LECTURE: à IMPORTANT. Imp *** EXTRA INFORMATION. ﺟداول اﻟﺻﻣﯾﻠﻲ ﻣوﺟودة آﺧر ﺛﻼث ﺳﻼﯾدز DOCTOR’S NOTE Objectives

Ø Define antibiotic, chemotherapy and selective toxicity. Ø Describe the difference between bactericidal and bacteriostatic Ø Recognize the narrow and broad spectrum antibiotics Ø Define the therapeutic index Ø Know the mechanism of action of antimicrobial agents Ø Recognize the various classes of antimicrobial agents (action, spectrum and side effects.) Ø Explain the criteria for an ideal antimicrobial. v v ANTIMICROBIAL AGENTS Toxicity SELECTIVE TOXICITY: The ability to kill or inhibit the growth of a microorganism without harming the host cells.

Therapeutic Index: The RATIO of the dose toxic to the host to the effective therapeutic dose. Examples : High à more safety , less toxicity ANTIBIOTICS: CHEMOTHERAPY: à High Natural compounds produced by • Synthetic compound. Aminoglycosides à low microorganism which inhibit the B à the lowest Low à less safety , more toxicity growth of other microorganism. • Antimicrobial agents. **ﺻﻧﻊ اﻟﺷرﻛﺎت ﻣش طﺑﯾﻌﯾﺔ** :penicillin Like v Activity: v Mechanisms of Action of antimicrobials 1) Inhibition of synthesis.

Activity of antimicrobial agent 2) alteration of cell membrane

BACTERICIDAL : BACTERIOSTATIC: kills bacteria prevents multiplication 100% will kill the And help our immune 3) Inhibition of protein synthesis bacteria system to overcome them

4) Inhibition of nucleic acid synthesis

The best Spectrum of activity

5) Anti-metabolite OR competitive antagonism.

Broad spectrum : Narrow spectrum: Gram positive & Gram negative bacteria selected organism ﺣﺗﻰ اﻟﮭواﺋﯾﺔ واﻟﻼھواﺋﯾﺔ v Mechanisms of Action of antimicrobials

1) Inhibition of 2) alteration of 3) Inhibition of 4) Inhibition of 5) Anti-metabolite cell wall Cell membrane protein synthesis nucleic acid OR synthesis synthesis Competitive antagonism.

Inhibit folate metabolism Aminoglycosides Beta –Lactam Rifamycins antimicrobial agents Trimethoprim Tetracyclines o Quinolones o Chloramphenicol o Cephamycin Sulfamethoxazole o ( & ) Macrolides o () Metronidazole o Beta-Lactamase inhibtors

Vancomycin ( ) v 1) Inhibition of cell wall synthesis v Beta –Lactam antimicrobial agents β- Lactam antibiotics Penicillins Cephalosporins *Contain: Beta-lactum ring and organic acid § Benzyl Penicillin : § 1st Generation : Act mainly on gram +ve Ex: Cephradine *It can be natural or semi-synthetic Ex: Penicillin V Ceohalexine act on +ve Benzathine Penicillin *Bactericidal Procaine Penicillin = Penicillin G § 2nd Generation : Ex: § Isoxazolyl Penicillins : *Bind to penicillin binding protein (PBP) and Cephamycin () Act on staphylococcus aureus interfere with trans-peptidation reaction. Ex: § 3rd Generation : Expanded spectrum *Toxicity: mainly § Amino-Penicillins : Ex : 1/Hypersensitivity (allergy) Act on Enterobacteria 2/Anaphylaxis Ex : 3/Diarrhea § 4th Generation : § Acylaminopenicillin : Ex : Cefepim Act on Psudomonas Ex: v 1) Inhibition of cell wall synthesis v v Beta –Lactam antimicrobial agents § Glycopeptides Beta-Lactamase inhibitors § Bactericidal § β-Lactams with no antibacterial activity § *inhibit cell wall synthesis. § Irreversibly bind to β-lactamase enzyme § Acts on Gram positive bacteria § Ex : , , only ( narrow spectrum). § Effective on staph. Penicillinases and broad spectrum β-lactamases. § Given by injection only. § eg. /clavulanic acid, /clavulanic acid and § Used for (MRSA) piperacillin /tazobactam. S.epidemidis Beta-Lactamase area enzymes in Bacteria act on pseudomembranous colitis Beta –Lactam antimicrobial agents and destroy Beta-lactin ring on them , so to solve these problem we creative Beta-Lactamase inhibitors To § Side effects: Red man syndrome inhibit these enzymes phlebitis, nephrotoxic & ototoxic.

