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Antimicrobial drugs can target:
- 1) the bacterial cell envelope
- 2) their biosynthetic processes
- 3) their ability to replicate
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describe the structure of gram + bacteria:
- have a Thick peptidoglycan layer, (structure that makes up the cell wall).
- Thus they are more sensitive to β-lactams, antibiotics that act on the cell wall.
- Human cells don’t have these thick walls! So this is how we target gram positive bacteria
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describe the structure of the cell wall:
- Made up of peptidoglycans, consisting of long sugar polymers, repeating units of two sugars.
- Peptides side chains extend from the sugars, creating cross links & making the cell wall stronger. This cross linking is due to the action of bacterial enzymes, called transpeptidases
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Gram + bacteria & infections that they cause:
- Streptococcus pyogenes: skin & soft tissue; pharyngitis
- Streptococcus pneumonia: sinusitis, otitis media, meningitis, community acquired pneumonia
- Staphylococcus aureus: pneumonia, endocarditis, skin & soft tissue, osteomyelitis
- Enterococcal infections: wound, intra-abdominal, endocarditis, UTI
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Gram - bacteria & infections they cause:
- Enterobacteriaceae: hospital acquired pneumonia, wound, intra-abdominal, UTI
- Pseudomonas aeruginosa: Hospital acquired pneumonia, wounds, UTIs
- Neisseria: meningitis, skin & joint, genitourinary
- Haemophilus influenzae: otitis media, sinusitis, community acquired pneumonia, meningitis
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class of penicillin:
essential core of penicillin is a:
- B-lactam
- four-member ring called a β-lactam ring
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penicillin MOA:
- Bind to the penicillin-binding proteins (PBPs) that normally function to assemble the peptidoglycan cell wall.
- This leads to destruction of the bacterial cell wall.
- (bind and destroy)
- Normally a new subunit is linked in the peptidoglycan chain.
- Penicillin binding proteins (PBP) are required for this linking.
- The beta lactam drug binds the PBP & prevents it from cross linking chains so the glycine (G) bridge is disrupted
- Inhibit the transpeptidase so it can’t cross-link
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what causes bacteria to have different sensitivities?
- Almost all bacteria have PBPs. (penicilliln binding proteins)
- Different bacteria have different amounts & different types of PBPs (ex Coli has 7 types & S. aureus 4)
- Different PBPs have different affinities for β-lactams; therefore, different bacteria will have different sensitivitities
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penicillin SE:
- N/V/D, abdominal pain, rash
- An estimated 3-10% of population is allergic.
- Serious reactions also include hepatotoxicity, seizures, nephritis, pseudomembranous colitis and hematologic abnormalities.
- Anaphylaxis is rare but life threatening
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CI to penicillin:
- hypersensitivity to drug or class.
- Cross reactivity between penicillin allergy & other
- β-lactam antibiotics is between 1-10%
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DI of penicillin:
- Probenecid.
- Competes at the proximal tubule with pen at the kidney. Kidneys will keep penicillin and kick out Probenecid. Combination may increase penicillin levels & extend duration of action. Increase [] of penicillin
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Since nearly all bacteria have cell walls, penicillins should have:
what type of resistance is a problem with the natural penicillins?
- broad spectrum of activity
- intrinsic & acquired resistance
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reasons for resistance to natural penicillins:
- Penetration: Natural penicillins penetrate poorly into intracellular compartment of human cells.
- Porins: Some Gram- bacteria have porins in their outer membrane that don’t allow passage of the natural penicillins
- Pumps: Some Gram- bacteria have pumps that do not allow accumulation of the natural penicillins.
- Penicillinases: Many bacteria (Gram + and -) make enzymes that degrade natural penicillin·
- Some bacteria don’t make peptidoglycan·
- Some bacteria make PBPs that natural penicillins don’t bind well
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what type of bacteria does penicillin work best on?
- gram +
- use for strep throat
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penicillin drugs:
- amoxicillin
- Augmentin (amoxicillin/Clavulanate)
- Penicillin VK
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dose and indication for amoxicillin:
Infections, bacterial 500-875 mg PO q 12ho Vary by infection type/severity
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dose and indication for Augmentin:
- infections, bacterial [500 mg/125 mg-875 mg/125 mg PO q12h]
- Take with food
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dose and indication for penVK:
- pharyngitis, streptococcal [500 mg PO bid x10 days]·
- Take 1h before or 2h after meals (empty stomach)
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what are the narrow spectrum penicillins?
