Micro 1 - Antimicrobial agents 1 Flashcards
Inhibitors of cell wall synthesis
• Β-lactam abx o Penicillins o Cephalosporins o Carbapenems o Monobactams
• Glycopeptides
o Vancomycin
o Teicoplanin
• Β-lactam abx
o Penicillins
o Cephalosporins
o Carbapenems
o Monobactams
• Β-lactam abx MOA
- Inactivate enzymes involved in the terminal stages of cell wall synthesis (no peptide cross-links) = transpeptidases/penicillin binding proteins (PBP)
- Bactericidal
These enzymes form peptide bonds between the peptidoglycan subunits of the cell wall NAM (N-acetylglucosamine) + NAG (N-acetylmuramic acid)
Weak cell wall bacteria lyse
renally excreted
B-lactam abx where are they ineffectiv?
o Ineffective against bacteria that lack peptidoglycan cell walls Mycoplasma, Chlamydia
Therefore in respiratory tract infections with these organisms (known as atypical organisms), different antibiotics are used
o Ineffective against bacteria that are in the stationary phase of the cell cycle/if the cell wall has already been formed
Flucloxacillin resistance
designed to be stable to b lactamases
o is alteration of the target – altered PBPs (peptide binding proteins)
Therefore flucloxacillin resistance is MRSA resistance alteration of the target
o β lactamase inhibitors
• Clavulanic acid (+ amoxicillin = co-amoxiclav)
Tanzobactam ( + piperacillin = Tanzocin/Piptazobactam)
Avibactam
Staph. Aureus, Gram -ves (E.coli, Pseudomonas) and anaerobes
Intra-abdominal infections
Cefuroxime + Metronidazole
or
co-amoxiclav
Ceftriaxone
generation
use
associated with
paediatric version
3rd
sepsis, meningitis, meningococcal septicaemia,
associated with C. diff diarrhoea
paediatric versin cefotaxime
which abx is associated with c difficile
ceftriaxone
abx against pseudomonas
cefatizidime
aminoglycosides (gentamicin + tobramycin)
quinolones (ciprofloxacin)
piperacillin
abx against ESBLs (extended spectrum b lactamases) + why
Carabapenems
ESBLs are ENZYMES can break down penicilins + cephalosporins
therefore mechanism of resstance = enzymatic inactivation of the antibiotic
how to remember the generations of cephalosporins
1st gen have “fa” or “pha” in their name except cefalor (2nd gen)
3rd gen end in “ime”, “one”, “ten” excpet cefuoxime (2nd gen)
examples of carbapenems
• Meropenem, Imipenem, Ertapenem
v broad specturm
Glycopeptides
examples
use
MOA
SE
- Vancomycin, Teicoplanin
- Slowly bactericidal – inhibit cell wall synthesis
• Active against Gram +ve organisms
o Important in treating serious gram +ve infections
MRSA infections (iv only) – Vancomycin, resistant to all β-lactam abx
o C. difficile oral vancomycin
• Large molecules unable to penetrate Gram -ve outer cell membrane
• Inhibit cell wall synthesis
o peptide at the end of the cell wall subunit will go on to form the peptidoglycan links
o this peptide is made up of amino acid subunits
o Vancomycin binds to D-Ala amino acid at the end of the peptide of the peptidoglycan precursor stops transglycosidase (which forms glycosidic links) + prevents transpeptidase binding + stops the formation of the peptide bonds osmotic lysis
o Stops formation of peptide bonds weak peptidoglycan cell walls of daughter cells bacteria lyse after dividing
• Nephrotoxic + to some extent ototoxic – monitor drug levels to prevent accumulation
Inhibitors of protein synthesis
Buy AT 30, CEL at 50
30s ribosome
• Aminoglycosides (e.g. gentamicin, amikacin, tobramycin)
• Tetracyclines (e.g. doxycline, tigecycline)
50s ribosome - chloramphenicol, erythromycin, linezolid
• The MLS group Macrolides (e.g. erythromycin)/ Lincosamides (clindamycin) / Streptogramins (Synercid)
• Chloraphenicol
• Oxazolidinones (e.g. Linezolid)
All bacteriostatic except aminoglycosides (bacteriocidal)
Aminoglycosides MOA
inhibitor of protein synthesis
Inhibitor of protein synthesis
• Bind to amino-acyl site of the 30s ribosomal subunit
o Cause misreading of codons along the mRNA
o Prevent elongation of the polypeptide chain
• Bactericidal
• Require specific transport mechanism to enter cells
• Poor oral absorption – has to be given IV
tetracyclines MOA
Inhibitor of protein synthesis
30s ribosome
- Bacteriostatic (stops bacteria from reproducing)
