Lecture 1 Antimicrobial Agents PDF

Lecture 1 Dr. Amany Gad Chemotherapeutic antimicrobial agents In this part, we will study: Antibacterial agents: Different classes of antibacterial agents Resistance to antibacterial agents Control of drug resistance. Non-Antibiotic Antimicrobial Agents Evaluation of antiba...

Lecture 1 Dr. Amany Gad Chemotherapeutic antimicrobial agents In this part, we will study: Antibacterial agents: Different classes of antibacterial agents Resistance to antibacterial agents Control of drug resistance. Non-Antibiotic Antimicrobial Agents Evaluation of antibacterial agents Antifungal agents Antiviral agents  Definitions Chemotherapeutic agent: Any chemical used internally in the treatment, relief or prophylaxis of a disease. Prophylactic agent: A drug used to prevent the incidence of a disease in a person at risk.  Antimicrobial Drugs Chemicals used to treat microbial infections by interfere with the growth m.o within host, including (antibacterial, antiviral, antiparasitic and antifungal) regardless of its origin.  Antimicrobial Agents Non- Antibiotics (Chemotherapeutic Agents) Antibiotics - Antiseptics Antibiotics are natural product produced by - Disinfectants bacteria and fungi - Preservatives which kill or inhibit the growth of other m.o.  Antimicrobial Agents Disinfectant: Antimicrobial agent used only on inanimate objects Antiseptic: Antimicrobial agent used on animate object Bactericidal: agent that kills bacteria Bacteriostatic: agent that inhibits the growth of bacteria  Chemotherapeutic spectra Narrow spectrum antimicrobial agent The activity is limited to certain groups of microorganisms, e.g. Antibiotics that are active only on either Gram +ve bacteria or Gram -ve bacteria. Broad spectrum (extended spectrum) antimicrobial agent The antimicrobial agent covers a wide range of disease-causing microorganisms, e.g. Antibiotics that are active on both Gram +ve bacteria and Gram -ve bacteria. The ideal antimicrobial agent should be: 1. Microbiocidal rather than microbiostatic 2. Spectrum of activity should be broad 3. Resistant to microbial resistance 4. of selective toxicity 5. Non-allergic to host with minimal side effects 6. Able to achieve good tissue distribution with sufficient therapeutic concentration, especially at the site of infection 7. Remain active in the tissues and body fluids 8. Assisting the activity of host defense 9. Reasonable price  Classification of antibiotics Antibiotics are classified several ways. 1. On the basis of spectrum of activity 2. On the basis of the source 3. On the basis of chemical nature 4. On the basis of mode of action Categories of bacteria that are clinically important 1. According to the 2. According to the spectrum of action source A.antibiotics produced by bacteria  Antibacterial drugs. (bacitracin, polymixins and gramacidins)  Antifungal drugs. B. antibiotics produced by fungi  Antiviral drugs. (penicillins, cephalosporins and grisofulvin)  Antiprotozoal drugs. C. antibiotics produced by actinomycetes  Antihelminthic drugs. (chloramphenicol, streptomycin, erythromycin and vancomycin.) 3. According to 4. According to chemical nature mode of action - Peptides 1. Inhibition of cell wall synthesis - Glycopeptides 2. Inhibition of nucleic acid synthesis - Macrolides 3. Inhibition of protein synthesis - Aminoglycosides 4. Disruption of cell membrane structure or function - B-lactams 5. Inhibit synthesis of essential - Polyenes metabolites  Features of Antimicrobial Drugs: 1. Selective Toxicity 2. Effects of Combining Cause greater harm to Drugs microorganisms than to Combinations are host sometimes used to fight infections Synergistic: action of one drug enhances the activity of another or vice versa. e.g. 2 + 2 = 6 The larger the , the better the Antagonistic: activity of one chemotherapeutic agent. drug interferes with the action of another. e.g. 2 + 2 = < 4  Features of Antimicrobial Drugs: 3. Adverse effects 4. Resistance to Allergic Reactions: some people Antimicrobials develop hypersensitivities to antimicrobials. Some microorganisms inherently resistant to effects Toxic Effects: some of a particular drug. (Intrinsic antimicrobials toxic at high resistance) concentrations or cause adverse effects Other previously sensitive microorganisms can develop resistance through spontaneous Suppression of normal flora: mutations or acquisition of when normal flora killed, other new genes. (Extrinsic pathogens may be able to grow to resistance) high numbers Mechanisms of action of Antibacterial Drugs I- Inhibit cell wall synthesis II- Injury to plasma membrane III- Inhibit protein synthesis IV- Inhibit nucleic acid synthesis V- Inhibit synthesis of essential metabolites  Fleming and Penicillin Modern era in Antibiotics begins with Fleming. 