- Dicloxacillin
- Ocacillin
- Nafcillin
- The narrow spectrum penicillins have a bulky side chain that prevents binding of some staphylococcal β-lactamases.
- Unfortunately, these drugs are NOT able to bind the penicillin binding proteins of methicillin resistant S. aureus (MRSA) or S. epidermidis (MRSE)
- This group is generally used only to treat certain staphylococcal infections.
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what are the aminopenicillins and what are they used for?
- Ampicillin and Amoxicillin
- Used for: Otitis Media
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what are the β-Lactamase Inhibitor Combinations used for?
Used to expand the spectrum of the aminopenicillins
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what are the extended spectrum penicilins?
- paracillin & Ticarcillin
- The side chain of these penicillins is further modified to allow greater penetration into Gram negative bacteria.
- They also have increased resistance to the β-lactamases.
- Relative to the aminopenicillins (do you remember what these are?), these drugs have better coverage for Gram- negative bacilli including Pseudomonas aeruginosa.
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What could you do to make the extended spectrum penicillins even better?
- AddBeta lactamase inhibitor:
- Piperacillin-tazobactam (zosyn) IV
- Ticarcillin-clavulanate )Timentin) IV
- Zosyn: Hospital acquired pneumonia: multi-drug resistance likely (for severe infections)
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Each generations of the Cephalosporins are:
effective against a broader range of aerobic Gram - bacteria
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what is the structural advantage of cephalosporins vs penicillin?
- adv: cephalosporins have 2 sites (R and X site) that can be modified
- also, Bacteriocidal with similar actions to penicillins. Also have a β-lactam ring
- intrinsically more resistant to cleavage by β-lactamases
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MOA of the cephalosporins:
- All β-lactams have a similar mechanism of action.
- Two components needed for β-lactam activity:
- 1. must bind to penicillin binding protein
- 2. destruction of bacterial cell wall
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1st generation drugs:
- Cefadroxil (Duricef);
- cefazolin* sodium (Ancef, Kefzol),
- cephalexin (Keflex);
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2nd generation drugs:
- Cefaclor (Ceclor);
- cefuroxime (Ceftin, Zinacef (IV,IM));
- cefprozil (Cefzil);
- cefoxitin *;
- cefotetan*;
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3rd generation drugs:
- Cefdinir (Omnicef);
- Ceftibuten (Cedax);
- cefditoren (Spectracef);
- cefotaxime (Claforan)*;
- cefixime (Suprax);
- cefpodoxime (Vantin);
- ceftriaxone *(Rocephin);
- ceftazidime*(Fortaz,Tazicef)
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4th generation drugs:
Cefepime (Maxipime) IM,IV
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cephalosporins SE:
- Rarely can cause immediate hypersensitivity reactions including rash, urticaria or anaphylaxis. Cross-reactivity of between 1-10% with penicillin allergy.
- Anaphylaxis due to penicillins is an absolute contraindication for cephalosporin use.
- Other rare adverse effects include hematologic effects, Pseudomembranous colitis, nephrotoxicity
- Diarrhea, nausea, vomiting, rash, elevated liver enzymes may also occur.
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what is a DI of cefotetan?
- Cefotetan and ethanol can lead to a disulfiram-like reaction due to the difference in side chain group
- Pt should be warned: DO NOT DRINK ON THIS MED
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1st gen cephalosporins microbial spectrum.
gram + bacteria:
gram - bacteria:
- +: streptococcus pyogenes
- some viridans streptococci
- some staphylococcus aureus
- some streptococcus pneumonia
- -: some Escherichia coli
- some Klebsiella pneumoniae
- some Proteus mirabilis
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2nd gen cephalosporins microbial spectrum.
gram + bacteria:
gram - bacteria:
Anaerobic bacteria:
- +: activity similar to first generation
- exceptions: cefoxitin & cefotetan have little activity
- -: Escherichia coli
- klebsiella pneumoniae
- proteus mirabilis
- haemophilus influ
- Neisseria sp
- anaerobic: cefoxitin & cefotetan have moderate anaerobic activity
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3rd gen cephalosporin microbial spectrum.