- Reversibly bind to the ribosomal 30s subunit prevent binding of aminoacyl-tRNA to the ribosomal acceptor site inhibit protein synthesis
Tetracyclines
Use
SE
30s ribosome
• Broad-spectrum agents with activity against
o Bacteria with no peptidoglycan cell wall (e.g. chlamydiae, rickettsiae + mycoplasmas – atypical pneumonia)
o Intracellular pathogens (e.g. legionella, chlamydiae, rickettsiae & mycoplasmas)
o Most conventional bacteria
• Used as cover in
o Atypical pneumonia
o Skin infections
o Soft tissue infections
- Low levels in blood so not useful for bacteraemia
- Light-sensitive rash – particularly with doxycycline – warn patients to stay out of sunlight
- Can discolour growing teeth
- Can be deposited in growing bones Do not give to children, pregnant or breastfeeding women
Macrolides
examples
MOA
use
Inhibitor of protein synthesis
• Erythromycin (QDS), clarithromycin (BD), azithromycin (OD)
• Bacteriostatic
• Binds to peptidyl transferase of the 50s ribosomal subunit + inhibits peptide bond formation during translocation
o Stimulate dissociation of the peptidyl-tRNA
• In general, limited utility against gram -ve – do not use for E. Coli, Pseudomonas etc
• Newer agents (e.g. clarithromycin, azithromycin) can be used in some situations for treating gram -ves
o Azithromycin used to treat Salmonella typhae and in CF
o Azithromycin – long half-life, used in paediatrics
• Useful for treating Staphylococcal or Streptococcal infections in penicillin-allergic patients
• Also active against Campylobacter sp , Legionella pneumophilia, mycoplasma, pneumophilia
o Campylobacter enteritis long duration of symptoms, bloody diarrhoea
• Can be used in pregnancy + childhood
Chloramphenicol
MOA
Indications
SE
Inhibitor of protein synthesis
• Bacteriostatic
• Binds to peptidyl transferase of the 50s ribosomal subunit + inhibits peptide bond formation during translocation
- Eye drops – bacterial conjunctivitis
- Big indication meningococcal + pneumococcal meningitis in patients who are penicillin anaphylactic
o Risk of aplastic anaemia
o Risk of grey baby syndrome in neonates – inability to metabolise the drug
Oxazolidinones
example
MOA
Use
SE
Inhibitor of protein synthesis
Linezolid
- Can be both bacteriostatic (enterococci, staphylococci) and bactericidal (streptococci)
- Binds to the 23s component of the 50s subunit – prevents the formation of a functional 70s initiation complex (required for the translation process to occur)
- Highly active against Gram +ve organisms – MRSA (methicillin resistant staph aureus), VRE (vancomycin resistant enterococci)
- Not active against Gram -ves
• May cause thrombocytopenia (common, reversible) + >4 weeks of treatment may cause optic neuritis (may not be reversible)
Fluoroquinolones
example
MOA
Use
SE
ciprofloxacin, levofloxacin, moxifloxacin
Inhibitors of DNA synthesis
• Act on α-subunit of DNA gyrase predominantly
• Bactericidal
• Ciprofloxacin gram -ve organisms incl. Pseudomonas aeruginosa
• Newer agents (e.g. levofloxacine, moxifloxacin) gram +ve + intracellular (e.g. Chlamydia spp)
o Levofloxacine, moxifloxacin Used for atypical pneumonia treatment
• Used for o UTIs o Pneumonia o Atypical pneumonia o Bacterial gastroenteritis
• Side effects
o Lower seizure threshold – not used in epileptics or pt w a hx of seizure
o Tendonitis – particularly achilles tendonitis, not used in the elderly or pt on steroids
Nitroimidazoles
example
use
MOA
metronidazole, tinidazole
Inhibitors of DNA synthesis
• Bactericidal
• Used exclusively for anaerobes anaerobic bacteria (GI infections) + protozoa (e.g. Giardia, amoeba)
o Under anaerobic conditions an active intermediate is produced DNA strand breakage
Inhibitors of RNA synthesis
MOA
Use
SE
Resistance
Rifamycins, e.g. rifampicin & rifabutin
- Bactericidal
- Inhibits protein synthesis by binding to DNA-dependent RNA polymerase inhibits RNA polymerase inhibits initiation
• Active against Mycobacteria + Chalmydiae
o Main use TB (but always used in combination to prevent the development of resistance while on treatment)
o Other uses: other mycobacteria, chlamydia, prosthetic joint infections (can disrupt biofilms)
• Should never be used as a single agent resistance develops rapidly
• Monitor LFTs
