Antimicrobial Chemotherapy II

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					Microbiology                                                                     Transcriber: Sara McGowan
10/03/08                                                                                              38:49
Antimicrobial Chemotherapy II


17: In order to provide the proper treatment, you need to know what types of bacteria are likely to
cause the infection, so you can provide treatment while you’re waiting on lab results. It’s important that
you try to guide patient management with appropriate susceptibility tests.

18: Some of the terminology that you need to be familiar with. The minimum inhibitory concentration,
(MIC) is the lowest concentration of an antibiotic that inhibits visible bacterial growth. This is what is
measured by the numbers on the strip of the E-test. The MBC is not routinely done in the diagnostic
laboratory. It’s the amount of antibiotic that’s necessary that kills 99.9% of the bacteria in an inoculum.
You don’t usually have to kill all the bacteria in someone that has a normal immune system. As long as
you can stop it from growing, the host immune system will usually take care of the rest. If you have a
severe infection like endocarditis or meningitis or you have a patient with a suppressed immune system,
it’s more important to have an antibiotic that actually kills versus inhibiting bacteria. -Static drugs
inhibit growth and -cidal drugs kill them. You can measure –cidal activity of an antibiotic to see how
many bacteria it kills in vitro.

19: Agar disk diffusion is based on putting a filter paper disk with antibiotic on an agar plate that has
been inoculated with bacteria, incubate overnight and look for inhibition. The bigger the zone, the more
active the antibiotic. The zone sizes have been correlated with the MICs. You can look up on a table the
zone diameters to determine susceptibility. Why is 20mm susceptible and 15 mm resistant? When an
antibiotic is developed, a drug company has to determine the quantitative MICs and those are related to
the zone diameters. The bacteria are tested two ways: you measure the MIC of an antibiotic and then
you measure the zone that the antibiotic gives. If you know the MIC designation for susceptibility, you
can see which MICs give you that zone diameter. This is important for drug development.

For example, you have an oral or IV drug. You first determine the safe amount to give to someone
without side effects or toxicity. This is determined in animal studies. Then you have clinical trials to
determine what concentrations actually make people get better. You also have to measure the
concentration of the drugs. For example, you take a drug and you can get 4 ug per mL in the
bloodstream at the maximum dose without getting toxicity. So the circulating concentration is 4 ug and
you can measure how much it takes to inhibit the bacteria. If it takes 10 ug to inhibit the bacteria,
that’s not a good drug because it takes more drug to inhibit the bacteria than you can safely give to the
patient, so that would be resistant.

That’s how susceptible, intermediate or resistant are determined. If it’s susceptible drug, the MIC is
considerably lower than the safe amount you can get into a patient. If you have an intermediate
resistance, the MIC of the bacteria is close to what you can achieve in the body. If it’s resistant, it takes
more to inhibit the bacteria than you can give the patient. That’s how the data in the tables from MIC
and zone diameters are determined.

20: With the Etest, you measure the number on the strip. We did this with S. pneumoniae, measuring
penicillim, cephataxime and moxifloxacin. You saw that S. pneumoniae was resistant to the
Antimicrobial Chemotherapy II                                                                           pg. 2
Sara McGowan

cephataxime and penicillin. That’s a quantitative test. What’s the green bacteria? Pseudomonas (the
only green one he knows of).

21/22: In the hospital lab there’s the microscan machine. You put your microtiter plate in there. This
has the biochemicals analogous to the API strip across the top and dilutions of your antibiotics are at the
bottom. This is microbroth dilution MIC testing. If the antibiotic grows it will make turbidity and the
machine will read which wells have turbid growth. The lowest concentration with no bacterial growth is
the MIC. The machine is programmed with the antibiotic info and it gives you the interpretation of
results.

23: The agar dilution method is usually how drug companies determine the data. An agar plate is
treated with antibiotics and you plate bacteria to see if they grow. This can be used to screen for
oxacillin resistant S. aureus and vancomycin resistant Enterococcus. This is used to look at one antibiotic
at one concentration and it’s a qualitative test: is it susceptible or resistant? For most infections there
are several treatment options, but this is a yes or no for one drug so it’s used in a few special
circumstances.

