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Antimicrobial Chemotherapeutic Agents

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Plasmids Plasmid genes for antimicrobial resistance often control the formation of enzymes that inactivate the antimicrobial drugs such as -lactamases, ... – PowerPoint PPT presentation

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Title: Antimicrobial Chemotherapeutic Agents


1
Antimicrobial Chemotherapeutic Agents
2
Drug Resistance
3
  • In the clinical context an organism is said to be
    resistant
  • If it is not killed or inhibited by drug
    concentrations readily attainable in the patient
    this usually means blood and tissue
    concentrations.
  • However, an organism resistant to these may of
    course be sensitive to the higher concentrations
    attainable in urine or by topical application.
  • Even the broadest of broad-spectrum antibacterial
    drugs is ineffective against some bacterial
    genera, against some species of other genera, and
    usually against some strains of species that are
    in general sensitive to it.

4
Resistance
Inherent (non specific)
Acquired
5
Inherent (non specific) Resistance
  • Certain bacteria are, and as far as we know
    always have been, more or less resistant to some
    antibiotics.
  • For example, gram-negative bacteria, especially
    Ps. aeruginosa, are
    inherently resistant to a number of antibiotics
    that are very effective against gram-positive
    bacteria such as penicillin G, erythromycin,
    lincomycin.

6
Acquired Resistance
  • When a bacterial population adapts to the
    presence of an antibiotic, sensitive cells are
    gradually replaced by resistant cells as in the
    presence of antibiotic.
  • Resistant cells continue to grow at the expense
    of sensitive cells.
  • When a new antibiotic is introduced into clinical
    practice for the treatment of infections caused
    by bacteria that are not inherently resistant to
    the drug, the majority of infections respond to
    the new drug.

7
  • But following months or years of continuous use,
    resistant strains are reported.
  • The degree of resistance and the speed with which
    it develops varies with
  • ? The organism ? The drug.
  • Generally, the development of acquired bacterial
    resistance is common and must be usually expected
    with some exceptions.

8
  • Streptococcus pyogenes has remained sensitive to
    Penicillin G after 40 year's exposure to the
    drug.
  • Staph aureus develops slow or multisteps
    resistance to penicillin, chloramphenicol and
    tetracycline.
  • While Mycobacterium tuberculosis and various
    organisms develops sudden or one step resistance
    to Streptomycin.

9
Biochemical Mechanisms of Resistance
Production of drug-inactivating enzymes
Switch to alternative metabolic pathways
unaffected by the drug
?
?
Change in the antibiotic target site
?
Increased production of essential metabolite
?
. Reduction in cellular permeability to the
antibiotic
?
10
Inactivation of Aminoglycosides
Inactivation of ß-lactams
Inactivation of Chloramphenicol
11
Inactivation of Aminoglycosides
  • Inactivation of aminoglycosides by plasmid
    controlled adenylating , phosphorylating or
    acetylating intracellular enzymes of drug
    resistant gram negative bacteria.
  • Although the inactivating enzymes vary
    considerably in their substrate and
    specificities, known modifications are restricted
    to acetylation of amino groups and adenylylation
    or phosphorylation of hydroxyl groups.

12
Inactivation of ß-lactams
  • Inactivation of ß-lactams by ß -lactamases
    ( penicillinase,
    cephalosporinase ) into penicilloic or
    cephalosporoic acid.
  • ß -lactamases are

Gram-positive
Gram-negative
Chromosomally
Plasmid
Constitutive
Inducible
13
Penicilloic acid
14
  • The synthesis of gram positive ß-lactamase is
    induced by the antibiotic themselves and is
    released extracellularly and destroy antibiotic
    in the external environment.
  • Most strains of gram-negative cells, by contrast,
    synthesize ß-lactamases constitutively. i.e.
    continuously and are not released into the
    external environment (cell-bound or
    intracellular).

15
  • ? Chromosomally-mediaied ß-lactamases of gram
    negative hydrolyze cephalosporins more rapidly
    than penicillins and are inhibited by cloxacillin
    but not by clavulanic acid.
  • However, those of Aeromonas spp. and Klebsiella
    spp. are more active against penicillins and not
    inhibited by cloxacillin.

