Antibiotics Flashcards
who discovered penicillin and where was it found
Alexander fleming
-found as mold growing on S aureus culture that was inhibiting and killing his culture
-peni notatum
-fermentation needed for growth
-base of corn - peni loved it and rotting cantaloupe
What is chemotherapy
Use of any chemical or drug to treat any condition or disease
Chemotherapeutic agents
What are antimicrobial agents
Chemotherapeutic agents used to treat, prevent and control the spread of bacteria and infectious disease on animal tissue and non living materials
Antibacterial
Antifungal
Antiprotozoal
Antiviral
Antitubercular
can kill or suppress growth of microorganisms
What is the ideal antimicrobial agent
Kill or inhibit growth of the pathogen
-Kill pathogens before they mutate and develop resistance to the antimicrobic
-Cause no damage to the host
-Cause no allergic reaction in the host
-Be stable when stored in solid or liquid form
-Remain in specific tissues in the body long enough to be effective
What are antibiotics
treat or prevent disease can be
natural: peni, cephala (molds)
bactracin, erythro, tertra (bacteria)
Semi-synthetic (Amp or carbenicillin)
Synthetic - (fluoro, sulfoamides)
bacteria evolves alot so there has been a decline in AB because we cant keep up with the resistance
What are types of
Beta lactams with a beta lactam ring
PENICILLINS
Natural- Penicillin G
Ampicillin (semi syn)
Oxacillin (semi syn)
Piperacillin (semi syn)
CEPHEMS
CARBAPENEMS
Ertapenem
Meropenem
Imipenem
MONOBACTAM
Aztreonam
What are examples of
AMINOGLYCOSIDES
PHENICOLS
RIFAMYCINS
AMINOGLYCOSIDES
Gentamicin
Amikacin
Tobramycin
PHENICOLS
Chloramphenicol
RIFAMYCINS
Rifampin
Rifamycin
GLYCOPEPTIDE and GLYCOLIPOPEPTIDE
LINCOSAMIDE
LIPOPEPTIDE
MACROLIDE
GLYCOPEPTIDE and GLYCOLIPOPEPTIDE
Vancomycin
Teicoplanin
LINCOSAMIDE
Clindamycin
LIPOPEPTIDE
Daptomycin
Polymixin B -polysporin
Colistin - CNA agar
MACROLIDE (spoke with the lincoamdes because they are similar) - resp infections
Erythromycin
Azithromycin
synthetic forms
FOLATE PATHWAY INHIBITORS
FLUOROQUINOLONES
NITROFURANTOIN
FOLATE PATHWAY INHIBITORS
Trimethoprim/Sulfamethoxazole (SXT or Septra, Cotrimoxazole
-septra or katromoxa
FLUOROQUINOLONES - acicins
Ciprofloxacin
Norfloxacin
Levofloxacin
NITROFURANTOIN
Nitrofurantoin
What is the mode of action of penicillins
which are natural
what is Peni resistant
which are the co drugs
-mode of action interfere with cell wall synthesis
Natural - Peni V or G
Penicillinase resistant to B lactams Pen A- methi, oxaci, nafcillin, cloxa
the natural and Peni resistant are effective against gram positive organisms and Neisseria spp.
Extended spectrum are more effective against the GN like ampicillin (amino amp)**
Peni co drugs ( combined with beta lactamase inhibitor)
Amoxyxillin-clavulanic acid, Ampicillin-sulbactam, piperacillin-tazobactum
What are first generation CEPHEMS including cephalosporins
First generation
Good against GPs and moderate GNs activity
Cephalothin
Cefazolin
What are 2nd generation CEPHEMS including cephalosporins
Second generation
Better stability against beta lactamases - attack B lactam ring
Increased activity against GNs
Cefuroxime ,cefamandole
Cephamycins
Cefoxitin & Cefotetan
What are 3rd generation CEPHEMS including cephalosporins
-More active against Enterobacteriaceae family
- active against P. aeruginosa ceftazidime resistance occurring
-Less active on GP compared to 1st and 2nd
Cefotaxime, Cefpodoxime
Ceftazidime, Ceftriaxone (respiratory)
What are 4th generation CEPHEMS including cephalosporins
Fourth generation
Increased activity against GN bacteria -ceftazidime resistance in Pseudomonas
and even less against GP
Cefepime
What is Antitubercular
-M. tuberculosis
-slow growing and intracellular
-treated with 3 ABtics concurrently for 6 months
-increasing resistance due to immigration, travel, fatal in people with HIV
What ABtics are used with TB
