Principles of antimicrobial use

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History of antimicrobial therapy
Early 17th century The first recorded successful use of antimicrobial therapy involving the use of an extract from cinchona bark for the treatment of malaria.
1909 Paul Ehrlich's quest for a "magic bullet" that would bind specifically to particular sites on parasitic organisms leads to an arsenic derivative, salvarsan, with modest activity against syphilis. He also suggested that antimicrobial drugs would be most useful if the sites of action were not present in the organs and tissues of the human host.
1929 Alexander Fleming discovers penicillin.
1935 Discovery of prontosil, a forerunner of sulfonamides.
1940 Florey and Chain first use penicillin clinically.
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Principles of antimicrobial use
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12 Factors to consider when selecting
antimicrobial agents for therapy in patients 1.
Is an antimicrobial agent necessary? 2.
Identification of the pathogen 3. Empiric versus
directed therapy 4. Susceptibility of infecting
microorganism
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12 Factors to consider when selecting
antimicrobial agents for therapy in patients 5.
Need for bactericidal versus
bacteriostatic agent 6. Pharmacokinetic and
pharmacodynamic factors 7. Anatomical site of
infection 8. Cost 9. Toxicity
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12 Factors to consider when selecting
antimicrobial agents for therapy in patients
10. Host factors Allergy history Age
Renal function Hepatic function Pregnancy
status Genetic or metabolic abnormalities Host
defenses function
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12 Factors to consider when selecting
antimicrobial agents for therapy in patients
11. Need for combination therapy 12.
Antibiotic resistance concerns
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• 1. Is an antimicrobial agent necessary?

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viral infections that do not respond
to antibiotics noninfectious processes
mimicking a bacterial infection culture
isolation of an organism that is colonizing
an anatomical site and not causing an
infection
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In general, the clinician should resist
temptation to begin antimicrobial therapy unless
there is a reasonable probability that a
bacterial infection is present.
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When the downside risk of withholding therapy is
great, such as with bacterial meningitis or in
clinically unstable patients, therapy should be
started without delay even when the presence of a
bacterial infection is uncertain.
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Another indication for antimicrobials is
prophylactic therapy, which is intended to
prevent illness in someone at risk of infection.
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• 2. Identification
• of the pathogen

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Characterization of the organism is central to
selection of the proper drug.
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Presence and morphologic features of
microoganisms in body fluids that are normally
sterile.
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Culture the infective organism to arrive at a
conclusive diagnosis and to determine the
susceptibility of antimicrobial agents.
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3.Empiric versus directed therapy
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The acutely ill patient with infections of
unknown origina neutropenic patienta patient
with severe headache, a rigid neck, and
sensitivity to bright lights(meeningitis)
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Therapy is initiated after specimens for
laboratory analysis have been obtained but before
the results of the culture are available.
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The choice of drug in the absence of
susceptibility data the site of infection the
patient's history
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Broad-spectrum therapy may be needed initially
for serious infections when the identity of the
organism is unknown or the site makes a
polymicrobialinfection likely.
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A gram-positive coccus in the spinal fluid A
newborn infant most likely to be Group B
Streptococcus. sensitive to penicillin G. A
forty-year old patient most likely to be S.
pneumoniae. frequently resistant to penicillin
G, sensitive to a third-generation cephalosporin
or vancomycin.
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4.Need for bactericidal versus
bacteriostatic agent
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Bacteristatic drugs arrest the growth and
replication of bacteria at serum levels
achievable in the patient, thus limiting the
spread of infection while the bodys immune
system attachs, immoblilizes, and eliminates the
pathogens.
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Bactericidal drugs kill bacteria at drug serum
levels achievable in the patient. They are more
aggressive compare with bicteriostatic
antimicrobial drugs .
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A given agent may show bactericidal actions under
certain conditions but bacteriostatic actions
under others, depending on the concentration of
drug and the target bacteria.
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A bacteriostatic agent often is adequate in
uncomplicated infections because the host
defenses will help eradicate the microorganism.
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Bactericidal agents are required for management
of infections in areas "protected" from host
immune responses, such as endocarditic
vegetations and cerebrospinal fluid (CSF).
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5. Determination of antimicrobial
susceptibility of infective organisms
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In the laboratory, susceptibility is most often
measured using a disk diffusion test
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Stokes controlled sensitivity test
.
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In the Stokes controlled sensitivity test, a
control organism is inoculated on part of a plate
and the test organism is plated on the remainder.
Disks are placed at the interface and the zones
of inhibition are compared.
