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β-lactam Antibiotics

Linrongprofessor

Department of pharmacologyEmail:linrong@mail.xjtu.edu.cn

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β-lactam Antibiotics

β-lactam Antibiotics

Penicillins

β-Lactam CharacteristicsMechanism of ActionMechanisms of Resistance

Classification of penicillinsPharmacokineticsSpectrum of activityTherapeutic usesAdverse effects

Other PenicillinsPenicillinase-resistant penicillinsBroad-spectrum penicillinsAntipseudomonal penicilinsBeta-lactamase inhibitors

Mechanism of actionSpectrum of Activity and Clinical usesAdverse effects

Cephalosporins

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β-lactam Antibiotics

Monobactams

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

Penicillins

NO

S

Carbapenems

NO

NO

NO

S

Cephalosporins

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

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β-lactam Antibiotics

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β-Lactam Characteristics

l Same Mechanism of Action : Inhibit cell wall synthesis

l Bactericidal (except against Enterococcus sp.); time-dependent killers

l Short elimination half-lifel Primarily renally eliminated l Cross-allergenicity - except aztreonam

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ALL β-lactams

• Mechanism of ActionØ Interfere with cell wall synthesis by

binding to penicillin-binding proteins (PBPs) which are located in bacterial cell walls

Ø Inhibition of PBPs leads to inhibition of peptidoglycan synthesis→ Cell death

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β-lactam Antibiotics

β-lactam Antibiotics: β-Lactam CharacteristicsMechanism of ActionMechanisms of Resistance

1. Production ofβ-lactamase enzymes2. Trapping mechanism3. Modification of target PBPs4. Impaired penetration of drug to target PBPs5. The shortage of autolytic enzyme.6. The presence of an efflux pump.

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ALL β-lactams• Mechanisms of Resistance

1. production ofβ-lactamase enzymes« most important and most common« hydrolyzes beta-lactam ring causing

inactivation2. Trapping mechanism. w Some β -lactams tightly bind with β -

lactamase and stay outside the bacterial cell. Thus, these beta-lactams can’t enter the bacterial cell wall to combine with the PBPs.

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ALL β-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 β-lactams

• Mechanisms of Resistance5. 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 beta-

lactam antibiotics from the periplasm back across the cell wall via an efflux pump

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Mechanisms of Resistance1. Production ofβ-lactamase enzymes2. Trapping mechanism3. Modification of target PBPs4. Impaired penetration of drug to

target PBPs5. The shortage of autolytic enzyme6. The presence of an efflux pump.

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β-lactam Antibiotics

Penicillins Classification of penicillinsPharmacokineticsSpectrum of activityTherapeutic usesAdverse effects

Other Penicillins

Cephalosporins

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Alexander Flemingdiscovered penicillinin 1928

Penicillins

1928: Alexander Fleming isolated the antibiotic substance penicillin from the fungus Penicilliumnotatum 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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Penicillins1. 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-Amino-penicillanic acid.

3. The various penicillins differ in their side chain structure.

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• Penicillins are divided into natural and semisynthetic ones (antistaphylococcal,extended-spectrum 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

Classification of penicillins

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Penicillins-Chemistry

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Penicillins G

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• 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

Classification of penicillins

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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).

Classification of penicillins

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Mechanisms of Resistance - Penicillins

1. Inactivation of antibiotic byβ-lactamase enzymes

2. Modification of target PBPs3. Impaired penetration of drug to

target PBPs4. The presence of an efflux pump

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Mechanism of Action - Penicillins

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Penicillins GPharmacokinetics• 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 GSpectrum of activityvG+ cocci : Pneumococci , Staphylococci,

Streptococci , (many Staphylococci are now resistant)

vG- cocci: Meningococci and gonococcivG+ bacilli: Bacillus perfringens, bacillus

diphtheriaevSpirochetes: Treponema pallidum,

Leptospira. and Actinomyces

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Penicillins G

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Therapeutic usesqIt is the drug of first choice for treating the

infections of the above mentioned pathogens.qThe simultaneous administration of the relevant

antitoxin is often necessary for the treatment of diphtheria and tetanus. qThe combination of an aminoglycoside is also

necessary for bactericidal effects in enterococcalendocarditis.