gram + bacteria:
gram - bacteria:
spirochetes:
- +: Streptoococcus pyogenes
- Viridans streptococci
- many streptococcus pneumonia
- modest activity against staphylococcus aureus
- -: Escherichia coli
- Klebsiella pneumoniae
- Proteus sp
- Haemophilus influ
- Neisseria sp
- some Enterobacteriaceae
- Spirochetes: Borrelia burgdorferi
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Cefdinir dose and indication:
pneumonia, community-acquired [300 mg PO q12hx10 days]
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Cephalexin dose and indication:
infections, bacterial [1000-4000 mg/day PO divq6-12h]
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Most third generation cephalosporins do not have good activity against:
The side chain of ceftazidime was modified to:
- against P. aeruginosa.
- to increase its antipseudomonal activity.
- This modification makes it less active against S. aureus.
- bottom line: when you modify one, you can be taking away from another. there is no perfect drug
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4th gen cephalosporin, Cefepime, has very limited :
Anaerobic activity
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Ceftaroline (Teflaro), a new IV cephalosporin for:
it called to be what gen?
wha should this drug be used for?
- MRSA
- "5th gen" cephalosporin but it doesn't have the extended gram - coverage that you might expect from a higher-gen cephalosporin
- for drug-resistant infections
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what are the Carbapenems?
- “The big guns”
- Usually used for very severe infections or resistant organisms
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what kind of spectrum of activity do they have?
broad
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what are the Cabapenems drugs?
- Imipenem/cilastatin (Primaxin)
- Meropenem (Merrem)
- Ertapenem (Invanz)
- Doripenem (Doribax)
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kinetics of carbapenems:
- Administered parenterally
- Excreted renally
- Imipenim is hydrolyzed by an enzyme in the renal tubules. Cilastatin is added to prevent the metabolism of imipenim in the kidney.
- Renal impairment requires dosage adjustments (amount & frequency)
- Ertapenem (Invanz)is administered once daily – on test!!!!
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SE of carbapenems:
- N/V/D
- Rash
- Drug fever
- Neurotoxicity; seizures (may be on test)
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Doribax (Doripenem) 4th gen. Used for:
- for complicated urinary tract, kidney, andintra-abdominal infections...but save it for resistant cases.
- Carbapenems are broad-spectrum IV antibiotics...coveringmany gram-positive and gram-negative organisms and anaerobes. Keep in mind none of these agents work for MRSA.
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Aztreonam (Azactam) kills:
- Kills aerobic gram-negative bacteria
- monobactam
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Glycopeptide drugs:
Vancomycin
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Vancomycin is active against:
- Gram + bacteria
- A very large molecule which precludes it from passing through porins
do NOT miss this on the test
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MOA of glycopeptides:
- inhibits peptidoglycan synthesis
- Glycopeptides inhibit cell wall synthesis by attaching to the end of the peptidoglycan precursor.
- Due to the bulkiness of the vancomycin molecule, the enzyme that would incorporate the precursors into the growing peptidoglycan cannot access the precursor subunits.
- Binding of the glycopeptide antibiotic to the end stops peptidoglycan synthesis.
- Cell wall synthesis is needed by the bacteria.
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how does resistance occur?
- A change to the end of the amino acid precursor could mean that the glycopeptide antibiotic can no longer bind.*
- Bacteria can produce excess cell wall
- “Slimy way”- Staphylococcus epidermis can produce a film that blocks antibiotic penetration
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kinetics of glycopeptides:
- Glycopeptides are very poorly absorbed from the GI tract; therefore oral administration is very effective for GI infections.
- BUT, if infection is outside the GI tract, drug must be given IV
- Trough levels are monitored with vancomycin.·
- THIS IS A DRUG THAT NEEDS MONITORING
- Vancomycin half-life is 6 hours (don’t need to know)
- Renal excretion. Dose must be adjusted in renal impairment
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SE of glycopeptides:
- Red Man Syndrome (usually assoc with rapid infusion) ON TEST!!
- Fever
- Nausea
- Chills
- Rash
- Neutropenia (rare)
- Flushing
- Hearing loss, especially if given with an aminoglycoside
- Nephrotoxicity
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