antibiotics 101 puja van epps 1/20/14. beta-lactams core pcn structure core cephalosporin structure
TRANSCRIPT
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Antibiotics 101
Puja Van Epps1/20/14
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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 β-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 PositiveGroup A/B/C/G strep
S. pneumoniae* viridans streptococci gr.*, Strep milleri*
Enterococcus (feacalis>faecium)
Gram NegativeNeisseria meningitidis*Pasteuralla multocida Haemophilus ducreyi
AnaerobesActinomycesClostridial sp.
PeptostreptococcusFusobacterium
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 β-lactamase,
showing specificity for Penicillins First β-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 PositiveGroup A, B, C, G Strep
Strep pneumoViridans strep
MSSA
Gram NegativeE. 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 (>2wks)
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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 – Clarithro>Erythro>Azithro
Gram-Negative Aerobes – Azithro>Clarithro>ErythroNo 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 (>2wks),
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 P’s – Pseudomonas, Proteus and doesn’t 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