MRSA = resistant S.aureus systemic infections *** Mechanismﻣﮭم of action Classification of Antimicrobials

1) Inhibit cell wall synthesis Penicillins Cephalosphoeins Glycopeptides uBeta –Lactam antimicrobial agents Eg. Penicillin G Eg. 1st generation Penicillins ◦ +ve, some anaerobes = Cephalexin Eg. Vancomycin ◦ Cephalosporins Ampicillin +ve u Narrow spectrum Carbapenems ◦ Penicillin, +ve/-ve, 2nd generation u Cover Only +ve ◦ Monobactams (aztreonam) anaerobes = Cefuroxime u Used as last option ◦ Vancomycin Pipracillin +ve/-ve, Anaerobes As multidrug resistance Cover Pseudomonas Gram +ve uVancomycin ( Teicoplanin ) 3rd generation u = Ceftriaxone Can be given IV Inhibit peptoglycan -ve Inhibit peptoglycan Inhibit peptoglycan Side Effect = Side Effect = Note: all antibiotic cause GIT Side effect Side Effect = Red Man Syndrome Hypersensitivity Hypersensitivity Allergy, when you give =anaphylaxis shock Antihistamine =anaphylaxis shock = recover slowly v 2) Inhibit of Cell Membrane 2) Inhibit of Cell Polymyxin B : § a Peptide active against Gram negative bacteria only. Membrane § Bactericidal § Only used locally due to serious nephrotoxicity when used systemically . Eg. Colistin & Polymyxin B (ﻗطرة أذن – ﻗطرة ﻋﯾن) وھذا ﻛﺎن ﻗدﯾﻣﺎً أﻣﺎ اﻵن ﻓﻠﯾس ﻓﻘط ﺟزﺋﻲPolymyxin B Only used LOCALLY ^وھو ﻣﺿﺎد ﺟدﯾد ﯾﺳﺗﺧدم ﻟﻠﺣﺎﻻت اﻟﺻﻌﺑﺔ ﺟد ًا ﻟﻔﻌﺎﻟﯾﺗﮫ اﻟﻌﺎﻟﯾﺔ , ﻟﻛن ﻣﺷﻛﻠﺗﮫ أن ﻟﮫ ﻧﺳﺑﺔ ﺳﻣوﻣﯾﺔ ﻛﺑﯾرة ﺗﻘرﯾﺑﺎ ً

*Narrow Spectrum *Gram –ve Colistin : § a Peptide active against Gram negative bacteria only. *Used as multidrug resistance gram -ve § used for the treatment of multi-resistant organisms (MRO) such as Pseudomonas and Acinetobacter infections.

Side Effect *** = Nephrotoxicity v 3) Inhibit protein synthesis

Aminoglycosides Tetracyclines Chloramphenicol Macrolides § Bactericidal § Bacteriostatic § bacteriostatic § bactericidal § Broad spectrum § Erythromycin & Clindamycin § Acts only on Gram –ve bacteria § § not used for children under 8 yrs. Broad spectrum ( narrow spectrum) or pregnant women. § Good activity on :Legionella, § Side effects : Camylobacter, Gram negative § Oral absorption. § Streptococci & anaerobes are it affects bone marrow and positive infections for naturally resistant § Effective for Intracellular organisms cells and cause aplastic patients allergic to Penicillins anemia and Cephalosporins. Ex: Mycoplasma, Chlamydia, Rickettsiae § Ex : Gentamicin ,Brucella also for V. cholera & Nocardia § Used only for severe § Clindamycin acts on anaerobes Amikacin . infections not Neomycin § Side effects : teeth discoloration responding to § Side effects : GIT disturbance, Tobramycin GIT disturbance treatment by other Pseudomembraneous colitis § Classes antimicrobials , also (mainly clindamycin). § Given by injection . - Short acting: Tetracycline for the treatment of Rickettsial diseases. § New Macrolides : - Long acting: Minocycline § Side effects : Azithromycin & Clarithromycin § Used also topically for Less side effects , better Nephrotoxic & Ototoxic ,Doxycycline ( good CSF penetration). eye and ear infections penetration and longer half life. dose related. - New tetracycline : Tigycycline (covers MRSA,MSSA, some Gram *Chloramphenicol *Macrolides *Aminoglycosides negative bacteria and anaerobes) S30S ribosomal subunit 50 Sub Unit of 23 r RNA 50 Sub Unit of 23 r RNA

