Microbiology: Antimicrobial therapy - Abx

  1. Antimicrobial therapy
    -mechanism of action
    • 1. Block cell wall synthesis by inhibition of peptidoglycan cross-linking (β-lactams)
    • -Drugs: Penicillin, methicillin, ampicillin, piperacillin, cephalosporins, aztreonam, imipenem

    • 2. Block peptidoglycan synthesis
    • -Drugs: Bacitracin, vancomycin

    • 3. Block nucleotide synthesis
    • -Drugs: Sulfonamides, trimethoprim

    • 4. Block DNA topoisomerases
    • -Drugs: Fluoroquinolones

    • 5. Block mRNA synthesis
    • -Drugs: Rifampin

    • 6. Damage DNA
    • -Drugs: Metronidazole

    • 7. Block protein synthesis at 50S ribosomal subunit
    • -Drugs: Chloramphenicol, macrolides, clindamycin, streptogramins (quinupristin, dalfopristin), linezolid

    • 8. Block protein synthesis at 30S ribosomal subunit
    • -Drugs: Aminoglycosides, tetracyclines

    Image Upload 2
  2. Penicillins
    Mechanism, Drugs, Generation, main clinical use
    Penicillins have β-lactam rings; block cell wall synthesis by inhibiting peptidoglycan cross-linking

    • 1° gen: Gram-positive
    • ☉PCN
    • -Clinical: Strep (S. pyogenes, S. Pneumoniae); Neisseria meningitidis, Treponema pallidum, syphilis

    • 2° gen: Gram-positive; Staph
    • ☉Oxacillin
    • ☉Methacillin
    • ☉Nafcillin **Naf for staph
    • ☉Dicloxacillin
    • -Clinical: only MSSA

    • 3° gen: Gram-negative activity
    • (Aminopeniciliins)
    • ☉Amoxacillin
    • ☉Ampillicin
    • -Clinical: UTI, pneumonia, meningitis;
    • -HELPSS kill enterococci
    • + Clavulanic acid = Augmentin

    • 4° gen: Gram-negative activity
    • ☉Piperacillin
    • ☉Ticarcillin
    • -Clinical: Pseudomonas
  3. Penicillin
    Mechanism, clinical use, toxicity, resistance
    Penicillin G (IV and IM form); penicillin V (oral). Prototype β-lactam antibiotics

    • Mechanism:
    • 1. Bind penicillin-binding proteins (transpeptidases)
    • 2. Block transpeptidase cross-linking of peptidoglycan
    • 3. Activate autolytic enzymes

    • Clinical use: 
    • -Mostly used for gram-positive organisms (S. pneumoniae, S. pyogenes, Actinomyces) and syphilis (and Neisseria meningitidis, Treponema pallidum).
    • -Bactericidal for gram-positive cocci, gram-positive rods, gram-negative cocci, and spirochetes
    • -Not penicillinase resistant

    Toxicity: Hypersensitivity reactions, hemolytic anemia

    Resistance: β-lactamase cleave β-lactam ring
  4. Oxacillin/Methicillin, nafcillin, dicloxacillin (penicillinase-resistant penicillins)
    Mechanism, clinical use, toxicity
    • Mechanism: 
    • -Same as penicillin. Narrow spectrum; penicillinase resistant because of bulkier R group (blocks access of β-lactamase to β-lactam ring

    **"Use naf (nafcillin) for staph"

    • Clinical use: 
    • -S. aureus (except MRSA; resistant bc of altered penicillin-binding protein target site)

    • Toxicity:
    • -Hypersensitivity reactions;
    • -Interstitial nephritis
  5. Ampicillin, amoxicillin (aminopenicillins)
    mechanism, clinical use, toxicity, resistance
    • Mechanism:
    • -Same as penicillin. Wide spectrum; penicillinase sensitive
    • -Also combine with clavulanic acid to protect against β-lactamase.
    • -AmOxicillin has greater Oral bioavailability than ampicillin

    *AMinoPenicillins are AMPed-up penicillin

    • Clinical use: 
    • -Extended-spectrum penicillin
    • -Haemophilus influenzae, E. coli, Listeria monocytogenes, Proteus mirabilis, Salmonella, Shigella, enterococci

    *Coverage: ampicillin/amoxicillin HELPSS kill enterococci

    • Toxicity: 
    • -Hypersensitivity reactions; ampicillin rash; pseudomembranous colitis

