-lactam Antibiotics

professor Department of pharmacology Email:linrong@mail.xjtu.edu.cn

Linrong

-lactam Antibiotics
-lactam Antibiotics
-Lactam Characteristics Mechanism of Action Mechanisms of Resistance Classification of penicillins Pharmacokinetics Spectrum of activity Therapeutic uses Adverse effects
Penicillinase-resistant penicillins Broad-spectrum penicillins Antipseudomonal penicilins Beta-lactamase inhibitors Mechanism of action Spectrum of Activity and Clinical uses Adverse effects

Penicillins

Other Penicillins Cephalosporins

-lactam Antibiotics
All of the drugs in this group contain a -lactam ring in their structure
S S

N O O

Penicillins

Cephalosporins

share similar features of chemistry, mechanism of action, pharmacologic and clinical effects.

N O O

Carbapenems

Monobactams

-lactam Antibiotics

-Lactam Characteristics
l

l l l

Same Mechanism of Action : Inhibit cell wall synthesis Bactericidal (except against Enterococcus sp.); time-dependent killers Short elimination half-life Primarily renally eliminated Cross-allergenicity - except aztreonam
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ALL -lactams
Mechanism of Action

Interfere with cell wall synthesis by binding to penicillin-binding proteins (PBPs) which are located in bacterial cell walls Inhibition of PBPs leads to inhibition of peptidoglycan synthesis! Cell death
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-lactam Antibiotics
-lactam Antibiotics: -Lactam Characteristics
Mechanism of Action

Mechanisms of Resistance

1. Production of -lactamase enzymes 2. Trapping mechanism 3. Modification of target PBPs 4. Impaired penetration of drug to target PBPs 5. The shortage of autolytic enzyme. 6. The presence of an efflux pump.

ALL -lactams
Mechanisms of Resistance
1. production of -lactamase enzymes
most important and most common hydrolyzes beta-lactam ring causing inactivation

2. Trapping mechanism.
w Some -lactams tightly bind with lactamase and stay outside the bacterial cell. Thus, these beta-lactams can!t enter the bacterial cell wall to combine with the PBPs.

ALL -lactams
Mechanisms of Resistance
3. Modification of target PBPs.
w responsible for methicillin resistance in staphylococci and penicillin resistance in pneumococci.

4. Impaired penetration of drug to target PBPs.

w which occurs only in G- species, is due to impermeability of the outer membrane that is present in G- but not in G+ bacteria.
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ALL -lactams
Mechanisms of Resistance
5. The shortage of autolytic enzyme.
w Under this circumstance, the beta-lactams have normal inhibiting action, but their kill effects are very poor.

6. The presence of an efflux pump.

w Some organisms also may transport betalactam antibiotics from the periplasm back across the cell wall via an efflux pump
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Mechanisms of Resistance
1. Production of -lactamase enzymes 2. Trapping mechanism 3. Modification of target PBPs 4. Impaired penetration of drug to target PBPs 5. The shortage of autolytic enzyme 6. The presence of an efflux pump.
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-lactam Antibiotics
Penicillins Classification of penicillins Pharmacokinetics Spectrum of activity Therapeutic uses Adverse effects

Other Penicillins Cephalosporins

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Penicillins
Alexander Fleming discovered penicillin in 1928
1928: Alexander Fleming isolated the antibiotic substance penicillin from the fungus Penicillium notatum on September 15, for which he shared a Nobel Prize in 1945. Penicillin is a antibiotic used in the treatment of bacterial infections caused by susceptible.
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Penicillins
1. The structure of the penicillins consists of a thiazolidine ring connected to a beta-lactam ring, which is attached to a side chain. 2. All penicillins are derived from 6-Aminopenicillanic acid. 3. The various penicillins differ in their side chain structure.
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Classification of penicillins
Penicillins are divided into natural and semisynthetic ones (antistaphylococcal,extendedspectrum penicillins et .al) Natural penicillins: extracted from the cultural solution of penicillia.
! ! ! ! Prototype is penicillin G Is pH sensitive. Therefore not given orally. Effective against Gram-positive cells Susceptible to penicillinase
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Penicillins-Chemistry

