Bez nadpisu

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ANTIMICROBIAL THERAPY V. Geršl According to -
H.P.Rang, M.M.Dale, J.M.Ritter, P.K.Moore
Pharmacology, 5th ed. - R.A.Howland, M.J.Mycek
Lippincotts Illustrated Reviews Pharmacology,
3rd ed. Antimicrobial drugs (ATBs) - effective
in the treatment of infections because of their
selective toxicity - the ability to kill an
invading microorganism without harming the cells
of the host. The selective toxicity is relative
it is necessary to control the concentration
of ATB - to attack the microorganism while still
being tolerated by the host. Selective
antimicrobial therapy advantage of the
biochemical differences that exist between
microorganisms and human beings. SELECTION OF
ANTIMICROBIAL AGENTS depends on 1) the
organisms identity, 2) its susceptibility to an
agent, 3) site of the infection, 4) patient
factors, 5) safety of the agent, 6) cost of
therapy.
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A. Identification and sensitivity of the organism
is central to the selection of the proper drug.
It is essential to obtain a sample culture of
the organism prior to initiating treatment if
possible. Empiric therapy prior to organism
identification Ideally - to treat when the
organism was identified and its
susceptibility established. However, acutely ill
patients usually require immediate treatment
(after specimens for laboratory analyses are
obtained but before the results of the culture
are available). The choice of drug in the
absence of sensitivity data - influenced by
patient (e.g., age), site of the infection, and
results of the Gram stain. Possible - initiate
empiric therapy with ATB or a combination of
ATB covering infections by both G and G-
microorganisms.
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B. Selecting a drug In the absence of
susceptibility - influenced by the site of
infection, and the patient's history (hospital x
community-acquired, patient's travel record and
age). Broad-spectrum - when the identity of the
organism is unknown or the site makes a
polymicrobial infection likely. Also guided by
known association of particular organisms with
infection (e.g., a G coccus in the spinal fluid
of a newborn infant - most likely Streptococcus
agalactiae G coccus in older (cca 40 years)
patient - probably S. pneumoniae). C.
Determination of antimicrobial susceptibility of
infective organisms The susceptibility of
bacteria to specific ATB - guide in choosing
therapy. Some pathogens (streptococcus pyogenes,
Neisseria meningitidis) - usually have
predictable susceptibility to certain ATB. Most
G- bacilli, enterococci, and staphylococcal
species - often unpredictable susceptibility.
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1. Bacteriostatic vs. bactericidal drugs
Bacteriostatic - arrest the growth and
replication of bacteria at serum levels
achievable in the patient - they limit the spread
of infection while the body's immune system
attacks, immobilizes, and eliminates the
pathogens. If the drug is removed before the
immune system has scavenged the organisms, enough
viable organisms may remain to begin a second
cycle of infection. Bactericidal - kill bacteria
at drug serum levels achievable in the patient. -
often drugs of choice in seriously ill patients.
It is possible for ATB to be bacteriostatic for
one organism and bactericidal for another. 2.
Minimum inhibitory concentration (MIC) the
lowest concentration of ATB that inhibits
bacterial growth. Effective antimicrobial therapy
- ATB concentration in body fluids should be
greater than the MIC. 3. Minimum bactericidal
concentration (MBC) the lowest concentration of
antimicrobial agent that results in a 99.9
decline in colony count after overnight broth
dilution incubations.
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D. Effect of the site of infection on therapy
The blood-brain barrier - the single layer of
tile-like endothelial cells fused by tight
junctions that impede entry from the blood to the
brain of molecules, except those that are small
and lipophilic. 1. Lipid solubility of the
drug Compounds without a specific transporter
must pass from the blood to the CSF. The lipid
solubility is very important. E.g.,
lipid-soluble quinolones - penetration to the
CNS. Ionized b-lactam antibiotics (PNC) have
limited penetration through the intact BBB. In
infections (meningitis) - local permeability is
increased. Some b-lactam ATBs can then
significantly enter the CSF. 2. Molecular weight
Low M.w. - enhanced ability to cross the BBB
high M.w. (vancomycin) penetrate poorly. 3.
Protein binding of the drug A high degree of
protein binding in the serum - limited entry into
the CSF. The amount of free (unbound) drug in
serum, rather than the total amount is important
for CSF penetration.
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E. Patient factors 1. Immune system Elimination
of infecting organisms from the body depends on
an intact immune system. Decreased e.g. in
alcoholism, diabetes, immunosuppresion,
malnutrition, advanced age. Higher-than-usual
doses of bactericidal agents or longer courses of
treatment are required. 2. Renal dysfunction
Poor kidney function (10 or less of normal) -
accumulation in the body of ATB eliminated by
this route - serious adverse effects it is
necessary to adjust the dose or the dosage
schedule of ATB. Direct monitoring of serum
levels of some ATB (e.g., aminoglycosides) is
preferred to identify maximum and minimum values.
The renal function decreases with age. ATB that
undergo extensive metabolism or are excreted via
the biliary route may be favored. 3. Hepatic
dysfunction ATB that are concentrated or
eliminated by the liver (e.g., erythromycin and
tetracycline) - contraindicated patients with
liver disease.
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4. Poor perfusion Decreased circulation (e.g.,
in the lower limbs of a diabetic) - reduced
amount of ATB - difficult to treat. 5. Age
Renal or hepatic elimination processes are often
poorly developed in newborns - neonates
particularly vulnerable to the toxic effects of
chloramphenicol and sulfonamides. Young children
do not use TTC. 6. Pregnancy All ATB cross
the placenta. Adverse effects to the fetus are
rare, except for tooth dysplasia and inhibition
of bone growth encountered with the
tetracyclines. But - some anthelmintics are
embryotoxic and teratogenic. Aminoglycosides -
ototoxic effect on the fetus. 7. Lactation
Drugs may enter the nursing infant via the breast
milk. The total dose to the infant may be enough
to cause problems.
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• F. Safety of the agent
• Toxicity of the drug
• Many ATB (e.g. penicillins), are among to least
  toxic of all drugs because they interfere with a
  site unique to the growth of microorganisms.
• Other ATB (e.g. chloramphenicol) - less specific
  potential for serious toxicity.
• - Patient factors.
• G. Cost of therapy

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ROUTE OF ADMINISTRATION Oral route mild
infections, outpatient basis. If i.v. therapy
initially - the switch to oral agents occurs as
soon as possible. Some ATB (e.g., vancomycin,
the aminoglycosides, amphotericin) - poorly
absorbed from GIT - adequate serum levels cannot
be obtained by oral administration. Parenteral
administration - drugs that are poorly absorbed
from GIT, treatment of serious infections.
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• RATIONAL DOSING
• Rational dosing of ATB - based on their
  pharmacodynamics (relationship of drug
  concentrations to antimicrobial effects) and
  their pharmacokinetics
• Important pharmacodynamic properties with
  significant influence on the frequency of dosing
• concentration-dependent killing
• post-antibiotic effect.