    • Resistance: 
    • -β-lactamases cleave β-lactam ring
  6. Ticarcillin, Carbenicillin, Piperacillin (antipseudomonals)
    Mechanism, clinical use, toxicity
    • Mechanism:
    • -Same as penicillin. Extended spectrum

    • Clinical use: 
    • Pseudomonas spp. and gram-negative rods;
    • -susceptible to penicillinase; use with clavulanic acid

    *TCPTakes Care of Pseudomonas

    Toxicity: Hypersensitivity reactions
  7. β-lactamase inhibitors
    • Include Clavulanic Acid, Sulbactam, Tazobactam.
    • *CAST

    Often added to penicillin antibiotics to protect the antibiotic from destruction by β-lactamase (penicillinase)
  8. Cephalosporins
    Mechanism, Drugs, Generation, main clinical use
    • Cephalosporins are β-lactam drugs; inhibit cell wall synthesis (less susceptible to penicillinases)
    • Bactericidal

    • 1° gen: Gram-positive cocci
    • ☉Cefazolin
    • ☉Cephalexin
    • -Clinical use: PEcK; like 1°, 2° gen PCN (strep, staph, NOT syphillus)
    • -Proteus mirabilis, Ecoli, Klebsiella pneumoniae
    • *Used prior to surgery to prevent S. aureus wound infection

    • 2° gen: gram-positive cocci
    • ☉Cefoxitin
    • ☉Cefaclor
    • ☉Cefuroxime
    • -Clinical use: used in peds; HEN PEcKS
    • -Haemophilus influenzae, Enterobacter aerogenes, Neisseria spp., Proteus mirabilis, E. coli, Klebsiela pneumoniae, Serratia marcescens

    • 3° gen: Serious gram-negative infections resistant to other β-lactams
    • ☉Ceftriaxone - meningitis and gonorrhea
    • ☉Cefoxatime
    • ☉Ceftazidime - pseudomonas; NO strep coverage
    • -Clinical use: can use in renal failure (NOT cleared by kidney)

    • 4° gen: gram-positive organisms; Pseudomonas
    • ☉Cefepime
    • -Clinical use: 1° + 3° = 4°
    • -No staph coverage, no enterococcus coverage, no anearobic coverage
  9. Cephalosporins
    not covered
    • Organisms not covered by cephalosporins are LAME:
    • -Listeria
    • -Atypicals (Chlamydia, Mycoplasma)
    • -MRSA
    • -Enterococci
    • **Exception: Ceftaroline covers MRSA
  10. Cephalosporins
    • Hypersensitivity reactions
    • Vitamin K deficiency
    • Low cross-reactivity with penicillins
    • ↑ nephrotoxicity of aminoglycosides
  11. Aztreonam
    Mechanism, clinical use, toxicity
    • Mechanism:
    • -Monobactam resistant to β-lactamases
    • -Prevents peptidoglycan cross-linking by binding to PBP3 (inhibit cell wall synthesis)
    • -Synergistic with aminoglycosides
    • -No cross-allergenicity with penicillins

    • Clinical use: Gram-negative rods only
    • -No activity against gram-positive or anaerobes
    • -Used in penicillin-allergic individuals, or those with renal insufficiency who can't tolerate aminoglycosides

    • Toxicity:
    • -Usually nontoxic
    • -occasional GI upset
  12. Imipenem/cilastatin, meropenem
    Mechanism, clinical use, toxicity
    • Mechinism:
    • -Imipenem is broad-spectrum, β-lactamase-resistant carbepenem (class of β-lactams) 
    • -Always administer with cilastatin(inhibitor of renal dehydropeptidase I) to ↓ inactivation of drug in renal tubules
    • **With imipenem, "the kill is lastin' with cilastatin"

    • Clinical use: Gram-positive cocci, gram-negative rods, and anaerobes
    • -Wide spectrum, significant side effects limit use to life threatening infections
    • -Meropenem has reduced risk of seizures and is stable to dehydropeptidase I

    • Toxicity:
    • -GI distress
    • -Skin rash
    • -CNS toxicity (seizures) at high plasma levels
  13. Vancomycin
    mechanism, clinical use, toxicity, resistance
    • Mechanism:
    • -Inhibits cell wall peptidoglycan formation by binding D-ala D-ala portion of cell wall precursors
    • -Bactericidal

