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What do you need to know about antimicrobials?
- What is it?: chemical structure and class. Natural or synthetic product?
- How does it work?: target site and MOA
- When is it used?: spectrum of activity and important clinical uses
- What are the problems?: Toxicity and microbial resistance.
- Where does it go?: ADME
- How do we get it there?: Route of administration and product formulation
- How much does it cost?: Cost effectiveness
Empric vs. Definitive Therapy
- Empiric therapy: based on treatment of most likely organisms for a specific infection
- Definitive therapy: after organism is identified. May or may not have information on susceptibility and resistance.
Differences between Eukaryotic and Prokaryotic ribosomes
- Prokaryotes: 70S (50S and 30S subunits)
- Eukaryotes: 80S (60S and 40S subunits)
Differences between Eukaryotic and Prokaryotic cell walls
- Prokaryotes: complex structure containing lipids, proteins (receptors), and peptidoglycan
- Eukaryotes: Absent or composed of cellulose (plants) or chitin (insects, fungi)
5 most common targets for antimicrobial drug actions.
- inhibition of cell wall synthesis
- inhibition of protein synthesis
- inhibition of nucleic acid synthesis
- effects on cell membrane sterols (antifungal agents)
- inhibition of unique metabolic steps (antimetabolites like MTX and 5FU)
Difference between human and fungal cell membrane.
- Humans: Contain cholesterol.
- Fungi: Contain ergosterol.
Agents that interact with 30S ribosomal subunit
Agents that interact with 50S ribosomal subunit
- CAP (cholroamphenicol?)
Two general types of MOR
- Chromosomal mediated: spontaneous mutation
- Plasmid mediated: -
3 ways plasmids transfer from one cell to another
- cojugation: "swapping plasmids"
- bacteriophage-mediated transduction: virus transfers resisance genes
- transformation: uptake of resistance transposon by a sensitive bacterium after lysis of resistant bacteria (only clinically significant with Gm+ bacteria
8 specific MOR
- inactivation of drug by enzymes - usually plasmid mediated
- alteration of membrane permeability
- efflux pumps - active transport pump to remove antimicrobial agents
- alteration of intracellular target site
- alteration of intracellular target enzyme
- overproduction of target enzyme
- auxotrophs that bypass blocked step
- absence of autolytic enzymes
2 ways pathogens can alter membrane permeability to develop MOR
- change in porins
- change in transport proteins
3 types of host factors in antimicrobial treatment
- non-specific host defense mechanisms
- non-specific immunity
- acquired or adaptive immunity (antibody-mediated)
7 non-specific host defense mechanisms (natural barriers to entry of microorganisms)
- skin: defensins, PGLYRP-3 & 4
- mucous membranes: IgA production, lysozyme
- saliva: PGLYRP-4
- lungs: cilia, bronchial seretions - lysozyme
- liver: PGLYRP-2 (peptidoglycan amidase)
- GI tract: stomach acid, intestinal microflora, IgA, PGLYRP-3
- bladder: flushing, Tamm-Horsfall protein
- vagina: normal flora
- eye: tears, lysozyme, PGLYRP - 3 & 4
What are PGLYRPs?
peptidoglycan recognition proteins: proteins found in some tissues that recognized peptidoglycan in the cell walls of gram positive bacteria
2 types of non-specific immunity
- alternative complement pathway
- toll receptor recognition system
What is the alternative complement pathway?
An innate component of the immune system's natural defense against infections, which can operate without antibody participation.
What is toll receptor recognition system
Toll-like Receptors (TLRs) on the surface of T cells are recognition sensors for Pathogen-Associated Molecular Patterns (PAMPs) that are unique to different types of pathogens or damaged host tissues. When TLRs are activated, there is a release of cytokines.
2 components of acquired or adaptive immunity (antibody-mediated)
- Antigen recognition and antibody production
- classical complement pathway
5 antibodies and their role in microbial defense
- IgG: opsonic activity
- IgM: antibacterial lysis
- IgA: antiviral lysis
- IgD: ?
- IgE: anaphylaxis
3 types of host-immune responses that effect ability to ward off infection.
