ß -lactam antibiotics Liming Zhou Department of pharmacology.

ß-lactam antibioticsß-lactam antibioticsLiming ZhouLiming Zhou

Department of pharmacology Department of pharmacology

Classification of drugClassification of drug

The mechanism of antibacterial The mechanism of antibacterial actionaction

Bacteria ResistanceBacteria Resistance

ß-lactam antibiotics in this chapteß-lactam antibiotics in this chapter are classified into three sub-clar are classified into three sub-class.ss.

I. The penicillinsI. The penicillins II. CephalosporinsII. Cephalosporins III. Other β-lactamsIII. Other β-lactams

I. The penicillinsI. The penicillins A. natural penicillins: Penicillin A. natural penicillins: Penicillin

G and penicillin VG and penicillin V B. Semisynthetic penicillins.B. Semisynthetic penicillins.

II. CephalosporinsII. Cephalosporins A. First generation cephalosporinsA. First generation cephalosporins B. Second generation cephalosporinB. Second generation cephalosporin

ss C. Third generation cephalosporinsC. Third generation cephalosporins D.The fourth generation cephalospoD.The fourth generation cephalospo

rinsrins

III. Other β-lactamsIII. Other β-lactams A. CephamycinsA. Cephamycins B. CarbapenemsB. Carbapenems C. Monobactams C. Monobactams D. OxacephemsD. Oxacephems E.β-lactamase inhibitorE.β-lactamase inhibitor

The mechanism of The mechanism of antibacterial actionantibacterial action

The peptidoglycan is composed of glycan cThe peptidoglycan is composed of glycan chains of N-acetyglucosamine and N-acetylhains of N-acetyglucosamine and N-acetylmuramic acid.muramic acid.

The biosynthesis of peptidoglycan can be cThe biosynthesis of peptidoglycan can be considered in three stages which the last one onsidered in three stages which the last one involves the completion of the cross-link. involves the completion of the cross-link.

This is accomplished by a tranpeptidation rThis is accomplished by a tranpeptidation reaction, which involves transpetidase. eaction, which involves transpetidase.

The ß-lactam antibiotics combine with and The ß-lactam antibiotics combine with and inactivate the tranpeptidase. inactivate the tranpeptidase.


The tranpeptidase is inactivated by The tranpeptidase is inactivated by ß-lactam antibiotics, they are the tarß-lactam antibiotics, they are the targets of β-lactam antibiotics and are ngets of β-lactam antibiotics and are named penicillin-binding protein (PBamed penicillin-binding protein (PBPs). Ps).

The PBPs vary in their affinities for dThe PBPs vary in their affinities for different ß-lactam antibiotics and sevifferent ß-lactam antibiotics and several kinds of PBPs have confirmed. eral kinds of PBPs have confirmed.

Table -1 Characteristics of PBPs in Staphylococcus aureus.

PBPs Molecular size (KD) Functions

PBP-1 87 Primary glycopeptide transferase

PBP-2 50 Transpeptidase; react in non growth bacteria

PBP-3 75 Transpeptidase; concerned with forming of septum

PBP-3’ 70 Transpeptidase; concerned with forming of septum

PBP-4 41 Carboxypeptidase and transpeptidase in second stage cross

link of glycopeptide.

Bacteria ResistanceBacteria ResistanceIn generally, there are three main mecIn generally, there are three main mec

hanism of ß-lactam antibiotics resisthanism of ß-lactam antibiotics resistance. ance.

(1) Nearly all bacteria can produce β-(1) Nearly all bacteria can produce β-lactamase after contact with β-lactalactamase after contact with β-lactam antibiotics. m antibiotics. β-lactamase can inactiβ-lactamase can inactivate ß-lactam antibioticsvate ß-lactam antibiotics through ru through rupture the ß-lactam ring. Different mipture the ß-lactam ring. Different microorganisms produce a number of dcroorganisms produce a number of distinct β-lactamase. istinct β-lactamase.

