Microbiology pharm – HY mixed antimicrobials I

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HY points about each drug followed by a quiz at the end

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Beta-lactam HY points

MOA of beta-lactams (e.g., penicillin)

• d-Ala-d-Ala analogues that bind to penicillin-binding proteins (i.e., transpeptidase).
• Inhibit cell wall synthesis by blocking transpeptidase-mediated crosslinking of peptidoglycan.

Mechanism of organism resistance

• Beta-lactamase production.
• MSSA is resistant to methicillin-class beta-lactams because it produces beta-lactamase.
• “How does MSSA –> MRSA?” –> answer = altered penicillin-binding protein (PBP2); wrong answer = beta-lactamase production. Since MSSA is already resistant to beta-lactamase, that means becoming MSSA –> MRSA must be a different mechanism.

Relevance of the methicillin-class

As I talk about in the cephalosporin post, 90% of community Staph (i.e., MSSA, not MRSA) produce beta-lactamase, so penicillin, amoxicillin, and ampicillin will almost always not be effective.

• The only time these drugs can be considered for MSSA is if a beta-lactamase inhibitor is added (i.e., amoxicillin/clavulanate [Augmentin]; or ampicillin/sulbactam).
• But the point is: do not straight-up give penicillin or amoxicillin for an infection (usually skin) that could potentially be community Staph.

The methicillin-class agents (i.e., dicloxacillin, flucloxacillin, nafcillin, oxacillin, cloxacillin) are highly steric, so their beta-lactam ring is resistant to beta-lactamase. Therefore these drugs can be used against MSSA.

Skin infections like cellulitis, erysipelas, and impetigo can all be MSSA, which is why penicillin and amoxicillin are the wrong treatments.

• MSSA exceeds Strep pyogenes (Group A Strep) as the causal organism for cellulitis and impetigo (bullous and non-bullous).
• Group A Strep exceeds MSSA for ersyipelas, but MSSA still possible.

Classic outpatient Tx for cellulitis, erysipelas, and severe impetigo: oral dicloxacillin or oral cephalexin. The inpatient equivalents are IV flucloxacillin and IV cephazolin, respectively. First-generation cephalosporins (i.e., cephalexin and cephazolin) are essentially the equivalent of the methicillin-class beta-lactams in that they can cover MSSA.

As stated above, if MSSA –> MRSA, the mechanism of resistance is “altered penicillin-binding protein,” not “production of beta-lactamase,” because MSSA already produces a beta-lactamase.

Beta-lactam efficacy

First and foremost, it should be noted that beta-lactams are considered to be very efficacious drugs. If we can use one, we should, because they do the job well. How does that point apply most saliently to real-life medicine?

• Empiric Tx for endocarditis (i.e., before we know the organism) is gentamicin PLUS either vancomycin or ampicillin/sulbactam.
• The gentamicin covers gram-negatives (rods); the vancomycin covers gram-positives (including MRSA).
• However, let’s say the culture comes back positive for MSSA (i.e., we can use a methicillin-class beta-lactam); the question is:
  • Do we continue the vancomycin in order to minimize the chance of vancomycin resistance (i.e., stopping a drug early can increase this chance), OR do we switch to nafcillin?
  • And the answer is: yes, switch to nafcillin (6 weeks).
• This is because beta-lactams are very efficacious. Vancomycin isn’t very efficacious; it just happens to be useful against MRSA if that’s what the patient has.

If patient has syphilis (normally treated with penicillin) but has history of anaphylaxis, if the patient’s condition is latent-secondary, late-secondary, tertiary, or neurosyphilis, the answer is densensitize and give penicillin. You might say, “Why can’t we just treat with another agent?” It’s not that we can’t in theory; it’s just that penicillin is so efficacious that the benefit of desensitizing and giving it anyway exceeds that of just giving a non-beta-lactam.

