Beta lactams, DNA and RNA inhibitors

Question 1

What is the other name for transpeptidase (which you will recall forms the peptide crosslinks that stabilize peptidoglycan)?

Answer 1

Penicillin binding protein (PBP)

Question 2

What is the function of autolysins in peptidoglycan synthesis?

Answer 2

Autolysins break the linkages for the addition of new monomers

Question 3

What do the following drugs have in common?

Penicillin

Cephalosporins

Carbapenems

Monobactams

Answer 3

That #beta-lactam ring

Question 4

Penicillins can be sub-divided into 4 groups. Name them

Answer 4

Penicillin G – that’s me, the original G and the only real MVP. (IV or IM)

Semi-synthetic penicillins – those chicks that stay wearing that #synthetic hair, those girls naf and diclo (Nafcillin - IV and Dicloxicillin -PO)

Aminopenicillins – amp that amo (Ampicillin -IV and Amoxicillin - PO)

Anti-pseudomonal - piperacillin

Question 5

What is the mechanism of action of Beta lactams?

Answer 5

The beta lactam ring in the beta lactams mimics the terminal D-ala D-ala from the peptidoglycan monomer

The beta lactam ring the binds to the PBPs (aka transpeptidases) and prevents the cross linking of peptidoglycan monomers

Since the cell doesn’t have any cross bridges now, it’ll be susceptible to lysis (especially because the autolysins are still working to breakdown the peptidoglycan monomers for the addition of new ones, except now there aren’t new ones being added so that actually makes the membrane even weaker)

With the build up of osmotic pressure, the bacterial cell ends up lysing

Question 6

2 of the most common mechanisms of bacterial resistance to penicillins include ___

Answer 6

Beta lactamases are enzymes that hydolyze the beta lactam rings

Some beta lactamases are narrow spectrum (e.g. penicillinases – beta lactamase that’s only effective against penicillins), others are more extended spectrum

Modifying PBPs >> mechanism for MRSA (the PBP is encoded by the mecA gene; they modify the site to a PBP2 so the antibiotics won’t work against that bug)

Question 7

HSRs to penicillin include rash, hives/anaphylaxis, ___, immune-mediated cytopenias, ___ and ___ at high doses

Answer 7

HSRs to penicillin include rash, hives/anaphylaxis, serum sickness, immune-mediated cytopenias, acute interstitial nephritis and seizures at high doses

**note that these are shared with ALL the Beta lactam drugs**

Question 8

T/F: Penicillins are good for gram pos, variable for gram neg and have zero atypical coverage

Answer 8

Truth

Question 9

Fill in the table for what penicillin is still used for

Answer 9

See image below

Penicillin still used but infrequently, largely due to resistance via penicillinase

Great drug for Streptococci, and gram negative cocci (N. mening), some coverage for anaerobes- dental abscesses/human bites and used for Neurosyphilis

Even in case of allergy, you de-sensitize the pt then give em penicillin (true for neurosyphilis)

Question 10

Name the semi-synthetic penicillins

Answer 10

Semi-synthetic penicillins include Nafcillin, oxacillin and dicloxacillin (and #meth-icillin)

Question 11

What addition was made to the semi-synthetic penicillins to overcome resistance? (hint: its the reason why these don’t work against gram negs)

If these worked so well against Staph, how’d it develop resistance?

Answer 11

The semi-synthetics still have the beta lactam ring and added to it was a bulky side chain that can’t fit into many beta lactamases including penicillinase

Because of the way the drug is designed, it targets only gram pos bugs and is most effective against Staph

Resistance developed via alteration of PBP encoded by mecA gene to PBP2A

Question 12

Name the amino penicillins

How do they act differently from the other penicillins (hint: this is how they work against both gram pos and gram neg)?