Isoniazid ( side effect liver and peripheral nerve toxicity)
Rifampin (side effect GI upset, liver toxicity, flu syndrome, body fluid discoloration, skin eruptions, low platelets, anemia)
Pyrazinamide ( side effect liver toxicity, high uric acid)
Ethambutol ( side effect ocular toxicity)
Streptomycin (side effect renal and ear toxicity)
What are antifungal drugs
-binds to ergosterol (part of yeast and fungal cell membrane, D2 precursor)
-decreases ergosterol synthesis and disrupts fungal cell membrane
-ergosterol is essential for membrane permeability and fluidity
Polyenes – e.g.Nystatin (oral, topical), Amphotericin B (IV/intravenous)
5-fluorocytosine (5-FC)
Azoles – Ketoconazole, Fluconazole
What are anti viral drugs
what do they do
Blocks DNA replication
E.g. acyclovir for Herpes and Varicella
Inhibits viral replication
E.g. amantidine for influenzae virus
What are ANTI-HIV drugs
Nucleoside and Nucleotide reverse transcriptase inhibitors
Protease Inhibitors (prevent viral replication by selectively binding HIV -1 protease and blocking proteolytic cleavage of protein precursors needed for production of viral particles)
Non-nucleoside analog reverse transcriptase inhibitors
what is Bactericidal
potential “kills” microorganism
-need significant concentration and exposure
-If insufficient concentration exposure = organism can remain alive
Penicillins, Cephas, Aminoglycosides
what is Bacteriostatic
“inhibits” microorganism
-org remains alive for example s.pyogenes is susceptible to penicillin (bactericidal) and resistant to erythromycin (bacteriostatic)
-can become resistant or promote resistance by antimicrobic exposure.
used to treat endocarditis, meningitis, and osteomyelitis—indications that are often considered to require bactericidal activity.
chloramphenicol, clindamycin (can be bactericidal depending on the dose) , and linezolid
Erythromycin and other macrolides can be bactericidal at high concentrations
Broad Spectrum of Activity
against both GN and GP
-2nd and 3rd gen cephs
-Rifampin (GP, GN, N. meningitidis)
Clindamycin (most GP and some GN; highly active on anaerobes)
Narrow Spectrum of Activity
Active against one type of bacteria
-Vancomycin (mainly GP bacteria)
-Aminoglycosides (mainly GN and S. aureus; not effective against anaerobes)
-Linezolid (GP such as VRE, MRSA, Streptococci)
-Metronidazole (anaerobes, Trichomonas vaginalis) can be antiprotozoal as well
Antibiotic Targets and Mechanisms of their Action
- Inhibition of cell wall synthesis
- Interference of DNA replication
- Interference of DNA transcription
- Interference of mRNA translation
- Inhibition of Folate Synthesis
- Inhibition of BACTERIAL Cell Wall BIOsynthesis
Antibiotic groups: B-lactams, glycopeptides
-Cell wall not in mammal cells is needed for bacterial cell therefore good target by antimicrobials
What is a peptidoglycan
-part of bacterial cell wall that that is synthesized in 4 stage process
beta lactams join with enzymes (PBPs) that are involved in cross linking in final form of peptidoglycan
-beta lactams affect stage 3, 4
what are the cell wall differences in GN vs GP
both have multilayer cell wall structure with inner cell wall membrane
GP - thicker petidoglycan layer
GN- have another outer membrane seperated by a periplasmic space which has phospholipids, lipopolysaccrides and porins
GN- Beta lactams need to pass through the porins to reach the PbP
-effect on cell depending on agent and effect of PBP involved
What are beta lactams
-active moiety (functional group) is the 4 member B lactam ring
-ring interferes with cell wall production
-complexes with PBPs which will inhibit cell division forming long filamentous forms and formation of cell wall deficient type that will lyse under osmotic pressure
vanco and glycopeptides
what is Imipenem
Carbapenem - beta lactam class
-against GN
broad spectrum
-not active against MRSA or VRE
-stable against most B lactamases including ESBL and extended spec.