Synergism with aminoglycosides

• “Beta-lactams are synergistic with aminoglycosides” is a quote you should remember.
• Beta-lactam will disrupt the cell wall –> then aminoglycoside enters cell and disrupts protein synthesis (30s). Just memorize it.

Important allergies

• If Hx of rash to beta-lactam, yes, can still give cephalosporin as alternative (<10% crossover allergy).
• If Hx of anaphylaxis to beta-lactam, no, cannot give cephalosporin; use other agent instead (e.g., doxycycline). Exception is advanced syphilis (or pregnant patient with syphilis), in which the patient is desensitized to penicillin.
• Classically cause allergic interstitial nephropathy (aka tubulointerstitial nephritis, or just interstitial nephritis).
  • 55M + treated with nafcillin for MSSA endocarditis + now has rash + urinalysis shows WBCs on dipstick; Dx? –> answer = interstitial nephropathy.
  • Although classic, patient need not present with a rash. The key is beta-lactam, cephalosporin, or NSAID + now patient has WBCs (eosinophils) in the urine.
  • Methicillin not used clinically because ↑↑ risk of interstitial nephritis.
  • Do not confuse this with acute tubular necrosis (dirty/muddy brown granular casts in someone on gentamicin).

Pipericillin, ticarcillin

• Hard-hitting beta-lactams that cover Pseudomonas.
• Tazobactam or clavulanate added as beta-lactamase inhibitors.
• Pipericillin/tazobactam (Piptaz) is a HY combo for broad-spectrum nosocomial coverage.
  • E.g., 30M + hospital-acquired pneumonia; how do we treat? –> Piptaz + vanc is acceptable combo (covers both Pseudomonas as well as MRSA for nosocomial infections).

Carbapenems

• DIME –> (i.e., Doripenem, Imipenem, Meropenem, Ertapenem).
• Imipenem combined with cilastatin (i.e., imipenem/cilastatin), which decreases renal clearance + maintains serum levels.

MOA of carbapenems?

• Similar in structure to beta-lactams except a sulfur atom in position 1 is replaced with a carbon atom + an unsaturation has been introduced.
• Binds to penicillin-binding proteins (i.e., transpeptidase).
• Inhibits cell wall synthesis by blocking transpeptidase-mediated crosslinking of peptidoglycan.

When do we use carbapenems?

• Extremely hard-hitting agents reserved for multi-drug-resistant infections.
• If antibiotics are given for pancreatitis, carbapenems are notably effective.
• Cover Pseudomonas; however ertapenem is weak against Pseudomonas.

Important side-effects?

• Impipenem causes seizures.

Aztreonam

MOA of aztreonam?

• Mono-bactam antibiotic (similar to beta-lactams) in that disrupts cell wall synthesis.
• Binds to and inhibits penicillin-binding protein 3 (PBP3).

When do we use aztreonam?

• Can be used safely in persons with beta-lactam allergy. 
• Only covers gram-negatives.

Vancomycin

MOA of vancomycin? –> answer = disrupts cell wall synthesis by binding to d-Ala-d-Ala portion of cell wall precursors.

Use for vancomycin?

• Classic for MRSA
• Ampicillin-resistant Enterococcus
• Used empirically for meningitis (vanc + ceftriaxone), endocarditis (gentamicin + vanc).

When is vanc notably not effective in terms of MRSA Tx?

• Not good for skin. If patient has MRSA skin infection, use clindamycin, doxycycline, linezolid, or TMP/SMX.

Mechanism of resistance to vanc?

• d-Ala-d-Ala becomes d-Ala-d-Lac in the cell wall.
• Ala = alanine; Lac = lactate.

Toxicity of vanc? –> NOT Red–> Nephrotoxicity, Ototoxicity, Thrombophlebitis, Red man syndrome (histamine-induced flushing).

• Anti-histamine + slower infusion vanc –> decreased risk of Red man syndrome.

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1. MOA of beta-lactams (e.g., penicillin)?

d-Ala-d-Ala analogues that bind to penicillin-binding proteins (i.e., transpeptidase).

