Pharmaceutical Microbiology (Antimicrobial Agents) HELWAN University 2024-2025 PDF

ANTIMICROBIAL ANTIMICROBIAL AGENTS AGENTS DR. MOHAMMED SALAH ASSISTANT PROFESSOR OF MICROBIOLOGY AND IMUNOLOGY SEPTEMBER 2024 Who I am? 2  PRESENTATION T...

ANTIMICROBIAL ANTIMICROBIAL AGENTS AGENTS DR. MOHAMMED SALAH ASSISTANT PROFESSOR OF MICROBIOLOGY AND IMUNOLOGY SEPTEMBER 2024 Who I am? 2  PRESENTATION TITLE Lecture Outlines: 3  Background 4 Antimicrobial agents  Antimicrobial agents Discovery of Penicillin 1 1928 Alexander Fleming discovers the antibacterial properties of the Penicillium mold. 2 1929 Fleming publishes his findings, describing penicillin as a "mold juice" with the ability to kill various bacteria. 3 1940s Howard Florey and Ernst Chain purify and further develop penicillin, leading to its mass production and widespread use as an antibiotic. 5  Antimicrobial agents IMPORTANT DEFINITIONS 6  Antimicrobial agents An antibiotic is a type of antimicrobial substance that Antibiotic specifically targets bacteria. It can either kill bacteria (bactericidal) or inhibit their growth (bacteriostatic). An antiviral is a drug designed to treat viral infections by inhibiting the development and Antiviral replication of viruses. Unlike antibiotics, antivirals do not kill the virus but rather prevent it from multiplying. An antiprotozoal drug targets protozoa, which are Antiprotozoal single-celled organisms that can cause diseases in humans, such as malaria and amoebiasis. These agents can function as either fungicides, Antifungal which kill fungi, or fungistatics, which inhibit their growth. 7 8 Antimicrobial agents  Antimicrobial agents Bactericidal describes substances that kill bacteria outright. These agents lead to bacterial cell death through various mechanisms, such as disrupting cell wall synthesis, damaging cell membranes, or interfering with vital cellular functions. Bactericidal antibiotics are often preferred in severe infections where rapid bacterial eradication is necessary. Examples include penicillins and aminoglycosides. Minimum Inhibitory Concentration (MIC) is the lowest concentration of an antimicrobial agent required to inhibit visible growth of a microorganism after a specified incubation period. MIC is a critical measure in determining the effectiveness of antibiotics against specific pathogens. 9  ANTIMICROBIAL AGENTS E- Minimum Bactericidal Concentration (MBC) is the lowest concentration of an antimicrobial agent required to kill a particular bacterium. MBC is determined by subculturing samples from the MIC test onto antibiotic-free media and assessing bacterial viability. Antimicrobial Antibiotic Resistance spectrum Synergy Antibiotic Antimicrobial Spectrum Synergy in antimicrobial Resistance occurs when refers to the range of therapy refers to the bacteria evolve microorganisms that an enhanced effect achieved mechanisms to resist the antimicrobial agent can when two or more effects of antibiotics, effectively target. antimicrobial agents are making standard used together, resulting This spectrum can be treatments ineffective. in greater efficacy than broad (effective against when each agent is used This resistance can arise many types of bacteria) alone. This can lead to through genetic mutations or narrow (effective improved treatment or acquisition of resistance against a specific group outcomes and reduced genes from other bacteria. of bacteria). risk of resistance development. 10  Antimicrobial agents General Characteristics of Antimicrobial Drugs Selective General Characteristics of Toxicity Antimicrobial Drugs Therapeutic Dose Toxic Dose Therapeutic Index 11 General Characteristics of Antimicrobial Drugs Therapeutic Selective Toxicity Therapeutic Dose Toxic Dose Index The drug must The drug level The drug level at The ratio of the kill or inhibit the required for which the agent toxic dose to the microbial clinical treatment becomes too therapeutic dose pathogen while of a particular toxic for the host damaging the infection host as little as possible. TI=ED50/​TD50 TD50​is the dose at which 50% of the population experiences a toxic effect. ED50​is the dose at which 50% of the population experiences the desired therapeutic 12 effect.