Antibacterial & Antifungal Agents Flashcards
What is the purpose of antimicrobial agents?
In which 2 circumstances are they used?
they are used to kill microorganisms while preserving the life of the patient
they are used in treatment of established infections
and
prophylaxis of possible infections
What is the difference between treating an established infection and prophylactic treatment?
established infections:
- these are infections that have already been diagnosed
prophylactic treatment:
- this involves treatment of infections that haven’t yet happened, but may happen
- e.g. giving an antibiotic to someone in close contact with an infected person
What is meant by an antibmicrobial agent having selective toxicity?
they must kill the organisms whilst preserving the life of the patient
the antimicrobial must be non-toxic to the person with the infection
What are the 3 stages involved in the strategy of antibiotic use?
1. empiric therapy
- this is known as “best guess” therapy
2. targeted therapy
- this is used once the organism has been identified through laboratory tests
3. susceptibility-guided therapy
- you know exactly what the organism is and what it is susceptible to after antimicrobial susceptibilty results
What is the first stage in diagnosing an infection?
What type of antibiotic therapy should be used at this stage?
clinical diagnosis based on history and examination
you know the organism that is involved, but not exactly what is causing the disease
empiric therapy is used based on where the infection is, the organisms which are likely to cause it and the antibiotics that are effective against the suspected organisms
Once you have received results from laboratory examinations, what type of antibiotic therapy is used?
the lab results identify the organism that is causing the infection
targeted therapy is used based on the organism’s likely antimicrobial sensitivity
What type of therapy is used once you have received the antimicrobial susceptibility results?
susceptibility-guided therapy
you now know exactly what organism is causing the infection and which antibiotics it is sensitive to
How does the antimicrobial spectrum change as knowledge increases?
as the level of knowledge of the infecting organism increases, the antimicrobial spectrum of the agent(s) used decreases
What are the 3 stages involved in choosing the right empiric antimicrobial agent?
1. know the likely organism causing infection
- body site
- immunological status of patient
- microbiological history
2. select agent with appropriate antimicrobial spectrum
3. match pharmacokinetics with patient
- distribution
- interactions
- adverse effects
Why is it important to know a patient’s immunological status when choosing the right empiric antimicrobial agent?
an immunocompromised patient will have a different spectrum of organisms which are able to cause infection
What are the definitions of antimicrobial agents and antibiotics?
antimicrobial agents:
- these are any agents which kill microorganisms
- e.g. antibacterial, antifungal, antiviral
antibiotics:
- these are chemical products of microbes that inhibit or kill other organisms
What are the 3 main categories of antimicrobial agents?
- antibiotics
- synthethic compounds with similar effect e.g. sulfonamides
- semi-synthetic compounds i.e. modified from antibiotics
Why are semi-synthetic antimicrobials used?
these are antibiotics that have been chemically modified to improve them in some way
e.g. to make it less toxic or more broad spectrum
What is meant by a bacteriostatic/fungistatic organism?
What is an example?
this will not actually kill the organism, it will just inhibit growth
the immune system then destroys the organism
e.g. protein synthesis inhibitors
What is meant by a bacteriocidal/fungicidal antimicrobial?
What is an example?
these will kill the organism that they are targeting
e.g. cell wall-active agents
without a fully functional cell wall, the bacteria or fungi will die
What is meant by minimum inhibitory concentration (MIC)?
minimum concentration of antimicrobial agent at which visible growth is inhibited
What is meant by minimum bactericidal/fungicidal concentration (MBC/MFC)?
the minimum concentration of antimicrobial agent at which most organisms are killed
What is meant by synergy / synergism?
when the activity of two antimicrobials given together is greater than the activity of either if given separately
“additive effect” is used to describe this
What is meant by antagonism?
when the activity of two antimicrobials given together is less than the activity of either if given separately
i.e. the second antibiotic that is given will inhibit the function of the original antibiotic
Why is synergy and antagonism important in clinical practice?
there are some combinations of antibiotics which can be used together to improve patient outcome
there are some combinations which should not be used together
What is meant by the antimicrobial spectrum?
the range of bacterial/fungal species likely to be sensitive to a particular antibacterial/antifungal agent
What is the difference between a broad spectrum and a narrow spectrum antimicrobial?
broad spectrum:
- kills most types of bacteria/fungi encountered
narrow spectrum:
- kills only a narrow range of organisms
Why is it important to have knowledge of the antimicrobial spectrum?