16
1
2
R1 cl , R2 H (Cloxacillin)
17
  • Inducible types are found in microorganisms such
    as Pseudomonas spp., Proteus and other gram
    negative bacteria but infrequently in E. coli in
    which, as many enterobacter species, constitutive
    types could be isolated.

18
  • ? Different types of plasmid-mediated
    ß-lactamases were isolated.
  • TEM type enzymes are present in almost all gram
    negative bacteria.
  • These enzymes were first isolated from E. coli
    strains isolated, in Athens, from a young girl
    called Temoniera and was referred to as TEM
    enzyme.
  • Electrophoretically different type was then
    isolated from Pseudomonas aeruginosa (TEM-2).

19
E. coli OXA
Klebsiella spp. SHV
H. influenza ROB
Aeromonas spp. AER
Ps. aeruginosa LCR
20
Inactivation of chloramphenicol
  • Inactivation of chloramphenicol by
    chloramphenicol acetyl transferase (CAT).
  • Usually they are a plasmid-mediated enzymes which
    are inducible type in gram-positive bacteria but
    constitutive in gram-negative bacteria.
  • These enzymes acetylates the OH groups in the
    side chain of the drug.

21
  • Replacement of the terminal - OH group of this
    side chain, which is normally the first to be
    acetylated by an inert fluorine atom, yields a
    chloramphenicol derivative that is not
    susceptible to attack by CAT.

22
Chromosomal Resistance to Aminoglycosides
Resistance to Erythromycin
Resistance to Sulfonamides Trimethoprim
Resistance- to some Penicillins
23
Chromosomal Resistance to Aminoglycosides
  • It is associated with the loss or alteration of a
    specific protein in the 30S subunit of the
    bacterial ribosome that serve as a binding site
    in the susceptible organisms.

Resistance to Erythromycin
  • It is associated with alteration, of its receptor
    on the 5OS subunit of the ribosome.

24
Resistance- to some Penicillins
  • Resistance- to some penicillins due to loss or
    alteration of Penicillin Binding Proteins
    (PBPs).

Resistance to Sulfonamides Trimethoprim
  • Occurs by alteration of the tetrahydropteroat
    synthetase and tetrahydrofolate reductase,
    respectively, that have a much higher
    affinity for PABA than these drugs.

25
  • Bacterial cells altering the permeability of
    their cell membrane making it difficult for
    antimicrobials to enter.
  • This type of resistance is found in bacteria
    resistant to
  • Polymyxins.
  • Tetracyclines.
  • Amikacin some aminoglycosides.
  • Streptococci have a natural permeability barrier
    to aminoglycosides.
  • This can be partly overcome by combination with
    cell wall active drug, e.g. (penicillin).

26
  • The organism develop an altered metabolic pathway
    that bypasses the reaction inhibited by the drug
    e.g. some sulfonamide-resistan
    t bacteria do not require extra-cellular PABA
    but, like mammalian cells, can utilize preformed
    folic acid.

27
  • That is competitively antagonized by the drug in
    sensitive cells e.g. resistance to sulfonamides
    may be associated with high level of bacterial
    synthesis of PABA.

28
The origin of drug resistance
Non Genetic Origin
Genetic Origin
29
Non Genetic Origin
  • This involves metabolically inactive cells or
    loss of target sites.
  • Most antimicrobial agents act effectively only on
    replicating cells.
  • Mycobacteria survive for many years in tissue
    yet are restrained by the host's defenses and do
    not multiply.
  • Such persisting organisms are resistant to
    treatment and cannot be eradicated by drugs.
  • When they start to multiply they are fully
    susceptible to the drugs.

30
  • Loss of a particular target structure, often
    induced by the drug, may result in antimicrobial
    resistance.
  • Exposure of some gram-positive bacteria to
    penicillin results in the formation of cell
    lacking cell wall
    (i.e. L-forms).
  • These cells then are penicillin resistant, having
    lost the structural target site of the drug.
  • When these organisms revert to their bacterial
    parent forms resuming cell wall production, they
    are again fully susceptible to penicillin.

31
Genetic Origin
  • Most drug-resistant microbes emerge as a result
    of genetic change and subsequent selection
    processes by antimicrobial drugs.

