L.3.8. Antibiotics and Chemotherapetic Agents

7/30/2019 L.3.8. Antibiotics and Chemotherapetic Agents

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Antibiotics

(anti-microbials)


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Introduction Kock & Pasteur over a century

Discovered cause and effect Once found that

Needed an agent to be created to handle them

Antibiotics = a natural substance produced by a

micro-organism to kill another

Antiinfectives/Anti-microbrial = any agent (natural

or synthetic) that kills pathogens (microbes)

Key: it needs to kill the microbial cell and not be

toxic to normal healthy human cells


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Overview Antibiotics are a large and diverse group of drugs

which combat infections by suppressing the growth

and reproduction of bacteria.

Many bacteria are now resistant to antibiotics and

some are resistant to all known agents.

Antibiotics exploit the differencesbetween bacterial

and human cells.


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Classification Bacteriostatic (inhibit growth without death) or

Bactericidal (Kill)

Spectrum of Activity:

Mechanism of action:

Chemical Structure:


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Bacteriostatic vs Bactericidal Bacteriostatic allows for natural immunity to

deal with the microbe

Antibodies, Phagocytosis etc

Bactericidial may lead to release of toxins and

microbial contents leading to subsequentillness and inflammatory responses.


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Spectrum of Activity Relates to the number of microbes that are susceptible to the

action of the drug

Narrow (limited number) / Broad (wide)

Penicillin G is a narrow spectrum drug as it is only effectiveagainst gram-positive microbe

Tetracyclines are effective against gram-positive and gram-negative microbes (Broad)

Note: Never confusion these terms with potency levels of thedrugs or efficacy (ie. Narrow are weak, Broad are strong)


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Mechanism of Action:

1. Inhibition of Cell Wall Synthesis

2. Disruption of Cell Membrane

3. Inhibition of Protein Synthesis

4. Interference with Metabolic

Processes

NB:Bactericidal

Bacteriostatic


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Inhibition of Cell Wall Synthesis Most bacteria possess a cell wall to protect from

osmotic pressures

Interrupt this leads to new microbes beingsusceptible to external influences

Cell rupturesMicrobe death

Disruption of the microbial cell membrane

function. It affect cell membrane transportationin and out

Eg. Penicillinsm, cephalosporins and

vancomycin


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Inhibition of Protein Synthesis Proteins vital forgrowth and repair

Antibiotics act either at:

The site of protein synthesis (ribosome) or

Within the nucleus by inhibiting synthesis of nucleic acids

DNA replication / RNA synthesis = TRANSCRIPTION

Eg. Tetracyclines, aminoglycosides and macrolides(erythromycin)

Exploit structural differences between microbial andhuman cells

High dose can lead to toxicity


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Interference with metabolic processes

Agents are structurally similar to Para-

aminobensoic acid (PABA)component of

folic acid Essential for nucleic acid synthesis, without it

microbes can not produce the proteins for growth

Exploits: microbes need to create their own folic

acid we get it in our diets.

Eg Sulphonamides


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Antimetabolits:

Block the functioning of metabolic pathways by

competitively inhibiting the use of metabolitesby

key enzymes.

Sulfonamides and several other drugs inhibit folic

acid metabolism.


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Antibacterial DrugsSulfonamides or Sulfa Drugs:

Structural analogues compete with

metabolites in metabolic processes

because of their similarity.

The resulting inhibition of purineand pyrimidine synthesis leads to

cessation of bacterial growth or

death of the pathogen.


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Quinolones: are synthetic drugs that

contain the 4-quinolone ring. Ciprofloxacin,

norfloxacin, and ofloxacin are currently

used.

Quinolones act by inhibiting the bacterial

DNA gyrase or topoisomerase II, probably

by binding to the DNA gyrase complex.

Quinolones:


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Penicillin: Penicillin G or benzylpenicillin, the first

antibiotic to be widely used in medicine.

The mechanism of penicillin actions is still not

completely known.


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Cephalosporins: are a family

of antibiotics originally

isolated from the fungusCephalosporium, and their -

lactam structure is very

similar to that of the

penicillins.


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Antifungal DrugsTreatment of fungal infections generally has been less

successful than that of bacterial infections largely because

eucaryotic fungal cells are much more similar to human cells than

are bacteria. Many drugs that inhibit or kill fungi are therefore

quite toxic for humans.

Nystatin is a antibiotic from Streptomyces, is used to control

Candida infections of the skin and alimentary tract. It is thought todisrupt the mitotic spindle and inhibit cell division and it also may

inhibit protein and nucleic acid synthesis.


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Antiviral DrugsAntiviral drugs interfere with critical

stages in the virus life cycle (amantadine,

rimantadine and ritonavir)

Inhibit the synthesis of virus specific

nucleic acids (zidovudine, adenine

arabinoside, Acyclovir)

Interferon proteins inhibit virus

replication and may be therapeutically

useful in the future.


