MICRO: Antimicrobials 1 Flashcards
1
Q
Give 3 examples of selective targets of antibiotics.
A
- Peptidoglycan cell wall
- Inhibition of bacterial protein synthesis e.g. ribosomes
- DNA gyrase and other prokaryote-specific enzymes
2
Q
Give 2 classes of antibiotics invovled in inhibition of cell wall synthesis.
A
- beta lactams
- glycopeptides
3
Q
Give 3 examples of beta-lactam antibiotics.
A
- penicillins
- cephalosporins
- carbapenems
4
Q
Give 2 examples of glycopeptides.
A
- vancomycin
- teicoplanin
5
Q
Describe the cell walls of gram +ve and gram -ve bacteria.
A
- Most bacteria have a cell wall - those that do not are atypical organisms such as chlamydia or mycobacteria
- The cell is made up of peptidoglycan (PTG)
- thick in Gram positive
- thinner in Gram negative
- Between the peptidoglycan precursors, there are glycosidic and peptide bonds which gives the bacterial cell wall its rigidity and protects the bacteria from osmotic pressure, being lysed.
- Gram -ves have an outer membrane which can stop some antibiotics - this is a reason gram negatives tend to be more antibiotic resistant and are harder to treat
6
Q
What are transpeptidases also known as? What is their role in the cell wall?
A
penicillin binding proteins - involved in terminal stages of cell wall synthesis (form strong bonds between NAM + NAG peptidoglycan precursors to form a rigid cell wall)
7
Q
How do beta-lactam antibiotics act?
A
inhibition of transpeptidases –> daughter cell walls are weak and lyse = BACTERICIDAL
beta-lactams are a STRUCTURAL ANALOGUE of the enzyme substrate
8
Q
Which types of bacteria are beta-lactams most and least effective against (in general)?
A
- Active against rapidly dividing bacteria- if the bacteria are not dividing, it will not work (i.e. in the stationary phase)
- Ineffective against bacteria that lack a PTG cell wall
9
Q
What are the 4 classes of beta-lactam containing antimicrobial structures?
A
- Penicillins
- Cephalosporins
- Carbapenems
- Monobactam
They all have a beta-lactam ring structure.
Beta lactams can go “BACk to the PEN where the SPORes are ChILLIN”
10
Q
What chance is there of allergy to cephalosporins in a patient allergic to penicillins?
A
~5%
11
Q
Give 4 examples of penicillins.
A
- Amoxicillin
- Flucloxacillin
- Piperacillin
- Clavulanic acid and tazobactam
- Augmentin/co-amoxiclav
12
Q
What is tazocin and what is its use?
A
Tazobactam + piperacillin = tazobactam
Tazobactam protects piperacillin from enzymatic breakdown by beta-lactamases
13
Q
Which combination helps amoxicillin retain coverage against E coli?
A
Augmentin/co-amoxiclav - Clavulanic acid protects amoxicillin from enzymatic breakdown
NB: lots of E coli are now resistant to amox and S. aureus/other gram -ves produce beta-lactamses which also break it down
14
Q
Compare the actions of penicillin, amoxicillin, flucloxacillin and piperacillin.
A
-
Penicillin
- Active against Gram +ve organisms (Streptococci, Clostridia)
- Broken down by beta-lactamase
-
Amoxicillin
- Broad spectrum penicillin, extends coverage to Enterococci and Gram -ve organisms
- Now lots of E. coli are resistant
- Broken down by beta-lactamase
-
Flucloxacillin
- Similar to penicillin although LESS ACTIVE
- STABLE to b-lactamase produced by S. aureus
-
Piperacillin
- Similar to amoxicillin, broad spectrum, extends coverage to Pseudomonas and other non-enteric Gram -ves
- Broken down by beta-lactamase
- Used for HAI
15
Q
What are the advanatages of clavulanic acid and tazobactam?
A
They are beta-lactamase inhibitors
16
Q
Which beta-lactam is the most active?
A
Penicillin is the MOST ACTIVE b-lactam antibiotic
17
Q
Give an example of 1st, 2nd and 3rd gen cephalosporins. Compare the groups.
A
- Increasing activity against gram -ve bacilli
- 2nd generation- better for +ve organisms, good activity towards E. coli
- 3rd generation- better towards -ve organisms, weaker towards +ve organisms, used for HAP (especially Pseudomonas)
18
Q
Which cephalosporin is associated with C diff infection?
A
Ceftraixone (3rd generation)
19
Q
Which cephalosporin is stable to beta-lactases with similar coverage to co-amoxiclav but less stable against anaerobes?
A
Cefuroxime
20
Q
Which cephalosporin has good anti-pseudomonas activity?
