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Antimicrobial therapy
-mechanism of action
-drugs
- 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
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Penicillins
Mechanism, Drugs, Generation, main clinical use
Penicillins have β-lactam rings; block cell wall synthesis by inhibiting peptidoglycan cross-linking
: 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
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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
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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
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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
* AMino Penicillins 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
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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
* TCP: Takes Care of Pseudomonas
Toxicity: Hypersensitivity reactions
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β-lactamase inhibitors
- Include Clavulanic Acid, Sulbactam, Tazobactam.
- *CAST
Often added to penicillin antibiotics to protect the antibiotic from destruction by β-lactamase (penicillinase)
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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, E. coli, 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
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Cephalosporins
not covered
- Organisms not covered by cephalosporins are LAME:
- -Listeria
- -Atypicals (Chlamydia, Mycoplasma)
- -MRSA
- -Enterococci
- **Exception: Ceftaroline covers MRSA
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Cephalosporins
Toxicity
- Hypersensitivity reactions
- Vitamin K deficiency
- Low cross-reactivity with penicillins
- ↑ nephrotoxicity of aminoglycosides
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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
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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
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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)"
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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 30, CCEL at 50"
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Protein synthesis inhibitors
30S inhibitors
"Buy AT 30, CCEL at 50"
- A = Aminioglycosides [bactericidal]
- T = Tetracyclines [bacteriostatic]
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Protein synthesis inhibitors
50S inhibitors
"Buy AT 30, CCEL at 50"
- C = Chloramphenicol, Clindamycin [bacteriostatic]
- E = Erythromycin (macrolides) [bacteriostatic]
- L = Linezolid [variable]
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Protein synthesis inhibitors
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Aminoglycosides
mechanism, clinical use, toxicity, resistance
Gentamicin, Neomycin, Amikacin, Tobramycin, Streptomycin
**" Mean" (a minoglycoside) GNATS ca NNOT 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
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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
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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)
- Toxicity: MACRO
- -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
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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
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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
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Sulfonamides
Drugs, mechanism
- -Sulfamethoxazole (SMX)
- -Sulfisoxazole
- -Sulfadiazine
- Mechanism: Bacteriostatic
- -PABA antimetabolites inhibit dihydropteroate synthesis
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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
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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
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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
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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
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GI upset - -Super infections
- -Skin rashes
- -HA
- -Dizziness
- -Contraindicated in pregnancy
- Resistance:
- -Chromosome-encoded mutation in DNA gyrase
- -Plasmid-mediated resistance
- -efflux pump
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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
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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
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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 use: Mycobacterium tuberculosis
- -Only agent used as solo prophylaxis against TB
- Toxicity: **INH Injures Neurons and Hepatocytes
- -Neurotoxicity
- -Hepatotoxicity
- -Pyridoxine (vitamin B6) can prevent neurotoxicity, lupus
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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)
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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 use: M. tuberculosis
- Toxicity:
- -Hyperuricemia
- -Hepatotoxicity
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Ethambutol
Mechanism, clinical use, toxicity
- Mechanism:
- -↓ Carbohydrate polymerization of mycobacterium cell wall by blocking arabinosyltransferase
Clinical use: M. tuberculosis
- Toxicity:
- -Optic neuropathy (red-green color blindness)
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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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