Lecture 44: Antibacterials Flashcards
1
Q
what are the 2 most important classes of antibiotics that act on the bacterial cell wall
A
- beta lactams
- glycopeptides
2
Q
what was the first beta lactic discovered
A
penicillin
3
Q
what are the 4 main classes of beta lactams
A
- penicillins
- cephalosporins
- carbapenems
- monobactams
4
Q
what is penicillin betalactamase inhibitor combinations (BLICs)
A
a beta lactam combined w/ molecule designed to make antibiotic less susceptible to breakdown
- bacteria less likely to be resistant to BLICs than to penicillins
5
Q
describe beta lactam antibacterial MoA
A
- bacterial cell wall composed of peptidoglycan
- peptidoglycan chains cross linked by transpeptidase enzyme
- -> aka penicillin binding protein
- PBPs inhibited by beta lactams
- cell wall severely weakened
- results in bacterial cell lysis
6
Q
what is present in the structure of all beta lactams
A
beta lactam ring
7
Q
what is the difference in peptidoglycan between gram +ve and gram -ve bacteria
A
thickness differs
- thicker in gram +ve
- thinner in gram -ve
8
Q
what type of bacteria does benzylpenicillin mainly act on
A
gram +ve bacteria
- specifically beta-haemolytic streptococci
9
Q
how is penicillin usually administered
A
IV (benzylpenicillin)
10
Q
give examples of oral penicillin
A
- phenoxymethylpenicillin
- penicillin V
11
Q
why are oral penicillins not usually used
A
they are poorly absorbed
12
Q
what are oral penicillins normally used to treat
A
streptococcal tonsilitis
13
Q
what is the main pathogen target of benzylpenicillin and oral penicillins
A
beta-haemolytic streptococci
- group A strep
14
Q
what is benyzlpenicillin typically used to treat
A
- streptococcal tonsillitis
- streptococcal cellulitis/ soft tissue infection
15
Q
what penicillin drug has better oral absorption than penicillin V
A
amoxicillin
16
Q
what is amoxicillin used for
A
used as step-down from benzylpenicillin, acts against:
- strep pneumoniae
- beta-haemolytic streptococci
17
Q
what is amoxicillin a treatment choice for
A
- pneumonia
- infections caused by enterococcus faecalis and listeria monocytogenes
18
Q
what are the main pathogen targets of amoxicillin
A
- strep pneumoniae
- listeria monocytogenes
- enterococcus faecalis
- beta-haemolytic streptococci
19
Q
what are the common clinical indications of amoxicillin
A
- chest infection
- community acquired pneumonia
- listeria infections
20
Q
how is amoxicillin prepared
A
IV and oral
21
Q
why might amoxicillin not be sufficient by itself as treatment for enterococci
A
enterococci frequently part of polymicrobial infection
22
Q
what is flucloxacillin the treatment choice for
A
staphyloccocal aureus infection
23
Q
what is the main pathogen target of flucloxacillin
A
staph aureus
24
Q
what are the clinical indications of flucloxacillin
A
- skin/soft tissue infection
- bone/joint infection
- endocarditis
25
how is flucloxacillin prepared
IV and PO
26
what type of class betalactam is aztreonam
monolactam
27
what organisms is aztreonam activity limited to
gram -ve organisms
28
what are the clinical indications of aztreonam
- UTI
- as part of combination therapy for:
- -> intra-abdominal infections
- -> hospital acquired chest infections
29
how is aztreonam prepared
IV
30
when might aztreonam be used
in combination w/ other antibiotics in Px w/ penicillin allergy
31
what class of beta lactam are ceftriaxone and cefotaxime
third generation cephalosporins
32
what are 3 important things to remember regarding ceftriaxone and cefotaxime
- ceftriaxone is recognised cover for syphilis while cefotaxime is not
- ceftriaxone is contraindicated in neonates b/c it can displace bilirubin from binding to albumin --> hyperbilirubinaemia and potentially bilirubin encephalopathy
- ceftriaxone is drug on formulary for adults in most hospitals
33
what are the main pathogen targets of ceftriaxone and cefotaxime
- neisseria meningitidis
- streptococcus pneumoniae
- staph aureus
- beta-haemolytic streptococci
