Living Textbook MC610

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Cell Wall Biosynthesis Inhibitors

Stage I Inhibitors:

  1. Fosfomycin
  2. Source: Streptomyces spp.

    Spectrum: Broad; Gram positive and Gram negative

    Mode of Action: Bactericidal

    Toxicity: Nausea, vomitting ad diarrhea.

    Use: Uncomplicated urinary Tract Infections (UTI) caused by Enterococcus faecalis and E. coli

    Dosage: Powder 3 gm as a single dose, in half a cup of water.

    Mechanism of Action
    : Inhibits PEP transferase (Mur A) irreversibly. Not a very good structure analogy, which led to lower toxicity.

    Resistance: Target mutation (Cys to Asp) and mutation to glycerophosphate transporter.

  3. Cycloserine
  4. Source: Streptomyces spp.

    Spectrum: Broad; Gram positive and Gram negative

    Mode of Action: Bactericidal

    Toxicity: Neutotoxic, possibly as it may be a partial agonist at the NMDA receptor; CNS disturbance, anxiety, confusion and drowsiness. Rashes and seizures are possible and may lead to CDAD.

    Other Issues:Contraindicated in patients with epilepsy or severe depression or psychosis. Not recommended in preganancy. Dose adjustment in patients with CrCl < 50 ml/min.

    Use: Second line in UTI and TB

    Dosage: 250 mg capsule every 12 hours

    Mechanism of Action: Competetive inhibitor of Alanine racemase and transferase. It is 100 times more efficient than Alanine (Km/Ki around 100), no conformotional changes because of the isoxazole ring, and also transported actively into the cell.

    Resistance: Upregulation of the targets and diminished uptake via a mutation to its active traporter.

Stage II Inhibitors:

  1. Bacitracin
  2. Source: Bacillus spp.; A polypeptide

    Spectrum: Gram positive, can not cross Gram negative wall.

    Mode of Action: Bactericidal

    Toxicity: Nephrotoxicity, thus not usually used systemically.

    Dosage Forms: Skin and eye ointments usually in combination with other antibiotics that act on gram negative bacteria.

    Use: Skin and eye infections caused by Gram positive bacteria or in combination with agents useful in Gram negative bacteria. It is also used in systemically, if the benefits outweigh the risks.

    Mechanism of Action: Binds to pyrophosphatase in the presence of magnesium,thus preventing regeneration of
    Bactoprene. It is more active if zinc is already present in the preparation, aiding in the binding to pyrophosphatase.

    Resistance: Production of higher levels or decreased utilization of bactroprene phosphate. Also, active effluz of the drug.

  3. Vancomycin

Source: Actinomyces spp.; A glycopeptide.

Spectrum: Gram positive only; Can not penetrate Gram negative cell wall.

Mode of Action: Bactericidal

Toxicity: Hearing loss, nephrotoxicity and thrombophlebitis leading to erythroderma (red man syndrome), that usually arise if it is given via rapid infusion.

Dosage Forms: Oral for local intestinal infections, 250mg four times daily. Slow IV infusions, IM would cause necrosis.

Use: In methicillin-resistant staphylococcus infections (MRSA), including empiric therapy of suspected MRSA infections. Can also be used in endocarditis (in combination with aminolycosides) and in CAP and meningitis (in combinations). Locally used for Clostridium difficile colitis.

Resistance: Is becoming a problem, probably due to unlabeled, overuse and use of related compounds (e.g. Avoparcin) in animal feeds. Vancomycin Resistant Enterococci (VRE) are particularly problematic and there are reports of MRSA that are now resistant (VISA) to our last resort, Vancomycin.

Teicoplanin is a longer acting agent, but not yet approved in the US. It is also used via IM injections.

Related Agents: Newer agents, include Telavancin , Delbavancin and Oritvancin, which all have a longer duration if action. They are used for the same infections as Vancomycin, plus they show effectiveness in VRE.

Mechanism of Action: Binds to D-Alanyl-D-Alanine portion of the dipeptide at the end chains and prohibits it from being transported to the cell wall for cross-linking. Forms three hydrogen bonds.

Resistance appears to arise by changing the middle NH in D-Ala to an O, preventing one of the hydrogen bonds from forming and causing repulsion between the two oxygen atoms, thus less likely to form. These combined effects lower Vancomycin's binding ability by 1000 folds.

Clinical Applications:

General: Bactericidal.

Fosfomycin:

Coverage broad spectrum including includes E. coli and Enterococcus faecalis.

Indications and Uses:Uncomplicated acute cystitis UTI; one single dose

D-Cycloserine:

Coverage broad spectrum includes Mycobacterium tuberculosis, E. coli and Enterobacter spp. 

Indications and Uses:Second line in UTI and TB

Bacitracin:

Coverage Gram positive only includes Staphylococcus spp.

Indications and Uses:Topical (major use): skin and eye infection

Systemic (rare): pneumonia and empyema caused by Staphylococcus spp. If benefits outweigh risk.

Vancomycin:

Coverage Gram positive bacteria, including Staph, Strep, MRSA and C. difficile

Indications and Uses:Major use is in infections caused by MRSA or as empiric treatment when MRSA is suspected. It can also be used as a replacement for penicillin, when patients are allergic to β-lactams.

Treatment of infections caused by Clostridium difficile (local, oral), when metronidazole therapy fails.

Endocarditis caused by Gram positive bacteria such as staphylococcal, streptococcal or enterococcal species alone or in combination with aminoglycosides.

May be employed in CAP and bacterial meningitis, typically in combinations to cover some Gram negative bacteria.

Telavancin:

Coverage same as vancomycin plus VRE and VISA

Indications and Uses: SSSIs and HAP caused by susceptible organisms.