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91 Cards in this Set

  • Front
  • Back
Antibiotic:
*A chemical substance, produced by microorganisms, which has the capacity to inhibit the growth and even to destroy bacteria and other microorganisms, in dilute solutions.
bacteriostatic:

bacteriocidal:
*inhibits growth, but doesn't kill them.

*kills the bacteria.
Peak drug concentration is most important in:

Time above MIC is most important in:

AUC is most important in:
*Aminoglycoside, Fluoroquinolones

*Penicillin, ß-lactams

*Vancomycin
*Aminoglycoside, Fluoroquinolones

*Penicillin, ß-lactams

*Vancomycin
Describe the peak effect:
-The higher amount of drug you give, the more killing you get.
-The higher amount of drug you give, the more killing you get.
Describe the "time above MIC" effect. Compare to the peak effect.
left-peak effect
right-no peak effect
left-peak effect
right-no peak effect
What does "time above MIC" mean?
% of time in the dosing interval that the drug concentration is above the MIC
% of time in the dosing interval that the drug concentration is above the MIC
What does MIC mean?
*Minimal Inhibitory Concentration.
*Lowest concentration of an antibiotic that will inhibit bacterial growth.
What's the MIC here?
What's the MIC here?
2µg/mL
∆ b/t pharmacokinetics and pharmacodynamics?
What is SPA?
*A framework for treatment with antibiotics.
Source: history, physical, laboratory
Pathogen(s): based upon the source (Gram stain: rapid method to identify a pathogen)
Antibiotic: based upon the likely pathogen(s)
General timeline of initiating antibiotic treatment?
*Presentation (history, physical, lab)
-Antibiotics are started
*Culture results/Susceptibility results (usually 2 days later)
-Antibiotics are re-evaluated
Tgts in antibacterial agents:
*Cell wall, cell membrane
*Intracellular targets
-Ribosome (protein synthesis)
-Metabolism
-DNA synthesis
ß-lactams:
*Penicillins
*Cephalosporins
*Monobactams
*Carbapenems

*ß-lactamase inhibitors (fights bacteria's efforts to become resistant)
Penicillins:
*Penicillins
*Penicillinase resistant penicillins
*Aminopenicillins
*Anti-pseudomonal penicillins
Chemical features of Penicillins:
*Beta-lactam ring common to all beta-lactams
*Penicillin 5 sided ring with S at top
*Cephalosporins 6 sided S at top
*Carbapenems 5 with C at top, trans side chain
*Monobactams no side ring, side chains

