Let's talk about the sulfonamides.
Now sulfonamides, are weak
acids and their congeners
or structurally similar to a chemical
called Para-aminobenzoic acid (PABA).
Which, is actually shown
in illustration right here.
Now, these are bacteriostatic
inhibitors of folic acid synthesis
and they may also be involved in
the production of faulty folic acid.
So, mammals obtain their folic acid from the diet,
whereas bacteria have to manufacture it.
Now, most of this particular
drug is going to be excreted
in the urine.
So, trimethoprim is often
added to the sulfonamides,
these are selective inhibitors
of dihydrofolate acid reductase.
It inhibits the bacterial form, it
prevents formation of tetrahydrofolate.
Now, bacterial dihydrofolate
reductase is five times more sensitive
to trimethoprim than the human
version of the same enzyme.
So, from a trimethoprim point of view,
it's really a non-issue.
We combine sulfamethoxazole with trimethoprim,
to create an agent called Septra
which is sold commercially
are also called SMP/TMP.
Now, bacterial synergy is obtained
because we're acting on two different levels
of the folic acid production pathway.
Now, the sulfonamides work
on this particular enzyme
at the top of this structure
and trimethoprim works on
dihydrofolic acid reductase
at the middle of this structural pathway.
These drugs are concentrated in the bladder,
so, they're particularly
effective in bladder infections.
Now, we also use this agent in,
pneumocystis carinii infections
and toxoplasmosis infections
in HIV-positive patients.
So, it's not just used in
urinary tract infections alone.
Now, Septra toxicity includes
which, are actually surprisingly common
a lot of patients are allergic to sulfa
and they will have a cross allergy to this agent.
There are also cross allergies
with other agents as well.
So, an example for this is if patients
are allergic to Septr for example,
they may also be allergic to ACE inhibitors
and even rarer but but seen is ARB’s.
Now, another side effect with this medication is,
nausea vomiting and diarrhea
and very rarely you may get episodes of
Hemolysis is often seen too,
in patients who have G6PD deficiency,
so that's an important
consideration in some patients.
Let's move on to fluoroquinolones.
Now, we have several generations
of fluoroquinolones out there.
Let's talk at the them one at a time.
The first generation was norfloxacin.
It's not really clinically used
anymore because of toxicity issues
and lack of efficacy issues.
So, this was replaced with the
Ciprofloxacin being the prototypical one
and probably the best known
of the fluoroquinolones.
It has more gram-negative activity,
especially against gonococcus
and it's actually quite effective
against atypical bacteria like,
M. pneumoniae and C. pneumoniae.
The third-generation agents include levofloxacin
and these are less active
against gram-negative bacteria,
have a much greater activity
against gram-positive cocci
and MRSA and anaerobes.
So, levofloxacin which is called Levaquin
commercially is often used in pneumonia.
Now, the fluoroquinolones in general
have very good oral bioavailability
and they are eliminated through the kidney,
so, we have to be aware of renal function.
The other issue that we have to
be aware of is that this drug,
is actually blocked by
probenecid the excretion of it.
So, in patients who are also on probenecid
you may have toxic levels.
An agent called moxifloxacin has hepatic clearance
and may be used in renal failure.
These agents have half-lives
of three to nine hours,
so, they're most often given twice a day.
Some formulations though are
actually given once a day
and a good example is,
a formulation called “Cipro XL,” which is,
ciprofloxacin, a special kind of pill,
that allows it to be given once a day
and that's used most commonly
in epididymitis for example.
So, how do these agents work?
The mechanism of action of fluoroquinolones
is actually quite interesting.
They interfere with DNA topoisomerase II.
So DNA topoisomerase is the
enzyme that's responsible
for taking that helical twisted
and untwisting it, so that, we can get
access to the genetic information inside it.
So, by interfering with it, you
actually interfere with the first step
of DNA transcription.
Topoisomerase II is inhibited
in the gram-negative organisms
and type IV is inhibited in
the gram-positive organisms.
Now, I want to make sure that you know this
because this is a great exam question.
One of those useless pieces of information
that we love to put on exams for you.
So, make sure you remember this
and then once you pass your
exams you can forget it.
Now, these agents are bactericidal.
These agents also have a post antibiotic effect,
which is quite nice when you give them short term,
you know that there's going to be a long-term
beneficial effect with these agents.
In terms of how bacteria develop
a resistance to fluoroquinolones,
it's kind of an interesting phenomenon.
What they do is they change their porins,
so that, they actually reduce
the intracellular concentration
or accumulation of this drug.
The efflux mechanisms in M.
tuberculosis, S. aureus and S. pneumoniae
are also in play here.
The other thing that will happen too,
is that we'll see changes in the sensitivity
of the target enzymes.
So, sometimes that DNA topoisomerase, will have,
a point mutation that prevents the fluoroquinolone
from doing its job.
Now, these are interesting
in the sense that they are
actually, drug and bug specific.
So, gyrA is actually a gene that codes
for the resistance to certain fluoroquinolones
in the gonococcus bacteria.
In terms of toxicity, gastrointestinal distress,
skin rash, headache and insomnia
are quite commonly seen.
More rarely you will see phototoxicity,
now tendinitis and tendon
rupture has been reported,
in terms of fluoroquinolone toxicity.
It's important to note that we
do not recommend these agents
in pregnant women or in children who are growing
and the reason is,
because it may damage their cartilage
and they may develop arthropathy,
especially in patients who
are in their teenage years,
I find that a lot of physicians forget this
and they prescribe it to their teen kids,
who haven't finished growing.
So, do not do that, only in
fully grown mature adults.
Now, the newer agents in this
drug class may also prolong
the QT interval, so we have to be aware
of that potential problem as well.