Inhibit cell wall synthesis by blocking transpeptidase-mediated crosslinking of peptidoglycan.

2. a) Why is 90% of methicillin-sensitive Staph (MSSA) resistant to beta-lactams?

b) When MSSA –> MRSA, what’s the resistance mechanism?

a) MSSA is resistant to beta-lactams because it produces beta-lactamase.

b) Altered penicillin-binding protein (PBP2); wrong answer = beta-lactamase production. Since MSSA is already resistant to beta-lactamase, that means MSSA –> MRSA must be a different mechanism.

3. How do you treat cellulitis, erysipelas, and impetigo?

Mild impetigo: answer = topical mupirocin.

Classic outpatient Tx for cellulitis, erysipelas, and severe impetigo: oral dicloxacillin or oral cephalexin.

The inpatient equivalents are IV flucloxacillin and IV cephazolin, respectively.

First-generation cephalosporins (i.e., cephalexin and cephazolin) are essentially the equivalent of the methicillin-class beta-lactams in that they can cover MSSA.

90% of community Staph (i.e., MSSA, not MRSA) produce beta-lactamase, so penicillin, amoxicillin, and ampicillin will frequently not be effective. We need to use a heavily steric beta-lactam in the methicillin class instead.

MSSA exceeds Group A Strep for cellulitis and impetigo (bullous and non-bullous). For erysipelas, Group A Strep exceeds MSSA. Therefore if penicillin, amoxicillin, or ampicillin is used, some cases will be inadequately treated.

4. How do we treat MSSA vs MRSA?

 

For MSSA:

Most common treatments are a methicillin-class beta-lactam OR first-generation cephalosporin – i.e., oral dicloxacillin or oral cephalexin.

The inpatient equivalents are IV flucloxacillin and IV cephazolin, respectively.

First-generation cephalosporins (i.e., cephalexin and cephazolin) are essentially the equivalent of the methicillin-class beta-lactams in that they can cover MSSA.

For MRSA:

Vancomycin is standard.

For skin infections, since vanc has poor skin penetration, can use clindamycin, doxycycline, linezolid, or TMP/SMX.

5th generation cephalosporins (ceftobiprole, ceftaroline) can also be used.

5. a) What’s the empiric Tx for endocarditis?

b) If patient’s blood cultures come back positive for MSSA, do we change the antibiotics; why or why not?

First and foremost, it should be noted that beta-lactams are considered to be very efficacious drugs. If we can use one, we should, because they do the job well. How does that point apply most saliently to real-life medicine?

• Empiric Tx for endocarditis (i.e., before we know the organism) is gentamicin PLUS either vancomycin or ampicillin/sulbactam.
• The gentamicin covers gram-negatives (rods); the vancomycin covers gram-positives (including MRSA).
• However, let’s say the culture comes back positive for MSSA (i.e., we can use a methicillin-class beta-lactam); the question is:
  • Do we continue the vancomycin in order to minimize the chance of vancomycin resistance (i.e., stopping a drug early can increase this chance), OR do we switch to nafcillin?
  • And the answer is: yes, switch to nafcillin (6 weeks).
• This is because beta-lactams are very efficacious. Vancomycin isn’t very efficacious; it just happens to be useful against MRSA if that’s what the patient has.

6. What do we do if someone who has syphilis has a Hx of anaphylaxis to beta-lactams?

If patient has syphilis (normally treated with penicillin) but has history of anaphylaxis, if the patient’s condition is latent-secondary, late-secondary, tertiary, or neurosyphilis, the answer is densensitize and give penicillin. You might say, “Why can’t we just treat with another agent?” It’s not that we can’t in theory; it’s just that penicillin is so efficacious that the benefit of desensitizing and giving it anyway exceeds that of just giving a non-beta-lactam.

7. Beta-lactams are notably synergistic with which other antibiotic class?

“Beta-lactams are synergistic with aminoglycosides” is a quote you should remember.