24: You need to be familiar with these concepts. Susceptible and resistant are easy to understand. If
you have a bug with an intermediate result, you may be able to give maximum dosage, and you may be
able to get the concentration of antibiotic above the bacteria’s MIC. If you don’t have any other
alternatives, an intermediate may work. Or if you have a drug that’s concentrated in the urine and the
patient has a urinary tract infection, it may be appropriate.

25: There are a lot of things that are desirable properties in antibiotic design. You want it to have
selective toxicity: kills bacteria but not the patient. It needs to be water-soluble to get it spread out
through the tissues in the body. Ideally, you’d like it to kill bacteria but that’s not absolutely necessary.
It’s necessary if you have really sick patients with impaired immune systems and sever diseases, but in
most cases, a drug that inhibits bacteria but doesn’t kill it will work. You’d like to have high
concentrations achieved in the body and a long half-life. You get much better patient compliance if you
can give the medicine once a day versus 4 times a day.

You’d like for it to have a broad spectrum. If you don’t know what bacteria a patient has, you’d like one
drug that will get several different bugs. Unfortunately, with very sick patients, you often don’t know
what the bacteria is and you don’t have one antibiotic that will get all of the them, so you have to start
people with several drugs until you know what they have and you can treat it. You don’t want to miss
anything.

You also don’t want to affect the normal flora too much. If you give something for more than a few days
and upset the normal flora, the patient is a t risk for yeast infections or pseudomembranous colitis from
Clostridium. You’d like one that doesn’t easily induce resistance. You want it so potent that it kills the
bacteria in an essential component that the bacteria can’t recover from and develop resistant. Also,
you’d like one without toxicity or side effects. No single antibiotic gets a perfect score in all categories.
The ones on the market at least have several of these attributes.
Antimicrobial Chemotherapy II                                                                            pg. 3
Sara McGowan

26: Be aware of the concepts in choosing antibiotics for patients. Think about where the infection is,
what you’re treating, where the drug is concentrated, where it’s metabolized. If someone has kidney
failure, you don’t want to give them an aminoglycoside. If you’re using antibiotics, you may not be
managing the patient’s medical conditions, but you have to know about the condition in case you’re
giving them an antibiotic that may have an adverse effect on their condition. There may be
contraindications.

Some drugs can only be given parenterally (IV); they are not good for outpatient use. In order to
minimize resistance, you’d like a drug with long half like, kills bacteria quickly that you use for a short
period of time. The Z pack was revolutionary because it was only five days. It used to be ten days for
antibiotics. Azithromycin for respiratory infection is a five-day treatment. Some drugs are a one-day
treatment. Bactericidal versus bacteriostatic has been mentioned.

Some antibiotics kill by concentration, so the higher the concentration in the body, the greater the
killing. Others kill by time; the greater length of time above the MIC, the better they kill, but it doesn’t
increase with higher concentrations.

27: Already talked about.

28: In many cases you have to give multiple drugs together. You open the door for toxicities and
interactions, but sometimes you don’t know what you’re treating or you have more than one type of
infection at the same time. In TB, you have to use more than one drug to prevent resistance. In some
cases, like the trimethrim and the sulfamethoxazole you can get synergy. There are risks if you do this.
If you mix things together, you are likely to make people sick, you can get a super infection that has
come out because it’s resistant to both of them and treatment is usually more expensive.

You can also get antagonism. When people were first learning about antibiotics and someone had S.
pneumoniaea meningitis they would get penicillin, which kills streptococcus by inhibiting cell wall
formation. It makes sense to add tetracycline to the treatment that blocks protein synthesis. That
should kill the bacteria faster. The problem is that tetracycline is a static antibiotic, it doesn’t kill the
bacteria but its stops them from dividing. If they are not dividing, penicillin can’t kill them. That’s an
antagonistic effect. If you’re going to mix antibiotics, you mix cidal with cidal. Penicillin with
aminoglycoside works well together, because aminoglycosides are also cidal; they inhibit growth and kill
bacteria. Static and cidal together is usually not a good combination.

