antimicrobial chemotherapy

Question 1

what does bactericidal and minimal bactericidal concentrations mean?

Answer 1

bactericidal - antimicrobial that kills bacteria

minimal bactericidal concentration - minimum concentration of bactericidal needed to kill a given organism

Question 2

what do bacteriostatic and minimal inhibitory concentrations mean?

Answer 2

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.

Question 3

what are the 3 routes of administration?

Answer 3

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

Question 4

how do you classify bacteria based on shape and gram staining due to cell wall composition?

Answer 4

Cocci (spheres)

Bacilli (rods)

Spirals

Gram-positive (purple) → (thick peptidoglycan wall)

Gram-negative (pink)→ (thin peptidoglycan wall)

Question 5

what are 3 different areas of metabolic activity that antibiotics can act on to inhibit/kill bacteria?

Answer 5

1- Inhibition of cell wall synthesis

2- Inhibition of protein synthesis

3- Inhibition of nucleic acid synthesis

Question 6

what are two types of antibiotics that inhibit cell wall synthesis? give 2 examples of each

Answer 6

[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

Question 7

How do beta-lactams (Penicillins & Cephalosporins) inhibit cell wall synthesis?

Answer 7

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.

Question 7

Why are gram-negative organisms resistant to Benzylpenicillin?

Answer 7

Because Benzylpenicillin is unable to penetrate gram-negative cell wall

Question 8

How do glycopeptides (Vancomycin & Teicoplanin) inhibit cell wall synthesis?

Answer 8

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

Question 9

what are 5 antibiotics that inhibit protein synthesis? state type of antibiotic, whether they’re cidal/static and what they treat

Answer 9

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.

Question 10

Why do antibiotics that inhibit protein synthesis not affect both bacterial and mammalian ribosomes?

e.g. Aminoglycosides → Gentamicin

Answer 10

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

Question 10

what are aminoglycosides (Gentamicin)? how do they inhibit protein synthesis?

Answer 10

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)

Question 10

what are macrolides (erythromycin)? how do they inhibit protein synthesis?

Answer 10

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.

Question 11

what are tetracyclines? how do they inhibit protein synthesis?

Answer 11

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

Question 12

what are cyclic lipopeptides (daptomycin)? how do they inhibit protein synthesis?

Answer 12

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).

Question 12

what are oxazolidinones (linezolid)? how do they inhibit protein synthesis?

Answer 12

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

Question 12

what are 2 types of antibiotics used for the inhibition of nucleic acid synthesis?

Answer 12

[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.

Question 12

How do Purine synthesis inhibitors (Trimethoprim and Sulphamethoxazole) inhibit nucleic acid synthesis?

Answer 12

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

Question 13

what does the combination of trimethoprim and sulphamethoxazole make?

Answer 13

Combination = Co-trimoxazole → direct inhibition of DNA synthesis

Question 14

How do Fluoroquinolones (Ciprofloxacin & Levofloxacin) inhibit nucleic acid synthesis?

Answer 14

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.

Question 15

what are 2 types of resistance? give examples and state if lab sensitivity is neccessary

Answer 15

[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.

Question 16

what are two ways in which resistance is acquired?

Answer 16

[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).

Question 17

what is horizontal gene transfer?

Answer 17

when genetic material is moved between organisms using a method other than the Vertical transmission of DNA through reproduction.

Question 18

what are the 3 ways through which horizontal gene transfer is done?

Answer 18

conjugation: DNA transfers bacterial cells

transformation: naked DNA uptake by bacteria

transduction: bacterial DNA transferred by viruses (phage)

Question 19

how is β-lactamase production a method of resistance? give example

Answer 19

bacterial enzymes cleave the β–lactam ring of the antibiotic and thus render it inactive.

e.g.
Staph. aureus (hospital strains) & Gram-negative bacilli

Question 20

what are 2 ways to combat beta-lactamase? give two examples

Answer 20

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.

Question 21

what are extended-spectrum beta-lactamases?

Answer 21

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.

Question 22

what type of resistance does carbapenemase-producing enterobacteriaceae have? what is it?

Answer 22

→ 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

Question 23

what is carbapenem resistant enterobacteriaceae? what type of resistance does it have?

Answer 23

→ intrinsic resistance

a bacterium that is a member of the Enterobacteriaceae family resistant to the carbapenem class of antibiotics by any means

Question 24

what is a clinical problem relating to carbapenems?

Answer 24

gram negative organisms being extremely resistant to them

Question 25

what are penicillins, cephalosporins and carbapenems?

Answer 25

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

Question 26

what are beta lactamases? give an examples

Answer 26

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

Question 27

how do micro organisms develop resistance to beta lactams?

Answer 27

Alteration of penicillin binding protein (PBP) target site through horizontal gene transfer and natural selection

β–lactams will no longer bind.

Question 27

what is methicillin resistant staph.aureus? what 2 drugs can treat it?

Answer 27

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

Question 27

why can flucloxacillin be use to treated s.aureus not mrsa?

Answer 27

Flucloxacillin → β-lactamase resistant.

Can be used to treat β-lactamase producing S. aureus, but not MRSA.

Question 28

what is vancomycin (glycopeptide) resistance

Answer 28

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

Question 29

what is the incidence of adverse reactions to antimicrobials dependent upon?

Answer 29

dose and duration of therapy

Approx. 5% of hospitalised patients will develop adverse reaction(s) to antimicrobials.

Question 30

what are 9 side effects and toxicity of antibiotics?

Answer 30

[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.

Question 30

what is stevens-johnson syndrome?

Answer 30

a severe and sometimes fatal form of delayed hypersensitivity associated with the sulphonamides
(skin and mucous membranes are involved).

Question 31

what is pseudomembranous colitis?

Answer 31

Pseudomembranous colitis refers to swelling or inflammation of the large intestine (colon) due to an overgrowth of Clostridioides difficile (C difficile) bacteria.

Question 32

what are 4 patient factors to consider when prescribing antibiotics?

Answer 32

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.

Question 33

what does contraindication mean?

Answer 33

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.

Question 34

what are 2 indications for antimicrobials?

Answer 34

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.

Question 34

what are 2 drug related considerations?

Answer 34

[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

Question 34

what does indication mean?

Question 35

When antimicrobials are used in combination, what are the three possible outcomes:

And give an example of combination:

Answer 35

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.

Question 35

Why is it sometimes necessary to use antimicrobials in combination instead of monotherapy?

Answer 35

• 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).

Question 36

what are the rules of combining drugs?

Answer 36

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.

Question 37

Why do we have to take Penetration to site of infection of antibiotics into consideration in clinical practice?

Answer 37

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.

Question 38

Why must Gentamicin and Vancomycin be constantly monitored when administered to a patient?

Answer 38

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.

Question 38

what are 4 types of antifungal drugs?

Answer 38

[1] Polyenes

[2] Azoles

[3] Allylamines

[4] Echinocandins

Question 38

what are polyenes? give 2 examples:

Answer 38

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)

Question 39

what are azoles? give 2 examples:

Answer 39

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.

Question 40

what are allyamines? give an example:

Answer 40

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.

Question 41

what is aciclovir?

Answer 41

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.

Question 41

what are echinocandins? give 3 examples:

Answer 41

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.

Question 41

how do antiviral drugs work?

Answer 41

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.