Antibiotic modes of action and resistance Flashcards
Inhibitors of cell wall synthesis
B- lactams: penicillins, cephalosporins, carbapenems, monobactams
Glycopeptides: Vancomycin, teicoplenin
Synthesis of peptidoglycan
NAM/NAG alternatingly joined by glyosylase
Monomer join to PG via glycosylase
PG is x linked via aa side chains via transpeptidases
Beta-lactam mode of action
Bind to penicillin binding proteins (PBP’s-transpeptidase)
Prevents X linking from occuring leading to cell lysis
Also stimulates autolysins which breakdown the cell wall that also lead to cell lysis
Glycopeptide mode of action
Prevents glycosylase from adding PG monomers onto PG chain and prevents x-linking
Polymyxin (colistin) and lipopeptides
Act on cell membranes by binding to liposaccharides only on g-ve bacteria
Causes cell disruption leading to leakage
Fluoroquinolones
Ciprofloxacin, Levofloxacin
Binds to type 2 DNA gyrase (g-ve) and type 4 topoisomerase(g+ve)
Inhibits DNA replication and packaging and causes cell lysis
Aminoglycosides
Gentamycin, Bactericidal
Binds irreversibly to A site on 16s rRNA in 30s subunit
Causes misreading of codons along mRNA and interferes with translocation of tRNA from A to P site which disrupts membrane permeability
Inhibits protein synthesis
Tetracyclines
Doxycycline
Binds reversibly to A site on 16s rRNA in 30s subunit
Causes tRNA not to bind to A site. Selectivity through accumulating in cell and better binding to bacterial ribosome
Inhibitors of protein synthesis
50s: Macrolides, chloramphenicol, streptogramins, lincosamides, fusidic acid, oxazolidinones
30s: tetracyclines, aminoglycosides
Species of most concern?
MDR e.coli and TB
Aquiring resistance
Mutations and/or conjugation of plasmids
Beta lactam resistance
4 classes: A,C,D have serine at active site, B is a metallo lactamase requiring zinc
Beta lactamases can be produced which bind in peri plasmic space or medium
Or by altering Penicillin binding proteins through MecA gene. (causes methicillin resistence in s.aureus)
or reduce number/size of porins to decrease permeability and uptake
Beta lactamase inhibitors
Clavulanic acid (in co amoxiclav)
Tazobactam (in taxocin)
Sulbactam
Glycopeptide resistance (Vancomycin)
Change in aa sequeces reducing h bonds from 5 to 4 making it unstable
d-ala to d-lactate
Fluroquinolones (ciprofloxacin) resistance
Mutations alter structure of DNA gyrase or of topoisomerase 4 preventing binding
Tetracycline resistance
Efflux pumps
Actively pumps out drug molecules ensuring it never reaches the required concentration.
Basal rate is intrinsic resistance while upregulated is aquired
Multi drug efflux pumps
RND for g-ve, MFS for g+ve
AcrAB/TolC pump in e.coli
chromosomal RND pump
upregulation gives resistanc to fluoroquinilones, chloramphenicol etc
Main types of penicillins
Lactamase sensitive:benzypenicillin (pen g), benzythine benzylpenicillin, phenoxymethylpenicillin (pen v)
Lactamase resistant: Flucoxicillin, co-fluampicil, temocillin
Broad spectrum: amoxicillin, ampicillin, co-amoxiclav, augmentin
Antipseudomonal: piperacillin, tazocin, timentin
Benzypenicillin properties
High blood conc achieved quick non toxic good diffusion into body tissues low levels in CSF longpost antibiotic effect
Uses of pen G
Use immediately for meningitis throat infection endocarditis pneumonia cellulitis osteomyelitis
Meningitis causing microbes
Neisseria meningitidis
H.infuenzae
s.pneumoniae
Side effects of penicillins
Hypersensitivity (rash/anaphylaxis)
Neurotoxicity (increase with renal failure)
Renal failure (High salt affects electrolyte balance)
Diarrhoea and pseudomembraneous colitis
Cephalosporins
Made from cephalosporium acremonium, cephalosporin C
