8 - Antibacterials Part 1 Flashcards
What are the four characteristics that are important in the selection of appropriate drugs?
- Selective toxicity
- Type of organism
- Anatomical location
- Host status
What determines if something if bacteriostatis or bacteriocidal?
Clinically achievable levels in plasma, effect on most pathogens for which its considered useful.
MIC: minimal inhibitory (static) concentration
MBC: minimal bactericidal ocncnetration (kills 99.9%+ bacteria)
What are the types of infections in which -cidal drugs should have an advantage?
Immunocomprimised pts.
Following sites in immune competent pts:
-meningitis, endocarditis, deep bone infections, artificial device implants.
What is time dependent killing? When do these drugs work best and what drugs do this?
Amount (%) of time above the MIC.
These drugs work best when the concentration exceeds 4X MIC for >50% of the total time. Requires multiple doses.
B-lactams: penecillins, cephalosporins, monobactams.
What is concentration dependent killing? What drugs do this?
Maximize the peak concentration at Cmax; When Cmax/MIC ratio is > or equal to 8 it’s best.
Aminoglycosides do this.
What is concentration x time dependence? What drugs do this?
The area under the curve/MIC expressed in hours; usually >125 is desirable.
Quinolones.
What drugs target the cell wall?
B-lactams: penicillins, cephalosporins, carbapenems, monobactams, B-lactamase inhibitors.
Vancomycine, fosfomycin, and bacitracin.
What are general properties of B-lactams as a group?
Bacteriacidal (static under some conditions)
Activity is maximal on actively growing bacteria.
Effective against gram + and -
What is the mechanism of B-lactams? What causes symptoms?
Covalently bind PBPs; this is irreversibly and competitive. and inhibits the transpeptidase activity that catalyzes cell wall cross-links.
Bacterial lytic enzymes enhance breakdown of cross-links, accelerating cell lysis. This can cause symptoms such as chills, fever, and aching.
What are the three methods of resistance to B lactams?
Beta-lactamase: cleaves B lactam ring. Extracellular activity.
Altered PBPs, no longer bind B-lactam.
L-lactam cannot reach PBPs - intrinsic resistance of some gram -
What is an added benefit of B-lactamase (for the infecting bacteria)? How many B-lactamases are there?
It can protect other bacteria in the vicinity.
Normal flora may have B-lactamases.
Over 400 B-lactamases have been described.
B-lactams are _______-dependent killers.
Time dependent: keep the drug 4 fold above MIC for >50% total treatment time.
B-lactams have a short 1/2 life so they require shorter dosing intervals.
What are common properties of penicillins such as metabolism and location of distribution?
Low penetration into CSF, nicreases during meningitis.
Renal elimination - anion transport (anioinic drugs will have slow elimination.
Short half lives: 30 min to 3 hours
What is the route and spectrum of penicillin G and V?
Oral (V), IV/IM (G)
Spectrum:
- Anaerobes (esp gram +)
- Gram + (non-B lactamase making): NOT staph due to B lactamase, 1st line for strep throat
- limited gram negative: only works on non-B-lactamase producing gram negs (such as neisseria meningitidis)
- spirochetes: syphilis
What is added to penicillin G to lengthen the amount of time that it gets put into the bloodstream?
Slow release IM penicillins that have either procaine or benzathine.
-poorly soluble and dissolve away from injection site slowly for effective blood stream levels over time
THIS DOES NOT CHANEG THE HALF LIFE: they still have the same half life in the blood they just are released into the blood more slowly.
What can IM penicillin G benzathine be used to treat?
Syphilis
What penicillin should be used for B-lactamase positive staphylococci?
Methicillin type drugs such as oxacillin. These drugs are NOT degraded by staph B-lactamase.
S. aureas that are sensitive to these drugs are called methicillin sensitive staph aureas (MSSA).
What is the spectrum of ampicillin and amoxicillin?
Reasonable gram + spectrum: listeria, streptococcus, enterococcus.
Expanded gram - spectrum: neisseria, haemophilus, Escherichia, salmonella.
What has been the most common drug of initial choice for otitis media in otherwise healthy children and as an alternate choice for lyme disease in children and pregnant women?
Amoxicillin
What are the major differences between ampicillin and amoxicillin?