Bacteria ResistanceBacteria Resistance

(2) Many bacterial (2) Many bacterial can alter PBPscan alter PBPs with decrea with decreased affinity for ß-lactam antibiotics. This can sed affinity for ß-lactam antibiotics. This can result in failure of antibiotics binding to activresult in failure of antibiotics binding to active sites. e sites.

(3) The concentration of antibiotics in target (3) The concentration of antibiotics in target site is too low because of site is too low because of lacking of porin prolacking of porin proteintein, such us OmpF and OmpC. This permeab, such us OmpF and OmpC. This permeability block is particularly seen in resistance gility block is particularly seen in resistance gram-negative bacteria that possess a complex ram-negative bacteria that possess a complex outer layer. Increased active antibiotics effluouter layer. Increased active antibiotics efflux which reduce the drug in bacteria is the othx which reduce the drug in bacteria is the other reason for low concentration in target site er reason for low concentration in target site

PenicillinsPenicillins

I. Natural penicillinsI. Natural penicillins

Benzylpenicillin (Penicillin G)Benzylpenicillin (Penicillin G) It is the one of the natural penicillins It is the one of the natural penicillins

used clinically and instable in water used clinically and instable in water solution, gastric juice at pH 2.solution, gastric juice at pH 2.

StructureStructure

Antibacterial actionAntibacterial action Penicillin has great antibacterial activity tPenicillin has great antibacterial activity t

o a variety of sensitive bacteria. o a variety of sensitive bacteria. The antibacterial spectrum includes:The antibacterial spectrum includes: Gram-positive cocci: Streptococcus pyogGram-positive cocci: Streptococcus pyog

enes (group A, B, C, G, F), non-β-lactamase enes (group A, B, C, G, F), non-β-lactamase producing staphylococcus aureus, sensitivproducing staphylococcus aureus, sensitive streptococcus pneumoniae, aerobic Grae streptococcus pneumoniae, aerobic Gram positive cocci.m positive cocci.

Gram-positive bacilli: corynebacterium dGram-positive bacilli: corynebacterium diphtheriae; bacillus anthracis; anaerobic ciphtheriae; bacillus anthracis; anaerobic clostridium tetani; clostridium perfringens;lostridium tetani; clostridium perfringens; clostridium botulinum; actinomyces. clostridium botulinum; actinomyces.

Antibacterial actionAntibacterial action

Gram-negative cocci: nesseria meninGram-negative cocci: nesseria meningitides; neisseria gonorrhoeae.gitides; neisseria gonorrhoeae.

Spirochetes: Treponema pallidum; lSpirochetes: Treponema pallidum; leptospira spp.; borrelia burgdorferi. eptospira spp.; borrelia burgdorferi.

PharmacokineticsPharmacokinetics When oral administrated, penicillin G is rapidly deWhen oral administrated, penicillin G is rapidly de

stroyed by gastric acid and has poor absorption. Ofstroyed by gastric acid and has poor absorption. Often it is used by i.m or i.v. ten it is used by i.m or i.v.

The peak concentration time in blood is about 0.5 h,The peak concentration time in blood is about 0.5 h, and it is nearly completely eliminated mainly by th and it is nearly completely eliminated mainly by the kidney in 6 h when penicillin G is administrated be kidney in 6 h when penicillin G is administrated by i.m. y i.m.

The half-life is about 0.5 h. It has broad distributioThe half-life is about 0.5 h. It has broad distribution, but cannot pass the blood-brain barrier, cannot n, but cannot pass the blood-brain barrier, cannot reach the aqueous humor and succus prostaticus. reach the aqueous humor and succus prostaticus.

When having cerebra inflammation, it can pass the When having cerebra inflammation, it can pass the damaged blood-brain barrier into cerebrospinal fldamaged blood-brain barrier into cerebrospinal fluid.uid.