The mechanisms by which genetic change occur
are
Chromosomal Resistance
Extra Chromosomal Resistance
32
Chromosomal Resistance
  • This develops as a result of mutation in a gene
    locus that controls susceptibility to a given
    antimicrobial drug.
  • The presence of the drug serves as a selecting
    mechanism to suppress susceptible organisms and
    favor the growth of drug resistant mutant.
  • Spontaneous mutation occurs at a frequency of 10
    7 to 10 12.

33
  • Chromosomal mutants are most commonly resistant
    by virtue of a change in a structural receptor
    for a drug as in bacterial resistance to
    erythromycin, lincomycin, aminoglycosides and
    others by alteration of their target site in
    susceptible cells.
  • Prevention of the emergence of resistant mutants
    is one of the main indications for the clinical
    use of combinations of drugs.

34
  • But provided that the mechanisms of action of the
    two drugs are unrelated.
  • Therefore if both drugs are given in adequate
    dosage, the risk of the emergence of a resistant
    strain is very much less than if either is used
    alone.

35
Extra Chromosomal Resistance
Plasmids
Transposons
36
Plasmids
  • Bacteria often contain extra chromosomal DNA
    units known as plasmids.
  • Some of which alternate between being free and
    being integrated into the chromosome.
  • R factors are a class of plasmids that carry
    genes for resistance to one and often several
    antimicrobial drugs and heavy metals.

37
  • Plasmid genes for antimicrobial resistance often
    control the formation of enzymes that inactivate
    the antimicrobial drugs such as ß-lactamases, CAT
    and enzymes that inactivates aminoglycosides or
    enzymes that determine the active transport of
    tetracyclines across the cell membrane, and for
    others.

38
Transposons
  • The drug resistance (R) genes are often part of
    highly mobile short DNA sequences known as
    transposons (Transposable elements or jumping
    genes) that is able to move, from one position to
    another, between one plasmid and another or
    between a plasmid and a
    portion of the bacterial chromosome within a
    bacterial cell.

39
  • Thus, transposons are able to insert themselves
    into many different genomic sites with no
    homology with them.
  • Simple transposons (IS) only carry information
    concerned with the insertion function.
  • Simple transposons (IS) (i.e. insertion
    sequences) have no known effects
    beyond transposition and inactivation of the gene
    (or operon) into which they may insert.

40
  • Complex or composite transposons (Tn) contain
    additional genetic material unrelated to
    transposition, such as drug-resistance genes.
  • Such as penicillin, kanamycin, streptomycin,
    sulfonamides, tetracyclines, chloramphenicol ,and
    trimethoprim.

41
Mechanisms of Transmission of Genetic Material
and Plasmids
Transduction
Transformation
Conjugation
Transposition
42
Transduction
  • This is the main mechanism for transmission of
    antibiotic resistance between gram-positive
    cocci, and occurs in other bacterial groups.
  • Plasmid DNA is enclosed in a bacteriophage and
    transferred by the virus to another bacterium of
    the same species e.g. the plasmid carrying the
    gene for ß-lactamase production can be
    transferred from a penicillin-resistant to a
    susceptible staphylococcus if carried by a
    suitable bacteriophage.

43
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44
Transformation
  • Naked DNA passes from one cell of a species to
    another cell, thus altering its genotype.
  • This can occur through laboratory manipulation
    and perhaps spontaneously.

45
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46
Conjugation
  • This is the commonest method by which, multi-drug
    resistance spreads among different genera of
    gram-negative bacteria.
  • But also occurs among some gram-positive cocci.

47
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48
  • The usual plasmid found in resistant
    gram-negative bacteria consists of two distinct
    but frequently linked elements
  • One or more linked genes each conferring
    resistance to a specific antibacterial drug
    (resistance
    determinants).
  • A resistance transfer factor (RTF) that enable
    the cell to conjugate with a sensitive bacterium
    and to transfer to It a copy of the entire
    plasmid.

49
R-factor
50
  • The entire linked complex of RTF and resistance
    determinants is known as R-factor and takes the
    form of a double stranded circular molecule of
    DNA.
  • A proportion of R-factor-bearing cells (R
    cells) possess hair-like structures that extend
    out from the bacterial surface known as pili.
  • The pili, whose synthesis is under the control of
    the RTF component of the R-factor are
    essential to the conjugation phenomenon with R'
    bacteria and the transfer of an R- factor.