it is important in choosing appropriate empiric antimicrobial therapy
the narrowest spectrum antibiotic that is appropriate should be used at all times
In general, how do antimicrobial agents work?
through inhibition of critical process in bacterial/fungal cells
“antimicrobial targets” are the critical processes in the cell that the antibiotic inhibits
What processes / molecules act as antimicrobial targets?
enzymes, molecules or physical structures
- cell wall
- protein synthesis
- DNA synthesis
- RNA synthesis
- membrane function
what is meant by the antimicrobial agent exhibiting selective toxicity?
the target is not present in the human host
or the target is present in the human host, but it is inaccessible to the antimicrobial agent
What is the bacterial cell wall made from?
What is the structure like?
peptidoglycan
this makes up the cell wall of gram-positive and gram-negative bacteria
it is a polymer of glucose derivatives - N-acetyl muramic acid (NAM) and N-acetyl glucosamine (NAG)
Why is the peptidoglycan cell wall a good target for selective toxicity?
there is no cell wall present in human cells
What are examples of cell wall synthesis inhibitors?
B-lactams and glycopeptides
B-lactams are most commonly used, but some patients have an allergy to penicillin, so the second line is glycopeptides
What do all the B-lactam antibiotics have in common?
they all contain the B-lactam ring
this is a four-membered ring structure (C-C-C-N)
How do B-lactam antibiotics work?
they interfere with the function of penicillin binding proteins
these are transpeptidase and carboxypeptidase enzymes that are involved in the cross-linking process that forms the peptidoglycan cell wall
What are the 4 main categories of B-lactam antibiotics?
- penicillins
- cephalosporins
- carbapenems
- monobactams
What are 3 examples of penicillins?
What is their antimicrobial spectrum like?
- benzylpenicillin
- amoxicillin
- flucloxacillin
they are relatively narrow spectrum
How has the antimicrobial spectrum of penicillins changed over time and why?
they were originally broad spectrum antibiotics but are now relatively narrow spectrum
this is due to the increasing number of organisms becoming resistant to the antibiotic
What are examples of cephalosporins?
What is their antimicrobial spectrum like?
- cefuroxime
- ceftazidime
they are broad spectrum
(all generally start with “cef”)
What are examples of carbapenems?
- meropenem
- imipenem
they are extremely broad spectrum antibiotics
currently, most bacteria that cause infection are sensitive to meropenem
What is an example of a monobactam?
How are they different to the other B-lactam antibiotics?
aztreonam
most B-lactams have a double ring structure
aztreonam has only a single ring structure and consequently has Gram-negative activity only
In which types of patients is aztreonam commonly used?
in patients with an allergy to penicillins or other beta-lactams
What are the 2 most commonly used glycopeptides?
- vancomycin
- teicoplanin
How do glycopeptides work?
they are large molecules that bind to terminal amino acids on NAM pentapeptides
this inhibits the binding of transpeptidases, and consequently peptidoglycan cross-linking
Which types of bacteria are glycopeptides effective against?
Gram-positive bacteria
they are unable to penetrate the Gram-negative outer membrane
What is the process of protein synthesis like in a bacterium?
translation of RNA into a protein takes place on the ribosome
this involves ribonucleoprotein complexes (2/3 RNA, 1/3 protein)
50S (large) and 30S (small) subunits combine to form the 70S initiation complex
What type of antibiotics are protein synthesis inhibitors?
they are bacteriostatic
they inhibit the process of protein synthesis at some point e.g. prevent binding of the ribosomal subunits
What are the 6 main categories of protein synthesis inhibitors?
What are examples of aminoglycosides?
- gentamicin
- amikacin
gentamicin is commonly used, but is quite toxic
What are examples of macrolides?
macrolides:
- erythromycin
- clarithromycin
lincosamides:
- clindamycin
What are examples of tetracyclines?
doxycycline
tigecycline and eravacycline are synthetic derivatives of tetracyclines with a similar mechanism of action and a much broader spectrum
When is linezolid used?
in gram positive infections
When is mupirocin used?
it is a topical agent for staphylococcus / streptococcus infection
What are the main DNA synthesis inhibitors?
trimethoprim and sulfonamides
How do trimethoprim and sulfonamides work?
both agents inhibit folate synthesis
sulfonamides:
- inhibit the enzyme dihydropteroate synthase
trimethoprim:
- inhibit the enzyme dihydrofolate reductase
When is trimethoprim commonly used?
to treat urinary tract infections
What is co-trimoxazole?
