Treatment and Prevention of Bacterial Disease: Antimicrobial Agents Flashcards
Antimicrobial Agents
Chemicals used to prevent or treat diseases caused by infectious agents.
act by interfering with the growth of the microorganisms.
Needs to exhibit selective toxicity, because its actions are taken within the host.
Alexander Fleming
In 1928, observed the growth of S. aureus on an agar plate was inhibited in the area surrounding a fungal colony.
Mold was identified as Penicillium crysogenum
Antibiotic
chemical substance produced by a microorganism that interferes with some functions of structure or process essential to microbial growth (Bacteriosatic) or survival (Bacteriocidal)
Antimicrobial Agent
chemical substance derived from a microorganism or produced by chemical synthesis that inhibits the growth or kills microorganisms.
Antimicrobial Agents uses
- Therapy
- Prophylaxis
- Metaphylaxis
- Growth Promotion
- Therapy
Treatment of infectious diseases
- Prophylaxis
Treatment of healthy animal to prevent the onset of disease
- Metaphylaxis
Treatment of clinically healthy animals in the same flock or herd that has one or a few animals showing clincal signs
- Growth Promotion
Inclusion of antibiotics int he feed to promote growth. Antibiotics approved for use include ionophore antibiotics, have no theraputic applications in humans, hence considered not medically important.
Classification of Antibiotics
- Class of microorganism
- Chemistry and structure
- Antibacterial spectrum of activity
- Mechanism of inhibory action.
- Class of Microorganisms
Antimicrobial agents are classified into: Antibacterial, Antifungal, and Antiviral agents based on the class of microorganism affected.
Antifungal and Antiviral are active only against fungi and viruses.
However, some imidazole antifungal agents ahve activity against some bacteria.
- Based on Chemistry and Structure
Most useful for establishing chemical structure-antibiotic activity relationships.
- Natural, Semisynthetic, Synthetic
- Can have generations
-
Better antibiotics:
- higher efficacy, broad spectrum, long acting, less resistance
4.
- higher efficacy, broad spectrum, long acting, less resistance
Beta-lactams
Have a four-membered cyclic amide ring, called beta-lactam.
Penicillins, cephalosporins, carbapenems, and monobactams.
Aminoglycosides
Contain a two or more amino monosaccharides connected by glycosidic linkages.
Amikacin, gentamicin, kenamycin, neomysin, streptomycin, tobramycin.
Macrolides
Macrocyclic lactones to which two sugars are attached.
Macrolide antibiotics are grouped according to the size of the macrocyclic lactone rings, can be 14, 15, or 16 membered.
- 14-membered macrolide:
- erythromycin
- 15-membered macrolide:
- azithromycin
- Subgroup called azalides
Phenicols
Contain a p-nitrobenzene with dichloroacetamide group attached.
Include Chloramphenicol and its synthetic analog Florfenicol
Quiolones and Fluoroquinolones
Completely Synthetic molecules.
Nalidix acid was the first antibiotic synthesized, as a byproduct of the purification of the antimalarial drug chloroquine.
Addition of Fluorine to the quinolone ring created Fluoroquinolones.
Sulfonamides
Synthetic
Called sulfa drugs
derived from sulfanilamide
Diaminopyrimidines
Synthetic
Trimethoprim is the most important antibiotic of this group.
Derivative of diaminopyrimidine
Mitromidazoles
Synthetic
Consist of a nitro group joined to a heterocyclic ring
Metronidazole
Orthosomycins
Chemically they are oligosaccharides with the presence of one or more orthodiester bonds, which are unusual bonds in nature
Avilamycin
Nitrofurans
Class of Synthetic compounds characterized by the presence fo a 5-nitro-2-furanotyl group
Furazolidine
Narrow Spectrum Antibiotics
Antibiotics that affect Gram Positive bacteria or that Mainly affect Gram Negative bacteria.
Broad Spectrum Antibiotics
Antibiotics that affect a broad range of Gram Positive and Gram Negative bacteria
Know the Image
Bactericidal
Antibioticcs kill the bacteria
Bacteriostatic
Antibiotics prevent the growth of the bacteria.
