Alice Prince

Beta-Lactam Antibiotics and Vancomycin

Beta-lactam antibiotics

Penicillins
Cephalosporins
Carbapenems
Monobactams

I. General principles of
antibiotic activity:

Anti-bacterial drugs have

selective toxicity, that is they interact with a target present on the bacterial cell,
the prokaryote, that is not present in the mammalian host, the eukaryote. For the
-lactam drugs, this target is the cell wall. Mammalian cells lack cell walls, which
for the bacteria are a critically important barrier protecting the organism from not
only the vagaries of osmotic stresses, heat and viruses but also as a protection
from anti-microbial peptides, and host defense mechanisms.

The major properties of an antibiotic that determine its activity against specific
bacteria are then associated with the: 1- affinity of the drug for the target, 2-
the permeability of the drug - how well it can get to its target; and 3- stability
to bacterial enzymes that inactivate or destroy the drug.

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1- What are the targets for the -lactam antibiotics?
Although the discovery of penicillin by Alexander Fleming was serendipitous (he
noticed a mold, the penicillium mold, killing the staphylococci he was growing on
an agar plate), there has since been a tremendous effort to understand exactly
how penicillins and related compounds actually KILL bacteria. These drugs are
CIDAL to actively growing organisms. Strominger noted a structural
resemblance between the backbone of penicillin G and the D-ala-D-ala portion
of the pentapeptide side chain of the peptidoglycan that is cross linked to make
bacterial cell walls. Spratt examined this association further and defined the
PENICILLIN BINDING PROTEINS (PBPs), by radioactively labeling penicillin G
and identifying the proteins that were directly bound. These PBPs are the
enzymes needed for peptidoglycan (cell wall) synthesis and fall into two groups:
the carboxy-peptidases, which cleave the terminal D-ala from the pentapeptide
releasing ATP and exposing the amino acid to be cross linked and the
transpeptidases which perform the cross-linking reaction.

Exactly how interfering with the cross-linking of the bacterial cell wall
actually kills the organism remains unclear. However, -lactam antibiotics are
only CIDAL to actively growing organisms. There are autolytic enzymes that are
necessary for cell division and growth and data to suggest that the activity of the
penicillins also triggers this autolytic activity resulting in bacterial death.

The affinity of a specific -lactam drug for these PBPs will determine, to a
major degree, its potency. The physiology of these PBPs in bacteria is important
in determining the susceptibility to a specific -lactam drug. The number of
copies of a given PBP, whether they are essential, or whether they can be
mutated will all contribute to overall susceptibility.

Clinical example: Staphylococcus aureus is a common pathogen which is often

susceptible to -lactam antibiotics, penicillin and cephalosporins. By mutating
PBP2, the affinity of this essential PBP is substantially DECREASED and the
organisms become resistant to this entire class of antibiotics. The clinical lab
uses a gene probe to identify the mutant PBP2a - and if present, labels the
isolate MRSA or methicillin resistant Staphylococcus aureus.

2- Permeability properties - How does the -lactam drug get to its target,
the penicillin binding proteins in the bacteria ?? The permeability properties
of a given drug are critical to its activity and depend upon how they can gain
access to PBPs in the organism as well as whether the organism is EXTRA-
cellular, in the bloodstream for example, or sequestered within a macrophage.
Complicating this more, the bacteria could be encased in a mucus plug in the
airways or deep within an intra-abdominal mass.

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Permeability issues in Gram positive versus Gram negative bacteria.
Starting at the level of the organism, there are inherent differences in the nature
of the cell walls of Gram positive as opposed to Gram negative bacteria that
determine susceptibility. Gram negative organisms have an outer cell wall, a
lipoprotein barrier studded with protein channels or porins. Charged antibiotics,
such as the -lactams, must get
through the porin proteins to
reach their targets, the PBPs
which are on the inside of the
outer lipoprotein cell wall. A
potential space, the periplasmic
space occupies the region
between the outer cell wall and
the peptidoglycan. Bacteria
actively regulate what goes
through these porins: electrolytes,
amino acids and various sugars.
For some organisms the porins
must be large to enable the bacteria to take up pre-formed compounds that they
need for growth. Since the porins are large, they do not pose a major barrier to
the relatively small -lactam antibiotics. Examples of these organisms with large
porins which are relatively susceptible to -lactam drugs are the Gram negative
respiratory pathogens such as the Hemophilus and Neisseria species.

