Antibiotics 101

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Antibiotics 101

• Puja Van Epps
• 1/20/14

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Beta-lactams
Core PCN structure
Core Cephalosporin structure
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Beta-lactams

• Beta-lactamases are enzymes produced by some
  bacteria that provide resistance against beta
  lactams through hydrolysis of the ß-lactam ring

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Natural Penicillins

• Bicillin L-A (Penicillin G benzathine) IM only
• Penicillin G (IV)
• Penicillin V PO

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Natural Penicillins- Spectra
Groups Important Organisms
Gram Positive Group A/B/C/G strep S. pneumoniae viridans streptococci gr., Strep milleri Enterococcus (feacalisgtfaecium)
Gram Negative Neisseria meningitidis Pasteuralla multocida Haemophilus ducreyi
Anaerobes Actinomyces Clostridial sp. Peptostreptococcus Fusobacterium
Other Treponema pallidum
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Natural Penicillins

• Bicillin Primary, secondary, latent and late
  latent syphillis
• PCN G Neurosyphillis systemic infection due to
  susceptible bacteria (Streptococci)
• PCN V Group A strep pharyngitis

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Anti-staphylococcal Penicillins

• Nafcillin, oxacillin, methicillin, dicloxacillin
  (PO)
• Penicillinase is a specific type of ß-lactamase,
  showing specificity for Penicillins
• First ß-lactamase to be identified PCN R in S.
  aureus
• Major Uses
• Methicillin-susceptible S. aureus or
  Coagulase Negative Staph PCN-susceptible strains
  of Streptococci
• No gram negative activity

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Aminopenicillins

• Ampicillin/amoxicillin Augmentin (Amox-Clav)
  Unasyn (Amp-Sulbactam)
• Amp/amox Great for susceptible streps and
  enterococcus very limited GN activity cover
  anaerobes
• Addition of Clavulanate or Sulbactam enhances
  Gram negative activity
• No activity against MSSA without the
  beta-lactamase inhibitor.

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Aminopenicillins

• Important holes in coverage
• Pseudomonas sp.
• Atypical gram negatives mycoplasma pneumoniae,
  chlamydia pneumoniae, legionella sp.
• Enterobacter sp.
• If susceptible Ampicillin is the DOC for
  Enterococcus and Listeria

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Anti-Pseudomonal Penicillins

• Ticarcillin, Ticar-Clav, Piperacillin, Pip-Tazo
• Generally good gram positive, gram negative and
  anaerobic coverage
• Ticarcillin and Piperacillin without their
  beta-lactamase inhibitor DO NOT cover MSSA
• Important holes in coverage MRSA (ESBL, KPC,
  or other resistant GN)
• Stenotrophomonas maltophilia Ticar-Clav is
  second line, Pip/Tazo does not cover.

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Cephalosporins

• 5 generations, increasing gram negative coverage
  with each generation

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First Generation Cephalosporins

• Cefadroxil, Cephalexin (PO)
• Cefazolin (IV)

Gram Positive Group A, B, C, G Strep Strep pneumo Viridans strep MSSA
Gram Negative E. coli, Klebsiella sp., Proteus mirabilis
Anaerobes No activity
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First Generation Cephalosporins

• Important holes in coverage
• MRSA, Enterococcus, Pseudomonas, anerobes

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Second Generation Cephalosporins

• Cefuroxime (IV, PO), Cefotetan (IV), Cefoxitin
  (IV)
• In addition to the coverage of 1st generation
• - H. influenzae, M. catarrhalis, Neisseria
  sp., and anearobic coverage (variable)
• Important holes in coverage
• - MRSA, Enterococcus, Pseudomonas

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Third Generation Cephalosporins

• Ceftriaxone, Cefotaxime, Ceftazadime (IV)
• Cefixime, Cefdinir (PO)
• In general less active against gram-positive
  aerobes than previous generations, but have
  greater activity against gram-negatives
• Cefotaxime and Ceftriaxone have the best gram
  coverage in the group
• Only Ceftazadime covers Pseudomonas

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Third Generation Cephalosporins

• Major holes in coverage
• - Enterococcus, MRSA, Pseudomonas (except
  Ceftazidime), /- Acinetobacter, Listeria
• Ceftazidime crosses BBB, Ceftriaxone in inflamed
  meninges

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Fourth Generation Cephalosporins

• Cefepime (IV)
• gram-positives similar to first generation
• gram-negatives broad, including Pseudomonas
• Major holes MRSA, poor anaerobic coverage,
  listeria
• Crosses BBB

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Fifth Generation Cephalosporin

• Ceftaroline (IV)
• Major advantage
• - MRSA
• Major holes in coverage
• - Pseudomonas, enterococcus and anaerobes
• CAP, SSTI

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Cephalosporin Review

• Antipseudomonal
• Ceftazadime and Cefepime
• Anti-MRSA
• Ceftaroline
• Anti-Enterococcal
• None (Ceftaroline has in-vitro activity
  against E. faecalis)
• Enterobacter sp. can develop resistance to
  cephalosporins during treatment, therefore not
  the treatment of choice

