Beta lactams, DNA and RNA inhibitors Flashcards
What is the other name for transpeptidase (which you will recall forms the peptide crosslinks that stabilize peptidoglycan)?
Penicillin binding protein (PBP)
What is the function of autolysins in peptidoglycan synthesis?
Autolysins break the linkages for the addition of new monomers
What do the following drugs have in common?
Penicillin
Cephalosporins
Carbapenems
Monobactams
That #beta-lactam ring
Penicillins can be sub-divided into 4 groups. Name them
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
What is the mechanism of action of Beta lactams?
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
2 of the most common mechanisms of bacterial resistance to penicillins include ___
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)
HSRs to penicillin include rash, hives/anaphylaxis, ___, immune-mediated cytopenias, ___ and ___ at high doses
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**
T/F: Penicillins are good for gram pos, variable for gram neg and have zero atypical coverage
Truth
Fill in the table for what penicillin is still used for
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)
Name the semi-synthetic penicillins
Semi-synthetic penicillins include Nafcillin, oxacillin and dicloxacillin (and #meth-icillin)
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?
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
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)?
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
The only penicillins that target Pseudomonas are ___
Piperacillin – broader spectrum (not formulated alone, used in comb with beta lactamase inh)
Only one that covers Pseudomonas
Who all are the Beta lactamase inhibitors?
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)**
Why don’t ampicillin-sulbactam and piperacillin-tazobactam work against MRSA?
How does amoxicillin-clavulanic acid work?
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)
What are the mechanisms of resistance for cephalosporins?
•Intrinsic Resistance **main mechanism**
–Pseudomonas, Enterococci
•Altered Membrane Permeability
–Porins, Pseudomonas
•Altered PBPs
–Most agents not active against MRSA
•β-lactamases
–AmpC and ESBLs
Who all are the 1st gen cephalosporins? What do these work against? What are the clinical uses of these drugs?
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)
The 2nd generation cephalosporins include __ and __, and have good anaerobic activity and work as intraabdominal surgery prophylaxis
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
___ and ___ are the 3rd gen cephalosporins and they have activity against Pseudomonas
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*
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 ___
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**
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?
Ceftaroline
**this drug is also en exception to the increasing spectrum rule - its only kinda okay for gram negs**
Under what circumstances would you use cephalosporins together with beta-lactamase inhibitors?
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)
What are the common carbapenems discussed?
Imipenem
Meropenem
Ertapenem
(Doripenem - not really used like that)
Against which bugs do carbapenems work against?
What makes ertapenem different from the other carbapenems?
•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
Which class of drugs was developed to address the allergic reactions to penicillins?
Monobactams (Aztreonam) was developed overcome allergic rxns to penicillins
What type of bugs/infections are treated with aztreonam?
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
What are the common glycopeptide and lipoglycopeptide agents discussed?
Vancomycin
What is the mechanism of action of glycopeptides?
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
What class of bacteria has resistance to Vancomycin? (hint: NOT Staph, or at least not that much of Staph)
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)
What is the mechanism of resistance of vancomycin intermediate staph aureus?
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
Do glycopeptides only treat gram pos? Explain your reasoning
•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)
T/F: Glycopetides work just as well as beta lactams and are used in the same clinical cases
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
What is unique about the mechanism of action of dalbavancin?
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
Some of the adverse events involving glycopeptides include Red Person syndrome which is characterized by ___, nephrotoxicity and otoxicity at high levels
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
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
Daptomycin
What is the mechanism of action of daptomycin?
see below
**daptomycin = death without lysin**
T/F: Daptomycin is more commonly used for both gram positive and gram negtive infections
Under which conditions would you give this drug?
•Complicated Gram-positive infections
–Skin/Soft Tissue
–Bacteremia/Endocarditis
Which drug is inhibited by pulmonary surfactant and is therefore ineffective in cases of pneumonia?
Daptomycin
What are 2 unique adverse effects of daptomycin?
eosinophilic pneumonia and rhabdomyolysis (some damage to skeletal muscle, according to google)
2 drugs that had to make a comeback due to resistance are __ and __
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)
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___
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
Other cell envelope agents include bacitracin and fosfomycin. What are these used for and what bugs do they cover?
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
The classes of drugs that inhibit dna include __ and ___, nitrofurantoin and imidazoles
The classes of drugs that inhibit dna include quinolones and fluoroquinolones, nitrofurantoin and imidazoles
Examples of fluoroquinolones include: ciprofloxacin, __, __, gemifloxacin and ofloxacin
Examples of fluoroquinolones include: ciprofloxacin, levofloxacin, moxifloxacin, gemifloxacin and ofloxacin
**note that these drugs are among the most C.diff-ogenic**
Describe the mechanism of action of fluoroquinolones
Act at DNA gyrase or topo to inhibit DNA uncoiling >> no replication
Resistance to fluoroquinolones develops rapidly esp during treatment (more on population level but sometimes on individual level)
Resistance is mostly caused by___
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
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?
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
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
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
Fluoroquinolones are contraindicated in __ and ___ due to possible damage to cartilage, can prolong QT intervals and cause tendon rupture
Fluoroquinolones are contraindicated in pregnancy and kids under 18 due to possible damage to cartilage, can prolong QT intervals, and cause tendon rupture
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
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
What is the mechanism of action of metronidazole (tinidazole)?
Enters bacterial cell by diffusion and produces free radicals that damage dna
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
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
What are the protozoa that are treated with metronidazole?
GET GAP on the Metro (giardia, entamoeba, trichomonas, gardnerella vaginalis, anaerobes and H.pylori)
**also treats Chrohn’s disease**
Some of the adverse effects of imidazoles include a metallic taste, CNS effects (rare) and __ effect with alcohol
Some of the adverse effects of imidazoles include a metallic taste, CNS effects (rare) and disulfram-like effect with alcohol (flushing, vomitting)
Which class of antibiotics works by inhibiting RNA?
Rifamyacins/Fidaxomicin
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
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
Rifamycins are primarily used for ___ and are used as prophylaxis for ___ infection.
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)**
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)
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)
Fidaxomicin is a non-absorbable oral drug that also acts against RNA polymerase. Under what clinical circumstances would you use this drug?
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**
