Post on 31-Dec-2015
description
Antibiotics 101
Puja Van Epps1/20/14
Beta-lactams
Core PCN structure
Core Cephalosporin structure
Beta-lactams
Beta-lactamases are enzymes produced by some bacteria that provide resistance against beta lactams through hydrolysis of the β-lactam ring
Natural Penicillins
Bicillin L-A (Penicillin G benzathine) – IM only
Penicillin G (IV) Penicillin V = PO
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
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
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
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.
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
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.
Cephalosporins
5 generations, increasing gram negative coverage with each generation
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
First Generation Cephalosporins
Important holes in coverage – MRSA, Enterococcus, Pseudomonas,
anerobes
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
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
Third Generation Cephalosporins
Major holes in coverage –
- Enterococcus, MRSA, Pseudomonas (except Ceftazidime), +/- Acinetobacter, Listeria
Ceftazidime crosses BBB, Ceftriaxone in inflamed meninges
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
Fifth Generation Cephalosporin
Ceftaroline (IV) Major advantage:
- MRSA
Major holes in coverage:
- Pseudomonas, enterococcus and anaerobes
CAP, SSTI
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
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
Carbapenems
Major holes in coverage:
- Atypicals (Legionella, Mycoplasma) , MRSA, VRE, Stenotrophomonas maltophilia, KPC+
Ertapenem does not cover:
- Pseudomonas, Acinetobacter, Enterococcus
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+
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)
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
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)
Macrolides
Clarithromycin, Erythromycin, Azithromycin
Inhibit protein synthesis by reversibly binding to the 50s ribosomal unit
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.
Anti-MRSA drugs
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
Vancomycin
Red-Man Syndrome– flushing, pruritus, rash– related to rate of infusion– resolves spontaneously – may lengthen infusion
NOT AN ALLERGY
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
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)
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.
Clindamycin
Inhibits protein synthesis by binding exclusively to the 50S ribosomal subunit
Major uses - MRSA (some isolates), anaerobic
coverage
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
Tetracylines
Doxycyline, Minocyline Good gram pos, neg and anaerobic
coverage Major uses MRSA, anti-malarial prophylaxis,
rickettsial infections, Borrelia burgdorferi
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