03_penicillins

					              Beta-lactam antibiotics and other
                   cell wall synthesis inhibitors


                                     Öner Süzer
                            www.onersuzer.com
                          osuzer@istanbul.edu.tr




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                       History

• In 1928 Alexander Fleming observed that a culture
  plate on which Staphylococci were being grown had
  become contaminated with a mold of the genus
  Penicillium, and that bacterial growth in the vicinity
  of the mold had been inhibited.
• He isolated the mold in pure culture and
  demonstrated that it produced an antibacterial
  substance, which he called penicillin.



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            Extraction and synthesis

• This substance was extracted by Florey and Chain in
  1940 from Penicillium notatum and they showed that
  it had powerful chemotherapeutic properties in
  infected mice and that it was non-toxic.
• Its remarkable antibacterial effects in man were
  clearly demonstrated in 1941 in a policeman who had
  Staphylococcal and Streptococcal septicemia with
  multiple abscesses.
• Ten years later virtually unlimited quantities of
  penicillin G were available for clinical use.

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                    Beta lactams

• After the isolation of the nucleus, 6-aminopenicillanic
  acid, numerous semisynthetic penicillins were
  developed that are stable at acid pH, resistant to β-
  lactamase, and active against both Gram-positive
  and Gram-negative bacteria.
• The penicillins are classified as β-lactam drugs
  because of their unique four-member β-lactam ring.
• Structural integrity of the 6-aminopenicillanic acid
  nucleus is essential for the antibacterial activity.


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Site of substitution




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       Clinical limitations of penicillin G

• It is unstable at acidic pH
• It is susceptible to destruction by β-lactamase
  (penisillinase)
• It is relatively inactive against Gram-negative bacilli.




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                Mechanism of action

• Penicillins, like all β-lactam antibiotics inhibit bacterial
  growth by interfering with a specific step in bacterial
  cell wall synthesis.
• Cell wall is composed of a complex cross-linked
  polymer, peptidoglycan.
• The polysaccharide contains alternating amino
  sugars N-acetylglucosamine and N-acetylmuramic
  acid. A five amino-acid peptide is linked to the N-
  acetylmuramic acid sugar. This peptide terminates in
  D-alanyl-D-alanine.

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            Penicillin-binding proteins

• Penicillin-binding proteins catalyze the
  transpeptidase reaction that removes the terminal
  alanine to form a cross link with a nearby peptide,
  which gives cell wall its structural rigidity.
• β-lactam antibiotics are structural analogs of the
  natural D-Ala-D-Ala substrate and they are covalently
  bound to penicillin binding proteins.




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Cell envelope of Gram-negative bacterium




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        Peptidoglican synthesis




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                                                   12
 Transpeptidation reaction




        Transpeptidase




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Cell wall synthesis inhibitors


                         Phosphonomycin
                                ↓
                           Cycloserine
                                ↓
                            Bacitracin
                                ↓
                           Vancomycin
                                ↓
                            Penicillin
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                                             13
  Comparison of the structure of cell walls




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    Bectericidal and bacteriostatic effects

• With penicillins, transpeptidation reaction is inhibited,
  peptidoglycan synthesis is blocked and the cell dies.
• Furthermore, autolysins, bacterial enzymes that
  remodel and break cell wall are activated.
• Penicillins and cephalosporins are classically
  bactericidal. However, the cell should be actively
  growing and synthesizing cell wall.
• But some organisms have defective autolytic
  enzymes and are inhibited but not lysed, thus
  penicillins are bacteriostatic in these organisms.

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            Resistance to penicillins




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       The production of ß-lactamases

• There are more than 100 different types of this
  enzyme. The process is genetically controlled
  commonly with plasmids.
• β-lactamase production is particularly important in
  Staphylococci but other organisms such as Neisseria
  gonorrhoeae and Hemophilus species also produce
  these enzymes where as β-hemolytic Streptococci do
  not.
• In developed countries at least 80% of Staphylococci
  now produce β-lactamase.

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         Other resistance mechanisms

• A reduction in the permeability of the outer
  membrane.
  Thus there is a decreased ability of the drug to
  penetrate to the target site.

• The occurrence of modified penicillin binding sites.
  This mechanism is responsible in methicillin
  resistance in Pneumococci.