*Side chains confer specific properties (absorption, etc.)
What is necessary for ß-lactams to work?
How can that be inactivated?
What effects can side chains have?
*Intact ß-lactam ring necessary for anti-bacterial activity
*Enzymes (beta-lactamases) inactivate
*Side chains effect spectrum of activity and other properties such as half-life and acid stability
How to ß-lactams work?
*Inhibits cell wall synthesis.
*Synthesis of peptidoglycan requires about 30 enzymes
*Penicillins are dipeptides (alanine and ß-dimethylcysteine) that competively inhibit cross-linkage (transpeptidase) of cell.
*Look like D-alanyl-D-alanine.
*Covalently bind to their target; IRREVERSIBLE.
Significance of peptidoglycan in the action of ß-lactams:
-Cross linking of NAM and NAG with Transpeptidase and D-alanyl-D-alanine.
-Antibiotics weaken the cross-linking and make bacteria EXPLODE.
-Cross linking of NAM and NAG with Transpeptidase and D-alanyl-D-alanine.
-Antibiotics weaken the cross-linking and make bacteria EXPLODE.
Significance of antibiotic side chains in acting against gram neg bacteria?
-Side chains make antibiotics more or less likely to get through porins in a gram neg bacteria.
-There are many types of porins.
-Side chains make antibiotics more or less likely to get through porins in a gram neg bacteria.
-There are many types of porins.
Significance of PBPs:
*Penicillin binds to PBP (penicillin binding proteins)
*Transpeptidase is a PBP
*Other PBPs for example in E. coli are necessary for maintaining rod like shape and for septum formation during division
Spectrum of Activity of Penicillin:
*Natural Penicillin: penicillin G
*Streptococci, enterococci, T. pallidum, B. burgdorferi, N. meningitidis, actinomyces
*Procaine PenG short-acting. Streptococci, mouth anaerobes, meningococcus, listeria
*Benzathine long acting: T. pallidum, rheumatic fever prophylaxis
*Penicillin V potassium: oral
How well does penicillin work against meningitis?
*Poor penetration into uninflamed meninges; drug gets in better when it's infected
*Some ~5% of serum concentration found in the CSF when the meninges are inflamed. Hence, able to use penicillin to treat meningitis when caused by susceptible bacteria.
How many units is a mg of penicillin?
*1 international unit of crystalline penicillin G sodium = 0.6 µg
*1 mg of penicillin G sodium = 1667 units
Penicillinase-Resistant Penicillins:
*IV: nafcillin, oxacillin, (methicillin)
*p.o. dicloxacillin
*Anti-staphylococcal; not hydrolyzed by penicillinase produced by staph.
*Less active than penicillin G
*Adverse effects: leukopenia, renal
*Nafcillin: biliary excretion (all others are renally cleared)
What are the aminopenicillins?
*Ampicillin, amoxicillin
*Some Gram negative activity
What are the Anti-pseudomonal Penicillins?
*Carboxypenicillins: carbenicillin, ticarcillin
*Ureidopenicillins: piperacillin: more active than ticarcillin against P. aeruginosa; some gram negative rods and Bacteroides; they are inactivated by some of the common beta-lactamases
What types of adverse effects can we get from penicillins?
*Hypersensitivity
*Anaphylaxis
*Granulocytopenia
*Seizures
Describe the first generation cephalosporins:
*Cephalothin, cefazolin t1/2 2 hr, cephalexin
*Staph, strep, some gram negative, not pseudomonas; poor anaerobe activity
*Not active against enterococci
Describe the 2nd generation cephalosporins:
*Cefoxitin, cefotetan (cefamycins: methoxy at position 7) more active against gram negative and anaerobes (B.fragilis)
*Cefuroxime active against ampicillin resistant H. flu; penetrates into CSF
*Oral: cefuroxime axetil, cefaclor, cefprozil, loracarbef
What are some adverse reactions due to Cephalosporin side chains?
MTT (methyl-tetrazole-thiomethyl) at position 3: cefamandole, cefotetan, moxolactam, associated with disulfiram-like reactions, hypoprothrombinemia, inhibition of vitamin K activation. Associated with bleeding.
Describe the 3rd generation cephalosporins:
*Ceftazidime, cefoperazone (MTT): good activity against gram negatives including Pseudomonas aeruginosa
*Less active against gram positives
*Penetrates CSF
*Cefotaxime, ceftriaxone: good gram negative activity, not P. aeruginosa, moderate gram positive activity
*Cefotaxime t1/2 1.1 hour
*Ceftriaxone t1/2 8 hours: home IV, gonorrhea; ceftriaxone gallstones
*Oral agents: cefixime, cefpodoxime
CSF Concentrations of Third-generation Cephalosporins:
Which ones get to the CSF better?
Describe the 4th generation cephalosporins:
*Cefepime t1/2 2.0 hours
*Active against gram negatives including P. aeruginosa and gram positives
What do cephalosporins NOT work against?
No cephalosporins are active against enterococci, listeria, legionella. Until recently, MRSA.
What is the new advanced generation of cephalosporins?
Ceftaroline: active against MRSA
Describe Monobactams:
*Aztreonam: monocyclic ß-lactam ring
*Active against gram negative rods including P. aeruginosa
*No activity against gram positives or anaerobes
*Aztreonam: monocyclic ß-lactam ring
*Active against gram negative rods including P. aeruginosa
*No activity against gram positives or anaerobes
Describe Carbapenems:
*Imipenem: hydroxyethyl side chain in trans orientation
*Imipenem is metabolized by a renal enzyme (dihydropeptidase)
*Cilastatin inhibits dihydropeptidase
*Meropenem hydroxyethyl side chain in cis orientation
*Different side chain on the side ring
*Not hydrolyzed by renal dihydropeptidase
*Ertapenem: long half-life 4.0 hours
Describe the activity of carbapenems; what are they effective against?
*Broad gram negative coverage
*Imipenem and Meropenem are active against *Pseudomonas aeruginosa
*Ertapenem is not active against P. aeruginosa
*S. aureus (methicillin susceptible) and streptococci
*Anaerobes
*Meropenem has increased gram negative activity and somewhat less gram positive compared to imipenem
Describe adverse effects from carbapenems:
Adverse effects: imipenem seizures
What are ß-lactamase Inhibitors?
examples?
*Drugs that block a bacterial enzyme that produces β-lactam resistance
*Clavulanic acid, sulbactam, tazobactam inhibit ß-lactamases.  They are used in combination with a beta-lactam antibiotic
*They are not antibacterial agents
*Drugs that block a bacterial enzyme that produces β-lactam resistance
*Clavulanic acid, sulbactam, tazobactam inhibit ß-lactamases. They are used in combination with a beta-lactam antibiotic
*They are not antibacterial agents
Describe uses and dosages of Clavulanate:
*Amoxicillin/clavulanate (augmentin); clavulanate  diarrhea