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Penicillins G

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Classification of penicillins
Semisynthetic penicillins: " Produce by growing Penicillium in culture so that only the nucleus is synthesized. Attach R group in lab. " Or, grow Penicillium, extract natural penicillin, remove R group, and attach wanted R group. " Have broader spectrum. Are effective against Gram-negative cells, too. " Are not resistant to penicillinases

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Classification of penicillins
Semisynthetic penicillins:
vAcid-stable penicillins (e.g. penicillin V); vPenicillinase-resistant penicillins (e.g. oxacillin); vExtended-spectrum penicillins (e.g. ampicillin and antipseudomonal); vAntistaphylococcal penicillins (e.g. nafcillin).
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Mechanisms of Resistance -

Penicillins

1. Inactivation of antibiotic by lactamase enzymes 2. Modification of target PBPs 3. Impaired penetration of drug to target PBPs 4. The presence of an efflux pump

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Mechanism of Action

- Penicillins

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Penicillins G
Pharmacokinetics It is relatively unstable in acid, thus the bioavailability is low. There is poor penetration into the cerebrospinal (CSF), unless inflammation is presetent. Active renal tubular secretion results in a short half-life.
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Penicillins G
Spectrum of activity
vG+ cocci : Pneumococci , Staphylococci, Streptococci , (many Staphylococci are now
resistant)

vG- cocci: Meningococci and gonococci vG+ bacilli: Bacillus perfringens, bacillus diphtheriae vSpirochetes: Treponema pallidum, Leptospira. and Actinomyces
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Penicillins G

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Penicillins G
Therapeutic uses
q It is the drug of first choice for treating the infections of the above mentioned pathogens. q The simultaneous administration of the relevant antitoxin is often necessary for the treatment of diphtheria and tetanus. q The combination of an aminoglycoside is also necessary for bactericidal effects in enterococcal endocarditis.
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Acid-stable Penicillins- penicillin V

vThe oral form of penicillins, vIndicated only in minor infections because of their relatively poor bioavailability, weaker antimicrobial activity, the need for dosing many times vNarrow antimicrobial spectrum.
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Penicillins: Adverse effects

Hypersensitivity ! 5 to 20 %
skin

rashes, fever, eosinophilia, angioedema, serum sickness, and anaphylactic shock. Cross-reactivity exists among all penicillins and even other -lactams The most serious hypersensitivity reaction is anaphylactic shock. (very rare, the ratio is about 0.5 to 1 of 10000 patients ) As soon as anaphylactic shock occurs, instantly inject adrenaline to deliver trachea edema and spasm.
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Penicillins : Adverse effects

Other adverse effects: Gastrointestinal upset, ( orally
administered preparations)

Nephrotoxicity, is very rare. Superinfections.

results from alterations in intestinal flora. A higher incidence occurs with broad-spectrum penicillins.
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-lactam Antibiotics
Penicillins
Classification of penicillins Pharmacokinetics Spectrum of activity Therapeutic uses Adverse effects

Other Penicillins

Acid-stable Penicillins- penicillin V Penicillinase-resistant penicillins Broad-spectrum penicillins Antipseudomonal penicilins Beta-lactamase inhibitors

Cephalosporins
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Acid-stable Penicillins- penicillin V

vThe oral form of penicillins, vIndicated only in minor infections because of their relatively poor bioavailability, weaker antimicrobial activity, the need for dosing many times vNarrow antimicrobial spectrum.
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Penicillinase-resistant penicillins
" Methicillin and isoxazolyl penicillins (e.g. oxacillin, cloxacillin and dicloxacillin) # They are the drugs of first choice for treating infections of the penicillase-productive aurococcus. But penicillin-susceptible strains of streptococci and pneumococci are also susceptible $ Enterococci and methicillin-resistant strains of staphylococci are resistant to these penicillins 31

Broad-spectrum penicillins
Ampicillin and amoxicillin " They are similar to penicillin G in the activity against gram-positive organisms but are weaker than the latter. # They are more satisfactory for the treatment of enterococci and streptococcus viridians.
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Broad-spectrum penicillins
$ They are similar to chloramphenicol in the activity against gram-negative organisms. % They are acid-resistant but are not penicillase-resistant. & Pseudomonas aeruginosa are fail to respond to these drugs.
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Antipseudomonal penicilins
carbenicillin, ticarcillin
" Extend the ampicillin spectrum of activity to P.aeruginosa and enterobacter species. But their activity to G+ cocci is less than that of ampicillin. # They are not acid-resistant and penicillase-resistant. $ Ticarcillin is more active than carbenicillin against P.aeruginosa and enterobacter species. 34