​​  Antimicrobial agents Classification of Antibiotics Antibiotics According to According to According to According to Source Chemical Mechanism of action Spectrum of activity structure Inhibition of Cell Wall Natural β-lactam Wide spectrum Synthesis Narrow Inhibition of Protein Semisynthetic Tetracyclines Synthesis spectrum Interference with synthetic Rifamycins Specific Nucleic Acids Disruption of Cell Aminoglycosides Membrane Integrity Inhibition of Macrolides Metabolic Pathways Ploypeptide antibiotics Chloramphenicol 13  I. According to the Nature and Source: (1)Natural source (microorganisms): a. Monobactams from Pseudomonas acidophila and Gluconobacter species. b. Streptomycin, tetracyclines, etc, from Streptomyces spp. c. Griseofulvin and some penicillins and cephalosporins from certain fungal genera (Penicillium, Cephalosporium) of the family Aspergillaceae. (2) Semisynthetic: (3) Synthetic: This means that part of the 1. Chloramphenicol molecule is produced by 2. Sulphonamides: Sulphanilamide, Sulphdiazine, microorganism and the product 3. Antitubercular compounds: Pyrazinamide and is then further modified by a Ethambutol chemical process. Examples: 4. quinolone : Nalidixic acid, Ciprofloxacin,. Many penicillins and 5. Imidazole derivatives: Metronidazole, Clotrimazole, cephalosporins. Miconazole.  Antimicrobial agents II. According to Chemical structure Class Example β-lactam A. Penicillins: Penicillin G, Penicillin V, Methicillin, Oxacillin, Cloxacillin, Fluxacillin, Ampicillin, Amoxacillin, carbencillin and Piperacillin. B. Cephalosporins: Cephaloridine, Chephalexin, Cephalothin. Tetracyclines Tetracycline, Oxytetracycline, Chlortetracycline, methacyline minocycline, thiacyclin. Rifamycins it consists of rifamycin A to E. Aminoglycosides Streptomycin, Gentamycin, Neomycin Amikacin Macrolides Erythromycin, Azithromycin, Sipramycin. Ploypeptide antibiotics Bacitracin, Polymyxins, Viomycin. Chloramphenicol: Chloramphenicol 15 II. According to Chemical structure (CONT.) ANTIMICROBIAL AGENT 16  Antimicrobial agents III. According to Spectrum of Activity Antibiotic class Definition Example Chloramphenicol, 1. Wide They are active against broad spectrum of tetracyclines, spectrum: bacteria either Gram +ve or Gram -ve Bacteria Kanamycin 2. Narrow They are active against limited number of Penicillin G, spectrum: microorganisms Polymixins Viomycin and They are the antibiotics that selectively used for 3. Specific: Cycloserine are one or to microorganisms used only for TB. 17  Antimicrobial agents IV. According to Mechanisms of Action 18  Antimicrobial agents These mechanisms highlight how antibiotics selectively target bacteria Mode while minimizing of Action effects Mechanism on human cells, making Description them Examples effective treatments for bacterial infections. A. Inhibition of Protein Binds to ribosomal subunits, Aminoglycosides, Synthesis blocking protein assembly Tetracyclines B. Inhibition of Cell Wall Disrupts peptidoglycan cross-linking β-lactams (e.g., Penicillin) Synthesis C. Interference with Inhibits DNA or RNA synthesis Fluoroquinolones, Rifampin Nucleic Acids D. Disruption of Cell Binds to membrane phospholipids Polymyxins Membrane Integrity causing leakage E. Inhibition of Metabolic Mimics substrates in metabolic Sulfonamides Pathways pathways 19 20 Antimicrobial agents  Protein Synthesis Inhibitor Protein synthesis inhibitor antibiotics are a class of antimicrobial drugs that target the bacterial Antibiotics ribosome, interfering with the process of protein synthesis. These antibiotics play a crucial role in the treatment of various bacterial infections. MS  Protein synthesis in prokaryotes WHAT IS THE RIBOSOME? Definition:  Bacterial ribosomes are essential cellular structures responsible for protein synthesis, composed of two subunits: the small (30S) and large (50S) subunits, which together form the 70S ribosome.  