*A/C 250 = amox 250 mg and clav 125 mg
*A/C 500 = amox 500 mg and clav 125 mg
*A/C 875 = amox 875 mg and clav 125 mg

*Amoxicillin/clavulanic acid
*Augmentin XR™ (2 tablets twice a day)
*each tablet contains amoxicillin trihydrate and amoxicillin sodium 1000 mg and clavulanate 62.5 mg
What are other ß-lactamase inhibitors besides Clavulanate?
*Ampicillin + sulbactam (Unasyn)
*Ticarcillin + clavulanate (Timentin)
*Piperacillin + tazobactam (Zosyn)
*Pip/tazo 3.375 gm q 6 hr (pip 3 gm, tazo 0.3)
*For P. aeruginosa 4.5 gm q 6 hr (16 gm pip per day) or 3.375 gm q 4 hr (18 gm pip per day)
Half life of common ß-lactam antibiotics?
Antibacterial Agent t1/2 (hours)
Penicillin G 0.5
Clavulanate 0.9
Ampicillin 1.0
Imipenem 1.0
Cefotaxime 1.1
Aztreonam 1.7
Cefazolin 2.0
Cefepime 2.0
Cefotetan 3.3
Ertapenem 4.0
Ceftriaxone 8.0
Describe glycopeptide antibiotics:
*Vancomycin, poorly absorbed orally

*Mechanism: bactericidal
*Inhibits cell wall synthesis;  bind to D-alanyl-D-alanine
*Vancomycin, poorly absorbed orally