A
ceftazidime
21
Q
Which enzyme confers resistance to all cephalosporins?
A
extended spectrum beta-lactamase producing organisms (ESBLs)
22
Q
Which beta-lactams are stable to ESBL organisms?
A
Carbapenems
23
Q
Give an example of carbapenems. Which organisms have shown resistance to carbapenems?
A
Meropenem, Imipenem, Ertapenem
Really broad spectrum, covering almost everything. But some organisms like Acinetobacter and Klebsiella have shown resistance with carbapenemase production.
24
Q
What is a common use of beta-lactams? What are the cautions for beta-lactam use?
A
Common use - meningitis; will not cross intact BBB but when inflamed can cross. Relatively non toxic
Cautions:
- Renally excreted
- Short t1/2 so prescribe multiple times a day
- Cross-allergenic - 10% cross reactivity of penicillins with cephalosporins/carbapenems
25
Can glycopeptides be used against gram -ves? Why?
No - large molecules so unable to penetrate the outer cell wall.
But active against gram +ve organisms
26
Which infection are glycopeptides useful for? Why should you monitor drug levels?
1. Serious MRSA infections - treated IV
2. C. difficile - PO vancomycin can be used
They are nephrotoxic - monitor for accumulation
27
Are glycopeptides bactericidal?
Yes slowly. They are cell wall synthesis inhibitors
28
What is the mechanims of action of glycopeptides?
* Vancomycin and Teicoplanin bind to the end of this chain (on the right) and **stop the transpeptidase** from binding and _CANNOT_ form the _peptide cross links_
* They also **stop** the **transglycosidase** from binding so get _no glycosidic bonds_ too
* So get a weakened cell wall and similarly, the daughter cells will lyse.
* = slowly bactericidal
29
Give 5 examples of inhibitors of protein synthesis.
* **Aminoglycosides**- e.g. Gentamicin, Amikacin, Tobramycin
* **Tetracyclines**- e.g. Doxycycline
* **MLS group -** Macrolides- e.g. Erythromycin / Lincosamides- e.g. Clindamycin / Streptogramins- e.g. Synercid (NOT used anymore)
* **Chloramphenicol**
* Used in CAP
* May use for meningitis and anaphylaxis
* **Oxazolidinones**- e.g. Linezolid
30
What does the clinical effect of aminoglycosides largely depend upon?
They have **concentration-dependent** bactericial activity - so want a high concentration early on for better clinical effect and outcome
31
What are the cautions with using aminoglycosides?
* Nephrotoxicity
* Ototoxicity
monitor levels
* *Most will have 1 dosing a day- enough to trough and not reach toxicity but monitor accumulation*
* *High trough levels over 24-48 hours are associated with toxicity*
* *Okay to give 1 big dose first (as this is where the physical effect comes from) but then follow policies for monitoring toxicity*
32
Are aminoglycosides useful for abscesses? Why?
Aminoglycosides are inhibited by low pH and so are not very effective in abscesses
33
Give 2 examples of aminoglycosides and their activity.
* **Gentamicin** and **tobramycin** particularly active against ***Pseudomonas aeruginosa***
* They also have a *SYNERGISTIC* combination with _b-lactams_
* _NO_ activity against _anaerobes_
34
What is the MOA of aminoglycosides?
* _Prevent elongation of the polypeptide chain_
* Bind to the 30S subunit of the ribosome and prevent elongation
* _Cause misreading of the codons along the mRNA_
35
What types of organisms are tetracyclines especially effective against?
Broad-spectrum agents with **activity against IC pathogens** (CRaMe.g. *chlamydiae, rickettsiae* and *mycoplasma*) as well as most conventional bacteria
\*these have a cell wall so penicillins are ineffective
36
What is the MOA of tetracyclines? How do they kill bacteria?
* Reversibly binds to the ribosomal **30S subunit**
* _Prevents binding of aminoacyl-tRNA_ (transfer RNA) to the _ribosomal acceptor site_, so inhibiting protein synthesis
* They are not bactericidal but BACTERIOSTATIC -
37
Which new tetracycline is not affected by most resistance mechanims that usually affect tetracyclines?
Tigecycline - so active against most MDR
38
When should tetracyclines not be given?
1. Children
2. Pregnant women
= they can be deposited in growing bone and discolour growing teeth
= can also cause a light sensitive rash so avoid sun
39
What is the MOA of macrolides?
* Bind to the **50S subunit** of the ribosome
* Interfere with translation
* Stimulate dissociation with peptidyl-tRNA
* Inhibit protein synthesis
40
Which antibiotics can be given against:
* atypical pneumonia e.g. mycoplasma?