Opportunist Gram negative bacteria (Pseudomonas, Enterobacter and many

others) can synthesize whatever they need from small sized components, a
simple carbon source for example. Their porins are highly regulated, relatively
small, and pose a major barrier for the entry of -lactams to the periplasmic
space and access to the PBPs. In addition, these organisms have EFFLUX
PUMPS which can be activated to pump the antibiotics back out the porins, even
if they do get to the site of peptidoglycan synthesis.
Thus, the -lactam antibiotics with the best permeability properties for
these Gram negatives are zwitterions, compact structures that are efficiently
taken up by these porins.

Gram positive bacteria lack an outer cell wall, but instead have multiple layers of
peptidoglycan. This peptidoglycan forms a loose mesh that does not pose a
significant permeability barrier to the hydrophilic -lactam compounds. -lactams
(and other classes of antibiotics) can have relatively bulky side chains and still
gain access to their target PBPs in these gram positive organisms.

3. Stability to bacterial enzymes - How do bacteria respond to these drugs ?

The third major principle of antimicrobial susceptibility is stability to bacterial

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enzymes. The fungi (penicillium and cephalosporium molds) are the sources of
many -lactam antibiotics and are soil
organisms which in nature grow in the same
ecological niche as many bacteria. Thus, the
bacteria evolved mechanisms to deal with the
presence of these natural antimicrobial
products, by the production of the -
lactamases. These enzymes cleave the -
lactam ring and destroy the ability of the -
lactam drug to bind to the target PBP. They
were first classified as either penicillinases,
such as the enzymes often produced by S. aureus, or cephalosporinases, the
chromosomal enzyme produced by many Enterobacteriacae. Enzymes were
then characterized by their molecular weight, requirement for a metal in the
active site, isoelectric point, and substrate profile. However, the consequences
of mutation and genetic exchange blurred these distinctions. Thus, the
nomenclature for the -lactamases is complex, confusing, and often changes.
The principles of -lactamase expression, however, are relatively simple.
Properties of -lactamases - The genes for -lactamase expression co-
evolved with the genes for the PBPs as both had similar targets. Thus, there are
chromosomal enzymes, such as AmpC, which are subject to the same
regulatory mechanisms as other bacterial operons: there is a two-component
sensing system that responds to the presence of -lactam structures; a response
regulator that activates (or derepresses) the target gene, the -lactamase etc.
What this means is that many organisms, particularly the Gram negative
opportunists, have INDUCIBLE -lactamase expression, that is chromosomally
mediated and turns on and off depending upon the presence of an inducer (i.e.
an antibiotic in clinical use). Mutants can be selected that are stably
derepressed - meaning that they are constitutively producing large amounts of
these enzymes that inactivate and destroy the -lactam drug. The chromosomal
enzymes may prefer either the 5-membered penicillin nucleus or the 6-
membered cephalosporin nucleus as a substrate. There are also metallo-based
chromosomal enzymes with a zinc moiety in the active site which are
exceptionally active against drugs in clinical use.
There are also plasmid-encoded -lactamases that are constitutively
expressed and can be readily transferred from one organism to another. The
most famous is TEM-1, named after a little girl Temora, who had an E. coli
urinary tract infection that turned out to be penicillin resistant - due to the
presence of this TEM enzyme that destroyed the antibiotic. The TEM family
has accrued many many point mutations and there are now >30 variants
identified. With the acquisition of these mutations, these plasmid mediated
enzymes have expanded their spectrum of activity to include not just simple
penicillins, but the 6-membered cephalosporin ring as well. These are aptly
named extended spectrum -lactamases, and since they are often plasmid
mediated, are transferable in places that many bacteria co-mingle - such as the
gut flora.

