‫بسم ال الرحمن الرحيم‬

Before starting , I wanted to notify some points, this lecture was the
lecture we had after the anatomy first exam , it was a real mess .. We were
a bit noisy, the record was not that clear... The lecture starts at slide
number 42.. The record we got starts 3 slides later...Slide 45 … I've just
copied the slides for the first missing three and for the other parts which
were not clear I've added some notes from our textbook. That was the best
we could do ,sorry for any mistake. The S.R

Synergism Versus Antagonism:

– Synergism is when 2 antimicrobial agents are used together to produce a

degree of pathogen killing that is greater than that achieved by either drug
alone. Synergism is a good thing!
– Antagonism is when 2 drugs actually work against each other. The
extent of pathogen killing is less than that achieved by either drug alone.
Antagonism is a bad thing!

Antimicrobial Combinations Indications for Use

_ Prevention of the emergence of resistant organisms
_ Polymicrobial infections
_ Initial therapy
_ Decreased toxicity
_ Synergism

Now the 2 concept that we need to understand whenever we talk about

:antimicrobial resistance
1. The MIC: minimal inhibitory concentration
The MIC is the lowest conc. Of any microbial agent require to inhibit the
growth of a microbe. In other words :the lowest concentration of the
antimicrobial agent required to achieve a bacteriostatic effect.
2. The MBC: minimal bactericidal concentration
The MBC the lowest conc. Of antimicrobial agent require to kills 99.9%
of the population, ex, if you have 1000 bacterial cells and you add a
certain conc. Of drug at the MBC, only 1 cell will survive. So MBC
.doesn't mean kill all organisms, just 99.9% of them or more

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We can see that a certain organism is susceptible to a certain drug, if you
can give the patient a certain dose of anti microbial agent that can be to
achieving the MIC at the certain infected tissue, because we cannot give
the patient unlimited amount of microbial agent, just only minimal conc.
Other while you cannot achieve the MIC conc. Of a tissue of the patient
.that you considered that the resistant to the drug
Susceptible: The MIC of the organism can be achieved
in the body at recommended doses.
.Resistant: The MIC cannot be achieved
Multiple ways that you can measure the MIC & MBC for a particular
drugs toward a particular pathogen, regard to MIC there is the (disk
diffusion test & dilution test), you can skip this because you will learn it
in the lab. Regarding the MBC there's also another way we usually go
.through a tube dilution method
Because you are going to learn all these in the lab. we will skip them in
.the theory
As you heard in lectures and news there are many microorganisms that
there are resistant to anti microbial agents.So the major problems in
:medicine regarding antimicrobial agent resistant
• a strain of Staphylococcus aureus called Methicillin Resistant
(MRSA)
• Vancomycin resistant enterococci (VRE) and
staphylococci(Vancomycin resistant)
• also Penicillin resistant Streptococcus pneumonia,causing bacterial
pneumonia in humans .now we are having more and more stains of
Penicillin resistant.
• Multiple antibiotic resistant Gram-negative bacilli ,localized with
various infections.
• Multiple antibiotic resistant Mycobacterium tuberculosis; Multi-
Drug Resistant (MDR-TB); Extensively Drug-Resistant (XDR-
TB).

Regarding the method of resistance, some organism are naturally

:resistant to a certain drugs because
1-They lack the target of the drug.

