Antimicrobials 1: Antibiotics

Here are some figures to summarise the following:

1) Antibiotics:

a) β-lactam antibiotics:

• Bactericidal (except against Enterococcus spp.); time-dependent and concentration dependant killers.
• Short elimination half-life (<2 hrs).
• Variable absorption - delayed by food.
• Distribution: widely, penicillins only get into the CSF via inflamed meninges
• Primarily renally eliminated (except nafcillin, oxacillin, ceftriaxone).
• Cross-allergenicity - except aztreonam.
• Mechanism of Action:
• interfere with cell wall synthesis by binding to penicillin-binding proteins (PBPs) which are located in bacterial cell walls.
• inhibition of PBPs leads to inhibition of peptidoglycan synthesis.
• are bactericidal.
• Mechanisms of Resistance:
• production of beta-lactamase enzymes.
• most important and most common.
• hydrolyzes beta-lactam ring causing inactivation.
• alteration in PBPs leading to decreased binding affinity.
• alteration of outer membrane leading to decreased penetration.
• Range of activity:
• Gm(+): MSSA, Str. pneumoniae, GBS, Enterococci.
• Gm(-): Neisseria spp.
• Trepenoma pallidium
• Anaerobes: Clostridia
• Penicillinase-Resistant Penicillins (e.g. methicillin)
• Aminopenicillins (e.g. amoxicillin) - extends Gm(-) cover
• Added protection against Listeria spp.
• Gm(-): Proteus spp., Salmonella & Shigella
• Carboxypenicillins (e.g. ticaracillin)
• Extends Gm(-) cover to include Enterobacter & Pseudomonas spp.
• Ureidopenicillins (e.g. piperacillin)
• Anaerobic cover & extends Gm(-) cover to include Serratia & some Klebsiella spp.
• β-lactamse inhibitor combos (e.g. augmentin)
• Extended action against BL producers.
• Clavulanic acid is a useful BL inhibitor.

b) Cephalosporins:

• Divided into 4 generations based on range of activity & resistance to β-lactams.
• 1st generation: mostly Gm(+) cover, with a little Gm(-) cover.
• 2nd generation: less Gm(+) cover, more Gm(-) cover, some have anaerobic cover (e.g. Moraxella spp., Haemophilus spp.)
• 3rd generation: even less Gm(+) cover but more Gm(-) cover. Ceftriaxone has activity against penicillin resistant Str. pnuemoniae. Ceftazidime has anti-pseudomonal activity.
• 4th generation: similar range of activity to 3rd gen but activity against β-lactamases. Poor inducer of ESBLs.

c) Carbapenems:

• Greatest range of activity - Gm(-), Gm(+) and anaerobes.
• See exclusion list for organisms not covered.
• Imipenem is combined with cilastin to prevent hydrolysis by dihydropeptidase at the renal brush border.

d) Monobactams (e.g. aztreonam)

• Pure Gm(-) action.
• Binds preferentiallyto PBP3 of Gm(-) anaerobes.

e) Fluroquinolones:

• All are structural derivatives of nalidixic acid.
• Fluorinated quinolones have a broader spectrum, excellent bioavailability and greater half-lives.
• Mechanism:
• Inhibit bacterial topoisomerases (needed for DNA synthesis)
• DNA gyrase: removes excessive +ve DNA helix supercoiling [target in Gm(-)]
• Topoisomerase IV: allows separation of interlinked DNA molecules [target in Gm(+)]
• Concentratio dependant killing, good oral bioavailability, good distribution, renal and hepatic excretion, not removed by HD.
• Resistance:
• Altered target sites: mutations in the genes that encode the topoisomerases
• Altered cell wall permeability: ↓↓porin expression
• Active efflux
• Cross resistance between FQs
• Spectrum of action:
• Gm(+): MSSA, pneumos, viridans & GBS
• Gm(-): Enterobacteriacae, Haemophilli, Moraxella & Neisseria, Pyo's
• Anaerobes: Bacteroides spp.
• Atypicals: Leigonella, mycoplasma, Chlamydia, Ureaplasma (see urea splitters), M.TB.

(f) Macrolides:

• Erythromycin: derived from Streptomyces erythreus.
• Mechanism of Action:
• Reversibly binding to 50s rRNA subunit - ↓protein synthesis
• BACTERIOSTATIC but may be bacteriocidal if in high concentrations and a very susceptible organism.
• Time dependant killing.
• Mechanisms of resistance:
• Active efflux: mef gene encodes an efflux pump for macrolides (low level resistance)
• Altered target sites: erm gene allows altered rRNA binding site.
• Spectrum of action:
• Azithro>Clarithro>Erythro
• No activityagainst Enterobacteriacae
• Anaerobes, atypicals, MAI & others
• Variable absorption & elimination
• Clari & Azithro are acid stable.
• Extensive distribution with minimal CSF absorption.
• All have hepative elimination, with clari having partial elimination, none of them are removed by HD.

g) Aminoglycosides:

• Streptomycin, gent, tobi, amikacin.
• Derived from an actinomycete, or are semi-synthetic derivative.
• Irreversibly binds to the 30S subunit - disrupting protein synthesis.
• Bacteriocidal.
• Mechanism of resistance:
• Alteration in aminoglycoside uptake
• decreased penetration of aminoglycoside
• Synthesis of aminoglycoside-modifying enzymes
• plasmid-mediated; modifies the structure of the aminoglycoside which leads to poor binding to ribosomes
• Alteration in ribosomal binding sites
• Spectrum of action:
• Gram-Positive Aerobes:
• most S. aureus and CoNS
• viridans streptococci
• Enterococcus spp.
• Gram-Negative Aerobes (not streptomycin)
• E. coli, K. pneumoniae, Proteus sp.
• Acinetobacter, Citrobacter, Enterobacter sp.
• Morganella, Providencia, Serratia, Salmonella, Shigella
• Pseudomonas aeruginosa (amik>tobra>gent)
• Mycobacteria

  • tuberculosis - streptomycin
  • atypicals - streptomycin or amikacin
• Poorly absorbed orally
• Equally distributed in the ECF (not CSF)
• Eliminated unchanged by the kidney (depends on GFR).

h) Vancomcyin:

• Complex tricyclic glycopeptide
• Produced by Nocardia orientalis
• Mechanism of action:
• Inhibits bacterial cell wall synthesis at a different site than beta-lactams
• Inhibits synthesis and assembly of the second stage of peptidoglycan polymers
• BACTERIOCIDAL (except for Enterococci)
• Spectrum of Action: Gm (+) only.
• Absorption
• absorption from gi tract is negligible after oral administration except in patients with intense colitis
• Use IV therapy for treatment of systemic infection
• Distribution
• widely distributed into body tissues and fluids, including adipose tissue; use TBW for dosing
• inconsistent penetration into CSF, even with inflamed meninges
• Elimination
• primarily eliminated unchanged by the kidney via glomerular filtration
• elimination half-life depends on renal function.

AMH