• Enzyme inducer Interactions with other drugs that are metabolised in the liver (e.g. COCP, warfarin)
• May turn urine, contact lenses, sputum, tears orange
o Resistance due to chromosomal mutation causes a single amino acid change in the β subunit of RNA polymerase fails to bind to rifampicin
Abx against MRSA, VRE
Linezolid (oxazolidinones) (inhibitor of protein synthesis)
Daptomycin (cell membrane toxin)
o Daptomycin is inhibited by surfactants – not used in pneumonia
o Linezolid is easier to use – used in MRSA pneumonia
o Daptomycin can only be used as IV, Linezolid can be used orally
o In general daptomycin isn’t used very commonly, linezolid is used more
Cell membrane toxins
Daptomycin
against gram +ve
MRSA, VRE
Colistin
against gram -ve
Pseudomonas aeruginosa, multi-drug resistant Acinetobacter baumannii and Klebsiella pneumoniae
nephrotoxic
only IV
Inhibitors of folate metabolism
examples
use
MOA
Sulfonamides - Sulfamethoxazole
o Only used in combination with trimethoprim as co-trimoxazole
• Diaminopyrimidines – trimethoprim
o Co-tramoxizole HAP, skin + soft tissue infections, PCP (pneumocystitis jiroveci pneumonia) in HIV/immunocompromised patients (prophylaxis + treatment)
- Act indirectly on DNA through interference with folic acid metabolism
- Synergistic action between the 2 drug classes act on sequential stages in the same pathway
- Sulphonamide resistance is common combine with trimethoprim (co-trimoxazole)
list the 4 mechanisms of drug resistance
BEAT
Bypass antibiotic sensitive step in pathway
Enzyme mediated drug inactivation
Impaired accumulation of drug
Modification or replacement of the drug’s target in the microbiome
Enzyme mediated drug inactivation
abx
b lactams
aminoglycosides
chlorampenicol
• Modification or replacement of the drug’s target in the microbiome
b lactams macrolides quinolones rifampicin chloramphenicol linezolid glycopeptides
reduced acuumulation
tetracyclines b lactams aminoglycosides quinolones chloramphenicol
bypass
trimethoprim
sulphonamides
cause of resistance in b lactam abx vs cause of resistance in penicillin resistance
• B lactamases are a major mechanism of resistance to β lactam abx in
o Staphylococcus aureus
o Gram negative bacilli (coliforms) – Pseudomonas, E.coli, Citrobacter, Enterobacter
Penicillin resistance is the result of the acquisition of a series of stepwise mutations in PBP genes
Penicillin resistance mediated by altered transpeptidases/penicillin binding proteins
e.g. MRSA
MRSA mechanism of resistance
o MRSA – altered transpeptidase/penicillin binding protein (PBP)
Resistant to all the β lactam abx
mecA gene encodes a novel PBP (2a)
low affinity for binding β lactams abx
Substitutes for the essential functions of high affinity PBPs at otherwise lethal concentrations of abx
Streptococcus pneumoniae mechanism of resistance
• Penicillin resistance is the result of the
acquisition of a series of stepwise mutations
in PBP genes.
• Lower level resistance can be overcome by
increasing the dose of penicillin used
Macrolides mechanism of resistance
altered target
• Enzyme adenine-N6 methyltransferase modifies 23S rRNA
o Encoded by erm (erythromycin ribosome methylation) genes
o UK erm is the commonest macrolide resistance mechanism
o Clindamycin is not an inducer of this mechanism therefore this looks sensitive in vitro
• Modification reduces the binding of MLS abx and results in resistance
o The MLS group Macrolides (e.g. erythromycin)/ Lincosamides (clindamycin) / Streptogramins (Synercid)
Staph aureus resistance
Staph. aureus resistance can be either enzymatic or altered binding (MRSA)
Which 2 bacteria dont have a cell wall
Mycobacterium
Chlamydia
As generations of cephalosporins increase…
Abx becomes less active against gram +ves and more active against gram -ve bacilli
Piperacillin
Gram positive organisms
Streptococci
Clostridia
amoxicillin
Enterococci
Gram negative organisms
flucloxacillin
MRSA
piperacillin
Pseudomonas
other non-enteric Gram negatives
clavulanic acid and tazobactam
S. aureus, Gram negatives and anaerobes
ceftazidime
anti-Pseudomona
cefuroxime
Gram
negatives
• Oral vancomycin can be used to treat
serious C. difficile infection
Gentamicin & tobramycin
particularly active vs. Ps.
aeruginosa
