Chemotherapeutic Agents or Anti-Microbials

8/14/2019 Chemotherapeutic Agents or Anti-Microbials

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Introduction toAntimicrobial Agents

Dr. SalmanKhan


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Chemotherapeutic Agents OR

Anti-microbials Some Definitions:

Anti-Biotics: These are chemical substancesproduced by various species of micro-organisms ( bacteria, fungi, actenomycetes)that suppress the growth of other micro-

organisms and may eventually destroy them.(antibacterials, antivirals, anti-fungals)


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Chemotherapeutic Agents OR

Anti-microbials Important consideration: Common

usage often extends the term

antibiotics to include syntheticantibacterial agents, such assulfonamides, quinolones, that are notproducts of microbes (Goodman & Gillman)

BUT: we will call them anti-bacterials ORantimicrobials OR Chemotherapeuticagents derived from non-living things

OR synthetically produced.


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Beta-lactamases: Bacterial enzymes( penicillinase, cephalosporinase) thathydrolyze the beta lactam ring of certain

penicillins and cephalosporins. Minimal Inhibitory concentration: lowest

concentration of antimicrobial drug capable ofinhibiting growth of an organism in a definedgrowth medium. (MIC)

Penicillin binding Proteins: Bacterialcytoplasmic membrane proteins that act asthe initial receptors for penicillins and other

beta-lactam antibiotics. (PBPs)


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Peptidoglycan, murein: Chains ofpolysaccharides and polypeptides that are

cross linked to form bacterial cell wall. Selective toxicity: More toxic to the invader

than to the host; a property of usefulantimicrobials.

Transpeptidases: bacterial enzymesinvolved in the cross-linking of linearPeptidoglycan chains, the final step in cell wallsynthesis.


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Targets for AntimicrobialDrugs that Bind to the30S bacterial ribosomalsubunit, leading to cell

death

Agents that interferewith nucleic acidsynthesis

Antimetabolites

Bacterial Cell WallSynthesis Inhibitors

Protein SynthesisInhibitors: interfere with30S or 50S bacterialribosome function

Agents that Increase Cell

Membrane Permeability


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Agents that increase cellmembrane permeability:polymixins (detergent)

colistimethate (detergent)

nystatin (Mycostatin)(polyene antifungal)

amphotericin B (polyene antifungal)

Antimetabolites sulfonamides

trimethoprim (generic)

Agents that interfere with nucleicacid synthesis:

rifamycins (rifampin (Rimactane)):inhibits DNA-dependent RNApolymerase

quinolones: inhibit gyrase

Drugs that bind to the 30Sbacterial ribosomal subunit,leading to cell death.

Bactericidal

Aminoglycosides (e.g.gentamicin(Garamycin), tobramycin (Nebcin))

Protein synthesis inhibitors: interferewith 30S or 50S bacterial ribosomefunction.

Bacteriostatic

chloramphenicol (Chloromycetin)

tetracyclineserythromycin

clindamycin

Bacterial cell wall synthesisinhibitors:

penicillins

cephalosporins

cycloserine

vancomycin (Vancocin)

bacitracin


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Bactericidal agentsAminoglycosides, bacitracin, beta-lactamantibiotics, isoniazid, metronidazole,polymyxins, pyrazinamide, quinolones,rifampin, vancomycin [Lampris & Maddix

98,p818 and Katzung8th2001p860] Bacteriostatic agents Chloramphenicol, clindamycin, ethambutol,

macrolides, nitrofurantoin, novobiocin,oxazolidinones, sulfonamides, tetracyclines,trimethoprim [Lampris & Maddix 98,p818 and

Katzung8th2001p860]


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Spectra of Anti-microbials The clinical SPECTRUM of organisms is indicated by various

terms. BROAD SPECTRUM includes drugs like the tetracyclinesthat have no strong predilection for gram positive or gramnegative organisms and may even act against such organisms

as Rickettsia or even protozoans. Few of the broad spectrumantimicrobials affect such a wide range of organisms.NARROW SPECTRUM Drugs, such as penicillin G, are primarilyactive against GRAM POSITIVE organisms. Gentamicin is anexample of a drug that is especially used to treat infections byGRAM NEGATIVE organisms. Some drugs have such a specialclinical niche that they are commonly referred to as a memberof that niche despite the fact that they do have other actions. The PENICILLINASE resistant penicillins (e.g., methicillin) andEXTENDED SPECTRUM penicillins (e.g., ticarcillin) areexamples. It is important to note that classifications based onspectrum do not imply that a drug will be active against allorganisms in the class. Some organisms are notorious for the

unpredictability of their response to an antimicrobial whereasothers are highly predictable.