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2-some drug require entry to the cell,so some drug cannot naturally enter
the cell membrane or the cell wall. So that’s what's called intrinsic
resistance or natural resistance. example of this sederemones eregenosa;
its membrane have very weak permeability towards a lot of drugs that can
fit another organisms.
In contrast to intrinsic resistance some organism acquire resistance to
drug that used to be active against it, example streptococcus pneumonia
that treat with penicillin but now they acquire a various gene or mutation
that make it resistant to penicillin. We have multiple ways to acquire
:resistance
> anti microbial agent before enter the cell need to bind a certain cell
membrane receptor ,so a mutation to the cell membrane receptor or
the drug binding side ,will make the drug not able to bind and the
microbe become resistant to the drug, sometimes the cell membrane
itself will encounter some mutation and will not allow the drug to
pass through the cell wall,
> Also some organism use enzyme or acquire enzyme that can
inactivate the drug, example B-Lactamases.
Usually the way bacteria acquire resistant gene is through manly
conjugation, if you remember when we talked about conjugation ,we said
a plasmid which has multiple genes that transfer through conjugation is
.called resistant factor or R factor
> Another mechanism in which bacteria can be resistant to multiple
drugs at the same time is by receiving a gene that encode for a
MDR pump (multidrug resistance), so this pump extent on the cell
membrane and take all the antibiotic that enter the cytoplasm and
pump it outside the cell .
(The table summarizes the various methods (table 9-7
That was about the general mechanism now will talk about specific
method regarding each of the important group of the anti microbial
.agent
For penicillin and cephalosporin which are both B-lactam drug, many
bacteria are able to escape from the Pencillin drug by producing β-
lactamese enzyme which can hydrolyze the B-lactam ring; for the drugs
that are B-lactamase resistant, the enzyme itself (that target the B-lactam
ring )can undergo mutation that don't allow the Penicillin or
. cephalosporin to bind

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For tetracycline we mentioned last time that many bacteria actively pump
tetracycline inside the cell so one way to become resistance to tetracycline
.is to pump the tetracycline out the cell
For Chloramphenicol and Aminoglycosides some bacteria basically
encode enzymes that chemically modify the 2 drugs to make them
.chemically inactive
For Sulfonamides & Trimethoprim, inhibit two enzymes in the
tetrahydrofolic acid pathway, bacteria become resistance by having
.backup copies of the two enzymes that are not affected by the drug
Finally Erythromycin & Lincomycin , target is rRNA in the 50S unit of
the ribosome, so one way that bacteria become resistance to the drug by
undergoing enzymatic modification (methylation) of 23S rRNA that will
.not allowed the drug to bind it
So here are the two B-lactamasese ,the penicillase which inactivate the B-
lactam ring in penicillin and penicillin derivatives. And the
cephalosporinase which hydrolyses the B-lactam ring of the
cephalosporin .So this is one way bacteria can become resistant to
Pencillin and cephalosporin ;and the second way I mentioned is that the
transpeptidases,which are diluted drugs undergo mutation that doesn't
.,allow this drug to bind
So this are some examples of aminoglycoside, and these basically can
metabolic by various enzymes of the bacteria so these become
Phosphorylated, Adenylated and Acetylated and thus making these drugs
. inactive
And this is how some bacteria become resistant to Sulfonamides &
Trimethoprim ,so these 2 enzymes, synthetase & dihydrofolate reductase,
are target by these 2 drugs, so the bacteria that's resistant to these drugs
replaces these enzymes with other versions that are not resistant to the
.drug
This is tetracycline resistance, so this enzyme is actively pumped inside
.the cell, and the resistance organism acquire a gene for the efflux pump

Some Strategies in the War Against Drug Resistance

(The doctor just read the slide .. Without adding a word )
> Education of healthcare professionals and patients
> Patients should stop demanding antibiotics every time they are, or
their child is, sick

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 > Physicians should not be pressured by patients and should prescribe
drugs only when warranted
> Clinicians should prescribe a narrow-spectrum drug if lab results
indicate that it kills the pathogen( don't need a broad spectrum,
don't need to kill all organism if you know the pathogen)
> Patients should destroy any excess or out-dated medications
> Antibiotics should not be used in a prophylactic manner( as if you
feel like .. an infection is to occur, you shouldn't take an
antimicrobial agent in order to prevent this infection, even before
happening )
> Healthcare professionals should practice good infection control
> Patients should take drugs in manner prescribed
> Elimination of antimicrobial agents from animal feeds
So they key words are Prevent Infection; Diagnose & Treat Effectively;
Use Antimicrobials Wisely.

