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Penicillins• In 1928, Alexander Fleming, working at St. Mary's

Hospital in London, observed that a culture plate on which staphylococci were being grown had become contaminated with a mould of the genus Penicillium, and that bacterial growth in the vicinity of the mould had been inhibited.

• He isolated the mould in pure culture and demonstrated that it produced an antibacterial substance called penicillin.

• This substance was subsequently extracted and its antibacterial effects analyzed by Florey and Chain and their colleagues at Oxford in 1940.

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Penicllins II• They showed that it had powerful chemotherapeutic

properties in infected mice and that it was non-toxic.

• Its remarkable antibacterial effects in humans were clearly demonstrated in 1941.

• A small amount of penicillin, extracted from crude cultures in the laboratories of the Dunn School of Pathology in Oxford, was tested on a policeman

• He had staphylococcal and streptococcal septicaemia with multiple abscesses, and osteomyelitis with discharging sinuses. He was in great pain and was desperately ill.

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Mechanism of action• All β-lactams interfere with the synthesis of the

bacterial cell wall peptidoglycan. • After attachment to binding sites on bacteria, they

inhibit the transpeptidation enzyme that cross-links the peptide chains attached to the backbone of the peptidoglycan.

• The final bactericidal event is the inactivation of an inhibitor of the autolytic enzymes in the cell wall.

• This leads to lysis of the bacterium. • Some organisms have defective autolytic enzymes and

are inhibited but not lysed-they are referred to as 'tolerant'.

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Resistance to PenicillinsProduction of β-lactamases• About 50 different types of β-lactamases have

been produced• Produced in staphylococci, Nesseria

gonorhoeae, Haemophillus spp.• This is overcomed by the use of clavulanic acid,

contains β-lactam ring and bind covalently to the enzyme or near its active site.

• Other β-lactamase inhibitors include sulbactam and tazobactam.

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Resistance to Penicillins IIReduction in the permeability of the other

membrane• Thus decreased ability of the drug to pnetrate

to the target site.• This occurs with Gram-ve organisms with an

outer membrane that limits the penetration of hydrophilic antibiotics.

Occurence of modified penicillin-binding sites• Particluar in methicillin-resistant staphylococci

(e.g. MRSA)

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Types of Penicillins• Earlier penicillins Benzylpenicillin (Penicillin G) Phenoxymethylpenicillin (Penicillin V)• β-lactamase-resistant penicillins Flucloxacillin, cloxacillin, dioxacillin, dicloxacillin,

methicillin, nafcillin• Broad-spectrum penicillins Ampicillin, pivampicillin, amoxicillin, becampicillin • Extended-spectrum penicillins Carbenacillin, ticarcilin, aziocillin, mezlocillin,

piperacillin (with antipseudomonal activity)

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Clinical Uses– Bacterial meningitis (e.g. caused by Neisseria meningitidis,

Streptococcus pneumoniae): benzylpenicillin, high doses intravenously – Bone and joint infections (e.g. with Staphylococcus aureus): flucloxacillin – Skin and soft tissue infections (e.g. with Streptococcus pyogenes or S.

aureus): benzylpenicillin, flucloxacillin; animal bites: co-amoxiclav – Pharyngitis (from S. pyogenes): phenoxylmethylpenicillin – Otitis media (organisms include S. pyogenes, Haemophilus influenzae):

amoxicillin– Bronchitis (mixed infections common): amoxicillin– Pneumonia: amoxicillin – Urinary tract infections (e.g. with Escherichia coli): amoxicillin– Gonorrhea: amoxicillin (plus probenecid) – Syphilis: procaine benzylpenicillin – Endocarditis (e.g. with Streptococcus viridans or Enterococcus faecalis) – Serious infections with Pseudomonas aeruginosa: piperacillin.

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Side effects• Hypersensitivity reactions, (main unwanted effect)

caused by the degradation products of penicillin, which combine with host protein and become antigenic

• Skin rashes and fever• Delayed type of serum sickness• Acute anaphylactic shock• Penicillins, particularly the broad-spectrum type given

orally, alter the bacterial flora in the gut. • This can be associated with GIT disturbances and

suprainfection by microorganisms not sensitive to penicillin

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CEPHALOSPORINS AND CEPHAMYCINS • Cephalosporins N and C, are chemically related to penicillin• Cephalosporin P, a steroid antibiotic that resembles fusidic

acid• They were first isolated from Cephalosporium fungus. • The cephamycins are β-lactam antibiotics produced by

Streptomyces spp and they are closely related to the cephalosporins.