    • Clinical use: Gram positive only
    • -Serious, multidrug-ressitant organisms, including MRSA, enterococci, and Clostridium difficile (Oral dose for pseudomembranous colitis)

    • Toxicity
    • -Nephrotoxicity
    • -Ototoxicity
    • -Thrombophlebitis
    • -diffuse flushing -- "red man syndrome" (prevented by pretreatment with antihistamines and slow infusion rate)
    • -Well tolerated in general: **Does NOT have many problems

    • Resistance:
    • -Occurs with amino acid change of D-ala D-ala to D-ala D-lac
    • **"Pay back 2 D-alas for vandalizing (Vancomycin)"
  14. Protein synthesis inhibitors
    mechanism, classes
    • Mechanism:
    • Specifically target smaller bacterial ribosome (70S, made of 30S and 50S subunits), leaving human ribosomes (80S) unaffected

    • Classes:
    • -30S inhibitors
    • -50S inhibitors

    **"Buy AT 30CCEL at 50"
  15. Protein synthesis inhibitors
    30S inhibitors
    "Buy AT 30CCEL at 50"

    • A = Aminioglycosides [bactericidal]
    • TTetracyclines [bacteriostatic]
  16. Protein synthesis inhibitors
    50S inhibitors
    "Buy AT 30CCEL at 50"

    • CChloramphenicol, Clindamycin [bacteriostatic]
    • EErythromycin (macrolides) [bacteriostatic]
    • LLinezolid [variable]
  17. Image Upload 4
    Protein synthesis inhibitors
  18. Aminoglycosides
    mechanism, clinical use, toxicity, resistance
    Gentamicin, Neomycin, Amikacin, Tobramycin, Streptomycin

    **"Mean(aminoglycoside) GNATS caNNOT kill anaerobes

    • Mechanism: bactericidal
    • -Inhibit formation of initiation complex **A "initiates" the Alphabet
    • -causes misreading of mRNA
    • -Blocks translocation
    • -Requires O2 for uptake; ineffective against anaerobes

    • Clinical use: Severe gram-negative rods
    • -Synergistic with β-lactams
    • -Neomycin for bowel surgery

    • Toxicity:
    • -Nephrotoxicity (especially in combo with cephalosporins)
    • -Neuromuscular blockade
    • -Ototoxicity (especially in combo with loop diuretics)
    • -Teratogen

    • Resistance
    • -Transferase enzymes that inactivate the drug by acetylation, phosphorylation, or adenylation
  19. Tetracyclines
    mechanism, clinical use, toxicity, resistance
    • Tetracycline, doxycycline, demeclocycline, minocycline
    • *Demeclocycline: ADH antagonist; acts as Diuretic in SIADH (rarely used as antibiotic)

    • Mechanism: bacteriostatic
    • -Binds 30S and prevents attachment of aminoacyl-tRNA
    • -Limited CNS penetration
    • -Doxycycline elimination: fecal (can be used in pts with renal failure)
    • -Do not take with milk, antacids, or iron-containing preparations (divalant cations inhibit absorption)

    • Clinical use:
    • -Borrelia burgdorferi, M. pneumoniae
    • -Accumulates intracellurly; effective against Rickettsia and Chlamydia

    • Toxicity:
    • -GI distress
    • -Discolored teeth
    • -Inhibition of bone growth in children, photosensitivity
    • -Contraindicated in pregnancy

    • Resistance:
    • -↓ uptake into cells or ↑ efflux out of cells by palsmid-encoded transport pump
  20. Macrolides
    mechanism, clinical use, toxicity, resistance
    Axithromycin, clarithromycin, erythromycin

    • Mechanism: bacteriostatic
    • -Inhibit protein synthesis by blocking translocation ("macroslides")
    • -bind to the 23S rRNA of the 50S ribosomal subunit

    • Clinical use:
    • -Atypical pneumonias (Mycoplasma, Chlamydia, Legionella)
    • -STDs (chlamydia)
    • -Gram-positive cocci (streptococcal infections in pts with allergies to PCN)

