Penicillins With Reference to Amoxicillin and Its Combinations

BY

NSOFOR IFUNANYA STEPHANIE

PENICILLINS WITH REFERENCE TO AMOXICILLIN AND ITS

COMBINATIONS

Definition of penicillins

Any of a group of antibiotic drugs obtained from penicillium moulds or produced synthetically, most active against gram-positive bacteria and used in the treatment of various infections and diseases.

Fungal mould- Penicillium notatum

Definition cont.d

The name "penicillium" was taken from the Latin word "penicillum" meaning "a painter's brush" because the fronds of the fungus were thought to look like a painter's brush.

Brief history of penicillins

Discovered by chance by Sir Alexander Fleming in 1928.

Alexander Fleming discovered that colonies of Penicillium mold growing in his bacterial cultures were able to stave off infection.

With more study, he found that the mold was flooding the culture with a molecule that killed the bacteria, penicillin.

History cont.d

50 drugs that are now classified as penicillin. Used in WWII and after.

Description of drug class

The term ‘penicillin’ is used generally for the entire group of natural and semi synthetic penicillins.

They are considered to be β-lactam antibiotics i.e. antibiotics containing the β-lactam ring.

Penicillins consist of a nucleus of 6-aminopenicillanic acid (6-APA) to which are attached various side chains in amide linkage.

Description cont.d

They all have the same ring structure, the penicillin nucleus, which consists of a fused thiazolidine ring and a beta-lactam ring with an amino group at the 6-position.

Common members

Some of the common members include;

Amoxicillin

Ampicillin

Common members cont.d

Benzylpenicillin

(Penicillin G)

Phenoxymethylpenicillin

(Penicillin V)


Flucloxacillin

Cloxacillin


Ticarcillin

Etc…

Classification of penicillins

Natural penicillins

- Penicillin G and Penicillin V Penicillinase resistant penicillins

- Flucloxacillin and temocillin Aminopenicillins

- Amoxicillin and ampicillin Extended-spectrum penicillins

- Ticarcillin and piperacillin

Mechanism of action

Penicillins are bactericidal and act by inhibiting cell wall synthesis by interfering with the synthesis of the peptidoglycan layer of the cell wall.

They act by inhibiting the cross-linkage between the linear peptidoglycan polymer chains of the bacterium

The cell wall provides structural support and protection for the cells of the organism.

Mechanism of action cont.d

The major function of the cell wall is to act as a pressure vessel, preventing over-expansion when water enters the cell.

And its major structural component is the peptidoglycan and it prevents osmotic lysis.

Without a strong cell wall, the bacterium would burst from osmotic pressure of water flowing into the cell.

Mechanism of Action

Formation of the cross-links

Mechanism of action

Resistance

Resistance to penicillins is considered to be due to the following four general mechanisms:

1. Inactivation of antibiotic by β-lactamase

2. Modification of penicillin binding proteins (PBPs)

3. Impaired penetration of drug to target PBPs

4. Efflux

Resistance

β-lactamase production is the most common mechanism of resistance.

β -lactamase such as the ones produced by Staph.aureus, Haemophilus spp and E.coli are relatively narrow in substrate specificity preferring penicillins in general

Resistance

Β-lactamases hydrolyse the β-lactam ring Either plasmid or chromosomally mediated

Resistance

Altered target PBPs are the basis of penicillin resistance in pneumococci and enterococci.

These organisms produce PBPs that have low affinity for binding penicillins

Consequently they are not inhibited except at relatively high, often clinically unachievable, drug concentrations.

Antimicrobial Spectrum

Penicillins are bactericidal in action. Its antimicrobial spectrum includes :

Streptococcus species Proteus species Enterobacter species H.influenzae Pneumococci Staphylococcus species Salmonella species

Antimicrobial spectrum cont.d

N.meningitidis P.multocida

Because of the problem of resistance, we have some of the strains of these organisms not being affected by penicillins today.

Pharmacokinetics

Absorption: Following oral administration, absorption of penicillins occurs mainly in the duodenum and upper jejenum, although a small amount may be absorbed in the stomach and large intestine.

Distribution: Penicillins are widely distributed following absorption from the GI tract or injection sites.