Minimum inhibitory concenttation (MIC)
Antimicrobial agents exert their actions:
- Inhibition of bacterial cell wall synthesis
- Inhibition of protein synthesis
- Disruption of the cell membrane
- Inhibition of Nucleic acid syntesis
- Acting as Antimetabolites
Antimicrobial Resistance (AMR)
No antibiotic inhibits all microorganisms and some are naturally resistant.
Antimicrobial drug resistance is the acquired ability of a microorganism to resist the effects of an antimicrobial is a function of the microorganism and does not involve the host and is a function or the microorganisms taht reside in the host.
Four Mechanisms for AMR
- Modify the target in the cell so that it no longer binds the antibiotic
- Destroy or inactivate teh antibiotic before it gets intot he cell
- Develop resistant biochemical pathway
- Pump the antibiotic out of the cell using specific and nonspecific transport proteins.
AMR 1. Modify the target in the cell so that it no longer binds the antibiotic
Transpepetidase - makes peptide bridge in peptidoglycan
Changes in penicillin-binding proteins can confer resistance to penicillin.
Changes in ribosomal proteins can confer resistance to streptomycin,
Changes are due to mutations, which occur spontaneously.
AMR 2. Destroy or Inactivate the antibiotic before it gets into the cell
Enzymes that modify the antibiotic to make it inactive.
Penicillinase (beta-lactamase) destroys penicillins.
AMR 3. Develop Resistant Biochemical Pathways
Sulfur Drug Specific
Sulfonamide inhibit the production of folic acid synthesis.
Some bacteria become resistant by modifying thier metabolism to take up preformed folic acid.
AMR 4. Pump the antiobtic of the the cell using specific and nonspecific transport proteins
These pumps present in the cytoplasmic membrane of Gram Negative and Gram Positive Bacterai are called Efflux Pumps.
The pump removes the abtibiotic faster than it can enter the cell.
Some are Single-component pumps and others are Multicomponent pumps.
Multicomponent Pumps are only present in Gram Negative Bacterai.
Transfer of Antibiotic Resistance
Genetic transfer of antibacterial resistance is of major signigicance becuase transfer often involves multiple antibiotics fenetic material.
Mechanism of resistance mediated by plasmids
Resistancce Genes located on plasmids are called R Plasmids.
R plasmid resistance is usually due to genes on the plasmid encoding new enzymes that inactivate the antibiotic, genes taht encode enzymes that either prevent antibiotic uptake or actively pump it out.
Mechanisms of resistance by transposons
Transposons are short sequences of DNA taht freely jump from plasmid to plasmid and from plasmid to chromosomes.
Called Jumping Genes
Transposon does not remain at the original site.
The frequency of transposition is characteristic of the transposon and the bacterial strain.
Integrons
These are a class of mobile genetic element often carried on plasmids and are different from transposons and insertion sequiences.
Do NOT have inverted repeats.
Associated with antibiotic resistance and other changes in bacteria.
- Inhibition of Cell Wall Synthesis
The following antibiotics inhibit cell wall synthesis.
Penicillins, Cephalosporins, Carbapenems, Glycopeptides (Vancomycin), and Bacitracin
Beta-Lactam Antibiotics
Penicillins, Cephalosporins, Carbapenems
share a characteristic structural component, the beta-lactam ring.
Rupture of the ring results in the loss of antibacterial activity.
Mainly active against Gram Positive bacteria becuase the antibiotics do not penetrate teh outer memebrane of Gram Negative bacteria.
Cell wall systhesis is prevented becuase the cross-linking between glycan molecules is inhibited.
Penicillins
Include 50 chemically related antibiotics, which are different by the chemical side chain attached to the beta-lactam ring.
Pen G was the first antibiotic discovered. Othere forms are Pen V, Procaine Penicillin, etc.
The long acting penicillins delay the absorption form the injection site, which reduces the need for frequent dosing.
Inhibit the cross-linking between glycan molecules in the peptidoglycan by binding to transpeptidase.
Cephalosporins
Contain the Beta-lactam ring with an additional 6-membered dihydrothiazine ring, which makes the structure inherently resistant to Beta-lactamases.
Have the same mode of action as Penicillin (inhibit cross linking of glycan protion of the peptidoglycan)
Classified in the order of their introduction since 1975 and are described soemwhat arbitrarily as ‘generations’ with later generataions exhibiting broad spectrum activity.