-can get through porin channels that other drugs cant
expensive
-can cause seizures
what is Meropenem
Carbapenem – beta lactam class
More soluble and more rapidly absorbed
Less adverse effects
What are Glycopeptides and glycolipopeptides
-blocks transpeptidation step
-decrease peptidoglycan layer
-targets step 3 and 4 of peptidoglycan biosynthesis of dividing bacteria. Decreased peptido are defective and can cause cells to lyse
-cannot cross the outer layer of GN bacteria so its limited to GP orgs like Staph, Enterococcus, or Strepto
vanco and glycopeptides
-cannot cross the outerlayer of GN bacteria the porins because they are too big
-NARROW SPECTURM
Interference with DNA replication
Antibiotic group: Quinolones/Fluoroquinolones
-topoisomerases I-IV are essential enzymes for DNA replication. They help control DNA topolgy (construction, twist), replication and cleavage of 2 units at the end of DNA replication
-Quinolones target topos 2 in Gn and 4 in GP but not both however newer ones can
2 control DNA gyrase
4 control DNA topology
What are Quinolones/Fluoroquinolones
-used to treat pneumonia
-increased risk of MRSA and C diff colonization
-interfere with RNA/DNA used in chemo
good to treat - staph, strep, entero, neisseria
Interference with DNA Transcription
which ABtics
transcription forms mature mRNA and structural RNA
- Mediated by RNA polymerase (tetramer) with ABtics targeting different subunits (4)
-can be used to treat meningococcal prophylaxes
Rifampin is a synthetic AB but it is used in a combination with other drugs to treat TB , Staph, S.pnuemo because on its own it can reduce its efficacy overtime and preventing resistant strains from surfacing
Interference of mRNA translation
Tetracyclines, aminoglycosides – target 30S
Macrolides, lincosamide, chloramphenicol – target 50S
30S and 50S rsubunits bind to mRNA before translation occurs.
Translation is mRNA into functional proteins = protein synthesis
What does Aminoglycosides binding to 30S cause
-bind to 30S = mistranslation
-production of aberrant proteins incorporated into the cell wall resulting in leakage and increased AB penetration
Nephrotoxic (kidney) and ototoxic (hearing)
What does TETRACYCLINE binding to 30S cause
-Polyketide class – targets 30S subunit
-REVERSIBLY inhibits protein synthesis by blocking peptide chain elongation
-not for 18 as it impacts bone growth and causing yellowing of teeth in those under 8
-not for pregnant women because it can interfere with fetal bone growth
What do macrolides binding to 50S cause
-binding to 50S rsubunits blocks peptide chain elongation inhibiting protein synthesis
-prevent its assembly
E.g. Erythromycin, Clarithromycin, Azithromycin
What do LINEZOLID binding to 50S cause
-Bind 50S ribosomes blocking initiation step of protein synthesis
-prevent its assembly
What does Lincosamides binding to 50S cause
binds 50S ribosome
-Clindamycin to treat Staph and Strep, TSS by blocking the M protein of Staph, treat protozoan infections, toxoplasma and malaria
- Inhibition of Folate Synthesis causes
what AB use this process
-interference of intracellular anabolic processes
-folic pathway provides precursors needed in DNA biosynthesis - mediated by 2 enzymes: dihydropteroate synthase and dihydrofolate reductase
E.g. sulfamethoxazole and trimethoprim (SXT)
UTI due to Enterobacteriaceae
Gastrointestinal, Respiratory
What is the action of Sulphonamides
competitively inhibits the binding of para aminobenzoic acid with dihydropteroate synthase
What is the action of Trimethoprim
blocks THF formation by preventing the action of dihydrofolate reductase
What are ABtic combinations used for
-treat mixed infections or anaerobic infections
-prevent ABtic resistance
-so we can use less of each AB to prevent toxicity
-work with Synergism, Antagonism, Indifference
What is Synergism
-combo therapy is better against the org than agent alone
-used in V strep to treat endocarditis with Peni + Gentamicin therapy uses agent active on the cell wall to increase aminoglycoside uptake
-when you see an enhanced zone between orgs is an indication of synergy
What is, Antagonism
using peni (active on the cell wall and needs orgs to replicate) and tetraclyine (bacteriostatic and wont let the org replicate) together is worse than using them alone
when the ZOI stops before it reaches the other zone for the next drug like a blunting
What is Indifference
combined therapy is no better than drug alone
how can resistance emerge
-over using ABtic - TOO LONG
-using the wrong dose
-when antimicrobials are used in animal feed or aquaculture
-globalization
Selection pressure - only strongest survive, susceptible bacteria removed
Continuous development - findings to offset resistance, slow , global concern
What did peni resistance start off as
resistance against S aureas then to GC
What did Sulfonamide Resistance start as
GC resistance followed by meningococcal resistance
What is Cloxacillin Resistance
used to treat Peni resistant S aureas
What is Vancomycin Resistance
-treats peni resistant and clozallini resistant S aureus
-no alternatives to fight infections by S aureus and Enterococcus
Control or Limit of Emerging Resistance
-decrease AB use
-Dr should ration
-control vet use - live stock
-antimicrobial stewardship
-using nanotechnology
Encapsulating drugs allows for more surface modification and stabilization for longer
how are vanco resistance genes transferred to s aureus
vancomycin resistance genes from Enterococcus faecalis could be transferred by horizontal gene transfer to S. aureus in experiments in vivo and in vitro
-transposon on plasmid confers vanA-type vancomycin resistance in enterococci.