Antipseudomonal penicilins
% Chiefly used to treat serious infections caused by G- microorganisms, particular P.aeruginosa, indole-positive proteus and enterobacter. & Generally used in combination with an aminoglycoside for pseudomonal infections.
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Beta-lactamase inhibitors
clavulanic acid, sulbactam, tazobactam " Inactivate bacterial beta-lactamases and are used to enhance the antibacterial actions of beta-lactam antibiotics. # Only have weak antibacterial action.

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Beta-lactamase inhibitors
$ Inhibitors of many but not all bacterial beta-lactamases and can protect hydrolyzable penicillins from inactivation by the enzymes. % Available only in fixed combinations with specific penicillins.
The companion penicillin, not the beta-lactamase inhibitor, determines the antibacterial spectrum of the combination.
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-lactam Antibiotics
-lactam Antibiotics Penicillins Other Penicillins Mechanism of action Cephalosporins Spectrum of Activity and Clinical uses Adverse effects
Penicillinase-resistant penicillins Broad-spectrum penicillins Antipseudomonal penicilins Beta-lactamase inhibitors

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Cephalosporins & Cephamycins

The cephalosporins are derivatives of 7amino-cephalosporanic acid and are closely related in structure to penicillin. They have a betalactam ring. They are relatively stable in dilute acid and are highly resistant to penicillinase.
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Although some bacteria can produce a beta-lactamase called cephalosporinase that acts on the cephalosporin nucleus to destroy its antibacterial activity, however, many of them are resistant to the enzyme.

Mechanism of action

Cephalosporins inhibit the peptidoglycan synthesis of bacterial cell wall in a manner similar to that of penicillin and are considered bactericidal.

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Spectrum of Activity and Clinical uses of Cephalosporins

All cephalosporins are active against most G+ cocci, including penicillinase-producing staphylococci and many strains of G- bacilli, but relatively ineffective against enterococci. Divided into 4 major groups called "Generations# Are divided into Generations based on
w parallel their chronological development w their antimicrobial spectrum
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Characteristics of the generations

- First-generation cephalosporins -Second-generation cephalosporins - Third-generation cephalosporins - Fouth-generation cephalosporins

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First Generation Cephalosporins

EXAMPLES: cephalothin, cefazolin, and cephalexin et al " They have a stronger antimicrobial action on G+ bacteria than that of the other generations, but they action on G- bacteria is relatively poor. # These cephalosporins have nephrotoxicity to a certain degree. $ They are NOT effective against pseudomonas.
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First Generation Cephalosporins

% Comparatively, they are stable for betalactamase (penicillinase ).
& They are chiefly used in treating infection of the penicillinase-productive aurococcus (S.aureus ) and surgical prophylaxisction.

' Cefazolin do not penetrate the central nervous system and can not be used to treat meningitis.
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Second Generation Cephalosporins

cefamandole, cefoxitin, cefaclor, cefonicid, cefuroxime, cefotetan, cefprozil. " Action of this generation on G+ bacteria is the same or a little bit less than that of the first generation. # Their antimicrobial action on G- bacteria is obviously increased $ Some of them are effective against anaerobes such as B.fragilis.
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Second Generation Cephalosporins

! Ineffective against p.aeruginosa. & They are stable to many kinds of betalactamases and have less nephrotoxicity than the first generation. ' Cefuroxime is the only second-generation drug that crosses the blood-brain barrier well enough to be used for the treatment of meningitis, especially H.influenzae meningitis, and sepsis.
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Third Generation Cephalosporins

cefotaxime, ceftizoxime, ceftriaxone, cefoperazone, ceftazidime, cefixime, cefpodoxime " The broadest spectrums of all cephalo# The highest activities against G- bacteria. $ The lowest activities against G+ bacteria. % The highest resistance to -lactamase.
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Third Generation Cephalosporins

& The best penetration into the CSF; almost no nephrotoxicity. ' Ceftizoxime have good activity against B.fragilis. ( Some of them are effective against P.aeruginosa and enteric bacilli.
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Third Generation Cephalosporins

) They are chiefly used in the infections of the urethral or biliary tract with the drug-resistant strains and Pseudomonas. * They are also used in some serious pneumonia, sepsis and meningitis.

