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Antibiotic resistance
A resistant organism is one that will not be inhibited or killed by an antibacterial agent at
concentrations of the drug achievable in the body after normal dosage
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However, within
species that are innately susceptible, there are also strains that develop or acquire
resistance
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Resistance may arise from; a single chromosomal mutation in one bacterial cell
resulting in the synthesis of n altered protein eg
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changes in
penicillin binding proteins in penicillin-resistant pneumococci
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Chromosomal mutations are relatively rare events and generally
provide resistance to a single class of antimicrobials
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Bacteria are able to acquire resistance genes on transmissible
plasmids, such plasmids often code for resistance determinants to several unrelated families
of antibacterial agents
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Some plasmids are promiscuous, crossing species barrier and the same
resistance gene is therefore found in widely different species, eg
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coli and
other enterobacterial and also accounts for penicillin resistance in Neisseria gonorrhoeae
and ampicillin resistance in H
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Resistance may be acquired from transposons and other mobile elements
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Multiple resistance genes may be organized into genetic elements called integrons
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A strong integron
promoter controls transcription of the inserted genes
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With their ability to capture, organize and rearrange different
antibiotic-resistance genes, integrons represent an important mechanism for the spread of
multiple antibiotic resistance in clinically important microorganisms
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SCCmec inserts into a unique target site on the staphylococcal chromosome
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transposons and plasmids
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alternatively , an additional (more
resistant) target (eg
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Access to the target site may be altered, decreasing the amount of drug that reaches the
target, either by; altering entry eg
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Enzymes that modify or destroy the antibacterial agent may be produced-drug inactivation,
eg
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Use and misuse of antimicrobial agents
Antimicrobial agents should only be used appropriately for prophylaxis or treatment
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Antibiotic susceptibility tests
Disk diffusion tests involve seeding the organism on an agar plate and applying filter paper
disks containing antibiotics
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The size of the inhibition zone is an indicator of
susceptibility of the isolate
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A dilution test provides a quantitative estimate of susceptibility to an antibiotic
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a test to find the lowest concentration that will inhibit visible growth of
the bacterial oslate in vitro)
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After overnight incubation,
the MIC is recorded as the highest dilution in which there is no macroscopic growth
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The concentration on the strip
at which growth is inhibited indicates the MIC
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An advantage of an MIC test is that it can be extended to
determine the MBC (minimum bacterial concentration), which is the lowest concentration of
an antibiotic required to kill the organism
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The antibacterial agent is
considered to be bactericidal if the MBC is equal to or not greater than fourfold higher than
the MIC
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One disadvantage of
MIC and MBC tests is that the result is read at only one point in time
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Killing curves are more time consuming and expensive than disk
diffusion methods
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turbidity, electrical impedance) in the presence of an antibacterial their indicator
system
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Combining antibacterial agents can lead to synergism, their activity is greater than the sum
of the individual activities, or antagonism, the activity of one drug os compromised in the
presence of the other
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Antimicrobial agents
Antimicrobials are chemicals used to inhibit the growth of or kill a specific microorganism or
group of organisms
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Antibacterial agents derived from natural sources, eg
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semi-synthetic, to improve their
antibacterial or pharmacological properties
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sulphonamides or quinolones
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This is more
achievable in microorganisms that are prokaryotes than in those that are eukaryotes, as
prokaryotes are structurally more distinct from the host cells
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Some antibacterial agents are bactericidal (kill
bacteria), others are bacteriostatic (inhibit growth of bacteria)
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In immunocompromised patients,
bacteriostatic drugs may be less efficacious
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folic acid metabolism), and cell membrane function
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Antibacterial agents
Penicillin
Peptidoglycan is a vital component of the bacterial cell wall and is a compound unique to
bacteria, therefore representing s target for selective toxicity
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Penicillins have a five membered beta-lactam ring
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carboxypeptidases, transglycosylases and
transpeptidases, capable of binding to penicillin and are responsible for the final stages of
cross-linking of the bacterial cell wall structure
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Penicillins are active against gram-positive organisms
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Benzylpenicillin
is excreted rapidly in urine and hence requires frequent doses