34
what are the clinical indications for ceftriaxone and cefotaxime
- meningitis
- OPAT (out px parenteral antimicrobial therapy)
- soft tissue infection
- intra-abdominal infections
35
how are ceftriaxone and cefotaxime prepared
IV
36
what is the second most important class of antibiotics that act on bacterial cell wall
glycopeptides
37
give the two main antibiotics in glycopeptide class
- vancomycin
| - teicoplanin
38
what are the only type of bacteria that glycopeptides are active against and why
- gram +ve bacteria
| - large polar molecules that are too bulky to penetrate the external membrane of gram -ve bacteria
39
why do glycopeptides stay in the anatomical compartment they are administered in
they are so big that they don't easily cross membranes
if given orally --> stay in gut
if given IV --> stay in blood
40
describe the MoA of Glycopeptides and how they differ to beta lactams
- Glycopeptides bind to peptidoglycan preventing peptidoglycan formation
- glycopeptides inhibit cell wall synthesis earlier than beta lactams; beta lactams act at a later stage inhibiting the cross linking of peptidoglycans
41
what is the key pathogen that glycopeptides act against
staph aureus esp MRSA
42
what are the main pathogen targets of Teicoplanin
- MRSA
| - gram +ves
43
what are the clinical indications of Teicoplanin
- OPAT (out px parenteral antimicrobial therapy)
- -> soft tissue infection
- -> intra abdominal allergies
- combination therapy in penicillin allergy
44
how is Teicoplanin prepared
IV only
45
how does the use of Teicoplanin and vancomycin differ
- spectrum of activity basically identical
- Teicoplanin can be give OD so more freq. used in OPAT
- vancomycin can be taken PO for C diff
46
what are the main pathogen targets for vancomycin
- MRSA
- C diff
- gram +ves
47
what are the clinical indications of vancomycin
- soft tissue infection
- combination therapy in penicillin allergy
- C diff colitis (only indication for PO)
- intra abdominal infections
48
how is vancomycin prepared
- PO only for C diff
| - IV only for all other infections
49
what are the 3 categories of antibiotics that act within the cell (non cell-wall active agents)
- protein synthesis inhibitors
- nucleic acid synthesis inhibitors
- miscellaneous antibiotics
50
what are the 3 classes of protein synthesis inhibitors
- macrolides
- aminoglycosides
- tetracyclines
51
what are the 3 most common macrolides and when is each most commonly prescribed
- clarithromycin --> predominantly prescribed
- erythromycin --> macrolide of choice in pregnancy
- azithromycin --> used by chest physicians
52
why is clarithromycin more predominantly prescribed
- it is better tolerated (erythromycin ^ gut motility and can cause nausea/vomiting/diarrhoea
- has better bioavailability (50-55% for clarithromycin vs 15-45% for erythromycin)
53
what is bioavailability
fraction of the administered drug that reaches the systemic circulation (always 100% for IV drugs by definition)
54
what are atypical bacteria, give examples, and what do they cause
- bacteria w/ cell wall deficit
- legionella
- chlamydia
- mycoplasma
- cause atypical pneumonias
55
what pathogens do macrolides have the most important activity against
cell wall deficit atypical bacteria
56
what are the main pathogen targets of clarithromycin
- strep pneumoniae
- haemophilus influenzae
- atypical chest pathogens
- -> legionella pneumophila
- -> chlamydia trachomatis
- -> mycoplasma pneumoniae
57
what is the clinical indication of clarithromycin
chest infections
58
how can clarithromycin be prepared
IV or oral
59
how is clarithromycin primarily used in hospital setting for CAP
in combination w/ beta lactam
60
what are the 3 most common aminoglycosides and when are they most commonly used
- gentamicin - 1st line
- amikacin - slightly better against highly resistant gram -ves
- tobramycin - slightly better pseudomonas cover
61
what pathogen is inherently resistant to aminoglycosides and how is this over come
