Antibacterial Agents

Antibacterial Agents

• Prontosil protects mice against systemic streptococcal infection and is curative for patients with similar infections
• First sulfa drugs were cleaved in the body to release p-aminobenzene sulfonamide
• Microorganisms produce compounds, antibiotics, that inhibit other microorganisms' growth
• Most modern antibiotics come from organisms living in the soil
• These organisms include bacterial species like Streptomyces and Bacillus, and fungi like Penicillium and Cephalosporium

Features of Antibacterial Agents

• Antibiotics cause greater harm to microorganisms than to human hosts due to selective toxicity
• Selective toxicity generally interferes with biological structures or biochemical processes common to bacteria but not to humans
• Toxicity of drugs is expressed as a therapeutic index
• A high therapeutic index means the drug is less toxic to the patient
• Antimicrobial action means drugs can kill or inhibit bacterial growth
• Bacteriostatic inhibits bacterial growth
• bactericidal kills bacteria
• Bacteriostatic drugs rely on the host immunity in order to eliminate a pathogen
• Bactericidal drugs are useful when the host defenses cannot control a pathogen

Spectrum of activity

• Antimicrobials vary with respect to range of organisms controlled
• Narrow spectrum antimicrobials work on a narrow range of organisms like Gram + only OR Gram - only
• Broad-spectrum antimicrobials work on a broad range of organisms like Gram + AND Gram -
• The disadvantage of broad spectrum antimicrobials is the disruption of normal flora, potentially leading to GI issues or yeast infections

Effects of antimicrobial drugs

• Sometimes combinations of antimicrobial drugs are used to treat infections
• The additive effect of combined drugs simply sums their individual effects
• A synergistic effect means the combined effects of 2 agonists exceed the effects predicted by the individual actions
• Antagonistic combines drugs interferes with each others action, like birth control with antibiotics

Tissue Distribution

• Drugs differ in how they are distributed, metabolized, and excreted
• Tissue distribution is an important factor for consideration when prescribing
• The rate of elimination of a drug from the body is expressed in half-life
• Half life is the time it takes for the body to eliminate one half the original dose in serum
• The half-life dictates the frequency of the dosage

Adverse effects

• Adverse effects include allergic reactions including allergies to penicillin that are often life-threatening
• Toxic effects like aplastic anemia (ineffective hematopoiesis) where the body cannot make RBC or WBC
• Toxic effects also include the suppression of normal flora and antibiotic-associated colitis, where pathogenic organisms are given the opportunity to establish themselves
• Antimicrobial resistance means microorganisms have innate or acquired resistance to antibiotics

Fecal transplant

• It has been shown in case studies that fecal transplants of protective floras can reestablish regular function and eliminate symptoms from C. DIFF

Mechanism of Action

• Mechanisms of action include inhibition of cell wall synthesis
• Mechanisms of action include interference with cell membrane integrity
• Mechanisms of action include inhibition of protein synthesis
• Mechanisms of action include inhibition of nucleic acid synthesis
• Mechanisms of action include inhibition of metabolic pathways
• Mechanisms of action include interference with essential processes of M. tuberculosis
• Interference with bacterial cell construction antimicrobials do not interfere with eukaryotic cells, due to a lack of cell walls in animal cells and differences in plant cells
• These drugs have a very high therapeutic index

Beta-Lactams

• This class includes beta-lactam drugs, vancomycin, and bacitracin
• Vancomycin targets peptide side chains that binds to D-Ala
• Bacitracin inhibits PTG precursor transport
• A shared chemical structure called a B-lactam ring is found in B-Lactams
• B-Lactams inhibit the function of penicillin-binding proteins (PBPs)
• Some B-lactam drugs are more active against Gram + cells
• Some B-lactam drugs are more active against Gram - cells
• This class of drugs includes penicillin

Resistance

• Resistance to B-lactams occurs via the prevention of interaction between the antibiotic & the PBP
• Beta-lactam resistance also includes modification of the binding of the antibiotic to the PBP by overproduction of PBP and/or modification of existing