- Groups with primary genetic immune deficiencies like X-linked agammaglobulinemia (bruton's disease)
- Groups with secondary immunodeficiencies like AIDS
- Other disease states or conditions associated with depressed immune function like diabetes
Penicillin Class MOA
- Dipeptide analogs of D-ala-D-ala
- Bind to penicillin binding proteins (PBPs)
- Inhibition of PBPs 1-3 is bacterialcidal
- PBP inhibition is a reult of acylation of the enzyme by attack of a serine residue on the B-lactam ring
- Only active against rapidly growing bacteria (requires cell wall biosynthesis)
- Penicillin G: IV, PO
- Penicilin G procaine: IM
- Penicillin G benzathine: IM, longer DOA, used for syphilus and others
- Penicillin V: PO
- Methicillin: IV, IM
- Oxacillin: IV, IM, PO
- Nafcillin:IV, IM, PO
- Cloxacillin: PO
Extended-Spectrum Penicillins (Aminopenicillins)
- Ampicillin: IV, IM, PO
- Amoxicillin: PO
- Bacampicillin: PO, prodrug to ampicillin but costly and not used much
Broad-Spectrum Penicillin (anti-Pseudomonal Penicillins)
- Carboxypenicillins: Cabenicillin indanyl (PO) and Ticarcillin (IV)
- Ureidopenicillins: Piperacillin (IV, with taobactam makes Zosyn) and Mezlocillin (IV)
- Amoxillin-clavulanic acid: PO
- Ampicillin-sulbactam: IV
- Ticarcillin-clavulanic acid: IV
- Piperacillin-tazobactam (Zosyn): IV
Three MOR for Penicillins
- inactivation by enzymes (B-lactamases)
- altered penicillin binding proteins (PBPs)
- altered permeability to penicillins
Penicillin G and Pen VK Spectrum
- -Strep. pneumoniae, Strep. viridans, Strep pyogenes: (penicillin-resistant strains of -Strep. pneumoniae are emerging)
- -Enterococcus faecalis, NOT E. faecium: (in combination with AGs)
- -N. menigitidis: (non penicillinases producing strains)
- -Treponema pallidum: (syphilis)
- -Listeria monocytogenes: (in newborn or elderly)
- -Corynebacterium diphtheriae: x
- -Anaerobes: clostridum perfringens and C. tetani (not C. difficile), BACTEROIDES FRAGILIS (non-penicillinase producing strains), fusobacterium, peptostreptococcus
Penicillin G and Pen VK Uses
- Gram positive cocci (5)-strep throat and scarlet fever - Strep. pyogenes is generally sensitive
- -pneumonia and meningitis due to Strep. pneumoniae
- -streptococcal skin and soft tissue infections caused by Strep. viridans, Group B Strep., Strep. pyogenes
- -Anaerobic streptococcal infections
- -Endocarditis due to Strep. Viridans and Enterococcus sp. (in combo with AG)
- Gram positive rods (2)-tetanus -gas gangrene
- Gram negative cocco-bacilli - Neisseria (2)
- -menigitis due to N. meningitidis
- -gonorrhea (no longer drug of choice, now third gen cephalosporins is first line)
Spectrum and Uses of Penicillinase-Resistant Penicillins
- Gm+ only, like Pen G, but spectrum includes Staph aureus and Staph epidermidis.
- Not active vs MRSA and MRSE
Spectrum of Amino-Penicillins
- Have similar Gram + pectrum to Penicillin V and K: x
- E. coli, Proteus mirabilis: (exp. for UTIs)
- Haemophilus influenzae: (resistance is common)
- Listeria: x
- Borrelia burgdoferi: alternative to doxycycline; DOC in childre under 8 and pregnancy
Uses of Amino-Penicillins
Note: Amoxicillin is the number one antibiotic sold in US
- Meningitis: ampicillin alternative choice to second generation cephalosporins.
- Bronchitis/Pneumonia: widely used, but resistance is a problem
- Prophylaxis for bacterial endocarditis: 2 gm amox PO 1 h prior to dental procedures, DOC
- Lymes Disease: alternate to doxycyline ( 1 g amox and 05 g probenicid q 8 h) or 20 mg/kg in children
- Susceptible strains of N. gonorrheae: this is an alternate
- Diarrhea: due to Salmonella, Shigella, and E. coli
DOC and dose for otitis media
Amoxicillin 90 mg/kg/day divided every 12 hours
3 most common otitis media pathogens
- Strep. pneumoniae
- Haemophilus sp.
- Moraxella catarrhalis (not a good pathogen)
Is Hib vaccine effective against otitis media?
Haemophilus sp. that cause otitis media are not encapsulated, so vaccine is not effective
6 most common menigitis pathogens.
- Srep. pneumoniae
- N. meningitidis
- group B Strep.
- Listeria monocytogenes
- H. influenzae
- E. coli
Uses of Broad Spectrum Peniillins
- pseudomonas aeruginosa infections
- mixed infections
- complicated urinary tract infections
- prostatitis dues to susceptible strains of various organisms
- surgical prophylaxis in intra-abdominal and gynecologic surgeries only
MOA of beta-lactamase inhibitors
suicide inhibitors that lock the enzyme in the acyl-enzyme intermediate because the deacylation step is very slow.
See page 49 of course packet for structure of the intermediate.
Is zithromax a good agent for otitis media?
How do you recognize a beta-lactamase structure?
Nothing to the left of the beta-lactam ring.
Uses for augmentin
- Upper respiratory tract infections (URIs) such as otitis media and sinusitis
- skin infections
- intra-abdominal infections
- gynecologic infections
DOC for Pseudomonas and Enterobacteriaciae (hospital acquired)
- skin and skin structure infections
- pelvic inflammatory disease and post partum endometritis
- community acquired and nosocomial acquired pneumonia
Do penicillins have a short or long half life?
