BACITRACIN/VANCOMYCIN/DAPTOMYCIN/FOSFOMYCIN

CYCLOSERINE/POLYMYXIN B
INTRODUCTION
In addition to the penicillins and cephalosporins, there are other agents that exert their antimicrobial
actions through an effect on bacterial cell walls. Four of these drugs, bacitracin, vancomycin,
fosfomycin and cycloserine exert their antimicrobial effect through inhibition of bacterial cell wall
synthesis. Daptomycin exhibits a unique antimicrobial mechanism of action, through depolarization of
bacterial membrane potential. On the other hand, the antibiotic action of the polymyxins is result of
their binding to and disruption of bacterial cell membranes (NOT CELL WALL).
BACITRACIN
Bacitracin is a peptide antibiotic that inhibits bacterial cell wall synthesis. It is effective versus a broad
range of gram-positive cocci and bacilli. Bacitracin is potentially nephrotoxic if given systemically;
therefore, bacitracin is rarely employed parenterally. Bacitracin is most commonly employed topically
to prevent supercial skin and eye infections following minor injuries. Intramuscular bacitracin has
been used in infants with staphylococcal pneumonia, but this application is uncommon since there are
other safer, equally efcacious antibiotics available.
Its poor absorption following topical application allows local antibacterial activity devoid of systemic
toxicity. Bacitracin is marketed as an ointment, often in combination with polymyxin B (Polysporin)
and neomycin (Neosporin). This combination is often employed in treatment of both dermatological
and ophthalmic infections.
VANCOMYCIN (VANCOCIN)
Vancomycin is a bactericidal glycoprotein that exhibits signicant activity against multiple
antimicrobial resistant microorganisms such as methicillin~resistant Staphylococcus aureus (MRSA).
However, vancomycin-resistant strains of MRSA, Enterococcus faecium and Enterococcus faecalis
have been observed. Therefore, vancomycin should only be used for treatment of serious multi-drug
resistant infections to reduce development of resistance.
A. Mechanism of action
Vancomycin inhibits bacterial cell wall synthesis by inhibiting synthesis of bacterial cell wall
phospholipids. Vancomycin also inhibits peptidoglycan polymerization or cross-linking, which
also contributes to cell lysis and the bactericidal effect.
B. Antibacterial spectrum

Narrow antimicrobial spectrum

Active against gram-positive bacteria
DOC for MRSA infections
First line agent for infections due to penicillin-resistant Streptococcus pneumoniae
Use generally restricted to treatment of severe infections due to B-lactam-resilient gram-

positive organisms (Streptococcus or Staphylococcus infections)

Primary indication of parenteral vancomycin is endocarditis or sepsis due to MRSA
First line agent for tetanus due to Clostridium tetani
Also indicated for treatment of patients exhibiting gram-positive infections who are allergic
to B-lactams
Commonly given in combination with an aminoglycoside (gentamicin) for treatment of
enterococcal infections (synergistic bactericidal effect) in B-lactam allergic patients
Employed orally to treat potentially fatal antibiotic-associated colitis due to staphylococcal or
Clostridium difficile overgrowth

C. Resistance
Resistance is increasing
Plasmid-mediated
Reduction in drug penneability
Altered target site
D. Pharmacokinetics
Vancomycin is not absorbed orally
Treatment of systemic infections requires slow i.v. infusion
Inammation allows penetration into the meninges
Administered orally only for the treatment of antibiotic-induced enterocolitis due to
staphylococcal or Clostridium difficile overgrowth
Metabolism of vancomycin is clinically insignicant
Most excreted by glomerular ltration
Dosage should be adjusted in presence of renal insufficiency
E. Adverse effects
Fever, chills, and/or phlebitis at the site of infusion
Flushing and shock
Due to histamine release following rapid infusion
Ototoxicity
Due to antibiotic accumulation in patients with renal failure
DAPTOMYCIN (CUBICIN)
Daptomycin is an i.v. cyclic lipopeptide that exhibits a similar antimicrobial spectrum of activity to
vancomycin. Lipopeptides are a novel class of antibiotics that exhibit concentration-dependent
bactericidal activity against aerobic G+ microorganisms. Daptomycin retains activity against gram
positive bacteria resistant to methicillin and vancomycin.
A. Mechanism of action
Daptomycin exerts its bactericidal effect through a unique mechanism of action. Lipopeptides interact
with bacterial membranes inducing a rapid depolarization of membrane potential. This reduction in
membrane potential leads to cell death through indirect inhibition of protein, DNA and RNA synthesis.
B. Antibacterial spectrum