1928 - Alexander Fleming observed the antibacterial effects of Penicillin. 1940 Florey and Chain extracted Penicillin Around the fungal colony is a clear zone where no bacteria are growing Zone of inhibition due to the diffusion of a substance with antibiotic properties from the fungus Mechanisms of antibacterial action  Summary of antimicrobial agents affecting cell wall synthesis Agents affecting the cell wall b-lactamase inhibitors b-lactamantibiotics Other antibiotics Clavulanic acid Sulbactam D- Cycloserine Tazobactam Vancomycin Teicoplanin Penicillins Cephalosporins Carbapenems Monobactams Impienem Penicillin G Meropenem Aztreonam Penicillin V Methicillin Oxacillin 1st generation 2nd generation 3rd generation 4th generation Cloxacillin Cephaloridine Cefamandol Ceftazidime Cefepime Flucloxacillin Cephalexin Cefoxitin Cefpirome Ampicillin Amoxicillin Cefotaxime Carbenicillin Ceftriaxone  1. Drugs that affect the bacterial cell wall Most bacterial cell walls contain a rigid girdle of peptidoglycan. Penicillin and cephalosporin block synthesis of peptidoglycan, causing the cell wall to lyse. Penicillins do not penetrate the outer membrane and are less effective against gram-negative bacteria. Broad spectrum penicillins and cephalosporins can cross the cell walls of gram-negative bacteria. Cell wall of Gr +ve (A) & Gr –ve (B) (Transpeptidases are referred to as penicilin-binding proteins PBPs) 3. The fusion of these precursors by a transpeptidase to a mature peptidoglycan wall (Transpeptidation). 2. Insertion of the disaccharide pentapeptide into the cell wall at a growing point by a transglycosylase. (Transglycosylation). 1. An isomerase converts two molecules of L-alanine to D- alanine and a ligase joins them together. -Disaccharide pentapeptides are synthesized in the cytoplasm and transported across the cytoplasmic membrane on a lipid carrier.  A)  -Lactam antibiotics Mechanism of action of beta-lactams: B-Lactam antibiotics are bactericidal, and act by inhibiting the synthesis of the peptidoglycan layer of bacterial cell walls which is important for cell wall intergrity through: The final transpeptidation step in the synthesis of the peptidoglycan is facilitated by transpeptidases known as penicillin-binding proteins (PBPs). Transpeptidases [penicillin-binding proteins (PBP)], are enzymes that are critical to the cross-linking of the cell wall of the bacterium. -lactams resemble the D-alanyl-D-alanine residues and bind to the transpeptidases irreversibly blocking their effect. Thus preventing the final crosslinking (transpeptidation) of peptidoglycan layer, disrupting cell wall synthesis.  Bacterial resistance to β-lactams By definition, all β-lactam antibiotics have a β- lactam ring in their structure. The effectiveness of these antibiotics relies on their ability to reach the PBP intact and their ability to bind to the PBP. Hence, there are two main modes of bacterial resistance to β-lactams: 1. Enzymatic hydrolysis of the β-lactam ring 2.Possession of altered penicillin-binding proteins  Enzymatic hydrolysis of the β-lactam ring If the bacterium produces the enzyme β-lactamase or the enzyme penicillinase, the enzyme will hydrolyse the β-lactam ring of the antibiotic, rendering the antibiotic ineffective. Penicillinase ( Lactamase)  -Lactam antibiotics This family includes: 1- Penicillins 2- Cephalosporins 3- Carbapenems 4- Monobactams So why there is sometimes recurrence of infection after penicillin treatment has been terminated?? Bacterial cells that are not undergoing multiplication can survive in the presence of penicillin…why? Because their peptidoglycan is unbroken and there is no reparative cross linking activity for the penicillin to block.  