Answer 12

Ampicillin and Amoxicillin (amp the amo)

The point of aminopenicillins was to develop drugs that had an extended spectrum of activity to include more gram negs

R group was modified to make a polar side chain to allow for entry into gram neg porins

Can target gram pos (+ve gram pos anaerobes) and gram neg (broader spectrum)

Does NOT cover Pseudomonas

Commonly used for community acquired URI/UTI/ENT infections, used in peds when kids are first exposed to antibiotics so they don’t have a lot of risk factors for acquiring resistant infections

Question 13

The only penicillins that target Pseudomonas are ___

Answer 13

Piperacillin – broader spectrum (not formulated alone, used in comb with beta lactamase inh)

Only one that covers Pseudomonas

Question 14

Who all are the Beta lactamase inhibitors?

Answer 14

Beta lactamase inhibitors: look like antibiotics but have no anti-bacterial activity

Called suicide inhibitors because they bind the bacterial beta lactamase so the antibiotic drugs can exert their effects

Allow for broader spectrum and overcoming resistance

(see below for inhibitors)

**The Sulbactam (like sultan) of the nation of Ampicillin would rather smoke a pipe (piperacillin) of tazobactam that release all that amo (Amoxicillin) on the Clavulanates (Clavulanic acid)**

Question 15

Why don’t ampicillin-sulbactam and piperacillin-tazobactam work against MRSA?

How does amoxicillin-clavulanic acid work?

Answer 15

Ampicillin-sulbactam: overcomes penicillinase resistance of S. aureus (not MRSA); adds ß-lactamase-producing GN and anaerobes; used IV

Amoxicillin-clavulanic acid: Similar to above, but PO

Piperacillin-tazobactam (doesn’t work against MRSA): overcoming penicillinase (not MRSA), ß-lactamase-producing GN and anaerobes (incl. Pseudomonas)

Question 16

What are the mechanisms of resistance for cephalosporins?

Answer 16

•Intrinsic Resistance **main mechanism**

–Pseudomonas, Enterococci

•Altered Membrane Permeability

–Porins, Pseudomonas

•Altered PBPs

–Most agents not active against MRSA

•β-lactamases

–AmpC and ESBLs

Question 17

Who all are the 1st gen cephalosporins? What do these work against? What are the clinical uses of these drugs?

Answer 17

Cefazolin (IV) and Cephalexin (oral) (**zolin and lexin are a fine first couple, except zolin does IV drugs and lexin takes em orally)

*these guys have excellent tissue penetration*

Spectrum of Activity

–Good Gram-positive activity

–Some Gram-negative activity

–Generally limited by resistance

Clinical Indications

–Surgical Prophylaxis

–Skin/Soft tissue infections (limited/resistance)

Question 18

The 2nd generation cephalosporins include __ and __, and have good anaerobic activity and work as intraabdominal surgery prophylaxis

Answer 18

Cefoxitin (IV) (that lazy dude that’s always sittin), Cefotetan (almost sounds like titan) (PO)

–Increased Gram-negative activity

–Good anaerobic activity

–Prophylaxis for intraabdominal surgery

Question 19

___ and ___ are the 3rd gen cephalosporins and they have activity against Pseudomonas

Answer 19

Ceftriaxone and Ceftazidime

(both of these dudes commit theft (ce). One of em like to do so alone and the other only steals dimes)

*Ceftriaxone – used for meningitis and community acquired pneumonia and Lyme disease*

*Ceftazidime - has activity against Pseudomonas*

Question 20

There’s only one drug in the 4th generation of cyclosporins which is ___ and its a broad spectrum antibiotic that works against Pseudomonas and is highly resistant to beta lactamases. One unique adverse effect is ___

Answer 20

There’s only one drug in the 4th generation of cyclosporins which is cefepime (iv) and its a broad spectrum antibiotic that works against Pseudomonas and is highly resistant to beta lactamases. One unique adverse effect is akinesis

**since its a 4th generation, those from 4 generations ago if they were still alive wouldn’t move much coz you know, they old or whatever**

Question 21

There’s only one drug in the 5th generation of cyclosporins that overcomes MRSA resistance by binding PBP2A. Unfortunately, it does NOT work against pseudomonas. What is this drug?

Answer 21

Ceftaroline

**this drug is also en exception to the increasing spectrum rule - its only kinda okay for gram negs**

Question 22

Under what circumstances would you use cephalosporins together with beta-lactamase inhibitors?

