Penicillins

Alexander Fleming

Between 1962 and 2000, no major classes of antibiotics were introduced

Fischbach MA and Walsh CT Science 2009

Microbial Sources of Antibiotics

9

Administration of Antibiotics

Spectrum of Activity

Drug Mechanisms of Action

The Beta-Lactam Antibiotics

• Cell wall active agents– Prevent the final step in the synthesis of the

bacterial cell wall

• Range from very narrow spectrum to very broad spectrum

β-Lactams

β-lactam ring

• Penicillin (over 50 compounds)– Share 4-sided ring (b lactam ring)

• Natural penicillins• Narrow range of action• Susceptible to penicillinase (b lactamase)

How do they work?

1. The β-lactam binds to Penicillin Binding Protein (PBP)

2. PBP is unable to crosslink peptidoglycan chains

3. The bacteria is unable to synthesize a stable cell wall

4. The bacteria is lysed

N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM), are two derivatives of glucose that form the polysaccharide chains that make up the backbone of peptidoglycan in the bacterial cell wall.

“Penicillin binding protein”

Peptidoglycan Synthesis

1. Precursors are cross-linked by PBP & then added to cell wall2. Penicillin enters the cell through porins & binds to PBP3. Binding results in release of lysins , which breaks down preformed cell wall4. After Penicillin binds to PBP, PBP can no longer synthesize protines essential for

integrity of cell wall.

Penicillinase (b Lactamase)

Classification– Natural penicillins

• Penicillin G,• Penicillin V• Benzathine Penicillin• Procaine Penicillin

– Semi-synthetic penicillins• Ampicillin, Oxacillin

• Structure– Thiazolidine ring– Beta-lactam ring– Variable side chain (R group)

• Bicyclic : (A) thiazolidine ring (B) β-lactam ring

N

S CH3

CH3

COOHO

ROCHN αThiazolidinering

ß-lactam ring

Acyl side-chainß

1

23

4

5

Examples

R=CH2

R=OCH2

BENZYL PENICILLIN (Penicillin G)

PHENOXYMETHYL PENICILLIN(Penicillin V)

Procaine Penicillin G

• a longer-acting, intramuscular alternative to benzyl penicillin, given 12 hourly.

Benzathine Penicillin G• longest acting• used almost exclusively in the prevention of

streptococcal pharyngitis (hence the prevention of rheumatic fever) and in the treatment of syphilis

Ist penicillin:• Penicillin G-active against G+ve and some G-ve

bacteria and Non-toxic• But not effective against wide range of bacteria• Ineffective on oral administration; only given by

Injection• Sensitive to β-lactamases (degradation)• Allergic reactions in some

Semi-synthetic method

• Fermentation gave 6-Aminopenicillanic acid (6-APA) which was treated synthetically with acid chlorides to give Penicillin analogues

N

S CH3

CH3

COOHO

RCOCl

NH2

N

S CH3

CH3

COOHO

RCOHN

Methicillin :

• First semi-synthetic Penicillin, resistant to penicillinase• Has 2 methoxy groups in ortho position on aromatic

ring in the side chain, which shield the lactam ring

• BUT: Only 1/50 th activity as Penicillin G against G+; inactive against G-

N

S CH3

CH3

COOHO

RCOHN

R Penicillin

C6H5O(CH)CH2CH3-

OMe

OMe

OCH2CH3

Propicillin

Methicillin

Nafcillin

Figure 20.6

The PENICILLINSNarrow spectrum penicillins

Penicillin G Penicillin V

Broad Spectrum Penicillins (Aminopenicillins) Amoxicillin Ampicillin Bacampicillin

Penicillinase-resistant Penicillins (Anti-staphyloccocal penicillins) Cloxacillin Nafcillin Methicillin Dicloxacillin Oxacillin

Extended-Spectrum penicillins (Anti-pseudomonal penicillins) Carbenicillin Mezlocillin Piperacillin Ticarcillin

Beta-lactamase inhibitors Clavulanic acid Sulbactam Tazobactam

The R group is responsible for the

activity of the drug, and cleavage of the beta-lactam ring will render the

drug inactive.

Chemical structure of penicillins

Therapeutic Indications of penicillins:• The penicillins are indicated for the

treatment of streptococcal infections• Syphilis• Tetanus

Adverse Effects of Penicillins

GI system effects- the major adverse effects of penicillin therapy involve the GIT.

Nausea, vomiting, diarrhea, abdominal pain, glossitis, stomatitis, gastritis, sore mouth and furry tongue.

The reason for some of these effects (superinfection) is associated with the loss of bacterial flora.

Adverse Effects of Penicillins

• Hypersensitivity reactions- rashes, pruritus, fever and urticaria

• These indicate mild allergic reaction. Wheezing and diarrhea may also occur.

• Anaphylaxis can also happen leading to shock or death. It occurs in 5-10% of those receiving penicillins.

• Pain and inflammation on injection sites

• The Cephalosporins have gradually replaced Penicillins in daily practice.

• The main advantage is the rarity of Anaphylactic reactions.

• Like the Penicillins, Cephalosporins are bactericidal and disrupt the synthesis of the Peptidoglycan layer of bacterial cell walls, important for bacterial cell wall structural integrity.

• Cephalosporins

Other Inhibitors of Cell Wall Synthesis

Figure 20.9

Cephalosporin• Cephalosporium acremonium (mold)• Widely administered today

– Diverse group (natural and semisynthetic)• Structure

– similar to penicillin except • Main ring is different• Two sites for R groups

THE CEPHALOSPORINS• Cephalosporins are sometimes grouped into

‘generations’  depending on their antimicrobial properties

• Each newer generation of cephalosporins has significantly greater Gram negative antimicrobial properties than the preceding generation.