Clinical usesClinical uses

1. Infection of streptococcus: S. pyogen1. Infection of streptococcus: S. pyogenes group A can caused pharyngitises group A can caused pharyngitis （（咽咽炎炎）） , scarlatina, scarlatina （（猩红热猩红热）） , , cellulitiscellulitis （（蜂窝织炎蜂窝织炎）） , suppurative arth, suppurative arthritis, pneumonia, puerperalritis, pneumonia, puerperal （分娩的）（分娩的） ffever and blood poisoning. S. pyogenes gever and blood poisoning. S. pyogenes group B, S. pneumoniae, S. viridans and roup B, S. pneumoniae, S. viridans and S. faecalis can caused respiratory infectS. faecalis can caused respiratory infection, meningitis, endocarditis, and blooion, meningitis, endocarditis, and blood poisoning. d poisoning.


2.Pneumococcal infections: pneum2.Pneumococcal infections: pneumococcal pneumonia, pneumococcal ococcal pneumonia, pneumococcal meningitis meningitis

3.Treatment of meningococcal men3.Treatment of meningococcal meningitis. ingitis.

4.Treatment of gonococcal infectio4.Treatment of gonococcal infections such as gonococcal urethritis, gons such as gonococcal urethritis, gonococcal arthritis and gonococceminococcal arthritis and gonococcemia.a.


5.Spirochete infection: Leptospirosis, 5.Spirochete infection: Leptospirosis, lues and recurrent fever.lues and recurrent fever.

6.Gram-positive bacilli infection: lock6.Gram-positive bacilli infection: lockjawjaw（破伤风）（破伤风） , diphtheria, diphtheria （白喉）（白喉） aand anthraxnd anthrax （炭疽）（炭疽） ..

7.Infections with sensitive anaerobes 7.Infections with sensitive anaerobes

Adverse reactionsAdverse reactions

The toxicity of penicillins is very low.The toxicity of penicillins is very low. Allergic reactions: drug rash, dermatAllergic reactions: drug rash, dermat

itis, serum sickness, itis, serum sickness, anaphylactic shanaphylactic shockock and hemolytic anemia. and hemolytic anemia.

Before using this kind of drugs, the Before using this kind of drugs, the medical institution must prepare drumedical institution must prepare drugs for treatment of anaphylactic shocgs for treatment of anaphylactic shock.k.

Adverse reactionsAdverse reactions

Jarisch-Herxheimer reaction: after pJarisch-Herxheimer reaction: after penicillin treatment of enicillin treatment of spirochetespirochete infe infection, some patients show symptoms ction, some patients show symptoms of ague, fever, laryngeal pain, headaof ague, fever, laryngeal pain, headache and tachycardia. It is sometimes che and tachycardia. It is sometimes life threaten. This reaction is due to tlife threaten. This reaction is due to the large number of kill spirochete, she large number of kill spirochete, so the dose at the beginning should noo the dose at the beginning should not be high. t be high.

Semisynthetic penicillinsSemisynthetic penicillins

Semisynthetic penicillinsSemisynthetic penicillinsOral administrationOral administration (acid stable) β-lacta (acid stable) β-lacta

mase non-stable penicillinsmase non-stable penicillins Penicillin V (phenoxymethylpenicilliPenicillin V (phenoxymethylpenicilli

n).n). Antibacterial actionAntibacterial action: This kind of peni: This kind of peni

cillins is similar with penicillin G with cillins is similar with penicillin G with the same antibacterial spectrum but lthe same antibacterial spectrum but lower activity.ower activity.

Semisynthetic penicillinsSemisynthetic penicillins

Clinical usesClinical uses: : It is used in slight infectIt is used in slight infection caused by gram-posotive cocci suion caused by gram-posotive cocci such as pharyngitis, amygdalitis(ch as pharyngitis, amygdalitis( 扁桃体扁桃体炎炎 ) and prophylactic use for rheumat) and prophylactic use for rheumatic fever.ic fever.

