Download Antibiotics II

CLASS: 10:00 – 11:00
DATE: December 8, 2010
PROFESSOR: Smith
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ANTIBIOTICS II
Scribe: Adam Baird
Proof:
Page 1 of 4
β-LACTAM ANTIBACTERIALS [S23]
a. Note: The antibacterial (true antibiotic) chloramphenicol is not active against Chlamydia (as indicated in the
book).
b. The β-lactam ring contains 3 carbons, 1 nitrogen, and 1 oxygen (sticking off of the side).
c. The β-lactams include the penicillins and cephalosporins. There are mono-bactams (which have a “naked” βlactam ring, meaning that it is not fused to a second ring).
d. Clavulanate is not an antibacterial (per say). It does not have sufficient antibacterial activity to be used (in and
of itself) to treat antibacterial infections.
e. Clavulanate is a β-lactam. It inhibits the enzymes that destroy β-lactam (which are the β-lactamases). So,
clavulanic acid is a β-lactamase inhibitor. It is used to extend the range of penicillins that are destroyed by βlactamases. So, amoxicillin is combined with clavulanic acid to extend the antibacterial spectrums (so that it
includes bacteria that produce β-lactamases). Without clavulanic acid, those bacteria would be resistant to
amoxicillin.
β-LACTAM ANTIBACTERIALS [S24]
a. β-lactam antibacterials:
1. Penicillins
2. β-lactamase inhibitors (combined with penicillin)
3. Cephalosporins
4. Carbapenems
5. Monobactams
b. The picture on the right is structure of penicillin V, which is only slightly different from the other naturally
occurring “original penicillin” (penicillin G). See next slide for more information…
PENICILLIN V POTASSIUM [S25]
FIVE MAJOR CLASSES OF PENICILLINS [S26]
a. Note: Understand that there are trends. As you move down this list, there is increased activity against Gramnegative strains and there is decreased potency against Gram-positive strains.
b. Note: The textbook lumps classes 4 and 5 together into one category. (They are very similar.)
c. Note: Penicillins are very active against Gram-positive cocci; they are destroyed by penicillinase.
d. Note: Class 2 penicillins are the only class resistant against penicllinase. (Penicillinase is a bacterial enzyme
that chiefly destroys penicillins by opening or hydrolyzing the β-lactam ring. β-lactamases, on the other hand,
has a broader spectrum. They are bacterial enzymes that destroy the β-lactam ring in both penicillins and
some cephalosporins. Cephalosporins, though, are generally more resistant to β-lactamases than penicillins.
e. Five major classes of penicillins:
1. Original Penicillin G and Penicillin V
a. Penicillin V differs from penicillin G only because it has an oxygen atom downstream (from
the β-lactam ring). This subtle modification changes penicillin G to penicillin V. Why is this
important? Because penicillin V is more stable in the acid conditions of the stomach.
Penicillin G is still used though; the dose just has to be higher to compensate for the
destruction of some of the penicillin G in gastric acid.
b. Penicillin G is most effective against staphylococci, streptococci, Gram-positives, et.
2. Penicillinase-Resistant:
a. Methicillin is the leading example in this class.
b. The orally effective penicillins in this class: oxacillin, cloxacillin, nafcillin (which isn’t used too
much because its absorption is somewhat unpredictable).
c. Methicillin is used mainly in clinical labs to identify bacteria that are resistant (because of the
capacity to produce penicillinase).
3. Amino-penicillins:
a. “Amino” simply indicates that there is a protonated nitrogen atom (amino group). The amino
group is protonated with an additional proton, giving the amino group a positive charge. So
amino-penicillins have a simple addition that confers charge.
b. Simple additions to make it more water-soluble.
c. They increase the reactivity to Gram-negative bacteria.
d. Recall: Gram-negatives have LPS (which is located in the outer membrane that serves as a
lipid barrier that is outside the plasma membrane). They have to get through the outer
membrane via an aqueous pore (made of protein), through which the drug has to diffuse (in
the aqueous pore), so that the charge (provided by the amino-penicillin) facilitates diffusion
through the outer membrane via the protein pore.
e. They have increased activity towards Gram-negative bacteria.