Amp: IV or oral. Can treat meningitis and GI infections because it’s available in IV and more stays in the GI tract when given orally (less bioavailability is good for GI infections.
Amoxicillin: oral only and better absorbed after oral dose
What are two penicillins with extended gram negative spectrum?
Ticarcillin and piperacillin
What is the effectiveness of ticarcillin?
Ticarcillin: extended gram - activity, some gram +. Good for some anaerobes, often used with B lactamase inhibitor. Includes
What is the effectiveness of piperacillin?
Gram negative spectrum like ticarcillin but can also kill pseudomonas and klebsiella and some bacteria that are ticarcillin resistant.
Often used with B lactamase inhibitor.
Describe the typing for allergic reactions to B-lactams?
I: anaphylactic, IgE II: cytotoxic, IgG and IgM III: immune complex: Ag/Ab IV: delayed, T cells, contact dermatitis V: idiopathic, maculopapular rash.
What is the severity of penicillin allergies?
Very severe! Few hundred deaths per year, 70% report having had penicillin previously, and 33% report prior allergic reaction.
Less common with synthetic penicillins, but all penicillins pose a risk.
How can you predict whether or not someone will have a severe penicillin allergic reaction? What is a more common type of allergic rxn that occurs with penicillin?
Pre-pen skin test, 90-95% reliable to identify those at risk for serious rxn.
Allergic rash is more common : <8% incidence
What are side effects of penicillins?
Fever Diarrhea Enterocolitis (including C. diff) Elevated liver enzymes Hemolytic anemia Seizures
***ALL antibacterials can cause enterocolitis
What is the function of clavulanic acid and tazobactam?
B-lactam analogs that bind irreversibly to B-lactamase and inhibit SOME types of B lactamases.
Restores utility of some b-lactams: ampicillin, amoxicillin, ticarcillin, and piperacillin.
Not all B-lactam resistance is due to B lactamase, what are two examples?
Penicillin resistant strep pneumonia is caused by changes in PBPs.
Methicillin resistant staph aureus (MRSA) is related to acquisition of new PBP2a encoded by MecA
What are common properties of cephalosporins? Distribution, half-life, mechanism?
Well distributed, only some reach the CSP though.
Majority require injection and have short half lives.
Same mechanism as penicillin, similar resistance mechanisms.
Which generations of cephalosporins can treat staphylococcus (MSSA), streptococcus, and gram negatives?
Staph: 1st gen has best MICs
Strep: all 3 generations have good activity
Gram negatives: 2nd can do some gram negs like haemophilus and neisseria; 3rd gen is good for many gram negs.
What are first generation cephalosporins used for?
Mostly gram +; good alternative for MSSA and Strep.
Commonly used for uncomplicated outpt skin infections and surgical prophylaxis (esp for skin flora).
What are two examples of 1st generation cephalosporins? What are important characteristics of each?
Cefazolin: best gram + activity of 1st gen; IV/IM; 1-2 hr half life
Cephalexin: oral, half life of 50 min
What are two examples of 2nd generation cephalosporins and their characteristics?
Cefuroxime: only 2nd gen that penetrates CSF, best for haemophilus, not good for enterics, and good tolerance to many gram neg B-lactamases.
Cefoxitin: anaerobes and some strains of B. fragilis; good tolerance to many gram neg B-lactamases
What are two examples of 3rd generation cephalosporins? What are each used for? What is their half life?
Ceftriaxone: very good for common types of meningitis, drug of choice for gonorrhea, long t1/2=6-9 hrs.
Ceftazidime: most active 3rd gen for pseudomonas aeruginosa, poorest for gram +s, abd short t1/2= 90 min
What are some of the gram negatives that the 3rd generation cephalosporins are effective at treating?
E. coli
Klebsiella
Enterobacter
Proteus
Also stable against many gram-neg B-lactamases
What is the fourth generation cephalosporin? What is it used for?
Cefepime: spectrum similar to ceftazidime except more resistant to type I B-lactamses
Empirical treatment of serious inpatient infections
What is the metabolism and side effects of cephalosporins?
Renal metabolism
Side effects: allergic reactions, nausea, vomiting, diarrhea, enterocolitis, and hepatocellular damage.
Describe what can occur with an allergy to cephalosporins?
Cross-allergies between penicillins and cephalosporins.