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                 Pharmacokinetics

• When given orally different penicillins are absorbed to
  differing degrees depending on their stability in acid
  and their absorption on to food.
• Parenteral administration of penicillin G can be
  intramuscular or intravenous.
• Intrathecal administration is inadvisable particularly
  with benzylpenicillin as it can cause convulsions.




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                     Distribution

• The drugs are widely distributed in the body fluids,
  passing into joints, into pleural and pericardial
  cavities, into the bile, the saliva, the milk and across
  the placenta.
• However they are lipid insoluble and they do not
  enter mammalian cells and do not cross intact blood-
  brain barrier.
• If the meninges are inflamed, they may reach
  therapeutically effective concentrations in the
  cerebrospinal fluid.

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                     Elimination



• Elimination of most penicillins is mainly renal and
  occurs rapidly, 90% being by tubular secretion.
• Excretion of penicillin by tubular secretion can be
  partially blocked by probenecid, which raises the
  plasma concentration and prolongs the action.




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                     Application

• Penicillin G has a relatively short half life so it must
  be frequently dosed, intravenously infused or slow
  release preparations such as procaine penicillin or
  benzathine penicillin should be given.
• Both slow-release preparations are applied
  intramuscularly.




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                        Dosing

• By one intramuscular injection of procaine penicillin
  clinically useful concentrations are maintained for 12-
  24 hours.
• After one intramuscular injection of benzathine
  penicillin, the plasma concentration of penicillin G is
  sufficient to treat Streptococcal infection for 10 days,
  and is sufficient to protect against β-hemolytic
  Streptococci for 3 weeks.



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                Unwanted effects

• One of the remarkable features of the penicillins is
  their relative freedom from direct toxic effects.
• Carbenicillin can produce hypokalemia, and because
  it contains 4.7 mEq Na+ per gram, it should perhaps
  be used with circumspection in cardiac disease.
• Hemostatic defects have been reported with this drug
  and with penicillin G.




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            Hypersensitivity reactions

• The main unwanted effects of the penicillins are
  hypersensitivity reactions, the basis of which is the
  fact that degradation products of penicillin combine
  with host protein and become antigenic.
• These are cross-reactions between various types of
  penicillins.
• Very high doses of penicillin G can cause seizures in
  kidney failure.



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              Allergic reaction types

• Skin rashes of various sorts, fever, delayed types of
  serum sickness with fever, urticarial skin eruptions, in
  severe cases generalized edema, multiple joint
  effusions, enlargement of spleen and lymph glands
  occurs infrequently.
• Much more serious is acute anaphylactic shock
  which may in some cases be fatal, but is fortunately
  very rare (probably 3-4/10000).
• Others include, vasculitis, interstitial nephritis, and
  various hematologic disturbances.
• The occurrence of these allergic reactions is
  unpredictable. Fortunately it is very rare in small
  children.
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         Gastrointestinal disturbances

• Another side effect of the penicillins, particularly the
  broad spectrum type given orally, is alternation of the
  bacterial flora in the gut.
• This can be associated with gastrointestinal
  disturbances and, in some cases, with suprainfection
  by microorganisms insensitive to penicillin.




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                  Cephalosporins

• Cephalosporins are similar to penicillins chemically,
  in mechanism of action, and toxicity.
• Cephalosporins are more stable to many β-
  lactamases and therefore have a broader spectrum
  of activity.
• Large-scale production of the common nucleus
  7-aminocephalosporanic acid has made possible of a
  vast array of cephalosporins.



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7-Aminocephalosporanic acid nucleus




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  First generation cephalosporins
   R1                            R2




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Second generation cephalosporins
  R1                       R2




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 Third generation cephalosporins




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                  Cephamycins

• Cephamycins (fermentation products of
  Streptomyces) and some totally synthetic drugs such
  as moxalactam resemble cephalosporins.
• Latamoxef is a synthetic cephomycin compound.




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      Cephalosporins and cephamycins




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  Mechanism of action for cephalosporins

• The same as that of penicillins.
• Resistance to this group of drugs has increased due
  to plasmid-encoded or chromosomal β-lactamase.
  There are certain kinds of β-lactamases which are
  more active in hydrolyzing cephalosporins than
  penicillins.
• Now forth generation of cephalosporins (e.g.
  cefepime) are available, these are comparable to
  third-generation but more resistant to some β-
  lactamases.