1- Penicillins A) Natural Penicillin G (benzyl penicillin) Penicillin V (phenoxymethyl penicillin). Disadvantages of natural penicillins - Produced by molds such as 1- Narrow spectrum. Penicillium notatum (Penicillium chrysogenum) through a 2- Easily inactivated since it is unstable in fermentation process. solution & is destroyed by heat, acid, alkali, oxidizing agents….etc. - Bactericidal to gram-positive cocci and bacilli, Neisseria (pathogenic 3- Should be given parentrally because they gram-negative cocci) and are partially destroyed in the stomach due to spirochetes. acidity. - Non active against most gram-negative rods or T.B. 4- Inactivated by penicillinase (-lactamase). - Low toxicity (except 5- Rapidly excreted in the urine, therefore the hypersensitivity reactions). dose should be is injected every six hours.  B) Semi synthetic penicillins i) Penicillinase-resistant: e.g. Methicillin. ii)Penicillinase and acid-resistant e.g. oxacillin, cloxacillin & flucloxacillin are taken orally. (Flucloxacillin is the antibiotic of choice for oral administration because of its high absorption). iii) Broad spectrum and acid-resistant e.g. Ampicillin and amoxicillin are taken orally and are effective against some enteric gram negative bacteria including: dysentery. Amoxicillin has better absorption than ampicillin. Amoxicillin is the drug of choice for upper respiratory tract infections. iv) Penicillins active against Pseudomonas aeruginosa e.g. Carbenicillin Carbenicillin is specially used in urinary tract infections caused by Pseudomonas aeruginosa.  2- Cephalosporins - Stable in acid pH. - Broad spectrum. -Many of them are resistant to penicillinase (β-lactamases). -Thus, cephalosporins are used as alternatives to penicillin in cases of resistance or penicillin allergy.  Classes of Cephalosporins 5th G 1) Based on route of administration: (MRSA) Oral cephalosporins. 4th Generation Parentral cephalosporins. (broader strain- CNS pseudomonas) 2) Based on Generation system: 3rd Generation And spectrum 1st generation ß-lactamase G-ve activity resistance anaerobic 2nd generation 3rd generation 2nd Generation (G-ve- 4th generation Hemophilus influenza) 5th generation 1st Generation (G+ve, G-ve (some derivative)) 28 28  Cephalosporins a- First generation b- Second generation c- Third generation Most are poorly absorbed through the gut wall and have Resistant to most Far more active (up to 100 to be injected enterobacterial β-lactamases. fold) than first and second generation cephalosporins, Cephaloridine: active against Cefamandol and Cefoxitin are and are active against gram-positive cocci, active against a wide range anaerobes and some are but is nephrotoxic. of gram-negative bacteria and active on Pseudomonas Cephalexin: can be given H. influenzae but not aeruginosa & CNS infections orally anaerobes Examples: Ceftazidime and Mostly given by injection. Cefotaxime. d- Fourth-generation e- Fifth-generation Effective against mutants resistant to “third- Are effective against generation" cephalosporins. MRSA Are active against P. aeruginosa and CNS infections (methicillin-resistant (meningitis) staphylococcus aureus) e.g. Ceftobiprole Examples: Cefipime: penetrates the outer membrane of Gram- negative bacteria faster than third generation cephalosporins. Administered parentrally. Cefpirome  3- Monobactams Aztreonam is resistant to beta-lactamases and has a great effect against gram negative infections, especially of the meninges, bladder, and kidneys. 4- Carbapenems Examples: Imipenem Meropenem Have the broadest antibacterial spectrum compared to other - lactams. Administered I.V. due to their poor oral bioavailability. Highly resistant to - lactamases. 5- - lactamases inhibitors These drugs are given in combination with - lactam antibiotics to prevent their degradation by - lactamases. Examples: clavulanic acid, sulbactam & tazobactam. Several antibiotic/beta-lactamase inhibitor combinations exist on the market: e.g - Augmentin: amoxicillin/clavulanic acid - Unasyn: Ampicillin/sulbactam.  ) Non  -Lactam antibiotics 1) D-Cycloserine Interfers with D-alanyl-D-alanine synthesis by inhibiting both alanine isomerase that converts L- alanine into D-alanine & D- alanyl-D-alanine ligase that catalyzes peptide bond formation between two D- alanine molecules. 2) Glycopeptides (Vancomycin & Teicoplanin) Inhibits peptidoglycan synthesis by blocking the transglycosylation reaction are often the only antibiotics effective against some MRSA strains Thank You