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 Often these -lactamase genes are flanked by repeated sequences or
transposable elements which enable them to move from the chromosome to a
plasmid or vice versa. Thus, there are reports of plasmid encoded ampC that
may lack the expected regulatory elements and be constitutively expressed.

Localization of -lactamases - In Gram negative bacteria, enveloped by their

outer cell wall, the -lactamases are strategically placed in the potential peri-
plasmic space where compounds entering the cell via the porins would be
immediately detected. Thus, there is an ecomomy of -lactamase production
and efficient use of the enzymes. There is a competition between the affinity of
the incoming antibiotic and its target PBPs and the affinity of the -lactamase for
the drug. If two drugs were entering at the same time, one with substantial
affinity for the -lactamase and one with more affinity for the PBP, it would be
possible to competitively inhibit the -lactamase and let the penicillin kill the
bacteria.

In Gram positive bacteria that lack this outer cell wall, -lactamases are similarly
synthesized and secreted into a cloud surrounding the organism. Thus,
antibiotics that approach the organism must be stable to these enzymes once
they reach the vicinity of the bacteria. However, since there are no porin protein
channels to squeeze through, bulky side chains that sterically inhibit -lactamase
activity can be added to the penicillins which are targeting Gram positive
organisms such as Staphylococci that produce -lactamases.

Clinical example - Amoxicillin is a well absorbed oral penicillin that kills Gram
positive and some Gram negative respiratory pathogens, most often used to treat
respiratory tract infections and otitis media. It is susceptible to -lactamase
destruction. By adding clavulanic acid, a specific -lactamase inhibitor, to the
amoxicillin formulation, the combination Augmentin (amoxicillin + clavulanate)
is active against -lactamase producing organisms in the respiratory tract, such
as Hemophilus or Neisseria. It is also active against staphylocci that are
producing -lactamases.
To target Gram positive organisms such as staphylococci, the anti-
staphylococcal penicillins were developed that contain a large side chain
(isoxazyl or methoxy groups) making the -lactam ring inaccessible to the
bacterial enzymes. These bulky penicillins do not get through the Gram negative
porins, thus these penicillins are narrow in spectrum, limited to the Gram
positives.

II - Specific Drugs -

How are the activities of different antibiotics compared ? How does a

clinician know which drug to choose - what is best for a given infection in a
specific patient? Easiest choices are based simply upon in vitro activity - what is
the least amount of a drug that will kill a given organism. Various assays are

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used, some of which can be automated to determine the rate of growth in the
presence of various concentrations of antibiotics:

Kirby - Bauer Disc diffusion - a filter paper disc is soaked in a standardized

concentration of an antibiotic and placed on a plate that has been inoculated (in a
lawn) with a known concentration of bacteria. Following incubation at 37 degrees
C overnight, the size of the zones surrounding the discs are measured and
compared to standards for each drug that reflect the amount of the drug
expected to be achieved in a patient. If the zone is large enough (i.e. more
bacterial killing at lower concentrations as the drug diffuses out of the disc) the
bacteria is considered susceptible; if the bacteria grow across the disc, they are
obviously resistant; if colonies pop up in the zones of inhibition, it suggests that
there is a mixed population or that mutants are arising at a high frequency.

E-strips - Are based on the same principle - filter paper soaked in graded
amounts of the drug - enabling the technician to directly read the concentration of
an antibiotic that kills the organism.

Minimum inhibitory concentrations (MIC) - More commonly, bacteria are

inoculated into 96 well microtiter plates with decreasing concentrations of
antibiotics. After overnight incubation turbidity is read spectrophotometrically and
the well without turbidity is considered the MIC.

