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Penicillins
all about penicillins!
58
Pharmacology
Professional
10/08/2011

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Term
penicillin history: isolating
Definition
1959-set off development of future penicillins by isolating 6-aminopenicillanic acid (semisynthetic)
Term
[image]
Definition
6-aminopenicillanic acid (penicillin)
Term
penicillin's mechanism of action
Definition
disrupts assembly of cell wall (interacts with enzymes that cross-link peptidoglycan)
Term
penicillin binding proteins (PBPs)
Definition
found on cell membrane of bacteria
catalyze transnpeptidation and carboxylation reactions important in cell wall assembly (penicillins bind with PBPs, inhibiting their ability to catalyze cell wall assembly)
Term
mechanisms of resistance to beta-lactam antibiotics
Definition
1. *destruction of the antibiotic by beta-lactamases*
2. failure to penetrate to PBP targets (gram -)
3. low affinity binding of antibiotic to PBP
Term
beta-lactamases
Definition
covalently react with beta lactam antibiotic to form an acyl enzyme intermediate which undergoes rapid hydrolysis
beta lactam ring opened and microbiological activity lost
Term
classification of beta lactamases
Definition
1. classified by affinity for beta-lactam compounds
2. classified by amino acid composition (ex. TEM-1, TEM-2)
3. encoding origin (ex. chromosomal or plasmid)
4. interactive characteristics (ex. constitutive or inducible)
Term
Staphlococcal beta-lactamases
Definition
-plasmid encoded, inducible by beta lactam compounds
-penicillinase
-exoenzyme that is liberated into the surrounding medium
-hydrolyzes penicillin before it reaches its target PBPs
Term
Gram - beta lactamases
Definition
-concentrated and strategically located in the periplasmic space between the inner cytoplasmic membrane and the outer lipopolysaccharide membrane
-protect PBPs from exposure to beta lactam compounds
-encoded on chromosomes or plasmids
-constitutive or inducible
-affinity for penicillins, cephalosporins, or both
Term
ideal penicillin
Definition
-stability at low pH
-slower renal elimination
-stability to beta-lactamases
-broader antimicrobial coverage
-better penetration into CSF
-no hypersensitivity reactions
Term
penicillin G spectrum of activity
Definition
Gram + aerobic cocci: Group A Strep, Group B Strep, S. viridans
Gram - aerobes: N. meningiditis
anaerobes: Clostridia (not difficile), Bacteroides (not B. fragilis)
Spirochetes: Treponema pallidum
Term
penicillin history: Who discovered penicillin?
Definition
penicillin was discovered in 1929 by Sir Alexander Fleming
Term
penicillin history: Who determined the structure and properties of penicillin?
Definition
In 1939 Florey and Chain became interested in the clinical potential of penicillin and determined its structure and properties.
Term
penicillin history: experimentation on mice
Definition
in 1940 penicillin protected mice from streptococcus
Term
penicillin history: sufficient quantity to treat patients
Definition
in 1941 penicillin was used to treat patients (British policeman with strep. and staph.)
Term
penicillin history: journey to America
Definition
in 1941 Florey went to US to get penicillin mass produced
Term
penicillin history: clinical trials
Definition
in 1942 penicillin underwent clinical trials and then was used to treat soldiers
Term
penicillin history: resistance discovered
Definition
in 1942 Abraham and Chain reported resistance by E. coli and S. aureus to penicillin
Term
penicillin G formulations: parenteral
Definition
penicillin usually combined with aqueous K
Pen GK parenteral standard: 1.7 mEq's of K per 1 million units given
rapid elimination so drug given q4h for serious infections
Term
procaine penicillin G
Definition
suspension (only IM)
not used anymore
procain is a local anesthetic
originally developed to try and lengthen the time the drug stays in the body
may cause worse allergic reactions than other penicillins
Term
benzathine penicillin G: type of drug, what it is effective against
Definition
suspension (only IM)
very long acting (1 month)
effective for all stages of syphilis, rheumatic fever prophylaxis and sometimes Strep pharyngitis
Term
penicillin V
Definition
po drug only
designed to resist acid hydrolysis
60-73% oral absorption
take on empty stomach
Term
probenecid (benemid)
Definition
non-penicillin compound used to block selective tubular secretion (kidney elimination) of penecillins, increasing their serum half-life
Term
What are the adverse reactions to penicillin G and V?