    • ToxicityMACRO
    • -Motility issues
    • -Arrhythmia caused by prolonged QT
    • -acute Cholestatic hepatitis
    • -Rash
    • -eOsinophilia
    • -Increases serum concentration of theophyllines, oral anticoagulants
    • Resistance:
    • -Methylation of 23S rRNA binding site
  21. Chloramphenicol
    mechanism, clinical use, toxicity, resistance
    • mechanism: Bacteriostatic
    • -Blocks peptidyltransferase at 50S ribosomal subunit

    • clinical use:
    • -Meningitis (H. influenzae, Neisseria meningitidis, S. pneumoniae)
    • -low cost, toxicities...
    • Toxicities:
    • -Anemia (dose dependent)
    • -aplastic anemia (dose independent)
    • -gray baby syndrome (in premature infants: lack liver UDP-glycouronyl transferase)

    • Resistance:
    • -Plasmid-encoded acetyltransferase that inactivates drug
  22. Clindamycin
    mechanism, clinical use, toxicity
    • mechanism: Bacteriostatic
    • -Blocks peptide transfer (transpeptidation) at 50S

    • Clinical use:
    • -Anaerobic infections (e.g. Bacteroides fragilis, Clostridium perfringens) in aspiration pneumonia or lung abscesses
    • -Oral infections with mouth anaerobes
    • **Treats anaerobes above the diaphragm (vs. metronidazole--treats anaerobes below diaphragm)

    • Toxicity:
    • -Pseudomembranous colitis (C. difficile overgrowth)
    • -Fever
    • -Diarrhea
  23. Sulfonamides
    Drugs, mechanism
    • -Sulfamethoxazole (SMX)
    • -Sulfisoxazole
    • -Sulfadiazine

    • Mechanism: Bacteriostatic
    • -PABA antimetabolites inhibit dihydropteroate synthesis
    • Image Upload 6
  24. Sulfonamides
    clinical use, toxicity, resistance
    • Clinical use:
    • -Gram-positive
    • -Gram-negative
    • -Nocardia
    • -Chlamydia
    • -Triple sulfas or SMX for simple UTI

    • Toxicity:
    • -Hypersensitivity reactions
    • -hemolysis if G6PD deficient
    • -Nephrotoxicity (tubulointerstitial nephritis)
    • -Photosensitivity
    • -Kernicterus in infants
    • -Displace other drugs from albumin (e.g. warfarin)

    • Resistance:
    • -Altered enzyme (bacterial dihydropteroate synthase), ↓ uptake, or ↑ PABA synthesis
  25. Trimethoprim
    mechanism, clinical use, toxicity
    • Mechanism: Bacteriostatic
    • -Inhibits bacterial dihydrofolate reductase

    • Clinical use: used in combination with sulfonamides
    • -TMP-SMX; causes sequential block of folate synthesis
    • -Combination used for UTIs, Shigella, Salmonella, Pneumocystis jirovecii pneumonia (tx and prophylaxis)

    • Toxicity:
    • -Megaloblastic anemia
    • -Leukopenia
    • -Granulocytopenia
    • **May alleviate with supplemental folinic acid [leucovorin rescue]

    **TMP: Treats Marrow Poorly
  26. Fluoroquinolones
    Mechanism, Drugs, Generation, main clinical use
    • Fluoroquinolones inhibit DNA gyrase (topoisomerase II) and topoisomerase IV
    • -Bactericidal
    • -Must not take with antacids

    • 1° gen:
    • ☉Nalidix acid (quinolone)
    • ☉Norfloxacin

    • 2° gen: mainly gram-negative in UTI/GI; pseudomonas
    • ☉Ciproflaxacin - anthrax bacillis
    • ☉Ofloxacin

    • 3° gen: Gram-positive and gram-negative
    • ☉Levofloxacin
    • ☉Sparfloxacin (not available in US)

    • 4° gen: Anaerobic, Pneumococcus, TB
    • ☉Moxifloxacin
    • ☉Gatifloxacin
  27. Fluoroquinolones
    clinical use, toxicity, resistance
    Clinical use: Gram-negative rods of UTI and GI tracts (including pseudomonas), Neisseria, and some gram-positive organisms

    • Toxicity:
    • 1. Tendonitis, tendon rupture (pt >60 yrs or those taking prednisone), myalgias
    • **Fluoroquinolones hurt attachments to your bones
    • 2. QT interval prolonged
    • 3. C. Difficiles
    • -GI upset
    • -Super infections
    • -Skin rashes
    • -HA
    • -Dizziness
    • -Contraindicated in pregnancy