*Tetracycline ** you don’t have to know them actually, just for your knowledge the S30S ribosomal subunit ribosome is compose of two subunit the large is 50S and the smal is 30S 3) Inhibit protein synthesis ***

Macrolides & Aminoglycosides Tetracyclines Chloramphenicol Lincosamides

Eg. Gentamicin Spectrum of activity Eg. Erythromycin & Amikacin Broad Spectrum the treatment of Clindamycin Tobramycin Rickettsial diseases = Broad spectrum neomycin

Spectrum of activity All are gram –ve Side Effect Eg. Clindamycin = Rickettsiae Bactericidal = bone marrow = spectrum acts on Mycoplasma Narrow spectrum a plastic anemia anaerobes Clamydia

Side Effect Side Effect New Macrolides : = Discoloration in children = Otoxicit and Azithromycin Nephrotoxicity Pregnant = destruct bone Clarithromycin of baby Bone Marrow Suppression

8th nerve effect ear and balance Side Effect = GIT pseudo- Increase drug = effect bone nerve membranous Colitis No renal problems v 4) Inhibition of nucleic acid synthesis. Rifampicin Quinolones § Bactericidal § Semi-synthetic § Bactericidal § acts on Gram positive bacteria and selected Gram negative bacteria. § Synthetic, bactericidal § Reserved for Tuberculosis (Anti TB) § inhibit DNA Gyrase and /or Topoisomerase. § Resistance develops quickly § Used in combination § Side effects : hepatotoxicity. & discoloration of body fluids § Generations: o 1st Generation: Nalidexic acid locally acting (Broad spectrum) Metronidazole o 2nd Generation: Fluoroquinolones (Narrow : Gram –ve) Ex. Ciprofloxacin, Norfloxacin, Ofloxacin,Levofloxacin § Bactericidal o 3rd Generation: Sparfloxacin, Gatifloxacin § Nitroimidazole active on anaerobic bacteria and also parasite. o 4th Generation: Moxifloxacin, Trovafloxacin (Anaerobes) § Causes DNA breakage. § Side effects: affects cartilage & heart § Used for the treatment of infections due to B.fragilis , Trichomonas vaginalis and also for amoebiasis and giardiasis. (Antiprotozoal) 4) Inhibition of nucleic acid synthesis. ***

Quinolones Metronidazone Rifampicin ..اﻟدﻛﺗور ﺗﻛﻠم ﻋﻧﮭﺎ ﺑس ﻣﺎ ﺿﻠﻠﮭﺎ ﺑﺎﻟﺟدول

Eg. Nalidixic acid 1st Generation =Broad spectrum Eg. Nitroimidazoles Anti-TB Gram +ve/–ve, Anaerobes Gram +ve/-ve anaerobes

Flouroquinolones Used with other drug Eg. Ciprofloxacin Bactericidal; anaerobes NOT alone. nd 2 Generation =Narrow spectrum Also Antiprotozoal Because it will create Gram –ve resistance immediately

4th Generation Eg. Moxifloxacin Side Effect Side Effect Anaerobes = GIT = Hepatotoxicity

Side Effect = Cartilage damage v 5) Antimetabolites (Folate inhibition)

§ Bacteriostatic 5) Inhibit folate metabolism/ Sulfonamides § Trimethoprim-Sulfamethoxazole ( TMP-SMX) bacterial growth Trimethoprim (اﺳم ﺗﺟﺎري) Septrin / Bactrim : called TMP-SMX of Combination § Sulfamethoxazole Eg. Sulfadiazine § Block sequential steps in folic acid synthesis

§ Used to treat : Nocardia, Chlamydia, Protozoa & P.cranii infection. Blocks folic acid synthesis

§ Used for the treatment of: upper & lower respiratory tract infections , otitis media, sinusitis & infectious diarrhea. Bacteriostatic § Side effects: GIT, hepatitis , bone marrow depression, hypersensitivity Grame –ve Used a lot in hospital

Side Effect *** = GIT *** v Classification of Antimicrobials

1) Inhibition of cell wall 3) Inhibition of protein 4) Inhibition of nucleic 5) Anti-metabolite OR synthesis synthesis acid synthesis Competitive antagonism. Miscellaneous

Aminoglycosides Beta –Lactam Inhibit folate metabolism antimicrobial agents Tetracyclines Rifamycins Metronidazole o Penicillins Trimethoprim o Cephalosporins Chloramphenicol o Carbapenems (imipenem & meropenem) Macrolides Quinolones Sulfamethoxazole o Monobactams (aztreonam) Clindamycin