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Concentration-dependent killing Some ATB
(aminoglycosides, fiuoroquinolones) - significant
increase in the rate of bacterial killing as the
concentration of antibiotic increases from 4- to
64-fold the MIC of the drug for the infecting
organism. Giving such drugs by a once-a-day
bolus infusion achieves high peak levels,
favoring rapid killing of the infecting pathogen.
Other ATB (b-Iactams, glycopeptides,
macrolides, clindamycin) do not exhibit this
property i.e., increasing the concentration of
ATB to higher multiples of the MIC does not
significantly increase the rate of kill. The
clinical efficacy of ATB that have a
nonsignificant, dose-dependent killing effect is
best predicted by the percentage of time that
blood concentrations of a drug remain above the
MIC. Called - concentration-independent or
time-dependent killing. E.g., for PNC and
cephalosporins, dosing schedules that ensure
blood levels greater than MIC for 60 70 of
the time was showed to be clinically effective.
Thus, severe infections are best treated by
continuous infusion of these agents rather than
by intermittent dosing.
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Post-antibiotic effect (PAE) A persistent
suppression of microbial growth that occurs after
levels of antibiotic have fallen below the MIC.
Antimicrobial drugs with a long PAE (several
hours) often require only one dose per day. E.g.,
aminoglycosides and fluoroquinolones,
particularly against gram-negative bacteria.
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CHEMOTHERAPEUTIC SPECTRA - Narrow spectrum (act
only on a single or a limited group of
microorganisms, e.g. INH is active only against
mycobacteria). - Extended spectrum (effective
against G organisms and also against a
significant number of G- bacteria - e.g.,
ampicillin has extended spectrum because it acts
against G and G- bacteria). - Broad spectrum
(e.g. tetracycline and chloramphenicol affect a
wide variety of microbial species). Their
administration can drastically alter the normal
bacterial flora and precipitate a superinfection
of an organism, e.g., candida. COMBINATIONS OF
ANTIMICROBIAL DRUGS It is better to treat
patients with the single agent that is most
specific for the infecting organism. It - reduces
the possibility of superinfection, - decreases
the emergence of resistant organisms, - minimizes
toxicity. However, situations in which
combinations of drugs are employed do exist
(e.g., the treatment of tuberculosis).
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DRUG RESISTANCE Bacteria are said to be
resistant to an antibiotic if their growth is not
halted by the maximal level of that antibiotic
that can be tolerated by the host. Some organisms
are inherently resistant to an antibiotic (e.g.,
gram-negative organisms are inherently resistant
to vancomycin). However, microbial species that
are normally responsive to a particular drug may
develop more virulent, resistant strains through
spontaneous mutation or acquired resistance and
selection. Some of these strains may even become
resistant to more than one antibiotic. A.
Genetic alterations leading to drug resistance
Resistance develops due to the ability of DNA to
undergo spontaneous mutation or to move from one
organism to another. - Spontaneous mutations of
DNA Chromosomal alteration by insertion,
deletion, or substitution of one or more
nucleotides within the genome. - DNA transfer of
drug resistance - of particular concern is
resistance acquired due to DNA transfer from one
bacterium to another.
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• B. Altered expression of proteins in
  drug-resistant organisms
• Modification of target sites E.g., S. Pneumoniae
  resistance to b-lactam ATB involves alterations
  in one or more of the major bacterial
  penicillin-binding proteins - decreased binding
  of ATB.
• - Decreased accumulation Decreased uptake or
  increased efflux of an antibiotic - drug is
  unable to access to the site of its action in
  sufficient concentrations to injure or kill the
  organism.
• - Enzymic inactivation The ability to destroy or
  inactivate ATB.
• Examples of ATB-inactivating enzymes 1)
  beta-lactamases ("penicillinases") hydrolytically
  inactivate the b-Iactam ring of penicillins,
  cephalosporins, and related drugs 2)
  acetyltransferases - transfer an acetyl group to
  ATB (inactivation of chloramphenicol,
  aminoglycosides and 3) esterases that hydrolyze
  the lactone ring of macrolides.
• Multiple drug resistance - significant problem
  (e.g., methicillin-resistant Staphylococcus
  aureus is also resistant to all ATBs except
  vancomycin and possibly ciprofloxacin, rifampin
  and imipenem/cilastatin).

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PROPHYLACTIC ANTIBIOTICS The use of ATB for the
prevention rather than the treatment of
infections. But, the indiscriminate use of ATBs
can result in bacterial resistance
and superinfection, prophylactic use is
restricted to clinical situations where benefits
outweigh the potential risks. Examples. -
Prevention of streptoccocal infections in
patients with history of rheumatic heart disease.
Patients may require years of treatment. -
Pretreatment of patients undergoing dental
extractions who have implated prosthetic devices
(e.g., artificial heart valves) to prevent
seeding of the prosthesis. - Prevention of
tuberculosis or meningitis in those who are in
close contact with infected patients. COMPLICATIO
NS OF ANTIBIOTIC THERAPY - Hypersensitivity -
Direct toxicity - Superinfections
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Classification of some antibacterial agents by
their sites of action. THFA tetrahydrofolic
acid PABA p-aminobenzoic acid
CELL WALL
CELL MEMBRANE
DNA
Inhibitors of cell membrane function
THFA
Ribosomes
Isoniazid Amphotericin B
mRNA
PABA
Inhibitors of nucleic acid function or synthesis
Inhibitors of protein synthesis
Inhibitors of cell wall synthesis
Inhibitors of metabolism
Tetracyclines Aminoglycosides Macrolides Clindamyc
in Chloramphenicol
Fluoroquinolones Rifampin
b-Lactams Vancomycin
Sulfonamides Trimethoprim
(according to Lippincotts Pharmacology, 2006)
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Summary of antimicrobial agents affecting cell
wall synthesis
INHIBITORS OF CELL WALL SYNTHESIS
b-LASTAMASE INHIBITORS
OTHER ANTIBIOTIC
Clavulanic acid Sulbactam Tazobactam
b-LASTAMASE ANTIBIOTIC
Bacitracin Vancomycin
CARBAPENEMS
MONOBACTAMS
PENICILLINS
CEPHALOSPORINS
Imipenem/cilastatin Meropenem Ertapenem
Amoxicillin Ampicillin Cloxacillin Dicloxacillin I
ndanyl carbenicillin Methicillin Nafcillin Oxacill
in Penicillin G Penicillin V Piperacillin Ticarcil
lin
Aztreonam
3rd GENERATION
1st GENERATION
2nd GENERATION
4th GENERATION
Cefepime
Cefadroxil Cefazolin Cephalexin Cephalothin
Cefaclor Cefamandole Cefprozil Cefuroxime Cefoteta
n Cefoxitin
Cefdinir Cefixime Cefoperazone Cefotaxime Ceftazid
ime Ceftibuten Ceftizoxime Ceftriaxone
(according to Lippincotts Pharmacology, 2006)
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INHIBITORS OF CELL WALL SYNTHESIS Selectively
interfere with synthesis of the bacterial cell
wall - a structure that mammalian cells do not
possess. The cell wall is a polymer called
peptidoglycan that consists of glycan units
joined to each other by peptide cross-links. To
be maximally effective, these agents require
actively proliferating microorganisms. Little
or no effect on bacteria that are not growing
!! The most important beta-lactam antibiotics
(named after the beta-Iactam ring that is
essential to their activity) and vancomycin
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PENICILLINS 1928, A. Fleming Belong among the
most widely effective ATBs and also the least
toxic drugs known - increased resistance limited
their use. The nature of their side chain
affects the spectrum, stability to stomach acid,
and susceptibility to bacterial degradative
enzymes (b-Iactamases). A. Mechanism of action
Bactericidal - they interfere with the last step
of bacterial cell wall synthesis
(transpeptidation or cross-linkage) - osmotically
less stable membrane. Cell lysis can then occur,
either through osmotic pressure or through the
activation of autolysins. Effective only against
rapidly growing organisms that synthesize a
peptidoglycan cell wall. Inactive against
organisms devoid of this structure (e.g.,
mycobacteria).
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1. Penicillin-binding proteins PNCs inactivate
proteins on the bacterial cell membrane. These
penicillin-binding proteins (PBPs) are enzymes
involved in the synthesis of the cell wall.
Exposure to PNC - not only prevent cell wall
synthesis, but also lead to morphologic changes
or lysis of susceptible bacteria.