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A common side effect of ampicillin treatment is a mild idiopathic reaction, usually
in the form of a rash
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Carbenicillin can cause platelet dysfunction and sodium
overload (because it is given as a sodium salt), especially in patients with liver failure, renal
failure, and congestive heart failure
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Penicillins may be administered
intramuscularly, intravenously or orally
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Members of the family differ more in their pharmacological properties than in
their spectrum of activity
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Tetracyclines inhibit
protein synthesis by binding to the small ribosomal subunit in a manner that prevents
aminoacyl transfer RNA from entering the acceptor sites in the ribosome
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Tetracyclines are administered
orally
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Tetracyclines are excreted in bile and urine
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Tetracycline use is restricted
due to widespread resistance
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staph
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candida)
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Example of tetracyclines include; tetracycline, doxycycline, demeclocycline,
minocycline, and tigecycline
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Trimethoprim prevents THFA
synthesis by inhibiting dihydrofolate reduction
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Sulfonamides are bacteriostatic compounds
that are structural analogues of and act in competition with para-aminobenzoic acid (PABA),
for the active site of dihydropteroate synthase, an enzyme that catalyses an essential
reaction in the synthetic pathway of tetrahydrofolic acid (THFA), which is required for the
synthesis of purines and pyrimidines and therefore nucleic acid synthesis
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Trimethoprim Is often given in
combination with sulfamethoxazole as co-trimethoxazole
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double mutation), and the fact that the two agents act
synergistically against some bacteria
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Co-trimoxazole
is active against a wide range of urinary tract pathogens and against s
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Co-trimoxazole
is used in the treatment of pneumonia caused by the fungus pneumocystis jiroveci
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Co-trimoxazole teearment can
cause neutropenia, nausea and vomiting
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The problem in developing
new antivirals has been due to the difficulty of interfering with viral activity in the cell without
adversely affecting the host
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Aciclovir
Acyclovir is used in the treatment of HSV and Varicella-zoster virus (VZV) infections
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Aciclovir is inactive
until phosphorylated by the herpes simplex virus thymidine kinase to acyclovir
monophosphate, which is then converted by cellular kinases to acyclovir triphosphate, which
inhibits the herpesvirus DNA polymerase
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The drug is also incorporated into viral
DNA, resulting in chain termination
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Otherwise,
aciclovir has an excellent safety profile
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As the oral bioavailability is only 15-20%, aciclovir is given
intravenously
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AZT is an analogue of the nucleoside thymidine in
which the hydroxyl group on the ribose is replaced by an azido group
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The azido group prevents the formation of
phosphodiester linkages
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AZT is given orally
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AZT is used in the
treatment of HIV
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Selective toxicity is more difficult to
achieve in the eukaryotic fungal cells than in the prokaryotic bacteria
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Antifungal resistance is increasing
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Thus the development of antifungals is a priority
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The exceptions are
flucytosine and griseofulvin which interfere with DNA synthesis, and caspofungin which
inhibits cell wall formation
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Azole compounds
Azole antifungals act by inhibiting lanosterol C14-demethylase, an important enzyme in
sterol biosynthesis
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Itraconazole and fluconazole are used in treatment of a variety of serious fungal infections
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Newer azole
compounds include posaconazole, which is used in aspergillosis unresponsive to
amphotericin B, and itraconazole, which is used in the treatment of invasive mucormycosis
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Amphotericin B and nystatin act by binding to
sterols in cell membranes, resulting in leakage of cellular contents and cell death
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Amphotericin is used in the treatment of serious fungal infections
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Nystatin is used in topical
formulations
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Drug resistance is an increasing problem
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Chloroquine is administered orally and is used in the treatment of P
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Quinine is administered orally or intravenously and is used as the treatment
against drug resistant p
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As red blood cells break down they release the haem
group which is toxic
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Quinine and its derivatives inhibit the parasite haem polymerase
enzyme
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Quinine is used to treat
severe malaria if artesunate, the drug of choice, is not available, though quinine requires
careful monitoring during treatment to avoid toxicity
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falciparum to chloroquine and mefloquine
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PZQ targets intracellular calcium
levels, thus disrupting the outer coat of helminth cells exposing helminth antigens to the host

immune system, additionally the structure of the worm is altered and as calcium levels are
affected so is muscle contraction and so the worm cannot attach to host gut wall and is thus
excreted

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