Penicillins G

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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 %Ø skin rashes, fever, eosinophilia, angioedema,

serum sickness, and anaphylactic shock. ØCross-reactivity exists among all penicillins

and even other β-lactamsØThe most serious hypersensitivity reaction is

anaphylactic shock. (very rare, the ratio is about 0.5 to 1 of 10000 patients )

ØAs soon as anaphylactic shock occurs, instantly inject adrenaline to deliver trachea edema and spasm.

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• Other adverse effects:ü Gastrointestinal upset, ( orally

administered preparations)ü Nephrotoxicity, is very rare.ü Superinfections.

results from alterations in intestinal flora. A higher incidence occurs with broad-spectrum penicillins.

Penicillins : Adverse effects

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β-lactam Antibiotics

Penicillins

Classification of penicillinsPharmacokineticsSpectrum of activityTherapeutic usesAdverse effects

Other Penicillins

Acid-stable Penicillins- penicillin VPenicillinase-resistant penicillinsBroad-spectrum penicillinsAntipseudomonal penicilinsBeta-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

① Methicillin and isoxazolyl penicillins(e.g. oxacillin, cloxacillin and dicloxacillin)

② 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

③ Enterococci and methicillin-resistant strains of staphylococci are resistant to these penicillins

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Broad-spectrum penicillins

Ampicillin and amoxicillin① They are similar to penicillin G in the

activity against gram-positive organisms but are weaker than the latter.

② They are more satisfactory for the treatment of enterococci and streptococcus viridians.

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③ They are similar to chloramphenicol in the activity against gram-negative organisms.

④ They are acid-resistant but are not penicillase-resistant.

⑤ Pseudomonas aeruginosa are fail to respond to these drugs.

Broad-spectrum penicillins

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Antipseudomonal penicilins

carbenicillin, ticarcillin① Extend the ampicillin spectrum of activity

to P.aeruginosa and enterobacterspecies. But their activity to G+ cocci isless than that of ampicillin.

② They are not acid-resistant and penicillase-resistant.

③ Ticarcillin is more active than carbenicillin against P.aeruginosa and enterobacter species.

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Antipseudomonal penicilins

④ Chiefly used to treat serious infections caused by G- microorganisms, particular P.aeruginosa, indole-positive proteusand enterobacter.

⑤ Generally used in combination with anaminoglycoside for pseudomonalinfections.

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Beta-lactamase inhibitors

clavulanic acid, sulbactam, tazobactam① Inactivate bacterial beta-lactamases and

are used to enhance the antibacterial actions of beta-lactam antibiotics.

② Only have weak antibacterial action.

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Beta-lactamase inhibitors

③ Inhibitors of many but not all bacterial beta-lactamases and can protect hydrolyzable penicillins from inactivation by the enzymes.

④ 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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β-lactam Antibiotics

β-lactam AntibioticsPenicillins

Other Penicillins

Penicillinase-resistant penicillinsBroad-spectrum penicillinsAntipseudomonal penicilinsBeta-lactamase inhibitors

Mechanism of actionSpectrum of Activity and Clinical usesAdverse effects

Cephalosporins

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Cephalosporins & Cephamycins

«The cephalosporinsare derivatives of 7-amino-cephalosporanic acid and are closely related in structure to penicillin.«They have a beta-lactam ring.«They are relatively stable in dilute acid and are highly resistant to penicillinase.

Although some bacteria can produce a beta-lactamasecalled cephalosporinase that acts on the cephalosporin nucleus to destroy its antibacterial activity, however, many of them are resistant to the enzyme.

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Mechanism of action

« Cephalosporins inhibit the peptido-glycan synthesis of bacterial cell wallin 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 onw parallel their chronological developmentw 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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EXAMPLES: cephalothin, cefazolin, and cephalexin et al

① They have a stronger antimicrobial action on G+

bacteria than that of the other generations, but they action on G- bacteria is relatively poor.

② These cephalosporins have nephrotoxicity to a certain degree.

③ They are NOT effective against pseudomonas.