Adverse Effects of the penicillins
- Hypersensitivity reactions: rashes and anaphylaxis
- cross reaction with cephlosporin is small: can use cephlasporin cautiously
- idiopathic reaction associated with mononucleosis and allopurinol: ampicillin and amoxicillin contraindicated
Are cephalosporins active against MRSA or MRSE?
What moiety is responsible for the broader spectrum (compared to penecillins) of chephalosporins?
the acyl side chain
Like penicillins, they also bind to penicillin binding proteins and inhibit cell wall biosynthesis in both Gm + and Gm - bacteria.
Penicillin vs. Cephalosporin general structure
First Generation Cephalosporin Prototypes
- cefazolin (IV)
- cephalaxin (oral)
Second Generation Cephalosporin Prototypes
- cefuroxime (IV)
- cefuroxime axetil (PO)
- cefoxitin (IV)
Third Generation Cephalosporin Prototypes
- cefotaxime (IV)
- ceftriaxone (IV)
- ceftibuten (oral)
Third Generation Antipseudomonal Cephalosporin Prototype
- production of beta-lactamases (in general they are more resistant to beta-lactamases)
- altered PBPs
- altered uptake (since they are bigger than the penicillins)
First Generation Cephalosporin Spectrum
Staph aureus: excellent against b-lactamase producing strains, not effective against MSRA and MSRE
Streptococci: not effective against penicillin-resistant Strep. pneumoniae
Other Gm + bacteria: except Enterococcus sp.
Gm - bacteria: moderate activity (see Q57 for specific organisms)
First Generation Cephalosporin Spectrum - Gm - organisms
- E. coli
- Proteus mirabilis
- Indole + Proteus sp (many strains resistant)
- Haemophilus influenzae (some strains resistant)
- Neisseria sp. (some gonococci resistant)
First Generation Cephalosporin Uses
- Skin infections due to MSSA and MSSE
- Lower respiratory tract infections
- Surgical prophylaxis for orthopedic and cardio operations (not gut operations)
- Staphylococcal infections (need sensitivity data!)
Second Generation Cephalosporin Spectrum
- Expanded activity against gram negative.
- Anaerobic infections (cefoxitin has OCH3 group above the beta-lactam ring which provide res to beta-lactamase)
Second Generation Cephalosporin Spectrum - Gm- species
- Neisseria sp
- H. influenzae
- Moraxella ctarrhalis
- E. coli
- Proteus mirabilis
Second Generation Cephalosporin Uses (7)
- community acquired pneumonia
- skin and soft tissue infection (MSSA and MSSE)
- UTIs ( require 7 days of treatment)
- Pelvic inflammatory disease (with doxycycline)
- upper respiratory tract infections
- mixed aerobic and anaerobic infections
- surgical prophylaxis
Cefamandole adverse effect of note.
bleeding problems due to methylthiotetrazole ring.
- unpleasant taste
- reasonable well absorbed (F=35-45%)
Which cephalosporing should you avoid taking with valproic acid and why?
Ceftidoren pivoxil (spectracef) because pivalic acid (released from prodrug) reduces carnitine levels.
What are ESBLs?
Extended spectrum beta lactamase.
Third Generation Cephalosporins Spectrum
further expansion of Gm negative spectrum to include hard to treat organisms usch as Morganela, Serratia, and Pseudomonas.
Third Generation Cephalosporins Spectrum (Gm -)
Almost always sensitive: E. coli (non-ESBL producing), klibsiella pneumoniae and oxytoca (non-ESBL), Proteus mirabilis and proteus vulgaris.
- Generally sensitive: morganella morganii, providencia retgerri, citrobacter freundii, serratia marcescens, Pseudomonas aeruginosa (ceftazidime only).
- Sometimes sensitive: enterobacter, citrobacter, acinetobacter (50% untreatable)
Third Gen Cephalosporin Uses (7)
- Gram negative septicemeia and other serious Gm - infections
- Pseudomonas aeruginosa infections (eq to zosyn)
- Meningitis (empiric treatment) - IV ceftriaxone or cefoaxime.
- Gonnorrhea - single shot ceftriaxone
- Complicated UTI
- Lyme disease (chronic)
Dr. Remmel's preferred meningitis agent
cefotaxime over ceftriaxone
it has a shorter half life but it is less highly protein bound.
Inappropriate uses (yet widely prescribed) of 3rd Gen Cephalosporins
- surgical prophylaxis (use 1st or 2nd generation)
- otitis media, URIs - cefixime and ceftibuten have poor Gm + activity
- Uncomplicated UTIs (unless resistant to TMP-SMX)
3rd Generation Cephalosporin with very good Gm + activity (except Enterobacteriaciae)
3rd gen Cephalosporin with good taste and reasonable Gm + activity
What should you monitor for with ceftriaxone?
4th Generation Cephalosporin with better activity against Citrobacter and Enterobacter.
What is Ceftaroline
A 5th Generation Cephalosporin just approved that is active against MSRA.
What allows cefipime to get through porins?
The positive charge