29: There are many cases to give prophylaxis, that is, give antibiotics to prevent infection rather than
treat. Dentists always give antibiotics to prevent endocarditis following dental work, if the patient has a
history of heart disease or murmur. There are ADA guidelines for standard care. Like the people who
cared for the patient in the ER with meningococcal meningitis are taking antibiotics to prevent infection.
People with AIDS get antibiotics to prevent opportunistic infections.

It sometimes causes problems and resistant organisms. It’s common practice for people who get repeat
urinary tract infections to get suppressive antibiotics, which can cause resistant bacteria to infect
Antimicrobial Chemotherapy II                                                                             pg. 4
Sara McGowan

anyway. It’s a standard of care with operations in the GI tract to give antibiotics intraoperatively to
prevent infection.

30: We use lots of antibiotics. The most common reason that antibiotics are given in the USA is for ear
infections in kids. Ear infections in kids are getting more common: 8-10 million Rx per year. Parents put
a lot of pressure on the pediatrician to give antibiotics. So, drug resistance is becoming a problem.

31: Penicillin came out around the time of WWII. Penicillin was the only antibiotic at the time and it was
used to treat everything and resistance came along, so antibiotic resistance has been around since the
dawn of antibiotics. When penicillin was introduced in 1943, all of S. aureus was susceptible to it and
within 2 years it was 90% resistant; it made beta-lactamase.

32: There is selective pressure from antibiotic use. Selective pressure is the environmental conditions
that enhance the ability of bacteria to develop resistance and proliferate. You can have spontaneous
mutation that naturally occurs to make bacterial resistance or there can be acquisition of new DNA from
a plasmid, transposon, bacteriophage or conjugation. Bacteria exchange genetic information and part of
that can be genes that encode antibiotic resistance.

Organisms with mutations in genes probably would not survive if it were not environmental conditions
that encouraged their emergence. Resistant bacteria usually aren’t more virulent and don’t grow as fast
or colonize as well. But the fact is that they can live when the susceptible bacteria can’t and we select
for them when we kill off everything else.

33: Where do we get antibiotic resistant bacteria? This diagram shows the different ways. There are the
day cares, people going back and forth from hospitals and nursing homes. Poor infection controlled
practices ease the spread of infections. There is a very low threshold for giving people antibiotics. Third
world countries you don’t need a prescription to get antibiotics. You can buy them at the store and take
them like you want. For example, someone comes from Mexico to have coronary artery bypass and
they bring resistant organisms with them to the hospital and leave them behind. We put antibiotics in
animal food, which makes the bacteria immune to the antibiotics and we get bacteria from
contaminated animal food.

34: There are a lot of reasons we’re seeing more of this in the hospital. People are sicker than ever.
Unless you are really bad off, you don’t get to stay in the hospital, so you’re sick and less able to fight
infection. There are a lot of immunocompromised patients. There are a lot of devices put into people
and allow bacteria to get into their bodies easier. It’s difficult to police people with contagious diseases
and isolate them. Prophylaxis is given unnecessarily. For example, a surgeon was giving vancomycin to
every patient before heart surgery and they stayed on it for their stay in the hospital. He was breeding
vancomycin-resistant bacteria in these people.

35: Why do some bugs get resistant and others don’t? When penicillin came out, staph was susceptible
and was resistant within 2 years. S. pyogenes has been around for the same length of time and is 100%
susceptible to penicillin still. It’s because of the genetic makeup of the bacteria.
Antimicrobial Chemotherapy II                                                                         pg. 5
Sara McGowan

There are a lot of things that favor resistance. Think of three organisms: S. aureus, Enterococcus, P.
aeruginosa. They are three organisms that are resistant to a lot of antibiotics and they share these
factors in common: they are intrinsically resistant to a lot of antibiotics already, they readily exchange
genetic information with other bacteria, they readily survive in adverse environmental conditions, they
easily colonize, infect and transmit infections and they can be present in the body without you knowing
that they are there. Those are the ingredients of successful bacteria that become resistant.