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Beta-lactams

(penicillins,

cephalosporins)

Broad-spectrum antibiotics*. Flucloxacillin and co-

amoxiclav are effective against some penicillin-

resistant organisms.

Aminoglycosides

(streptomycin,

gentamicin, tobramycin)

Effective against gram negative bacteria e.g.Pseudomonas. Reserved for serious infections e.g.septicaemia, meningitis, hospital-acquired

pneumonia.

Glycopeptides

(vancomycin,

teicoplanin)

Effective against Staphylococci resistant to otherdrugs, including many strains of MRSA**.

Tetracyclines(doxycycline,

minocycline)

Broad-spectrum antibiotics

Table 1 Summary of some common antibiotics


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Macrolides

(erythromycin)

Broad-spectrum antibiotics, prescribed if patient is

allergic to penicillins.

Metronidazole Prescribed for surgical prophylaxis, bacterial

vaginosis, pressure sores, leg ulcers.

Quinolones

(ciprofloxacin)

Effective against gram negative bacteria,

gonorrhoea, gastro-intestinal infections.

Antitubercular drugs

(rifampicin, isoniazid,

rifabutin, streptomycin)

Reserved for treatment/ containment of

tuberculosis(TB).

sulphonamides (co-

trimoxazole,

trimethoprin)

Co-trimoxazole is reserved for serious infections

associated with HIV/AIDS. Trimethoprin is

prescribed for urinary tract infections.

* Broad spectrum antibiotics are used when the infectious agent is unknown.

Narrow spectrum antibiotics are prescribed when the micro-organisms have been identified from

tissue samples.

** Many bacteria produce an enzyme which destroys beta lactam antibiotics. In addition to this,

MRSA (methicilin-resistant Staphylococcus aureus) produces an inactivating protein which

confers resistance to most other antibiotics.


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Indications for antibiotics include:

Treating bacterial infections in accordance withculture and sensitivity testing or (second best)

knowledge of prevalent organisms.

Prophylaxis:

surgery e.g. gastro-intestinal surgery, joint replacement.

meningitis contacts

surgical/ dental procedures in patients with artificial heartvalves or heart valve lesions.


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Administration:

Dose depends on many factors: nature and severity of infection; weight, age and renal

function of patient. Some doses (e.g. gentamicin, vancomycin) are determined

by therapeutic monitoring of venous blood samples,extracted prior to dosing.

Severe infections require intravenous infusion. Observe veins carefully for signs of phlebitis, particularly

with penicillins and vancomycin.


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Intramuscular injections are painful andavoided, unless essential, in children. A warmcompress may reduce pain.

Food affects absorption (table 2).

For other routes, see individual products(BNF).


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Table 2. Oral Administration of antibiotics

Antibiotic Problem Precaution

Tetracyclines,

Quinolones

Absorption impaired by

iron, zinc or calcium in

the stomach

Taken either 1 hour before or 2

hours after tablets containing these

minerals or dairy products.

Doxycycline

Minocycline

Oesophageal or gastric

irritation

Taken with food and a full glass of

water

Ampicillin

Erythromycin Rifampicin

Absorption reduced by

food in the stomach

Taken 1 hour before or 2 hours

after meals

Amoxycillin Absorption reduced by

high fibre diets, e.g. bran

or bulk laxatives e.g.

methylcellulose

Dose increases may be required

Most antibiotics Absorption impaired by

antacids, particularly

those containing

magnesium and

aluminium

Antibiotic taken 1 hour before or 2

hours after antacids


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Adverse effects of antibiotics can be

considered as:

those occurring with all antibiotics (table 3);

those restricted to specific agents (table 4).


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Table 3. Problems Associated with All Antibiotics

Problem Precautions

Resistance Minimise antibiotics unless bacterial sensitivity is

known.

Ensure adequate doses, making allowances for drug-

food interactions.

Complete course.

Avoid spreading infection by observing hospital policies

for hand-washing, asepsis, and single-use equipment.

Try to prevent contact between MRSA and vancomycin-resistant Enterococci by separating patients harbouringthese bacteria. Such contact could allow development of

vancomycin-resistant MRSA.

Hypersensitivity

1-10% of patients arehypersensitive to

penicillins.

Thorough patient history.

Pre-therapy assessment of breathing pattern and skin tofacilitate detection of any changes.

Administer intravenous therapy slowly.


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Superinfection Minimise use of broad-spectrum antibiotics.

Monitor fluid and electrolyte balance if diarrhoea and

vomiting occur and be alert for Chlostridium difficileinfections.

Small frequent meals may alleviate gastro-intestinal

disturbance.

Stomatitis may be alleviated by ice cubes and mouth

care.

Monitor for infections due to fungi (e.g. Candida),Pseudomonas, Enterobacteria.

If aminoglycosides are administered, monitor for

worsening of TB and Herpes infections.

Therapeutic failure Ensure adequate doses and prompt administration.

Certain antibiotics, particularly aminoglycosides,

have a narrow margin between therapeutic dose andtoxicity.