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Carbapenems

• Ertapenem, Doripenem, Imipenem, Meropenem
• Broadest spectrum of activity
• Have activity against gram-positive and
  gram-negative aerobes and anaerobes
• Bacteria not covered by carbapenems include MRSA,
  VRE, MR coagulase-negative staph
• Additional ertapenem exceptions
• Pseudomonas, Acinetobacter, Enterococcus

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Carbapenems

• Major holes in coverage
• - Atypicals (Legionella, Mycoplasma) , MRSA,
  VRE, Stenotrophomonas maltophilia, KPC
• Ertapenem does not cover
• - Pseudomonas, Acinetobacter, Enterococcus

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Monobactam

• Aztreonam binds preferentially to PBP 3 of
  gram-negative aerobes
• No gram positive or anaerobic activity
• Major uses Hospital acquired infections in
  patients with anaphylaxis to any beta lactams
  (does not have cross reactivity)
• Important gram neg holes Acinetobacter, ESBL,
  KPC

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Fluoroquinolones

• Ciprofloxacin, Levofloxacin, Moxifloxacin
• Broad spectrum of activity, excellent
  bioavailability, tissue penetration
• Cipro has poor gram coverage
• Disadvantages resistance, expense, C diff
• Advantages Atypical coverage, Antipseudomonal
  (Cipro, Levo)

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Aminoglycosides

• Gentamicin, Tobramycin, Amikacin
• inhibit protein synthesis by irreversibly
  binding to 30S ribosome, bactericidal
• For gram use in combination with cell wall
  agents
• Broad spectrum gram neg coverage including
  Pseudomonas and Acinetobacter
• Also have mycobacterial coverage

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Aminoglycosides adverse effects

• Nephrotoxicity
• Nonoligouric renal failure from damage to the
  proximal tubules
• Underlying CKD, Age, other nephrotixins,
  duration, high troughs
• Ototoxicity
• 8th cranial nerve damage - vestibular and
  auditory toxicity irreversible
• Related to duration of therapy (gt2wks)

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Macrolides

• Clarithromycin, Erythromycin, Azithromycin
• Inhibit protein synthesis by reversibly binding
  to the 50s ribosomal unit

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Macrolides

• Gram-Positive Aerobes ClarithrogtErythrogtAzithro
  
• Gram-Negative Aerobes AzithrogtClarithrogtEryth
  ro
• No activity against any Enterobacteriaceae or
  Pseudomonas
• Anaerobes activity against upper airway
  anaerobes
• Atypical Bacteria Excellent
• Also cover Mycobacterium avium complex,
  Campylobacter, Borrelia, Bordetella, Brucella.

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Anti-MRSA drugs
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Vancomycin

• Inhibits synthesis and assembly of the second
  stage of peptidoglycan polymers
• Gram-positive bacteria excellent coverage
• Major uses
• MRSA, MSSA (in PCN all), PCN R streptococci
• No activity against gram-negatives or anaerobes
• If MIC to Vancomycin in MRSA is 2, Do not use
  

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Vancomycin

• Red-Man Syndrome
• flushing, pruritus, rash
• related to rate of infusion
• resolves spontaneously
• may lengthen infusion
• NOT AN ALLERGY

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Daptomycin

• Lipopeptide binds to components of the cell
  membrane and causes rapid depolarization,
  inhibiting intracellular synthesis of DNA, RNA,
  and protein
• Major uses
• - SAB, Right-sided IE caused by S. aureus,
  VRE
• Indicated for SSTI, R sided IE
• Do not use for lung infections including MRSA PNA
  pulmonary surfactant inhibits Daptomycin

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Linezolid

• Binds to the 50S ribosomal subunit near the
  surface interface of 30S subunit causes
  inhibition of 70S initiation complex which
  inhibits protein synthesis
• Active against wide range of Gram bacteria,
  limited to no Gram negative or anearobic activity
• Major uses
• MRSA, VRE.
• Major problem
• thrombocytopenia with prolonged use (gt2wks),
  bacteriostatic (cidal against Enterococcus)

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Tigecyline

• Binds to the 30S ribosomal subunit of susceptible
  bacteria, inhibiting protein synthesis.
• Broad spectrum of activity including
• - MRSA, VRE, gram negatives (including
  resistant GN)
• Major holes-
• The 3 Ps Pseudomonas, Proteus and
  doesnt get in the urine
• Indicated for complicated SSTI, intra-abdominal
  infections, CAP
• Major problems GI issues, and shown to have
  increased mortality in serious infections
  monotherapy only as a last resort.

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Clindamycin

• Inhibits protein synthesis by binding
  exclusively to the 50S ribosomal subunit
• Major uses
• - MRSA (some isolates), anaerobic coverage

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Clindamycin

• A positive D test indicates the presence of
  macrolide-inducible resistance to clindamycin
  produced by an inducible methylase that alters
  the common ribosomal binding site for macrolides,
  clindamycin

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Tetracylines

• Doxycyline, Minocyline
• Good gram pos, neg and anaerobic coverage
• Major uses
• MRSA, anti-malarial prophylaxis, rickettsial
  infections, Borrelia burgdorferi

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Trimethoprim, TMX-Sulfa

• Inhibit various steps within the folic acid
  biosynthetic pathway
• Good gram pos and gram neg coverage (CA-MRSA)
• Important uses Pneumocystis, Stenotrophomonas
  maltophilia, Nocardia
• Major holes
• Pseudomonas, anaerobes