Lecture 44: Antibacterials Flashcards
what are the 2 most important classes of antibiotics that act on the bacterial cell wall
- beta lactams
- glycopeptides
what was the first beta lactic discovered
penicillin
what are the 4 main classes of beta lactams
- penicillins
- cephalosporins
- carbapenems
- monobactams
what is penicillin betalactamase inhibitor combinations (BLICs)
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
describe beta lactam antibacterial MoA
- 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
what is present in the structure of all beta lactams
beta lactam ring
what is the difference in peptidoglycan between gram +ve and gram -ve bacteria
thickness differs
- thicker in gram +ve
- thinner in gram -ve
what type of bacteria does benzylpenicillin mainly act on
gram +ve bacteria
- specifically beta-haemolytic streptococci
how is penicillin usually administered
IV (benzylpenicillin)
give examples of oral penicillin
- phenoxymethylpenicillin
- penicillin V
why are oral penicillins not usually used
they are poorly absorbed
what are oral penicillins normally used to treat
streptococcal tonsilitis
what is the main pathogen target of benzylpenicillin and oral penicillins
beta-haemolytic streptococci
- group A strep
what is benyzlpenicillin typically used to treat
- streptococcal tonsillitis
- streptococcal cellulitis/ soft tissue infection
what penicillin drug has better oral absorption than penicillin V
amoxicillin
what is amoxicillin used for
used as step-down from benzylpenicillin, acts against:
- strep pneumoniae
- beta-haemolytic streptococci
what is amoxicillin a treatment choice for
- pneumonia
- infections caused by enterococcus faecalis and listeria monocytogenes
what are the main pathogen targets of amoxicillin
- strep pneumoniae
- listeria monocytogenes
- enterococcus faecalis
- beta-haemolytic streptococci
what are the common clinical indications of amoxicillin
- chest infection
- community acquired pneumonia
- listeria infections
how is amoxicillin prepared
IV and oral
why might amoxicillin not be sufficient by itself as treatment for enterococci
enterococci frequently part of polymicrobial infection
what is flucloxacillin the treatment choice for
staphyloccocal aureus infection
what is the main pathogen target of flucloxacillin
staph aureus
what are the clinical indications of flucloxacillin
- skin/soft tissue infection
- bone/joint infection
- endocarditis
how is flucloxacillin prepared
IV and PO
what type of class betalactam is aztreonam
monolactam
what organisms is aztreonam activity limited to
gram -ve organisms
what are the clinical indications of aztreonam
- UTI
- as part of combination therapy for:
- -> intra-abdominal infections
- -> hospital acquired chest infections
how is aztreonam prepared
IV
when might aztreonam be used
in combination w/ other antibiotics in Px w/ penicillin allergy
what class of beta lactam are ceftriaxone and cefotaxime
third generation cephalosporins
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
what are the main pathogen targets of ceftriaxone and cefotaxime
- neisseria meningitidis
- streptococcus pneumoniae
- staph aureus
- beta-haemolytic streptococci
what are the clinical indications for ceftriaxone and cefotaxime
- meningitis
- OPAT (out px parenteral antimicrobial therapy)
- soft tissue infection
- intra-abdominal infections
how are ceftriaxone and cefotaxime prepared
IV
what is the second most important class of antibiotics that act on bacterial cell wall
glycopeptides
give the two main antibiotics in glycopeptide class
- vancomycin
- teicoplanin
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
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
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
what is the key pathogen that glycopeptides act against
staph aureus esp MRSA
what are the main pathogen targets of Teicoplanin
- MRSA
- gram +ves
what are the clinical indications of Teicoplanin
- OPAT (out px parenteral antimicrobial therapy)
- -> soft tissue infection
- -> intra abdominal allergies
- combination therapy in penicillin allergy
how is Teicoplanin prepared
IV only
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
what are the main pathogen targets for vancomycin
- MRSA
- C diff
- gram +ves
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
how is vancomycin prepared
- PO only for C diff
- IV only for all other infections
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
what are the 3 classes of protein synthesis inhibitors
- macrolides
- aminoglycosides
- tetracyclines
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
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)
what is bioavailability
fraction of the administered drug that reaches the systemic circulation (always 100% for IV drugs by definition)
what are atypical bacteria, give examples, and what do they cause
- bacteria w/ cell wall deficit
- legionella
- chlamydia
- mycoplasma
- cause atypical pneumonias
what pathogens do macrolides have the most important activity against
cell wall deficit atypical bacteria
what are the main pathogen targets of clarithromycin
- strep pneumoniae
- haemophilus influenzae
- atypical chest pathogens
- -> legionella pneumophila
- -> chlamydia trachomatis
- -> mycoplasma pneumoniae
what is the clinical indication of clarithromycin
chest infections
how can clarithromycin be prepared
IV or oral
how is clarithromycin primarily used in hospital setting for CAP
in combination w/ beta lactam
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
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
what are the main pathogen targets for aminoglycosides
- staphylococci
- gram -ves
what are the clinical indications of aminoglycosides
- sepsis
- UTI
how are aminoglycosides prepared
IV only
what are the most important clinical features of aminoglycosides
- rapidly bactericidal
- synergistic effect w/ beta lactams
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
what are the 3 most common tetracyclines
- doxycycline
- minocycline
- tetracycline
which tetracycline is most commonly used in hospital setting
doxycycline
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
what are the pathogen targets for doxycycline