• Unfortunately this is accompanied by a decreased efficacy against Gram positive bacteria.  

First Generation cephalosporins

Second generation cephalosporins

Third Generation cephalosporins

Fourth generation cephalosporins: have true broad-spectrum activity

THE CEPHALOSPORINS

• First Generation cephalosporins- are largely effective against the same gram-positive organisms affected by penicillin.

• Second generation cephalosporins- are effective against those strains as well as Haemophilus influenza, Entreobacter aerogenes and Nesseria sp. These drugs are less effective against gram positive bacteria

THE CEPHALOSPORINS

• Third Generation cephalosporins- are relatively weak against gram-positive bacteria but more potent against gram-negative bacteria, to include Serratia marcescens.

• Fourth generation cephalosporins- developed to fight against the resistant gram-negative bacteria. The first drug is cefepime.

First generation cephalosporins cefadroxil Cefazolin Cephalexin Cephalotin Cephapirin Cephadrine

Second Generation cephalosporins Cefaclor Cefamandole Cefonizind Cefotetan Cefoxitin Cefmetazole Cefprozil Cefuroxime

Third Generation Cephalosporins Cefnidir Cefixime Cefoperazone Cefotaxime Cefpodoxime Ceftazidime Moxalactam

Fourth Generation Cephalosporins Cefepime Cefpirome Cefquinome

The different R groups allow for versatility and improved effectiveness.

Classification

• Cephalosporins– 1st Generation

• Cephalexin, Cefazolin– 2nd Generation

• Cefoxitin, Cefuroxime, Cefotetan– 3rd Generation

• Cefotaxime, Ceftriaxone, Ceftazidime– 4th Generation

• Cefepime

Gram-negative cell Gram-positive cell

Outer membrane

PeptidoglycanPeptidoglycan

PenicillinBinding proteins(PBPs)

Inner (cytoplasmic) membrane

Cephalosporin• The mechanism of action

– The cephalosporins are primarily BACTERICIDAL.

– They interfere with the cell-wall building ability of bacteria when they divide.

– They prevent the bacteria from biosynthesizing the framework of their cell wall.

– The weakened cell wall will swell and burst causing cell death.

Cephalosporin• Pharmacokinetics

– Only a few cephalosporins are administered orally, most are administered parenterally.

– Their half-lives are short and they are excreted mainly in the urine.

• Contraindications and Precautions– The drugs are contraindicated in patients

with known allergies to cephalosporins and penicillins.

Cephalosporin

Adverse Effects• GI system- Nausea, vomiting, diarrhea,

anorexia, abdominal pain and flatulence are common effects.

• CNS – headache, dizziness, lethargy and paresthesias have been reported.

• Renal system- nephrotoxicity in individuals with pre-existing renal disease

• Hypersensitivity

Cephalosporin

Drug-Drug interactions• ALCOHOL- many patients experience a

disulfiram-like reactions when taken with some specific cephalosporins ( cefamandole, cefoperazone or moxalactam).

• The patient may experience flushing, headache, nausea, vomiting and muscular cramps. This may occur even up to 72 hours of cephalosporin discontinuance.

Resistance to Penicillin and its derivatives is caused by a specific enzyme: many gram-negative bacteria

produce penicillinase (b-lactamase)

β-Lactamase Inhibitors

• How do you evade a β-lactamase?1. Use a non-β-lactam agent2. Steric Inhibition

Penicillins with large side chains Cephalosporins

3. β-lactam + β-lactamase inhibitors Not all β-lactamases are inhibitable (!)

Combined antibiotic therapy

Combining different antibiotics can sometimes aid in treatment of infections.

Obviously this type of therapy only prevails when chemicals are compatible and act at different sites or within different pathways.

Inhibition of the “Resistance” Enzyme

Augmentin: Clavulanic acid + Amoxycillin.

•By combining the b-lactam antibiotic with an inhibitor of the b-lactamase (clavulanic acid) produced by the microbe, overcomes this mode of resistance and allows the antibiotic to become effective again.

Augmentin

Clavulanic acid

Inhibitor

Augmentin is amoxycillin + clavulanic acid

• Augmentin is effective against susceptible bacteria causing infections of the middle ear (otitis media), tonsillitis, throat infections(pharyngitis), laryngitis, bronchitis, sinusitis, and pneumonia. It is also used in treating urinary tract infections, and skin infections.

• DOSING: Augmentin should be taken on a full stomach to reduce stomach upset. No more than one tablet should be taken at a time since the extra clavulanic acid can cause stomach upset.

• Recommended adult doses are 500 mg every 8-12 hours, 250 mg every 8 hours, 875 mg every 12 hours

– Sulbactam (ampicillin/sulbactam: Unasyn)– Tazobactam (piperacillin/tazobactam: Zosyn)

Sulbactam• Unasyn (Amp/Sulbactam)• Spectrum: Amp + most anaerobes + many enteric Gm

(-) rods, OSSA• DoC: for GNR mixed infection – E.coli, Proteus,

anaerobes when Pseudomonas is not implicated– Diabetic foot (once Pseudomonas ruled out)– Wound infections

• Sulbactam alone is very active against Acinetobacter spp.

Tazobactam

• Zosyn (Pip/Tazo)• THE most broad-spectrum penicillin• Tazobactam may improve the activity of

piperacillin vs. gram-negative rods, including anaerobes

• 4.5g IV q8h = 3.375g IV q6h• 4.5g IV q6h for Pseudomonas