What is the Intrinsic (chromosomal) MECHANISMs of Antibiotic Resistance
-natural members of species , passed vertically to progeny cells - predictable
-bacteria differs in cell wall composition differences in resistance and susceptibility
-resistance can be hydrophobic or hydrophilic nature of Abtic
-resistance can depend on cell wall impermeability to AB, formation of biofilms and efflux
-intrinsic resistance can also be chromosomally mediated enzymatic inactivation of antibiotics that penetrate the cell wall
2 cell structures in cell wall cause resistance due to impermeability :
how is it seen in GN
1-Lipopolysaccharide composition (lipid + polysacc joined by covalent bond found in GN)
2-composution of outer membrane proteins OMP called porins. They all nutrients in and waste out , restrict influx of ABtics
Natural and passed vertically to progeny
-in GNb outer membrane is impermeable to large molecules like Vanco whereas Lactobacillus does not have a cell wall precursor which allows Vanc to bind and inhibit wall synthesis
examples of impermeability as intrinsic method of ABtic resistance
Example 1: Vancomycin vs. GN (Ab too large to enter wall)
Example 2: Vancomycin vs Leuconostoc and Lactobacillus (Organism w/o cell wall precursor target for vancomycin)
Example 3: Enterococci – low levels of penicillin
(Organism has PBPs with low attraction for penicillin)
Example 4: Pseudomonas – lots of Ab (impermeable OMP; OMP + efflux system)
Intrinsic (Chromosomal) – BIOFILMS – bacterial community
-irreversible attachment of orgs on surface can be single or multiple species
-they form a matrix in nutrient rich environment increasing metabolic efficiency
-outside of matrix protects the replication on the inside
from ABtic exposure
can be:
Innate -part of biofilm pathway with presister cells found deep in the biofilm differentiating into a phenotypically resistant state - slow grower
induced -induced by exposure have potential to produce biofilm but its not turned on until AB exposure
Intrinsic (Chromosomal) – EFFLUX
-efflux pumps found in GN and GP
-natural in both susceptible and resistant
-transporter proteins that remove toxic substances from within cells
-resistance to antimicrobial agent, class, or cross resistance = multidrug resistance
Intrinsic (Chromosomal) – ENZYMATIC INACTIVATION
most common resistance mechanism
production of enzymes that destory ABtics before they reach the target
B-lactam Ab bind to PBPs – Organisms can continue to produce cell walls
Enzyme opens or cleaves the beta-lactam ring which makes it unable to attach to the PBPs (penicillin-binding proteins)
Beta lactamase hydrolyze β-lactam antibiotics
4 classes: A,B, C,D
Class B: metallo-based mechanism of action requiring zinc ions to disrupt β-lactam ring
Class A,C,D: Serine-based mechanism
-structure between PBPs and Classes A,C,D beta lactamases similar = may have evolved from PBPs
What is the Acquired MECHANISM of Antibiotic Resistance
-distinct from parent - horizontal transfer of pre existing genes
-Efflux (via plasmids)–Streptococcus macrolide resistance
-Acquisition of new targets
MRSA acquired staph cassette chromosome mec (SCCmec) =Methicillin resistance which encodes a PBP2A with reduced affinity to B lactams
Resistance to Sulfonamides in GP and GN; new enzyme in folate pathway not affected by AB
some can use both in and extrinsic
Acquired – Mechanisms
Target Site Modification
-Chromosomal mutation (transformation and recombination) -found in quinolones
-Enzymatic target site alteration
-ERM gene confers macrolide resistance found on plasmids and transposons
-VRE (both vanA (highly onto MRSA), vanB confer vanc resistance)
vanA transmissibility is a concern because it transmits resistance from Enterococcus to Staph
Acquired – Mechanisms
Enzymatic inactivation of AB
-Plasmid mediated β-lactamase resistance like on
Extended spectrum beta lactamases (ESBL) for GN infections
some aminoglycoside resistant antibiotics can produce an enzyme that prevents recognition of the 16S binding site (and therefore no inhibition of mRNA translation)
What is dissemination - EXCHANGE OF GENEs
Lateral Gene Transfer (LGT)
-spreading Ab resistance
-physical movement of DNA and incorporating it in the recipient genome -Transduction, conjugation, transformation using plasmids, transposons, insertion sequences abd integrons
cell membrane is targeted by
poly mixin
rifampin targets
RNA polymerase
DNA synthesis is targeted by
Nalidixic acid
Flouroquinolones
Sulfamides and Triemethoprim target
essential metabolites by targeting enzymes in the folate pathway
some bacteria can produce b lactamase which can destroy or hydrolyze b lactam ring
-PBP and serine have similar structure since they are kinda the same B lactam drug can bind to either.
if they bind to the beta lactamase they will be destroyed .
GN the beta lactamase is found in the periplasmic space and GP orgs they are released from the cell