Pharmacokinetics cont.d

Metabolism: Penicillins are mainly metabolized in the liver by the hydrolysis of the β-lactam ring to penicilloic acids which are microbiologically inactive.

Excretion: They are rapidly excreted in urine mainly by tubular secretion and glomerular filtration.


Penicillins diffuse well into body tissues and fluids

Penetration into the cerebrospinal fluid is poor except when the meninges are inflamed


Penicillin G differs from other penicillins by being acid labile.

It is 60% protein bound unlike the penicillinase resistant penicillins that are highly bound (95-98%) but are acid stable

Indications

Penicillins are used to treat infections caused by both gram-positive and negative organisms but mostly for the gram-positive organisms.

Some of which include susceptible staph infections, streptococci infections and enterobacter infections.

E.g. – Upper and lower respiratory tract infections, otitis media, skin infections etc.

Adverse effects

Most of the serious adverse effects are due to hypersensitivity but some GI effects and CNS effects are associated with its use such as nausea and headache respectively.

All penicillins are cross-sensitizing and cross-reacting.

Adverse effects cont.d

Hematologic effects: a coagulation disorder characterized by prolonged bleeding time, abnormal platelet aggregation, an increase antithrombin III activity and interference with conversion of fibrinogen to fibrin has been reported but this is rare.


GI effects: Some of the general GI adverse effects include nausea, vomiting and diarrhoea but they are generally considered to result from local irritation by penicillins

Clostridium difficile-associated diarrhoea and colitis (also known as antibiotic-associated pseudomembranous colitis) caused by toxin-producing clostridia resistant to the drug has also been reported.


Renal effects: Acute interstitial nephritis, manifested as fever, proteinuria and hematuria has been reported rarely with IV pen G but in patients who have received prolonged therapy.

CNS effects: Pen G is very irritating to central and peripheral nervous systems. Neurotoxic reactions include hallucinations, confusion, lethargy, dysphasia, twitching, mycolonic seizures etc.


Local effects: The most common local effects include phlebitis and thrombophlebitis, pain at the injection site.

Others include erythema, vein irritation and sterile abscess

Precautions and Contraindications

In patients with severe renal failure care must be taken to avoid cerebral irritation which can further lead to encephalopathy. This also applies to patients receiving high doses of penicillins.

Penicillin is relatively safe for use in pregnancy and breast-feeding mothers.

Its use in contraindicated in penicillin hypersensitivity.

Drug interactions

Penicillins are known to alter the international normalized ratio (INR) when administered with anticoagulants

They reduce the excretion of methotrexate

Probenecid reduces the excretion of penicillins thereby leading to increased plasma concentrations.

Drug interactions cont.d

Sulfinpyrazone also reduces the excretion of penicillins

Absorption of phenoxymethyl pencillin is reduced by neomycin

Effects of penicillins are possibly antagonised by tetracyclines.


Piperacillin enhances effects of non-depolarising muscle relaxants and suxamethonium.

Penicillins inactivate the oral typhoid vaccine

The antibacterial activity of aminoglycosides and penicillins may be synergistic in vitro against some organisms.


Concomitant use of penicillin V or ampicillin with oral contraceptives may decrease efficacy of the contraceptive.

Amoxicillin: Definition

Amoxicillin is a broad-spectrum, bacteriolytic, β-lactam antibiotic used to treat bacterial infections caused by susceptible microorganisms.

It is usually the drug of choice within the class because it is better absorbed, following oral administration, than other β-lactam antibiotics.


Its structure is almost the same as ampicillin, the only difference is the presence of the –OH group which is responsible for its easy oral absorption.

Amoxicillin: Mechanism of action

It has the same mechanism of action as the penicillins which is by inhibition of cell wall synthesis.

Antimicrobial spectrum

Streptococcus species Pneumococci (except highly resistant) Enterococcus faecalis Proteus species Amoxicillin is inactivated by β-lactamases

(including pencillinase) therefore it is less effective against staph species.

Pharmacokinetics

Absorption: The drug has a bioavailability of about 89% following oral administration.

