Antibiotics Flashcards
What is ‘selective toxicity’?
An ideal antimicrobial agent exhibits selective toxicity, which means that the drug is harmful to a pathogen without being harmful to the host.
List four mechanisms of action under which antimicrobial drugs can be discuseed.
(1) Inhibition of cell wall synthesis
(2) Inhibition of cell membrane function (e.g., cell wall integrity)
(3) Inhibition of protein synthesis
(4) Inhibition of nucleic acid synthesis
What are the four main categories of Beta lactam antibiotics? And what is their mechanism of action?
Penicillins
Cephalosporins
Monobactams
Carbapenems
All Beta -lactam drugs are selective inhibitors of bacterial cell wall synthesis –targeting peptidoglycan (Peptidoglycan (unique to bacteria) consists of polysaccharides and a highly cross-linked polypeptides. This cross-linkage is an important drug target.)
What is penicillin’s mechanism of action?
Penicillins binds to bacterial PBPs (Penicillin Binding Proteins)–some of which are enzymes involved in transpeptidation of the peptidoglycan component of the bacterial cell wall. Penicillins’ binding to PBP blocks final transpeptidation and thus peptidoglycan synthesis is inhibited. It interferes with the releasing of the D-Alanine and thus the cell wall cannot grow poperly.
As you get more advanced in the penicillin family, what are you getting more coverage of?
You get more gram negative coverage with the more recently developed, higher class, antibiotics.
What are the four subcategories of penicillins?
Natural penicillins
Anti-staphylococcal penicillins
Aminopenicillins (Ampicillin, Amoxicillin)
Anti-pseudomonal penicillins (Piperacillin)
How good is penicillin’s coverage of Streptococcus pyogenes (Group A)?
EXCELLENT! Drug of choice!!!
Describe natural penicillins spectrum of activity
(1) Streptococcus examples
- Group A (excellent)
- Pneumococcus (major resistance problems - up to 40% are non-susceptible to penicillin.)
- Viridans (coverage okay—however, resistance occasionally)
(2) Enterococcus (some)
(3) Few Gram negative cocci: Neisseria meningitides okay; but now too much resistance among Neisseria gonorrhoeae
(4) Gram-positive anaerobes (some mouth flora - often used for dental abscess)
(5) Spirochetes (e.g., syphilis)
What are aminopenicillins? List two examples.
Amionpenicllins are Beta Lactams. They were discussed after natural penicillins in class. Cover even more than penicillins. Ampicillin (IV) and Amoxicillin (PO) are examples of aminopenicillins.
What is the spectrum of activity for aminopenicilins?
Similar to penicillin plus (better gram negative coverage, but still simple coverage) -
- More enterococcus are susceptible
- Some “simple” community-acquired Gram-negatives (e.g., E. coli, Proteus, Haemophilus influenzae), although resistance is rising
- Important/unique use: Listeria (Gram-positive rod causing meningitis in neonates and immunocompromised pts)
Give an example of an Anti-pseudomonal ureidopenicillins.
Piperacillin (IV)
What, because of developed resistance can natural penicillins no longer be used to treat?
Neisseria gonorrhoeae
What is the benefit to piperacillin?
Similar to ampicillin plus greatly improved Gram-negative coverage including for hospital-acquired organisms (e.g., Pseudomonas, Enterobacter, Acinetobacter)
Much more gram negative coverage!!
What are penicillin and ampicillin, piperacillin all still susceptible to?
Penicillin and ampicillin, and piperacillin are susceptible to Beta-lactamases and thus have poor staphylococcal activity and poor Gram negative anaerobic coverage
What is beta-lactamase?
Beta-lactamases can cleave the beta-lactam ring of penicillin, ampicillin, piperacillin. This was brought up in relation to staphylococci, which are able to produce this enzyme, and thus this is an example of a bacteria evolving to evade antibiotics, beta lactam antibiotics.
What did pharm do in response to the discovery of beta-lactamase?
Started adding beta-lactamase inhibitors, clavulanate (to amoxicillin PO), sulbbactam (to ampicillin IV), tazobactam (to piperacillin IV). This change expands the coverage to include methicillin-sensitive Staphylococci and more anaerobic coverage, including gram negative anaerobes. (Now have really great anaerobic coverage.)
Nafcillin (IV) and Dicloxacillin (po) also work against bacteria with beta-lacatamase, becuase they are not affected by these enzymes
What is special about Nafcillin (IV) and
Dicloxacillin (po)?
They are part of the penicillin family. They are penicillinase-resistant penicillins. The bacteria evolved beta lactamase, and these handle this because they are not affected by these enzymes.
What is methicillin and when is it used?
Methicillin was the first penicillinase-resistant penicillin developed, but it is no longer used secondary to high incidence of intestinal nephritis (kidney toxicity)
Discuss Nafcilin (IV) and Dicloxacillin (po) coverage.