36: What does it mean? People stay in the hospital longer or unnecessarily. More people die from
infection. People get the wrong treatment if the doctors don’t know they have resistant bacteria in
their hospital or community. You have to use more expensive and toxic drugs because the cheaper less
toxic ones don’t’ work. You have to do more lab tests on the patients to monitor safety because you use
toxic drugs. It means the spread of bacteria in the hospital that there’s no treatment for. Once they are
in the hospital they never go away.

37: It’s important to remember that it doesn’t make the organism more virulent, it’s just harder to treat.

38: There are two kinds of resistance: innate and acquired. We don’t worry about the innate. Innate
resistance is the example of vancomycim that works on gram-positive but not gram-negative bacteria.
Mycoplasmas are innately resistant to beta-lactams because they don’t’ have a cell wall; there’s nothing
for beta-lactam to inhibit. Chlamydia are innately resistant to beta-lactams because they only work on
extracellular bacteria, they don’t penetrate host cells. The innate or primary resistances have always
been there and they always will be. We are worried about the acquired resistance. That’s what we
have some means of influencing.

39: This reviews the different ways that bacteria pick up resistance genes. There are plasmids and
transposons that bring in new genes. Transformation is the uptake of free DNA from the environment
that may contain resistance genes. Bacteriophage are viruses that can enter with resistance genes. It’s
the acquired resistance that you worry about. There are also mutations, which is the changing of
genetic information to allow resistance.

40: S. pneumoniae, the most common cause of otitis media and community acquired pneumonias, was
universally susceptible to penicillin for many years. In the past 10 years, we’re seeing resistance
because of clonal spread. In 1978, a strain of penicillin resistant S. pneumoniae was identified. It
probably got resistant from transformation from a viridans strep. This bug has spread all over the world.
If you look at the strains of S. pneumo in the US that are penicillin resistant, most of them are one of 9
or 10 different clonal groups. It’s driven by selective pressure. When you get infected by this organism,
you’re not getting a plasmid bringing anything in or a mutation, you’re picking up a bug that’s already
resistant and there’s only about a dozen different strains spreading around the country. Just like the
hospital with MRSA, there are a handful of strains that go from patient to patient. It’s the same strains
that cause the same infections; it’s the same bug that we can never get rid of. It’s important to
understand that this is a clonal spread of just a few strains that are everywhere and are spread from
person to person.
Antimicrobial Chemotherapy II                                                                         pg. 6
Sara McGowan

41: This is an example of this. Enterococcus is a big problem in the hospital. There is vancomycin
resistant Enterococcus. These are pulsed field gel electrophoresis. This is how we type bacteria. These
are 14 patients at UAB hospital that were admitted in 1997, 1998 and 1999. They all got a vancomycin
resistant Enterococcus while they were at the hospital. From the DNA bands, broken up by restriction
enzymes, you see that everyone is identical. Every one of theses patients had exactly the same strain of
bacteria over a three year period of hospitalization in different parts of the hospital.

42: What’s going on in the bacteria, how are they developing resistance? There are multiple
mechanisms of resistance. Some bacteria have several different mechanisms of resistance that are
going on at the same time. There are sometimes multiple mechanisms of resistance to the same drug,
but just like there are a limited number of ways an antibiotic can inhibit bacteria there’s also a limited
number of ways bacteria can develop resistance. On way is the inactivation by enzymes; this is beta-
lactamase. There are other enzymes that bacteria can produce to break down other antibiotics, but this
is the best known one. Break down the antibiotic before it can get into the bacteria.

Another way is metabolic bypass. Trimethrim and sulfamethoxazole inhibits folic acid synthesis in
bacteria. The resistant bacteria figured out another way to get folic acid that doesn’t use the
intermediate that the sulfonamide inhibits.