*Mechanism: bactericidal
*Inhibits cell wall synthesis; bind to D-alanyl-D-alanine
Describe Vancomycin:
*Most gram positive bacteria; not gram negatives or anaerobes
*Less efficacious against S. aureus when compared to anti-staphylococcal ß-lactams (less rapidly bactericidal and clinically less efficacious)
*New problem: VISA and VRSA (Vancomycin Intermediate S. aureus / Vancomycin Resistant S. aureus)
Adverse effects from Vancomycin?
*Nephrotoxicity was a problem in the past
*Nephrotoxicity seen when used in combination with an aminoglycoside
*Red-neck (red-man) syndrome (histamine)
*Ototoxicity, rash
Describe Fosfomycin:
*Interferes with an early step in peptidoglycan synthesis
*Active against gram positive and gram negative bacteria
*Use: Oral agent used to treat uncomplicated urinary tract infections
Describe polypeptide antibiotics:
*Polymyxin is a polypeptide
*Polymyxin B and polymyxin E = colistin
*Poor diffusibility
*Polymyxin are cationic detergents that disrupt the cell membrane causing an increase in permeability
*Bactericidal
Uses and side effects of polymyxins?
*Spectrum of activity: P. aeruginosa and other gram negatives except Proteus, Serratia, Providencia, Neisseria
*Nephrotoxic, hence they are rarely used systemically
*Resurgence in use in hospitals where there are multi-drug resistant gram negative organisms
Describe Lipopeptide antibiotics:
*Daptomycin: cyclic lipopeptide
*Binds to bacterial membranes and causes rapid depolarization of the membrane potential
*Bactericidal
What is Daptomycin useful against?
What is it not useful for?
Side effects?
*Active against Staphylococci, streptococci and enterococci including vancomycin resistant strains
*Does not penetrate well into the lung (daptomycin is not indicated for the treatment of pneumonia)
*Adverse effects: myopathy
What are antibacterial agents with Intracellular targets?
*Target: Ribosome
-aminoglycosides
-MLS (K)
-tetracyclines
-chloramphenicol
-oxazolidinones
*Metabolism
*DNA
Describe aminoglycoside antibiotics:
examples?
*Two or more amino sugars joined in a glycosidic linkage to hexose. Highly water soluble.
*Gentamicin, tobramycin, amikacin
*Streptomycin (TB, enterococcus: synergy with penicillin)
*Neomycin B (topical)
How do aminoglycoside antibiotics work?
*Bactericidal; concentration dependent killing
*Uptake into bacterial cell dependent on electrochemical gradient of inner membrane; this gradient is generated by aerobic metabolism
*Hence, these drugs are inactive in an anaerobic environment such as an abscess
*Block protein synthesis by binding to 30S ribosome and blocks initiation of protein synthesis, misreading of genetic code, premature termination of translation
What bugs are aminoglycosides effective against?
*Active against aerobic gram negative rods
*Often synergistic with ß-lactams
*Inhibit staph
*Tularemia, plague
*Streptomycin Mycobacterium tuberculosis
*Active against aerobic gram negative rods
*Often synergistic with ß-lactams
*Inhibit staph
*Tularemia, plague
*Streptomycin Mycobacterium tuberculosis
Side effects of aminoglycosides?
*Nephrotoxic and ototoxic (auditory and vestibular) (neomycin severe nephrotoxicity precludes use as a parenteral agent)
*Need to monitor levels
*Streptomycin is more ototoxic
*Neuromuscular blockade
What are the MLS antibiotics?
*Macrolides
Ketolides
*Lincosamides
*Streptogramins
What are important chemical features of Macrolides?
*14-membered carbon ring with an aminosugar and a neutral sugar (cladinose)
*Erythromycin in an aqueous environment at a low pH undergoes internal rearrangements and forms inactive compounds
*Newer macrolides are more acid stable
*14-membered carbon ring with an aminosugar and a neutral sugar (cladinose)
*Erythromycin in an aqueous environment at a low pH undergoes internal rearrangements and forms inactive compounds
*Newer macrolides are more acid stable
How do macrolides work?
*Inhibits protein synthesis: binds to 50S subunit of the ribosome
*Usually bacteriostatic
What bugs do macrolides work against?
*Streptococci, staph, enterococci is variable
*C. diphtheriae, mycoplasma, chlamydia, legionella, Moraxella catarrhalis
*New macrolides activity against H. flu
*Helicobacter pylori clarithromycin in combination with other antimicrobial agent
*New macrolides active against atypical mycobacteria such as MAI (mycobacterium avium intracellulare) resistance may develop on monotherapy.
Adverse effects of Macrolides?
*Adverse effects mainly GI: nausea, vomiting
*Cardiac arrhythmia
*Clarithromycin metallic taste
*Erythromycin estolate: cholestatic hepatitis
Describe Lincosamides:
*Lincomycin and Clindamycin
*An amino acid derivative attached to a sulfur containing sugar
*Mechanism of action: same as a macrolide
*Active against most strep and staph
*Most anaerobes including Bacteroides fragilis
*Good for aspiration pneumonia
*Adverse effects: diarrhea; C. difficile
Describe streptogramins:
*Streptogramins are naturally occurring compounds found in combinations
*They are macrocyclic lactone peptolides
*Quinupristin (streptogramin B) and dalfopristin (streptogramin A) [synercid®]
How do Streptogramins work?
*Inhibit protein synthesis
*Streptogramin B (SgB) binds to ribosome at a site that overlaps with macrolides and lincosamides
*Streptogramin A (SgA) binds to ribosome at a nearby site
*SgA and SgB are synergistic
What are streptogramins effective against?
what are they NOT good against?
side effects?
*Streptococci, staphylococci
*Enterococcus faecium (bacteriostatic)
*Not active against E. faecalis