CLASS: 10:00 – 11:00
Scribe: Adam Baird
DATE: December 8, 2010
Proof:
PROFESSOR: Smith
ANTIBIOTICS II
Page 2 of 4
f. They have increased activity towards Gram-negative bacteria. As the activity of Gramnegatives increases, the activity of Gram-positive decreases.
4. Carboxy-penicillins:
a. The carboxyl group is ionized and has a negative charge.
b. Simple additions to make it more water-soluble.
c. They increase the reactivity to Gram-negative bacteria.
d. Recall: Gram-negatives have LPS (which is located in the outer membrane that serves as a
lipid barrier that is outside the plasma membrane). They have to get through the outer
membrane via an aqueous pore (made of protein), through which the drug has to diffuse (in
the aqueous pore), so that the charge (provided by the carboxy-penicillin) facilitates diffusion
through the outer membrane via the protein pore.
e. They have increased activity towards Gram-negative bacteria. As the activity of Gramnegatives increases, the activity of Gram-positive decreases.
5. Ureido-penicillins:
a. Additional modifications.
b. More activity towards Gram-negatives.
V.
CLASSES OF β-LACTAMS [S27]
a. There are a huge variety of β-lactam destroying enzymes in bacteria. They can be categorized in 4 different
criteria:
1. Substrate specificity
2. Inducible vs. constitutive
a. Inducible meaning exposure to the antibiotic stimulates the expression of the β-lactamases
gene and protein
b. Constitutive meaning the bacteria produce the β-lactamases even when they are not exposed
to antibiotics
3. Secreted (into the environment) by Gram-positive vs. periplasmic in Gram-negative
a. Gram-positives produce a large amount because it is excreted into the culture medium, into
the surround tissues (like at the site of infection, for example) and then it diffuses away.
b. Gram-negatives produce a little of the β-lactamases, but it’s trapped between the outer and
inner membranes, which just happens to be where it is needed to greet the penicillin as it
comes out of the pore that traverses the outer membrane. Recall: the space between the
inner and outer membrane is called the periplasmic space. This is where the β-lactamase
resides in Gram-negatives.
4. Gene location (chromosome or plasmid)
VI.
BACTERIAL ANATOMY [S28]
a. We’ve already discussed the information on this slide.
VII.
NO TITLE [S29]
a. You can go back and review this slide on your own. Study it. It simply reinforces what was said about βlactamase.
VIII.
AMOXICILLIN AND CLAVULANATE [S30]
a. Let’s get back to talking about clavulanate (the β-lactamase inhibitor) and in this case, amoxicillin.
IX.
β-LACTAMASE INHIBITORS [S31]
a. β-lactamase inhibitors:
1. Clavulanate
a. Clavulanate, at very high concentrations (that aren’t achievable therapeutically), would have
antibacterial activity; at very low concentrations, clavulanate would be a very potent inhibitor
of β-lactamase (which is why is works in combination with a penicillin, like amoxicillin).
2. Sulbactam
a. There is another β-lactamase inhibitor in clinical use that is called sulbactam (which is
combined with ampicillin).
b. Note: Ampicillin is not penicillinase-resistant. “Am” indicates an amino group. Ampicillin is
destroyed by penicillinase. Methicillin is penicillinase-resistant. Be sure to keep these straight.
X.