Oxazolidinones Miscellaneous : including Vancomycin Metronidazole many thing of different kinds (linezolid)

Streptogramins

Quinupristin dalfopristin

###ﻣﮭم ﺗﻌرف اﻻﻣﺛﻠﺔ ﺗﺣت ﻛل ﻧوع ﻣﻣﻛن ﯾﺳﺄﻟك ﺑﺎﻹﺧﺗﺑﺎر(ﺗﺣﺗﮭﺎ ﺧط ) *** ###ﻣﮭم ﺗﻌرف اﻻﻣﺛﻠﺔ ﺗﺣت ال Bacteriostatic and Bactericidal Narrow spectrum Bactericidal Antibiotic for Anaerobic Penicillin Can cause Nephrotoxicity as side effect ü Metronidazole Cephalosporins ü Aminoglycosides ü Moxifloxacin Carbapenems ü Colistin & Polymyxin B ü Clindamycin Monobactams Can cause hepatotoxicity as side effect Vancomycin ü Rifampin Antibiotic for +ve gram only Aminoglycosides Can cause Hypersensitivity as side effect ü Vancomycin Fluoroquinolones ü Penicillins ü Cephalexin Metronidazole ü Cephalosphorins Antibiotic for -ve gram only Rifampin ü Colistin & Polymyxin B We can not use it with pregency women ü Aminoglycosides ü Tetracyclines ü Fluoroquinolones Bacteriostatic ü Sulfadiazine

Tetracyclines Doxycycline Macrolides Sulfonamides v ###ﻣطﺎﻟﺑﯾن ﻓﻘط ﺑﺎل Effect Antituberculous agents: Side First line: second line: o Isonlazide (inh) o streptomycin Anti TB Elhambiotd Pyrazinamide o Rifampicin o PASA isoniazide (INH) o Ethambutol o ,

Side Effect o Pyrazinamide o capreomycin Side Effect = Hepatotoxicity peripheral Side Effect = Optic neurititis If the 1st line does not work, neuropathy = Hepatitis, arthraglia (color blindness) (gout) nd + turn urine and tears into they use the 2 line red/pink + Hepatotoxicity

***

Antibiotics class ACTION USE S/E Hepatotoxicity Bacteriocidal T.B treatment and Anti TB isoniazide (INH) peripheral neuropathy (pyridoxine (vitamin All lung tissue prophylaxis B6))

bactericidal Elhambiotd concentrated lung alveoli TB treatment Optic neurititis phagolysosome Acid environment of Pyrazinamide TB treatment Hepatitis, arthraglia (gout) macrophages Antibiotic Resistance in Bacteria Types of Resistance Innate resistance (primary resistance) Acquired resistance (primary resistance) Selective pressure resistance o Naturally resistance. Called 1) Mutation: 2) Gene Transfer: Bacteria Mutant (like 1 in 10000) Constitutive resistance. And when Antibiotic used lead to kill all Ex: Mycobacterium Acquired from other sensitive stray o Eg: Streptococcus & anaerobes Resistance to bacteria are resistant to gentamicin. Streptomycin . Called Horizontal Resulting in survival of resistance stray

Either Plasmid mediated o Called Vertical using sex pilli (resistance transferred within same o Mutation during species) replication in DNA formation Or through Transposons (can transfer resistance o Mother to child from gram +ve to –ve) Cross resistance : • Resistance to one group confer resistance to other drug of the same group . eg. Resistance to erythromycin and clindamycin Dissociate resistance: • resistance to gentamicin does not confer resistance to tobramycin . Antibiotic Resistance in Bacteria

Mechanisms of resistance Principles of antimicrobial therapy Criteria for ideal antimicrobial agent