Adverse reactionAdverse reaction: it can cause allergic : it can cause allergic reaction (most slight reaction) and gareaction (most slight reaction) and gastrointestinal reaction (burning sensastrointestinal reaction (burning sensation, nausea, vomiting and diarrhea) tion, nausea, vomiting and diarrhea)

B Penicillinase-resistant penicB Penicillinase-resistant penicillinsillins

Methicillin; Dicloxacillin; Cloxacillin aMethicillin; Dicloxacillin; Cloxacillin and Oxacillin belong to this kind of penicnd Oxacillin belong to this kind of penicillins. illins.

Only methicillin is not stable in acid anOnly methicillin is not stable in acid and the other can administer orally.d the other can administer orally.

Antibacterial activityAntibacterial activity: it has powerful a: it has powerful activity on penicillinase producing S. aurctivity on penicillinase producing S. aureus, less activity on streptococcus, and eus, less activity on streptococcus, and resistance to gram-negative bacteria. resistance to gram-negative bacteria.

B Penicillinase-resistant penicB Penicillinase-resistant penicillinsillins

Clinic usesClinic uses: : These antibiotics also have many resiThese antibiotics also have many resi

stant bacteria now. stant bacteria now. The dicloxacillin has the lowest resisThe dicloxacillin has the lowest resis

tant bacteria at present. tant bacteria at present. MRSA: Methicillin of resistance to S. MRSA: Methicillin of resistance to S.

aureus aureus

C Broad spectrum penicillinsC Broad spectrum penicillins This kind of penicillins include ampiThis kind of penicillins include ampi

cillin, amoxicillin. cillin, amoxicillin. Antibacterial activityAntibacterial activity: ampicillin and : ampicillin and

have amoxicillin similar action to pe have amoxicillin similar action to penicillin G sensitive bacteria. Antibactnicillin G sensitive bacteria. Antibacterial activity to gram-negative bactererial activity to gram-negative bacteria for these penicillins is greater thaia for these penicillins is greater than that for Penicillin G. n that for Penicillin G.

C Broad spectrum penicillinsC Broad spectrum penicillins

PharmacokineticsPharmacokinetics: : The absorption of ampicillin and amoThe absorption of ampicillin and amo

xicillin is about 30% and 90% respectixicillin is about 30% and 90% respectively. vely.

When inflammation occurring, effectiWhen inflammation occurring, effective concentration of these drugs can obve concentration of these drugs can obtained in tympanitis effusion, bronchitained in tympanitis effusion, bronchia secretion, ascitic fluid, articular cavia secretion, ascitic fluid, articular cavity effusion and cerebrospinal fluid. ty effusion and cerebrospinal fluid.

D D PenicillinsPenicillins of treatment for P of treatment for Pseud. aeruginosa infectionseud. aeruginosa infection

These drugs include Carbenicillin and These drugs include Carbenicillin and piperacillinpiperacillin

Antibacterial activity:Antibacterial activity: The antibacte The antibacterial spectrum of these drugs is effectrial spectrum of these drugs is effective for pseud. aeruginosa and bacilluive for pseud. aeruginosa and bacillus proteus. s proteus.

Therapeutic uses:Therapeutic uses: It is usually used t It is usually used to infection of Pseud. aeruginosa and o infection of Pseud. aeruginosa and ß-lactamase producing bacteria that ß-lactamase producing bacteria that resistant to ampicillin. resistant to ampicillin.

E Penicillins of treatment for GraE Penicillins of treatment for Gram-negative bacilli infectionm-negative bacilli infection

These drugs include mecillinam and teThese drugs include mecillinam and temocillinmocillin

Antibacterial activity:Antibacterial activity: The antibacter The antibacterial spectrum of these drugs is effectiial spectrum of these drugs is effective for ve for Gram-negative bacilli infection,Gram-negative bacilli infection,

Therapeutic uses:Therapeutic uses: These penicillins c These penicillins can be used in urinary tract infection.an be used in urinary tract infection.

CephalosporinsCephalosporins Cephalosporins are thCephalosporins are th

e semisynthetic antibie semisynthetic antibiotics derived from 7-Aotics derived from 7-Amino cephalosporanimino cephalosporanic acid (7-ACA)—the cec acid (7-ACA)—the cephem nucleus of cephphem nucleus of cephalosporins.alosporins.

