Antimicrobial Agents Flashcards
1
Q
What are the 2 main ways of classifying bacteria?
A
- gram stain
- either positive or negative
- gram positive have the ability to retain crystal violet stain on their thick outer peptidoglycan wall
- appear dark blue/violet
- negative dont have an outer wall
- they don’t stain with crystal violet but with safarin red (counterstain) to appear red/pink
- Morphology
- cocci (spherical)
- bacilli (rod-shaped)
- spirilla (spiral shaped)
2
Q
What are the clinically important gram positive cocci?
A
- staphylococci
- streptococci
- entercocci
3
Q
What are the clinically important gram positive bacilli?
A
- clostridia
- bacillus (anthrax)
- corynebacterium (diphtheria)
- listeria
4
Q
What are the clinically important gram negative cocci?
A
Neisseria
5
Q
What are the clinically important gram negative bacilli?
A
- enterobacteria (E.coli, klebsiella, salmonella, shigella, proteus)
- pseudomonas
- campylobacter
- moraxella
- haemophilus
- legionella
6
Q
What is an obligate aerobe bacteria?
A
Uses O2 for metabolism.
Can only survive if O2 is present, but O2 can be toxic so it must be able to manufacture specific enzymes to detox O2 waste products.
7
Q
What are obligate anaerobic bacteria?
A
Cannot survive in the presence of O2/metabolise in the absence of O2.
They do not contain enzymes to detoxify O2. Anaerobic metabolism is less efficient but carries the advantage that these bacteria can survive in places aerobes cannot eg human gut (bacteroides).
8
Q
What are facultative anaerobes?
A
Survive with or without O2, but prefer access to O2 for more efficient metabolism.
9
Q
How are gram positive staphylococci divided?
A
Coagulase positive (aureus).
Coagulase negative (epidermidis).
10
Q
How are gram positive Streptococcus divided?
A
On their ability to break down blood:
- haemolytic (alpha and beta haemolytic)
- non-haemolytic (gamma haemolytic)
11
Q
What are the important obligate anaerobes?
A
Bacteroides group and Clostridia.
12
Q
What are the 3 actions of antimicrobials?
A
- Action on cell wall synthesis
- Inhibition of protein synthesis
- Inhibition of nucleic acid synthesis
13
Q
What antimicrobials act on cell wall synthesis?
A
Glycopeptides (eg vancomycin)
Bind to terminal residues of peptidoglycan chain - preventing formation of the peptide cross links.
14
Q
What antimicrobials act on cell wall integrity?
A
Beta lactams
15
Q
What antimicrobials act on protein synthesis?
A
50S inhibitors
- macrolides
- lincosamides
- chloramphenicol
30S inhibitors
- tetracyclines
- aminoglycosides
16
Q
What antimicrobials inhibit nucleic acid synthesis?
A
DNA synthesis
- metronidazole
DNA gyrase
- quinolones
DNA dependent RNA polymerase
- rifampicin
Folic acid metabolism
- trimethoprim
17
Q
What are the beta-lactam antibiotics? What is their mechanism of action?
A
- Penicillins, cephalosporins, carbapenems, monobactems
- Act on cell wall synthesis
- rely on integrity of beta-lactam ring for bacteriocidal activity
- bind to and inhibit the enzyme that catalyses the cross linking between peptidoglycan polymer chains in the bacterial cell wall, causing weakening followed by cell lysis (bacteriocidal)
18
Q
What are the glycopeptides antibiotics? What is the MOA?
A
- vancomycin, teicoplanin
- interfere with cell wall synthesis by binding to peptidoglycan chains preventing formation of the peptide cross-linking
19
Q
What subunits do bacterial and mammalian ribosomes consist of?
A
Bacterial ribosomes - 50S and 30S
Mammalian - 60S and 40S
20
Q
What is the MOA of macrolides?
A
Eg erythromycin
Bind to the 50S subunit inhibiting peptide chain translocation.
21
Q
What is the MOA of tetracyclines?
A
Inhibits protein synthesis by binding to 30S subunit and inhibits binding of aminoacyl-tRNA
22
Q
What is the MOA of aminoglycosides?
A
Eg gentamicin
Inhibits protein synthesis by causing misreading of mRNA.
Binds to 30S subunit.
23
Q
What is the MOA of lincosamides?
A
Eg clindamycin
Inhibits protein synthesis by disrupting function of the 50S subunit -inhibiting bacterial protein synthesis.
24
Q
What is the MOA of chloramphenicol?
A
Inhibits protein synthesis by inhibiting peptidyl transferase activity of the 50S subunit, stopping transpeptidation
25
What is the MOA of trimethoprim?
* inhibits nucleic acid synthesis
* inhibits dihydrofolate reductase which is needed in purine/pyrimidine synthesis (bacteriostatic)
26
What is the MOA of quinolones?