Definition
penicillin allergy and hypersensitivity reactions
central nervous system toxicity
pregnancy risk factor: B
Term
What are the penicillin allergy and hypersensitivity reactions?
Definition
anaphylaxis
drug fever
eosinophilia (increase in eosinophils)
interstitial nephritis
Term
Describe penicillins central nervous system toxicity
Definition
seizures with high doses/decreased renal function
Term
Name the penicillinase-resistant penicillins in the US market
Definition
methicillin
nafcillin
oxacillin
cloxacillin
dicloxacillin
Term
What are penicillinase-resistant penicillins?
Definition
specifically designed to resist beta-lactamase destruction by Staph aureus
also referred to as anti-staphlococcal pcn's or PRP's
uniquely eliminated by biliary excretion and renal excretion so no dosing adjustments necessary
Term
methicillin
Definition
the prototype of PRP's but is no longer used because of very high incidence of interstitial nephritis
"arm" protect beta-lactam ring from disruption
poorly absorbed from GI tract so IV drug
excreted via biliary and renal
Term
nafcillin
Definition
a penicillinase-resistant penicillin
preferred over methicillin
poorly absorbed from GI tract (IV drug)
eliminated via biliary and renal excretion
Term
List the isoxazolyl penicillins
Definition
oxacillin
cloxacillin
dicloxacillin
Term
What are isoxazolyl penicillins?
Definition
penicillinase-resistant penicillins
specifically designed to resist hydrolysis by acid pH and Staph penicillinases (oral administration)
anti-Staph penicillin
Term
oxacillin
Definition
a PRP--isoxazolyl penicillin
used interchangeably with methicillin
IV, IM, PO
fallen to wayside
Term
cloxacillin
Definition
PRP
isoxazolyl penicillin
PO
Term
dicloxacillin
Definition
PRP
isoxazolyl penicillin
PO
1/2 dose of cloxacillin, improved absorption
Term
List the broad-spectrum penicillins
Definition
2nd generation: ampicillin and amoxicillin
3rd generation: carbenicillin and ticarcillin
4th generation: azlocillin, mezlocillin, piperacillin
Term
List the penicillin/beta-lactamase combination inhibitors
Definition
augmentin, timentin, unasyn, zosyn
Term
broad spectrum penicillins
Definition
variable activity against gram - bacilli
increased activity due to increasing ability to penetrate the gram - cell wall
generally they are hydrolyzed by gram - beta lactamases
Term
ampicillin
Definition
2nd generation penicillin
broad-spectrum
spectrum of activity similar to penicillin
more active against Enterococci and H. influenzae
not active against S. aureus or M. catarrhalis (b/c beta-lactamase production)
active against non pcn'ase producing E.coli and P. mirabilis
effective against many strains of Salmonella and Shigella
*not active against P. aeruginosa or most nosocomial Enterobacteriaceae*
about 40% bioavailability
diarrhea a big side effect
beta-lactamase inhibitor (sulbactam) helps spectrum of activity
Term
amoxicillin
Definition
2nd generation penicillin
broad-spectrum
oral replacement for ampicillin due to better bioavailability and less diarrhea
used in the treatment of otitis media, bacterial sinusitis, bacterial exacerbations of chronic bronchitis, and some Salmonella infections
higher incidence of skin rashes
problems: diarrhea, N/V, C. difficile
Term
carbenicillin
Definition
3rd generation
broad-spectrum
historical interest only
1st penicillin with activity against P. aeruginosa
not active against beta lactamase producing strains
rapid development of resistance
very high doses needed, many toxicities
Term
carbenicillin indanyl
Definition
3rd generation penicillin
broad-spectrum
oral form for UTI's by pseudomonas only
concentrates in urine so you can get an effective amount of drug
for P. aeruginosa
Term
