antibacterial Resistance is developing fast Newer Antibacterial entry is slow:

Why Worry???? Antibacterial Resistance is developing fast Newer Antibacterial entry is slow

End of antibiotics - the ultimate consequence:

End of antibiotics - the ultimate consequence

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