Answer 22

In the case of resistant infections

Ceftolozane/tazobactam

Ceftazidime/avibactam

•Spectrum and clinical indications

Excellent GN activity, including Pseudomonas

Overcomes resistance to some ß-lactamases, like common ESBLs

FDA approval: UTI, intra-abdominal infections (but need second agent for anaerobes)

Question 23

What are the common carbapenems discussed?

Answer 23

Imipenem

Meropenem

Ertapenem

(Doripenem - not really used like that)

Question 24

Against which bugs do carbapenems work against?

What makes ertapenem different from the other carbapenems?

Answer 24

•VERY BROAD SPECTRUM

Gram-positive (no MRSA); Gram-negative, including Pseudomonas (except ertapenem: mostly given IV in the outpatient setting because of its long half life; structurally different so now it doesn’t cover Pseudomonas like the rest of the drugs); Anaerobes

•Clinical Uses

Empiric treatment for serious infections, and for resistant infections

Question 25

Which class of drugs was developed to address the allergic reactions to penicillins?

Answer 25

Monobactams (Aztreonam) was developed overcome allergic rxns to penicillins

Question 26

What type of bugs/infections are treated with aztreonam?

Answer 26

Only works for gram negs and covers Pseudomonas

Not as effective as the other drugs and have a ltd spectrum so they’re used in combo with other drugs to cover gram pos infections as well

Question 27

What are the common glycopeptide and lipoglycopeptide agents discussed?

Answer 27

Vancomycin

Question 28

What is the mechanism of action of glycopeptides?

Answer 28

Bind terminal D-ala D ala and prevents polymerization of the peptidoglycan monomers (you will recall that the terminal D-ala-D-ala is needed for this), thus it inhibits cell wall synthesis

Also inhibits transglycosylase (new chains) and inhibits transpeptidase (cross-links) at that terminal D-ala-D-ala

Question 29

What class of bacteria has resistance to Vancomycin? (hint: NOT Staph, or at least not that much of Staph)

Answer 29

Staph don’t have very much resistance to Vancomycin but Enterococci does

Through genetic transfer, the bacteria change the binding site from D-ala-D-ala to D-ala-D-Lac (on vanA gene, other van genes B-D most commonly seen in clinic along with A

Mostly seen in Vancomycin Resistant Enterococci (VRE)

Question 30

What is the mechanism of resistance of vancomycin intermediate staph aureus?

Answer 30

Clinical activity (not so much resistance) is due to thickened cell wall of vancomycin intermediate staph

VISA has a thick cell wall. The drug gets bound up in the periphery so it never makes it into the cell wall to inhibit cell wall synthesis

Question 31

Do glycopeptides only treat gram pos? Explain your reasoning

Answer 31

•Gram-positive ONLY

Staphylococci (including MRSA)

Streptococci (not used for this unless there’s allergy to Penicillin)

Enterococci (if susceptible)

GP anaerobes (e.g. C. difficile)

•No Gram-negative (intrinsic resistance - drug does not penetrate cell wall)

Question 32

T/F: Glycopetides work just as well as beta lactams and are used in the same clinical cases

Answer 32

Falsehood. They don’t work as well as beta lactams and are only used in cases of severe infection, documented resistant gram pos infections and real allergy to beta-lactam antibiotic

Question 33

What is unique about the mechanism of action of dalbavancin?

Answer 33

Dalbavancin has a very long half life so can give 7 days of coverage

Has anaerobic coverage (C diff) – orally (the IV vancomycin doesn’t penetrate the gut enough to kill C. diff)

The type of patient that would be given this type of medication is the one with significant skin and soft tissue infection and doesn’t meet criteria to be hospitalized or doesn’t want to be hospitalized or will likely not be compliant with oral medication

Question 34

Some of the adverse events involving glycopeptides include Red Person syndrome which is characterized by ___, nephrotoxicity and otoxicity at high levels

Answer 34

Red person syndrome: intense flushing as the drug is going in/feeling really hot/pt gets really red

This is an infusion rxn so it’s NOT an HSR, and the histamine release is NOT IgE mediated. Treatment is to give the drug more slowly

Question 35

There’s only one drug in the class of cyclic lipopeptides and that is ___ whose lipophilic tail helps it to get into the membrane of Gram pos bugs

Answer 35

Daptomycin

Question 36

What is the mechanism of action of daptomycin?