MBC - Minimum bactericidal concentration - In liquid culture a small number

of organisms does not result in turbidity - but if the liquid were placed on solid
media, colonies could arise if there were still a few bacteria present. The MBC is
measured by plating out the apparently clear liquid media and establishing the
concentration where there is >99.9% killing.

Penicillins

First described by the abbess Hildegarde von Bingen in the 15th century (she
also wrote madrigals) as the good things that grow on trees - who identified the
penicillium mold as having anti-infective properties.

Penicillin G is the prototype - -lactam ring + a thiazolidine ring +

R-groups - which are side chains that influence pharmacologic properties. It is
not -lactamase stable but nonetheless is highly active against streptococci,
spirochetes (cause syphilis and Lyme disease) and meningococci. Pen G is not
acid stable so it is given parenterally: either intravenously or in a repository form
(procaine pen G or benzathine pen G) which is given intramuscularly.

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Ampicillin - Amoxicillin - The addition of a charged NH3 group improves the
penetration of the penicillin nucleus through Gram negative porins in organisms
such as E. coli while retaining excellent
activity against Streptococci; the OH-
group in amoxicillin provides stability to
stomach acid. Neither ampicillin nor
amoxicillin is -lactamase stable so they
are often given in combination with a -
lactamase inhibitor:
Ampicillin + sulbactam = Unasyn - used
parenterally for a wide variety of infections
including those caused by anaerobic
bacteria, Gram positive and Gram negative
organisms.
Amoxicillin + clavulanic acid = augmentin -
Oral drug that is commonly used for
respiratory infections; it covers S. aureus also since the clavulanate inhibits the
staphylococcal -lactamase, as well as -lactamase-producing Hemophilus and
Moraxellae.

Anti-staphylococcal penicillins -
Oxacillin
Methicillin
Nafcillin
The anti-
staphylococccal penicillins,
also refered to as semi-
synthetic (which is true for
most of the penicillins - as
they are partially produced
by molds with chemical
modifications) were
developed in the 1950s to
deal with the growing
problem of Staphylococcal
infections due to penicillin-
resistant organisms. These
S. aureus strains produced -lactamases with primarily penicillinase activity.
Adding a large bulky side chain (methoxy or isoxazoyl groups) protected the -
lactam bond and did not interfere with penetration to the target PBPs since these
Gram positive bacteria have no outer cell walls. Cloxacillin and di-cloxacillin are
oral forms of these drugs, used for staphylococcal infections.

Anti-pseudomonas penicillins - Piperacillin (carbenicillin and ticarcillin are

older drugs no longer in use) - To kill the opportunists, the Gram negative
bacteria with tightly regulated porin channels and multiple efflux systems, semi-

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synthetic or broad spectrum
penicillins were developed that
have charged R- side chains to
improve permeability through the
porins and with structural
properties that increase affinity
for the PBP3 target. Piperacillin
has a piperazine ring - a
compact charged group that
significantly increases the activity
of the drug against P.
aeruginosa, a common Gram
negative opportunist.
Piperacillin is formulated with a -lactamase inhibitor - tazobactam = Zosyn -
which provides protection against the plasmid mediated -lactamases,
particularly those of the TEM type. Unfortunately the tazobactam does not
provide protection against the derepressed chromosomal -lactamase of
P.aeruginosa (ampC) which has predominantly cephalosporinase activity.
However, the combination of piperacillin+ tazobactam does provide broad
spectrum activity against Gram positive bacteria (streptococci and staphylococci)
as well as many of the enteric Gram negative (E. coli, Klebsiellae, Proteus
species) and opportunistic pathogens (P. aeruginosa).