• Semi-synthetic broad-spectrum cephalosporins have been produced by addition, to the cephalosporin C nucleus, of different side-chains.

• These are water-soluble and relatively acid stable.• They vary in susceptibility to β-lactamases.

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Types of Cephalosporins and Cephamycins Category

Important Properties Other Similar Drugs

Oral drugs

Cefalexin First-generation compounds that have reasonable activity against Gram+ve and modest activity against Gram-ve organisms

Cefachlor is a second-generation compound with greater potency against Gram-ve organisms, but it can cause unwanted cutaneous lesions

Parenteral drugs

Cefuroxime Second-generation compounds that show only moderate activity against most Gram+ve organisms but reasonable potency against Gram-ve organisms

Cephamandole, cefoxitin , good activity against Gram-ve organisms, resistant to β-lactamase from Gram-ve rods, good potency against Bacteroides fragilis, bowel flora

Cefotaxime Third-generation compounds, which are less active against Gram+ve bacteria than those of the second generation but more active against Gram-ve bacteria. Has some activity against pseudomonads

Ceftizoxime ; ceftriaxone excreted largely in the bile; cefperazone, excreted mainly in the bile, can cause decrease of vitamin K-dependent clotting factors

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Mechanism of action• Same as that of the penicillins-interference with bacterial

peptidoglycan synthesis after binding to the β-lactam-binding proteins.

• Resistance to this group of drugs has increased because of plasmid-encoded or chromosomal β-lactamase.

• Nearly all Gram-ve bacteria have a chromosomal gene coding for a β-lactamase that is more active in hydrolysing cephalosporins than penicillins.

• In several organisms a single-step mutation can result in high-level constitutive production of this enzyme.

• Resistance also occurs if there is decreased penetration of the drug as a result of alterations to outer membrane proteins or mutations of the binding-site proteins.

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Clinical Uses• Septicaemia (e.g. cefuroxime, cefotaxime) • Pneumonia caused by susceptible organisms • Meningitis (e.g. cefriaxone, cefotaxime) • Biliary tract infection • Urinary tract infection (especially in

pregnancy, or in patients unresponsive to other drugs)

• Sinusitis (e.g. cefadroxil)

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Pharmacokinetics• Mostly available in injection and few oral dosage forms• Injections administered IM (which may be painful with

some agents) or IV. • After absorption they are widely distributed in the

body• Some, such as cefoperazone, cefotaxime, cefuroxime

and ceftriaxone, also cross the blood-brain barrier. • Excretion is mostly via the kidney, largely by tubular

secretion• 40% of ceftriaxone and 75% of cefoperazone are

eliminated in the bile

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Side effects• Hypersensitivity reactions (similar to

penicillins)• Some cross-reactions occur (about 10% of

penicillin-sensitive individuals will have allergic reactions to cephalosporins)

• Nephrotoxicity (with cefradine)• Alcohol intolerance• Diarrhoea can occur with oral cephalosporins

and cefoperazone

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OTHER β-LACTAM ANTIBIOTICS • Carbapenems and monobactams were developed to deal

with β-lactamase-producing Gram-ve organisms resistant to penicillins.

• Imipenem, an e.g. of a carbapenem, acts in the same way as the other β-lactams

• It has a very broad spectrum of antimicrobial activity, being active against many aerobic and anaerobic Gram+ve and Gram-ve organisms.

• Many of the MRSA are less susceptible, and resistant strains of P. aeruginosa have been reported.

• Imipenem was originally resistant to all β-lactamases but some organisms now have chromosomal genes that code for imipenem-hydrolyzing β-lactamases.

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Side effects• Similar to other β-lactams• Nausea and vomiting (most frequent)• Neurotoxicity (occur with high plasma

concentrations)

Other e.g.• Meropenem is similar to imipenem but is not

broken down by proximal tubule dehdropeptidase.

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Monobactams• The main monobactam is Aztreonam• A simple monocyclic β-lactam with a complex substituent, which

is resistant to most β-lactamases. • This has an unusual spectrum-being active only against Gram-ve

aerobic rods, including pseudomonads, Neisseria meningitidis and Haemophilus influenzae.

• It has no action against Gram+ve organisms or anaerobes. • Given parenterally and has a plasma half-life of 2 hours

Side effects • Similar to those of other β-lactam antibiotics • Do not cause allergic reactions in penicillin-sensitive individuals.