* penicillin allergic patients with staph infection ?
Both MACROLIDES
They have minimal activity against gram -ve organisms due to their outer membrane but useful for:
* Staphylococcus + Streptotoccus in penicillin allergic patients
* Campylobacter/legionella pneuumophilia/mycoplasma
41
What are the advatages of newer macrolides?
Clarithromycin/azithromycin have improved pharamacological properties:
* longer t1/2 so less frequent dosing
* azithromycin has some gram -ve activity and can be used for Salmonella typhi or bronchiectasis in CF patients
42
Why are macrolides often combined with beta lactams e.g clindamycin and flucloxacillin?
To inhibit protein synthesis when bacteria make toxins in the stationary phase of growth (when beta-lactams are not effective) E.g. in *Group A Streptococcus* and **necrotising fasciitis**
43
What is the MOA of chloramphenicol?
* Binds to the peptidyl transferase of the 50S ribosomal subunit and inhibits the formation of peptide bonds during translation
* BACTERIOSTATIC
44
Why is chloramphenicol rarely used/what are its risks?
* Rarely used (apart from the eye preparations and special indications) because of risk of:
* **Aplastic anaemia**
* **Grey baby syndrome** in neonates due to inability to metabolise drug
45
Which clinical situation is chloramphenicol often used for?
Penicillin allergic patients with meningitis (because they have activity against pneumococcus and meningococcus)
## Footnote
*Sometimes for CAP as the side-effects are less problematic than beta-lactams*
46
What is the MOA of Oxazolidinones (Linezolid)?
* Binds to the **23S component** of the **50S subunit** to prevent formation of a functional 70S initiation complex (required for the translation process to occur)
* Novel MoA and NOT derived from a natural source
47
Which organisms are oxazolidinones effective against?
**Gram +ve including MRSA and VRE**
*NOT effective against most gram -ves*
48
What are the side-effects of oxazolidinones?
Thrombocytopeanie with prolonged use (2-4 weeks)
Optic neuritis (\>4 weeks)
Resistance is rare
49
What class are ciprofloxacin, levofloxacin and moxifloxacin? Compare their actions.
Fluoroquinolones
* Ciprofloxacin- good for Gram -ves including *P. aeruginosa*
* Levofloxacin- in the middle
* Moxifloxacin- good for Gram +ves (inc. pneumococcus) but worse for Gram-ves
50
Name 2 classes of inhibitors of DNA synthesis. What is their general action?
Bind to topoisomerase and DNA gyrase
1. Quinolones e.g. ciprofloxacin
2. Nitromidazoles e.g. metromidazole
51
What is the MOA of fluoroquinolones?
Act on the **a-subunit of DNA gyrase** predominantly, but together with other antibacterial actions, are essentially **bactericidal**.
52
What organisms are fluoroquinolones effective against?
Broad antibacterial activity especially gram -ve e.g. pseudomonas aeruginosa
Newer agents (levo/moxi) have increased gram +ve activity and IC e.g. against *chlamydia* and *legionella, pneumococcus and haemophilus*
53
What are the side effects of fluoroquinolones/quinolones?
* Tendonitis
* C. diff outbreaks
Other:
* Resistance - 25% of E coli
* Caution in hypotensive/tachycardic patients
54
What route of administration is good for quinolones?
PO - well absorbed and good bioavailability
55
What is the MOA of nitromidazole?
Under **anaerobic conditions**, an **active intermediate** is produced which causes **DNA strand breakage**
Rapidly bactericidal + resistance is rare
56
What are... useful for treating clinically?
1. Quinolones
2. Nitromidazoles
1. UTI, pneumonia, atypical pneumonia, bacterial gastroenteritis
2. UTI - nitrofurans are related compounds (e.g. nitrofurantoin); not absorbed systemically
57
What organisms are nitromidazoles effective against?
Active against **anaerobic bacteria** and **protozoa** (e.g. Giardia)
58
Name a class of inhibtors of RNA synthesis and give 2 examples.
Rifamycins e.g. rifampicin, rifabutin
59
What is the MOA of rifamycins? What organisms are they useful against?
**Inhibits protein synthesis** by binding to DNA-dependent **RNA polymerase** thereby **inhibiting initiation**
Bactericidal
Active against certain bacteria, including *Mycobacteria* and *Chlamydiae*
60
What is the only way that rifampicin should be used and why?
IN COMBINATION with another antibiotic as resistance develops rapidly
except for short-term prophylaxis e.g. against meningococcal infection otherwise never use alone
61
What is the MOA of resistance against rifampicin?