These penicillinase-resistant (anti-staph) penicillins only cover methicillin-sensitive staphylococci and some streptococci (particularly beta-hemolytic—like Group A)
- No coverage against methicillin-resistant Staphylococcus aureus (MRSA). Most coagulase-negative staphylococci are also methicillin-resistant.
- No coverage against enterococci
How do cephalosporins act?
They too contain a Beta lactam ring and target cell wall synthesis
As you increase in class of the cephalosporins, what coverage do you get more of?
More gram negative coverage!
What is the spectrum of activity for 1st generation cephalosporins (Cefazolin (IV), cephalexin (po)) ?
Gram-positives: methicillin-sensitive Staphylococcus aureus (MSSA), Beta-hemolyitic Streptococci, penicillin-sensitive Strep pneumoniae
Some “simple” community-acquired aerobic Gram negative rods
NOT MRSA (none of the commonly used cephalosporins have activity against MRSA) NOT enterococcus (no cephalosporin has activity against enterococcus)
What is the benefit of 2nd generation cephalosporin (Cefuroxime (IV/po), cefoxitin (IV)) coverage and when is it used?
2nd generation coverage, Cefuroxime (IV/po), cefoxitin (IV), has More Gram-negative coverage. Cefuroxime particularly for better respiratory coverage (e.g., outpatient pneumonia)—Haemophilus influenzae, Streptococcus pneumoniae, some enteric Gram negatives. Cefoxitin unique feature—decent anaerobic coverage too. However, these 2nd generation drugs are being phased out.
What is the added benefit of 3rd generation (Ceftriaxone (IV), cefotaxime (IV)) cephalosporin?
- greater activity against gram-negative bacteria
- maintains gram-positive coverage
- Ceftriaxone has activity against Borrelia burgdorferi (Lyme disease).
- **Ceftriaxone, cefotaxime cross blood-brain barrier—effective for treatment of central nervous system infections (e.g., meningitis)
What is going on with 4th generation (Cefepime (IV)) cephalosporins?
Most advanced, greater and greater gram negative coverage – very broad coverage – can now cover the resistant gram negatives found in hospitals.
Like the third generation can cross the blood brain barrier and can treat meningitis – used in healthcare setting
What is ceftraroline?
*New drug: ceftaroline is only cephalosporin
with activity against MRSA
With cephalosporins what allergy are you worried about?
Cross-allergenicity between the penicillins and cephalosporins is uncertain but is probably around 5–10%
As a physician should you use narrow or broad spectrum antibiotics first?
Use most narrow-spectrum antimicrobial whenever possible. Save broadest-spectrum antimicrobials for the patients who most need them the most. With liberal use of antibiotics, including our current “broad-spectrum” antibiotics, drug resistance can be expected to further increase.
Does penicillin have good activity against Group A streptococci?
Yes
Does penicillin have good activity against Staphylococci?
No
Does ampicillin have good activity against enterococcus?
Yes
Does ampicillin have good activity against Staphylococci?
No
What agent can be added to ampicillin to deal with beta-lactamases commonly produced by Staphylococci?
Sulbactam
Does ampicillin-sulbactam have good activity against methicillin-sensitive Staphylococci?
Yes
Which has activity against Pseudomonas and overall a wider Gram negative spectrum, ampicillin or piperacillin?
Piperacillin
Does piperacillin have good activity against Staphylococci?
No
Does piperacillin-tazobactam have good activity against methicillin-sensitive Staphylococci?
Yes
Do Amoxicillin-clavulanate and Piperacillin-tazobactam have good activity against GI anaerobes?
YES!
Does dicloxacillin have good activity against Group A streptococci and methicillin-sensitive Staphylococci?
Yes
As a general rule, 3rd and “4th” generation cephalosporins have more or less coverage against Gram-negative bacteria than the 1st gen?
More
Does cefazolin have good activity against methicillin-sensitive Staphylococcus aureus (MSSA)?
Yes
. Can cefazolin be used to treat MSSA meningitis?
No, cefazolin does not cross blood-brain barrier. This is a 1st generation. Only 3rd and 4th generation can cross the blood brain barrier.
Can ceftriaxone be used to treat Neisseria meningitides meningitis?
Yes, 3rd generation, can cross the blood brain barrier.
Does ceftriaxone have good activity against Pseudomonas?
NO - psudomonas coverage comes with 4th generation
Which cephalosporin has most activity against Pseudomonas?
Cefepime, 4th generation
Which cephalosporin has activity against enterococci?
NONE!
Which cephalosporin has activity against MRSA?
Only ceftaroline - newest cephalosporin
What are the 3 carbapenems and what is their route?
Impienem-cilastatin, Meropenem, and Ertapenem. All are IV
What organism does ertapenem fail to cover as well as its family members?
-Gram negatives, particularly PSEUDOMONAS
What is the spectrum of coverage for the principal carbapenems?
Imipenem, Meropenem
- Gram (+): Staphylococccus, Streptococcus, Enterococcus faecalis
- Gram (-): Very broad - broader than piperacillin or cefepime.
- Anaerobes: Good coverage
Not covered - MRSA, enterococcus faecium