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The use of a sensitive control shows that the
antibiotic is active, so that if the test
organism grows up to the disk it may safely be
assumed that the test organism is resistant to
that drug.
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An alternative measure of susceptibility is to
determine the Minimum Inhibitory Concentration
(MIC) and the Minimum Bactericidal Concentration
(MBC) of a drug.
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A series of broths are mixed with serially
diluted antibiotic solutions and a standard
inoculum is applied. After incubation, the MIC is
the first broth in which growth of the organism
has been inhibited.
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The more resistant an organism is, then the
higher will be the MIC.
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The MBC is measured by inoculating the broths
used for MIC determinations onto drug-free
medium. The MBC is the first dilution at which no
growth is observed.
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Cidal drugs have MBC values that are close to the
MIC value for particular organisms. With static
agents, the MIC is much lower than the MBC.
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The MIC/MBC test of a moderately resistant
bacteriostatic drug. Note that once the bacteria
are removed from the drug they can grow on drug
free medium at most concentrations.
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The MIC/MBC test of a moderately resistant
bactericidal drug. The bacteria removed from the
drug cannot grow on drug free medium. One tube
difference is allowed in this test.
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6. Pharmacokinetic and pharmacodynamic
factors
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Oral peak concentrations 1 to 2 hours may be
delayed by food or delayed intestinal transit
vary widely in their oral bioavailability
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Most life-threatening infections are treated, at
least initially, with IV agents.
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Parenteral therapy ensures adequate serum levels,
and, for many agents, higher drug levels can be
achieved when administered IV.
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The amount of drug that reaches the
extravascular tissues and fluids depends on
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? the concentration gradient between plasma and
target tissue, ? degree of drug binding to
plasma and tissue proteins, molecular size,
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? degree of ionization and lipid solubility of
the drug, ? its rate of elimination or
metabolism.
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concentration-dependent killing
Fluoroquinolones and aminoglycosides kill
bacteria faster at higher concentrations.
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Post-antibiotic effect (PAE) These agents also
continue to inhibit growth of bacteria for
several hours after the concentrations of the
drug fall below the MIC in the serum.
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The Post-Antibiotic Effect (PAE) shows the
capacity of an antimicrobial drug to inhibit the
growth of bacteria after removal of the drug from
the culture.
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To determine the PAE a liquid culture with an
initial count of 106 to 107 colony forming units
(CFU) per ml is exposed to a certain
concentration of the drug for a certain time. A
control group is left untreated.
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After the given time, drug of the treated
culture is removed, e.g., by dilution 11000 in
fresh, drug-free medium. The same procedure is
applied to the untreated control. The time it
takes for both colonies to increase their CFU by
1 log10 is measured.
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PAE is defined as the time needed by a culture
that was treated with an antibiotic to
increase in number (CFU) by 1 log10 compared to
untreated controls, and is usually given in
hours.
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The PAE provides additional time for the immune
system to remove bacteria that might have
survived antibiotic treatment before they can
eventually regrow after removal of the drug from
the animal's organism.
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A longer PAE can therefore influence the clinical
outcome of antimicrobial therapy.
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Most ß-lactam agents do not exhibit
concentration-dependent killing nor do they have
a prolonged post-antibiotic effect.
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7. Anatomical site of infection
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The site of infection often influences not only
the agent used but also the dose, route, and
duration of administration.
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The desired peak concentration of drug at the
site of infection should be at least 4 times the
MIC.
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However, if host defenses are adequate, peak
oncentrations may be much lower and even be equal
to the MIC and still be effective.
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When host defenses are absent or inoperative,
peak concentrations 8- to 16-fold greater than
the MIC may be required.
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Blood-Brain Barrier
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1.Lipid solubility (quinolones vs
penicillin)2.Molecular weight (vancomycin)3.Prot
ein binding
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Readily Enter CSFChloramphenicolSulfonamidesTr
imethoprim ?????? Rifampin ???
Metronidazole ???
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Enter CSF When Inflammation PresentPenicillin G
Ampicillin????Pipera
cillin???? Oxacillin????Nafcillin?
??? Cefuroxime????Cefotaxime?
??? Ceftriaxone ????Ceftazidime????
Aztreonam???Ciprofloxacin????
Vancomycin????Meropenem????Cefepime???
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Do Not Enter CSF Adequately to Treat Infection
Cefazolin ????
Cefoxitin???? Erythromycin?????
Clindamycin????
Tetracycline ??? Gentamicin????
Tobramycin ????
Amikacin????