When is it used?
it is a combination of trimethoprim and sulfamethoxazole
it is an antibacterial agent that is effective against Pneumocystis jirowecii and Toxoplasma gondii
What is the role of fluoroquinolones?
they are DNA synthesis inhibitors
they inhibit one or more of two related bacterial enzymes
DNA gyrase and topoisomerase IV are involved in the remodelling of DNA during DNA replication
What are examples of fluoroquinolones?
- ciprofloxacin
- levofloxacin
What is the main RNA synthesis inhibitor that is used?
How does it work and when is it commonly used?
Rifampicin
this is an RNA polymerase inhibitor that prevents synthesis of mRNA
it is the cornerstone of anti-tuberculous chemotherapy
What are the 2 different categories of cell membrane agents?
gram-negatives:
- colistin
- polymyxin E
gram-positives:
- daptomycin
the cell membrane is important in homeostasis and must be fully functioning in order for the cell to survive
When is colistin used?
What are the risks associated with its use?
it causes nephrotoxicity
it had stopped being used, but has started being used again due to the increase in resistant gram-negative pathogens
it is used in the treatment of carbapenem resistant bacteria
How does daptomycin work?
it is a cyclic lipopeptide that causes destruction of the outer membrane or cytoplasmic membrane
When is metronidazole used?
this is a DNA synthesis inhibitor that is only effective against anaerobic organisms
Which drugs act on the following locations of the bacterial cell?
What are the 2 main classes of fungi?
filamentous:
- “moulds”
- have a mycelium (hairy growth)
yeasts:
- unicellular structures
- divide by budding
What is cryptococcus and what can it cause?
it is a yeast that can cause meningitis in immunocompromised patients
What is meant by a dimorphic fungus?
it exists in both yeast and mould forms
they are the causes of “endemic mycoses”
What fungus does not fit into any of the categories (yeast, mould, dimorphic)?
Pneumocystis jiroveci
this does not respond to any antifungal agents
Why is it more difficult to develop antifungals with selective toxicity?
fungal cells are more similar to human cells
e.g. the nucleus contains chromosomes
this means that it is more difficult to develop antifungals with selective toxicity
What is the cell wall of a fungal cell made from?
B-1,3-glucan
this is a glucose based polymer
the fungus needs to keep on reforming its cell wall - if this process is interrupted then the cell dies
What are the main targets for antifungal treatment?
- DNA synthesis
- Protein synthesis
- Cell wall
- Ergosterol in the cell membrane
How is a fungal cell membrane different to a human cell membrane?
the inner membrane is a bilayer composed of ergosterol
humans have cholesterol in their cell membranes instead
What enzyme is involved in synthesis of the fungal cell wall?
B-1,3-glucan synthase
What is the main antifungal cell wall inhibitor?
How does it work?
echinocandins
they inhibit B-1,3-glucan synthase enzyme
What are examples of echinocandins?
- anidulafungin
- caspofungin
- micafungin
What are the 3 categories of antifungal cell membrane agents?
- azoles
- terbinafine
- amphotericin B (and nystatin)
What are examples of azoles?
When are they used?
clotrimazole:
- used topically to treat thrush infection
- systemically toxic
fluconazole and voriconazole:
- given systemically - IV or orally
- used to treat deep fungal infections within the body
- e.g. candida in the blood, aspergillus in the lung
How does terbinafine work?
What is it commonly used to treat?
it inhibits the synthesis of ergosterol by inhibiting squalene epoxidase
it is used to treat athlete’s foot and other superficial fungal infections
How does amphotericin B work?
What is the problem with using this?
it binds to ergosterol and causes physical damage to the membrane
it is not good at selective toxicity as it will also bind to cholesterol
it has a narrow therapeutic window - if too much is given for too long then the host starts to suffer
What is the antifungal protein/DNA synthesis inhibitor?
5-fluorocytosine
How does 5-fluorocytosine work?
- entry into the cell requires cytosine permease
- converted into 5-fluorouracil by cytosine deaminase
- 5-fluorouracil is incorporated into fungal RNA to inhibit protein synthesis
- it is metabolised to 5-fluorodeoxyuridine monophosphate which inhibits DNA synthesis
Which antifungals work by the following mechanisms?