- streptococci
- use aminoglycosides in combination of beta lactam which breaks down cell wall to allow amino glycoside access to bacterial ribosome
62
what are the main pathogen targets for aminoglycosides
- staphylococci
| - gram -ves
63
what are the clinical indications of aminoglycosides
- sepsis
| - UTI
64
how are aminoglycosides prepared
IV only
65
what are the most important clinical features of aminoglycosides
- rapidly bactericidal
| - synergistic effect w/ beta lactams
66
what are the draw backs of aminoglycosides
- nephrotoxicity and ototoxicity
| - they're hydrophilic so stay in 'water ways' i.e. ^ conc in blood and urine, don't penetrate well into tissue
67
what are the 3 most common tetracyclines
- doxycycline
- minocycline
- tetracycline
68
which tetracycline is most commonly used in hospital setting
doxycycline
69
what are important contraindications of tetracyclines and why
- children under 12
- pregnancy
- bind to calcium and deposited in actively calcifying teeth (results in staining) and bones of unborn/growing children
70
what are the pathogen targets for doxycycline
- MRSA isolates
- staphylococci
- streptococci
- haemophilus influenzae
- atypical chest pathogens
- -> legionella pneumophila
- -> chlamydia trachomatis
- -> mycoplasma pneumoniae
71
what are the clinical indications for doxycycline
- chest infection
| - oral MRSA treatment
72
how is doxycline prepared
oral
73
what are the 3 main classes of nucleic acid synthesis inhibitors
- quinolones
- nitroimidazoles (most common is metronidazole)
- trimethoprim
74
what are the 3 most common quinolones
- ciprofloxacin (better in gram -ve)
- levofloxacin
- moxifloxacin (better in gram +ve)
75
what is the MHRA health warning regarding the use of quinolones
should no longer be prescribed for non severe infections due to risk of tendonopathy and tendon rupture
76
what are the main pathogen targets for ciprofloxacin
- pseudonyms aeruginosa
| - gram -ves
77
what are the clinical indications of ciprofloxacin
- oral treatment for pseudonyms aeruginosa
| - part of combination therapy in penicillin allergic patients
78
how is ciprofloxacin prepared
IV or oral
79
why else is the use of ciprofloxacin restricted
assc. w/ MRSA and C diff
80
what are the main pathogen targets of levofloxacin/moxifloxacin
- streptococcus pneumoniae
- atypical chest pathogens
- haemophilus influenzae
81
what are the clinical indications of levofloxacin/moxifloxacin
chest infection (CAP in penicillin allergic px
82
how is levofloxacin/moxifloxacin prepared
IV or oral
83
what is the only type of pathogen that metronidazole is active against
true anaerobes
84
what are the main pathogen targets of metronidazole
- anaerobes
| - C diff
85
what are the clinical indications of metronidazole
- polymicrobial infections
- -> intra abdominal infections
- C diff colitis
86
how is metronidazole prepared
IV or oral
87
what is trimethoprim solely used for
treatment of uncomplicated lower UTIs
88
what are the main pathogen targets of trimethoprim
- aerobic gram -ves
- -> E. coli
- -> klebsiella
- -> proteus
89
what is the clinical indication of trimethoprim
uncomplicated lower UTIs
90
how is trimethoprim prepared
oral
91
what are the two examples of miscellaneous antimicrobials
- nitrofurantoin
| - fidaxomicin
92
what are the main pathogen targets of nitrofurantoin
- gram -ves
| - enterococcus faecalis
93
what is the only clinical indication of nitrofurantoin
uncomplicated lower UTIs
94
how is nitrofurantoin prepared
oral only
95
what are the contraindications of nitrofurantoin
- px w/ glucose 6-phosphate dehydrogenase deficiency (risk of haemolytic anaemia)
- at term in pregnancy (risk of Haemolysis of immature neonatal RBC)
- px w/ renal impairment (reduced renal excretion --> treatment failure)
96
what class of antibiotics is fidaxomicin the first of
macrocyclic
97
what is the only indication of fidaxomicin
C diff colitis
98
how is fidaxomicin prepared
oral only