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Endocarditis MeningitisOsteomyelitis foreign
body abscesses organisms that can survive
within phagocytic cells (Mycobacterium,
Salmonella)
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8. Cost
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9. Toxicity
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Because of nephrotoxicity and ototoxicity,
aminoglycoside use has decreased with the
development of ß-lactams and fluoroquinolones
with broad gram-negative activity.
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10. Host factors
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Allergy history
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Significant allergy appears to be more common
with ß-lactams, particularly penicillins, and
sulfonamides.
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In anaphylactic reactions to penicillins, the IgE
antibody is usually directed at the penicillin
nucleus, so the potential for allergic reactions
to other penicillins is high.
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Age
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Renal function
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Antimicrobial agents that require dosage
adjustment include aminoglycosides, vancomycin,
certain penicillins, most cephalosporins,
carbapenems(?????), and quinolones.
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Failure to adjust dosage can lead to ototoxicity
from aminoglycosides and neurotoxicity from
penicillins, imipenem, or quinolones.
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Aminoglycosides can cause renal toxicity and
should be used with caution in patients with
preexisting renal insufficiency.
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aminoglycosides vancomycin certain penicillins
most cephalosporins carbapenems ?????
quinolones
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Hepatic function
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Antimicrobials metabolized in the liver include
chloramphenicol, erythromycin, clarithromycin,
rifampin, nitroimidazoles, and some of the
quinolones.
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Pregnancy status
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Agent Potential Toxicity
Sulfonamides Hemolysis in newborn with glucose-6-phosphate dehydrogenase deficiency
Tetracyclines Limb abnormalities, dental staining, inhibition of bone growth
Trimethoprim Altered folate metabolism
Quinolones Abnormalities of cartilage
Vancomycin Possible auditory toxicity

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Agent Potential Toxicity
Aminoglycosides Eighth nerve damage
Chloramphenicol Gray baby syndrome
Erythromycin estolate Cholestatic hepatitis (???????) in mother
Metronidazole Possible teratogenicity ???
Nitrofurantoin Hemolytic anemia
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Genetic or metabolic abnormalities
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Genetic abnormalities of enzyme function may
alter the toxicity of certain agents.
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hemolysis in glucose-6-phosphate
dehydrogenase-deficient people can be provoked by
sulfonamides, nitrofurantoin, pyrimethamine
(????), sulfones(?), and chloramphenicol.
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Host defenses function
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An absence of white blood cells predisposes a
patient to serious bacterial infection, and
bacteriostatic agents are often ineffective in
treating serious infections in neutropenic hosts.
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The critical white blood cell count is between
500 and 1000 mature polymorphonuclear cells/mm3.
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11. Antimicrobial combinations
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To treat a life-threatening infection To treat a polymicrobial infection Empiric therapy when no one agent is active against potential pathogens To achieve synergy (obtain enhanced antibacterial activity) To prevent the emergence of resistant bacteria To permit the use of a lower dose of one of the antimicrobial agents
Box 44-3 Reasons for concurrent use of more than one antimicrobial agent in a patient
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indifferent effects The combined activity
equals the sum of the separate activities.
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Synergism ( ??) is present if the activity of the
combined antimicrobial agents is greater than the
sum of the independent activities.
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Combinations of antibiotics are antagonistic when
the activity of the combination is less than
could be achieved by using the agents separately.
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The combination of an inhibitor of cell-wall
synthesis with an aminoglycoside antibiotic
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The combination of agents acting on sequential
steps in a metabolic pathway
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The combination of agents in which one (such as
an inhibitor of ß-lactamases) inhibits an enzyme
that inactivates the other compound, such as
clavulanate with amoxicillin
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Antibiotic decision making after therapy has
started
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Infection Duration (days)
Streptococcal pharyngitis 10
Otitis media ??? 5-10
Sinusitis ??? 10
Uncomplicated urinary tract infection 3
Pyelonephritis ???? 14
Cellulitis ???? 3 days after inflammation resolves

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Infection Duration (days)
Pneumococcal pneumonia 3-5 days after fever resolves
Other pneumonia variable, often 14
Bacteremia variable, often 10-14 days without endocarditis
Endocarditis 28-42
Meningitis 7-14
Osteomyelitis 42
Septic arthritis 21
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12. Antibiotic resistance concerns
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Prevalence of antibiotic resistant bacteria
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Resistance in nosocomial (??) infections
Nowadays, About 70 percent of the bacteria that
cause infections in hospitals are resistant to at
least one of the drugs most commonly used for
treatment
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Resistance in nosocomial (??)infections Some
organisms are resistant to all approved
antibiotics and can only be treated with
experimental and potentially toxic drugs (e.g.
