Antimicrobials Flashcards
Antibiotic MOAs and classes
Cell wall synthesis inhibitors:
- Penicillins
- Cephalosporins
- Carbapenems
- Monobactams
Peptidoglycan formation inhibitor (D-ala-D-ala binding):
- Glycopeptides/Vancomycin
Inhibit topoisomerase II and IV:
- Fluoroquinolones
30S ribosomal subunit:
- Aminoglycosides
- Tetracyclines
50S ribosomal subunit:
- Clindamycin
- Chloramphenicol
- Macrolides (Erythromycin)
- Linezolid
Folic acid synthesis inhibitors:
- Trimethoprim-sulfamethoxazole
Other:
- Metronidazole
- Lincosamides
- Anti-TB agents
Beta-lactam MOA
Beta-lactams bind to penicillin-binding-proteins (PBPs, aka transpeptidases) and block transpeptidase cross-linking of peptidoglycan in cell wall
Beta-lactam: bacterial mechanisms of resistance
- cleavage of beta-lactam ring via beta-lactamases
- alteration of binding site (PBP), seen in Staph aureus and Strep pneumoniae
General beta-lactam side effects
- rash
- GI upset
- hypersensitivity reactions (types I-IV)
Beta-lactam drugs
- Penicillins (penicillin G, ampicillin, amoxicillin, methicillin)
- Cephalosporins (cephalexin, cefuroxime, ceftriaxone, cefepime)
- Carbapenems (imipenem-cilastatin*, meropenem, doripenem)
- Monobactams (atreonam)
*imipenem is combined with cilastatin, a dehydropeptidase inhibitor, which prevents breakdown of imipenem in kidneys
Carbapenem
- resistant to β-lactamase
- used to treat extended-spectrum beta-lactamase-producing bacteria (ESBL)
beta-lactam + beta-lactamase inhibitor combinations
- Amoxicillin-Clavulanic acid
- Ampicillin-Sulbactam
- Piperacillin-Tazobactam
“-bactam”
Glycopeptides (Vancomycin) MOA
Inhibits peptidoglycan formation by binding to the D-ala-D-ala of the peptide terminus, inhibiting transglycosylation
Gold standard for treating MRSA and coagulase-negative Staph
Vancomycin: bacterial mechanisms of resistance
the last D-ala residue is replaced by D-lactate, so vancomycin cannot bind
Vancomycin side effects
- nephrotoxicity
- ototoxicity
- Vancomycin flushing reaction / infusion reaction (mast cell degranulation with release of histamine, not a true allergy)
Ribosomal protein synthesis inhibitors
Buy “AT” 30, “CCEL” at 50
30S ribosomal subunit inhibitors:
A - Aminoglycosides (amikacin, gentamicin, streptomycin)
T - Tetracyclines (doxycycline, tetracycline)
50S ribosomal subunit inhibitors:
C - Clindamycin
C - Chloramphenicol
E - Erythromycin (Macrolide class)
L - Linezolid
Aminoglycoside MOA
binds to 30S ribosomal subunit, inhibiting initiation complex and leading to misreading of mRNA ==> mistranslation
Aminoglycoside bacterial method of resistance
bacterial transferases inactivate drug by acetylation, phosphorylation, adenylation
Aminoglycoside side effects
- nephrotoxicity
- ototoxicity
- teratogenicity
Tetracycline MOA
binds to 30S ribosomal subunit and prevents attachment of aminoacyl-tRNA
Tetracycline side effects
(Doxycycline)
- photosensitivity
- drug deposits in bones/teeth ==> inhibition of bone growth and teeth discoloration in children
- drug-drug interaction: divalent cations can bind to tetracycline and inhibit drug absorption
great for treating organisms that don’t gram-stain well
- gram-negative bacteria
- spirochetes & zoonotics
Tigecycline
tetracycline-derivative, binds to 30S ribosomal subunit
used for MRSA and VRE
Clindamycin MOA
blocks translocation at 50S subunit, preventing peptide chain elongation
Clindamycin side effects
- C. diff overgrowth, causing Pseudomembranous Colitis
Chloramphenicol MOA
blocks peptidyltransferase at 50S subunit
not really used clinically anymore
Chloramphenicol side effects
- anemia
- gray baby syndrome: permature infants lack liver UDP-glucuronyltransferase
Macrolide (Erythromycin) MOA
blocks translocation by binding to 23s rRNA component of 50S subunit, preventing peptide chain elongation
Macrolide side effects
- GI motility ==> vomiting
- prolongation of QT interval ==> cardiac arrythmias
- drug-drug interactions with erythromycin
Linezolid MOA
prevents formation of the initiation complex by binding to 23S rRNA of the 50S subunit
used to treat MRSA and vancomycin-resistant Enterococcus (VRE)