99
compare fidaxomicin and vancomycin in C diff treatment
- fidaxomicin is as efficacious as oral vancomycin
- fidaxomicin has lower risk of relapse
- fidaxomicin is more expensive
100
describe the 3 main types of resistance mechanisms that bacteria can have
- enzymatic degradation
- -> prod of enzymes that breakdown antibiotics
- target site modification
- -> alters site where antibiotic acts reducing efficacy
- restricted access
- -> efflux pumps actively remove antibiotic
- -> membrane penetration barrier (down regulation in number of porins that give antibiotic access to bacterium - reduced permeability)
101
what is the most important example of enzymatic degradation
resistance to beta lactams
- -> beta lactamases (prod by both gram +ves and -ves
- -> break down beta lactam ring
102
which bacteria produce the most clinically important beta lactamases
gram -ves e.g. E.coli and klebsiella
103
describe how antibiotics have been developed w/ more resilience to beta lactamases
- inherent resilience
- protector molecule added
- -> penicillin-BetaLactamase Inhibitor Compounds (BLICs)
104
what are the 2 most commonly encountered beta lactamase inhibitors
- clavulanate --> combined w/ amoxicillin to form co-amoxiclav
- tazobactam --> combined w/ piperacillin to form piperacillin-tazobactam
105
outline how BLICs provide resilience to beta lactams
- BLICs resemble beta lactam structure
- protect antibiotic by:
- -> acting as surrogate substrate for beta lactamase
- -> binding to beta lactamase, permanently inactivating it
106
describe the relationship between activity spectrum of beta lactams and their resilience to beta lactamases
the higher the spectrum of gram -ve activity, the lower the resilience to gram -ve beta lactamases
107
what are the main pathogen targets of co-amoxiclav
- gram -ves
| - can be used broadly when pathogen unknown or likely polymicrobial infection
108
what are the clinical indications of co-amoxiclav
- intra abdominal (polymicrobial)
- complicated UTIs (gram -ves)
- complicated ENT infections
109
how is co-amoxiclav prepared
IV or oral
110
what are the main pathogen targets of piperacillin-tazobactam
- pseudomonas aeruginosa
| - gram -ves
111
what are the clinical indications of piperacillin-tazobactam
- sepsis
| - infection in severely immunosuppressed px where source is unknown
112
how is piperacillin-tazobactam prepared
IV
113
which BLIC is better against gram -ves
piperacillin-tazobactam
114
what is one of the broadest spectrum antimicrobials
meropenem
115
what are the main pathogen targets of meropenem
almost anything
| - breadth of cover is the most important aspect
116
what are the clinical indications of meropenem
- severe sepsis
| - infection in severely immunosuppressed px where source is unknown
117
how is meropenem prepared
IV
118
what is the most clinically important beta-lactamase and why
carbapenemases
- prod by gram -ves
- capable of breaking down all beta lactams
- usually no beta-lactam treatment options
- gene encoding enzyme is plasmid mediated so can be passed between bacteria of the same or different genera
119
what does carbapenemase production indicate about a bacteria
- it is likely be multi-drug resistant
| - capable of sharing resistance mechanisms w/ other bacteria
120
where do gram -ves tend to reside and how is this a serious issue for a px w/ CPO (carbapenemase-producing organisms)
```
human bowel (w/ hundreds of millions of other bacteria)
- px likely colonised for life
```
121
what happens to a px that is colonised w/ CPO
- isolated in a side room w/ contact infection control precautions
- health care workers need to don PPE when providing physical care
122
what is the most important example of the target site modification mechanism of antimicrobial resistance
flucloxacillin resistance in staph aureus resulting in MRSA
123
outline the target site modification mechanism of beta lactam resistance
- PBPs cross link peptidoglycan
- beta lactams act on PBP