Empiric therapy
Sometime if we had medical emergence the physician can't wait for lab
results ,so if the physician knows that there's an infection and highly
suspects that E.coli is the cause of this infection he can start to give the
patient the drug that he knows is effective with E.coli . so basically the
physician make an "educated guess" based on past experience with the
type of infection disease and the most effective drugs. And there are many
factors that determine what drug we have to give the patient in the empiric
.therapy
> One important aspect is called pocket chart, (the doctor read some
of the chart's numbers you can find it in the slide and read it all if u
want). Pocket chart For aerobic Gram-negative bacteria. The chart
is a quick reference whenever empiric therapy is necessary. So
based on this chart if you get a patient with medical emergence
with resistant E.coli you can give the patient one of these affective
drugs listed in the orange arrow in the table (vertically).
> You have to know if the patient allergic to any drugs, many people
allergic to penicillin and you can't give them Penicillin because
they might have prophylactic shock (I'm not sure about this) and
might die even.
> The age of the patient is very important, not all drugs can be given
to all age's groups.

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 > If the patient is pregnant ,some drugs are known as teratogenic
,meaning that they can lead to growth abnormalities .
> Whether the patient is Inpatient or outpatient, whether need to stay
in hospital or can go home; if he's an inpatient (needs to go inside,
hospital or clinic) you can give him some drugs that can't be given
outpatients; some drugs should be administrated intravenously and
therefore can’t be prescribed to outpatients which can be given
optical or oral agents.
> Site of infection is very important; not all drugs are active to all
body tissues, or some might concentrate in other tissue more than in
others.
> Some antimicrobial; agent might have cross reaction with other
microbial agents that can be harmful to the patient.
> If the patient has any medical problems.
> If the patient is leukopenic or immunocompromised; patient with
compromised immune system should not be given bacteristatic
agents, should only be given bacteriocidial agents.
> The cost of the drug.

Undesirable Effects of Antimicrobial Agents:

 One side effect (reason, outcome) of not using antimicrobial agents

properly is that you will end up with new strains that are resistant to
resistance drug; this is known as selecting for resistant organisms.
 If it's given (the antimicrobial agent) randomly, not carefully, the
patient may become allergic to the agent.
 Many agents are toxic to humans and some are very toxic.
 With prolonged use,(at each infection,) a broad-spectrum antibiotic
may destroy the normal flora, resulting in an overgrowth of bacteria
known as a super infection .The person has no longer indigenous
micro flora and thus becoming more susceptible to infections
caused by opportunistic invaders.

Slide 68 : Selecting for drug-resistant organisms

This is located in your body ,when you have an infection :most of the
organisms in that site will be sensitive to the antimicrobial agent that is to

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be given ,and a few will have already a developed mutation that make
them resistant to the drug … the continuation was not clear ,I'll copy the
referred part from the textbook:
The first picture is indigenous micro flora of a patient before initiation of
antibiotic therapy. Most members are susceptible (sensitive) to the
antibiotic to be administrated; very few are resistant.
The second picture: after antibiotic therapy has been initiated, the
susceptible organisms are dead, only few resistant organisms remain;
The third picture: as a result of decreased competition for nutrients and
space, the resistant organisms multiply and become predominant
organisms in the patient's indigenous micro flora.

You all know that we have human infection with protozoa and fungi and
also with viruses.
 Antiprotozoal Agents: Antiprotozoal agents are usually toxic to
the host.
They work mainly by :
- Interfering with DNA and Rna synthesis
- And by interfering with protozoal metabolism
 Antifungal Agents: Most antifungal agents work in one of 3ways:
– By binding with cell membrane sterols
– By interfering with sterol synthesis
– By blocking mitosis or nucleic acid synthesis

We have a problem with antiprotozoal and antifungal agents ,these two

organisms are eukaryotes ,so many of the targets ,to some extents, are
somewhat similar to human pathogens ,so human structures and human
enzymes. So they are associated with higher toxicity than antimicrobial
agents.

 Antiviral agents are the newest agents to develop because don't

undergo (don't have) any active metabolism. They use up host cells
to replicate themselves and some drugs have been developed that
are effective in certain viral infections, but not others; they work by
inhibiting viral replication within cells; (you can't target
antimicrobial cell and make an antiviral agent)
In some cases you have to give antiviral agent mixed, several drugs that
are administered at the same time ,together, are being used, as to treat
HIV infection.

Done By : Yazeed Al-Ajlooni and Sara Ibdiwi

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