antimicrobial chemotherapy Flashcards
what does bactericidal and minimal bactericidal concentrations mean?
bactericidal - antimicrobial that kills bacteria
minimal bactericidal concentration - minimum concentration of bactericidal needed to kill a given organism
what do bacteriostatic and minimal inhibitory concentrations mean?
Bacteriostatic - an antimicrobial that inhibits the growth of bacteria.
Minimal inhibitory concentration (M.I.C.) is the minimum antimicrobial concentration needed to inhibit a given organism’s growth.
what are the 3 routes of administration?
topical → Applied to a surface (skin or to mucous membranes)
Systemic → Taken internally (orally or parenterally)
Parenteral → Administered intravenously (I.V.) or intra-muscularly (I.M.), occasionally subcutaneously
how do you classify bacteria based on shape and gram staining due to cell wall composition?
Cocci (spheres)
Bacilli (rods)
Spirals
Gram-positive (purple) → (thick peptidoglycan wall)
Gram-negative (pink)→ (thin peptidoglycan wall)
what are 3 different areas of metabolic activity that antibiotics can act on to inhibit/kill bacteria?
1- Inhibition of cell wall synthesis
2- Inhibition of protein synthesis
3- Inhibition of nucleic acid synthesis
what are two types of antibiotics that inhibit cell wall synthesis? give 2 examples of each
[1] Penicillins and Cephalosporins → beta-lactams
(contain beta-lactam rings in their structure)
They are Bactericidal antibiotics, effective mostly against gram-positive bacteria.
[2] Vancomycin and Teicoplanin → Glycopeptides
They are Bactericidal antibiotics, they act only against gram-positive bacteria.
Can only be given parenterally
How do beta-lactams (Penicillins & Cephalosporins) inhibit cell wall synthesis?
They disrupt peptidoglycan synthesis by binding to the enzymes (penicillin-binding proteins, PBPs) responsible for cross-linking the carbohydrate chains.
When they bind to the enzyme (PBP) they inhibit/deactivate it.
Why are gram-negative organisms resistant to Benzylpenicillin?
Because Benzylpenicillin is unable to penetrate gram-negative cell wall
How do glycopeptides (Vancomycin & Teicoplanin) inhibit cell wall synthesis?
They disrupt peptidoglycan synthesis by inhibiting the assembly of peptidoglycan precursors so that the enzyme (PBP) cannot bind to them.
They act on cell wall synthesis at a stage before β-lactams.
Vancomycin → careful I.V. infusion to avoid high concentrations → toxicity
Teicoplanin → less toxic than vancomycin → single daily dosing
what are 5 antibiotics that inhibit protein synthesis? state type of antibiotic, whether they’re cidal/static and what they treat
Gentamicin → Aminoglycosides
They are Concentration-dependent bactericidal antibiotics,
Treatment of serious Gram-negative infection (e.g. coliform).
Erythromycin → Macrolides
They are bactericidal or bacteriostatic antibiotics.
Alternatives to penicillins in the treatment of Gram-positive infections
in patients who are penicillin allergic.
Tetracyclines
They are bacteriostatic antibiotics.
Treatment of Gram-positive infections
Linezolid → Oxazolidinones
Bacteriostatic or bactericidal antibiotics depend on the bacteria being treated.
Treatment of Gram-positive infections.
Daptomycin → Cyclic Lipopeptide
They are strong bactericidal antibiotics.
Treatment of Gram-positive infections.
Why do antibiotics that inhibit protein synthesis not affect both bacterial and mammalian ribosomes?
e.g. Aminoglycosides → Gentamicin
Protein synthesis involves the translation of messenger RNA at the ribosome and differences between the bacterial ribosome and the mammalian ribosome allow selective action on bacterial protein synthesis.
Bacterial ribosome → 70S
Mammalian ribosome → 80S
what are aminoglycosides (Gentamicin)? how do they inhibit protein synthesis?
concentration-dependent bactericidal antibiotics
bind to 70S ribosome
impairs translational proofreading
misreading of the RNA message or/and premature termination
inaccurate translated protein product.
e.g. Gentamicin → requires careful dosing (Toxic)
what are macrolides (erythromycin)? how do they inhibit protein synthesis?
they’re bactericidal/ static antibiotics
stop the elongation of the peptide
interferes with sites A and P in the enzyme.