ticarcillin
Definition
3rd generation penicillin
broad-spectrum penicillin
mostly historical interest
replaced carbenicillin (twice as effective)
only IV drug
rapid resistance by Pseudomonas: must be combined with other agents like aminoglycosides
not active against Enterococci or Klebsiella
good against anaerobes including B. fragilis
salt required to make drug soluble (careful of sodium overload)
acquired platelet disfunction (platelets would not clot)
used for Pseudomonas infections w/ aminoglycoside, 2nd line agent against B. fragilis, and resistant UTI's
Term
azlocillin
Definition
4th generation penicillin
broad-spectrum
monosodium salt
activity: Pseudomonas only
not mainstream anymore
too narrow
Term
mezlocillin
Definition
4th generation
broad-spectrum
monosodium salt
similar in spectrum to ticarcillin
not mainstream
Term
piperacillin
Definition
4th generation
broad-spectrum
broader coverage with activity against Klebsiella, Pseudomonas, Serratia, Enterobacter, Enterococci and anaerobes
most active penicillin against Pseudomonas
mostly used with a beta-lactamase inhibitor
major empiric drug
not good against MSSA or MRSA
Term
piperacillin + tazobactam (zosyn)
Definition
4th generation
broad-spectrum
widely used in hospitals for treatment of nosocomial infections
gram+aerobes: MSSA, Strep, Enterococci
gram-aerobes: enteric gram - rods, pseudomonas
gram+ and gram- anaerobes: especially B. fragilis
moderate activity against gram-rods producing "advanced" beta lactamases
poor activity against MRSA, ESBL's produced by gram-rods
very potent for empiric therapy
only for serious infections
only parentarel
Term
adverse gastrointestinal effects of penicillins
Definition
most common side effect associated with oral agents
diarrhea (most common w/ampicillin, amoxicillin)
N/V
epigastric distress
Term
adverse skin effects caused by penicillin
Definition
rash most common with ampicillin/amoxacillin 5-10%
patients with mononucleosis are at increased risk
Term
adverse hemotologic effects to penicillin
Definition
neutropenia (decrease in WBCs)3-8% generally with high doses and longer therapies
platelet dysfunction: prolonged bleeding times, risk factor--thrombocytopenia and azotemia, mostly ticarcillin 73%, piperacillin 43%, mezlocillin 25%, cefotaxime 17%
Term
adverse CNS effects
Definition
high doses, high levels in CNS associated with seizures
risks: renal impairment, patient w/ history of seizure disorder, meningitis
Term
adverse metabolic effects
Definition
hyperkalemia (high potassium), hypokalemia (low K), hypernatremia (high Na)
risks: renal impairment
Term
adverse hepatic effects
Definition
transient elevations in hepatic transaminases
hepatitis (inflammation of hepatocyte)/cholestasis (bile slowed or stopped)
Term
thrombophlebitis
Definition
hardening of vein/area where you gave the drug due to irritation (IV administration)
Term
Jarixch-Herxheimer reaction
Definition
very specific
occurs with spirochete infections (usually syphilis)
dropped blood pressure, generalized inflammatory response, fever, chills, sweating, tachycardia, myalgias, hyperventilation
begins 2 hours after administration of dose and last about a day
give with antihistimine, corticosteroid
Term
drug interactions: increased effect
Definition
anticoagulants: increases anticoagulant effect of coumadin
probenecid: increases amoxicillin levels
allopurinol: increases incidence of rash
methotrexate: increases exposure (effect) to methotrexate
Term
drug interactions: decreased effect
Definition
antibiotics and oral contraceptives
patient counseling implications
Term
list the suicide inhibitors
Definition
tazobactam, sulbactam, clavulanic acid
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