Specificty, selectivity determined by R groups 1 and 2
Properties of cephalosporins
resistant to b-lactamases
good drugs but limited by c.difficle risk
affinity for pbp’s in g+ve
outer membrane penetration in g-ve
Side effects of cephalosporins
Hypersensitivity (rash/anaphylaxis/inflammation)
Diarrhoea, nausea, c.difficile super infection
Vomiting, headaches, dizziness, renal toxicity, hemorrhage (rare)
2nd gen cephalosporins
cefuroxime , cefaclor, cefadroxil
ceftriaxone, cefotaxime is 3rd gen
Carbapenems
Imipenem, meropenem
v resistant to b lactamase
broad spectrum
for p.aeruginosa and ESBL
Glycopeptides
Vancomycin oral for c.difficile
teicoplanin injection for systemic infections
Active against g+ve not g-ve
PK of glycopeptides
High CSF penetration
Renal excretion
Side effects: pain, thrombophlebitis, renal toxicity, ototoxicity, blood disorders, anaphylactoid reactions
Polymyxins
Colistin
Active on g-ve bacteria, last resort iv
Highly nephro and neurotoxic
Lipopeptides
daptomycin
Active on g+ve bacteria causes depolarisation of membrane
Used for skin/soft tissue infections, endocarditis caused by resistant g+ve bacteria
Side effects: nephrotoxicity, myopathy, peripheral neuropathy, colitis
Fluoroquinolones
ciprofloxacin, levofloxacin,
Synthetic, broad spectrum, bactericidal
Active against g-ve and intracellular pathogens. ltd use against streptococci and enterococci
Side effects: gi disturbance,cns, tendon damage, rash, photosensitivity, renal impairment. Interacts with CYP450
Rifamycins
Rifampicin
Bactericidal, inhibits rna polymerase, given in combo to reduce resistance
Treats tb, meningitis, prosthetic infections
Rifamycin PK
well distributed, >90% metabolised
side effects are hepatotoxicity, fever, rash, hypersensitivity, GI disturbance, orange/red secretion
increased metab of warfarin, OCP’s
Nitroimidazoles
Metronidazole
Anaerobic infections, GI + genital +abdominal+dental infections
Nitroimidazole PK
Well distributed including CSF, hepatic metabolism, renal excretion
Side effects are nausea, vomiting, diarrhoea/constipation, taste, candida super infection
neuropathy, hives, rash, red/brown urine
Makes people more sensitive to urine
Nitrofurantoin
Targets fucking everything
Used for non catheterised UTI caused by g+ve and g-ve aerobic bacteria
Aminoglycosides
For serious aerobic bacteria infections Eg. septacaemia, complicated UTI, nosocomial RTI
Active mostly against g-ve psuedomonas
Streptomycin for TB, mycoplasma
Aminoglycoside PK
Can be given orally for gut decontamination as it is not absorbed
Poor penetration for cells and CSF
Renally excreted
Side effects:Reversible nephro/ototoxicity
Tetracyclines
Broad spectrum
Oral for acne, rti, ssti’s
Staphylococci and streptococci now resistant
Tetracycline PK
60-80% absorption but well distributed including foetal.
No CSF penetration
Renal and bile excretion
Side effects:GI superinfections, teeth discolouring, headache, vertigo, hepatotoxicity, phototoxicity
Macrolides
Erytromycin, clarithromycin
Alternative to penicillin for treating strep infection
Oral for rti, sti, gi,ssti
Macrolide PK
Acid labile so given as enteric coated
Rapid absorption, well distributed except CSF
Bile excretion
Side effects are gi superinfections, cholestatic jaundice, ototoxicity, allergy, arrythmia
Fusidic acid
Narrow spectrum for staph infections
Effects EF-G which supply energy for translocation
Chloramphenicol
Broad spectrum
Topical use in eye infection
Oral for meningitis or typhoid fever
Chloramphenicol PK
Well absorbed everywhere, metab in liver, renal excretion
Side effects: bone marrow suppression, grey baby syndrome, gi flora disturbed, neuritis, aplastic anaemia
