Microbiology pharm – HY mixed antimicrobials II

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

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Polymyxins (i.e., Colistin)

MOA of polymyxins?

• Cationic polypeptide tail that acts as detergent on cell membrane –> leakage of cellular components + death.

Use for polymyxins?

• Last resort for multi-drug-resistant gram-negatives (i.e., Pseudomonas).
• Not effective against gram-negative diplococci (i.e., Neisseria gonorrhea/meningitides).
• Used as part of Thayer-Martin agar for culturing Neisseria. 
  • Thayer-Martin = Vancomycin + Polymyxin + Nystatin (VPN client).

Toxicity of polymyxins? –> answer = neurotoxicity, ototoxicity.

Sulfonamides (“sulfa drugs”; i.e., sulfamethoxazole, sulfadiazine)

MOA of sulfonamides? –> answer = inhibit dihydropteroate synthase.

Highest-yield uses for sulfonamides?

• Sulfamethoxazole as part of trimethoprim/sulfamethoxazole (TMP/SMX) –> used for many different types of infections, but notably for Pneumocystis jirovecii pneumonia (PJP) in immunocompromised patients (both prophylaxis and treatment).
• TMP/SMX classic treatment for simple UTIs.
• TMP/SMX can be used for MRSA skin infections (vanc has poor skin penetration).
• TMP/SMX is prophylaxis for toxoplasmosis (however treatment is sulfadiazine/pyramethamine).

Important side-effects of sulfa drugs?

• Type I hypersensitivity skin eruptions (IgE crosslinking on mast cells); in increasing order of severity:
  • Morbilliform rash (maculopapular; measles-like)
  • Erythema multiforme (skin lesions with multiple shapes)
• Type III hypersensitivity (due to immune complex deposition):
  • Serum sickness –> rash presenting 3-5 days after administration of drug (if immediate, the allergy is type I instead).
    • Presents as arthritis or erythema nodosum.
    • Arthus reaction is a type of serum sickness that is localized to the skin at an injection site (if the drug was injected).
  • Erythema nodosum –> not a rash; EN is a panniculitis (inflammation of subcutaneous fat) classically of the shins, but can also appear on the arms; USMLE will ask the hypersensitivity type this is (answer = III).
• Type IV hypersensitivity (due to T cell response):
  • Stevens-Johnson syndrome
    • Positive Nikolsky sign (sloughing of skin with friction)
    • Diffuse bullae; resemble pemphigus vulgaris.
    • Treat in a burns unit. Use of steroids and IVIG are controversial.
  • Toxic epidermal necrolysis (>30% body surface area involvement); often fatal.
    • Treat in a burns unit. Use of steroids and IVIG are controversial.
• Membranous glomerulonephritis (MG):
  • Sulfonamides classically cause MG (nephrotic syndrome; “spike and dome” appearance of subepithelial immunoglobulin and complement deposition).
  • Do not confuse this with aminoglycosides (gentamicin, amikacin) causing acute tubular necrosis (muddy/dirty brown granular casts).

Dapsone

MOA of dapsone? –> same as sulfonamides (dihydropteroate synthase inhibitor), but structurally distinct.

When do we use dapsone?

• Clarithromycin + ethambutol +/- dapsone is a combo used for treatment of Mycobacterium avium intracellulare.
• Dapsone can be used in Leprosy.

Important side-effect of dapsone?

• Classically causes hemolysis in G6PD deficiency.

Trimethoprim, pyrimethamine, methotrexate

MOA of these three agents? –> answer = dihydrofolate reductase inhibitors.

• Methotrexate is not an antibiotic; it is a DMARD for RA and also an immunosuppressant, but you need to know these three drugs are all dihydrofolate reductase inhibitors.
• Pyrimethamine is used with sulfadiazine to treat Toxoplasmosis (TMP/SMX is prophylaxis).

When do we use trimethoprim?

• Almost always used as the TMP/SMX combo, which has numerous uses. As mentioned above, classic for Pneumocystis jirovecii, simple UTIs, and MRSA skin infections.

When do we use pyrimethamine?

• Sulfadiazine + pyrimethamine used to treat toxoplasmosis (prophylaxis = trimethoprim/sulfamethoxazole).

Daptomycin

MOA of daptomycin? –> answer = forms pores in cell membrane –> “disrupts the charge barrier.”

When do we use daptomycin?

• Notably effective against Enterococci.
• Treatment for Enterococci = ampicillin first; if resistant, go to vancomycin; if resisntant, use another agent like daptomcyin or the streptogramins.

Side-effects of daptomycin?

• Increased creatine kinase (CK) and myopathy.

Fluoroquinolones (e.g., ciprofloxacin, levofloxacin)

MOA of fluoroquinolones?

• Inhibit DNA gyrase (prokaryotic topoisomerase II/IV)
• Topoisomerase is an enzyme that induces a “nicking” in the DNA during replication in order to prevent supercoiling.
• Inhibition of topoisomerase –> nicking cannot occur –> DNA supercoils + breaks –> cell death.
• Should be noted that DNA gyrase specifically refers to the prokaryotic enzyme. For instance, etoposide and teniposide are chemotherapeutic topoisomerase II inhibitors, but they do not inhibit DNA gyrase.

HY uses for fluoroquinolones?

• Prostatitis (ciprofloxacin)
• Pyelonephritis (ciprofloxacin)
  • If patient is septic, ceftriaxone can be used (also on NBME).
• Pneumonia
  • Empiric Tx for community-acquired pneumonia (CAP): azithromycin (macrolide).
  • Empiric Tx for CAP if patient has received antibiotics in the past 3 months: levofloxacin (fluoroquinolone).
  • Empiric Tx for CAP (inpatient; non-ICU): fluoroquinolone, OR azithromycin + a beta-lactam.
  • Empiric Tx for CAP (inpatient; ICU): beta-lactam, PLUS either a fluoroquinolone or azithromycin.
• Diverticulitis
  • Classic Tx is metronidazole PLUS a fluoroquinolone or Augmentin (amoxicillin/clavulanate).

HY side-effect of fluoroquinolones?

• Cartilage damage (tendonopathy).
  • 82M + recently treated for prostatitis + goes metal detecting a lot + sore ankle; what’s the MOA of the drug he was treated with? –> answer = inhibition of topoisomerase II.

Metronidazole

MOA of metronidazole? –> answer = causes the formation of toxic metabolites that damage DNA.

When do we use metronidazole? –> GET GAP on the Metro

• Giardia lamblia (Giardiasis)
• Entamoeba histolytica (amoebiasis)
• Trichomonas vaginalis (trichomoniasis)
• Gardnerella vaginalis (bacterial vaginosis)
• Anaerobes below the diaphragm
  • Classic Tx is metronidazole PLUS a fluoroquinolone or Augmentin (amoxicillin/clavulanate).
  • Anaerobes above the diaphragm = clindamycin.
• Pylori –> second-line Tx for H. pylori (first-line = CAP  = clarithromycin, amoxicillin, PPI; if urease breath test still positive 4 weeks after treatment, assume Abx resistance and replace the clarithromycin and amoxicillin with metronidazole, tetracycline, bismuth). In other words:
  • First-line for H. pylori = CAP = clarithromycin, amoxicillin, PPI (e.g., omeprazole).
  • Second-line for H. pylori = metronidazole, tetracycline, bismuth, PPI.
  • P used to be able to stand for psuedomembranous colitis (C. difficile), but metro is now no longer used first-line as of February 2018; oral vancomycin is now used first-line across the board, not oral metronidazole.

Any notable side-effect of metronidazole?

• Disulfiram-like reaction if patient drinks alcohol (nausea, vomiting).

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