- if change in PBP shape, beta lactam can't bind
- peptidoglycan cross linking continues
- bacterium is resistant to beta-lactam
124
outline how flucloxacillin resistance in staph aureus results in MRSA
- in staph aureus, acquisition of mecA gene results in altered PBP called PBP2A
- flucloxacillin can't bind to PBP2A --> staph aureus resistant
- now termed MRSA
125
what are the treatment options of MRSA
- clindamycin
- vancomycin
- Teicoplanin
126
what happens to Px colonised w/ MRSA
- isolated in a side room w/ contact precautions to prevent px-to-px spread of MRSA
127
outline the restricted access mechanism of antimicrobial resistance
restricted access arises by:
- antibiotic failing to get into bacterial cell due to loss of porins (access channels)
- antibiotic being actively pumped out of bacterial cell due to ^ prod of efflux pumps
128
why is restricted access antimicrobial resistance particularly problematic
can affect more than one antibiotic class
129
give an example of bacteria w/ restricted access resistance and describe its resistances
pseudomonas aeruginosa
- intrinsically resistant to most antibiotics
- acquires resistance mechanisms --> MDR
- most common mechanism is efflux pump
130
what 6 drugs are active against pseudomonas aeruginosa
- Piperacillin‐tazobactam
- meropenem
- ceftazidime
- aminoglycosides
- ciprofloxacin
- aztreonam
131
what is the only drug active against pseudomonas aeruginosa w/ restricted access
aminoglycosides
132
why is antibiotic allergy documentation important
- prevent life threatening drug reaction
- avoid unnecessary drug restriction
- antimicrobial stewardship
- -> reduce use of 'reserve' antibiotics
133
what is the most common antibiotic allergy
beta-lactams
134
what is important to ask about when taking an allergy history
SEVERITY
- time of onset, relative to dose
- symptoms of evolution, duration
- -> rash type:
- maculopapular
- urticarial
- bullous
- -> involvement of mucosal surfaces or internal organs
- treatment required
DUE TO ANTIBIOTIC
- exposure prior to reaction
- other meds at time of reaction
- antibiotic or relative tolerated since ?
- other drug allergies
- similar reaction in absence of drug ?
135
what kind of allergic reactions are of major concern
- have a fast onset
- involve urticarial rash
- include swelling e.g. of lips or tongue
- breathing difficulties
- required antihistamine treatment
136
what is sepsis
- life threatening organ dysfunction caused by disregulated host response to infection
- interplay between host and pathogen
137
why is sepsis important to treat quickly
chance of death ^ by 10% appx for every hour antibiotics delayed
138
how to recognise sepsis
- can use tools and scores
- well known scores:
- -> SOFA score from third international consensus definitions
- sepsis screening tool from sepsis 6 (UK sepsis trust)
qSOFA (quick sequential organ failure assessment score) criteria:
- resp rate >22
- glasgow coma scale of 13 or less
- SBP of 100 or less
(UK sepsis trust lists 10 features)
139
what is crucial in sepsis investigation and why
identify the pathogen
- ensures effective therapy
- allows rationalisation of antibiotics
- -> maintains antibiotic efficacy for next px
- -> reduces collateral damage for px
140
how can you identify the pathogen in sepsis
SEPTIC SCREEN
send samples; sample the tissues that you think are infected or inflamed
- blood cultures (critical)
- -> peripheral and central line if present
- -> determine if px is bacteraemic (has replicating bacteria in blood)
- urine culture
- sputum culture
- wound swab
141
what is important to consider when choosing a suitable antibiotic for a potentially septic px
- likely source of infection; any signs pointing towards particular anatomical source
- what pathogens tend to cause infection in that site (is px known to be colonised w/ any resistant organisms)
- known antibiotic allergies px
142
what type of antibiotics tend to be used to treat sepsis
broad spectrum