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                      Resistance

• Resistance also occurs if there is decreased
  penetration of the drug due to alternations to outer
  membrane proteins or mutations of the binding-site
  proteins.




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                 Pharmacokinetics

• Some cephalosporins may be given orally but most
  are given parenterally (IM or IV).
• They are widely distributed in the body like penicillins.
• Some such as cefoperazone, cefotaxime,
  cefuroxime, ceftriaxone, and ceftazidime also cross
  the blood-brain barrier and are drugs of choice for
  meningitis due to Gram-negative intestinal bacteria.




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                     Elimination

• Excretion is mostly via kidney, largely by tubular
  secretion but 40% of ceftriaxone and 75% of
  cefaperazone is eliminated in the bile.




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                 Unwanted effects

• Hypersensitivity reactions very similar to those that
  occur with penicillins may be seen.
• Nephrotoxicity and intolerance to alcohol (disulfiram
  like reaction) has been reported.
• Diarrhea may occur with oral forms. Many second
  and particularly third generation cephalosporins are
  ineffective against Gram-positive organisms,
  especially methicillin resistant Staphylococci and
  Enterococci.
• During treatment with such drugs, these resistant
  organisms as well as fungi, often proliferate and may
  induce superinfection.
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      Carbapenems and monobactams

• These drugs were developed to deal with β-
  lactamase producing Gram-negative organisms,
  which were resistant to broad spectrum and extended
  spectrum penicillins.
• Carbapenems are derived from Streptomyces
  species and one example is the semisynthetic
  imipenem which acts in the same way as the other β-
  lactams.



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                    Carbapenems




                                           Imipenem
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                      Imipenem

• It has a very broad spectrum of antimicrobial activity
  being active against many aerobic and anaerobic
  Gram-positive and Gram-negative organisms
  including Listeria, Pseudomonas, and most
  Enterobacteriaceae.
• Meticillin resistant Staphylococci are less susceptible.
• Imipenem is partly broken in the kidney by a
  dehydropeptidase in the proximal tubule, and is
  therefore given in combination with cilastatin, a
  specific inhibitor of this enzyme.
• Pamipenem is under investigation.

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                    Meropenem

• It is similar to imipenem.
• It is not degraded by dehydropeptidase, thus no
  cilastatin is needed.
• Excessive levels in kidney failure can cause seizures
  with imipenem but not with meropenem.




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                   Monobactams




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                    Aztreonam

• The main monobactam is aztreonam, which is
  resistant to most β-lactamases. It has an unusual
  spectrum being active only against Gram-negative
  aerobic     rods   including   Pseudomonas,      N.
  menengitidis and H. influenza.
• It has no action against Gram-positive organisms or
  anaerobes.
• New injectable monobactams under investigation are
  carumonam and tigemonam.


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   β-lactamase inhibitors (clavulanic acid,
          sulbactam, and tazobactam)

• These agents resemble β-lactam molecules but they
  have very weak antibacterial action.
• They are potent inhibitors of many bacterial β-
  lactamases and can protect hydrolyzable penicillins
  from inactivation by these enzymes.




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             β-lactamase inhibitors




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    Fixed combinations with β-lactamase
                inhibitors

• They are available only in fixed combinations with
  specific penicillins:
• Ampicillin + sulbactam
• Amoxicillin + clavulanic acid
• Ticarcillin + clavulanate potassium
• Piperacillin + tazobactam sodium




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                     Vancomycin


• It is an antibiotic
  produced by
  Streptococcus orientalis.
• It is only active against
  Gram-positive bacteria
  except Flavobacterium.




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                Mechanism of action

• Vancomycin inhibits cell
  wall synthesis by binding
  firmly to the D-Ala-D-Ala
  terminus of nascent
  peptidoglycan penta-
  peptide. This inhibits the
  transglycosylase,
  preventing further
  elongation of
  peptydoglycan and
  cross-linking.
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    Administration and pharmacokinetics

• It is administered orally only for antibiotic associated
  enterocolitis, caused by Clostridium difficile.
  Otherwise administered IV.
• The drug is widely distributed in the body and in
  cerebrospinal fluid when meninges are inflammated.
• 90% is excreted by glomerular filtration.




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                      Teicoplanin

• It is very similar to vancomycin, but it can be
  administered IM as well as IV.




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         Phosphonomycin (fosfomycin)

• It inhibits a very early stage of cell wall synthesis.
• As an analog of phosphoenolpyruvate, it is struc-
  turally unrelated to any other antimicrobial agent.
• It inhibits the cytoplasmic enzyme enolpyruvate
  transferase.
• It is active against both Gram-positive and Gram-
  negative organisms and is approved for use in
  uncomplicated urinary tract infections.
• In vitro synergism occurs when phosphonomycin is
  combined with β-lactam antibiotics, aminoglycosides,
  or fluoroquinolones.
• It is available in both oral and parenteral formulations.
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Bacitracin




• It inhibits cell wall formation by interfering with
  dephosphorylation in cycling of the lipid carrier that
  transfers peptidoglycan subunits to the growing cell
  wall.
• It is markedly nephrotoxic if administered systemically.
• It is poorly absorbed in topical use. Thus topical
  application results in local antibacterial activity without
  significant systemic toxicity.
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                    Cycloserine

• It is a structural analogue of D-alanine.
• It inhibits the incorporation of D-alanine, into
  peptidoglycan pentapeptide inhibiting alanine
  racemase, which converts L-alanine to D-alanine.
• Cycloserine inhibits many Gram-positive and Gram-
  negative organisms, but it is used almost exclusively
  to treat tuberculosis resistant to first line agents.




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     Similarity of cycloserine and alanine




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                                                                  36
Cell wall synthesis inhibitors


                         Phosphonomycin
                                ↓
                           Cycloserine
                                ↓
                            Bacitracin
                                ↓
                           Vancomycin
                                ↓
                            Penicillin
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Fluoroquinolones


      Öner Süzer




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              The fluoroquinolones

• The fluoroquinolones are synthetic antibiotics
  recently introduced into clinical practice.
• They include the broad spectrum agents
  ciprofloxacin, ofloxacin, norfloxacin, enoxacin,
  lomefloxacin and narrower-spectrum drugs used in
  urinary tract infections cinoxacin and nalidixic acid.
• The last one is the first introduced quinolone and is
  not flourinated.



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              Mechanism of action


• These agents inhibit
  topoisomerase II (a DNA
  gyrase), the enzyme that
  produces a negative
  supercoil in DNA,
  permitting transcription
  or replication.




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                   Ciprofloxacin

• Ciprofloxacin is the most commonly used
  fluoroquinolone and is described as the type agent.




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              Antibacteriel spectrum

• It is a broad spectrum antibiotic effective against
  many     organisms      resistant    to    penicillins,
  cephalosporins, and aminoglycosides, including;
  Enterobacter, H. influenzae, penicillinase producing
  N. gonorrhea, Campylobacter, and Pseudomonas.
• Of the Gram-positive organisms Streptococci and
  Pneumococci are only weakly inhibited.




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      Antibacteriel spectrum (continued)

• It should be avoided in methicilin-resistant
  Staphylococci. Intracellular organisms such as M.
  tuberculosis, Mycoplasma, Chlamydia, Legionella,
  and Brucella species are inhibited to a variable extent
  and there is only low activity against anaerobic
  bacteria.
• To prevent emergence of resistance, ciprofloxacin
  should be reserved for organisms resistant to other
  drugs.


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     Pharmacokinetics of flourokinolones

• They are well absorbed when given orally.
  t ½:
• Ciprofloxacin and norfloxacin » 3.3 h
• Ofloxacin. » 5 h.
• Lomefloxacin. » 8 h




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                    Distribution

• The drugs concentrate in many tissues particularly in
  the kidney, prostate and lung also in phagocytes.
• Most do not cross the blood-brain barrier except for
  ofloxacin, which reaches in the cerebrospinal fluid
  90% of its serum concentration.




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               Unwanted effects

• Infrequent, usually mild and reversible.
• Such as gastrointestinal disorders, skin rashes,
  artropathy, CNS symptoms (headache, dizziness),
  photosensitivity, hypersensitivity reactions.
• They are contraindicated in patients under 18
  because of the risk of chondrotoxicity and
  arthropathy.




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Thank you...




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Description: Antibiotics