They are similar to peThey are similar to penicillins in terms of mnicillins in terms of mechanism of action, cechanism of action, chemical structure, anhemical structure, and toxicities d toxicities

First generation cephalosporinsFirst generation cephalosporins

Cefazolin; Cefadroxil; Cefalexin; CefalCefazolin; Cefadroxil; Cefalexin; Cefalothin; Cefapirin; cefradine. othin; Cefapirin; cefradine.

First generation cephalosporinFirst generation cephalosporinss

Pharmocological propertiesPharmocological propertiesIt exhibits good activity against gram-positive bacteIt exhibits good activity against gram-positive bacte

ria, but less activity against gram negative organiria, but less activity against gram negative organisms: sms:

(a) greater activity to gram-positive bacteria than (a) greater activity to gram-positive bacteria than the second and third generation, the second and third generation,

(b) Less stable than second and third generation t(b) Less stable than second and third generation to β-lactamase, o β-lactamase,

(c) Less activity than second and much less activit(c) Less activity than second and much less activity than third generation to gram-negative bacilli; y than third generation to gram-negative bacilli;

(d) some drugs have kidney toxicity.(d) some drugs have kidney toxicity.

First generation cephalosporinFirst generation cephalosporinss

Clinical usesClinical uses These antibiotics are often used to These antibiotics are often used to

treat gram-positive bacteria treat gram-positive bacteria infection.infection.

Injecting route drugs are used for Injecting route drugs are used for moderate infection caused by moderate infection caused by aerobic bacteria and some severe aerobic bacteria and some severe infection by sensitive bacteria.infection by sensitive bacteria.

Second generation cephalosporiSecond generation cephalosporins:ns:

Cefuroxime, cefamandole, cefaclCefuroxime, cefamandole, cefaclor ceforanideor ceforanide

Second generation cephalospoSecond generation cephalosporinsrins

Pharmocological propertiesPharmocological properties Second-generation drugs exhibit enhanced Second-generation drugs exhibit enhanced

activity against gram-negative bacteria, bactivity against gram-negative bacteria, but much less enhancement compared to tut much less enhancement compared to third generation agents: hird generation agents:

(a)(a) better anti-bacteria activity to gram-negabetter anti-bacteria activity to gram-negative than first generation cephalosporins, tive than first generation cephalosporins, but less than do third generation drugs,but less than do third generation drugs,

(b)(b) (b) more stability to β-lactamase than fir(b) more stability to β-lactamase than first generation cephalosporins, st generation cephalosporins,

(c)(c) (c) less kidney toxicity than first generati(c) less kidney toxicity than first generation. on.

Second generation cephalospoSecond generation cephalosporinsrins

Clinical usesClinical uses It is the first choice drugs for gram-nIt is the first choice drugs for gram-n

egative bacteria infectious diseases, egative bacteria infectious diseases, and the other indications are similar and the other indications are similar with first generation cephalosporins.with first generation cephalosporins.

Third generation cephalosporinsThird generation cephalosporins

Cefotaxime, ceftazidime, ceftriaxone, Cefotaxime, ceftazidime, ceftriaxone, cefoperazone, ceftizoxime, cefixime,ccefoperazone, ceftizoxime, cefixime,cefodizimeefodizime

Third generation cephalosporinThird generation cephalosporinss

Pharmocological propertiesPharmocological propertiesThird-generation drugs exhibit the lest activity agaiThird-generation drugs exhibit the lest activity agai

nst gram-positive bacteria, but most potent activinst gram-positive bacteria, but most potent activity against gram-negative bacteria :ty against gram-negative bacteria :

(a) extended antibacterial spectrum, include Pseud. (a) extended antibacterial spectrum, include Pseud. aeruginosa; aeruginosa;

(b) less activity on gram-positive bacteria than first (b) less activity on gram-positive bacteria than first and second generation; and second generation;

(c) most active on gram-negative bacteria; (c) most active on gram-negative bacteria; (d) high stability with β-lactamase; (d) high stability with β-lactamase; (e) easy penetrate to different tissues, and then hav(e) easy penetrate to different tissues, and then hav

e broad distribution; e broad distribution; (f) little kidney toxicity.(f) little kidney toxicity.

