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: - MRSAMajor 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