1- Permeability changed v Indication v Has selective toxicity v Choice of drug 2- Modification of site of action, v Route v Causes no hypersensitivity e.g. Mutation. v Dosage v Penetrate tissues quickly v Duration 3- Inactivation by enzymes . v Distribution v Resistance does not develop quickly v E.g. Beta- Lactamase & aminoglycoside Excretion v Has no effect of normal flora inactivating enzymes. v Toxicity v Combination use as in tuberculosis v Broad spectrum 4- Passing blocked metabolic reaction (SYNERGISTIC, ANTAGONISTIC or ADDIDITIVE) e.g. PABA ( para amino benzoic acid) àà folic acid , and is plasmid v USE (PROPHYLAXIS, EMPIRIC or DEFINITE) Long term: ## ﻣﮭﻣﺔ ^^ :term mediated. Short Meningitis Tuberculosis, rheumatic fever recurrent urinary tract infections, Antibiotics class Examples Mechanisms Spectrum of Activity S/E INHIBITION OF CELL WALL Bactericidal-most active against gram +; synthetic and potentiated penicillin have improved gram – Natural; penicillin G Semi- coverage Penicillin G synthetic: , ampicillin- +ve, some anaerobes Penicillins clavulanic acid, ampicillin- Ampicillin sulbactam Penicillin, +ve/-ve, anaerobes Pipracillin Pipracillin Cover Pseudomonas

1ST generation: cephalothin, Inhibit peptoglycan Bactericidal Hypersensitive, anaphylaxis cephalexin, synthesis necessary 1st gen: Gram +, limited Gram - GIT 2nd generation: for cell-wall 2nd gen: Gram+, improved Gram – and CEPHALOSPHORINS Cefuroxime formation some anaerobes. 3rd generation: ceftriaxone, 3rd gen: limited Gram+, excellent Gram- ceftazidime and anaerobes 4th generation:

Inhibit Red man syndrome Glycopeptides Vancomycin Bacteriocidal; Gram+ve bacteria only MRSA Nepro and ototoxicity synthesis Inhibition of cell Membrane Alter cell memnrano Polymyxin Colistin Bacteriocidal; Gram-ve bacteria Nephrotoxicity permeability Antibiotics class Examples Mechanisms Spectrum of Activity S/E Inhibition of protein synthesis (Ribosome) Aminoglycosides Gentamicin, amikacin, Bind 30S ribosomal subunit; Bactericidal; Gram-, Ototoxicity snd tobramycin, neomycin inhibit peptide elongation includingPseudomonas and Nephrotoxicity Mycobacterium, Streptococcus and anaerobes are resistant

Tetracyclines Tetracyclines, doxycycline Bind 30S subunit; inhibit Bacteriostatic; Gram+ and Gram -; Teeth discoloration RNA function Rickettsiae, Mycoplasma, Clamydophila GIT photosensitivity

Chloramphenicol Chloramphenicol Bind 50S subunit, inhibit Bacteriostatic; broad Gram+ and Gram- BM a plastic anemia protein synthesis spectrum

Macrolides and Erythromycin Bind 50S subunit; inhibit Bacteriostatic; Gram+, Legionella, GIT pseudo-membranous Azithromycin protein synthesis Camphylobacter, Mycoplasma, colitis Clarithromycin Chlamydophila, Ricketstsiae, good anaerobic spectrum lincosamides Clindamycin Antibiotics class Examples Mechanism Spectrum of Activity S/E INHIBITION OF NUCLEIC ACID SYNTHESIS

Bactericidal; Gram +ve and Nalidixic acid, Ciprofloxacin, Inhibits DNA gyrase, gram -ve, INCLUDING Flouroquinolones Gatifloxacin preventing supercoiling Cartilage damage Pseudomonas at a higher Moxifloxacin →DNA degradation dosage

Metabolized by anaerobes Bactericidal; anaerobes Nitroimidazoles Metronidazole to intermediates that GIT (Also antiprotozoal) prevent DNA synthesis

Bactericidal; Gram +ve and Discoloration of body fluid Rifampicin Rifampicin DNA degradation gram –ve bacteria hepatotoxicity INHIBITION OF BACTERIAL GROWTH

Competitive analogue of Bacteriostatic → bactericidal para-aminobenzoic acid Trimethoprim-sulfadiazine, when combined. Gram –ve Sulfonamides (PABA) →inhibits GIT ormethoprim sulfa Chlamydia, nocardia, dihydrofolate reductase protozoa and pneumocystic →blocks folic acid synthesis Contact us : THE TEAM : THE TEAM :

• Waleed Aljamal • Shrooq Alsomali • Ibrahim Fetyani • Rawan Alqahtani Twitter : • Meshal Eiaidi • Hanin Bashaikh • Khalid Alhusainan • Jawaher Alkhayyal @microbio436 • Hussam Alkhathlan • Reem Alshathri • Faisal Alqumaizi • Ohoud Abdullah • Abdulaziz Alangari • Ghadah Almazrou • Khalid Alshehri • Lama Al-musallm • Nasir Aldosarie • Mohammad Al-Kahil