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Table 4. Toxicity associated with antibiotics

Site Antibiotic Precaution

Brain:

ConvulsionsConfusion

Penicillins

CephalosporinsQuinolones

aminoglycosides

Avoid intrathecal route.

Caution in patients with histories ofconvulsions and/or renal failure.

Avoid co-administration of quinolones

and NSAIDs.

Peripheral

nerves:

pain,

numbness,

tingling

aminoglycosides Monitor. Alternative drugs may be

needed.

Inner ear

(hearing &

balance)

Gentamicin

Vancomycin

Rarely:Erythromycin

Avoid other drugs affecting the ear.

Avoid in pregnancy and breastfeeding,

if possible.Ensure patient can hear and balance is

not affected.

Mobilise carefully.

Monitor tinnitus.

Administer intravenous therapy slowly.


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Liver Erythromycin

RifampicinIsoniazid

Rarely:

Tetracyclines

Cephalosporins

Co-amoxiclav

Undertake liver function tests if use

prolonged.Avoid in people with history of alcoholism.

Pancreas Cotrimoxazole Be alert for severe vomiting and painradiating to the back.

Check blood glucose concentration.

Growing

bones & teeth

Tetracyclines

Avoid in pregnant women & children.


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Kidney Gentamicin

Vancomycin

Cotrimoxazole

Rarely:

CephalosporinsPenicillins

Tetracyclines

Check serum creatinine and urea

to assess renal function before and

during therapy.

Seek alternative drug in those over

65.Ensure adequate hydration,

including replacing any losses due

to diarrhoea and vomiting.

Skin

(photosensitivity)

Tetracyclines,

Quinolones

Avoid prolonged exposure to

sunlight. Use high factor, high star

sunscreen

Bone marrow Chloramphenicol

Cotrimoxazole

Rarely:

Cephalosporins

Aminoglycosides

Avoid in patients with history/

family history of bone marrow

problems or taking other drugs

potentially toxic to the marrow (e.g.

carbimazole, carbamazepine,antipsychotics).

Check full blood count routinely

and if sore throat or fever develop.


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Cautions and contraindications

History of hypersensitivity - Patients allergic tocephalosporins are often allergic to penicillins and

vice versa. Patients allergic to diuretics or celecoxibor oral hypoglycaemics may be allergic tosulphonamides.

Glandular fever (Epstein-Barr virus infection),cytomegalovirus infection greatly increase the riskof developing a penicillin-induced rash.


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Impaired renal function causes some drugs to

accumulate e.g. penicillins, tetracyclines,

vancomycin, ciprofloxacin, teicoplanin.

Impaired liver function causes some drugs to

accumulate e.g. metronidazole, rifampicin.

Myasthenia gravis. Aminoglycosides and

quinolones exacerbate this condition.


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Porphyria. Avoid sulphonamides, cephalosporins,erythromycin, flucloxacillin, rifampicin, trimethoprin

Pregnancy: Penicillins are usually the antibiotics of firstchoice. Tetracyclines, trimethoprin, cotrimazole,glycopeptides and aminoglycosides are avoided if possible.

Breastfeeding allows small amounts of antibiotic to passfrom mother to infant. Hypersensitivity responses andadverse effects may occur in the infant. Breastfeeding is notadvised in some severe infections.


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Drug Interactions

Adverse effects are cumulative when drugs causing similarproblems are co-administered. For example, drugs damagingthe inner ear (e.g. gentamicin, vancomycin, teicoplanin,cisplatin, furosemide), are rarely combined (table 4).

Susceptible people suffer an antabuse-like reaction if theytake even a small amount of alcohol with certain antibiotics,

usually metronidazole or cephamandole. This results indilatation of all the blood vessels, causing flushing, severeheadache and profound hypotension. Faints, falls andcardiovascular collapse may follow.


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Oral contraceptives Rifampicin and rifabutin render all oral contraceptives

ineffective. All broad spectrum antibiotics increase the risk of 'pill

failure' for combined oral contraceptives.

Many antibiotics are incompatible with other drugs

when co-administered in intravenous infusions. Forexample, if gentamicin is combined with heparin or a

penicillin, its antibiotic activity will be lost.


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Aminoglycosides intensify the action of muscle

relaxants such as suxamethonium. Their use

must be highlighted when the patient istransferred to the anaesthetic team.

Macrolides cause accumulation of other drugse.g. digoxin, corticosteroids, anti-coagulants.


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Textbook References

Karch AM (2006) Focus on Nursing Pharmacology,3rd Edition. Lippincott Williams & Wilkins

Rang et al (2003) Pharmacology, 5th Edition.

Churchill Livingstone. Lilley et al (2005) Pharmacology and the Nursing

Process, 4th Edition. Mosby

Page et al (2002) Integrated Pharmacology, 2ndEdition. Mosby.

Martini (2005) Principles of Anatomy andPhysiology, Pearson Education Publishers

Documents

L.3.8. Antibiotics and Chemotherapetic Agents