Linezolid side effects
- bone marrow suppression ==> pancytopenia (decrease in RBCs, WBCs, platelets)
- serotonin syndrome
Fluoroquinolone MOA
inhibits prokaryotic topoisomerase II (DNA gyrase) and topoisomerase IV ==> inhibition of DNA synthesis
ex: levofloxacin
Fluoroquinolone side effects
- tendonitis/tendon rupture
- QT prolongation
- drug-drug interactions with divalent cations
- teratogenicity
Folic acid synthesis inhibitors MOA
- Trimethoprim:
inhibits bacterial dihydrofolate reductase - Sulfonamides (Sulfamethoxazole):
inhibits dihydropteroate synthase
when used in combination, they act synergistically and are bactericidal, and also decrease the likelihood of bacteria developing resistance to either of the drugs
- Dapsone
inhibition of dihydrofolic acid synthesis via competitive inhibition of para-aminobenzoic acid (PABA) for dihydropteroate synthetase
–> different structure from Sulfonamides, but similar MOA
Folic acid synthesis inhibitor side effects
Trimethoprim:
- hyperkalemia (increased K+ levels)
- bone marrow suppression
Sulfonamides:
- hypersensitivity reactions
- hemolysis if G-6-PD deficient
- Steven-Johnson syndrome (bad skin disorder)
- photosensitivity
Daptomycin MOA
binds to cytoplasmic membrane ==> creates transmembrane channels ==> depolarizes cell
used for MRSA, vancomycin-resistant Enterococcus (VRE)
Daptomycin side effects
- myopathy
- rhabdomyolysis
- inactivated by pulmonary surfactant (cannot be used in pneumonia cases)
Polymyxin MOA
cationic polypeptides bind to cell membrane (detergent-like) ==> disrupt cell membrane ==> bacterial cell death
used for very drug-resistant gram-negative rod infections
“Polymyxins nix your nephrons and neurons”
Polymyxin side effects
- nephrotoxic
- neurotoxic
Treatments for MRSA
Very Deadly Like Children Die Too
- Vancomycin
- Daptomycin
- Linezolid
- Clindamycin
- Doxycycline
- TMP-SMX
Treatments for VRE
- Linezolid
- Daptomycin
Treatments for ESBL bacteria
Extended-spectrum beta-lactamase bacteria: E. coli, Klebsiella
Tx: carbapenems (imipenem-cilastatin)
Anti-tubercular drugs
(anti-TB drugs)
RIPE:
- Rifampin
- Isoniazid
- Pyrazinamide
- Ethambutol
General treatment: 4 drugs for 2mo, then just Rifampin and Isoniazid for 4mo = 6mo total
Latent treatment: Rifampin for 4mo, Isoniazid (with Vit B6) for 9mo
Isoniazid MOA
inhibits mycolic acid synthesis
Isoniazid side effects
- hepatotoxicity
- peripheral neuropathy due to vitamin B6 deficiency <- supplement pts with vit B6 to prevent neurotoxicity
“INH: Injures Neurons and Hepatocytes”
Rifampin MOA
inhibits bacterial DNA-dependent RNA polymerase ==> Ramps up cyt P450 ==> prevents mRNA synthesis
Rapid resistance if used alone
Rifampin side effects
- many drug interactions because Rifampin is a potent inducer of CYP450 system (drug metabolism pathway)
- Rifampin causes Red-orange discoloration of all body fluids
Pyrazinamide side effects
- hepatotoxicity
- hyperuricemia
Ethambutol MOA
inhibits arabinosyltransferase ==> inhibits cell wall synthesis
Ethambutol side effects
- optic neuropathy
- can cause red-green colorblindness and decreased visual acuity
“EYEthambutol”
Dapsone
used for leprosy, non-TB mycobacteria, some parasitic infections
MOA:
- inhibits dihydropteroate synthase
Side effects:
- hemolysis in patients with G-6-PD deficiency
- methemoglobinemia
Treatable viruses
- Herpesviruses: HSV, CMV, VZV
- Influenza A and B
- RSV
- Papillomavirus
- HIV
- Hepatitis B and C
Goal: minimize spread
Antivirals for HSV and VZV
- Acyclovir
- Valacyclovir
- Famciclovir
Acyclovir MOA
- guanosine analog
- acyclovir ==> acyclovir monophosphate ==> acyclovir diphosphate ==> acyclovir triphosphate (active product)
- competitive inhibitor of Herpesvirus DNA polymerase, stops lengthening of DNA strand
Acyclovir side effects
- wide range of uses
- IV formulation side effects: crystalline nephropathy, acute renal failure
- MOR: mutation of thymidine kinase
Valacyclovir and Famciclovir
- oral prodrugs (need to be converted to active form)
- Valacyclovir ==> Acyclovir
- Famciclovir ==> Penciclovir
- better bioavailability than Acyclovir