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Combination Therapy Combination chemotherapy may be

warranted to: Decrease the likelihood of emergence of

resistant mutants. A single agent will beeffective against sensitive organisms, but notagainst those that have developed a mutated"target" site, which is no longer susceptible orhas diminished susceptibility to the drug. Inthis case the single drug will select out themutant, resistant strain. This effect is morelikely when the concentration of theantibacterial agent approximates the MIC(minimum inhibitory concentration).


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A second agent, which acts by a differentmechanism, may prevent the emergence ofthe resistant strain (e.g. impenem +aminoglycoside for systemic Pseudomonas).

To take advantage of additive/synergisticaction against some bacteria. Combination oftrimethoprim-sulfamethoxazole (Septran) is

effective against many enteric gram negativebacteria. And the combination becomesbactericidal.


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Advantages of combinations Some combinations frequently synergistic

trimethoprim plus sulfonamide Enterococcal endocarditis with penicillin and

streptomycin Cryptococcal meningitis with amphotericin B

plus flucytosine Mixed infections

Decrease development of resistant organismsas in treatment of tuberculosis with isoniazidplus pyrazinamide and rifampin

Serious, life-threatening infections of unknownorigin or in sepsis or meningitis


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Disadvantages of combinations

Interference with action of cidalantibiotic that depends on rapid growth

by a static antibiotic that inhibits growth Increased risk of toxicity to patient

Increased cost

Increased risk of development ofresistant organisms in patient orpopulation by use of antibacterials nottruly needed


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Mechanisms for chemotherapeuticdrugs resistance

Bacterial resistance may occur because the drugdoes not reach its target site, drug is inactivated,or there is some sort of molecular alteration in

the target itself, possibly due to mutation. Resistance may occur because enzymes at or near the

cell surface inactivate the antibiotic; the cell membraneis impermeable to the drug; there is an absence ofaqueous channels (porins) through which the drug will

reach the cell interior; there is a lack of a necessarytransport system to support drug translocation; thetransport mechanism is present but inoperative due toanaerobic metabolism; there are target site changesthat results in reduced or absent antibacterial drugefficacy.


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How Bacteria Acquire

Resistance Resistance may be acquired by vertical transfer,

i.e. acquired by mutation and then passed to daughtercell

Mutations: Specific genetic mutations are themolecular basis for resistance to streptomycin(ribosomal mutation), to quinolones (DNA gyrase genemutation) and to rifampin (Rimactane) (RNA polymerasegene mutation)

o The mutation to rifampin is an example of a single-stepmutation: In this case E. coli or Staph. aureus exposureto rifampin results in highly resistant strain due to apoint mutation in the RNA polymerase gene such thatthe polymerase protein no longer binds rifampin


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More usually, acquired by horizontal transfer ofresistance factors from a donor cell, perhaps of adifferent species by transformation whichinvolves the incorporation of DNA found free

environment into the bacterial genomeo An example of this process is the basis of penicillin

resistance in. pneumococci and Neisseria gonorrhea. Penicillin-resistant pneumococci produce different PBPs

(penicillin-binding proteins). These different PBPs

exhibit relatively low affinity for penicillin compared towild type pneumococci. These different PBPs arise from integration of foreign

DNA which were most likely from a closely relatedstreptococcal strain into the PBP gene by a process ofhomologous recombination


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Transduction-based resistance occurs when abacteriophage which includes bacterial DNA in itsprotein coat infects the bacteria. This bacterial DNA may

contain a gene confiring resistance to antibacterialdrugs.

Examples of this process:

Staphylococcus aureus strain resistance development topenicillin may occur by transduction (Some

bacteriophages carry plasmids [extrachromosomal self-replicating DNA] that code for penicillinase

Other phages can transfer genes which conferresistance to tetracycline (Achromycin), erythromycinestolate (Ilosone), and chloramphenicol

(Chloromycetin).


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Conjugation is another important mechanism forsingle and multi-drug resistance development. Inconjugation direct passage of resistance-conferring DNA between bacteria proceeds by

way of a bridgeo The genetic material transfer in conjugation

requires two elements: an R-determinantplasmid which codes for the resistance and aresistance-transfer factor (RTF) plasmid whichcontains the genes necessary for the bacterialconjugation process. Occasionally twoplasmids join to form a complete R factor

o Some genes that are responsible for resistance

are located on transposons which can movefrom location to location within lasmid and


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Conjugation mediated resistance is particularlyimportant in gram-negative bacilli.

o Enterococci may contain plasmids that spreadresistance among gram-positive organisms

Vancomycin (Vancocin) resistance in enterococcalstrains appears to occur as a result of the conjugationmechanism.