Distribution: It is 15-25% bound to plasma protein. Amoxicillin crosses the placenta. Small but negligible amounts are distributed into breast milk


Metabolism: In the liver, the elimination half-life is about 1-2 hours, prolonged in neonates and the elderly

Excretion: Mainly in the urine (50-70%). About 60% as unchanged drug. Small amounts appear in the bile and faeces especially with high doses


Amoxicillin is the only oral acid-stable penicillin whose bioavailability is not significantly affected by low pH of the GI tract

Unlike ampicillin, its absorption is not affected by the presence of food in the stomach.

Produces higher plasma concentrations.

Clinical uses

It is indicated for use in the following conditions:

Otitis media Sinusitis Bronchitis Low or moderate severity community acquired

pneumonia

Clinical uses cont.d

Pneumococcal infection prophylaxis Adjunct in listerial meningitis

Dosage regimen

Adult and child over 5yrs, 250mg every 8 hours, dose doubled in severe infection.

Child( 1 month – 1 yr)- 62.5mg every 8hours, dose doubled in severe infection

1-5yrs, 125mg every 8 hours, dose doubled in severe infection.

Otitis media- 500mg every 8 hours; Child- 40mg/kg daily in 3 divided doses( max 1.5g daily)

Dosage regimen cont.d

Pneumonia( Adult over 18yrs)- 0.5-1g every 8 hours.

Dental abscess( Adult over 18yrs)- 3g repeated after 8 hours

Adverse effects

Hematologic effect: In addition to eosinophilia and hemolytic anemia, other hematologic adverse effects include anemia, leukopenia, neutropenia, agranulocytosis, and thrombocytopenia have been reported in patients receiving amoxicillin. But discontinuation of the drug causes a reversal of these effects


GI effects: Some of the most frequent GI adverse reactions to orally administered amoxicillin include nausea, vomiting, anorexia, epigastric distress, diarrhoea and gastritis, but these effects appear to be dose related.

Hypersensitivity reaction (urticaria, fever, joint pains)

Precautions

Renal and liver Impairment Erythematous rashes common in glandular

fever Increased risk of erythematous rashes in

cytomegalous infection and acute or chronic lymphocytic leukaemia

Contraindications

Its use is contraindicated in hypersensitivity to penicillins

Interactions

Amoxicillin has the same drug interactions with penicillins including an increased risk of rash when given with allopurinol

Amoxicillin + Clavulanic acid

Amoxicillin is susceptible to degradation by β-lactamase producing bacteria.

For this reason, it is often combined with clavulanic acid, a β-lactamase inhibitor.

A mixture of amoxicillin( as the trihydrate or as the sodim salt) and clavulanic acid( as potassium clavulanate)


Clavulanic acid itself has no significant antibacterial activity.

By inactivating beta lactamases, it makes the combination active against beta-lactamase-producing bacteria that are resistant to amoxicillin.

Mechanism of action

The β-lactam ring which accounts for its similarity in structure with the β-lactam antibiotics allows the molecule to interact with β-lactamase.

Clavulanic acid is a suicide inhibitor, covalently bonding to a serine residue in the active site of the β-lactamase.

This restructures the clavulanic acid molecule, creating a much more reactive specie that is attacked by another amino acid present.


This inactivates the enzyme and also restores the antimicrobial activity of amoxicillin against lactamase-secreting-resistant bacteria.

Antimicrobial Spectrum

Staph.aureus E.coli H.influenzae Legionella species Nocardia species M. catarrhalis Klebsiella species Many bacteroides

Comparison of antimicrobial spectrum of amoxicillin and coamoxiclav

Amoxicillin Coamoxiclav

-Streptococcus spp -Nocardia spp

-Non-penicillinase produ -Staph.aureus

cing staph spp -E.coli

-Enterococcus faecalis -H.influenzae

-Proteus spp -Legionalla spp

-M.catarrhalis

-Klebsiella spp

-Many bacteroides

Pharmacokinetics

Absorption: Amoxicillin trihydrate and clavulanate potassium are both generally stable in the presence of acidic gastric secretions and are well absorbed after administration.

Distribution: They are both distributed into the lungs, pleural and peritoneal fluid. Low concentrations are attained in sputum and saliva.


