l.3.8. antibiotics and chemotherapetic agents
TRANSCRIPT
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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