Carbapenems and other Cell Wall Inhibitors (Anti-Biotics)

Question 1

Name the 4 carbapenems?

Answer 1

Imipenem, Meropenem, Ertapenem, Doripenem (DIME)

Question 2

How is the distribution and half life of carbapenems?

Answer 2

Good body distribution including CSF, 1 hr half life, except ertapenem which is 4 hrs.

Question 3

Describe the function of Imipenem-cilastatin formulation?

Answer 3

Imipenem is degraded in the brush border of our proximal tubule by the enzyme DEHYDROPEPTIDASE I, and to get around this dehydration we use cilastatin. NOT A BETA LACTAMASE INHIBITOR, it just inhibits our own enzyme.

Question 4

What is the activity of carbapenems?

Answer 4

These are nukes, broad spectrum but reserved for serious infections that are resistant to other drugs. Its activity includes gram +/-, aerobic and anarobic. Hits penicillin resistant s. pneumoniae, penicillin sensitive E. faecalis BUT NOT E. FAECIUM! Hits ESBL and AmpC beta lactamases, so tx of choice for ESBL expressing enterobactericeae, p. aeruginosa (NOT ERTAPENEM), anarobes like B. fragilis.

Question 5

What are the resistance to carbapenems?

Answer 5

MRSA, C. Diff, E. Faecium, Stenotrophomonas Maltophilia (a bug similar to pseudomonas), Class B Zn dependent metalloprotease beta lactamase (called carbapenemases), Class A serine protease (KPC).

Question 6

What is the effect of the Class B zinc dependent metalloprotease beta lactamase known as carbapenemases?

Answer 6

Cleaves penicillins, cephalosporins and carbapenems, and beta lactamases does nothing for these.

Question 7

What is Ertapenem is especially not active against that the rest of the carbapenems might have activity against? What do we use it for?

Answer 7

Not active against pseudamonas and acinetobacter. Used for intra abdominal and pelvic infections caused by gram +, enterobactericeae and B. fragilis.

Question 8

When would we use imipenem-cilastatin and meropenem?

Answer 8

For hospitalized patients who failed on other beta lactamase tx. Skin, soft tissue, bone, joint, intra abdominal, genital, and lower resp.

Question 9

What is an adverse effect to watch out for in patients with renal insufficiency receiving Imipenem esp but carbapenems in general?

Answer 9

Lower threshold for seizures.

Question 10

What are the general class AE’s of carbapenems?

Answer 10

Hematologic problems like bleeding, agranulocytosis, and leukopenia. GI n/v/d. C. Diff superinfection.

Question 11

What is THE DRUG that is super effective against gram neg, aerobic cocci and bacilli? This includes enterobactericeae and P. Aeruginosa.

Answer 11

Aztreonam, it is a drug in a class of its own. ONLY PARENTERAL and thus can only be used in hospital infections.

Question 12

What are resistant to Aztreonam?

Answer 12

Gram +, ESBL, Amp C beta lactamase containing bacteria, and some enterobactericeae and pseudomonas who have PBP’s with low affinity for aztreonam.

Question 13

When would we use the inhalation formulation for Aztreonam?

Answer 13

Pseudomonas lung infections in cystic fibrosis patients.

Question 14

When would we use Aztreonam?

Answer 14

For UTIs, LRIs, intra abdominal infections, skin/skin structure infections, and gynocologic infections.

Question 15

Cross reactivity of Aztreeonam?

Answer 15

Generally shown to be safe to use with pt’s allergic to penicillin, no cross resistance with the exception of ceftazimide (3rd gen cephalosporin) due to similar side chain.

Question 16

AE’s of Aztreonam?

Answer 16

Thrombophlebitis, pain at the injection site, possible HS rxn, C. diff superinfection.

Question 17

There are 8 drugs that work against pseudamonas, what are they?

Answer 17

3/4 carbapenems work (Imipenem-cilastatin, Doripenem, Meropenem) and also Aztreonam. Ceftazidime and Cefepime. Ticercillin and Pipercillin.

Question 18

What class of drug is Vancomycin?

Answer 18

It is a glycopeptide.

Question 19

What is the activity of Vanco?

Answer 19

It’s a huge molecule so there is no way it fits into porin channels, thus it is only active against gram + organisms.

Question 20

Administration of Vanco?

Answer 20

IV only, give orally only when C. Diff infection (because vanco has poor oral absorption so the bacteria will stay in the gut lumen).

Question 21

Whats the T(1/2) of vanco and is it time dependent/independent killing?

Answer 21

About 6 hr half life, time dependent killing.

Question 22

How does Vanco work?

Answer 22

It binds to the D-Ala-D-Ala portion of the cell wall preventing the transglycolyse step (step before transpeptidation), therefore the sugars are prevented from attaching from one another, aka peptidoglycan polymerization is prevented.

Question 23

What specific Gram + activity does vanco have?

Answer 23

Hits only gram + anyway, and is bacteriocidal in all but E. Faecalis and Faecium where it is bacteriostatic. Hits MRSA, MRSE, penicillin resistant S. pneumo.

Question 24

What bugs have intrinsic resistance to vanco?

Answer 24

Gram neg and mycobacterium

Question 25

How does enterococci and s. aureus gain resistance to vanco?

Answer 25

Enterococci have VanA gene resistance, in which the D-Ala-D-Ala sequence is changed to something like D-Ala-D-lactate or serine and decrease vanco binding. S aureus can acquire this VanA plasmid. Aureus can also sequester Vanco by making cell wall abnormally thick and prevents vanco from getting to its target.

Question 26

What are AE's to vanco?

Answer 26

HS rxn, red man syndrome (from the neck up the skin becomes really red, this is due to too fast an infusion of vanco). Phlebitis at injection site, oto and nephrotox ESP WHEN USED WITH AMINOGLYCOSIDES! NSAIDS increase vanco levels.

Question 27

What class is Daptomycin under? How does structure determine activity?

Answer 27

Cyclic lipopeptide. Bulky so only gram + activity. However excellent Gram +, works on everything Vanco would including Vanco resistant (MRSA, MRSE, VISA, VRSA and possibly VRE).

Question 28

How is Daptomycin administered? Half life? Killing effect?

Answer 28

IV only, IM would be toxic to muscle and poor oral absorption. 8-9 hr half life, and concentration dependent killing.

Question 29

MOA of Daptomycin?

Answer 29

Daptomycin binds to cytoplasmic membrane where it sticks its lipophilic tail into the membrane (Ca dependent), pokes a hole basically where all the intracellular K+ leaks out, loss of depolarization, arrests RNA, DNA and protein synthesis --> death of cell without lysis.

Question 30

Activity of Daptomycin and VRE?

Answer 30

Daptomycin tx right sided VRE endocarditis but not left sided.

Question 31

Where is Daptomycin inactive against?

Answer 31

Gram neg bacteria have inherent resistant, not left sided VRE endocarditis. Not pneumonia due to inactivation by pulmonary surfactants.

Question 32

What are the AE's of Daptomycin?

Answer 32

MYOPATHY! Eosinophilic pneumonia, peripheral neuropathy.

Question 33

DDI's of Daptomycin?

Answer 33

Statins would be additive in terms of muscle toxicities on top of Daptomycin tox.