    • Resistance:
    • -Chromosome-encoded mutation in DNA gyrase
    • -Plasmid-mediated resistance
    • -efflux pump
  28. Metronidazole
    Mechanism, clinical use, toxicity
    • Mechanism: Bactericidal, antiprotozoal
    • -Forms free radical toxic metabolites in the bacterial cell that damage DNA

    • Clinical use**GET GAP on the Metro with metronidazole!
    • -**Treats anaerobic bacteria infections below diaphragm (vs. clindamycin... anaerobic above diaphragm)
    • -Giardia
    • -Entaboeba
    • -Trichomonas
    • -Gardnerella vaginalis
    • -Anaerobes (Bacteroides, C. difficile)
    • -Used with PPI and clarithromycin for "triple therapy" against H. Pylori

    • Toxicity:
    • -Disulfiram-like reaction with alcohol
    • -HA
    • -Metallic taste
  29. Antimycobacterial drugs
    bacterium, prophylaxis, treatment
    • M. tuberculosis:
    • -Prophylax with Isoniazid
    • -Tx: Rifampin, Isoniazid, Pyrazinamide, Ethambutol (RIPE; 2 for 4, and 4 for 2)

    • M. avium-intracellulare:
    • -Prophylax: Azithromycin
    • -Tx: Azithromycin, rifampin, ethambutol, streptomycin

    • M. leprae:
    • -Tx: long-term tx with dapsone and rifampin for tubercloid form
    • -add clofazimine for lepromatous form
  30. Isoniazide (INH)
    mechanism, clinical use, toxicity
    • Mechanism
    • -↓ synthesis of mycolic acids
    • -Bacterial catalase-peroxidase (KatG) needed to convert INH to active metabolite
    • -Different INH half-lives in fast vs. slow acetylators

    • Clinical useMycobacterium tuberculosis
    • -Only agent used as solo prophylaxis against TB

    • Toxicity**INH Injures Neurons and Hepatocytes
    • -Neurotoxicity
    • -Hepatotoxicity
    • -Pyridoxine (vitamin B6) can prevent neurotoxicity, lupus
  31. Rifampin
    Mechanism, clinical use, toxicity
    • Rifampins 4 R's:
    • -RNA polymerase inhibitor
    • -Revs up microsomal P-450
    • -Red/orange body fluids
    • -Rapid resistance if used alone

    • Mechanism:
    • -Inhibits DNA-dependent RNA polymerase

    • Clinical use: M. tuberculosis
    • -Delays resistance to dapsone when used for leprosy
    • -Used for meningococcal prophylaxis and chemoprophylaxis in contacts of children with Haemophilus influenzae type B

    • Toxicity:
    • -Minor hepatotoxicity and drug interactions (↑ P-450)
    • -Orange body fluids (nonhazardous)
  32. Pyrazinamide
    Mechanism, clinical use, toxicity
    • Mechanism: uncertain
    • -Acidify intracellular environment via conversion to pyrazinoic acid (?)
    • -Effective in acidic pH of phagolysosomes, where TB engulfed by macrophages is found

    Clinical useM. tuberculosis

    • Toxicity
    • -Hyperuricemia
    • -Hepatotoxicity
  33. Ethambutol
    Mechanism, clinical use, toxicity
    • Mechanism
    • -↓ Carbohydrate polymerization of mycobacterium cell wall by blocking arabinosyltransferase

    Clinical useM. tuberculosis

    • Toxicity:
    • -Optic neuropathy (red-green color blindness)
  34. Antimicrobial prophylaxis
    condition, medication
    • Meningococcal infection: Ciprofloxacin (drug of choice), rifampin for children
    • Gonorrhea: Ceftriaxone
    • Syphilis: Benzathine penicillin G
    • History of recurrent UTIs: TMP-SMX
    • Endocarditis with surgical or dental procedures: PCNs
    • Pregnant women carrying group B strep: Ampicillin
    • Prophylaxis of strep pharyngitis in child with prior rheumatic fever: Oral PCN
    • Prevention of post surgical infection due to S. aureus: Cefazolin
    • Prevention of gonococcal or chlamydial conjunctivitis in newborn: Erythromycin ointment
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Microbiology: Antimicrobial therapy - Abx