Discovered before 1975 spelled with a ceph, and the later ones are spelled wiht a cef.
- First Gen:
- primarily against Gram Positive
- Second Gen:
- Against both Gram Positive and Gram negative
- Third Gen:
- Decreased Gram Positive, and increased Gram Negative activity
- Fourth Gen:
- Increased Gram Positive and Gram Negative antibacterial activities
Ceftiofur
Third Generation Cephalosporin with activity agianst Gram Positive and Gram Negative bacteria that is widely used to treat respiratory infections of cattle, swine, and horses and urinary tract infections in dogs and cats.
Resistance to Cephalosporins
There are three basic mechanisms of resistance to cephalosporins:
- Modification of penicillin binding proteins
- Reduced permeability and increased efflux
- Enzymatic inactivation by beta-lactamases
Of these the most important is beta-lactamase production and as many as 400 distinct beta-lactamases have been described.
Extended-spectrum Beta-lactamase (ESBL) that confers resistance to third generation cephalosporins is of public health concern.
Carbapenems
Beta-lactam antibiotic.
Differ from penicillins by the substitution of a CH2 group for the sulfur in the 5-membered ring attached to the Beta-lactam ring.
Broad spectrum activity against both Gram positive and Gram negative bacteria, and are widely used in human medicine to treat multi-drug resistant Gram negative bacterial infections or mixed aerobic and anaerobic infections.
NO veterinary-labeled carbapenems
Two used off label for veterianry medicine are Imipenam and Meropenam. Used for the treatment of cephalosporin-resistant enteric bacteria.
Beta-Lactamase Inhibitors
Clavulanic Acid and Sulbactum
Another approach to combat Beta-lactamase induced resistance is to combine penicillins with potassium clavulanate or sulbactam.
Do not have antimicrobial activity by themselves or may have some weak activity.
Irreversible binding of the inhibitors of Beta-lactamases allows Beta-lactam antibiotics to exert antimicrobial activities.
Beta-Lactamases Inhibitor: Clavulanic Acid
synthetic compound and is combined with amoxicillin in the ratio of 4:1 in veterinary formulations.
Spectrum of activity similar to that of a first and second generation cephalosporins.
Beta-Lactamases Inhibitors: Sulbactum
Synthetic derivative of 6-aminopenicillinic acid and is comined with ampicillin
Bacitracin
Polypeptide antibiotic effective primarily against Gram Positive Bacteria
Inhibits cell wall synthesis at a different stage than penicillins or cephalosporins.
Interferes with synthesis of linear strands of peptidoglycan.
Restricted for topical application because of nephrotoxicity when administered parenterally.
Used orally in the prevention and treatment of necrotic enteritis caused by Clostridium perfringens in swine and chickens.
Vancomycin
Glycopeptide that also inhibits cell wall synthesis
Inhibition is agian due to blocking of the cross links, but the antibiotic binds to the peptide precursor and not the transpeptidase enzyme.
Antibiotic not approved for use in animals, but is used extra label in dogs, cats, and horses.
In humans, the antibiotic is used to treat MRSA infections.
Vancomycin Resistant Enterocci (VRE)
which are of serious human health concern as a nosocomial infection.
- Inhibition of Protien Synthesis
Many types of antibiotics inhibit protein synthesis by interacting with the ribosome.
Most antibiotics that inhibit protein synthesis have broad spectrum activity.
Exception is certian macrolides which are effective primarily agianst Gram Positive Bacteria
Aminoglycosides and Aminocyclitols
Irreveribly bind the 30S ribosomal subunit, and change the shape.
Distorted shape blocks initiation of translation and causes misreading of mRNA by the ribosomes, thus interrupting protein synthesis.
Macrolides
Reversibly bind to the 50S ribosomal subunit and inhibit transpeptidation and translocation process, causing premature detachment of incomplete polypeptide chains
Tetracyclines
Reversibly bind to the 30S ribosomal subunit, blocking the attachment of tRNA to the RNA-ribosome complex and prevents the addition of amino acids to the elongating peptide chain.
Phenicols
Chloramphenicol
Bind to the 50
Linocosamide
Bind to the 50S ribosomal subunit, and inhibit peptidyl transferase.