Metabolism: This drug is extensively metabolized in the liver

Excretion: Clavulanic acid is excreted in urine principally by glomerular filtration and amoxicillin by renal tubular filtration.

Pharmacokinetics

Dosing in the fasted or fed state has minimal effect on the drug hence can be taken without regard to meals, however its administration with meals reportedly may minimize adverse GI effects.

Clinical use

It is indicated for use in infections due to beta-lactamase-producing strains where amoxicillin alone is not appropriate including:

Respiratory tract infections Bone and joint infections Genito-urinary and abdominal infections Cellulitis Animal bites

Clinical uses cont.d

Severe dental infections with spreading cellulitis or dental infections not responding to first-line treatment.

Otitis media Sinusitis

Commercially available preps

There are various available forms of this drug on the market and they include:

Powder for oral suspension Chewable tablets Tablets Extended-release tablets


Injection

-powder for reconstitution, coamoxiclav 500/100 (amoxicillin 500 mg as sodium salt, clavulanic acid 100 mg as potassium salt),

-powder for reconstitution, coamoxiclav 1000/200 (amoxicillin 1 g as sodium salt,clavulanic acid 200 mg as potassium salt)

Dosage regimen

By mouth,

Adult - one 250/125 strength tablet every 8 hours; increased in severe infection to one 500/125 strength tablet every 8 hours

Child – 1month-1year, 0.25ml/kg of 125/32 suspension every 8 hours, dose doubled in severe infection; 1-6years, 5ml of 125/31 suspension every 8 hours, dose doubled in severe infection.


By mouth

Child- 6-12 years, 5ml of 250/62 suspension every 8 hours, dose doubled in sever infection.

Severe dental infection (generally not first-line)

Adult and child over 12years, one 250/125 strength tablet every 8 hours for 5days.


By intravenous injection over 3-4 minutes or by intravenous infusion- 1.2g every 8 hours.

Child- 1-3 months, 30mg/kg every 12 hours

3 months – 18 years, 30mg/kg ( max 1.2g) every 8 hours

Adverse effects

Same as amoxicillin including hepatitis Cholestatic jaundice Stevens-johnson syndrome Toxic epidermal necrolysis Exfoliative dermatitis Rarely prolongation of bleeding time Dizziness


Headache Convulsions( particularly with high doses or in

renal impairment) Superficial staining of teeth with suspensions Phlebitis at injection site

Precautions

Maintain adequate hydration with high doses additional to the precautions associated with amoxicillin.

Liver function should be monitored in liver disease

Risk of crystalluria with high doses (particularly during parenteral therapy)

Contraindications

Penicillin hypersensitivity, History of co-amoxiclav-associated or

penicillin-associated jaundice or hepatic dysfunction

Drug interactions

Amoxicillin/Clavulanic acid has no specific interaction information but since it belongs to amoxicillin, the same drug interactions are expected.

Patient counseling points

History of penicillin allergy

May be taken with or without food but better with food as it may prevent stomach upset.

Keep taking this medicine until the course is finished, unless you are told to stop.

Space the doses evenly throughout the day.

Counseling points cont.d

If a dose is missed, take as soon as you remember,

If it is almost time for the next dose, and you take 2 doses a day, take the one you missed and the next dose 5 to 6 hours later.

If you take 3 doses a day, take the one you missed and the next dose 2 to 4 hours later. Then go back to your regular schedule.

Counseling points Cont.d

Suspensions should be refrigerated and discarded between 7days and 10days

Any signs of reaction should be reported immediately.

References

AHFS-America Hospital Formulary Service,

Drug Information Book,

Published by Authority of the Board of the American Society of Health System Pharmacist,

7272, Wisconsin Avenue, Bethesda, MD 20814

Pages 264-363

References cont.d

British National Formulary, 54th Edition,

September, 2007,

Published by Royal Pharmaceutical Society of Great Britain, 1 Lambeth High Street, London, SEI 7JN, UK and

BMJ Publishing Group Ltd,

Tavistock Square, London WCIH 9JP, UK

Pages 332-339

References cont.d

Martindale,2005

The Complete Drug Reference,

1 Lambert High Street, London SEI, 7JN, UK,

Penicillins With Reference to Amoxicillin and Its Combinations

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