Eg ciprofloxacin
* inhibits nucleic acid synthesis
* inhibits DNA gyrase, the enzyme that compresses DNA into super coils
27
What is the MOA of metronidazole?
(a 5- Nitroimidazole)
* inhibits nucleic acid synthesis
* inhibits and damages DNA synthesis - exact mechanism unclear
28
What is the MOA of rifampicin?
Inhibits nucleic acid synthesis.
Prevents RNA transcription by inhibiting DNA dependent RNA polymerase.
29
What antibacterials are bacteriostatic? When is this important?
All antibacterials are bacteriocidal except for:
* macrolides
* lincosamides (clindamycin)
* chloramphenicol
* tetracyclines
* trimethoprim
Bacteriostatic agents should not be used in the immunosuppressed, only bacteriocidal agents, because it is host mechanisms that are involved in the final removal of bacteria.
30
What groups are the penicillins divided into?
* narrow spectrum (benzylpenicillin, flucloxacillin)
* broad spectrum (amoxicillin, ampicillin)
* antipseudomonal (piperacillin, ticarcillin)
* Beta-lactamase resistant (flucloxacillin)
31
What are the classifications of beta lactams?
* the penicillins
* cephalosporins
* carbapenems
* monobactams
32
Why do narrow spectrum penicillins have no gram negative activity?
Because gram negative bacteria have an outer phospholipid membrane hindering access of penicillins to the cell wall beneath
33
How do broad spectrum penicillins have gram negative activity?
They are more hydrophobic and can pass through pores in phospholipid membranes.
However, they're inactivated by beta-lactamases.
Combining a broad spectrum penicillin with a beta-lactamase inhibitor (clavulanic acid) overcomes this.
34
What are antipseudomonal penicillins?
Eg piperacillin
* broad spectrum (gram +ve, -ve and anaerobes)
* Beta-lactamase sensitive
* therefore can be combined with beta-lactamase inhibitor (eg piperacillin with tazobactam to make tazocin)
* more staphylococci produce penicillinase (a beta lactamase)
* low toxicity, short half life, renal excretion unchanged
* hypersensitivity in 10%, anaphylaxis 0.01%
* SEs include encephalopathy and diarrhoea
* tissue penetration good but meninges need to be inflamed for it to cross the BBB
35
What is the commonest cause of community acquired pneumonia?
Pneumococcal pneumonia.
Will respond to broad spectrum penicillin such as amoxicillin.
36
Why does a hospital acquired pneumonia require different antibiotics to a community acquired?
A severe CAP or HAP are higher risk of being gram negative bacteria.
They require a broad spectrum cephalosporin (ciprofloxacin or an antipseudomonal beta lactam).
37
What are the cephalosporins?
eg ciprofloxacin
Beta lactams but their beta-lactam ring is less susceptible to beta-lactamases.
Similar structure to penicillins but broader spectrum.
Used in treatment of pneumonia, sepsis, meningitis and for surgical prophylaxis.
Most excreted unchanged in urine. Cefotaxime is an exception, being 50% metabolized in the liver.
38
What is ceftriaxone?
A cephalosporin which is highly protein bound (95%) with a long half life (5.5 - 11h). Given once daily.
39
What are the generations of cephalosporins?
With each generation - gram positive cover is maintained while gram negative cover increases.
* 1st generation
* eg cefradine - used for surgical prophylaxis with gram positive organisms (ortho)
* 2nd generation
* eg cefuroxime - more stable beta lactam ring and more gram -ve cover
* often used for prophylaxis in bowel surgery but lack sufficient anaerobic cover to be used alone (add metronidazole)
* 3rd generation (cefotaxime, ceftriaxone, cepftazidine)
* further gram -ve activity
* some demonstrate activity against pseudomonas (ceftazidime)
* broad spectrum encourages superinfection
40
Why are carbapenems not active against MRSA despite their broad spectrum?
Because MRSA is resistant due to changes in it's penicillin binding proteins
41
What are the carbapenems?
* eg meropenem
* extensive spectrum - cover gram +ve, gram -ve, aerobic and anaerobic organisms
* carbapenems are highly beta-lactamase resistant
* often used in neutropenic sepsis and serious multi-resistant gram negative sepsis
* not effective against MRSA, E. faecalis and some strains of pseudomonas
* can cause convulsions
* excreted unchanged by kidneys
42
What is the only available monobactam?
Aztreonam. It's limited to gram negative aerobic bacteria.
43
What are glycopeptides?
Eg vancomycin, teicoplanin
They have broad gram positive spectrum, useful in treating MRSA septicaemia and endocarditis. However vanc-resistance Staphylococcus aureus and Entercoccus are appearing
Gram negative cover is limited due to them being large polar molecules, can't penetrate outer lipid layer of these bacteria.
44
How does teicoplanin compare to vancomycin?
Teicoplanin has a similar spectrum to vancomycin, but is more potent, longer duration (once daily), better tissue penetration and better tolerated.