They inhibit the bacterial protein biosynthesis, by preventing peptidyltransferase from adding the growing peptide attached to tRNA to the next amino acid
inhibits ribosomal translation.
what are tetracyclines? how do they inhibit protein synthesis?
they’re bacteriostatic antibiotics that prevent the attachment of tRNA to the A site on the ribosome.
binds to the 30S and 50S subunits of microbial ribosomes
prevents the introduction of new amino acids to the nascent peptide chain.
A significant percentage (10% or more) of Staph. aureus, Strep. pyogenes and Strep. pneumonia strains are resistant to them
what are cyclic lipopeptides (daptomycin)? how do they inhibit protein synthesis?
they’re strong bactericidal antibiotics
alters the curvature of the membrane
creates holes that leak ions
causing rapid depolarization
inhibits protein, DNA and RNA synthesis
cell death.
e.g. Daptomycin → against MRSA & used in serious infections
(when other antibiotics don’t work).
what are oxazolidinones (linezolid)? how do they inhibit protein synthesis?
they’re bacteriostatic or bactericidal antibiotics that prevent the formation of 70S subunit complex
inhibits the ribosomal 50S subunit.
No 70S complex = no Protein synthesis
e.g. Linezolid → given orally, held in reserve for treatment of serious infection
what are 2 types of antibiotics used for the inhibition of nucleic acid synthesis?
[1] Trimethoprim and Sulphamethoxazole → Inhibition in purine synthesis
They are Bacteriostatic antibiotics, but when combined they are Bactericidal
When combined they form → co-trimoxazole
[2] Ciprofloxacin and Levofloxacin → Fluoroquinolones
They are Bactericidal antibiotics,
particularly effective against Gram-negative organisms, including Pseudomonas
Used orally as well as parenterally.
How do Purine synthesis inhibitors (Trimethoprim and Sulphamethoxazole) inhibit nucleic acid synthesis?
they’re bacteriostatic
when combined they become Bactericidal antibiotics that Inhibit DNA synthesis either directly, or indirectly by interrupting the supply of precursors for DNA synthesis.
e.g.
Trimethoprim → indirect inhibition of DNA synthesis
- Treatment of urinary tract and chest infections
(less likely than cephalosporins to cause Clostridium difficile infections).
Sylphamethoxazole → indirect inhibition of DNA synthesis
what does the combination of trimethoprim and sulphamethoxazole make?
Combination = Co-trimoxazole → direct inhibition of DNA synthesis
How do Fluoroquinolones (Ciprofloxacin & Levofloxacin) inhibit nucleic acid synthesis?
they’re bactericidal antibiotics that directly inhibit DNA synthesis by inhibiting an enzyme called DNA gyrase which prevents DNA duplication.
e.g.
Ciprofloxacin → interference with cartilage growth → not used in children
Levofloxacin → may have more activity against Gram-positives (e.g. the pneumococcus), sometimes used in chest infections.
what are 2 types of resistance? give examples and state if lab sensitivity is neccessary
[1] Intrinsic resistance - all strains of a given species are naturally resistant to an antibiotic
e.g.
Streptococci → resistant to aminoglycosides
Gram-negative organisms → resistant to vancomycin
(unable to penetrate cell wall)
Lab sensitivity testing is irrelevant
[2] Acquired resistance - may be present in some strains but not in others
e.g.
30% of E.coli strains are resistant to ampicillin
Lab sensitivity testing is required to establish the sensitivity of any bacteria isolated from a patient.
what are two ways in which resistance is acquired?
[1] Spontaneous mutation → if positive, it will be retained throughout the generations.
A change in structure or function that no longer allows the antibiotic to act (the target may have changed).
“Mistakes” happen spontaneously during DNA replication, repair, or recombination.
[2] spread of resistance
The gene/s that code for resistance can spread from organism to organism or from species to species.
Genes can be carried on:
1- Plasmids (extrachromosomal packages of DNA)
2- Transposons (packets of DNA which insert themselves into the chromosome).
what is horizontal gene transfer?
when genetic material is moved between organisms using a method other than the Vertical transmission of DNA through reproduction.
what are the 3 ways through which horizontal gene transfer is done?
conjugation: DNA transfers bacterial cells
transformation: naked DNA uptake by bacteria
transduction: bacterial DNA transferred by viruses (phage)
how is β-lactamase production a method of resistance? give example
bacterial enzymes cleave the β–lactam ring of the antibiotic and thus render it inactive.
e.g.
Staph. aureus (hospital strains) & Gram-negative bacilli
what are 2 ways to combat beta-lactamase? give two examples
1- Modification of antibiotic side chain by combination producing new antibiotic-resistant to β-lactamase
e.g.
co-amoxiclav → amoxicillin plus the β-lactamase inhibitor clavulanic acid.