The "50S" in 50S ribosomes refers to the sedimentation coefficient measured in Svedbergs (S), a unit that indicates how fast particles move in a centrifuge. This coefficient is related to the size, shape, and density of the ribosomal subunit. Structure 1. Subunits:30S Subunit: Contains 16S rRNA and approximately 21 ribosomal proteins. 2. 50S Subunit: Comprises 23S and 5S rRNA along with about 33 ribosomal proteins. Function  Protein Synthesis: Ribosomes serve as the site for mRNA translation, where they decode mRNA sequences into polypeptide chains. The process involves:  Protein synthesis in prokaryotes Initiation complex in prokaryotes  Protein synthesis inhibitors  Classification:- (mechanism of Protein synthesis  sites of drug action inhibition) 1. Tetracyclines block aminoacyl tRNA from Inhibitors for 30S Inhibitors for 50S binding to the A site. ribosomal ribosomal 2. Aminoglycosides cause misreading of the subunits subunits genetic code mRNA Aminoglycosides Chloramphenicol 3. Macrolides, chloramphenicol block peptidyl Tetracyclines Macrolides transferase 4. Macrolides and clindamycin block the Lincosamides translocation step Streptogramines Lenizolid  Antimicrobial agents Basically, In each antibiotic we will take about: 27 28 Antimicrobial agents   30S ribosomal subunits: Aminoglycosides Mechanism of action:- Each aminoglycoside acts by binding to the 30S subunit of the bacterial ribosome, which causes mismatching between the mRNA codon and the charged aminoacyl- tRNA. This in turn promotes protein mistranslation. Aminoglycosides are primarily classified as bactericidal antibiotics. Mechanism of resistance:- 1. Decreased accumulation within the bacterium (efflux pumps) 2. Drub inactivation:- bacterial enzymes such as acetyltransferases which modify the drug and prevent it from binding ribosomes 3. Modification of target site mutation of the bacterial ribosome 30S Efflux pump Efflux pumps are critical transport proteins in bacteria that play a significant role in antibiotic resistance by expelling various toxic substances, including antibiotics, from the cell. thereby reducing their intracellular concentrations conferring antibacterial resistance 30 Antibacterial spectrum:- Aminoglycosides have excellent activity against: 1. Aerobic Gram-negative bacteria including Pseudomonas aeruginosa 2. Some aerobic Gram-positive bacteria 3. Mycobacterium tuberculosis because:- 4. Small in size 5. Positive charge  Gentamicin is the most commonly used of the aminoglycosides. It is active against both aerobic Gram-negative > aerobic Gram-positive bacteria.  Tobramycin has the same spectrum of activity as gentamicin and is used similarly.  Strains of aerobic Gram-negative bacteria that are resistant to gentamicin and tobramycin may remain susceptible to amikacin  30S ribosomal subunits: Aminoglycosides Synergistic effect:- Uptake of aminoglycosides is enhanced by antibiotics that inhibit bacterial cell wall synthesis, such as B-lactams and vancomycin Side effects (toxicity):- 1. Nephrotoxicity (reversible): and renal function often returns to normal after discontinuation of the drug 2. Ototoxicity (irreversible) consists of two types: a) Auditory impairment, which may lead to irreversible hearing loss, and b) Vestibular toxicity, which results in disturbances in balance.  30S ribosomal subunits: Tetracycline and Glycylcyclines Members:- Tigecycline, a member of a related class of antibiotics called the glycylcyclines, has recently been approved for use. Mechanism of action  The structure allows the tetracyclines to interact with the 30S subunit of the bacterial ribosome and prevent binding by tRNA molecules loaded with amino acids to the A site on mRNA, hence protein synthesis is blocked.  