*Adverse effects: arthralgias, myalgias, phlebitis
Describe the structure of Ketolides:
14-membered macrolide ring with cladinose at position 3 replaced by keto and 11,12 carbamate bridge
14-membered macrolide ring with cladinose at position 3 replaced by keto and 11,12 carbamate bridge
How do ketolides work?
What are they effective against?
side effects?
*Binds to ribosome near where macrolides bind (domain V) and also binds to domain II of the 23S rRNA
*Strep, staph, H. flu. Additionally, active against macrolide resistant Streptococcus pneumoniae
*Adverse events: visual
How do tetracyclines work?
*Inhibits protein synthesis by binding to ribosomes (bacteriostatic)
*Staph, strep, gram negatives, anaerobes
*Rickettsia, ehrlichia, mycoplasma, borrelia, pasteurella, brucella, yersinia, francisella, Vibrio cholera, chlamydia, bacillus, plasmodium (malaria)
SEs of tetracyclines:
*Adverse effects: GI upset
*Minocycline vertigo
*Demeclocycline photosensitivity
*Deposited in bone and teeth, discolored teeth
*Antagonizes penicillin when treating pneumococcal meningitis
Special considerations for tetracyclines:
outdated-
absorption-
*Fanconi syndrome from outdated (expired) tetracycline. Tetracycline degrades over time.

*Absorption decreased by divalent and trivalent cations (calcium, magnesium, iron, aluminum, etc)
Describe the Glycylcyclines:
*Tigecycline
*Derivative of tetracycline
*Same mechanism of action as tetracycline
*Increased spectrum of activity: active against many tetracycline resistant gram positive bacteria (MRSA, streptococci, enterococci), gram negative bacteria and anaerobes
*Adverse effects: nausea, vomiting
Describe Chloramphenicol:
*Bactericidal/bacteriostatic
*Binds to 50S ribosome (also binds to mitochondrial ribosome)
*Not commonly used in US.
*Gram positives, gram negatives, B. fragilis, rickettsiae, chlamydia, mycoplasma
*Adverse effects: bone marrow; Aplastic anemia 1:24,500 to 1:40,800, higher rate of leukemias in those that recover
*Grey baby syndrome: lower conjugation, lower excretion
Describe Oxazolidinones:
*Linezolid: a synthetic compound!

*Inhibits protein synthesis
bacteriostatic: S. aureus, enterococci
bactericidal: S. pneumoniae

*Adverse effect: thrombocytopenia
Describe Sulfonamides:
*Similar in structure to para-aminobenzoic acid (PABA) that is used in the synthesis of folate
*Susceptible organisms are those that must synthesize their own folate
*Bacteria and humans that use preformed folate are not affected
*Substitutions at the amide result in compounds that are more active and may affect absorption, solubility, GI tolerance
*Bacteriostatic
*Competitively inhibit incorporation of PABA into dihydro-folic acid; microbial enzyme: dihydropteroate synthetase
What are sulfonamides good against?
*Gram positive and gram negative bacteria, nocardia; However, many bacteria have developed resistance
*Sulfadiazine plus pyrimethamine to treat toxoplasmosis
*Silver sulfadiazine (topical) treat infected burns
SEs of sulfonamides:
*Adverse effects: GI upset, WBC abnormalities, thrombocytopenia, rash, hypersensitivity, death