2- Introduction of a 2nd component to the antibiotic protecting it from enzymatic degradation
e.g.
Flucloxacillin: (antistaphylococcal) is a modified form of penicillin.
what are extended-spectrum beta-lactamases?
they’re enzymes that mediate resistance to extended-spectrum (third-generation) cephalosporins.
Antibiotic resistance transferred by conjugation (using plasmids) to resist cephalosporins:
The problem in hospitals by some Gram-negative organisms.
Patients are isolated to stop organisms from spreading.
what type of resistance does carbapenemase-producing enterobacteriaceae have? what is it?
→ acquired resistance
a bacterium that is a member of the Enterobacteriaceae family resistant to the carbapenem class of antibiotics through the production of a carbapenemase
what is carbapenem resistant enterobacteriaceae? what type of resistance does it have?
→ intrinsic resistance
a bacterium that is a member of the Enterobacteriaceae family resistant to the carbapenem class of antibiotics by any means
what is a clinical problem relating to carbapenems?
gram negative organisms being extremely resistant to them
what are penicillins, cephalosporins and carbapenems?
beta lactam class of antibiotics
They were highly effective antibiotic agents used for the treatment of severe or high-risk bacterial infections (reserved for known or suspected multidrug-resistant (MDR) bacterial infections).
But nowadays they are less useful because of bacteria acquired resistance → carbapenemase production
what are beta lactamases? give an examples
e.g. carbapenemase
they are enzymes that cleave beta-lactam rings, so they don’t allow them to bind to the enzyme (PBP) and thus there is no disruption of cell wall synthesis
how do micro organisms develop resistance to beta lactams?
Alteration of penicillin binding protein (PBP) target site through horizontal gene transfer and natural selection
β–lactams will no longer bind.
what is methicillin resistant staph.aureus? what 2 drugs can treat it?
MRSA is any strain of S. aureus that has developed, through horizontal gene transfer and natural selection, multiple drug resistance to β-lactam antibiotics.
It can be treated with
Vancomycin → glycopeptide
Linezolid → oxazolidinone
why can flucloxacillin be use to treated s.aureus not mrsa?
Flucloxacillin → β-lactamase resistant.
Can be used to treat β-lactamase producing S. aureus, but not MRSA.
what is vancomycin (glycopeptide) resistance
Glycopeptides - treatment of serious Gram-positive infection
Recently vancomycin resistant enterococci (VRE) have emerged
they have an altered structure peptidoglycan precursor to which vancomycin normally binds.
This could be a major problem if it spreads to MRSA
→ because it will be resistant to both B-lactam & Vancomycin
what is the incidence of adverse reactions to antimicrobials dependent upon?
dose and duration of therapy
Approx. 5% of hospitalised patients will develop adverse reaction(s) to antimicrobials.
what are 9 side effects and toxicity of antibiotics?
[1] Allergic reactions
Any antimicrobial: commonly associated with the β-lactam.
[2] Immediate hypersensitivity → within minutes
→ Anaphylactic shock (parenteral administration of the antibiotic).
IgE mediated occurs within minutes of administration.
Itching, urticaria, nausea, vomiting, wheezing and shock.
Laryngeal oedema may prove fatal unless the airway is cleared.
[3] Delayed hypersensitivity → hours or days
→ Immune Complex or Cell Mediated Mechanism.
Rashes, fever, serum sickness and erythema nodosum may also occur.
Rashes are usually maculopapular and restricted to the skin.
[4] Gastrointestinal side effects
Nausea and vomiting are common.
Diarrhoea associated with toxin production by Clostridium difficile.
C. difficile anaerobic gram-positive bacillus asymptomatic (commensal) in the GI tract, overgrowth of normal flora during antibiotic therapy and produces toxins.
Mild form → C. difficile associated diarrhoea (CDAD) or infection (CDI)
Life threatening condition → pseudomembranous colitis
Diagnosis → done by detection of toxin in the stool by enzyme immunoassay (EIA).
Treatment → with oral metronidazole or oral vancomycin
(not absorbed from the GI tract, only circumstance in which the oral form is used).
[5] Thrush → overgrowth of the yeast Candida albicans, resulting in oral and/or vaginal candidiasis.
This may be a complication in therapy using penicillins or cephalosporins
[6] Liver toxicity
→ check patient history and liver health
The liver is susceptible to a variety of side effects
→ Transient elevation of liver enzymes or severe hepatitis.