It does demonstrate more resistance however.
45
What toxicity is associated with glycopeptides?
* nephrotoxicity
* ototoxicity
* thrombocytopaenia
* neutropaenia
* (all reversible on stopping treatment)
46
Why must plasma levels of glycopeptides be monitored?
Because individual variation in kinetics exists and toxicity is common
47
What should vancomycin trough levels be?
Below 10-15 mg/L
48
How are glycopeptides eliminated?
Unchanged in the urine
49
What happens to glycopeptides in the gut?
Minimal systemic absorption from the healthy gut - so can be used to treat antibiotic associated pseudomembranous colitis
50
Why must IV administration of vancomycin be slow?
To avoid risks of phlebitis and **histamine release (red man syndrome)**
51
What are the macrolides?
* eg erythromycin, clarithromycin, azithromycin
* similar but broader spectrum of activity to penicillin (hence why used in those with penicillin allergy)
* mainly cover gram positive organisms (resp tract, soft tissue infections)
* specific activity against mycoplasma and legionella
* generally well tolerated
52
What macrolide has the longest half life?
Azithromycin (40 - 60hrs)
Also has increased gram negative cover.
Single dose will treat chlamydial urethritis.
53
Where are macrolides metabolized?
Metabolized and excreted mainly by liver
54
What are the SEs of macrolides?
* GI upset (mainly erythromycin as prokinetic)
* prolonged QT interval
* thrombophlebitis if given IV
* **potent inhibitors of cytochrome P450** leading to a number of interactions
55
What are the aminoglycosides?
* eg gentamicin, streptomycin (used for Mycobacterium TB)
* used for gram negative cover, which includes pseudomonas
* also have some gram +ve activity (Staphylococcus and Streptococcus)
* large polar molecules that require active transportation into the cell
* act synergistically with penicillins and glycopeptides (which break down the cell wall and allow the aminoglycosides better cellular access)
56
How are aminoglycosides excreted?
Renal excretion
57
What are aminoglycosides toxic to?
Kidneys and VIII cranial nerve (auditory)
58
Can aminoglycosides be given orally?
No, they must be given IV because of their low lipid solubility.
59
How do aminoglycosides affect neuromuscular transmission?
* they impair neuromuscular transmission
* decrease prejunctional release and reduce post junctional sensitivity to ACh
60
What drugs do macrolides increase levels of?
They inhibit cytochrome P450
* augments levels of warfarin
* theophylline
* digoxin
* midazolam
* alfentanil
61
What SEs of the aminoglycosides are permanent?
The ototoxicity tends to be permanent (risk increased on furosemide, another ototoxic).
Nephrotoxicity tends to be reversible (via acute tubular necrosis and more likely if also on cephalosporin).
62
What group of Abx is the only orally active anti-pseudomonal?
Quinolones
63
What are the quinolones?
Eg ciprofloxacin and levofloxacin
* synthetic, broad spectrum Abx used for bacterial gastroenteritis and serious multiple or resistant infections
* levoflox has increased pneumococcal cover so useful in LRTI
* spectrum is mainly gram negative but has action against gram +ves such as Streptococcus and Enterococcus
* increases risk of MRSA and C. Diff
* good oral absorption
* wide distribution with excellent CNS penetration
64
What effect does ciprofloxacin have on cytochrome P450?
Inhibits cytochrome P450
65
What SEs do quinolones have?
Low toxicity but SEs include:
* nausea
* vomiting
* abdominal pain
* convulsions
* prolonged QT interval
66
How are quinolones excreted?
Mainly unchanged in urine and faeces
67
What is the drug of choice against anaerobes?
Metronidazole
Used (along with cephalosporin or gentamicin to cover gram negatives) in prophylaxis for bowel, biliary or gynaecological surgery.
68
What is metronidazole active against?
* anaerobes
* bacteroides - gut flora, clostridia
* protozoa
* anaerobic conditions predominate in abscesses (dental, abdominal, pelvic) hence it's use here as well as in abdominal peritonitis
69
What is metronidazole?
* well tolerated
* SEs (rare) include rash, pancreatitis, peripheral neuropathy, (flushing and hypotension if combined with alcohol)
* distributes widely in CSF, cerebral abscesses, prostate and pleural fluid
70
How is metronidazole excreted?
Unchanged in urine
71
Why do quinolones increase the risk of convulsions?
They antagonise GABA
72
What will reduce the oral bioavailibility of quinolones?
Compounds containing multivalent cations such as magnesium or calcium.
73
What drug would you use agains clostridia, giardia lamblia and bacteroides fragilis?
Clostridia is an anerobe cuasing pseudomembranous colitis
Giardia is a GI parasite causing watery diarrhoea
Bacteroides fragilis is a gram negative bacillus and obligate anerobe of the gut - involved in 90% of anaerobic peritoneal infections
METRONIDAZOLE will cover these
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