Mechanisms of resistance to penicillins

Mutations in PBPs - Bacteria spontaneously undergo mutation at a frequency

of approximately 10-6-7. In the presence of an antibiotic, mutations that enhance
survival are selected and eventually organisms with these mutations can
predominate. Streptococcus pneumoniae, a very common Gram positive
respiratory pathogen, can accumulate mutations in the PBPs and become
relatively or absolutely resistant to penicillin. When these organisms die and
lyse, their DNA is taken up by other streptococci (they are naturally
transformable) and in the presence of antibiotic selective pressure, the now
transformed penicillin-resistant organisms are maintained in the population.
A DNA cassette which encodes a mutant PBP2 in S. aureus is also a
common clinical problem and causes methicillin resistant S. aureus (MRSA).

-lactamase production - Both Gram positive and Gram negative organisms

can produce -lactamases that cause clinically significant antibiotic resistance.
In Gram positives, this is a major problem with S. aureus which classically
produces a penicillinase. In some recent outbreaks, staphylococci were found to
be producing -lactamases with cephalosporinase activity as well. Again, there
can be mutations in the -lactamase genes that alter the activity of the enzyme,
and in the presence of selective pressure, these mutants flourish.
Gram negative bacteria can express both chromosomal -lactamases as well as
plasmid mediated enzymes with a wide variety of activities.

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Permeability - The expression of efflux pumps in both Gram negative and in
Gram positive bacteria is a major cause of antibiotic resistance. The drugs are
rapidly removed from the cell by an inducible pump system. In Gram negative
organisms, such as P. aeruginosa, there are >20 different efflux systems that
have been identified.

Pharmacology - In general, the penicillins are charged molecules with

distribution limited to the extracellular space. With inflammation, they can
achieve bactericidal levels in the CSF and are used to treat meningitis. The
penicillins are handled by the kidneys, primarily by tubular secretion and
achieve high levels in the urine in patients with normal renal function. Each drug
has somewhat different pharmacokinetic properties. There is some biliary
excretion (significant for nafcillin) and therapeutic levels are achieved in bile.
Adverse effects that are most important include allergy, both immediate IgE-
mediated hypersensitivity reactions that include anaphylaxis, and delayed
responses such as rash.

Cephalosporins

The cephalosporins look and act

much like the penicillins. Their
basic structure consists of a 6
membered dihydrothiazine ring
with substitutions at the #3
position generally affecting their
pharmacological properties and
changes at the #7 position
affecting antimicrobial activity (more or less). As this dihydrothiazine backbone
was more amenable to chemical manipulation, there was a great deal of drug
development centered upon new and improved cephalosporins during the 1970s
and 1980s. This was in direct response to the increasing sophistication of
medical practice, ICUs, neonatal medicine and the associated problems of
hospital -associated infection and the selection of multiply antibiotic resistant
bacteria.
In the late 1940s Giuseppe Brodtzu identified the antimicrobial activity
associated with the cephalosporium mold while he was vacationing in Sardinia.
Cepahalosporin C was found to have broad activity against both Gram positive
and Gram negative bacteria, and was resistant to degradation by staphylococcal
penicillinases (-lactamases). Unfortunately, it did not cross the blood brain
barrier and was ineffective for meningococcal meningitis and was not further
developed until the clinical need for more potent, -lactamase stable drugs
developed. As the cephalosporin nucleus was inherently stable to the
penicillinases made by staphylococci, the drugs came into wide use during the S.

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aureus outbreaks in hospitals that were problematic in the 1950s, and
derivatives were synthesized with more desirable properties - less painful to
inject intra-muscularly, longer half life (Cephalothin).

Properties of the cephalosporins - As members of the -lactam class of

antimicrobials, the activity of the cephalosporins is a function of their affinity for
PBPs, their permeability properties, and their stability to -lactamases. A few
salient features are worth remembering. The cephalosporins, as a group DO
NOT bind well to the PBPs of Enterococci - which are, accordingly, entirely
resistant to cephalosporins. It is also important to understand that the
cephalosporins, as a group, are much more potent inducers of the Gram
negative chromosomal -lactamases, the members of the ampC family, which
(ironically) have cephalosporin activity. Thus, if there are sizable populations of
bacteria present, sub-inhibitory levels of cephalosporins may well select out
mutants with derepressed chromosomal -lactamase activity resulting in clinical
failures of therapy.