Antivirals for CMV
- Ganciclovir
- Valganciclovir
- Cidofovir
- Foscarnet
- Letermovir
these drugs also work to treat HSV and VZV, but are only used if pt is resistant to Acyclovir
Ganciclovir and Valganciclovir
Ganciclovir:
- IV formulation only
- side effects: bone marrow toxicity (neutropenia) <- due to DNA polymerase being targeted, dividing cells are affected
- MOR: mutated viral protein kinase
Valganciclovir:
- prodrug of Ganciclovir
- oral drug only
Cidofovir
- used for CMV, acyclovir-resistant HSV
- nucleotide analog
- direct inhibitor of DNA polymerase
- already has phosphate on it, so does not require viral kinase phosphorylation; can be used when there is a mutation in the viral thymidine kinase
- MOR: mutated cellular kinase
- side effects: nephrotoxicity
Foscarnet
- used for ganciclovir-resistant CMV or acyclovir-resistant HSV
- pyrophophate analog
- inhibition of DNA polymerase via binding to pyrophosphate binding-site
- does not require any kinase activation
- side effects: nephrotoxicity
- MOR: mutated viral DNA polymerase
“Foscarnet = pyro”fos”phate analog”
Antivirals for Influenza A & B
inhibition of influenza neuramindase (“N”):
- Zanamavir: inhaled, contraindicated in asthma
- Oseltamivir: oral
- Baloxavir: new drug
Antiviral for RSV
Ribavirin:
- inhibits RNA-dependent RNA polymerase
- side effects: dose-related hemolytic anemia, teratogenic
Palivizumab:
- targets F glycoprotein on RSV surface
- used for prevention of RSV in high-risk infants and children
Antifungals
- Polyenes (Amphotericin B, Nystatin)
- Azoles (“-azole”)
- Echinocandins (“-fungin”)
- 5-Fluorocytosine
- Allylamines (Terbinafine)
- Griseofulvin
Amphotericin B
- binds to ergosterol
- used for serious, systemic mycoses: Cryptococcus, Blastomyces, Coccidioides, Histoplasma, Candida, Mucor
- side effects: fever/chills (“shake and bake”), hypotension, kidney dysfunction
- side effects due to drug binding to cholesterol
“Amphotericin ‘tears’ holes in the fungal membrane by forming pores.”
amphibians have fungi? amphotericin B
Nystatin
- same mechanism as Amphotericin B: binds to ergosterol, forming pores in membrane
- topical use only
5-Fluorocytosine (Flucytosine)
- inhibits DNA and RNA biosynthesis by conversion to 5-fluorouracil
- used for systemic fungal infections in combination with Amphotericin B: Cryptococcus meningitis
- side effects: bone marrow suppression
Azoles
- inhibits fungal sterol (ergosterol) synthesis by inhibiting cyt P-450 enzyme
- used for local/less serious systemic mycoses
- relatively friendly drug
Allylamines (Terbinafine)
- inhibits squalene epoxidase (early ergosterol synthesis)
- used for dermatophytoses (onychomycosis, nail infections)
- side effects: GI upset
Echinocandins
- “-fungin”: Anidulafungin, caspofungin, micafungin
- inhibits cell wall synthesis (beta-glucan)
- used for Candida
- side effects: GI upset
“Echinocandins work against Candida”
Griseofulvin
- disrupts mitosis by interfering with microtubule function
- used for dermatophytes (tinea, ringworm)
- side effects: teratogenic, carcinogenic
Antiprotozoa
Metronidazole:
- G - Giardia
- E - Entamoeba
- T - Trichomonas
“The METRO: GET out of his way!”
Metronidazole side effects
- disulfiram-like reaction when taken with alcohol: flushing, tachycardia, hypotension, abdominal pain, vomiting
- metallic taste
Antiparasitics
Albendazole/Mebendazole:
- pinworm (“worms are bendy”)
- MOA: microtubule inhibitors
Ivermectin:
- Strongyloides
- MOA: paralyzes parasite by enhancing GABA transmission and cell hyperpolarization
Primaquine:
- liver hypnozoite stage of Plasmodium vivax/ovale
- side effects: hemolytic crisis in those with G-6-PD deficiency
Chloroquine:
- sensitive malaria
Antimalarials
Chloroquine:
- sensitive spp
- blood stage (schizont)
Mefloquine:
- resistant spp
- blood stage (schizont)
Atovaquone/Proguanil:
- resistant spp
- liver schizont
Quinidine or Artestunate:
- life-threatening infection
- blood stage (schizont)
- side effects: cinchonism, long QT syndrome
Primaquine:
- P vivax and P ovale
- liver hypnozoite stage
- hemolytic anemia in patients with G-6-PD deficiency