Beta-lactam will disrupt the cell wall –> then aminoglycoside enters cell and disrupts protein synthesis (30s). Just memorize it.

8. Can we give a cephalosporin to someone with a history of penicillin allergy?

If Hx of rash to beta-lactam, yes, can still give cephalosporin as alternative (<10% crossover allergy).

If Hx of anaphylaxis to beta-lactam, no, cannot give cephalosporin; use other agent instead (e.g., doxycycline). Exception is advanced syphilis (or pregnant patient with syphilis), in which the patient is desensitized to penicillin.

9. What renal diagnosis do beta-lactams cause?

Classically cause allergic interstitial nephropathy (aka tubulointerstitial nephritis, or just interstitial nephritis).

• • 55M + treated with nafcillin for MSSA endocarditis + now has rash + urinalysis shows WBCs on dipstick; Dx? –> answer = interstitial nephropathy.
  • Although classic, patient need not present with a rash. The key is beta-lactam, cephalosporin, or NSAID + now patient has WBCs (eosinophils) in the urine.
  • Methicillin not used clinically because ↑↑ risk of interstitial nephritis.
  • Do not confuse this with acute tubular necrosis (dirty/muddy brown granular casts in someone on gentamicin).

10. When is pipericillin/tazobactam used?

Hard-hitting beta-lactam combo that covers Pseudomonas and is used for broad-spectrum nosocomial coverage.

Tazobactam is a beta-lactamase inhibitor.

• E.g., 30M + hospital-acquired pneumonia; how do we treat? –> Piptaz + vanc is acceptable combo (covers both Pseudomonas as well as MRSA for nosocomial infections).

11. MOA of carbapenems?

Similar in structure to beta-lactams except a sulfur atom in position 1 is replaced with a carbon atom + an unsaturation has been introduced.

Binds to penicillin-binding proteins (i.e., transpeptidase).

Inhibits cell wall synthesis by blocking transpeptidase-mediated crosslinking of peptidoglycan.

12. What’s the major side-effect of imipenem?

Impipenem causes seizures.

13. Name four carbapenems.

DIME –> (i.e., Doripenem, Imipenem, Meropenem, Ertapenem).

14. What drug is imipenem almost always combined with, and why?

Imipenem combined with cilastatin (i.e., imipenem/cilastatin), which decreases renal clearance + maintains serum levels.

15. When do we use carbapenems?

Extremely hard-hitting agents reserved for multi-drug-resistant infections.

If antibiotics are given for pancreatitis, carbapenems are notably effective.

Cover Pseudomonas; however ertapenem is weak against Pseudomonas.

16. a) What is aztreonam?

b) When do we use it?

a)

Mono-bactam antibiotic (similar to beta-lactams) in that disrupts cell wall synthesis.

Binds to and inhibits penicillin-binding protein 3 (PBP3).

b)

Can be used safely in persons with beta-lactam allergy. 

Only covers gram-negatives.

17. MOA of vancomycin?

Disrupts cell wall synthesis by binding to d-Ala-d-Ala portion of cell wall precursors.

18. Use for vancomycin?

Classic for MRSA

Ampicillin-resistant Enterococcus

Used empirically for meningitis (vanc + ceftriaxone), endocarditis (gentamicin + vanc).

19. When is vancomycin notably not effective in terms of MRSA Tx?

Not good for skin (poor skin penetration). If patient has MRSA skin infection, use clindamycin, doxycycline, linezolid, or TMP/SMX.

20. Mechanism of resistance to vancomycin?

d-Ala-d-Ala becomes d-Ala-d-Lac in the cell wall.

Ala = alanine; Lac = lactate.

21. Toxicity of vancomycin? (4)

NOT Red–> Nephrotoxicity, Ototoxicity, Thrombophlebitis, Red man syndrome (histamine-induced flushing).

• Anti-histamine + slower infusion vanc –> decreased risk of Red man syndrome.

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