Microbiology: Antimicrobial therapy - Abx

• 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

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

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

• 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

• 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

• 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

• Include Clavulanic Acid, Sulbactam, Tazobactam.
• *CAST

Often added to penicillin antibiotics to protect the antibiotic from destruction by β-lactamase (penicillinase)

• 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

• Organisms not covered by cephalosporins are LAME:
• -Listeria
• -Atypicals (Chlamydia, Mycoplasma)
• -MRSA
• -Enterococci
• **Exception: Ceftaroline covers MRSA

• Hypersensitivity reactions
• Vitamin K deficiency
• Low cross-reactivity with penicillins
• ↑ nephrotoxicity of aminoglycosides

• 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

• 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

• 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)"

• 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"

"Buy AT 30, CCEL at 50"

• A = Aminioglycosides [bactericidal]
• T = Tetracyclines [bacteriostatic]

"Buy AT 30, CCEL at 50"

• C = Chloramphenicol, Clindamycin [bacteriostatic]
• E = Erythromycin (macrolides) [bacteriostatic]
• L = Linezolid [variable]

Protein synthesis inhibitors

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

• 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

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

• 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

• 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

• -Sulfamethoxazole (SMX)
• -Sulfisoxazole
• -Sulfadiazine

• Mechanism: Bacteriostatic
• -PABA antimetabolites inhibit dihydropteroate synthesis
• 

• 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

• 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

• 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

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

• 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

• 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

• 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

• 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)

• 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

• Mechanism: 
• -↓ Carbohydrate polymerization of mycobacterium cell wall by blocking arabinosyltransferase

Clinical use: M. tuberculosis

• Toxicity:
• -Optic neuropathy (red-green color blindness)

• 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