Aminoglycosides
Used to treat infections caused by aerobic Gram negative bacteria, and some Gram positive bacteria like staphylococci.
Bactericidal effect is markedly influenced by pH, being most active at alkaline pH. Another factor affecting activity is the presence of purulent debris, which binds to aminoglycosides and inactivates them.
Surgical debridement and or drainage increases efficacy of the aminoglycosides.
Contain Hexose nucleus to which amino sugars are linked by glycosidic bonds.
Actively transported into bacterial cells by a process that requires oxygen.
Aminocyclitols
Differ from aminoglycosides in that aminocyclitols lack an amino sugar and a glycosidic bond.
Spectinomycin is the only aminocylitol used in veterinary medicine. Bacteriostatic.
Active against a broad range of pathogens and is used for the treatment of neonatal E.coli infections in pigs and avian salmonellosis.
Macrolides
Group of antibiotics named because they contain 13 to 16-member macrocyclic lactone ring connected to two or more sugar molecules.
Produced by Streptomyces sp.
Macrolides: Tylosin
Isolated from Streptomyces fradiae.
structure is similar to erythromycin, with similar antibacterial spectrum and is more active against Mycoplasma.
In pigs it is used as a growth promoter in the feed. Its used in the prevention and treatment of swine dysentery and mycoplasmal infections is being replaced by tiamulin.
In cattle it is used to treat pneumonia, foot rot, metritis, pink eye, and mastitis caused by Gram Positive cocci.
In feedlot cattle fed high-grain diets, tylosin is used very commonly in this country for prevention of liver abcesses.
Tilmicosin
Semisynthetic Macrolide, derived from Tylosin.
Effective against Gram Negative respiratory pathogens.
Long-acting formulation for use in bovine respiratory use
*TOXIC TO HUMANS* causes cardiovascular toxicity
In swine, it is used ONLY orally in the feed and in water, in the control of pneumonia.
Macrolides: Azithromycin
Not approved for use in animals, but used extra label in dogs, catc, horses
Macrolides: Tulathromycin
Semisenthetic macrolide
Approved to treat or prevent bovine and swine respiratory diseases.
Macrolides: Gamithromycin
15-membered ring, called azalides, approved for the treatment and control of bovine respiratory diseases
Macrolides: Tildipirosin
Semisynthetic 16-membered macrolide derived form naturally occurring tylosin
Approved for the control of respiratory diseases in cattle
Macrolides: Tylvalosin
Semisynthetic marcolide with a broad spectrum activity
Reaches high concentrations in the cell
Approved in 2012 for the control of swine proliferative enteritis caused by intracellular bacterial pathogen.
Treatment and prevention of pneumonia in swine, swine proliferative enteritis, and mycoplasmosis in poultry.
Tetracyclines
Were the first broad spectrum antibiotic to be discovered and are widerly used in human and animals.
Naphthacene ring structure and they are used as hydrochlorides.
Bacteriostatic antibiotics
First Gen:
- Chlortetracycline,
- Oxytetracycline
- Tetracycline
Second Gen:
- Doxycycline
- Minocycline
Third Gen:
- Glycylcyclines
- Aminomethylcyclines
- Flurocyclines
Phenicols: Chloramphenicol
Broad spectrum bacteriostatic antibiotic with activity against Gram Positive, Gram negative, mycoplasmas, Chlamydia, RIchettsia.
Potent inhibitor of protein sysnthesis by binding irreversibly to a receptor site on teh 50s subunit of the bacterial ribosome and interferes with the formation of peptides by blocking the action of peptidyl transferase.
Has serious toxicity effects and causes aplastic anemia and neutropenia in humans
Phenicols: Florfenicol
Synthetic analog of chloramphenicol.
Broad spectrum activity and mechanism of action are similar to that of chloramphenicol.
Does not cause aplastic anemia
Pleuromutilins
Used exclusively in animals, mainly swine.
Inhibitory activity against Gram positive bacteria, with moderate activity against Gram negative anaerobic bacteria and mycoplasma.
Binding to the 50S ribosomal subunit.
Tiamulin
Semisynthetic antibiotic derived form pleuromutilin, a diterpine class of antibiotic.
The antibiotic inhibits protein synthesis by binding to the 50S ribosome.
