Ch 14: Antimicrobial Drugs Flashcards
Antibiotic
a substance produced by living organisms which kill or inhibit the growth of bacteria
antimicrobial agent
a chemical whch is synthesized to kill or inhibit the growth of bacteria or microorganims
there are also anti-viral, anti-fungal, anti-protozoan compounds
bacteriostatic
compound inhibits the growth of bacteria without killing it as long as it is present
(when the compound is removed the bacteria can grow again)
prolonged exposure can lead to death by the immune system killing them
bactericidal
if enough of the compound is absorbed by the bacteria they are killed
Wide spectrum
active against many types and groups of bacteria
ex/ gram positives and Gram negatives => BOTH
narrow spectrum
active agaisnt few types of only one group of bacteria
ex/ only Gram-positives or only Staphylococcus
most narrow spectrums work against Gram +
antibiotics against gram negatives are very rare. Most antibiotics that target them are wide spectrum, killingh off both gram + and - bacteria
MIC
minimal inhibitory concentration
lowest concentration of an antibiotic whihc stops the growth of that species of bacteria under the conditions tested
important because the higher the dose of an antibiotic the worst the side effects
common
MLC
minimal lethal concentration
lowest concentration of an antibiotic which kills all the bacteria (of that species)
not as common as MIC
AUC
area under the curve
integrated time where in vivo concentration of the antibiotic is greater than the MIC
if drug is dosed by time interval there will be spikes in concentration of the drug in the blood and troughs as teh drugs is eliminated
want to maintain the concentration of the drug in the blood above the MIC
Therapeutic index
the ratio of the dose of the antibiotic whihc is toxic to a human to the dose whihc is effective at inhibiting of killing the bacterium
a measurement of selective toxicity
toxic to bacteria but not to humans
the higher the therapeutic index, the more useful the antibiotic
good and bad MIC range
good
=> 1mg/ml
really good 0.1/0.05 or less
=> fluroquinolines and some penicillines agaisnt gram + and streptococci
with pseudomonas aerginosa, can be upwards of 16
Oral administration of antimicobials
rug must be acid stable, absorb through the stomach or intestines
parenteral administration of antimicrobials
intraventous or intramuscular
drug acid labile or unable to absorb through GI tract
drug may be sparingly soluable - need continuous infusion
maintains higher concentration in blood/ tissue
Targets of antibiotics
antimetabolites (metabolism)
inhibition of cell wall (peptidoglycan) synthesis
inhibition of DNA/RNA biosynthesis
Inhibition of protein biosynthesis
Inhibition of energy production
Antimetabolites
compounds which interfere with cellular metabolism
=> mostly the small molecule metabolism
the only commercially available antimetabolite are the sulfoanamides (sulfa drugs)
really not antibiotics - synthetic chemicals
=> discovered by extension of Ehrlich’s search for a magic bullet screening of organic chemicals
Sulphanilamide
what does it do
competitive inhibitor of p-aminobenzoic acid and prevents the incorporation of p-ABA into folic acid
folic acid is a co-factor in many essential enzymes including C1 metabolism needed for the biosynthesis of purines, pyrimidines, methionine
Bacterial targets of Sulphanilamide
broad spectrum antimicrobial agents
GAS Strep pneumonia Staphylococci Neisseria spp Haemophilus influenzae Bordetella pertussis Yersinia pestis Chlamydia spp
The use of Sulphanilamide today
the use of sulphonamides is now limited by widespread resistance in bacteria and toxicity
most common sulfa drugs now used are sulfisoxazole and sulphamethoxale
use is restricted to treating UTIs
Dapsone- the main drug used in leprosy treatment
Inhibition of cell wall biosynthesis
most important target is peptidoglycan biosynthesis
most important inhibitors of peptidoglycan synthesis are the beta-lactams
penicillin was discovered in 1928 by Fleming
=> observed lysis of Staphylococcus colonies on a plate contaminated with mold (penicilliium notatum) (today penicillum crysogenmum is used commercially)
Bacterial targets of penicillin