Third generation cephalosporinThird generation cephalosporinss

Clinical usesClinical uses These drugs are used for severe These drugs are used for severe

gram-negative resistant bacilli gram-negative resistant bacilli infection. infection.

And also used for complex infection.And also used for complex infection.

The fourth generation cephalosporinThe fourth generation cephalosporinss

Cefepime and cefpirome have similaCefepime and cefpirome have similar antibacterial activity with third genr antibacterial activity with third generation on most gram-negative bacilleration on most gram-negative bacilli, but more stable to β-lactamase.i, but more stable to β-lactamase.

Other β-lactamsOther β-lactams

CephamycinsCephamycins Natural product is cephamycin and the Natural product is cephamycin and the

semisynthetic cefoxitin is in clinical ussemisynthetic cefoxitin is in clinical use. e.

It has similar antibacterial activity witIt has similar antibacterial activity with second-generation cephalosporins, ah second-generation cephalosporins, and good activity to anaerobe. It is used nd good activity to anaerobe. It is used for mixed infection of aerobe and anaefor mixed infection of aerobe and anaerobe. robe.


CarbapenemsCarbapenems Carbapenems includes Imipenem, mCarbapenems includes Imipenem, m

eropenem and panipenem. eropenem and panipenem. It has most powerful bactericidal effIt has most powerful bactericidal eff

ect on most bacteria, and has super bect on most bacteria, and has super broad antibacterial spectrum. road antibacterial spectrum.

Nearly all gram-negative and gram-pNearly all gram-negative and gram-positive bacteria infection can be treatositive bacteria infection can be treated with this kind of drug.ed with this kind of drug.


MonobactamsMonobactams Aztreonam and carumonam belong to MonobaAztreonam and carumonam belong to Monoba

ctams. ctams. It is highly resistant to ß-lactamases. It is highly resistant to ß-lactamases. It is effective in treating Gram-negative urinarIt is effective in treating Gram-negative urinar

y tract infections, lower respiratory tract, skin,y tract infections, lower respiratory tract, skin, intra abdominal, gynecologic infections and s intra abdominal, gynecologic infections and septicemia. epticemia.

Aztreonam may be given together with other aAztreonam may be given together with other antibiotics which are active against Gram-positintibiotics which are active against Gram-positive bacteria and anaerobes in mixed infections. ve bacteria and anaerobes in mixed infections.


OxacephemsOxacephems Latamoxef and flomoxef belong to OLatamoxef and flomoxef belong to O

xacephems. xacephems. It has similar spectrum, antibacterial It has similar spectrum, antibacterial

activity with ceftazidime. activity with ceftazidime. It has better activity on anaerobe thaIt has better activity on anaerobe tha

n first, second and third generation cn first, second and third generation cephalosporins.ephalosporins.


β-lactamase inhibitorβ-lactamase inhibitor This kind of drug include clavulanic This kind of drug include clavulanic

acid, sulbuctam and tazobactam. acid, sulbuctam and tazobactam. These agents are potent inhibitors of These agents are potent inhibitors of

many kind of ß-lactamases and are umany kind of ß-lactamases and are used together with penicillins to protesed together with penicillins to protect them from inactivation.ct them from inactivation.

Home workHome work

1. How are agents in this chapter 1. How are agents in this chapter classified?classified?

2. What are the major differences 2. What are the major differences among the cephalosporin antibiotics among the cephalosporin antibiotics by generations?by generations?

3. Describe the pharmacological 3. Describe the pharmacological effects of penicillin G.effects of penicillin G.

ß -lactam antibiotics Liming Zhou Department of pharmacology.

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