Bacteriostatic and its spectrum activity is similar to macrolides, but also is effective against Gram negative anaerobes and Mycoplasma.
Lincosamides
Lincomycin, Clindamycin, Pirilmycin.
Bacteriostatic and interfere with protein synthesis by binding 50S ribosome.
Gram negative bacteria are resistant because of impermeanle outer membrane.
Lincosamides: Lincomycin
Approved for use in swine and poultry.
Lincosamides: Clindamycin
Semisynthetic derivative of lincomycin and is used primarilly in small animals to treat anearobic infections caused by Gram negative bacteria or soft tissue infections caused by S. aureus.
Lincosamides: Pirlimycin
Exclusive animal drug and has activity against Gram Positive bacteria.
Used as an intramammary infusion to treat mastitis.
Orthosomycins
Group includes Avilamycin
Mode of action is to inhibit binding to aminoacyl-tTRNA to the 30s ribosome subunit and thereby inhibit protein synthesis.
Primary antibacterial activity is against Gram Positive bacteria.
It is effective for the treatment of enteritis caused pathogenic E. coli becuase it prevents attachment of E. coli.
Used in feed.
Streptogramins
Mixture of two structurally unrelated molecules: Macrolactones and Cyclic hexadepsieptides.
Effective against Gram Positive bacteria
Streptogramins: Viriginiamycin
Used for growth promotional benefits and as a therapeutic agaen in poultry and swine for a few decades.
Once approved as a feed additive for feedlot cattle for growth promotion and prevention of liver abscesses.
No longer used in the US.
Streptogramins: Synercid
Used in treatment of Life-Threatening infections caused by glycopepetide resistant Enterococcus faecium and other multi drug resistant Gram Positive bacterial pathogens.
Bacteria that become resistant to Strptogramins also exhibit cross-resistance to macrolides and lincosamides
- Disruption of the Cytoplasmic Membrane
Polymyxins
Cyclic decapeptides, contain a 7-amino acid ring attached to a 3-amino acid tail, to which a fatty acyl group is attached.
Have detergent like action, hence react with phospholipids of cell membranes and disrupt their integrity.
Effective against Gram negative bacteria
Used only in topical applications because of systemic toxicity
They are not absorbed form the gastrointestinal tract.
At low dose, binds to endotoxin, hence used in equine colic.
- Disruption of the Cytoplasmic Membrane
Colistin
Mode of action of colistin is not fully elucidated, but involves binding to lipopolysaccharides and phospholipids in the outer membrane of Gram negative organisms, which result in membrane disruption and cell death.
Active against a wide variety of Gram Negative bacteria and is not active against Gram positive bacteria, which lack an outer memebrane
Used in both human and in animals in some countries (Not in the US)
Humans only in the US
- The inhibition of Nucleic Acids
Rifamycins
Structurally related to macrolides and inhibits the synthesis of mRNA
Bacteriacidal, generally effective against Gram positive bacteria
Rifampin
Has the ability to penetrate tissues and reach theraputic levels even in encapsulated abcess.
Resistance develops rapidly and hence not often used alone
In animals, used in combination with a macrolide to treat pneumonia in horses and potomac horse fever.
- Inhibition of Nucleic Acids
Novobiocin
Inhibits DNA gyrase, an enzyme involved in supercoiling of DNA
Bacteriostatic and is effective against S. aureus
Most Gram Negative bacteria are resistant.
- Inhibition of Nucleic Acids:
Quinolones and Fluoroquinolones
Totally synthetic antimicrobial compounds.
Nalidixic Acid in 1962, which only had a limited clinical use because of narrow spectrum of activity. poor pharmacokinetic properties, and toxicity
The addition of Fluoride to the quinolone yielded a new calss of antibiotics
Fluoroquinolones have a broader antimicrobial spectrum and improved pharmacokinetic properties.
Enrofloxacin
Was the first Fluroquinolone marketed exclusively for animal use.
Treating Gastrointestinal, soft tissue, and respiratory infections, including bovine respiratory disease complex.
Approved for use to control E. coli infections and chickens and E.coli and P. multocida infections in turkeys. Approval was removed in 2005 because of human food safety concerns associatied with the Selection of ciprofloxacin resistant
- Inhibition of Nucleic Acids:
Nitroimidazoles
Mechanism of action is that after the entry into the cell, the nitro group is reduced to produce a variety of unstable intermediates, and many of them are antimicrobial.