Alterations in some of these target
molecules - resistance to PNCs.
Methicillin-resistant Staphylococcus aureus
(MRSA) apparently arose because of such an
alteration. 2. Inhibition of transpeptidase
Some PBPs catalyze formation of the
cross-linkages between peptidoglycan chains. PNCs
inhibit this transpeptidase-catalyzed reaction.
3. Production of autolysins G cocci produce
degradative enzymes (autolysins - that
participate in the remodeling of the bacterial
cell wall). In the presence of PNC - the
degradative action of the autolysins proceeds in
the absence of cell wall synthesis.
Antibacterial effect of a PNC - the result of
both inhibition of cell wall synthesis and
destruction of cell wall by autolysins.
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Antibacterial spectrum The antibacterial spectrum
is determined, in part, by their ability to cross
the bacterial peptidoglycan cell wall and to
reach the penicillin-binding proteins. In
general, gram-positive microorganisms have cell
wall that are easily traversed by PNC and
therefore (in the absence of resistance) are
susceptible to these drugs. Gram-negative
microorganisms have an outer lipid membrane
surrounding the cell wall - a barrier to the
water-soluble PNCs. This presents a barrier to
the water-soluble PNCs that cannot reach the
site of action. However, gram-negative bacteria
have proteins inserted in the lipopolysaccharide
layer that act as water-filled channels (porins)
that permit transmembrane entry. Pseudomonas
aeruginosa lacks porins, making these
organisms intrinsically resistant to many
antimicrobial agents. Note For this reason,
PNCs have little use in the treatment
of intracellular pathogens.
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1. NATURAL PENICILLINS a. PENICILLIN
G (benzylpenicillin) - infections caused by a
number of gram-positive and gram-negative
cocci,gram-positive bacilli, and spirochetes.
Susceptible to inactivation by beta-lactamases. b.
PENICILLIN V - a spectrum similar to penicillin
G, but it is not used for treatment of
septicemia because of its higher minimum
bactericidal concentration (MLC). Penicillin V
is more acid-stable than penicillin G.
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2. ANTISTAPHYLOCOCCAL
PENICILLINS METHICILLIN NAFCILLIN OXACILLIN CLOX
ACILLIN DICLOXACILLIN penicillinase-resistant
PNCs Use treatment of infections caused by
penicillinase-producing staphylococci.
Methicillin-resistant strains are usually
susceptible to vancomycin, and possibly to
ciprofloxacin, rifampin.
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3. EXTENDED SPECTRUM PENICILLINS
AMPICILLIN and AMOXICILLIN Destroyed by
?-lactamases !!! Antibacterial spectrum similar
to penicillin G, but are more effective against
gram-negative bacilli - extended-spectrum PNCs.
Ampicillin - drug of choice for the
gram-positive bacillus Listeria monocytogenes.
Widely used in the treatment of respiratory
infections amoxicillin is employed
prophylactically by dentists for patients with
abnormal heart valves who are to undergo
extensive oral surgery. Resistance - a problem
because of their inactivation by plasmid-mediated
penicillinase (E. coli and H. influenzae -
frequently resistant). Formulation with a
beta-lactamase inhibitor (e.g. clavulanic acid,
sulbactam) can protect the PNC from enzymatic
action.
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4. ANTIPSEUDOMONAL PENICILLINS
CARBENICILLIN TICARCILLIN PIPERACILLIN S.
aureus are resistant. Piperacillin is the most
potent. Effective against many G- bacilli,
ineffective against Klebsiella (it constitutes
penicillinase). Formulation of ticarcillin or
piperacillin with clavulanic acid or tazobactam
extends the antimicrobial spectrum (i.e. it
includes penicillinase-producing organism).
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5. ACYLUREIDO PENICILLINS MEZLOCILLIN also
effective against E. aeruginosa as well as a
large number of gram-negative organisms. It is
susceptible to breakdown by beta-lactamase. AZLOCI
LLIN 6. REVERSED SPECTRUM PNCs MECILLINAM More
potent against Gram-negative enteric bacteria,
hydrolyzed by beta-lactamases. Pivmecillinam is
a pro-drug, hydrolyzed to mecillinam.
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Penicillins and aminoglycosides The
antibacterial effects of all the b-Iactam
antibiotics are synergistic with the
aminoglycosides. Because cell wall synthesis
inhibitors alter the permeability of bacterial
cells, these drugs can facilitate the entry of
other ATBs (aminoglycosides). This can result in
enhanced antimicrobial activity. These drug
types should never be placed in the same infusion
fluid, because on prolonged contact, the
positively charged aminoglycosides form an
inactive complex with the negatively charged
PNCs.
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• C. Resistance
• Natural resistance - organisms that lack the
  peptidoglycan cell wall
• (e.g. mycoplasma) or have cell wall that is
  impermeable to the drug.
• Acquired resistance to PNCs by plasmid transfer
  - clinical problem.
• Beta-lactamase activity Enzymes hydrolyze the
  cyclic amide bond
• of the beta-lactam ring - loss of bactericidal
  activity. Enzymes are
• constitutive or (more commonly) acquired by the
  transfer of plasmids.
• Some of the beta-lactam ATBs are poor substrates
  for beta-lactamases
• and resist cleavage - they have activity against
  beta-lactamase
• producing organisms.
• - Decreased permeability of PNCs through the
  outer cell membrane
• prevents reaching the target penicillin-binding
  protein. The presence of an efflux pump can also
  reduce the amount of intracellular drug.
• - Altered penicillin binding proteins Modified
  PBPs show a lower
• affinity for beta-lactam antibiotics, requiring
  greater concentrations
• of the drug to effect binding and inhibition of
  bacterial growth.