PENICILLIN TOLERANCE [S32]
a. Penicillin-tolerance is a type of “resistance”, but it is not a resistance caused by the production of enzymes
that destroy the penicillin – it’s different than that. Penicillin-tolerance strains of staph and trep have been
isolated from patients with persistent or relapsing infections.
b. β-lactams are static (not cidal) towards autolysin deficient strains. The penicillin-tolerant strains are deficient
in some enzymes that degrade the cell wall; these cell wall degrading enzymes are called autolysins. Why
CLASS: 10:00 – 11:00
Scribe: Adam Baird
DATE: December 8, 2010
Proof:
PROFESSOR: Smith
ANTIBIOTICS II
Page 3 of 4
would a bacterium degrade its own cell wall though? In order to complete cell division, cell wall degradation
must occur (in a very controlled manner) with the accompaniment of synthesis.
c. β-lactams have the same MIC (minimal inhibitory concentration). MIC is the same for penicillin-tolerant and
penicillin-sensitive strains. So what’s the difference between penicillin-tolerant and penicillin-sensitive then?
The MBC (which is much higher for the penicillin-tolerant strains compared to the penicillin-sensitive strains).
d. The deficiency in autolysins may explain the relative insensitivity of slow growing bacteria to β-lactams. So
the bacteria that are most sensitive to the β-lactams are those in a rapid stage of growth (as opposed to those
in the lag phase, which are not growing rapidly and have autolysin deficiencies and are less sensitive to
cephalosporins and penicillins).
XI.
NO TITLE [S33]
XII.
CEPHALOSPORINS [S34]
a. Almost all of the cephalosporins begin with “ceph” – except for a few, like streptomycin, which isn’t used very
much anymore (but is sometimes still used against tuberculosis).
b. The other cephalosporins are used against a wide variety of infections (against both Gram-positive and
Gram-negative strains).
c. They have a broad spectrum. They are less susceptible to β-lactamase and less allergenic than penicillins.
d. There is about 5 – 10% cross-allergenicity between cephalosporins and penicillins.
e. Cephalosporins have a β-lactam ring that is fused to another ring. Notice that there are two sites of
modification. There are two R-groups (R1 and R2). This allows for an alteration of either the antibacterial
spectrum or the pharmacokinetic properties. The other R-group is more influential on the antibacterial
spectrum than the other R-group. One R-group is more influential on the pharmacokinetic properties than the
other R-group. This means that it is “wide open” for pharmaceutical companies (to produce a variety of
cephalosporins).
XIII.
VANCOMYCIN HCL [S35]
a. What is used for treating an infection that is resistant to methicillin and is a Gram-positive bacterium (like
Staphylococcus aureus)? Vancomycin.
b. Vancomycin inhibits cell wall synthesis. It is a large molecule (notice the chemical structure).
c. It binds do D-Ala-D-Ala group of the amino acid chain of the cell wall.
d. It is bactericidal toward Gram-positive and anaerobes.
e. It has been around for a long time. Historically, though, in its “early days”, it produced some toxicity (limiting
its use), but there wasn’t much methicillin-resistant staphylococcus aureus around either.
f. It became possible to make more pure preparations of vancomycin, which reduced many of the side effects
and reduced the toxicity.
XIV.
VANCOMYCIN [S36]
a. It’s help in treating endocarditis caused by MRSA.
b. Vancomycin synergizes with gentimicin (and all other aminoglycosides). The combination of the vancomycin
with aminoglycide is much more effective than either drug individually. Note: penicillins in combination with
aminoglycosides also has synergistic killings too.
c. In this case, for example, penicillin and vancomycin are bactericidal. Aminoglycosides are also bactericidal.
This synergism generally occurs only when two bactericidal drugs are combined. On the other hand, a
bactericidal drug combined with a bacteriostatic drug, for example, might lead to antagonism (where the
combination is less effective that the individual drugs alone).
d. Vancomycin is also used to treat pseudomembranous colitis (bloody diarrhea that also can be lifethreatening), which is caused by Clostridium difficile.
e. When taking a broad-spectrum antibiotic, the normal flora may be entirely wiped out. The GI tract, in turn, is
“opened up” for superinfection (by a pathogen like Clostridium, for example). This tends to occur more
frequently with an antibiotic called clindamycin. If a patient is being treated with clindamycin and they develop
pseudomembranous colitis, then the treatment is altered to oral vancomycin. Recall: Vancomycin is huge. It
has a molecule weight of 1500. It is generally not given orally. It has to be given parenterally for treating
Staphylococcus aureus. Because the pseudomembranous colitis, in this case, is in the GI tract, vancomycin
must be administered orally. Note: It is well tolerated and can be administered outside of the hospital.
