ESBL
  • Treatment:
    • Carbapenem
    • In mild illness, outpatient oral therapy, consider:
      • fosmomycin
      • nitrofurantoin
AmpC
  • Enterobacter spp, Serratia spp, Citrobacter spp
    • The above 3 organisms are known to have native expression of AmpC Beta-lactamases
      • other organisms can acquire AmpC by plasmid exchange, among these: E. coli, Klebsiella spp, and Salmonella spp
    • AmpC Beta-lactamase does not equal ESBL
    • Never use a third generation cephalosporin in a very ill / septic patient with an Enterobacter infection, even if the Enterobacter is not reported as being AmpC producing
    • Overview of AmpC: most commonly seen in Enterobacter species. AmpC expression can be seen in two situation: induction or selection. AmpC --> resistance to beta lactams. Resistant to beta lactams through 3rd generation cephalosporins. Ceftriaxone use will kill off bacteria that repress AmpC producers; thus, do not use ceftriaxone in a severe infection in the presence of AmpC producing organism. 
    • Treatment:
      • 1st line: carbapenem
      • Also consider: Cefepime (see Tamma et al, CID 2013:57 (6): 781 - 8)
MecA
  • Staph aureus
    • MecA encodes for PBP2', which is an altered penicillin binding protein 

ANTIBIOTICS
I. Beta Lactams

Beta lactams inhibit enzymes located beneath the cell wall (penicillin binding proteins). 
Inhibition leads to build-up up pre-cursors --> activation of autolytic system --> bactericidal effect

1. Penicillins (1940s)
    • Penicillin
      • Use: Syphilis
        • Early Latent, primary, secondary
          • Benzathine penicillin G 2.4 million units IM once
        • Late Latent:
          • Benzathine penicillin G 2.4 million units IM wkly x 3 wks
            • if any dose more than 2 days late, re-start Tx
        • Neuro:
          • Benzathine penicillin G 2.4 million units IM daily + probenecid 500mg PO qid for 10-14 days
      • Formulations:
        • IM/IV: 
          • Acqueous PCN G: 2-4 million units IV q4h
          • Benzathine PCN (Bicillin L-A) 2.4 million units IM
            • note: do NOT confuse with Benzathine/procaine PCN (Bicillin C-R)
        • Oral: 
          • PCN VK: 250-500mg PO q6h
      • History
        • Pen G came out in 1940s, followed by resistance by penicillinase-producing Staph. aureus
    • Penicillinase-resistant penicillins
      • Acyl side chain was added, that prevented disruption of the beta lactam ring by penicillinase
      • Drugs: 
        • methicillin
        • oxacillin
        • nafcillin
    • Aminopenicillins
      • Developed for increased G- coverage
    • Ureidopenicillins
      • Have added coverage for Enterobacteriaceae (Klebsiella spp., Enterobacter spp.) and Pseudomonas aeruginosa
      • *Many G- bacteria became resistant due to beta-lactamase  production
        • thus, beta-lactamase inhibitors were developed
      • Drugs:
        • Piperacillin
    • Beta-lactamase inhibitors
      • These inhibit non-group 1 Beta-lactamases
        • note: ineffective against G- bacteria that produce other types of beta-lactamases, including ESBL
      • Drugs:
        • Clavulananic acid
        • Sulbactam
        • Tazobactam
2. Cephalosporins (1960s)
  • First gen
    • Most active against aerobic, G+ cocci, including MSSA
    • Drugs:
      • Cefazolin
      • Cephalexin
  • Second gen
  • Third gen
    • most active against G- aerobic organisms
    • Ceftazidime active against P. aeruginosa
  • Fourth gen
    • Extended spectrum: G+, G-, and P. aeruginosa
    • Drugs:
      • Cefepime
  • Fifth gen
    • Ceftaroline
3. Carbapenems (1980s - 1990s)
  • Broad spectrum: aerobic and anaerobic G+ and G-
  • Note: Stenotrophomonas maltophilia typically resistant to carbapenems
  • Imi more active against G+ cocci, mero more active against G- bacilli
  • Ertapenem not active against Pseudomonas or enterococci
  • Drugs:
    • Imipenem
    • Meropenem
    • Ertapenem
    • Doripenem
  • Clinical use:
    • Febrile neutropenia
    • ESBL
4. Monobactams
  • Does not have affinity for penicillin-binding proteins of G+ and anaerobic bacteria
  • ONLY active against aerobic G- bacilli
  • Similar coverage to aminoglycosides, but not nephrotoxic
  • May be used with caution in patients with significant PEN allergy
  • Drugs:
    • Aztreonam
  • Clinical use:
    • G- pneumonia
    • Complicated and uncomplicated UTI
    • Intra-abdominal infx (combined with Metro)
    • Diabetic foot infx (combined w/ anaerobic and G+ coverage)
    • Osteomyelitis caused by G- bacilli
II. Aminoglycosides (1940s - 1960s)
  • Binds irreversibly to 30S & inhibits protein synthesis
    • Irreversibly binding likely explains bactericidal property
  • Cover Pseudomonas
  • Covers aerobic G- bacilli
  • Uptake of aminoglycosides is facilitated by inhibitors of cell well systehsis (i.e. Beta-lactams and clycopeptides)
  • Aminoglycosides show concentration dependent killing and a prolonged post-ABx effect
  • Streptomycin for MDR TB
  • Amikacin can be useful against Gent resistant G- bacilli
  • Drugs:
    • Streptomycin
    • Gentamicin
    • Tobramycin
    • Amikacin
  • Clinical uses: 
    • Enterococcal endocarditis (in combination with ampicillin)
    • Pseudomonal infx (combined with either (1) beta-lactam/beta-lactamase or (2) 3rd or 4th gen cephalosporin)

III. Macrolides and ketolides
  • Macrolides (1950s)
    • Inhibit 50S (--> T-RNA dissociating from ribosome)
    • Bacteriostatic
    • Cover G+ and G-
    • Spectrum: Strep, including group A & Strep. pneumo; also MSSA, Legionella, Chlamydia spp., Neisseria spp., Bordatella pertussis, and Campylobacter jejuni
    • The two new macrolides (Azithro, Clarithro) are more stable, have a longer half-life, and are better tolerated; they also have broader spectrum against MAC, H. influenzae, and Chlamydia
    • Drugs:
      • Azithromycin
      • Clarithromycin
      • Erythromycin
  • Ketolides
    • new class with activity against G+ organisms that are resistant to macrolides
    • They have a higher affinity for the ribosome binding site, and also bind domain II of the 23SrRNA
    • Active against Strep. pneumo, Strep. pyogenes
    • Drugs:
      • Telithromycin
    • Clinical use:
      • CAP
      • Acute exacerbation of chronic bronchitis
      • Acute sinusitis
IV. Tetracyclines
V. Fluoroquinolones
VI. Lincosamides
  • Clindamycin
VII. TMP/SMX
VIII. Glycopeptides
  • Vancomycin
  • Teicoplanin
VIIIa. Lipoglycopeptide
  • Telavancin

IX. Streptogramins
  • Quinupristin/dalfopristin
X. Oxazolidinones
  • Linezolid
    • Do not use long term if can be avoided
      • risk of optic neuritis, blindness
XI. Lipopeptides
  • Daptomycin
XII. Glyclcyclines
  • Tigecycline (derivative of minocycline)

  • Anti-pseudomonal
  • Anti-MRSA
  • Anaerobic coverage
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