Tetracyclines are primarily classified as bacteriostatic antibiotics.  30S ribosomal subunits: Tetracycline and Glycylcyclines Bacterial resistance 1. Exogenous genes are acquired that encode efflux pumps, 2. Ribosomal protection proteins:- These factors alter the conformation of the bacterial ribosome such that tetracyclines no longer bind them but protein translation remains unaffected. Antimicrobial spectrum (Broad spectrum)  30S ribosomal subunits: Tetracycline and Glycylcyclines Specific activities 1. The strength of this class of drugs, however, is its activity against atypical bacteria. 2. Advantages of doxycycline over tetracycline? “The spectrum of activity of doxycycline is essentially the same as tetracycline. It is more commonly used because of its longer half-life, which allows for twice per day dosing”  The spectrum of activity of minocycline is similar to that of the other tetracyclines except that this agent is preferable for the treatment of MRSA infections. Tigecycline Mechanism of action: The key modification is the addition of a glycyl amide group to the core tetracycline structure. That lead to 1. Prevents recognition of tigecycline by many bacterial efflux pumps and 2. Makes it insensitive to modifications of the 30S ribosomal subunit.  30S ribosomal subunits: Tetracycline and Glycylcyclines Antimicrobial spectrum of tegicycline “tigecycline has an impressively broad antimicrobial spectrum“ 1. It is active against most aerobic Gram-negative bacteria, including multidrug-resistant Acinetobacter spp except P. aeruginosa, 2. Most aerobic Gram-positive bacteria, including MRSA 3. anaerobic bacteria 4. excellent activity against atypical bacteria.  30S ribosomal subunits: Tetracycline and Glycylcyclines Side effects of tetracycline (toxicity) The tetracyclines are relatively safe drugs, 1. Tetracyclines should not be given to pregnant women and given cautiously to children younger than the age of 8 years? It is potent chelator of metal ions such as calcium. This may result in the gray to yellow discoloration of actively forming teeth and deposition in growing bone. 2. An exception is the blue-black hyperpigmentation of skin and mucous membranes observed relatively frequently with minocycline use. 3. Gastrointestinal side effects such as nausea, vomiting, and esophageal ulceration are also seen, as is hepatotoxicity.  50S ribosomal subunits: Chloramphenicol Mechanism of action:- The structure of chloramphenicol allows for binding to the 50S subunit of the ribosome, where it blocks binding of tRNA loaded with an amino acid and block peptidyl transferase enzyme. Chloramphenicol is primarily classified as a bacteriostatic antibiotic Bacterial resistance :- 1. Inactivation of chloramphenicol:- Resistance occurs when bacteria acquire genes that encode for an enzyme that acetylates chloramphenicol, which prevents it from effectively binding to its target. 2. Efflux pumps that recognize this agent have also been described. Antimicrobial spectrum (Broad spectrum) 3. The most effective antibiotics against anaerobes 4. Excellent activity against atypical bacteria. 5. Many aerobic Gram-positive bacteria. 6. Many aerobic Gram-negative bacteria  50S ribosomal subunits: Chloramphenicol Side effects (toxicity):- 1. causes reversible dose-dependent bone marrow suppression during the course of therapy leading to aplastic anemia 2. This agent can also lead to a fatal condition in neonates called gray baby syndrome and to neurologic abnormalities such as optic neuritis. Key words: Chloramphenicol has a broad spectrum of activity Limited use Grey baby syndrome Aplastic anemia Bone marrow suppression  50S ribosomal subunits: Macrolides and Ketolides  50S ribosomal subunits: Macrolides and Ketolides I. Members:- Telithromycin is a recently approved member of a structurally related class of antibiotics called the ketolides. II. Mechanism of action:- Macrolides bind tightly to the 50S subunit of the bacterial ribosome at a location that blocks translocation step of protein synthesis. Macrolides are primarily classified as bacteriostatic antibiotics, III. Bacterial resistance:- 1. Inhibition of drug entry and accumulation 2. Enzyme-mediated ribosome binding site alteration: by methylating (-CH3) the portion of the 50S ribosome 3. Mutation of the ribosome binding site 4. The is a cross resistance between macrolides and clindamycin 5. Resistance to one member of the macrolide group usually implies resistance to all members.  50S ribosomal subunits: Macrolides and Ketolides IIIV- Spectrum of activity 1. They are not effective against most bacteria in any one group. 2. They are very useful agents for the treatment of specific types of infections, such as respiratory infections, 3. Not effective against 1. MRSA. 2. Gram-negative bacilli are resistant. 3. most anaerobic infections are resistant  Clarithromycin has somewhat greater activity against aerobic Gram-positive bacteria than erythromycin.  One of the main advantages of azithromycin is that it is taken up in high amounts by tissues and then slowly released over subsequent days. Thus, a 5-day course of oral therapy results in Ketolides (Antimicrobial spectrum) Mechanism of action:- 1. Telithromycin binds to the same site of the 50S subunit of the bacterial ribosome as the macrolides but 2. has an additional alkylaryl extension which binds to a second distinct site on the ribosome. This result in:- 1. More broad spectrum of activity due to tighter binding and continued interaction even in the presence of some enzymes that cause resistance to macrolides. 2. Reduce resistance by efflux pump: This tighter binding also limits export of telithromycin by macrolide efflux pumps. So: Telithromycin is active against many strains of Gram- positive cocci that are resistant to macrolides.  50S ribosomal subunits: Macrolides and Ketolides Macrolides and Ketolides (toxicity):- 1. Erythromycin: gastrointestinal symptoms such as nausea, vomiting, and diarrhea and with thrombophlebitis following intravenous administration. 2. Clarithromycin and azithromycin:- are usually tolerated quite well 3. Telithromycin use is associated with gastrointestinal complaints, headache, and dizziness. In addition, cause visual disturbances  50S ribosomal subunits: Lincosamide I. Members: 1. Clindamycin :- the most common 2. Lincomycin 3. Iboxamycin  50S ribosomal subunits: Lincosamide II. Mechanism of action:  The lincosamide antibiotics bind to the 50S subunit of the bacterial ribosome The binding occurs at a site overlapping the A (aminoacyl) and P (peptidyl) sites, inhibit the activity of the peptidyl transferase enzyme, so block translocation step which is crucial for protein synthesis.  Prevent production of bacterial toxins, and they are often used for this reason as adjunctive therapy against toxin-produced  Lincosamides are primarily bacteriostatic, meaning they inhibit bacterial growth and reproduction rather than directly killing bacteria.  Most Aerobic Gram-negative bacteria are intrinsically resistant to clindamycin because their outer membranes resist penetration by this drug. III. Antimicrobial spectrum 1. Aerobic Gram-positive bacteria including MRSA ****** 2. Anaerobic bacteria. 3. It is not useful against aerobic Gram-negative bacteria XX  50S ribosomal subunits: Lincosamide Mechanisms of resistance:- 1. Target Site Modification: methylation of the 23S rRNA in the 50S ribosomal subunit 2. Efflux Pumps: efflux pumps that actively expel the antibiotic from the cell, reducing its intracellular concentration and effectiveness 3. Drug Inactivation Cross-resistance often occur between clindamycin and macrolides Side effect:- 1. Antibiotic associated pseudomembranous colitis? Clindamycin kills many components of the normal bacterial flora in the bowel, allowing for overgrowth by C. difficile, which is resistant to this drug. 2. Clindamycin has also been associated with diarrhea and with rash.  50S ribosomal subunits: Streptogramines I. Members (Quinupristin/Dalfopristin):- Streptomyces spp. naturally secrete pairs of antibiotics from the streptogramin family that work together synergistically to kill other bacteria (cidal activity) II. Mechanism of action:- Each of the antibiotics of the streptogramins binds to the 50S subunit of the bacterial ribosome inhibiting the elongation step of protein synthesis.  Each AB alone: moderate bacteriostatic activity  Together: strong bacteriocidal activity? This synergy is explained by the fact that each compound alone inhibits a different step in the process of protein elongation and that dalfopristin induces a conformational change in the ribosome that enhances binding of quinupristin.  50S ribosomal subunits: Streptogramines III. Mechanism of resistance:- 1. Modification of the 50S ribosomal subunit (Target site) such that a conformational change in the subunit prevents streptogramin binding, 2. Enzymatic inactivation of the streptogramins, 3. Production of efflux pumps. VVVVIP: to cross-resistance between quinupristin and dalfopristin, as macrolides and clindamycin? Because quinupristin and dalfopristin bind to the same region of the ribosome as macrolides and clindamycin IV. Antimicrobial spectrum 4. Gram-positive bacteria, including MRSA***** 5. Some aerobic Gram-negative bacteria 6. Some anaerobes  50S ribosomal subunits: Streptogramines III. Mechanism of resistance:- 1. Modification of the 50S ribosomal subunit (Target site) such that a conformational change in the subunit prevents streptogramin binding, 2. Enzymatic inactivation of the streptogramins, 3. Production of efflux pumps. VVVVIP: to cross-resistance between quinupristin and dalfopristin, as macrolides and clindamycin? Because quinupristin and dalfopristin bind to the same region of the ribosome as macrolides and clindamycin IV. Antimicrobial spectrum 4. Gram-positive bacteria, including MRSA***** 5. Some aerobic Gram-negative bacteria 6. Some anaerobes  50S ribosomal subunits: Streptogramines V. Side effects (Toxicity) Adverse effects related to the site of infusion are very common when quinupristin/ dalfopristin is given through a peripheral intravenous catheter. These include pain, inflammation, and thrombophlebitis. For this reason, it is recommended that this drug be given through a central venous catheter.  50S ribosomal subunits: Lenizolid I. Members: The only member is Linezolid is one of class of antibacterial agents called oxazolidinones that are completely synthetic compounds.  50S ribosomal subunits: Lenizolid II. Mechanism of action 1. By binding the 50S subunit of the bacterial ribosome, it prevents association of this subunit with the 30S subunit, thus precluding ribosome assembly. III. Bacterial resistance 1. Modification of target site:- single amino acid mutation within the gene encoding a portion of the ribosome. 2. Some aerobic Gram-negative are intrinsically resistant to linezolid because they produce efflux pumps active against this compound.  50S ribosomal subunits: Lenizolid VI. Antimicrobial spectrum 1. Linezolid has excellent activity against most aerobic Gram-positive bacteria, including MRSA**** 2. Linezolid is available in both oral and intravenous formulations and achieves similarly high serum levels when given by either route. V. Side effects (toxicity):- 3. Linezolid is in general well tolerated. Like most antibiotics, it causes gastrointestinal symptoms such as nausea, vomiting, and diarrhea. 4. Thrombocytopenia, anemia, and leukopenia occur relatively frequently but are reversible.  Nitrofurantoin I. Mechanism of action The mechanism of action of nitrofurantoin remains poorly characterized but it may bind ribosomes and inhibit translation. II. Antimicrobial spectrum Used for treatment of acute cystitis not for pyelonephritis? Because nitrofurantoin achieves only low levels in the blood but is concentrated in urine, it has been used almost exclusively for the treatment of acute cystitis and It is not recommended for pyelonephritis because these infections are often associated with bacteremia.  Nitrofurantoin I. Mechanism of action The mechanism of action of nitrofurantoin remains poorly characterized but it may bind ribosomes and inhibit translation. II. Antimicrobial spectrum Used for treatment of acute cystitis not for pyelonephritis? Because nitrofurantoin achieves only low levels in the blood but is concentrated in urine, it has been used almost exclusively for the treatment of acute cystitis and It is not recommended for pyelonephritis because these infections are often associated with bacteremia.  Nitrofurantoin I. Mechanism of action The mechanism of action of nitrofurantoin remains poorly characterized but it may bind ribosomes and inhibit translation. II. Antimicrobial spectrum Used for treatment of acute cystitis not for pyelonephritis? Because nitrofurantoin achieves only low levels in the blood but is concentrated in urine, it has been used almost exclusively for the treatment of acute cystitis and It is not recommended for pyelonephritis because these infections are often associated with bacteremia.  Ribosomal subunits: Nitrofurantoin Nitrofurantoin has activity against 1. many of the organisms that commonly cause urinary tract infections, including aerobic Gram-negative bacteria (except P. aeruginosa) and 2. aerobic Gram-positive bacteria. III. Toxicity 3. Nausea, vomiting, rash, 4. pulmonary hypersensitivity reactions and 5. pneumonitis.  Bacterial resistance to protein synthesis inhibitors  Antibiotics Targeting Bacterial DNA & RNA  Fluoroquinolones Members: The fluoroquinolones are a synthetic group of antibacterial agents The most commonly used antibiotics today? 1. The fluoroquinolones have broad spectra of activity 2. high absorbance when given orally, 3. and favorable toxicity profiles Generations:- 4. First generation fluoroquinolones: Norfloxacin, Ciprofloxacin, Ofloxacin 5. Second generation: Levofloxacin 6. Third generation: Moxifloxacin, Gemifloxacin, Gatifloxacin  Mechanism of action Fluoroquinolones target DNA gyrase and topoisomerase IV with varying efficiency in different bacteria and inhibit their control of supercoiling within the cell, resulting in impaired DNA replication (at lower concentrations) and cell death (at lethal concentrations thereby enabling these agents to be both specific and bactericidal  Mechanism of resistance 1. Mutation of target site: Resistance to quinolones results from spontaneous mutations that occur in specific regions of the genes encoding DNA gyrase and topoisomerase IV. 2. Efflux pump A second mechanism of resistance is the overexpression of efflux pumps in some bacteria.  Antimicrobial spectrum In general: The quinolones have broad activity against various bacteria. They have bactericidal activity 1. Their strength is their activity against aerobic gram negative bacteria. 2. They are also effective against some gram positive 3. bacteria, many atypical bacteria, and even some mycobacteria. Ciprofloxacin: 4. Ciprofloxacin is the most potent of the quinolones against aerobic gram-negative bacteria 5. and is effective against Pseudomonas aeruginosa. Levofloxacin and ofloxacin :- Levofloxacin and ofloxacin are very closely related.  Antimicrobial spectrum Ofloxacin is a racemic mixture of an active and an inactive stereoisomer, whereas levofloxacin is composed solely of the active stereoisomer. Thus, these two agents have the same spectra of activity, but levofloxacin is generally twofold more potent and, as a result, more commonly used. Levofloxacin and ciprofloxacin:- 1. Levofloxacin as ciprofloxacin against aerobic gram-negative bacteria 2. Active against P. aeruginosa. 3. Relative to ciprofloxacin, levofloxacin has enhanced activity against aerobic gram-positive.  Fluoroquinolones (toxicity) Side effects Fluoroquinolones are well tolerated. Why ???? Because human gyrases and topoisomerases are quite dissimilar to the corresponding bacterial enzymes, 1. GIT side effects 2. Skin rash 3. Headache & dizziness Contraindications: 4. Pregnancy 5. children younger than 18 years  Metronidazole Mechanism of action:- Metronidazole is a small synthetic molecule that can passively diffuse into bacteria. 1. Nitro group, this group must be reduced (i.e., accept electrons) for metronidazole to be active. 2. anaerobic bacteria possess proteins, which are capable of donating electrons to this nitro group (reduction). 3. Aerobic bacteria, however, lack these proteins, for this reason, metronidazole’s spectrum of activity is limited to obligate anaerobic bacteria. 4. Once reduced, the nitro group is thought to form free radicals that lead to breaks in DNA molecules and subsequent bacterial death.  Metronidazole Bacterial resistance:- (rare) When it does occur, it is thought to result from a decrease in the capacity of the electron transport proteins to reduce the nitro group of metronidazole. Antimicrobial spectrum:- 1. all anaerobic gram-negative bacteria and 2. most anaerobic gram-positive bacteria. Side effects:- Metronidazole is relatively well tolerated 1. nausea and epigastric discomfort. 2. It can also cause an unpleasant metallic taste. 3. headache, dizziness, and peripheral neuropathy  Rifamycines Members Mechanism of action Rifamycins act by inhibiting bacterial RNA polymerase. Bacterial resistance Resistance develops relatively easily and can result from one of several single mutations in the bacterial gene that encodes RNA polymerase. Rifamycins are usually used in combination with other agents??? Because single mutations are sufficient to lead to resistance, rifamycins are usually used in combination with other agents to prevent the emergence of resistant strains.  Rifamycines Antimicrobial spectrum 1. Many of the rifamycins are frequently used in combination regimens for the treatment of mycobacterial infections. 2. Rifampin has been used along with other antibiotics to treat staphylococcal infections. Toxicity:- 1. Rifamycins commonly cause gastrointestinal complaints, 2. skin rashes 3. Rifampin causes an orange-red discoloration of tears, urine, and other body fluids, which can lead to patient anxiety. Antibiotics inhibit metabolic pathways  Sulfa drugs (antimetabolite) Members:- Sulfa drugs are very old synthetic This class of synthetic antibacterial agents Includes: 1. Trimethoprim-sulfamethoxazole (synergy), 2. Dapsone. 3. Sulfisoxazole, is used in conjunction with erythromycin to treat otitis media in children.  Sulfa drugs (antimetabolite) Mechanism of action:- Because human cells do not synthesize folic acid. Trimethoprim-sulfamethoxazole inhibits bacterial growth by preventing the synthesis of tetrahydrofolate (THF), the active form of folic acid. 1. Sulfamethoxazole does this by mimicking para-aminobenzoate (PABA) and thereby competitively inhibiting the enzyme dihydropteroate synthase that normally incorporates PABA into the synthesis pathway of THF. 2. Trimethoprim, on the other hand, is a structural analog of dihydrofolate and therefore inhibits dihydrofolate reductase  Sulfa drugs (antimetabolite) Bacterial resistance 1. producing altered forms of their target enzymes that are not inhibited by the antibiotics or 2. changes in permeability that prevent the accumulation of the antibiotics within bacteria. 3. Some strains overproduce PABA, Antimicrobial activity (static+static/cidal) 1. Trimethoprim-sulfamethoxazole has synergistic activity against some aerobic gram-positive and aerobic gram-negative bacteria. 2. Anaerobes and atypical bacteria tend to be resistant to trimethoprim- sulfamethoxazole. Uses:- It is commonly used to treat urinary tract infections and bacterial pharyngitis  Sulfa drugs (antimetabolite) Side effects (toxicity) 1. gastrointestinal effects 2. as well as fever, 3. rash, 4. leukopenia, thrombocytopenia, 5. hepatitis, 6. hyperkalemia. 76 77 78 79 PRESENTATION TITLE