XV.
VANCOMYCIN RESISTANT G+ BACTERIA [S37]
a. For completeness, this topic is mentioned, but you are not responsible for this material.
b. In the 1990s, there was a problem with vancomycin (when vancomycin resistance really began to increase).
The bacteria is now not only resistant to methicillin, they are also resistant to vancomycin.
XVI.
“BAD BUGS, NO DRUGS” [S38]
a. The point: the more a bacterial agent is used, the more resistance develops against it. The use of the
bacterial agent, then, must be reserved (so as to use the “big guns” only when needed).
b. This is why new antibacterials need to be developed. It is an on-going effort.
CLASS: 10:00 – 11:00
Scribe: Adam Baird
DATE: December 8, 2010
Proof:
PROFESSOR: Smith
ANTIBIOTICS II
Page 4 of 4
c. We now know how to target specifics, like the rRNA of bacteria (which is encoded by multiple bacterial
genes), making it very difficult for the bacteria to become resistant (because they would have to modify many
copies in order to become resistant).
d. Even still, it takes much effort, time, money, etc. in order to develop these new antibacterials.
XVII. VANCOMYCIN RESISTANT G+ INFECTIONS [S39]
a. Streptogramins can treat vancomycin-resistant infections.
XVIII. VANCOMYCIN RESISTANT [S40]
a. Oxazolidinones can treat vancomycin-resistant infections.
XIX.
STREPTOMYCIN: THE FIRST AMINOGLYCOSIDE [S41]
a. Streptomycin comes from the soil bacterium, Streptomyces.
b. A professor and grad student at Rutgers discovered streptomycin.
c. It was the first powerful antibiotic for Gram-negatives.
d. Structurally, streptomycin is referred to as an aminoclycoside. The key to the structure: the amino group. It
has many nitrogen atoms. Notice that 6-carbon ring doesn’t contain an oxygen atom (so it’s not a true sugar,
even though it may look like it). It is a cyclotol.
XX.
AMINOGLYCOSIDES [S42]
a. The many amino groups make it a polycationic (multiple positive charges).
b. It is not well absorbed from the GI tract, so it has to be given parenterally.
c. Structurally, the aminoglycosides (beside having many amino groups) have multiple hydroxyl groups (–OH
group).
d. The bacteria are able to make modifications to those amino groups and those hydroxyl groups.
e. They are essentially “amino-sugars”.
f. They are selectively toxic (because they preferentially inhibit the bacterial ribosome).
g. They are bactericidal (a distinctive feature of aminoglycosides). Antibacterials that act on the bacterial
ribosome and inhibit protein synthesis are generally not bactericidal; they are generally bacteriostatic.
Aminoglycosides, then, are distinctive (which is why they synergize with antibiotics that block cell wall
synthesis). Recall: Cell wall synthesis inhibitors are also bactericidal.
h. The target is the initiation stage of protein synthesis. The aminoglycosides also bind to the rRNA and
influence and disrupt the coding of the mRNA (a misread). This causes an advantage of certain genetic
conditions, where a patient might have a stop codon in an important gene, which may predispose the patient
toward a particular syndrome or disease, like cystic fibrosis, for example. This means that the
aminoglycosides would have to have an effect of the patient’s ribosome (not the bacterial ribosome). So,
aminoglycosidse can also be used to treat genetic disease.
i. Serious infections caused by Gram-negative bacilli and mycobacteria (which causes tuberculosis).
j. Aminoglycosides administration: IV or IM
XXI.
AMINOGLYCOSIDES [S43]
a. Resistance: due to decreased accumulation of the aminoglycoside (by the Gram-negative bacteria).
b. Toxicity: kidney, inner ear (both may be reversible though if detected early).
[End 46:00 mins]