Answer 36

see below

**daptomycin = death without lysin**

Question 37

T/F: Daptomycin is more commonly used for both gram positive and gram negtive infections

Under which conditions would you give this drug?

Answer 37

•Complicated Gram-positive infections

–Skin/Soft Tissue

–Bacteremia/Endocarditis

Question 38

Which drug is inhibited by pulmonary surfactant and is therefore ineffective in cases of pneumonia?

Answer 38

Daptomycin

Question 39

What are 2 unique adverse effects of daptomycin?

Answer 39

eosinophilic pneumonia and rhabdomyolysis (some damage to skeletal muscle, according to google)

Question 40

2 drugs that had to make a comeback due to resistance are __ and __

Answer 40

Polymixin B and Colistin

(we had to go back to the old “list”- colistin - of drugs and “mix” things up coz this resistance has really been a “b” - polymixin B)

Question 41

Polymixn B and Colistin are given either IV or ___. They cover gram negatives, including Pseudomonas, except Morganella, Proteus, ___ and ___

3 significant toxicities include bronchospasms when inhaled, __ and neurotoxicity

These drugs are only used when___

Answer 41

Polymixn B and Colistin are given either IV or inhaled. They cover gram negatives, including Pseudomonas, except Morganella, Proteus, Serratia and Burkholderia (King Proteus and his queen Serratia had to take their son Morgan and move back to Burkholderia coz they weren’t accepted by the Polymixin government)

3 significant toxicities include bronchospasms when inhaled, nephrotoxicity and neurotoxicity

These drugs are only used in the case of a serious, resistant gram neg infection

Question 42

Other cell envelope agents include bacitracin and fosfomycin. What are these used for and what bugs do they cover?

Answer 42

Bacitracin:

Topical; Bacitracin is used in the nose to reduce the chance of Staph aureus the infection around the time of surgery

Covers gram pos only

Fosfomycin: Oral (powder); UTI only

Question 43

The classes of drugs that inhibit dna include __ and ___, nitrofurantoin and imidazoles

Answer 43

The classes of drugs that inhibit dna include quinolones and fluoroquinolones, nitrofurantoin and imidazoles

Question 44

Examples of fluoroquinolones include: ciprofloxacin, __, __, gemifloxacin and ofloxacin

Answer 44

Examples of fluoroquinolones include: ciprofloxacin, levofloxacin, moxifloxacin, gemifloxacin and ofloxacin

**note that these drugs are among the most C.diff-ogenic**

Question 45

Describe the mechanism of action of fluoroquinolones

Answer 45

Act at DNA gyrase or topo to inhibit DNA uncoiling >> no replication

Question 46

Resistance to fluoroquinolones develops rapidly esp during treatment (more on population level but sometimes on individual level)

Resistance is mostly caused by___

Answer 46

Resistance develops rapidly (more on population level but sometimes on individual level – happens with fluoroquinolones)

Mostly caused by mutations in chromosomal genes (genes = gyrA and parC, also those for efflux pumps), less so plasmid mediated

Question 47

Fluoroquinolones have a broad range of activity. They work against gram neg (including Pseudomonas) and gram pos (not so much). They also cover ___ and ___ and are part of a multi-drug regimen for ___

Which particular fluoroquinolone works very well against Pseudomonas?