* ALTERED TARGET
* Resistance due to **chromosomal mutation**
* This causes a single AA change in the b-subunit of RNA polymerase which then fails to bind to Rifampicin
62
Which infections is rifampicin useful for clinically?
1. TB
2. complex prosthetic joint infections + endocarditis (has biofilm disrupting activity)
63
Name two drugs which are membrane toxins.
daptomycin
colistin
64
What are ths uses of daptomycin? What is its MOA? What can be used as an alternative for?
* Cyclic lipopeptide
* **Gram +ve** ONLY [utility against enterococci is limited and resistance can develop. Good activity mainly against *S. aureus*]
* MRSA and VRE as an alternative to linezolid and Synercid
65
What are the uses of colistin? What is its MOA?
* A polymyxin antibiotic that _destroys the outer cell membrane_ of **Gram -ve organisms** including;
* *P. aeruginosa,*
* *Acinetobacter baumannii*
* *Klebsiella pneumoniae*.
* Particularly useful for MDR carbapenemase producing organisms
Cons:
* It is not absorbed by mouth
* Nephrotoxic
* Should be reserved for use against multi-resistant organisms
66
Give 2 examples of inhibitors of folate metabolism.
Sulfonamides and Diaminopyrimidines (e.g. trimethoprim)
67
What is the MOA of sulfonamides/diaminopyrimidines?
Act directly on DNA **through interference** with **folic acid metabolism**
**Act sinergistically -** they act on sequential parts of the same pathway
68
What are the cilnical uses of diaminopyrimidines? What is a disadvantage?
trimethoprim - community acquired UTI but up to 40% of E coli is resistant
69
How can resistance to sulfonamides be overcome?
Sulphonamide resistance is common
Combination of **sulphamethoxazole + trimethroprim** (Co-trimoxazole) is useful in certain situations e.g. treating *Pneumocystis jiroveci* pneumonia)
Broad spectrum- covers lots of coliforms
70
What is co-trimoxazole? What is it useful for?
Sulphamethoxazole and trimethoprim - pneumocystis jiroveci pneumonia
71
Name 4 ways in which bacteria can become resistant to an antibiotic.
Can be affected by multiple mechanisms
1. **Chemical modification or inactivation of the antibiotic** E.g. b-lactamase enzyme production
2. **Modification or replacement of target in the microbe**
3. **Reduced antibiotic accumulation** - Impaired uptake/ enhanced efflux
4. **Bypass antibiotic sensitive step**
72
How do coliforms and S aureus become resistant to beta-lactams?
Beta-lactamase production
73
What type of resistance does MRSA display? Describe it.
Altered target - mecA gene encodes a new PBP (2a) --\> low affinity for all beta-lactam antibiotics.
74
What is the type of resistance of S. pyogenes to penicillin? Can it be overcome?
**Altered target** - stepwise mutations in PBP genes
Sometimes can be overcome with:
* increasing dose but not in meningitis (as not all crosses the BBB anyway)
* adding vancomycin in pneumococcus infection
75
What antibiotic class do ESBLs confer resistance against? What organisms most commonly produce this?
Break down cephalosporins - especially produced by E. coli and Klebsiella
76
In which infections is beta-lactamase production not the mechanim or resistance against penicillin?
pneumococci and MRSA
77
Why is tonsillitis treated with penicillins (hint: resistance)?
Penicillin resistance not reported in Group A (S. pyogenes), B, C, or G ß haemolytic Streptococci.
78
Which beta-lactam/beta-lacatamase inhibitor combination can sometimes be used for ESBLs?
Augmentin/Tazocin - but treatment failures have been reported
79
What is the danger with ESBLs?
They spread quickly - via plasmids or transposons
80
What is the % resistance indicating you can no longer use an antibiotic for empiric treatement?
10%
e.g. ESBLs in E coli
81
What is the mechanim of resistance against macrolides? Describe it.
Altered targets
* Adenine-N6 methyltransferase **modifies 23S RNA** --\> reduces the binding of macrolides --\> resistance
* Encoded by ***erm*** (erythromycin ribosome methylation) genes
* It is an **inducible** mechanism
* IV- clindamycin does NOT induce this mechanism so it can look sensitive but eventually it will select out resistant organisms --\> treatment failure
82
What 2 ways can be used to reduce the spread of antibiotic resistance?
1. Control antibiotic usage and encourage good prescribing habits
2. Improve standards of hospital hygiene and encourage handwashing to reduce dissemination of resistant organisms
83
Which mechanism mediates Flucloxacillin resistance in *S. aureus*?
Alteration of the target
84
By which mechanism is ESBL *E. coli* resistant to Ceftriaxone?
Enzymatic inactivation of the antibiotic (as it is extended spectrum _b-lactamase_)