Penicillins

• Highly effective with low toxicity
• Organic acid with B-lactam ring
• Obtained from culture of the mold Penicillium chrysogenum
• Modified through acid stability compounds and increased absorption
• Resistance to B-lactamase
• Natural penicillins have a narrow spectrum and are effective against Gram + and some Gram - cocci
• Penicillinase-resistant penicillin are developed in the lab where side chains prevent inactivation from penicillinase enzymes
• Broad-spectrum penicillins are modified, have a broader spectrum and are more effective against Pseudomonas species
• augmentin = amoxicillin + clavulanic acid
• This combination increases spectrum and augments amoxicillin efficacy

Beta-lactams - Cefalosporins

Originally isolated from mold Cephalosporium Chemical structures are resistant to inactivation by certain B-lactamases Wider spectrum compared to pennicillins/has longer half life

Carbapenems/Monobactams

Carbapenems and monobactams are widely prescribed Have a board spectrum, act against gram - bacteria aerobically

Carbapenemases

Found in a broad range of bacteria More common is the Klebsiella pneumoniae carbapenemase (_KPC) Class B is more common is the New Delhi metallo-B-lactamase (NDM) Class A is primarily found in Acinetobacter

Vancomycin

• Vancomycin extracted from Streptomyces orientalis
• Vancomycin disrupts cell wall PTG synthesis and interacts with D-ala – D-ala termini of pentapeptide chain
• Does not cross outer membrane of Gram (-) bacteria
• Important in treating infections caused by oxacillin-resistant staphylococci and other Gram + bacteria resistant to β-lactams
• Should be given intravenously due to poor absorption from intestinal tract

Daptomycin

• The lipopeptide Daptomycin is naturally occurring and is produced by Streptomyces roseosporus
• It binds irreversibly to membranes resulting in depolarization
• It is more potent against Gram + and cannot penetrate the Gram - cell wall
• It has good activity against multi-drug resistant staphylococci and enterococci (including vancomycin-resistant strains)

Bacitracin

• Isolated from Bacillus licheniformis
• Used for skin infections caused by Gram (+) bacteria esp Staphylococcus and Group A Streptococcus
• Inhibits the precursor thru the cytoplasmic membrane to the cell all
• Resistance in Gram negative bacteria is caused by antibiotic not being able to penetrate bacterial all

Polymixins

Are derived from Bacillus Polymyxa with cyclic polypeptides to be inserted in bacterial membranes. are potent against Gram -

• Are capable of causing serious nephrotoxicity Use is limited to external treatment of localized, topical infections such as external otitis, eye infections, and skin infections caused by sensitive organisms Polymyxin E is for some systmeic infections caused by multidrug resistant Gram negative rods

Mech of Action for AntiB Agents

Inhibition includes:

• Cell wall synthesis
• cell membrane
• protein synthesis nucleic acid synthesis
• essential processes of M tuberculosi
• Interfering with processes of TB is a separate category because of different cell-wall

Interference With processes of TB

Limited range of antimicrobials in tx Numerous conditions, slow growth waxy covering- mycolic acis TB regimen incluse -Rifampin -Isoniazid -Pyrazinamide -ethambutol TB and leprosy - cycloserine -Clofazimine -binds dna -targets myobacterium

Oxazolidinones

• Mechanism of Action: This class includes linezolid, with narrow spectrum binding to the 50S ribosomal subunit to Interferes with initiation of protein synthesis which is effective against variety of Gt bacteria Has activity against all staphylococci, streptococci, and enterococci including those strains resistant to penicillins, vancomycin, and the aminoglycosides. It is generally reserved for treatment of multidrug-resistant enterococci

Chloramphenicol, binds 50S ribosomal subunint

Blocks peptide elongation Broad-spectrum, bacteriostatic Used last resort For life threatening infections Lethal side effect aplastic anemia

Macrolides is binded to 23s

used to treat pulmonary infections caused by mycoplasmia Most G(- ) organisms most effective Often used for Pts allergic to penicillin Case study

Quinolones

Quinolones are Chemotherapeutic, broad spectrum and bactericidal that blocks DNA Topoisomeraxe Are resistance from chromosomal mutations Spectrum activity in AB narrow/braod and extended to gram +/- Bacteria by interfering with cell formation