Bacterial or protozoal DNA causing breakage in DNA strands and inhibiting DNA synthesis
The reduction occurs under anaerobic conditions, which is why they have excellent activity against anaerobes and protozoa.
Are not used in food animals because of potential carcinogenicity.
- Inhibition of Nucleic Acid:
Quinoxalene Derivatives
Carbadox: used for growth promotion and prevent swine dysentery, swine proliferative enteritis, and swine enteritis caused by Salmonella and Clostridium
Inhibits bacterial DNA synthesis and denatures preexisting DNA
More active under anaerobic than aerobic conditions
- Inhibition of Nucleic Acid:
Nitrofurans
Break bacterial DNA strands caused by the reduced prducts of nitrofurans
- Acts as Antimetabolites
Sulfonamides or Sulfa Drugs
First synthetic antimicrobial agents used to treat bacterial infections
Mammalian cells do not synthesize folic acid, but bacteria synthesize their own folic acid. Therefore, sulfa drugs are effective only against bacterial cells.
Broad spectrum of activity and are bacteriostatic, but in combination with diaminopyramidines they beocme bacteriacidal
- Acts of Antimetabolites:
Diaminopyrimidines
Interfere with folic acid synthesis by inhibiting dihydrofolate reductase
Some have marked specificity for bacterial dihydrofolare reductases, which convert dihydrofolate to tetrahydrofloate and others for protozoal enzymes.
Broad spectrum activity against Gram positive and Gram negative bacteria
They are used only in combination with Sulfonamides
Miscellaneous Antimicrobials
Isoniazid
They hydrazide of isonicotinic acid with a narrow spectrum of activity.
Vitamin analog and the most effective antimicrobial agent against tuberculosis
Effective only against Mycobacterium tuberculosis, becuase it inhibits synthesis of myolic acid a cell wall component.
Always used in combination with other antimicrobials because resistance development.
Miscellaneous Antimicrobials
Ionophore Antibiotics
Ionophore Antibiotics are products of Streptomyces are used for prwth promotion and for anticoccidial activity.
Narrow spectrum activity against Gram Positive Bacteria
No therapeutic activity agianst bacterial infections.
No human use
Miscellaneous Antimicrobials
Bambermycins
Flavomycin
Semisynthetic antibiotic produced by Streptomyces spp.
Primarily active against Gram Positive Bacteria and the mechanism of action is by inhibiting peptidoglycan synthesis
Used in feedlot cattle, swine, chickens, and turkeys for increased weight gain in imporoved feed efficiency
Combinations of Antibiotics
Antibacterial combination is additive or indifferent if the combined effects of the antibiotics equal the sum of their independent activities measured separately.
The efficacy of two antibiotics give simultaneously is sometimes greater than the effect of either given alone. Synergism
Indications for the use of antimicrobial combinations
- Treatment of polymicrobial infections
- Bactericidal combinations are effective in serious infections where host defenses are impaired
- Enzymatic destruction of drug may be overcome by using a combination
- Combination may decrease drug toxicity and provide broad spectrum activity in severe but undefined infections.
Metaphylactic Use of Antibiotics
Antibiotics are administered prophylactically to preempt outbreak or spread of infectious diseases in a herd.
Generally, the dosage used is same as therapeutically
Disadvantage is emergence of drug resistance, residues in meat, and cost.
Prohylactic use in surgery
Prophylactic use of antibiotics are highly effective and necessary in preventing certain postoperative infections and are used in surgical procedures are associated with risk.
Include cardiovascular, intestinal tract, emergency caesarian, orthopedic procedures, neurological procedures, and generally any surgical procedures that take >4 hours.
Antibiotics should be at the site of surgery or at the time of bacterial contamination.
One dose of broad spectrum or long acting antibiotic is given intravenously immediately before surgery.
Antimicrobials in Animal Feeds for Growth Promotion
Since 1950s, it has been known that continuous andministration of low concentrations of antimicrobials int he feeds promores growth increased body weight and feed conversion and reduces stress-associated diseases in food animals.
Have been available without veterinary oversight and decisions to use have been based on nutritional and economic considerations.