- MRSA isolates
- staphylococci
- streptococci
- haemophilus influenzae
- atypical chest pathogens
- -> legionella pneumophila
- -> chlamydia trachomatis
- -> mycoplasma pneumoniae
what are the clinical indications for doxycycline
- chest infection
- oral MRSA treatment
how is doxycline prepared
oral
what are the 3 main classes of nucleic acid synthesis inhibitors
- quinolones
- nitroimidazoles (most common is metronidazole)
- trimethoprim
what are the 3 most common quinolones
- ciprofloxacin (better in gram -ve)
- levofloxacin
- moxifloxacin (better in gram +ve)
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
what are the main pathogen targets for ciprofloxacin
- pseudonyms aeruginosa
- gram -ves
what are the clinical indications of ciprofloxacin
- oral treatment for pseudonyms aeruginosa
- part of combination therapy in penicillin allergic patients
how is ciprofloxacin prepared
IV or oral
why else is the use of ciprofloxacin restricted
assc. w/ MRSA and C diff
what are the main pathogen targets of levofloxacin/moxifloxacin
- streptococcus pneumoniae
- atypical chest pathogens
- haemophilus influenzae
what are the clinical indications of levofloxacin/moxifloxacin
chest infection (CAP in penicillin allergic px
how is levofloxacin/moxifloxacin prepared
IV or oral
what is the only type of pathogen that metronidazole is active against
true anaerobes
what are the main pathogen targets of metronidazole
- anaerobes
- C diff
what are the clinical indications of metronidazole
- polymicrobial infections
- -> intra abdominal infections
- C diff colitis
how is metronidazole prepared
IV or oral
what is trimethoprim solely used for
treatment of uncomplicated lower UTIs
what are the main pathogen targets of trimethoprim
- aerobic gram -ves
- -> E. coli
- -> klebsiella
- -> proteus
what is the clinical indication of trimethoprim
uncomplicated lower UTIs
how is trimethoprim prepared
oral
what are the two examples of miscellaneous antimicrobials
- nitrofurantoin
- fidaxomicin
what are the main pathogen targets of nitrofurantoin
- gram -ves
- enterococcus faecalis
what is the only clinical indication of nitrofurantoin
uncomplicated lower UTIs
how is nitrofurantoin prepared
oral only
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)
what class of antibiotics is fidaxomicin the first of
macrocyclic
what is the only indication of fidaxomicin
C diff colitis
how is fidaxomicin prepared
oral only
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
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)
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
which bacteria produce the most clinically important beta lactamases
gram -ves e.g. E.coli and klebsiella
describe how antibiotics have been developed w/ more resilience to beta lactamases
- inherent resilience
- protector molecule added
- -> penicillin-BetaLactamase Inhibitor Compounds (BLICs)
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
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
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
what are the main pathogen targets of co-amoxiclav
- gram -ves
- can be used broadly when pathogen unknown or likely polymicrobial infection
what are the clinical indications of co-amoxiclav
- intra abdominal (polymicrobial)
- complicated UTIs (gram -ves)
- complicated ENT infections
how is co-amoxiclav prepared
IV or oral
what are the main pathogen targets of piperacillin-tazobactam
- pseudomonas aeruginosa
- gram -ves
what are the clinical indications of piperacillin-tazobactam
- sepsis
- infection in severely immunosuppressed px where source is unknown
how is piperacillin-tazobactam prepared
IV
which BLIC is better against gram -ves
piperacillin-tazobactam
what is one of the broadest spectrum antimicrobials
meropenem
what are the main pathogen targets of meropenem
almost anything
- breadth of cover is the most important aspect
what are the clinical indications of meropenem
- severe sepsis
- infection in severely immunosuppressed px where source is unknown
how is meropenem prepared
IV
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
what does carbapenemase production indicate about a bacteria
- it is likely be multi-drug resistant
- capable of sharing resistance mechanisms w/ other bacteria
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
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
what is the most important example of the target site modification mechanism of antimicrobial resistance
flucloxacillin resistance in staph aureus resulting in MRSA
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
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
what are the treatment options of MRSA
- clindamycin
- vancomycin
- Teicoplanin
what happens to Px colonised w/ MRSA
- isolated in a side room w/ contact precautions to prevent px-to-px spread of MRSA
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
why is restricted access antimicrobial resistance particularly problematic
can affect more than one antibiotic class
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
what 6 drugs are active against pseudomonas aeruginosa
- Piperacillin‐tazobactam
- meropenem
- ceftazidime
- aminoglycosides
- ciprofloxacin
- aztreonam
what is the only drug active against pseudomonas aeruginosa w/ restricted access
aminoglycosides
why is antibiotic allergy documentation important
- prevent life threatening drug reaction
- avoid unnecessary drug restriction
- antimicrobial stewardship
- -> reduce use of ‘reserve’ antibiotics
what is the most common antibiotic allergy
beta-lactams
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 ?
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
what is sepsis
- life threatening organ dysfunction caused by disregulated host response to infection
- interplay between host and pathogen
why is sepsis important to treat quickly
chance of death ^ by 10% appx for every hour antibiotics delayed
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)
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
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
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
what type of antibiotics tend to be used to treat sepsis
broad spectrum