MRSA?????, Pseudomonas???)
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Resistance in community acquired infections
Staphylococci - up to 60 MRSA (Methicillin
Resistant Staph Aureus)
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Resistance in community acquired infections
Pneumococci (Streptococcus pneumoniae) - 25
resistant to penicillin, while a further 25 are
resistant to more than one antibiotic
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Resistance in community acquired infections
Mycobacterium tuberculosis - 5 are multiple drug
resistant (MDR)
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Antibiotic resistance can be intrinsic or
acquired. Pseudomonas aeruginosa outer membrane
Acquired resistance can be due to mutation of
existing genetic information or acquisition of
new genes.
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Spontaneous mutation mutation and selection
of antibiotic resistant mutants in the
presence of the antibiotic vertical gene
transfer to progeny results during normal
cell division
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Lateral or horizontal gene transfer (HGT)
genetic material contained in small packets
of DNA can be transferred between individual
bacteria of the same species or of
different species
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Three mechanisms of HGT Conjugation ??
Transformation ?? Transduction ??
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Conjugation occurs when there is direct
cell-cell contact between two bacteria and
transfer of small pieces of DNA called plasmids
takes place
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Transformation pieces of DNA are taken up from
the external environment
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Transduction bacteria-specificviruses
(bacteriophages) transfer DNA between two
closely related bacteria
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Mechanisms of bacterial resistance to antibiotics
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reduced uptake into cell 1. Reduced uptake
into cell2. Active efflux of antibiotic from the
cell 3. Eliminate or reduce binding of
antibiotic to cell target 4. Enzymatic
cleavage or chemical modification
inactivates antibiotic molecule5. Metabolic
bypass of inhibited reaction 6. Overproduction
of antibiotic target
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Reduced uptake into cell Antibiotic must be
transported by cell.A mutation in the transport
system genecould eliminate uptake.
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Decreased uptake has been described for
aminoglycosides, some ß-lactams, tetracyclines,
and others.
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Active efflux of antibiotic from the cell
Antibiotic is pumped out of the cell at a rate
equal to the rate of entry
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Efflux pumps are the main mechanism of resistance
for tetracyclines and have also been described
for quinolones.
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Eliminate or reduce binding of antibiotic to cell
target Antibiotic must be bound to cell surface
before transport. Mutation in thebinding protein
gene reduces ability of antibioticto bind to
cell surface
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Enzymatic cleavage or chemical modification
inactivates antibiotic molecule Antibiotic is
degraded or chemically modified in some way
losing functionality
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ß-lactamases catalyze the hydrolysis of
penicillins, cephalosporins, and other ß-lactams.
When hydrolyzed, the ß-lactam is unable to bind
to bacterial transpeptidases and other enzymes
needed for cell wall synthesis and repair.
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Many enzymes have been described that inactivate
aminoglycosides.
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Metabolic bypass of inhibited pathway
Bacterium develops a new pathway which bypasses
the inhibited reaction(s)
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Some thymidine-requiring streptococci are not
inhibited by trimethoprim and sulfonamides.
because the resistant bacteria produce adequate
concentrations of thymidine nucleotides by an
alternative pathway and as a result survive
exposure to these drugs. exposed to these agents.
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Overproduction of antibiotic target Bacterium
speeds up the inhibited reaction or produces
excessive amount of the antibiotics target,
thereby mopping up the antibiotic and allowing
the uninhibited reaction to proceed
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Combating Antibiotic Resistance
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Defining the Problem Not enough new
antibiotics to cope with the development of
resistance to old antibiotics
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Defining the Problem Widespread misuse of
antibiotics in agriculture and by patients and
health care workers in med/vet situationse.g.use
of antibiotics as feed additives given to farm
animals topromote growthunnecessary antibiotic
prescriptions
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Solving the problem Pharmaceutical companies
need new, less costly strategies to develop
antimicrobials
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Solving the problem Regulate use of
antibiotics as feed additives promote growth
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Solving the problem Stop administration and
uses of antibiotics for viral infections or
non-medical purposes
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Antimicrobial prophylaxis in surgery. Medical
Lett 2001 4392. Gold HS, Moellering RC Jr.
Antimicrobial-drug resistance. N Engl J Med 1996
3351445-1453. Steinberg JP, Blass MA.
Non-surgical antibiotic prophylaxis. In
Schlossberg D Current therapy of infectious
diseases, Philadelphia, Mosby-Harcourt Health
Sciences, 2000.