Shared side chains are associated with increased likelihood of allergic cross-rxn
What can extended spectrum B-lactamases (ESBLs) inactivate? What can be used to treat organisms with this activity?
Inactivate penicillins and other drugs considered to be B-lactamase resistant such as 3rd gen cephalosporins and monobactams (aztreonam).
Carbapenems are treatment of choice for these organisms, specifically imipenem.
What drug is a broad spectrum carbapenem used to treat extended spectrum B lactamases? What are the therapeutic uses? What can it be given with?
Imipenem - for mixed infections, ill-defined infections, and those non-responsive or resistant to other drugs.
Given with cilastatin to prevent hydrolysis by renal dipeptidases (allows it to stay in our system longer).
What are the side effects of Imipenem?
Allergic rxns: some cross allergies with penicillins and cephalosporins.
Seizures, dizziness, confusion.
Nausea, vomiting, diarrhea, pseudomembranous colitis, and superinfection.
What drug is used against gram-negative aerobic robs and does NOT have allergic cross-reactions with B-lactams? What are side effects of this drug?
Aztreonam
Seizures, anaphylaxis, transient EKG changes, cramps, nausea, vomiting, and enterocolitis.
What is the function of vancomycin?
Not a B-lactam. Bactericidal.
Inhibits cell wall synthesis by binding free carboxyl end (D-ala-D-ala) o the pentapeptide and thereby interfering with cross-linking and elongation of the PG chain.
What types of bugs is vancomycin useful against?
Gram positives ONLY
Staph, including MRSA
Strep pneumoniae, including penicillin resistant, hemolytic strep.
Enterococcus
C. diff enterocolitis (1st line)
How is Vancomycin given?
IV for systemic infections (usually serious infections)
Oral for C. diff enterocolitis
What is vancomycin now an empirical treatment for?
Bacterial meningitis in adults or children.
Usually given with a 3rd generation cephalosporin.
What are the side effects of vancomycin?
“red man” or “red neck” syndrome
Nephrotoxicity
Ototoxicity (damage to middle ear)
Phlebitis (hypersensitivity, skin rashes, neutropenia, pain and spasm).
What drug can be used to treat uncomplicated UTIs caused by E. coli or enterococcus? What is this drug’s mechanism of action?
Fosfomycin
Blocks N-acetylmuramic-acid, which is needed to PG synthesis.
What are side effects of fosfomycin?
Headache, diarrhea, nausea, and vaginitis.
What drug interferes with cell wall synthesis by interfering with carriers that move early wall components through the cell membrane and is used topically only? What is the spectrum of this? What is a side effect?
Bacitracin
Gram positive spectrum, including strep and penicillin resistant staph.
Side effect: allergic dermatitis
What two drugs target the cell membrane?
Daptomycin and polymyxin B
What drug acts as a cationic detergent that binds LPS in the OM of gram negatives and is only used topically? What can it be used against?
Polymyxin B
Used against gram negatives including pseudomonas.
Not routinely used systemically due to serious nephro and neurotoxicity.
What bactericidal drug binds to the bacterial cytoplasmic membrane and causes rapid membrane depolarization?
Daptomycin
What are the uses of daptomycin? What can’t it be used for?
Gram + spectrum used for complicated skin and skin structure infections such as staph aureas (MSSA and MRSA), strep pyogenes and agalactiae, and enterococcus
Bacteremia.
NOT for pneunomia or vanco resistant enterococcus (VRE)
What are the side effects of daptomycin?
Nausea, diarrhea, GI flora alterations, muscle pain and weakness (<3%).
What drugs target nucleic acids?
Fluorinated quinolones: norfloxacin, cirprofloxacin, and moxifloxacin.
Nitrofurantoin, rifambin, and metronidazole.
What is the mechanism of quinolones?
Inhibit DNA gyrase and thereby interfere with control of DNA replication and repair.
Bactericidal
What is killing by quinolones best predicted by?
AUC24/MIC
Area under the curve / minimal inhibitory concentration
What are the uses for norfloxacin? How has this changed recently?
Urinary tract infections: IDSA and medical letter have been advising against quinolones as 1st line agents for therapy of routine UTIs.
In 2016 FDA changed labeling saying quinolones should not be used as 1st line for UTIs unless there are no other options.