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• Pharmacokinetics
• Administration The route of administration of a
  b-Iactam antibiotic is determined by the
  stability of the drug to gastric acid and by the
  severity of the infection.
• E.g. Penicillin V, amoxicillin,
  amoxicillinclavulanic acid are only available as
  oral preparations.
• Others are effective by the oral, IV, or IM
  routes. Some PNCs only IV or IM.
• b. Depot forms Procaine penicillin G and
  benzathine penicillin G - administered IM serve
  as depot forms. Slowly absorbed into the
  circulation and persist at low levels over a long
  time period.

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2. Absorption Most of PNCs incompletely absorbed
after oral administration and reach the
intestine in sufficient amounts to affect the
composition of the intestinal flora. However,
amoxicillin is almost completely absorbed it
is not appropriate therapy for the treatment of
salmonella-derived enteritis (therapeutically
effective levels do not reach the organisms in
the intestinal crypts). Absorption of PNC G
and all the penicillinase-resistant PNCs is
impeded by food in the stomach they must be
administered 30-60 minutes before meals or 2-3
hours postprandially. Other PNCs are less
affected by food.
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3. Distribution Distribution of the free drug is
good. All PNCs cross the placental barrier but
none have been shown to be teratogenic.
Penetration into certain sites (e.g. bone or
cerebrospinal fluid) is insufficient for therapy,
unless these sites are inflamed. During the
acute phase (first day), the inflamed meninges
are more permeable to PNC increased ratio in
the amount of drug in CNS compared to the amount
in the serum. As the inflammation subsides,
permeability barriers are reestablished. Levels
in the prostate are insufficient to be effective
against infections. 4. Metabolism Host
metabolism of the beta-Iactam antibiotics is
usually insignificant.
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5. Excretion The primary route - tubular
secretion and glomerular filtration of the
kidney. Patients with impaired renal function -
adjust dosage regimens ! T1/2 of penicillin G
can increase from a normal of 0.5-1.0 hour to 10
hours in renal failure. Probenecid inhibits the
secretion of penicillins !! Nafcillin -
eliminated primarily through the biliary route.
Note This is also the preferential route for
the acylureido penicillins in cases of renal
failure. PNCs are also excreted into breast
milk and into saliva.
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E. Adverse reactions PNCs are among the safest
drug, although adverse reactions do occur. -
Hypersensitivity The most important. The major
cause is metabolite, penicilloic acid, which
reacts with proteins and serves as a hapten to
cause an immune reaction. Cca 5 of patients have
some kind of reaction (from urticaria to
angioedema and anaphylaxis). Cross-allergic
reactions can occur among the beta-lactam
antibiotics ! - Diarrhea Caused by a
disruption of the normal balance of intestinal
microorganism, a common problem. Especially in
agents that are incompletely absorbed or with
extended spectrum. Also pseudomembranous colitis
may occur.
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• - Nephritis Acute interstitial nephritis in high
  doses of methicillin.
• Neurotoxicity PNCs are irritating to neuronal
  tissue and can provoke
• seizures if injected intrathecally or if very
  high blood levels
• are reached Epileptic patients are especially at
  risk.
• - Platelet dysfunction decreased
  agglutination (observed with
• the antipseudomonal PNCs and, to some extent wit
  penicillin G).
• Concern when treating patient predisposed to
  hemorrhage or
• receiving anticoagulants.
• Cation toxicity PNCs generally administered as
  the Na or K salt.
• Toxicity may be caused by the large quantities
  of Na or K.
• - Hoigné syndrom (if the suspension of PNC is by
  mistake injected
• i.v. embolisation of pulmonary veins
  tachypnea, anxiety, dyspnea)
• - Nikolaus syndrom (suspension of PNC by mistake
  i.a.
• embolisation in arteries even amputation
  necessary)

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CEPHALOSPORINS b-Iactam antibiotics that are
closely related both structurally and
functionally to the penicillins. Mostly produced
semisynthetically. They have the same mode of
action as penicillins, and they are affected by
the same resistance mechanisms. However, they
tend to be more resistant than the PNCs to
b-Iactamases. A. Antibacterial spectrum
Classified as first, second, third, or fourth
generation, based largely on their bacterial
susceptibility patterns and resistance to
b-Iactamases. They are ineffective against MRSA,
L. monocytogenes, Clostridium difficile, and the
enterococci.
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First generation They act as penicillin G
substitutes they are resistant to the
staphylococcal penicillinase also have activity
against Proteus mirabilis, E. coli, and
Klebsiella Pneumoniae (the acronym PEcK) .
Second generation Greater activity against
three additional G- organisms H. influenzae,
Enterobacter aerogenes, and some Neisseria
species (HENPEcK) Activity against
gram-positive organisms is weaker. They are,
however, effective against Bacteroides fragilis
cefoxitin is the most potent.
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Third generation Inferior to first-generation
in activity against G cocci, but they have
enhanced activity against gram-negative bacilli,
as well as most other enteric organisms plus
Serratia marcescens. Ceftriaxone or cefotaxime -
agents of choice in the treatment of meningitis.
Ceftazidime - against Pseudomonas aeruginosa.
Fourth generation Cefepime - must be
administered parenterally. Wide spectrum, active
against streptococci and staphylococci (but only
those that are methicillin-susceptible). Also
effective against aerobic G- organisms (e.g.,
enterobacter, E. coli, K. pneumoniae, p.
mirabilis, and p. aeruginosa).
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B. Resistance The same as those described for
the penicillins. Note Although they are not
susceptible to hydrolysis by the staphylococcal
penicillinase, cephalosporins may be susceptible
to extended spectrum b-Iactamases. C.
Pharmacokinetics - Administration Some orally,
most of cephalosporins must be administered IV or
IM because of their poor oral absorption.
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- Distribution All distribute very well into
body fluids. However, adequate therapeutic levels
in the CSF, regardless of inflammation, are
achieved only with the third-generation
cephalosporins (ceftriaxone or cefotaxime -
effective in the treatment of neonatal and
childhood meningitis caused by H. influenzae).
Cefazolin - prophylaxis prior to surgery because
of its half-life and activity against
penicillinase-producing S. aureus. Its ability to
penetrate bone is especially useful in orthopedic
surgery. All cephalosporins cross the placenta.
- Fate Biotransformation is not clinically
important. Elimination through tubular secretion
and/or glomerular filtration. Doses must be
adjusted in severe renal failure !!!
Cefoperazone sef oh PER a zone and ceftriaxone
- excreted in bile into the feces - frequently
employed in patients with renal insufficiency.
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D. Adverse effects The cephalosporins produce a
number of adverse affects. - Allergy Patients
who have had an anaphylactic response to PNCs
should not receive cephalosporins. The
cephalosporins should be avoided or used with
caution in individuals who are allergic to PNCs
(cca 15 show cross-sensitivity). In contrast,
the incidence of allergic reactions to
cephalosporins is 1-2 in patients without a
history of allergy to PNCs. - Disulfiram-like
effect When cefamandole, cefotetan, or
cefoperazone if ingested with alcohol or
alcohol-containing medications. They block the
second step in alcohol oxidation - accumulation
of acetaldehyde. - Bleeding Associated with
agents that contain the MTT group - because of
anti-vitamin K effects. Administration of the
vitamin corrects the problem. - Nephrotoxicity,
diarrhea.
42
OTHER BETA-LACTAM ANTIBIOTICS A. CARBAPENEMS -
IMIPENEM, MEROPENEM Synthetic beta-lactam ATB.
Imipenem is compounded with cilastatin to protect
it from metabolism by renal dehydropeptidase. 1.
Spectrum Imipenem/cilastatin is the broadest
spectrum beta-lactam antibiotic currently
available. It is active against
pencillinase-producing gram-positive and
gram-negative organisms, anaerobes, and
pseudomonas aeruginosa, although other
pseudomonas strains are resistant. However,
resistant strains of P. aeruginosa have been
reported. Imipenem resists hydrolysis by most
beta-lactamases, but not the metallo-beta-lactamas
es. The drug plays a role in empiric therapy.
Meropenem has antibacterial activity similar to
that of imipenem.
43
2. Pharmacology Administered i.v., penetrates
well into CNS. Excreted by glomerular filtration
and undergoes cleavage by a dehydropeptidase
found in the brush border of the proximal renal
tubule to form an inactive metabolite that is
potentially nephrotoxic. Compounding the imipenem
with cilastatin, (dehydropeptidase inhibitor)
protects the parent drug from cleavage and thus
prevents the formation of a toxic metabolite.
This allows the drug to be active in the
treatment of urinary tract infections. Note The
dose must me adjusted in patients with renal
insufficiency. MEROPENEM it is not cleaved in
the kidney !! 3. Adverse effects nausea,
vomiting, and diarrhea. Eosinophilia and
neutropenia are less common. High levels of
these agents may provoke seizures.
44
MONOBACTAMS - AZTREONAM Aztreonam is unique
because the beta-lactam rings is not fused to
another ring. Monobactams also disrupt cell wall
synthesis. The drug's narrow antimicrobial
spectrum precludes its use alone in empiric
therapy. Aztreonam is resistant to the action of
beta-lactamases. Spectrum primarily directed
against the enterobactericeae. Aztreonam is
unique among the beta-lactam group because of
its effectiveness against Pseudomonas aeruginosa
and other aerobic gram-negative bacteria, and
because of its lack of activity against
gram-positive organisms or anaerobes. Pharmacology
IV or IM, excreted in the urine can
accumulate in patients with renal
failure. Adverse effects relatively nontoxic,
but it may cause phlebitis, skin rash, and
occasionally, abnormal liver function tests. Low
immunogenic potential, little cross-reactivity
with antibodies induced by other beta-lactam
an alternative for patients allergic to
penicillin.
45
BETA-LACTAMASE INHIBITORS Hydrolysis of the
beta-lactam ring (either by enzymatic cleavage a
beta-lactamase or by acid) destroys
antimicrobial activity. Beta-lactamase
inhibitors, e.g. CLAVULANIC ACID and SULBACTAM,
TAZOBACTAM contain a beta lactam ring, but they
do not have significant antibacterial activity.
They bind to and inactive beta-lactamases
protection of the antibiotics that are normally
substrates for these enzymes. The beta-lactamase
inhibitors are formulated with the penicillin
derivatives to protect the latter from enzymatic
inactivation AUGMENTIN (amoxycillin and
clavulanic acid) TIMENTIN (ticarcillin and
clavulanic acid) Piperacillin
tazobactam Ampicillin sulbactam Not all
beta-Iactamases are inhibited. E.g., tazobactam
(compounded with piperacillin) does not affect p.
aeruginosa beta-Iactamase. Therefore, this
organism remains refractory to piperacillin.
46
OTHER AGENTS AFFECTING THE CELL WALL
VANCOMYCIN TEICOPLANIN (similar, longer
acting) The emergence of staphylococci resistant
to most antibiotics except vancomycin led to the
reintroduction of this agent. 1. Action
Inhibition of the synthesis of the cell wall
phospholipids as well as peptidoglycan polymers.
This prevents the transglycosylation step
in peptidoglycan polymerization and weakening the
cell wall and damaging the underlying cell
membrane. 2. Antibacterial spectrum
Bactericidal. Present use - infections caused by
methicillin-resistant staphylococci,
and pseudomembranous colitis caused by
Clostridium difficile or staphylococci.
47
Effective primarily against gram-positive
organisms . It may be lifesaving in the treatment
of MRSA, methicillin-resistant Staphylococcus
epidermidis infections and enterococcal
infections. Increase in resistant strains - the
increase in vancomycin-resistant bacteria (e.g.,
Enterococcus faecium, Enterococcus faecalis) it
is necessary to restric the use of vancomycin to
the treatment of serious infections caused by
b-Iactam-resistant, gram-positive microorganisms,
or for patients with gram-positive infections who
have a serious allergy to the b-Iactams. Oral
vancomycin - limited to treatment for potentially
life-threatening antibiotic-associated colitis
due to C. difficile or staphylococci. Used in
individuals with prosthetic heart valves and in
patients undergoing implantation with prosthetic
devices. Vancomycin acts synergistically with
the aminoglycosides - can be used in the
treatment of enterococcal endocarditis.
48
3. Resistance due to plasmid-mediated
changes. 4. Pharmacology Slow i.v. infusion -
treatment of systemic infections or for
prophylaxis. Vancomycin is not absorbed after
oral administration - treatment of
antibiotic-induced colitis due to C. difficile.
Inflammation allows penetration into the
meninges - often necessary to combine with other
ATB e.g., ceftriaxone. Metabolism minimal
(90 - 100 excreted by glomerular filtration)
adjust dosage in renal failure accumulation of
the drug. The normal half-life 6-10 hours over
200 hours in end- stage renal disease. 5. Adverse
effects Serious problem (fever, chills, and/or
phlebitis at the infusion site). Flushing ("red
man syndrome"). Shock as a result of rapid
administration. Rashes. Ototoxicity and
nephrotoxicity - more common when administered
with other drug (e.g., an aminoglycoside) that
can also produce these effects.
49
B. BACITRACIN - a mixture of polypeptides that
inhibits bacterial cell wall synthesis. Active
against a wide variety of gram-positive
organisms. Use is restricted to topical
application because of its nephrotoxicity.
C. POMYMYXIN B and COLISTIN Cationic
detergent properties, bactericidal on G
(pseudomonas, coliform) not absorbed from
GIT Adverse effect neuro- and nephrotoxicity Use
gut sterilisation, topical treatment (eye, ear,
skin)
50
Protein Synthesis lnhibitors A number of ATBs
exert their antimicrobial effects by targeting
the bacterial ribosome, which has components that
differ structurally from those of the mammalian
cytoplasmic ribosome. The mammalian
mitochondrial ribosome, however, more closely
resembles the bacterial ribosome. Thus, although
drugs that interact with the bacterial target
usually spare the host cells, high levels of
drugs such as chloramphenicol or the
tetracyclines may cause toxic effects as a result
of interaction with the mitochondrial ribosomes.
51
PROTEIN SYNTHESIS INHIBITORS
TETRACYCLINES
Demeclocycline Doxycycline Minocycline Tetracyclin
e
AMINOGLYCOSIDES
Amikacin Gentamicin Neomycin Netilmicin Streptomyc
in Tobramycin
MACROLIDES/KETOLIDES
Azithromycin Clarithromycin Erythromycin Telithrom
ycin
CHLORAMPHENICOL
CLINDAMYCIN
QUINUPRISTIN/DALFOPRISTIN
(according to Lippincotts Pharmacology, 2006)
LINEZOLID
52
TETRACYCLINES Closely related compounds that
consist of 4 fused rings with a system of
conjugated double bonds. CHLORTETRACYCLINE,
OXYTETRACYCLINE, TETRACYCLINE, DEMECLOCYCLINE,
METHACYCLINE, DOXYCYCLINE, MINOCYCLINE A.
Mechanism of action Entry into susceptible
organisms - both by passive diffusion and by an
energy-dependent transport protein mechanism.
Nonresistant strains concentrate the
tetracyclines intracellularly. They bind
reversibly to the 30S subunit of the bacterial
ribosome, thereby blocking access of the amino
acyl-tRNA to the mRNA-ribosome complex at the
acceptor site. Thus, bacterial protein synthesis
is inhibited.
53
B. Antibacterial spectrum Broad spectrum
antibiotics also effective against organisms
other than bacteria. The drugs of choice for
rickettsial, mycoplasma and chlamydial
infections. C. Resistance Widespread resistance
limits their clinical uses. Inability of the
organism to accumulate the drug. Any organism
resistant to one tetracycline is resistant to
all. The majority of penicillinase-producing
staphylococci are now also insensitive to
tetracyclines
54
D. Pharmacology 1. Absorption adequately but
incompletely absorbed after p.o. Dairy foods in
the diet decrease absorption because of
the formation of nonabsorbable chelates of the
tetracyclines with calcium ions. Nonabsorbable
chelates are also formed with other divalent and
trivalent cations (e.g. those found in magnesium
and aluminium antacids, and in iron
preparations). Doxycycline and minocycline
completely absorbed. Note This presents a
problem if the patient self-treats the epigastric
upsets caused by tetracycline ingestion with
antacids.
55
2. Distribution concentration in the liver,
kidney, spleen, and skin and bind to tissues
undergoing calcification (e.g.,teeth, bones), or
to tumors that have a high calcium content e.g.
gastric carcinoma). Penetration into body fluids
is adequate. Though all enter the CSF, levels are
insufficient for therapeutic efficacy, except for
MINOCYCLINE. It not only enters the brain in the
absence of inflammation but it also appears in
tears and saliva therefore effective in
eradicating the meningococcal carrier state. All
TTCs cross the placental barrier and concentrate
in fetal bones and dentition.
56
3. Fate All concentrate in the liver, partially
metabolized and conjugated to form soluble
glucuronides. Drug and/or its metabolites are
secreted into the bile, most TTCs are reabsorbed
in the intestine and enter the urine by
glomerular filtration. Doxycycline can be
employed for treating infections in renally
compromised patients, because it is
preferentially excreted via the bile into the
feces!!! Obstruction of the bile duct and
hepatic or renal dysfunction can increase their
half-lives. TTCs are also excreted in breast
milk.
57
E. Adverse effect - Gastric discomfort
Epigastric distress commonly results from
irritation of the gastric mucosa. This can be
controlled if the drug is taken with foods oher
than dairy products. - Effects on calcified
tissues Deposition in the bone and primary
dentition occurs during calcification in growing
children discoloration and hypoplasia of the
teeth and a temporary stunting of growth. Use in
pregnancy and in children younger than 8 years
(or before the second dentition) should be
avoided !!! - Hepatotoxicity.
58

• - Phototoxicity Most frequently with
  doxycycline and demeclocycline
• - Vestibular problems (e.g., dizziness, nausea,
  vomiting) occur with
• minocycline, which concentrates in the
  endolymph of the ear and
• affects function
• - Superinfections These infections may occur
  with candida
• (e.g. in the vagina) or with resistant
  staphylococci in the intestine.
  Pseudomembranous colitis due to an overgrowth of
  Clostridium difficile was also reported.
• - dysmicrobia, hypovitaminosis B and K
• - anorectal and anogenital syndrome (itching in
  anal and genital area)
• - antianabolic effect - hypodynamia
• decreased activity of pancreatic lipase and
  amylase
• - very good penetration into ischemic tissues
  (abscesses...)

59
F. Contraindications Renally-impaired patients
should not be treated with any of the
tetracyclines except doxycycline. Children
(under eight years of age), pregnant women,
nursing mothers.
60
AMINOGLYCOSIDES Mainstays of treatment of
serious infections due to gram-negative
bacilli. Use is limited by the occurrence of
serious toxicities - efforts to replace them with
safer ATBs (3rd generation cephalosporins,
fluoroquinolones, imipenem/cilastatin). A. Mode
of action Inhibit bacterial protein synthesis
susceptible organisms have an oxygen-dependent
system that transports the ATB across the cell
membrane. They then bind to the isolated 30S
ribosomal subunit. They synergize with
beta-Iactam ATBs (enhance diffusion of
aminoglycosides into the cell). Their
polycationic nature precludes their easy passage
across tissue membranes.
61
B. Antibacterial spectrum Effective in the
empirical treatment of infections suspected of
being due to aerobic gram-negative bacilli,
including Pseudomonas aeruginosa. To achieve an
additive or synergistic effect, aminoglycosides
are often combined with a b-Iactam antibiotic, or
vancomycin, or a drug active against anaerobic
bacteria. All aminoglycosides are bactericidal.
The exact mechanism of their lethality is
unknown, because other antibiotics that affect
protein synthesis are generally bacteriostatic.
Note They are only effective against aerobic
organisms, because strict anaerobes lack the
oxygen-requiring transport system.
62
Bactericidal, effective only against aerobic
organisms (anaerobes lack the oxygen-requiring
transport system). Streptomycin - used to treat
tuberculosis (kanamycin also effective), plague,
tularemia. Commonly used aminoglycosides
AMIKACIN, GENTAMICIN, TOBRAMYCIN and
STREPTOMYCIN Further aminoglycosides NEOMYCIN,
NETILMICIN, KANAMYCIN
63
C. Resistance Rapid onset mostly, three
following mechanisms - Decreased uptake The
oxygen-dependent transport system for
aminoglycosides or porins is absent. - Altered
receptor The 30S ribosomal subunit binding site
has a lowered affinity for aminoglycosides. -
Enzymatic modification important,
plasmid-associated (synthesis of
e.g.,acetyltransferases, nucleotidyltransferases,
and phosphotransferases - nine or more of
these enzymes !) modify and inactivate
antibiotics. Each type of enzyme has its own
specificity, therefore, cross-resistance is
not an invariable rule. Netilmicin and amikacin
are less vulnerable to these enzymes than other
antibiotics of this group !!
64
D. Pharmacology 1. Administration The highly
polar polycations structure of aminoglycosides
prevents adequate absorption after
oral administration all aminoglycosides
EXCEPT NEOMYCIN must be given parenterally to
achieve adequate serum levels. The severe
adverse effects (e.g.nephrotoxicity) of neomycin
precludes parenteral administration !! Its use
is limited to topical application or oral
treatment in hepatic coma to reduce the
intestinal bacterial population !!!
65
The bactericidal effect is concentration and time
dependent - the greater the concentration of
drug, the greater the rate at which the organisms
die. They also have a postantibiotic effect.
Because of these properties, once-daily dosing
with the aminoglycosides can be used - fewer
toxicities. The exceptions are pregnancy,
neonatal infections, and bacterial endocarditis,
in which they are administered every eight hours.
Note The dose that is administered is
calculated based on lean body mass, because these
drugs do not distribute into fat.
66
2. Distribution All have similar pharmacokinetic
properties. They penetrate most body fluids well
except for the cerebrospinal fluid (penetration
is poor even when the meninges are inflamed!).
Except for neomycin, they may be administered
intrathecally. High concentrations accumulate in
the renal cortex and in the endolymph and
perilymph of the inner ear their nephrotoxic
and ototoxic potential. All cross the placental
barrier and may accumulate in fetal plasma and
amniotic fluid. 3. Metabolism Metabolism does
not occur in the host. All aminoglycosides are
rapidly excreted into the urine, predominantly
by glomerular filtration. Accumulation occurs in
patients with renal failure, and requires dose
modification.
67
E. Adverse effects It is important to monitor
plasma levels of gentamicin, tobramycin,
netilmicin, and amikacin to avoid concentrations
that cause dose-related toxicities !! Patient
factors (e.g. old age, previous exposure to
aminoglycosides, gender, liver disease) tend to
predispose to adverse reactions. The elderly are
particularly susceptible to nephrotoxicity and
ototoxicity !!
68
1. Ototoxicity Vestibular and cochlear -
directly related to high peak plasma levels and
the duration of treatment. ATBs accumulates in
the endolymph and perilymph of the inner ear, and
toxicity correlates with the number of destroyed
hair cells in the organ of Corti. Deafness may
be irreversible, it is known to affect fetuses in
utero. Patients simultaneously receiving other
ototoxic drug (e.g., diuretics furosemide,
bumetanide, ethacrynic acid or cisplatin) -
particularly at risk. Vertigo and loss of
balance (especially in patients receiving
streptomycin) may also occur, because these drugs
affect the vestibular apparatus. 2.
Nephrotoxicity Retention of the aminoglycosides
by the proximal tubular cells disrupts
calcium-mediated transport processes - this
results in kidney damage (from mild, reversible
impairment to severe, acute tubular necrosis,
which can be irreversible).
69
3. Neuromuscular paralysis Mostly after direct
intraperitoneal or intrapleural application of
large doses of aminoglycosides. The mechanism
responsible is a decrease in both the release of
acetylcholine from prejunctional nerve endings
and the sensitivity of the postsynaptic site.
Patients with myasthenia gravis are particularly
at risk. Prompt administration of calcium or
neostigmine can reverse the block. 4. Allergic
reactions Contact dermatitis - a common reaction
to topically applied neomycin.
70
SPECTINOMYCIN an aminocyclitol, structurally
related to aminoglycosides, interacts with the
30S ribosomal subunit to inhibit protein
synthesis. Administered as a single i.m.
injection only for treatment of acute gonorrhea
caused by penicillinase-producing Neisseria
gonorrhea and/or uncomplicated gonorrhea of the
genitalia or rectum, in patients who are
allergic to PNC. Spectinomycin-resistant
gonococci have been reported (resistance appears
to be a chromosomal mutation but no
cross-resistance to other effective agents
occurs). Hypersensitivity reactions can develop.
71
MACROLIDE ANTIBIOTIC ERYTHROMYCIN,
AZITHROMYCIN, CLARITHROMYCIN (methylated form of
erythrom.) TELITHROMYCIN - derivative of
erythromycin (a ketolide) SPIRAMICIN,
ROXITHROMYCIN, YOSAMICIN ATBs with a macrocyclic
lactone structure to which one or more deoxy
sugars are attached. ERYTHROMYCIN - few
indications where it is a drug of first choice,
mostly as an alternative to penicillin in
allergy to beta-lactam ATBs.
72
A. Mechanism of action Bacterial protein
synthesis ceases after their binding irreversibly
to a 50S subunit of the bacterial ribosome
inhibition of the translocation step of protein
synthesis. Generally bacteriostatic (may be
cidal - depending on the concentration and on
the type of microorganisms).
73
B. Antibacterial spectrum - Erythromycin
against many of the same organisms as PNC G
(i.e. especially G bacteria and spirochaetes,
also N.gonorrhoae, Chlamydia, Mycoplasma and
Legionella) used in patients allergic to the
PNCs. Antistaphylococcal antibiotic. -
Clarithromycin similar to erythromycin, but it
is also effective against Haemophilus influenzae.
Activity against intracellular pathogens (e.g.,
Chlamydia, Legionella, Moraxella, Urea plasma
species) and Helicobacter pylori, is higher than
that of erythromycin. - Azithromycin Less
active against streptococci and staphylococci
than erythromycin more active against
respiratory infections due to H. influenzae and
Moraxella catarrhalis. The preferred therapy for
urethritis caused by Chlamydia trachomatis. -
Telithromycin spectrum similar to azithromycin.
74
C. Resistance Resistance to erythromycin - a
serious clinical problem. Most strains of
staphylococci in hospital isolates are resistant
to this drug. Several mechanisms 1) the
inability of the organism to take up ATB or the
presence of an efflux pump (it limits the amount
of intracellular drug) 2) a decreased affinity
of the 50S ribosomal subunit for ATB 3) the
presence of a plasmid-associated erythromycin
esterase. Clarithromycin and azithromycin show
cross-resistance with erythromycin, but
telithromycin can be effective against
macrolide-resistant organisms.
75
D. Pharmacology 1. Administration Absorbed
orally. Food interferes with absorption of
Erythro- and Azithromycin but can increase that
of clarithromycin. Azithromycin - available for
IV infusion, but IV erythromycin - high
incidence of thrombophlebitis, intramuscular
injections are painful. 2. Distribution
Distributed well in all body fluids except the
CSF. Erythro - one of the few ATBs that diffuses
into prostatic fluids and has the unique
characteristic of accumulating in macrophages.
All drugs concentrate in the liver.
Inflammation allows for greater tissue
penetration. Also clarithromycin, azithromycin,
and telithromycin are widely distributed in the
tissues. Serum levels of azithromycin are low
the drug is concentrated in neutrophils,
macrophages, and fibroblasts. It has the longest
half-life and largest Vd.
76
3. Metabolism Erythromycin, telithromycin and
other are extensively metabolized. They inhibit
the oxidation of a number of a drugs through its
interaction with the CYP-450 system. Interference
with the metabolism of drugs such as theophylline
and carbamazepine has been reported for
clarithromycin. Clarithromycin is oxidized to the
14-hydroxy derivative, which retains antibiotic
activity. 4. Excretion Erythromycin and
azithromycin concentrated and excreted in an
active form in the bile. Partial reabsorption
occurs via enterohepatic circulation. Inactive
metabolites are excreted into the urine. In
contrast, clarithromycin and its metabolites are
eliminated by the kidney as well as the liver
(adjust dosage in compromised renal function!).
77
E. Adverse effects - Epigastric distress -
common - it can lead to poor compliance for
erythromycin. Clarithromycin and azithromycin -
better tolerated by the patient, but GIT problems
are also most common side effects. - Cholestatic
jaundice - especially with the estolate form of
erythromycin, presumably as the result of a
hypersensitivity reaction to the estolate form
(the lauryl salt of the propionyl ester of
erythromycin). - Ototoxicity Transient deafness
- erythromycin, especially at high dosages. F.
Contraindications Patients with hepatic
dysfunction - treat with caution - if at all -
with erythromycin, telithromycin, or azithromycin
- they accumulate in the liver. Patients renally
compromised telithromycin with caution.
Telithromycin may worsen myasthenia gravis.
78
G. Interactions Erythromycin, telithromycin,
and clarithromycin inhibit the hepatic metabolism
of a number of drugs, which can lead to toxic
accumulations of these compounds. E.g.,
Erythromycin and Clarithromycin inhibit the
hepatic metabolism of theophylline, warfarin,
astemizole, terfenadine, carbamazepine,
cyclosporine and statins toxic accumulations
of these drugs !!! Interaction with digoxin may
occur in some patients - ATB eliminates a species
of intestinal flora that ordinarily inactivates
digoxin.
79
QUINUPRISTIN/DALFOPRISTIN A mixture of two
streptogramins (30 70). Reserved for the
treatment of vancomycin-resistant Enterococcus
faecium (VRE). A. Mechanism of action Each
component binds to a separate site on the 50S
bacterial ribosome, forming a stable complex.
They synergistically interrupt protein synthesis.
The combination is bactericidal and has a long
postantibiotic effect.
80

• B. Resistance
• Enzymatic processes (e.g., a ribosomal enzyme
  that methylates the target bacterial ribosomal
  RNA site can interfere in quinupristin binding).
  
  Enzymatic modification can sometimes change
  the action from bactericidal to bacteriostatic.
• Plasmid-associated acetyl transferase
  inactivates dalfopristin.
• Active efflux pump.
• C. Antibacterial spectrum
• The combination drug is active primarily against
  G cocci, incl. those resistant to other ATBs
  (e.g., MRS). Primary use - treatment of
  Enterococcus faecium infections, (incl. VRE
  /vancomycin/ strains).
• Note In the latter case, the effect is
  bacteriostatic
• The drug is not effective against Enterococcus
  faecalis.

81
D. Pharmacology I.v. in 5 dextrose solution
(incompatibilzy with saline). They penetrate
macrophages and polymorphonucleocytes important
(because VRE are intracellular). Levels in the
CSF are low. Both compounds undergo metabolism.
The products are less active than the parent in
the case of quinupristin and are equally active
in the case of dalfopristin. Most of drugs and
metabolites - cleared through the liver and
eliminated via the bile into the feces. Urinary
excretion is secondary.
82
E. Adverse effects - Venous irritation common
when administered through a peripheral line. -
Arthralgia, myalgia when higher levels of the
drugs are employed. - Hyperbilirubinemia Total
bilirubin is elevated in about 25 of patients,
resulting from a competition with the antibiotic
for excretion. F. Interactions Ability of
quinupristin/dalfopristin to inhibit CYP3A4
isozyme - concomitant administration with drugs
metabolized by this pathway may lead to
toxicities. Interaction with digoxin - the same
mechanism as in erythromycin.
83
LlNEZOLID New ATB against resistant G
organisms (e.g., methicillin- and
vancomycin-resistant S. aureus,
vancomycin-resistant Enterococcus faecium and
Enterococcus faecalis, and PNC-resistant
streptococci). It is a synthetic oxazolidinone.
A. Mechanism of action Inhibition of bacterial
protein synthesis by inhibiting the formation of
the 70S initiation complex. It binds to a site on
the 50S subunit near the interface with the 30S
subunit. B. Resistance Decreased binding to the
target site. Cross-resistance with other ATBs
does not occur.
84
C. Antibacterial spectrum Primarily against G
organisms (e.g., staphylococci, streptococci, and
enterococci, as well as Corynebacterium species
and Listeria monocytogenes) - its main clinical
use. Moderately active against Mycobacterium
tuberculosis. Bacteriostatic (cidal against the
streptococci and Clostridium perfringens). D.
Pharmacokinetics Completely absorbed on oral
administration. I.v. is also available. Widely
distributed in the body. Two metabolites
(oxidation products) - one has antimicrobial
activity. CYP450 enzymes are not involved in
their formation. Excretion - both by renal and
nonrenal routes.
85

• E. Adverse effects
• Well-tolerated.
• GIT upset, nausea, and diarrhea
• headache and rash
• thrombocytopenia in cca 2 (when longer than 2
  weeks) - reversible.
• Although no reports on linezolid inhibition of
  MAO activity - patients are cautioned not to
  consume large quantities of tyramine-containing
  foods. (early oxazolidinones showed to inhibit
  MAO activity - reversible increase in the
  pressor effects of pseudoephedrine was shown).

86
CHLORAMPHENICOL active against a wide range of
gram and gram organisms because of its
toxicity - use is restricted to life-threatening
infections. A. Mode action It binds to the
bacterial 50S ribosomal subunit and inhibit
protein synthesis at the peptidyl transferase
reaction. Because of the similarity of mammalian
mitochondrial ribosomes to those of bacteria,
protein synthesis in these organelles may be
inhibited at high circulating chloramphenicol
levels - producing bone marrow toxicity!!
87
B. Antimicrobial spectrum Broad-spectrum
antibiotic, active also against other
microorganisms (e.g. rickettsiae). P. aeruginosa
is not affected, nor are the chlamydiae.
Excellent activity against anaerobes. Mostly
bacteriostatic (or bactericidal - to
H.influenzae), depending on the organism. C.
Resistance - Presence of an R factor (which codes
for an acetyl Co A transferase that inactivates
chloramphenicol). - Inability to penetrate the
organism. Change in permeability may be the basis
of multidrug resistance.
88
D. Pharmacology Administered intravenously or
orally. Completely absorbed after the oral route
(its lipophilic nature). Widely distributed
including t