More common in patients with pre-existing liver disease and in pregnancy.
Tetracycline and the anti-tuberculous drugs isoniazid (INH) and rifampicin have been associated with such hepatotoxicity.
[7] Renal toxicity → check patient history and kidney health
The kidney is the most important route of drug excretion.
Nephrotoxicity is dose related more common in patients with pre-existing renal disease.
Most common with the aminoglycoside group
(e.g. gentamicin, netilmicin and amikacin) or with vancomycin.
Levels of these antibiotics in the blood should be regularly monitored.
Nephrotoxicity is usually reversible but may be permanent.
[8] Neurological toxicity
A- Ototoxicity
This is most often seen following aminoglycoside or vancomycin use.
B- Optic Neuropathy
Ethambutol (an anti-tuberculous drug) associated with dose related optic nerve damage.
Regular monitoring of optic nerve function during therapy is recommended.
C- Peripheral neuropathy
Metronidazole and nitrofurantoin produce reversible peripheral neuropathy of uncertain mechanism.
The anti-tuberculous drug isoniazid acts by competitive inhibition with pyridoxine (vitamin B6), may induce peripheral neuropathy.
D- Encephalopathy and Convulsions
High dose penicillin and cephalosporin or
(if the dose is not reduced in the presence of renal impairment).
[9] Haematological Toxicity
Toxic effect on the bone marrow resulting in:
- Selective depression of one cell line
(e.g., neutropenia) - Unselective depression of all bone marrow elements
(e.g., pancytopenia).
Co-trimoxazole (sulphonamide and trimethoprim) act by competitive inhibition of folic acid synthesis in both bacteria and mammalian cells.
The resulting folate deficiency leads to megaloblastic anaemia after prolonged therapy.
The toxicity of some antivirals requires close monitoring of blood counts is required
(e.g.: zidovudine (HIV), ganciclovir (CMV)).
Anti MRSA agent linezolid also causes bone marrow suppression and may lower platelet counts.
what is stevens-johnson syndrome?
a severe and sometimes fatal form of delayed hypersensitivity associated with the sulphonamides
(skin and mucous membranes are involved).
what is pseudomembranous colitis?
Pseudomembranous colitis refers to swelling or inflammation of the large intestine (colon) due to an overgrowth of Clostridioides difficile (C difficile) bacteria.
what are 4 patient factors to consider when prescribing antibiotics?
Patient Characteristics to consider when prescribing antibiotics:
[1] Age
Certain drugs contraindicated in children
(e.g., Ciprofloxacin, thought to affect developing cartilage).
[2] Renal Function
Many antimicrobials are excreted by the kidneys.
Tend to accumulate in the body in cases of renal failure.
Doses will need to be decreased proportional to the degree of renal insufficiency
[3] Liver Function
Antimicrobials may be metabolised by the liver and excreted in bile.
Doses should be decreased in hepatic insufficiency or alternate drug should be chosen if possible.
[4] Pregnancy
Some antimicrobials contraindicated in pregnancy.
- mutagenic: induce mutation in foetal chromosomes
- teratogenic: associated with congenital abnormalities
or both (e.g., metronidazole and trimethoprim).
Others are contraindicated because effects on unborn foetus are unknown
Safe to use - penicillins, cephalosporins and the urinary antiseptic nitrofurantoin.
what does contraindication mean?
a contraindication is a condition or factor that serves as a reason to withhold a certain medical treatment due to the harm that it would cause the patient.
what are 2 indications for antimicrobials?
Indication for Antimicrobials
[1] Prophylaxis - Administration of antimicrobials to prevent the future occurrence of infection.
Given when:
Patient exposed to other patients with highly communicable disease
Or shortly about to be subjected to surgical procedures with high post-operative infection rates.
e.g. abdominal operations
Dosage should cover the period of risk only (usually one dose pre-operatively).
Not be extended to avoid selecting out resistant organisms.
[2] Therapy - When the organism(s) causing infection is unknown, empirical antimicrobial therapy may have to be commenced if urgent treatment is required.
Take into account the site and type of infection and the likely causative organisms and their common antimicrobial susceptibility patterns
e.g.
An adult admitted to hospital with a community acquired lobar pneumonia
is likely to be infected with pneumococci and thus
an agent such as benzylpenicillin or amoxicillin should be included.
Intra-abdominal infection would require an agent or combination or agents
that are likely to cover coliform and anaerobic organisms.