First generation cephalosporins - house cephalosporins

Cefazolin - parenteral
Cephalexin - oral
The development of the cephalosporins is conveniently divided into generations
These initial broad spectrum agents have excellent activity against community
acquired bacteria; streptococci, many S. aureus, Enterobacteriaciae, E. coli,
Klebsiellae, and Proteus mirabilis. While rarely considered the drug of choice for
a specific indication, they are often used for surgical prophylaxis, given
immediately at the time of surgery, or for skin and soft tissue infections (but not
bites). As more resistant Gram negative infections became common, and the
importance of -lactamase producing anaerobes in the bowel was appreciated,
the use of second generation cephalosporins increased.

Second generation cephalosporins -

Cefoxitin, cefotetan and cefuroxime

Cefoxitin and cefotetan are very -lactamase stable - and active against many
aerobic and anaerobic Gram negative rods, but they have somewhat less activity
against Gram positive organisms than the first generation cephalosporins. Thus,
they are used primarily to treat infections arising from the bowel flora. (Note as
cephalosporins they do not have activity against enterococci, also common in the
gut flora.)

Cefuroxime retains excellent activity

against many Gram positive bacteria,
but has improved -lactamase
stability and is active against the
Gram negatives in the respiratory

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tract, such as Moraxellae and Hemophilus. It is often used to treat some
respiratory tract infections - but has been supplanted by more active drugs.

Third generation cephalosporins

Cefotaxime
Ceftriaxone
Ceftazidime

Cefotaxime and ceftriaxone - These drugs were developed to treat the

increasingly resistant Gram negative rods that were seen in hospitalized patients.
However, due to their enhanced activity, high blood levels, and pharmacokinetic
properties, they have enjoyed widespread use against a number of common
infections. Both are highly active agents against pneumococci (penicillin-
susceptible and most penicillin-resistant), Hemophilus, Meningococci,
Gonococci, and many enteric Gram negative bacteria. Both get into the CSF and
with their intrinsic activity against the common causes of bacterial meningitis (S.
pneumoniae and N. meningitidis) are the agents of choice for presumed
meningitis.
Ceftriaxone is exceptionally active and is highly protein bound with a long half
life. It can be given once (or twice) a day intramuscularly or intravenously for
serious infections, making it ideal for many indications in an outpatient setting,
where compliance may be an issue or when prolonged therapy may be needed,
as in CNS Lyme disease.
Ceftazidime - This is the cephalosporin that is used for P. aeruginosa infection.
Ceftazidime has the piperazine side chain also present in piperacillin. It is also
active against many other Gram negative enteric and opportunistic pathogens,
but has limited Gram positive activity (as compared with the first generation
cephalosporins or cefotaxime). As a cephalosporin, it can induce chromosomal
-lactamases and thus should be used selectively.

Fourth generation
Cefipime has increased Gram positive as well as Cefipime
Gram negative activity and is used in settings where
broad spectrum coverage is needed. It is also very
active against P. aeruginosa and many of the
opportunistic Gram negative pathogens that are found
in hospitalized patients.

Carbapenems -
Imipenem
Meropenem
Ertapenem

This family of -lactam-like agents has lost the -lactam ring itself, while still
acting much like a penicillin or cephalosporin. They have very high affinity for
PBP2, which is present in low copy number and is accordingly an excellent target

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for the antibiotic. In general,
they have improved
permeability properties and
can selectively use OprD, a
porin channel that is not
usually activated by the
more common efflux pumps.
While they lack a -lactam
ring and were initially
thought to be entirely -
lactamase stable, there have
been organisms that have
developed enzymes to break
down these agents as well.
These are very very broadly active drugs and it is easier to remember the
organisms that are not killed: Stenotrophomonas and Burkholderia (opportunistic
Gram negatives) and Enterococci. They penetrate into the CSF and, in fact,
imipenem is associated with CNS toxicity in patients with renal failure,
meropenem perhaps less so.

