Module 10 Flashcards
What makes ß-lactams chemically reactive? How is this chemical reactivity related to the therapeutic activity, the low oral bioavailability of some ß-lactams, the resistance of some bacteria to ß-lactams, the inactivation of penicillin by aminoglycosides when mixed in the same IV bottle, and the major adverse reactions associated with ß-lactam use?
○ The general structure of penicillin is shown below. The 4-membered ring is called a ß-lactam. A lactam is an amide that forms a ring. It is a ß-lactam because the nitrogen is on the carbon ß to the carbonyl group. In general lactams and other amides are not reactive, but ß-lactams are weakly reactive because of ring strain. Specifically, the carbonyl group has an sp2 hybridized carbon whose optimal bond angle is 120°, but it is forced to be 90°. Attack on the carbonyl group by a nucleophile (amino or thiol group) such as a lysine amino group on proteins leads to opening the ring and relief of the ring strain. This chemical reactivity is required for the therapeutic activity of ß-lactams. Specifically, penicillins covalently bind to and inactivate the transpeptidase and other penicillin-binding proteins that are involved in making the cell wall of bacteria.
○ Penicillin G undergoes some degree of ring opening in the acidic environment of the stomach. The ring opening of amoxicillin is less, but not zero. This decreases their oral bioavailability.
○ Given the requirement of the chemical reactivity of the ß-lactams for their therapeutic activity, one mechanism of resistance is the synthesis of ß-lactamases by bacteria to inactivate penicillins.
○ Since ß-lactams react with nucleophilic amino groups, they react with aminoglycosides if mixed in the same iv bag. This also occurs in vivo, but given that the concentrations in vivo are so much lower than in the iv bag this is not significant in vivo.
○ ß-lactams also slowly react with proteins. Although it varies with the ß-lactam, about 1% of the administered dose ends up irreversibly bound to proteins. Some patients develop an allergic reaction to these “foreign” proteins.
What is the degree of cross reactivity between cephalosporins and penicillins? Specifically, if a patient is allergic to penicillins, how likely is it that they will have an allergic reaction to a cephalosporin?
In general the cross reactivity is low (probably <5%); however, it is side-chain dependent. Specifically, ampicillin, cephalexin, cefaclor, and loracarbef all have the same side chain, and amoxicillin and cefadroxil have the same side chain. The cross reactivity with the newer cephalosporins is probably even less, presumably because of very different side chains. Of course it is possible to have a reaction to both penicillins and cephalosporins independent of cross reactivity.
Why are the concentrations of ß-lactams lower in the CSF than in the blood (at least 2 reasons)?
○ Because there are active transporters in the blood/brain barrier that transport them out of the brain.
○ Because even if the free concentration were the same in the brain and blood, the total concentration in the blood would be higher because the protein concentration is higher in the blood.
○ Although all ß-lactam antibiotics have a negative charge, there is a fraction that is uncharged and is free to move across the blood/brain barrier. There are active transporters, OAT3 for benzylpenicillin, that actively transplant ß-lactams out of the brain. However, in most cases therapeutic levels in the brain can be achieved.
The total concentration is equal to the free + the protein bound fraction, but it is only the free fraction that is free to equilibrate. Given that the protein concentration in the blood is higher than that in the cerebrospinal fluid, even if the free concentration were in equilibrium, the total concentration would be higher in the blood. The % protein binding varies among the ß-lactams. It is only about 20% for most common ß-lactams.
Vancomycin is often given to patients with a history of penicillin allergy? How often would you guess that this is actually necessary, and what are the drawbacks to this course of action?
○ More than 90% of patients who think they are allergic to penicillin are not. In many cases the patient developed a rash when treated with amoxicillin, but that is not a good predictor of later allergy to penicillins and other ß-lactams.
○ However, the consequences of giving a penicillin to someone who is truly allergic can be quite serious.
○ The only way to make sure is penicillin skin testing including using the minor determinants (The minor determinants are degradation products of penicillin. Most reactions are caused by the major determinants, which are formed by covalent binding of the ß-lactam carbonyl group to proteins. Although allergies to the minor determinants are less common than to the major determinants, if anything they are more severe.) However, such testing is not widely available, and it is not perfect because some penicillin allergies are specific to a specific penicillin. Cross reactivity between penicillins and cephalosporins is estimated to be about 5%. The use of vancomycin has several drawbacks: it is much more expensive; it requires IV administration; it is associated with a higher risk of side effects; and it leads to more resistance to vancomycin, which is often used to treat infections that are resistant to penicillin.
How would you deal with a patient who requires prophylactic antibiotics before a dental procedure, but has a history of a rash when she was given penicillin as a child and has gastrointestinal intolerance to erythromycin?
○ It depends. If the patient has easy access to a centre that can perform skin testing including with the minor determinants that would be the best option (It is also good for future reference to know if the patient is allergic to penicillins.)
○ If that is not a practical option, it depends on how severe the intolerance to erythromycin is. About 50% of patients will have some GI upset but can take erythromycin, while in others the symptoms can be quite severe. Azithromycin has less GI side effects than erythromycin, but they can also be severe with azithromycin. So depending on how bad the intolerance was, erythromycin or azithromycin may be the best choice. Clindamycin has its own GI side effects
What are the adverse reactions associated with the use of isoniazid, and what are the risk factors associated with these adverse reactions?
○ Neuropathy, hepatitis, drug fever
○ Isoniazid can cause all of these adverse reactions.
○ The neuropathy is caused by the depletion of vitamin B6. Isoniazid chemically reacts with the aldehyde group of pyridoxal phosphate to form a hydrazide. (It also reacts with other reactive carbonyl compounds such as pyruvate, and that is one of the major metabolites of isoniazid.)
○ In general, prophylactic treatment with 50 mg/day of vitamin B6 will prevent the neuropathy.
○ Isoniazid is probably associated with the highest risk of idiosyncratic drug-induced liver failure of any common drug. The risk increases with age.
○ It can also cause drug fever, a lupus-like syndrome, and various other immune mediated adverse reactions.
If the transaminases increase in a patient being treated with isoniazid the drug should be immediately stopped to prevent liver failure.
○ False
○ Isoniazid causes an increase in ALT in up to 20% of patients, but liver failure occurs in less than 1/1,000 patients. If isoniazid is important for the treatment of the patient, as long as the patient is carefully monitored, and the ALT does not go above about 3 – 5 times the upper limit of normal, and they do not develop symptoms such as decreased appetite, right upper quadrant pain or fever, in most cases the ALT will return to normal despite continued treatment.
○ Symptoms are important, and in the US it is no longer standard of care to monitor ALT, but rather carefully instruct the patient if they have any of the above symptoms to immediately stop the isoniazid and see their physician to have their ALT checked. The problem with ALT monitoring is that it is only done monthly, and the patient can become quite ill between the blood tests. In general, ALT monitoring is still done in Canada.