The treatment prescribed should always be reviewed
once the results of culture and antibiotic sensitivity tests become available.
what are 2 drug related considerations?
[1] Spectrum of antimicrobial agent
The antibiotic chosen should normally be effective against the known or likely causative organism(s).
Ideally the choice will be based on the results of sensitivity tests
after the infecting organism has been isolated, but it may not always be possible to wait until this result is available and an educated guess must be made.
[2] Monotherapy vs. combination
The simplest approach i.e. monotherapy, is generally best, but sometimes it is necessary to use antimicrobials in combination
what does indication mean?
When antimicrobials are used in combination, what are the three possible outcomes:
And give an example of combination:
1- Their effects are additive.
2- They are antagonistic and their combined effect is less than the sum of their individual contributions.
3- They are synergistic and their combined effect is greater than the sum of their individual contributions.
e.g. combination of penicillin and gentamicin.
(streptococcal infective endocarditis).
Penicillin breaks down the streptococcal cell wall,
and allows gentamicin access to the ribosome.
Why is it sometimes necessary to use antimicrobials in combination instead of monotherapy?
- To cover mixed infection by more than one organism.
- Because two antimicrobials sometimes have an enhanced effect together.
-To minimise the development of resistant strains to any one agent
(especially in the treatment of TB or HIV).
what are the rules of combining drugs?
Combination of two cidal drugs or two static drugs is additive or synergistic
Combination of one static and one cidal drug may result in antagonism
Commonly used bacteriostatic drugs include:
macrolides (e.g. erythromycin), tetracyclines and trimethoprim.
Why do we have to take Penetration to site of infection of antibiotics into consideration in clinical practice?
Because Antimicrobial with high serum concentrations, appropriate spectrum and excellent safety profile, but unable to penetrate to the site of infection is of little use in clinical practice.
Why must Gentamicin and Vancomycin be constantly monitored when administered to a patient?
Gentamicin and Vancomycin have a low therapeutic index.
This means that the difference between a therapeutic and a toxic dose is small.
Serum levels should be monitored, the decision to use them influenced by availability or facility to measure the drug.
what are 4 types of antifungal drugs?
[1] Polyenes
[2] Azoles
[3] Allylamines
[4] Echinocandins
what are polyenes? give 2 examples:
Bind to ergosterol this results in an increase in the permeability of the cell wall by making pores.
Active against both yeasts and filamentous fungi.
They bind to other sterols (e.g. cholesterol) in mammalian cell membranes → toxicity.
e.g.
1- Amphotericin B
→ only drug for IV use to treat serious systemic fungal infection
→ Extremely toxic (renal & hepatic toxicity)
→ Lipid complexed types have reduced side effects
→ Resistance to it is unusal
2- Nystatin
→ drug available for topical use (e.g. cream & pessaries & oral suspension)
what are azoles? give 2 examples:
antifungal drugs that inhibit ergosterol synthesis
e.g.
[A] Imidazoles
→ miconazole & ketoconazole (irrelevant)
[B] Triazoles
1- Fluconazole → Oral and parenteral treatment of yeast infections.
No serious toxicity problems. Resistance among some Candida species is emerging.
2- Itraconazole
Active against both yeasts and filamentous fungi, including Aspergillus spp. and dermatophytes.
3- Voriconazole
To treat aspergillosis.
what are allyamines? give an example:
antifungal drugs that suppress ergosterol synthesis
act at a different stage of the synthetic pathway from azoles.
e.g.
Only one in use is Terbinafine
Active against dermatophyte infections of the
skin (e.g., ringworm, athlete’s foot) and nails (onychomycosis).
Mild infections are treated topically and more serious infections (including onychomycosis) orally.
what is aciclovir?
Aciclovir is an anti-herpes virus drug that is a nucleoside analogue, It must first be converted into its active form by an enzyme (thymidine kinase) coded for by the virus genome.
It is specific for virus-infected cells and has very low toxicity for uninfected host cells.
Extremely active against Herpes Simplex virus and is active against Varicella Zoster virus.
what are echinocandins? give 3 examples:
new class of antifungal drugs that inhibit the synthesis of glucan polysaccharide in several types of fungi.
used for serious Candida and Aspergillus infections
e.g. caspofungin, micafungin and anidulafungin.
how do antiviral drugs work?
Antibiotics have no action against viral infections
There are no virucidal agents (i.e. those that will kill the virus)
but that they are all virustatic (i.e. inhibit growth and/or replication)
Many anti-viral drugs are nucleoside analogues which interfere with nucleic acid synthesis.