*Newborns: kernicterus (sulfa displaces bilirubin from albumin)
Describe Trimethoprim:
*Dihydrofolate reductase (DHFR) inhibitor
*Potentiates sulfonamides
*20 to 100 more potent than sulfa
*Penetrates into prostate
*Used in combination with sulfa to treat Pneumocystis jiroveci (formerly: Pneumocystis carinii), Stenotrophomonas, Tropheryma whippelii
*Adverse effects: megaloblastic anemia, leukopenia, granulocytopenia
Bactrim:
*Sulfamethoxazole to TMP 800 mg to 160 mg (5:1)
*TMP/SMX should not be used to treat Group A streptococcal pharyngitis since it does not eradicate the streptococcus
Describe Quinolones:
*Derivatives of nalidixic acid
*Newer quinolones have a fluorine at position 6

*Inhibit DNA synthesis
*Gram negatives: primary target is topoisomerase II (aka DNA gyrase) (introduces negative supercoils into DNA)
*Gram positives: primary target is topoisomerase IV
*Bactericidal
What are the quinolones good against?
*Nalidixic acid gram neg. however rapid development of resistance
*Ciprofloxacin, norfloxacin, ofloxacin mainly gram negative
*P. aeruginosa ciprofloxacin however increasing resistance
*Moxifloxacin improved gram positive activity, e.g. Strep pneumoniae
*Levofloxacin: in vitro more active than ciprofloxacin less active than gati/moxi against Strep. pneumoniae
*Quinolones active against intracellular bacteria such as chlamydia, mycoplasma, legionella, brucella
SEs from quinolones:
*Adverse effects
-seizures
-rash
-tendon rupture***
*Hypoglycemia: gatifloxacin
*Arthropathy in immature animals. Hence, not given to children.***
Absorption considerations in quinolones:
Absorption decreased by divalent cations (calcium, magnesium, iron, etc)
Describe rifamycins:
*Rifampin and rifabutin
*Macrocyclic compounds that are soluble in organic solvents. Hence, they diffuse through lipids.
*Inhibit bacterial DNA dependent RNA polymerase
*Active against mycobacteria, most gram positive and many gram negative
*Mutational resistance rapidly develops; hence it must be used in combination with other antibacterial agents
*Rifabutin: MAI
*Rifampin: M. tuberculosis
SEs from rifamycins:
*Adverse effects: turns body fluids (urine, saliva, tears, sweat) orange-red
*Rash, hepatotoxicity
Describe metronidazole:
*Alters cell membrane electrochemical potential
*Anaerobic bacteria: Bacteroides fragilis, Clostridium difficile
*Protozoa: Trichomonas, giardia
*Disulfiram-like reaction
Describe Nitrofurantoin:
adverse effects?
*Damages DNA
*Active against E. coli, enterococci
*NOT for treatment of pyelonephritis or prostatitis

*Adverse effects
*Hypersensitivity, rash, fever chills, leukopenia, granulocytopenia, hemolytic anemia, cholestatic jaundice, hepatocellular damage, acute pneumonitis
*Long term use can lead to interstitial pulmonary fibrosis
Describe Methenamine:
*Urinary tract antiseptic
*Releases formaldehyde at an acidic pH
*Nearly all bacteria are susceptible
*Proteus and other urea splitting bacteria raise urinary pH
When to use a Bactericidal Antibacterial Agent: 3
*Meningitis
*Osteomyelitis
*Endovascular infection (e.g. endocarditis)
What kinds of interactions can different antibiotics have with each other?
synergy, antagonism, indifference
synergy, antagonism, indifference
Preferred treatment for endocarditis:
Penicillin plus an aminoglycoside.
Penicillin plus an aminoglycoside.
Give an example of an antagonistic antibiotic interaction: