Download Free Medical Antimicrobial Agents PowerPoint Presentation

Antimicrobial Agents PowerPoint Presentation

DOWNLOAD MEDICAL POWERPOINT PRESENTATION

About This Presentation

Description : Check out this medical titled "Antimicrobial Agents” by Prof. Khaled H. Abu-Elteen.

This medical is about antimicrobial agents, substances or drugs that are used to treat or prevent infections caused by microorganisms such as bacteria, viruses, fungi, and parasites. These agents work by either killing or inhibiting the growth of these microorganisms.

There are several classes of antimicrobial agents that work in different ways. Some of the most common classes of antimicrobial agents include Antibiotics, Antivirals, Antifungals and Antiparasitics.

While antimicrobial agents are essential for treating and preventing infectious diseases, their overuse and misuse can lead to the development of antimicrobial resistance. This occurs when microorganisms evolve to become resistant to the drugs that are designed to kill or inhibit their growth, making infections more difficult to treat and control. Therefore, it is important to use these agents judiciously and only when necessary.

Tags : Antimicrobial Agents, infections, microorganisms, bacteria, viruses, fungi, parasites, Antibiotics, Antivirals, Antifungals Antiparasitics, Infectious Disease, Infectious Disease

Published on : Jun 01, 2023 | Views : 1422 | Downloads : 3

Shareable Url :

Embed Code :

Comment

Transcript

Slide 1-

Antimicrobial Agents Prof. Khaled H. Abu-Elteen
Slide 2-

What is an Antibiotic? An antibiotic is a selective poison. It has been chosen so that it will kill the desired bacteria, but not the cells in your body. Each different type of antibiotic affects different bacteria in different ways. For example, an antibiotic might inhibit a bacteria's ability to turn glucose into energy, or the bacteria's ability to construct its cell wall. Therefore the bacteria dies instead of reproducing.
Slide 3-

Antibiotics Substances produced by various species of microorganisms: bacteria, fungi, actinomycetes- to suppress the growth of other microorganisms and to destroy them. Today the term antibiotics extends to include synthetic antibacterial agents: sulfonamides and quinolones.
Slide 4-

Where do antibiotics come from? Several species of fungi including Penicillium and Cephalosporium E.g. penicillin, cephalosporin Species of actinomycetes, Gram positive filamentous bacteria Many from species of Streptomyces Also from Bacillus, Gram positive spore formers A few from myxobacteria, Gram negative bacteria New sources explored: plants, herps, fish
Slide 5-

ppt slide no 5 content not found
Slide 6-

Selective toxicity The more distantly related the invader, the more targets available for the drug to hit The less likelihood of direct toxic effects. Prokaryotes biochemically least similar Fungi and Protozoa are eukaryotes, so more closely related to humans. Helminths (worms) also animals Viruses use our own cell machinery Cancer cells ARE our cells.
Slide 7-

ppt slide no 7 content not found
Slide 8-

History of Antimicrobial Therapy 1909 Paul Ehrlich Differential staining of tissue, bacteria Search for magic bullet that would attack bacterial structures, not ours. Developed salvarsan, used against syphilis.
Slide 9-

1929 Penicillin discovered by Alexander Fleming 1940 Florey and Chain mass produce penicillin for war time use, becomes available to the public. 1935 Sulfa drugs discovered 1944 Streptomycin discovered by Waksman from Streptomyces griseus
Slide 10-

Sir Alexander Fleming
Slide 11-

Fleming’s Petri Dish
Slide 12-

Historical distinctions Antibiotics: substances produced by organisms that have inhibitory effects on other organisms. Penicillin, streptomycin Synthetic drugs: produced in a lab. Salvarsan, sulfa drugs Nowadays, most antimicrobials are semi-synthetic Distinction between “antibiotics” and “synthetic drugs” slowly being abandoned.
Slide 13-

Selective toxicity means safer for host Antibiotics generally have a low MIC Minimum inhibitory concentration Effective at lower doses Good therapeutic index ( Ti) Safer; larger quantity must be administered before harmful side effects occur. e.g. Ti = LD50 / ED50 Where LD = lethal dose ED = effective dose
Slide 14-

Bacteriostatic vs. Bactericidal Antibiotics differ by mode of action Bacteriostatic compounds inhibit the growth of bacteria Holds invaders in check; host immune system does the killing Bactericidal compounds directly kill the bacteria Location and severity of infection affect choice of antibiotic E.g. CNS infection calls for bactericidal treatment.
Slide 15-

VI. Antibacterial Agents A. Inhibitors of cell wall synthesis 1. Penicillins 2. Cephalosporins 3. Other antibacterial agents that act on cell walls B. Disrupters of cell membranes 1. Polymyxins 2. Tyrocidins C. Inhibitors of protein synthesis 1. Aminoglycosides 2. Tetracyclines 3. Chloramphenicol 4. Other antibacterial agents that affect protein synthesis a. Macrolides b. Lincosamides D. Inhibitors of nucleic acid synthesis 1. Rifampin 2. Quinolones E. Antimetabolites and other antibacterial agents 1. Sulfonamides 2. Isoniazid 3. Ethambutol 4. Nitrofurans
Slide 16-

ppt slide no 16 content not found
Slide 17-

Antibiotic Mechanisms of Action Transcription Translation Translation Alteration of Cell Membrane Polymyxins Bacitracin Neomycin
Slide 18-

Review and Overview of Bacterial Targets Bacterial cell walls Except for Mycoplasma and relatives, all bacteria of the Domain Eubacteria possess peptidoglycan Peptidoglycan provides shape and structural support to bacterial cells Bacterial cytoplasm is generally hypertonic compared to their environment Net flow of water: into cell Wall under high osmotic pressure
Slide 19-

Cell walls continued Chemical structure of peptidoglycan contributes to its function Polysaccharide chains composed of 2 alternating sugars, N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM) Cross-linked in 3 dimensions with amino acid chains A breach in peptidoglycan endangers the bacterium
Slide 20-

Peptidoglycan Molecule Cross links are both horizontal and vertical between glycan chains stacked atop one another.
Slide 21-

There is no molecule similar to peptidoglycan in humans, making drugs that target cell wall synthesis very selective in their toxicity against bacteria.
Slide 22-

Gram positive & Gram Negative Gram positive bacteria have a thick cell wall Peptidoglycan directly accessible from environment Gram negative bacteria have a different wall Thin layer of peptidoglycan Surrounded by an outer membrane composed of lipopolysaccharide, phospholipids, and proteins Outer membrane is a barrier to diffusion of molecules including many antibiotics Some hydrophobic antibiotics may diffuse in. Porins allow passage of only some antibiotics
Slide 23-

Gram negative cell structure
Slide 24-

1-Inhibition of cell wall synthesis beta-lactam containing antibiotics inhibit transpeptidase; bacteria cannot synthesize reinforced cell wall and they lyse when they try to grow Vancomycin and cyclo-Ser inhibit specific binding of Ala’s in crossbridges to transpeptidase in many gram+ bacteria Bacitracin inhibits secretion of NAG and NAM subunits All of these only kill growing bacteria
Slide 25-

Cell wall synthesis inhibitors
Slide 26-

Penicillins Penicillins contain a b-lactam ring which inhibits the formation of peptidoglycan crosslinks in bacterial cell walls (especially in Gram-possitive organisms) Penicillins are bactericidal but can act only on dividing cells They are not toxic to animal cells which have no cell wall
Slide 27-

ppt slide no 27 content not found
Slide 28-

Synthesis of Penicillin b-Lactams produced by fungi, some ascomycetes, and several actinomycete bacteria b-Lactams are synthesized from amino acids valine and cysteine
Slide 29-

b Lactam Basic Structure
Slide 30-

Penicillins Clinical Pharmacokinetics Penicillins are poorly lipid soluble and do not cross the blood-brain barrier in appreciable concentrations unless it is inflamed (so they are effective in meningitis) They are actively excreted unchanged by the kidney, but the dose should be reduced in severe renal failure
Slide 31-

Penicillins Resistance This is the result of production of b-lactamase enzyme in the bacteria which destroys the b-lactam ring It occurs in e.g. Staphylococcus aureus, Haemophilus influenzae and Neisseria gonorrhoea
Slide 32-

Penicillins Examples There are now a wide variety of penicillins, which may be acid labile (i.e. broken down by the stomach acid and so inactive when given orally) or acid stable, or may be narrow or broad spectrum in action
Slide 33-

Penicillins Examples Benzylpenicillin (Penicillin G) is acid labile and b-lactamase sensitive and is given only parenterally It is the most potent penicillin but has a relatively narrow spectrum covering Strepptococcus pyogenes, S. pneumoniae, Neisseria meningitis or N. gonorrhoeae, treponemes, Listeria, Actinomycetes, Clostridia
Slide 34-

Penicillins Examples Phenoxymethylpenicillin (Penicillin V) is acid stable and is given orally for minor infections it is otherwise similar to benzylpenicillin
Slide 35-

Penicillins Examples Ampicillin is less active than benzylpenicillin against Gram-possitive bacteria but has a wider spectrum including (in addition in those above) Strept. faecalis, Haemophilus influenza, and some E. coli, Klebsiella and Proteus strains It is acid stable, is given orally or parenterally, but is b-laclamase sensitive
Slide 36-

Penicillins Examples Amoxycillin is similar but better absorbed orally It is sometimes combined with clavulanic acid, which is a b-lactam with little antibacterial effect but which binds strongly to b-lactamase and blocks the action of b-lactamase in this way It extends the spectrum of amoxycillin
Slide 37-

Penicillins Adverse effects Allergy : Patient should be always asked about a history of previous exposure and adverse effects Superinfections (e.g.caused by Candida ) Diarrhoea : especially with ampicillin, less common with amoxycillin Rare: haemolysis, nephritis
Slide 38-

Penicillins Drug interactions The use of ampicillin (or other broad-spectrum antibiotics) may decrease the effectiveness of oral conraceptives by diminishing enterohepatic circulation
Slide 39-

Cephalosporins They also owe their activity to b-lactam ring and are bactericidal. Produced from a fungus Cephalosporium acremonium. Good alternatives to penicillins when a broad -spectrum drug is required should not be used as first choice unless the organism is known to be sensitive
Slide 40-

Cephalosporins BACTERICIDAL- modify cell wall synthesis Interfere at the final step of peptidoglycan synthesis ( Transpeptidation) CLASSIFICATION- first generation are early compounds Second generation- resistant to β-lactamases Third generation- resistant to β-lactamases & increased spectrum of activity Fourth generation- increased spectrum of activity
Slide 41-

Cephalosporins FIRST GENERATION- eg cefadroxil, cefalexin, Cefadrine - most active vs gram +ve cocci. An alternative to penicillins for staph and strep infections; useful in UTIs SECOND GENERATION- eg cefaclor and cefuroxime. Active vs enerobacteriaceae eg E. coli, Klebsiella spp,proteus spp. May be active vs H influenzae and N meningtidis
Slide 42-

Cephalosporins THIRD GENERATION- eg cefixime and other I.V.s cefotaxime,ceftriaxone,ceftazidine. Very broad spectrum of activity inc gram -ve rods, less activity vs gram +ve organisms. FOURTH GENERATION- cefpirome better vs gram +ve than 3rd generation. Also better vs gram -ve esp enterobacteriaceae & pseudomonas aerugenosa. I.V. route only
Slide 43-

ppt slide no 43 content not found
Slide 44-

Cephalosporins Adverse effects Allergy (10-20% of patients with penicillin allergy are also allergic to cephalosporins) Nephritis and acute renal failure Thrombophlebitis Superinfections Gastrointestinal upsets when given orally
Slide 45-

Vancomycin This interferes with bacterial cell wall formation and is not absorbed after oral administration and must be given parenterally. It is excreted by the kidney. It is used i.v. to treat serious or resistant Staph. aureus infections and for prophylaxis of endocarditis in penicillin-allergic people.
Slide 46-

Vancomycin Adverse effects Its toxicity is similar to aminoglycoside and likewise monitoring of plasma concentrations is essential. Nephrotoxicity Allergy
Slide 47-

2- Inhibition of protein synthesis Aminoglycosides (bactericidal): streptomycin, kanamycin, gentamicin, tobramycin, amikacin, netilmicin, neomycin Macrolides Chloramphenicol, Lincomycin, Clindamycin (bacteriostatic)
Slide 48-

Protein synthesis inhibitors Need to affect bacteria, not mitochondria Aminoglycosides (streptomycin, gentamicin) change shape of 30S ribosome subunit Tetracycline blocks access to A site of 30S subunit Chloramphenicol block peptide bond formation from 50S subunit Macrolides (erythromycin) block 50S subunit action Antisense NAs bind to beginning of mRNA and block translation
Slide 49-

Protein synthesis inhibitors
Slide 50-

Ribosomes: site of protein synthesis Prokaryotic ribosomes are 70S; Large subunit: 50 S 33 polypeptides, 5S RNA, 23 S RNA Small subunit: 30 S 21 polypeptides, 16S RNA Eukaryotic are 80S Large subunit: 60 S 50 polypeptides, 5S, 5.8S, and 28S RNA Small subunit: 40S 33 polypeptides, 18S RNA
Slide 51-

Differences in structure between prokaryotic and eukaryotic ribosomes make antibiotics that target protein synthesis fairly selectively toxic against bacteria.
Slide 52-

Aminoglycosides (bactericidal)streptomycin, kanamycin, gentamicin, tobramycin, amikacin, netilmicin, neomycin (topical) Mode of action - The aminoglycosides irreversibly bind to the 16S ribosomal RNA and freeze the 30S initiation complex (30S-mRNA-tRNA) so that no further initiation can occur. They also slow down protein synthesis that has already initiated and induce misreading of the mRNA. By binding to the 16 S r-RNA the aminoglycosides increase the affinity of the A site for t-RNA regardless of the anticodon specificity. May also destabilize bacterial membranes. Spectrum of Activity -Many gram-negative and some gram-positive bacteria Resistance - Common Synergy - The aminoglycosides synergize with β-lactam antibiotics. The β-lactams inhibit cell wall synthesis and thereby increase the permeability of the aminoglycosides.
Slide 53-

AminoglycosidesClinical pharmacokinetics These are poorly lipid soluble and, therefore, not absorbed orally Parenteral administration is required for systemic effect. They do not enter the CNS even when the meninges are inflamed. They are not metabolized.
Slide 54-

Aminoglycosides Clinical pharmacokinetics They are excreted unchanged by the kidney (where high concentration may occur, perhaps causing toxic tubular demage) by glomerular filtration (no active secretion). Their clearance is markedly reduced in renal impairment and toxic concentrations are more likely.
Slide 55-

Aminoglycosides Resistance Resistance results from bacterial enzymes which break down aminoglycosides or to their decreased transport into the cells.
Slide 56-

Aminoglycosides Examples Gentamicin is the most commonly used, covering Gram-negative aerobes, e.g. Enteric organisms (E.coli, Klebsiella, S. faecalis, Pseudomonas and Proteus spp.) It is also used in antibiotic combination against Staphylococcus aureus. It is not active against aerobic Streptococci.
Slide 57-

Aminoglycosides Examples Tobramycin: used for pseudomonas and for some gentamicin-resistant organisms. Some aminoglycosides,e.g. Gentamicin, may also be applied topically for local effect, e.g. In ear and eye ointments. Neomycin is used orally for decontamination of GI tract.
Slide 58-

Aminoglycosides Adverse effects The main adverse effects are: Nephrotoxicity Toxic to the 8th cranial nerve (ototoxic), especially the vestibular division. Other adverse effects are not dose related, and are relatively rare, e.g. Allergies.
Slide 59-

Macrolides (bacteriostatic)erythromycin, clarithromycin, azithromycin, spiramycin Mode of action - The macrolides inhibit translocation by binding to 50 S ribosomal subunit Spectrum of activity - Gram-positive bacteria, Mycoplasma, Legionella (intracellular bacterias) Resistance - Common
Slide 60-

Macrolides Examples and clinical pharmacokinetics Erythromycin is acid labile but is given as an enterically coated tablet It is excreted unchanged in bile and is reabsorbed lower down the gastrointestinal tract. It may be given orally or parenterally
Slide 61-

Macrolides Examples and clinical pharmacokinetics Macrolides are widely distributed in the body except to the brain and cerebrospinal fluid The spectrum includes Staphylococcus aureus, Streptococcuss pyogenes, S. pneumoniae, Mycoplasma pneumoniae and Chlamydia infections.
Slide 62-

Macrolides – side effects Nauzea, vomitus Allergy Hepatitis, ototoxicity Interaction with cytochrome P450 3A4 (inhibition)
Slide 63-

Chloramphenicol, Lincomycin, Clindamycin (bacteriostatic) Mode of action - These antimicrobials bind to the 50S ribosome and inhibit peptidyl transferase activity. Spectrum of activity - Chloramphenicol - Broad range; Lincomycin and clindamycin - Restricted range Resistance - Common Adverse effects - Chloramphenicol is toxic (bone marrow suppression) but is used in the treatment of bacterial meningitis.
Slide 64-

Clindamycin Clindamycin, although chemically distinct, is similar to erythromycin in mode of action and spectrum. It is rapidly absorbed and penetrates most tissues well, except CNS. It is particularly useful systematically for S. aureus (e.g.osteomyelitis as it penetrates bone well) and anaerobic infections.
Slide 65-

ClindamycinAdverse effects Diarrhoea is common. Superinfection with a strain of Clostridium difficile which causes serious inflammation of the large bowel (Pseudomembranous colitis)
Slide 66-

Chloramphenicol This inhibits bacterial protein synthesis. It is well absorbed and widely distributed , including to the CNS. It is metabolized by glucoronidation in the liver. Although an effective broad-spectrum antibiotics, its uses are limited by its serious toxicity.
Slide 67-

Chloramphenicol The major indication is to treat bacterial meningitis caused by Haemophilus influenzae, or to Neisseria menigitidis or if organism is unknown.It is also specially used for Rikettsia (typhus).
Slide 68-

Chloramphenicol Adverse effects A rare anemia, probably immunological in origin but often fatal Reversible bone marrow depression caused by its effect on protein synthesis in humans Liver enzyme inhibition
Slide 69-

Tetracyclines (bacteriostatic)tetracycline, minocycline and doxycycline Mode of action - The tetracyclines reversibly bind to the 30S ribosome and inhibit binding of aminoacyl-t-RNA to the acceptor site on the 70S ribosome. Spectrum of activity - Broad spectrum; Useful against intracellular bacteria Resistance - Common Adverse effects - Destruction of normal intestinal flora resulting in increased secondary infections; staining and impairment of the structure of bone and teeth.
Slide 70-

ppt slide no 70 content not found
Slide 71-

Tetracyclines Examples and clinical pharmacokinetics Tetracycline, oxytetracycline have short half-lives. Doxycycline has a longer half-life and can be given once per day. These drugs are only portly absorbed. They bind avidly to heavy metal ions and so absorption is greatly reduced if taken with food, milk, antacids or iron tablets.
Slide 72-

Tetracyclines Examples and clinical pharmacokinetics They should be taken at least half an hour before food. Tetracyclines concentrate in bones and teeth. They are excreted mostly in urine, partly in bile. They are broad spectrum antibiotics, active against most bacteria except Proteus or Pseudomonas. Resistance is frequent
Slide 73-

Tetracyclines Adverse effects Gastrointestinal upsets Superinfection Discolouration and deformity in growing teeth and bones (contraindicated in pregnancy and in children < 12 years) Renal impairment (should be also avoided in renal disease)
Slide 74-

3- Metabolic inhibitors Sulfonamides (sulfanilamide) are structural analogs of PABA, a molecule crucial for Nucleic acid synthesis humans do not synthesize dihydropteroic acid from PABA Trimethoprim interferes in next step DHF -> THF
Slide 75-

Mechanism of Action ANTIMETABOLITE ACTION (cont’d) tetrahydrofolic acid
Slide 76-

Sulfonamides and trimethoprim Sulfonamides are rarely used alone today. Trimethoprim is not chemically related but is considered here because their modes of action are complementary.
Slide 77-

Sulfonamides, Sulfones (bacteriostatic) Mode of action - These antimicrobials are analogues of para-aminobenzoic acid and competitively inhibit formation of dihydropteroic acid. Spectrum of activity - Broad range activity against gram-positive and gram-negative bacteria; used primarily in urinary tract and Nocardia infections. Resistance - Common Combination therapy - The sulfonamides are used in combination with trimethoprim; this combination blocks two distinct steps in folic acid metabolism and prevents the emergence of resistant strains.
Slide 78-

Trimethoprim, Methotrexate, (bacteriostatic) Mode of action - These antimicrobials binds to dihydrofolate reductase and inhibit formation of tetrahydrofolic acid. Spectrum of activity - Broad range activity against gram-positive and gram-negative bacteria; used primarily in urinary tract and Nocardia infections. Resistance - Common Combination therapy - These antimicrobials are used in combination with the sulfonamides; this combination blocks two distinct steps in folic acid metabolism and prevents the emergence of resistant strains.
Slide 79-

ppt slide no 79 content not found
Slide 80-

Sulfonamides and trimethoprimMode of action Folate is metabolized by enzyme dihydrofolate reductase to the active tetrahydrofolic acid. Trimethoprim inhibits this enzyme in bacteria and to a lesser degree in animal s, as the animal enzyme is far less sensitive than that in bacteria.
Slide 81-

Sulfonamides and trimethoprimClinical pharmacokinetics It is the drug of choice for the treatment and prevention of pneumonia caused by Pneumocystis carinii in immunosupressed patients. Trimethoprim is increasingly used alone for urinary tract and upper respiratory tract infections, as it is less toxic than the combination and equally effective.
Slide 82-

Sulfonamides and trimethoprimAdverse effects Gastrointestinal upsets Less common but more serious: sulfonamides: allergy, rash, fever, renal toxicity trimethoprim: anemia, thrombocytopenia -cotrimoxazole: aplastic anemia
Slide 83-

4-Interference with nucleic acid synthesis Bacterial DNA is negatively supercoiled Supercoiling is maintained by gyrase, a type II topoisomerase. Inhibition of gyrase and type IV topoisomerase interferes with DNA replication, causes cell death Eukaryotic topoisomerases differ in structure
Slide 84-

Quinolones (bactericidal)nalidixic acid, ciprofloxacin, ofloxacin, norfloxacin, levofloxacin, lomefloxacin, sparfloxacin Mode of action - These antimicrobials bind to the A subunit of DNA gyrase (topoisomerase) and prevent supercoiling of DNA, thereby inhibiting DNA synthesis. Spectrum of activity - Gram-positive cocci and urinary tract infections Resistance - Common for nalidixic acid; developing for ciprofloxacin
Slide 85-

(cont’d) Mechanism of Action INHIBITION OF DNA/RNA SYNTHESIS
Slide 86-

Quinolones The quinolones are effective but expensive antibiotics. With increased use, resistance to these drugs is becoming more common.
Slide 87-

Quinolones Examples and clinical pharmacokinetics Nalidixic acid, the first quinolone, is used as a urinary antiseptic and for lower urinary tract infections, as it has no systemic antibacterial effect. Ciprofloxacin is a fluoroquinolone with a broad spectrum against Gram-negative bacilli and Pseudomonas,
Slide 88-

Quinolones Examples and clinical pharmacokinetics It can be given orally or i.v. to treat a wide range of infections, including respiratory and urinary tract infections as well as more serious infections, such Salmonella. Activity against anaerobic organism is poor and it should not be first choice for respiratory tract infections.
Slide 89-

Quinolones Adverse effects Gastrointestinal upsets Fluoroquinolones may block the inhibitory neurotransmitter, and this may cause confusion in the elderly and lower the fitting threshold. Allergy and anaphylaxis
Slide 90-

Quinolones Adverse effects Possibly damage to growing cartilage: not recommended for pregnant women and children
Slide 91-

Metronidazole Metronidazole binds to DNA and blocks replication. Pharmacokinetics It is well absorbed after oral or rectal administration and can be also given i.v. It is widely distributed in the body (including into abscess cavities) It is metabolized by the liver.
Slide 92-

Metronidazole Uses Metronidazole is active against anaerobic organisms (e.g. Bacteroides, Clostridia), which are encountered particularly in abdominal surgery. It is also used against Trichomonas, Giardia and Entamoeba infections.
Slide 93-

Metronidazole Uses Increasingly, it is used as part of treatment of Helicobacter pyloris infestion of the stomach and duodenum associated with peptic ulcer disease. It is used also to treat a variety of dental infections, particularly dental abscess.
Slide 94-

Metronidazole Adverse effects Nausea, anorexia and metallic taste Ataxia In patients, who drink alcohol, may occur unpleasant reactions. They should be advised not to drink alcohol during a treatment.
Slide 95-

Nitrofurantoin This is used as a urinary antiseptic and to treat Gram-negative infections in the lower urinary tract. It is also used against Trypanosoma infections. It is taken orally and is well absorbed and is excreted unchanged in the urine.
Slide 96-

Nitrofurantoin Adverse effects Gastrointestinal upsets Allergy Polyneuritis
Slide 97-

Fucidin Fucidin is active only against Staphylococcus aureus (by inhibiting bacterial protein synthesis) and is not affected b-lactamase. It is usually only used with flucloxacillin to reduce the development of resistance. It is well absorbed and widely distributed, including to bone It can be given orally or parenterally. It is metabolized in the liver.
Slide 98-

Antibiotics for leprosy Leprosy is caused by infection with Mycobacteria leprae. A mixture of drugs are used to treat leprosy, depending on the type and severity of the infection and the local resistance patterns.
Slide 99-

Antibiotics for leprosy Rifampicin is used, which is related to the sulphoamides. Rifampicin and Rifamycin block synthesis of m-RNA. Its adverse effects include haemolysis, gastrointestinal upsets and rashes.
Slide 100-

5- Cell membranes as targets Bacterial cell membranes are essentially the same in structure as those of eukaryotes Antibiotics also affect Gram neg. cell walls, ie. Outer membrane together with cell membrane Anti-membrane drugs are less selectively toxic than other antibiotics. Many antifungal drugs ( Polyenes as Amphotericin B, Nystatin) make use of cell membrane differences.
Slide 101-

Cell membrane disruptors Amphotericin B binds to ergosterol of cell membranes of fungi, causing lysis of cell Azoles (fluconazole) and allyamines (turbinafine) block ergosterol synthesis Polymixin disrupts bacterial cell membranes, but is toxic to people
Slide 102-

Antibiotic resistance Inherent: Outer membrane of Gram negative bacteria, wall-less bacteria. Mutations: change in transport protein, ribosome, enzyme, etc. Normally harmful mutations are selected FOR in the presence of antibiotic. Plasmids: through conjugation, genetic information allowing cell to overcome drug.
Slide 103-

Mechanisms of drug resistance Alteration of target: active site of enzyme changes, ribosome changes. Alteration of membrane permeability: transport protein changes, drug no longer enters; drug that does enter is actively pumped out. Enzymatic destruction of drug: penicillinases (beta lactamases) “End around” inhibitor: bacteria learns to use new metabolic pathway, drug no longer effective.
Slide 104-

Drug resistance Beta- lactamase is now wide-spread and often is found on plasmids New synthetic versions of penicillin have been developed that are not cleaved by beta-lactamase Other resistances develop
Slide 105-

Spectrum of action of antimicrobials
Slide 106-

Spectrum When specific testing is not done or delayed, antibiotic with a broad spectrum is administered Broad spectrum antibiotics can penetrate Gram – outer membranes, resist inactivation, etc. Shotgun: better chance of inhibiting pathogen Death of normal microbiota results in overgrowth of resistant bacteria (endogenous infection; “superinfection”) or allows invasion by outside opportunists.
Slide 107-

Drug administration Antibiotics administered oral, i.v., i.m.,i.p Same caveats apply, i.e. acid instability, delayed absorption with food for oral i.v. gives higher, quicker concentrations, reaches more compartments with sufficient dose quickly
Slide 108-

Combination therapy Some valuable reasons why combination therapy is used Synergistic effects between two drugs Polymicrobial infections, e.g. abdominal injuries Avoid Antagonistic effects.
Slide 109-

Chemotherapy for viruses
Slide 110-

Antifungal Agents A. Imidazoles and triazoles B. Polyenes 1. Amphotericin B 2. Nystatin C. Griseofulvin D. Other antifungal agents 1. Flucytosine 2. Tolnaftate 3. Terbinafine Antiviral Agents A. Purine and pyrimidine analogues 1. Idoxuridine and trifluridine 2. Vidarabine 3. Ribavirin 4. Acyclovir 5. Ganciclovir 6. Zidovudine B. Amantadine C. Treatment of AIDS
Slide 111-

ppt slide no 111 content not found
Slide 112-

ppt slide no 112 content not found
Slide 113-

Antiviral drugs Antiviral chemotherapy is still in its infancy. Viruses are more difficult ‘targets’ than bacteria: they are most vulnerable during reproduction, but all use host cell organelles and enzymes to do this, so that antiviral compounds are often as toxic to host cells as to virus.
Slide 114-

Antiviral drugs (cont.) Current antiviral drugs are thought to work in one of the following ways: 1- inhibition of viral ‘uncoating’ shortly after penetration into the cell; they are best for prophylaxis or very early in the disease course (e.g.amantadine) 2- interference with viral RNA synthesis and function (e.g. ribavirin)
Slide 115-

Antiviral drugs (cont.) 3- interference with DNA synthesis (e.g. cytarabine and Vidarabine) 4- inhibition of viral DNA polymerase (e.g.acyclovir, Penciclovir and gancyclovir) 5- inhibition of reverse transcriptase at retroviruses such as HIV (e.g.zidovudine, Azidothymidine(AZT))
Slide 116-

AcyclovirMode of action It is active against Herpes simplex and Herpes zoster. Acyclovir targets virus-infected cells quite specifically, and inhibit viral replication and this explains the drug`s relatively low toxicity.
Slide 117-

Acyclovir (cont.)Therapeutic uses It is the drug of first choice for Herpes simplex and zoster infections, because of the great efficacy and lower toxicity than the alternatives. The drug has little activity against cytomegalovirus or Epstein-Barr virus.
Slide 118-

Acyclovir (cont.)Therapeutic uses Herpes simplex infections of skin, mucous membranes and cornea Life-threatening Herpes simplex infections; acyclovir i.v. reduces mortality Herpes zoster that is less sensitive to acyclovir than H. simplex .It is used for early topic or oral treatment of zoster.
Slide 119-

Zidovudine (AZT)Mode of action HIV virus is an RNA virus capable of including the synthesis of a DNA transcript of its genome, which can then become integrated into the host cell`s DNA, thereby allowing viral replication. Synthesis of the initial DNA transcript involves the enzyme reverse transcriptase. Zidovudine is a potent inhibitor of reverse transcriptase.
Slide 120-

Purine and pyrimidine analoguesMode of action These drugs are effective against DNA viruses The compounds structurally resemble purine and pyrimidine nucleosides The resulting DNA molecule is more easily fragmented, leading to transcription errors. They also inhibit viral DNA polymerase.
Slide 121-

Purine and pyrimidine analoguesExamples and clinical pharmacokinetics Idoxuridine: it is not absorbed from the gut, and is used topically Vidarabine: cannot be given orally because it is metabolized in the gut - it is usually given i.v. or topically
Slide 122-

Purine and pyrimidine analoguesTherapeutic uses Idoxuridine: may be used topically for Herpes simplex and zoster but is too toxic for systemic use and has largely been supplanted by aciclovir Vidarabine: may be used for life-threatening systemic Herpes infections
Slide 123-

Zone of Inhibition 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
Slide 124-

Susceptibility vs. Resistanceof microorganisms to Antimicrobial Agents Success of therapeutic outcome depends on: Achieving concentration of ATB at the site of infection that is sufficient to inhibit bacterial growth. Host defenses impaired- bactericidal agents Complete ATB-mediated killing is necessary
Slide 125-

Susceptibility vs. Resistance(cont.) Dose of drug has to be sufficient to produce effect inhibit or kill the microorganism: However concentration of the drug must remain below those that are toxic to human cells – If can be achieved – microorganism susceptible to the ATB If effective concentration is higher than toxic- microorganism is resistant
Slide 126-

Susceptibility Tests 1. Broth dilution - MIC test 2. Agar dilution - MIC test
Slide 127-

32 ug/ml 16 ug/ml 8 ug/ml 4 ug/ml 2 ug/ml 1 ug/ml Sub-culture to agar medium MIC = 8 ug/ml MBC = 16 ug/ml Minimal Inhibitory Concentration (MIC) vs. Minimal Bactericidal Concentration (MBC)
Slide 128-

Susceptibility Tests Agar diffusion  Kirby-Bauer Disk Diffusion Test (cont’d)
Slide 129-

Susceptibility Tests “Kirby-Bauer Disk-plate test” Diffusion depends upon: Concentration Molecular weight Water solubility pH and ionization Binding to agar (cont’d)
Slide 130-

Susceptibility Tests “Kirby-Bauer Disk-plate test” Zones of Inhibition (~ antimicrobial activity) depend upon: pH of environment Media components Agar depth, nutrients Stability of drug Size of inoculum Length of incubation Metabolic activity of organisms (cont’d)
Slide 131-

ppt slide no 131 content not found
Slide 132-

Antibiotic Susceptibility Testing 8 4 0 2 1 Tetracycline (μg/ml) MIC = 2 μg/ml Determination of MIC Chl Amp Ery Str Tet Disk Diffusion Test
Slide 133-

Resistance (cont.) Bacteria produce enzymes at or within the cell surface –inactivate drug Bacteria possess impermeable cell membrane prevent influx of drug. Transport mechanism for certain drug is energy dependent- not effective in anaerobic environment. ATB as organic acids penetration is pH –dependent.