There can be decreased permeability. The bacteria have genes that synthesize proteins or other
components of the envelope that prevent the drug from getting in. They may have a gene that encodes
for an efflux pump that binds the antibiotic and it goes in the cell and it pumps it back out. Erythromicin
resistance works like that.

The second most important mechanism of resistance is altered target. Fluoroquinolones inhibits DNA
gyrase, but if there’s a mutation in the DNA gyrase, the binding site of the quinolone is not recognized so
it doesn’t work anymore. An altered penicillin binding protein is what happened with MRSA. The
penicillin binding protein is mutated and it doesn’t bind the beta-lactams.

Most resistance can be classifies in one of those mechanisms.

43: Two mechanisms of beta-lactam resistance. Regular staph is resistant because of beta-lactamase
that breaks down the beta-lactams. MRSA is resistant because it has a different penicillin binding
protein that the beta-lactam can’t bind to.

44: Quinolone resistance by efflux pumps and mutations in the binding sites of the enzymes.

45: Many macrolide resistance mechanisms. Esterases break down macrolides. There can be efflux and
altered binding sites. In S. pneumoniae, some of the macrolide resistant strains have methylated their
ribosome. A gene encodes a methylase and the methyl group binds to the ribosomes and the antibiotic
can’t get in.

46: Already talked about
Antimicrobial Chemotherapy II                                                                       pg. 7
Sara McGowan

47: This is important for dentists and optometrists because you may be the first line in the healthcare
system that someone may come to. Anyone that you see that has a large abscess or lesion anywhere on
their body, it’s very likely to be MRSA because MRSA is no longer just a problem in the hospital. This is
important because the treatment is different from what many primary care physicians are used to
treating. They would normally treat with a macrolide or a beta-lactam, but they don’t work. You usually
have to use more aggressive treatment. Clindamycin and sulfonamides usually will work. Draining the
abscess is important. We now see most staph are methicillin resistant. It complicates treatment and is
very easily spread and now these community-acquired staph are getting into the hospital. We have to
use vancomycin on severe infections.

48: This is over the last 10 years at UAB. It’s gone from less than 30% to about 60% and 5 out of every
1000 people admitted to the hospital have an MRSA infection. This is important because Medicare and
insurance companies say they are no longer going to pay for infections and complications that people
get while they are in the hospital. So, hospitals have to work harder to prevent infections because they
are note getting reimbursed.

49: Another big problem (numerically not as big a problem as MRSA) is extended spectrum beta-
lactamase producing gram-negative bacteria. These bacteria produce beta-lactamases that have
mutated so that even the beta-lactamase stable drugs like cephalosporins will no longer work. This is
mainly in E. coli and Klebsiella. Now we have to use more expensive drugs like carbapenems to treat
these infections.

In the laboratory it’s hard to find resistance as quick as possible. The FDA just approved a new PCR test
to identify MRSA faster. Normally, you take the patients blood and culture it and look for bacterial
growth, do a gram stain and plate the specimen. Now, if you have a gram-positive organism growing, a
PCR test can be done right then and determine if it’s MRSA. Results are 24 hours sooner. The machine
is one hundred thousand dollars and it’s $50 per test, so is it worth it? They are using it at the VA and
screening every patient for MRSA with a nasal swab and PCR. Results are given in 45 minutes and if they
have MRSA they are isolated. The federal government thinks it’s worth it because one MRSA infections
costs about 35 thousand dollars to treat, so you don’t have to prevent that many before you’ve paid for
it. Especially since you can’t get reimbursed for it anymore and patients are suing hospitals for
infections they get.

50: What can we do for drug resistance? Educate doctors that you don’t give antibiotics for viruses and
patients not to expect them, so you limit unnecessary antibiotics. Give the right dose and take it for as
long as you’re supposed to. Don’t give prophylaxis when it’s not necessary. Try to target the most likely
bug with the right drug and once you find out the bug that’s in your patient, change the treatment to
match the bug. The CDC has guidelines about antibiotic use that physicians and healthcare providers
should follow.

				
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