51
Transposition
  • A transfer of short DNA sequences (transposon)
    occur between a plasmid and another or between a
    plasmid and a portion of the bacterial chromosome
    within a bacterial cell.

52
Transferable or infective drug resistance is
important for the following reasons
  1. The transferable plasmids commonly determine
    resistance to several unrelated drugs.
  2. Such plasmids are transferable not merely to
    related strains of the same species but to
    strains of other species and genera for example,
    antibiotic-resistant but harmless organism in
    human or animal intestine
    (E. coli) can confer antibiotic resistance,
    by plasmid transfer, on pathogenic but previously

    antibiotic-sensitive bacteria of other genera
    which the host happens to ingest (such as typhoid
    or dysentery bacilli).

53
  1. It is possible for multiple-resistant
    enterobacteria to develop in farm animals and be
    transmitted to man. Development of this
    resistance is due to the widespread use of
    antibiotics especially cheap types, as food
    supplements for young animal to accelerate their
    growth by partial suppression of their intestinal
    flora.

54
Specific and Cross Resistance
  • Specific resistance When the organism acquire
    resistance to a certain drug but Its
    susceptibility to other drugs is unaffected.
  • Cross resistance Microorganisms resistant to a
    certain drug may also be resistant to other drugs
    that share a mechanism of action.

55
  • Such relationship exist mainly between agents
    that are closely related
  • Polymyxin B and Polymyxin E.
  • Erythromycin and Oleandomycin.
  • Neomycin and kanamycin.
  • However, it may also exist between unrelated
    chemicals ? Erythromycin-Lincomycin.

56
  • When the active nucleus of the chemicals is so
    similar, extensive cross-resistance is to be
    expected e.g. resistance to one of the
    tetracyclines imparts resistance to the other
    members of the group e.g. resistance to one
    sulfonamide cause resistance to hundreds of other
    sulfonamides.

57
Antibiotic Policies
  • Abuse of antibiotics, is avoided for many reasons
    including the following
  • To prevent the emergence of antibiotic
    resistance.
  • To reduce the cost of antibiotic use.
  • To prevent antibiotic toxicity.

58
General Principles of Optimal Antibacterial
Therapy
  • Unless there is a valid reason for giving an
    antibiotic, the patient would probably be better
    off without it.

1
Treatment of Known or Suspected Infection
Prevention of Bacterial Infection
Peri-operative Prophylaxis
Patients at Special Risk
59
  • In cases when immediate drug treatment is
    necessary.

2
It is bad treatment to use broad-spectrum
antibiotics when an infective condition can be
treated with a more specific
agent.
3
It is essential to use bactericidal and not
bacteriostatic therapy.
4
It is essential to use combination of
antimicrobial drugs in certain situations.
5
60
For treatment of superficial infections it is
important to use either antiseptic or antibiotics
which are rarely or never used systemically.
6
  • Give enough, for long enough, and then stop
    treatment with the antibiotic.

7
To reduce the spread of microbial resistance,
avoid the use of antibiotics as food supplement
for animals or for preservation of human food
stuffs, avoid liberation of antibiotic powders
and solutions into the environment.
8
61
To reduce the emergence of antibiotic-resistant
strains, an antibiotic policy has to be
introduced for a hospital or area e.g.,
using antibiotics in rotation, keeping a
particular antibiotics and permitting their use
only on rare and special occasions, or insisting
on combined therapy.
9
62
Drug combination
  1. To provide broad coverage.
  2. For initial (blind) therapy when the patient is
    seriously ill and results of cultures are
    pending.
  3. To provide synergism when organisms are not
    effectively eradicated with a single agent alone
    e.g., in enterococcal endocarditis both
    penicillin and
    an aminoglycoside are given because their
    combined effect is greater than the sum of their
    independent activities.

63
  • To prevent emergence of resistance, as in the
    treatment of tuberculosis.
  • Inappropriate use of combinations could result
    in
  • Antagonism it occurs when a bactericidal agent is
    used with a bacteriostatic one as in penicillins
    plus tetracycline or Chloramphenicol.
  • Sulphonamides do not antagonize penicillins,
    possibly because their bacteriostatic action is
    too low.
  • An increase in the number or severity of adverse
    reactions.
  • Increased coast.

64
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