Answer 47

Fluoroquinolones have a broad range of activity. They work against gram neg (including Pseudomonas) and gram pos (not so much). They also cover atypicals and anaerobes (Moxifloxacin) and are part of a multi-drug regimen for Mycobacteria

Ciprofloxacin works well against Pseudomonas

Question 48

The clinical uses of fluoroquinolones include respiratory tract infections, ___(except moxifloxacin – doesn’t concentrate at high enough levels to exert effect) and traveler’s diarrhea (resistance limits). It used to also be used for __ but that stopped due to resistance

Answer 48

The clinical uses of fluoroquinolones include respiratory tract infections, UTIs (except moxifloxacin – doesn’t concentrate at high enough levels to exert effect) and traveler’s diarrhea (resistance limits). It used to also be used for gonorrhea but that stopped due to resistance

Question 49

Fluoroquinolones are contraindicated in __ and ___ due to possible damage to cartilage, can prolong QT intervals and cause tendon rupture

Answer 49

Fluoroquinolones are contraindicated in pregnancy and kids under 18 due to possible damage to cartilage, can prolong QT intervals, and cause tendon rupture

Question 50

Nitrofurantoin is a drug that inhibits/damages bacterial dna and is only used (IV/Orally). It’s active against ___ and is used in cases of ___. Adverse events include nausea and __ with chronic use

Answer 50

Nitrofurantoin is a drug that inhibits/damages bacterial dna and is only used orally. It’s active against gram pos and gram neg and is used in cases of resistant UTIs. Adverse events include nausea and pulmonary fibrosis with chronic use

Question 51

What is the mechanism of action of metronidazole (tinidazole)?

Answer 51

Enters bacterial cell by diffusion and produces free radicals that damage dna

Question 52

The imidazole drugs primarily target what type of bacteria (anaerobes/aerobic)?

T/F: This class of drugs also treats C.diff infection and can be given IV or oral since it has a first pass thru the biliary system

Answer 52

The imidazole drugs primarily target anaerobic bacteria, and also targets Bacteroides fragilis (has lots of resistance and is implicated in intra-abdominal infections/abscesses)

Truth. This class of drugs also treats C.diff infection and can be given IV or oral since it has a first pass thru the biliary system

Question 53

What are the protozoa that are treated with metronidazole?

Answer 53

GET GAP on the Metro (giardia, entamoeba, trichomonas, gardnerella vaginalis, anaerobes and H.pylori)

**also treats Chrohn’s disease**

Question 54

Some of the adverse effects of imidazoles include a metallic taste, CNS effects (rare) and __ effect with alcohol

Answer 54

Some of the adverse effects of imidazoles include a metallic taste, CNS effects (rare) and disulfram-like effect with alcohol (flushing, vomitting)

Question 55

Which class of antibiotics works by inhibiting RNA?

Answer 55

Rifamyacins/Fidaxomicin

Question 56

Examples of drugs in the rifamycin class influde ___, ___rifapentine and rifabutin

T/F: Because resistance to these drugs is high, they are never used alone and are only used in combination with anothe drug for serious infection

Answer 56

Examples of drugs in the rifamycin class include rifampin, rifapentine and rifabutin

Truth. Because resistance to these drugs is high, they are never used alone and are only used in combination with anothe drug for serious infection

A few R’s: rna polymerase inh, red/orange body fluids, rapid resistance if used alone

Question 57

Rifamycins are primarily used for ___ and are used as prophylaxis for ___ infection.

Answer 57

Rifamycins are primarily used for mycobacterial infections and are used as prophylaxis for Neisseria meningitidis infection.

**note also synergy for serious Gram-positive bacterial infections (no gram neg coverage) and Rifaximin for GI infections (traveler’s diarrhea)**

Question 58

A unique adverse effect of rifamycins is ___. There are also mild hematologic effects such as thrombocytopenia, leukopenia, anemia, and ___ (seen with co-administration or pre-existing liver disease)

Answer 58

A unique adverse effect of rifamycins is turning secretions orange. There are also mild hematologic effects such as thrombocytopenia, leukopenia, anemia, and hepatitis (seen with co-administration or pre-existing liver disease)

Question 59

Fidaxomicin is a non-absorbable oral drug that also acts against RNA polymerase. Under what clinical circumstances would you use this drug?

Answer 59

Poor activity against Gram negative enteric flora but used for C. difficile infection

**note also that this drug has no serious side effects and has fewer relapses than with oral vancomycin. Also costs lotsa money dollars**