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ANTIMICROBIAL DRUGS, Minimum inhibitory concentration (MIC): Determined by…

- - - - BETA LACTAM ANTIBIOTICS
        
        PENICILIN :
        When growing bacteria are exposed to these antibiotics the antibiotic binds to specific penicillin-binding proteins
        PBPs in the bacterial cell wall and inhibits assembly of the peptidoglycan chains.
        This, in turn, activates autolysins that degrade the cell wall, resulting in bacterial cell death.
        β-lactam antibiotics generally act as bactericidal
        agents
        Penicillin G is inactivated by gastric acid; thus it is used
        mainly as an intravenous drug
        Prokaryotic Cell Walls: basic structure is a chain of 10 to 65 disaccharide residues consisting of alternating molecules of N-acetylglucosamine and N-acetylmuramic acid.These chains are then cross-linked with peptide bridges that create a rigid mesh
        coating for the bacteria. The building of the chains and cross-links is catalyzed by specific enzymes (e.g., transpeptidases, transglycosylases, carboxypeptidases) that are are also called penicillin-binding proteins (PBPs)
        Penicillinase resistant penicillins such as methicillin and oxacillin are used to treat infections caused by susceptible staphylococci
        
        RESISTANCE TO BETA LACTAM ANTIBIOTICS :
        Bacteria can become resistant to β-lactam antibiotics by three general mechanisms:
        
        decreased concentration of the antibiotic at the cell wall target
        site
        
        decreased binding of the antibiotic to the PBP
        
        hydrolysis of the antibiotic by bacterial enzymes, β-lactamases
        
        The first mechanism of resistance is seen only in gram-negative
        bacteria.
        Gram-negative bacteria have an outer membrane that
        overlies the peptidoglycan layer. Penetration of β-lactam antibiotics into gram-negative rods requires transit through pores in this outer membrane. Changes in the proteins (porins) that form the walls of the pores can alter the size of the pore opening or charge of these channels and result in exclusion of the antibiotic.
        active efflux or pumping out of the antibiotic can decrease the
        antibiotic concentration in the cel
        
        Resistance can also be acquired by modification of the β-
        lactam antibiotic binding to the PBP .This can be mediated
        by:
        
        an overproduction of PBP (a rare occurrence),
        
        acquisition of a new PBP (e.g., methicillin resistance in Staphylococcus aureus),
        
        modification of an existing PBP through recombination or point mutation
        
        CEPHALOSPORINS:
        are β-lactam antibiotics
        The cephalosporins have enhanced activity against gram-negative bacteria compared with the penicillins
        This activity, in turn, varies among the different “generations” of cephalosporins.
        The activity of narrow-spectrum, first-generation antibiotics is primarily restricted to Escherichia coli, Klebsiella species, Proteus mirabilis, and oxacillin susceptible gram-positive cocci.
        Many of the expanded-spectrum, second-generation antibiotics have additional activity against Haemophilus influenzae, Enterobacter, Citrobacter, and Serratia
        The broad-spectrum, third-generation antibiotics and extended-spectrum, fourth-generation antibiotics are active against most Enterobacteriaceae and Pseudomonas aeruginosa.
        Extended-spectrum antibiotics offer the advantage of
        increased stability to β-lactamases
        
        CARBAPENEMES:
        Beta-lactam antibiotics with a broad spectrum of activity against Gram-negative bacteria (including Enterobacteriales) and Gram-positive bacteria.
        Carbapenems are active against ESBL-producing (ESBL stands for Extended Spectrum Beta-Lactamase. )Enterobacteriales.
        In hospitalised patients, carbapenems are therefore often the treatment of choice for infections with multidrug-resistant (including ESBL-producing) Enterobacteriales
        Carbapenem-resistant Enterobacteriales (CRE) can be resistant to carbapenems as a result of various mechanisms, including the acquisition of carbapenemase enzyme
        