Monobactams

Aztreonam - During the search for potent antimicrobials against Gram negative
organisms, this monobactam was found as a microbial product in New Jersey
sewage (in the Meadowlands !). It has a single ring and thus is stable to most -
lactamases but only binds to the PBPs of Gram negative bacteria. Aztreonam
can be used in penicillin allergic patients (since it has a different structure) and
has the excellent safety profile of a -lactam type antibiotic. Unfortunately, it can
be removed by efflux pumps that are expressed by some of the multi-resistant
Gram negative pathogens.

Resistance mechanisms are basically the same as for the penicillins. Some
species, notably the Enterococci, are inherently resistant to the cephalosporins
due to structural differences in their PBPs.

Pharmacology
The cephalosporins and related compounds, like the penicillins, are hydrophilic
and well distributed into extracellular compartments. They are variably protein
bound - with ceftriaxone being exceptionally highly protein bound, and have drug-
specific half lives. Cefotaxime is metabolized and des-acetyl cefotaxime is
excreted into the gut. Otherwise they are handled primarily by the kidney by
tubular secretion and some glomerular filtration.

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Other cell wall active antibiotics

Vancomycin -
Much of antimicrobial
development has been driven by
a specific clinical need (and
market). In the 1950s with major
outbreaks of staphylococcal
infection, another fungal product,
vancomycin was identified as
having excellent activity against
Gram positive bacteria,
particularly S. aureus. However,
the drug was not as good --
neither as active nor as readily
purified -- as the anti-
staphylococcal penicillins, and fell into disuse. However, with the emergence of
methicillin resistant S. aureus and the common occurrence of infection
associated with indwelling intravenous catheters caused by coagulase-negative
staphylococci (not especially virulent skin flora that are inherently -lactam
resistant due to altered PBPs) vancomycin has become an exceptionally widely
used drug.

Vancomycin targets the cell wall, interacting

with the D-ala-D-ala portion of the
pentapeptide side chain of staphylococci.
It blocks both the carboxypeptidase activity
as well as the transpeptidase. Thus, while
it took awhile for organisms to become
resistant, once vancomycin resistance is
established it can be a significant problem
in a given setting. Vancomycin does not
get into Gram negative bacteria. Since it is only active against Gram positives,
permeability is not an issue and there are no known bacterial enzymes (to
date.) that destroy the drug.
The spectrum of vancomycin is limited to Gram positives, Streptococci,
Clostridia, Listeria, and Bacillus species as well as the Staphylococci. It is active
against the highly penicillin resistant S. pneumoniae, and is used for
pneumococcal meningitis until the susceptibilities of the infecting organism are
known.

Resistance - Resistance to vancomycin first developed in the enterococci, and

was first reported in hospitals that used the drug orally thus exposing large
populations of these commensal flora to selective pressure. There are several

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genes that mediate vancomycin resistance. The most common enables the
bacteria to produce a D-ala-D-lactate dipsipeptide which thwarts vancomycin
binding. These genes are most often found in Enterococcus faecium (VRE) and
other enterococci. A major concern has been the spread of these genes to
staphylococci. S. aureus resistant to vancomycin have been reported but are
rare, and their prevalence is likely to increase.

Pharmacology - Since its initial isolation in the 1950s, vancomycin has been
highly purified and initial reports of nephrotoxicity were likely due to impurities.
The drug is eliminated by the kidneys and doses must be adjusted in renal
failure. It is 55% protein bound with a half life of approximately 7 hours (with
normal renal function). Although vancomycin allergy is uncommon, rapid infusion
of the drug is associated with RED MAN syndrome, a histamine mediated
flushing of the head and neck which may be associated with hypotension.

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