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Third Generation Cephalosporins

There are also some unique properties of individual 3th generation.
Ceftriaxone has the longest half-life(8h) of any cephalosporin. Cefixime is an oral preparation. Ceftazidime is the best anti-pseudomonal cephalosporin. Cefoperazone is eliminated(70%) in the bile, and is thus very useful in patients with renal failure.
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Adverse effects
qRelatively few and low qThe most common ones are Allergyhypersensitivity reactions (5%-10%)
anaphylaxis, fever, skin rashes, nephritis, granulocytopenia, and hemolytic anemia. q During treatment with third-generation drugs, these resistant bacteria, as well as fungi, often proliferate and may induce superinfections.
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Adverse effects
Nephrotoxicity: The first-generation cephalosporins have certain nephrotoxicity. (Renal damage, including interstitial nephritis and even tubular necrosis ) The second-generation have slight nephrotoxicity. The third-generation have almost no nephrotoxicity.
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The Other Beta-lactam antibiotics

Monobactams - Aztreonam
" Aztreonam is highly resistant to beta-lactamases # It is highly active against aerobic G- bacteria,

including P.aeruginosa and penicillinaseproducing strains of H. influenzae and gonococci. But it shows poor activity against G+ cocci and anaerobic bacteria.
$ The antimicrobial spectrum of aztreonam is

similar to that of aminoglycosides

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The Other Beta-lactam antibiotics

Carbapenems Imipenem et. al Imipenem is easily hydrolized by dehydropeptidase in the body, so the clinical preparation is the mixture made by imipenem and peptidase inhibitor named cilastatin. The mixture is called tienam. The antimicrobial spectrum of imipenem is the broadest one of all the beta-lactam antibiotics. It is active against G+, G- cocci (except methicillin-resistant staphylococci), enterobacteriaceae, P.aeruginosa, and anaerobic bacteria, including B.fragilis. 54

The Other Beta-lactam antibiotics

Carbapenems Imipenem et. al

Gonococci and H. influenzae strains that are resistant to both natural penicillin and ampicillin are still susceptible to imipenem. Imipenem is mainly used in urinary tract, respiratory tract, skin, and soft tissue infections. Imipenem could also be used in staphylococcal endocarditis, but not in CNS infections.
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Other inhibitions of cell wall synthesis

Vancomycin Vancomycin
Mechanism of action Pharmacologic effects Clinical Uses Adverse Effects
Vancomycin is an antibiotic produced by Streptococcus orientalis.
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Vancomycin Vancomycin
Mechanism of action
! Binds to precursor units of bacterial cell walls, inhibiting cell wall synthesis, also inhibits RNA synthesis

bactericidal antibiotic for gram-positive bacteria in concentration of 0.5-10 %g/mL.

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Pharmacologic effects
" Vancomycin is very effective against most staphylococci including those producing beta-lactamases+and other G+ cocci such as streptococcus viridans, enterococci, and pneumococcus. # It is also active against clostridium species, Corynebacterium diphtheriae, and Bacillus anthracis.
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Vancomycin: Clinical Uses

" Orally only for the treatment of antibioticassociated Pseudomembranous colitis caused by C.difficile. # Intravenous administration is mainly used for serious G+ coccal infections, such as enterocolitis, septicemia
# Especially for those caused by penicilin-resistant pneumococcus and staphylococci

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Vancomycin: Adverse Effects

"
#

Phlebitis
at the site of injection.

#
!

Nephrotoxicity and Ototoxicity

rare with monotherapy, more common when administered with other nephro- or ototoxins risk factors include renal impairment, prolonged therapy, high doses, high serum concentrations, other toxic meds
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Vancomycin: Adverse Effects

$ "Red-Man#or "red neck# Syndrome
! flushing, pruritus, erythematous rash on face and upper torso ! related to RATE of intravenous infusion; should be infused over at least 60 minutes ! resolves spontaneously after discontinuation ! Prevent: may lengthen infusion (over 2 to 3 hours) or pretreat with antihistamines in some cases
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