Conjugation is not a high efficiency mechanism forresistance development. Unfortunately, antibiotic use

provides selection pressures which facilitate theelaboration of resistance bacteria. Furthermore, entericbacteria carrying plasmids for multidrug resistance isnow a worldwide, serious concern.

Resistance acquired by horizontal transfer candisseminate rapidly through the bacterial population by

clonal spread as well as by continuing genetic material


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Complications Of Anti-biotic therapy Adverse Effects

Adverse effects of antimicrobials

may be divided into three broadcategories:

Allergic

Biological

Toxic


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Biological Adverse Effects of

Antimicrobials More likely

Broad spectrum drugs Alteration of normal flora Skin Mucous membranes Gastrointestinal tract Reproductive tract Likely pathogens yeasts Clostridium difficile Superinfection / Suprainfection


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Antibiotic Associated Enterocolitis ACCESS!!

ampicillin, tetracyclines, LINCOMYCIN, andother broad spectrum antibacterials

spectrum -- broad, effective against anaerobes

Antibiotic Associated Pseudomembranous

Enterocolitis Associated with overgrowth ofClostridium

difficile


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Direct Toxic Effects ofAntibacterials

Life threateningo Liver failure -- isoniazido Respiratory paralysis -- neuromuscular paralysis --

aminoglycosides Severeo Hearing loss (ototoxicity)-- aminoglycosideso Nephrotoxicosis -- proximal tubular cells --

aminoglycosideso Nephrotoxicosis -- tubular crystal formation --

Sulfonamideso Decreased immune function -- many

antibiotics


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o Bone / tooth malformation due to binding tocalcium -- tetracyclines

o Antibody production inhibited by --amphotericin B, cefoxitin, doxycycline,rifampin, cefotaxime, chloramphenicol,moxalactam, and trimethoprim-sulfamethoxazole.

o Microbiocidal activity impaired by -- amikacin,cephalothin, gentamicin, sulfonamides,tetracycline, and tobramycin


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Unpleasanto Mild abdominal discomfort / pain --

erythromycino Dizziness -- minocycline

o Mild vomiting

o Loose stools to mild diarrheao Tooth discoloration -- tetracyclines

A i t d I i t


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Appropriate and InappropriateUses of Chemotherapy

Appropriate Use Before the organism is identified: either

combination therapy or a single broad

spectrum agent may be used. After the organism is identified, a low-toxicity

regimen with a narrow-spectrum drug isindicated.

Selection of the drug should be governed byits selectivity for the most likely involvedbacteria and its toxicity.

First decide if an antibiotic is indicated sinceantibiotics may be toxic. Inappropriate use

may hinder diagnosis, and can result in


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Some Clinical Issues

Optimal empirical treatment requires knowledge ofthe antibiotic sensitivity of the organisms which ismost likely causing the infection.

Assessment with Gram's stain and other tests mustbe used to narrow the list of pathogens.

In life threatening situations, the selection of asingle narrow-spectrum agent may not be possibleand broad coverage would be indicated until a

definitive identification is possible.


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Inappropriate Uses

Treatment of Untreatable Infections The infection is viral. Antimicrobial treatment of measles, mumps and 90% of

upper respiratory infections are inappropriate. Treatment of fever of unknown origin: Antimicrobials are not antipyretic agents. Pyrexia of short duration, without localizing signs, is

most likely due to viral infection. Three infections may be associated with

prolonged fever: tuberculosis hidden intra-abdominal abscesses infective endocarditis. other causes: cancer, metabolic disorders, hepatitis,


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Improper dosage: Some drugs, such as the aminoglycosides, are frequently

administered at subtherapeutic dosages because of concern

about toxicity. Clinical treatment failure and selection of resistant strains may

result. Inappropriate Dependence on Chemotherapy

Alone:

Some disorders require both chemotherapy and asurgical procedure, especially if significant amount ofnecrotic tissue is present.

Example : Pneumonia in a patient with empyema(accumulation of pus) may be effectively manage

following drainage


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Lack of Adequate Bacteriological Information:

About one-half of antimicrobial therapy is given tohospitalized patients without support frommicrobiological data. [clinical judgment alone];

Antimicrobial therapy must be individualized, notadministered based on prescribing habit alone

Chemotherapeutic Agents or Anti-Microbials

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