        MONOBACTAMS: narrow-spectrum antibiotics that are active only against aerobic, gram-negative bacteria, inactive against anaerobes or gram-positive cocci
      - VANCOMYCIN:
        Vancomycin interacts with the D-alanine-D-alanine termini of the pentapeptide side chains which interferes sterically with formation of the bridges between peptidoglycan chains.
        glycopeptide that disrupts cell wall peptidoglycan synthesis in growing gram positive bacteria.
        used for the management of infections caused by oxacillin resistant staphylococci and other gram-positive bacteria resistant to β-lactam
        Vancomycin is inactive against gram-negative bacteria, because the molecule is too large to pass through the outer membrane pores
        some organisms are intrinsically resistant to because the
        pentapeptide terminates in D-alanine-D-lactate, which does not bind vancomycin
        some species of enterococci (particularly E. faecium and Enterococcus faecalis) have acquired resistance to vancomycin The genes for this resistance (primarily vanA and vanB),
      - DAPTOMYCIN :
        It has potent activity against gram-positive bacteria,
        but gram-negative bacteria are resistant because the drug cannot penetrate through the cell wall to the cytoplasmic membrane
      - BACITRACIN:
        for the treatment of skin infections caused by gram-positive bacteria
        Gram-negative bacteria are resistant most
        likely because of the failure of the antibiotic to penetrate into the bacterial cell.
      - POLYMYXINS:
        disrupting the membrane integrity
        most active against gram-negative rods,
        because gram-positive bacteria do not have an outer membrane.
        Polymyxins B and E (colistin)
        COLISTIN : is frequently being used to treat Carbapenem-resistant Enterobacteriaceae infections
        Colistin resistance among CRE isolates can develop rapidly
        in hospitals and countries with increasing use of colistin
        The discovery of transferable plasmid-mediated colistin
        resistance genes that can transmit colistin resistance more easily between bacteria has further increased the risk of colistin resistance spreading
      - ANTIBIOTICS EFFECTIVE AGAINST MYCOBACTERIA :
        interfere with mycolic acid synthesis or incorporation
        isoniazid, Ethionamide, Ethambutol, and Cycloserine: They are cell wall– active antibiotics used for the treatment of mycobacterial infections
        Isoniazid is bactericidal against actively replicating mycobacteria.
        Resistance to these four antibiotics results primarily from reduced drug uptake into the bacterial cell or alteration of the target sites.
        CLOFAZIMINE: is a lipophilic antibiotic that binds to mycobacterial DNA. It is highly active against M. tuberculosis, is a first-line drug for the treatment of Mycobacterium leprae infections
        PYRAZINAMIDE: is active against M. tuberculosis at a low pH, such as that found in phagolysosomes
    - - AMINOGLYCOSIDE:
        These antibiotics exert their
        effort by passing through the bacterial outer membrane, cell wall, and cytoplasmic membrane to the cytoplasm, where they inhibit bacterial protein synthesis by irreversibly binding to the 30S ribosomal proteins. This attachment to the ribosomes
        has two effects:
        production of aberrant proteins as the result of misreading of the
        messenger RNA (mRNA)
        interruption of protein synthesis by causing premature
        release of the ribosome from mRNA.
        They are commonly used to treat serious
        infections caused by many gram-negative rods (Enterobacteriaceae,Pseudomonas, Acinetobacter) and some gram-positive organisms.
        Penetration through the cytoplasmic membrane is an aerobic, energy-dependent process, so anaerobes are resistant to aminoglycosides, and susceptible organisms
        in an anaerobic environment ( abscess) do not respond to treatment.
        Streptococci and enterococci are resistant to aminoglycosides because the aminoglycosides fail to penetrate through the cell wall of these bacteria.
        Resistance to the antibacterial action of aminoglycosides can develop in one of four ways:
        (1) mutation of the ribosomal binding site,
        (2) decreased uptake of the antibiotic into the bacterial cell,
        (3) increased expulsion of the antibiotic from the cell,
        (4) enzymatic modification of the antibiotic
      - TETRACYCLINES:
        bacteriostatic antibiotics that inhibit protein synthesis in bacteria by binding reversibly to the 30S ribosomal subunits,thus blocking the binding of aminoacyl-transfer RNA (tRNA) to the 30S
        ribosome–mRNA complex.
        effective in thetreatment of infections caused by Chlamydia, Mycoplasma, and Rickettsia species
        and other selected gram-positive and gram-negative bacteria
        Resistance to the tetracyclines can stem from:
        decreased penetration of the antibiotic into the bacterial cell,
        active efflux of the antibiotic out of the cell,
        alteration of the ribosomal target site
        enzymatic modification of the antibiotic.
      - TIGECYCLINE:
        It inhibits protein synthesis in the same manner as the tetracyclines
      - LINEZOLID:
        The drug binds to the 50S ribosomal subunit, which distorts the binding site for tRNA, thus inhibiting formation of the 70S initiation complex
        Linezolid has activity against staphylococci, streptococci, and enterococci
      - CHLORAMPHENICOL :
        it disrupts protein synthesis in human bone marrow cells
      - MACROLIDE:Erythromycin, azithromycin, clarithromycin,roxithromycin
        Erythromycin is the model macrolide antibiotic Macrolides exert their effect by their reversible binding to the 23S
        ribosomal RNA (rRNA) of the 50S ribosomal subunit, which blocks polypeptide elongation
        Resistance to macrolides most commonly stems from methylation of the 23S rRNA, preventing binding by the antibiotic.
        Other mechanisms of resistance include inactivation of the macrolides by enzymes or mutations in the 23S rRNA and ribosomal proteins.
        They have been used to treat pulmonary infections caused by Mycoplasma, Legionella,and Chlamydia species, as well as to treat infections caused by Campylobacter species and gram-positive bacteria in patients allergic to penicillin
        Most gram negative bacteria are resistant to the macrolides.
      - CLINDAMYCIN:
        blocks protein elongation by binding to the 50S ribosome
        Clindamycin is active against staphylococci and anaerobic gram-negative rods but is generally inactive against aerobic gram-negative bacteria.
        Methylation of the 23S rRNA is the source of bacterial resistance.
    - - RIFAMPIN :
        binds to DNA-dependent RNA polymerase and inhibits initiation of RNA synthesis
        Rifampin is bactericidal for
        Mycobacterium tuberculosis and is very active against aerobic gram-positive cocci
        Because resistance can develop rapidly, rifampin is usually combined with one or more other effective antibiotics
      - METRONİDAZOLE
    - - SULFONAMIDES:
        preventing synthesis of the folic acid required by certain microorganisms.
        TRIMETHOPRIM:
        is another antimetabolite that interferes with folic acid metabolism