First Generation Cephalosporins

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④ Comparatively, they are stable for beta-lactamase (penicillinase ).

⑤ They are chiefly used in treating infection of the penicillinase-productive aurococcus(S.aureus ) and surgical prophylaxisction.

⑥ Cefazolin do not penetrate the central nervous system and can not be used totreat meningitis.

First Generation Cephalosporins

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Second Generation Cephalosporins

« cefamandole, cefoxitin, cefaclor, cefonicid, cefuroxime, cefotetan, cefprozil.

① Action of this generation on G+ bacteria is the same or a little bit less than that of the first generation.

② Their antimicrobial action on G- bacteria is obviously increased

③ Some of them are effective against anaerobes such as B.fragilis.

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④ Ineffective against p.aeruginosa.⑤ They are stable to many kinds of beta-

lactamases and have less nephrotoxicitythan the first generation.

⑥ Cefuroxime is the only second-generation drug that crosses the blood-brain barrierwell enough to be used for the treatment of meningitis, especially H.influenzaemeningitis, and sepsis.

Second Generation Cephalosporins

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« cefotaxime, ceftizoxime, ceftriaxone, cefoperazone, ceftazidime, cefixime, cefpodoxime

① The broadest spectrums of all cephalo-② The highest activities against G- bacteria.③ The lowest activities against G+ bacteria.④ The highest resistance toβ-lactamase.

Third Generation Cephalosporins

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⑤ The best penetration into the CSF; almost no nephrotoxicity.

⑥ Ceftizoxime have good activity against B.fragilis.

⑦ Some of them are effective against P.aeruginosa and enteric bacilli.

Third Generation Cephalosporins

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⑧ They are chiefly used in the infections of the urethral or biliary tract with the drug-resistant strains and Pseudomonas.

⑨ They are also used in some serious pneumonia, sepsis and meningitis.

Third Generation Cephalosporins

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« 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.

Third Generation Cephalosporins

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qRelatively few and low qThe most common ones are Allergy-

hypersensitivity reactions (5%-10%)Üanaphylaxis, fever, skin rashes, nephritis,

granulocytopenia, and hemolytic anemia. qDuring treatment with third-generation drugs,

these resistant bacteria, as well as fungi, often proliferate and may induce superinfections.

Adverse effects

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Adverse effects «Nephrotoxicity:üThe first-generation cephalosporins have

certain nephrotoxicity. (Renal damage, including interstitial nephritis and even tubular necrosis )üThe second-generation have slight

nephrotoxicity.üThe third-generation have almost no

nephrotoxicity.

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Monobactams - Aztreonam① Aztreonam is highly resistant to beta-lactamases

② It is highly active against aerobic G- bacteria, including P.aeruginosa and penicillinase-producing strains of H. influenzae and gonococci. But it shows poor activity against G+ cocci and anaerobic bacteria.

③ The antimicrobial spectrum of aztreonam is similar to that of aminoglycosides

The Other Beta-lactam antibiotics

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The Other Beta-lactam antibiotics

Carbapenems – Imipenem et. al• Imipenem is easily hydrolized by dehydro-

peptidase 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.

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The Other Beta-lactam antibiotics

Carbapenems – Imipenem et. al• Gonococci and H. influenzae strains that are

resistant to both natural penicillin and ampicillinare 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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• Mechanism of action• Pharmacologic effects• Clinical Uses• Adverse Effects

Other inhibitions of cell wall synthesis

VancomycinVancomycin

Vancomycin is an antibiotic produced by Streptococcus orientalis.

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• 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 µg/mL.

VancomycinVancomycin

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Pharmacologic effects

① Vancomycin is very effective against most staphylococci including those producing beta-lactamases，and other G+ cocci such as streptococcus viridans, enterococci, and pneumococcus.

② It is also active against clostridium species, Corynebacterium diphtheriae, and Bacillus anthracis.

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Vancomycin: Clinical Uses

① Orally only for the treatment of antibiotic-associated Pseudomembranous colitiscaused by C.difficile.

② 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

① Phlebitis– at the site of injection.

② 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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③ “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

Vancomycin: Adverse Effects

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