Narrow antimicrobial spectrum

Active against gram-positive bacteria
Spectrum of activity similar to that of vancomycin
Also synergistic effect in combo with aminoglycosides
Approved for treatment of complicated endocarditis, bacteremia, and skin and soft tissue
infections
Enterococcus faecalis (VRE)
Enterococcus faecium (VRE)
Very effective against Staphylococcus aureus, MRSA and VRSA
Streptococcus agalactiae
Streptococcus pyogenes

C. Pharmacokinetics
Administered by i.v. infusion
Metabolism unclear, inactivated by pulmonary surfactant
80% excreted by glomerular ltration
Doses reduced in patients with renal insufciency
D. Adverse effects
Headache, insomnia and dizziness
Abnormal liver function tests, jaundice and renal failure
GI disturbances
Constipation, diarrhea, nausea and vomiting
Injection site reactions and skin rashes
FOSFOMYCIN (MONUROL)
Fosfomycin inhibits synthesis of bacterial cell walls. Fosfomycin is effective against both grampositive and gram-negative microorganisms. Resistance can develop due to decreased permeability.
Fosfomycin exhibits synergistic antimicrobial activity in combination with aminoglycosides, B-lactams
or uoroquinolones.
Fosfomycin is only available for oral use in this country. It is excreted by the kidneys unchanged and
diarrhea is a common side effect. The drug is employed for treatment of uncomplicated urinary tract
infections (acute cystitis) in females and is safe to administer during pregnancy. Its major indication is
for single dose treatment of UTIs in females due to Enterococcus faecalis or E. coli.
CYCLOSERINE
Cycloserine is a second-line orally effective antimycobacterial agent that appears to exert its
tuberculostatic effect through inhibition of bacterial cell wall synthesis. It is regarded as a second-line
tuberculostatic agent since it has no more activity than the rst-line agents but exhibits considerably
more adverse effects.
Cycloserine is active against many gram-positive and gram-negative microorganisms. However,
cycloserine is almost solely employed in treatment of tuberculosis resistant to rst-line tuberculostatic
agents.

Cycloserine is widely distributed throughout body uids, including the CSF. The drug is metabolized to
a certain extent and both the metabolite and parent compound are eliminated by the kidneys.
Accumulation of cycloserine occurs in individuals exhibiting renal failure.
Adverse side effects mainly involve CNS toxicity, including headaches, tremors, psychosis
and convulsions. Peripheral neuropathies have also been reported in patients on cycloserine
therapy.
POLYMYXIN B
The polymyxins are a class of cationic, basic peptides that are effective against gram-negative bacteria
and are restricted to treating gram-negative bacterial infections. Polymyxins are highly bactericidal for
several gram-negative rods, including Pseudomanas. Due to their potential nephrotoxicity, polymyxin
B is the only polymyxin currently on the market.
A. Mechanism of action
Polymyxins behave similar to cationic detergents. Their mechanism of action involves binding to and
disruption of bacterial cell membranes.
B. Antibacterial spectrum
Polymyxins are quite effective against several gram-negative rods, such as Pseudomanas and are
employed to treat corneal ulcers and external otitis caused by Pseudomonas infections. Spectrum of
activity also includes E. coli, Enterobacter aerogenes, Klebsiella pneumoniae, Shigella, and
Haemophilus inuenzae. However, gram-positive organisms, as well as Proteus, Serratia and Neisseria
are resistant to the antimicrobial action of the polymyxins.
C. Pharmacokinetics
The sulfate salt of polymyxin B is water-soluble and very stable in solution. However, this antibiotic
exhibits poor tissue distribution and is now mostly limited to topical applications. Ointments containing
polymyxin B, in combination with neomycin and/or bacitracin are frequently employed to treat infected
supercial skin lacerations. Polymyxin B is largely restricted to ophthalmic and topical use.
Today, polymyxin B is rarely used systemically due to its potential for nephrotoxicity and neurotoxicity
and the availability of less toxic agents. However, polymyxin B is available for parenteral use in
treatment of bacteremia and UTIs due to susceptible gram negative organisms when other antibiotics
are contraindicated or ineffective.
D. Adverse effects
The major adverse effect associated with clinical use of the polymyxins is their potential for
nephrotoxicity. Because of this potential adverse effect, polymyxin B is the only polymyxin currently
on the market. Neurotoxicity has also been associated with administration of the polymyxins.