Fleming demonstrated the culture broth had antibacterial activity against
Staphylococci
Streptococcus pneumoniae
Nisseria meningitidis
Neisseria gonorrohoeae
but not against most Gram-negative bacteria
Penicillins G, V and semi-synthetics
Natural penicillins (G and V) are only active against Gram-positive bacteria (V is more acid labile- can take orally, cant do this with G)
semi-synthetic penicillins developed to oversome beta-lactamases
- methicillin (the M in MRSA)
- oxacillin (the form used in N. America)
- cloxacillin (or dixloxacillin)
- flucloxacillin
Broad spectrum penicillins (amino penicillins)
increased activity against Gram-negative bacteria
still active against Gram-positives
acid stable, oral
amocicillin, ampicillin
Penicillins active against Pseudomonas aeruginosa
ticarcillin, carbenicillin
also the extended spectrum penicilllins such as piperacillin
beta lactamase resistant penicillins
temocillin
Cephalosporins
chemically related to penicillin
beta lactam- dihydrothiazine rings
inhibit the same target as penicillin
wide spectrum of activity compared to penicillin
resistant to Staphylococcus Beta-lactamase
cephalosporin C original, base for semi-synthetic antibiotics
over 25 different ones now in use
First generation cephalosporins
cephaloridine was the first cephalosporin
=> cefadroxil, cephazolin
effective against S. aureus and penicllin resistant S. aureus
effective against teh streptococci and enterococci
effective against E. coli, Klebsiella pneumoniae, and proteus mirabilis
Second generation cephalosprins
cefoxitin
resistant to gram negative beta lactamases
wider spectrum of activity
Haemophilus, enterobacter
Third generation cephalosporins
effective against
pseudomonas aeruginosa, almost all Enterobacteriaceae, Neisseria gonorrhoeae
ceftriaxone, cefotaxime
Fourth generation cephalosporins
Gram positives and more Gram negatives
better against beta lactamase prodducers
cefeprime
Fifth generation cephalosporins
designed to be effective against beta lactamase producers and MRSA
ceftolazane (2014), ceftaroline (2010), ceftobiprole (2016)
Monobactams
Just a beta lactam ring, used against Gram-negative bacilli
axtreoman
Carbapenems
very wide spread activity
active against beta lactamases and ectended spectrum beta lactamases (ESBL)
doripenem, ertapenem, imipenem, meropenem
=> antibiotics of last resort
problems with beta lactam antibiotics
dont cross the blood-brain barrier and do not generally penetrate cells
Vancomycin
glycopeptide
also blocks transpeptidation by binding to the terminal d-ala-d-ala part of the pentpeptide of the peptidoglycan precursor
bactericidal, narrow-spectrum- gram-positives cocci and bacilli
was antibiotic of last resort for MRSA and enterococci
New glycopeptides - dalbavancin, oritavancin, telavancin
Inhibition of protein biosynthesis
aminoglycosides
inhibits elongation and icreases mis-reading of mRNA
bactericidal
broad-spectrum => Gram-positives, Gram-negatives and mycobacterium
often used iwth Beta lactams for synergy
primary use is for treating Gram-negative and Peudomonas aeruginosa infections
Aminoglycosides
inhibite protein biosynthesis
3-4 sugars, some substituted with amino groups
different aminoglycosides and their uses
streptomycin = antiTB
Gentamycin = anti-pseudomonad
tobramycin = replacement for gentamycin
neomycin = toxic, use in topical treatment
kanamycin= enterics but not PA
Amikacin = semi-synthetic, resistant to inactivating enzymes
plazomicin = new (2018)
why are less people allergic to penicillin today
the ways we make penicillin are more pure, and there is less junk that causes the allergy
Tetracycline
introduced in 1948
bacteriostatic
blocks binding of amino-tRNAs to ribosomes
wide-spectrum
staph and strep but not enterococci
Gram-negatives except PA and some enterics
mycoplasma
Clamydia and Rickettsia
Spirochetes => BOrrelia burgoferii
Tetracycline uses
used to treat respiratory and urinary tract infections
used to treat many STDs
used to treat intracellular bacteria
newer tetracyclines
=> doxycyclines, minocycline
=> tigecycline
=>omadacycline, eravacycline, sarecycline
Macrolides
inhibition of protein biosynthesis
a very large lactone ring with attached sugars
14 or 16 C atoms int eh ring
bacteriostatic
wide spectrum of activity
mostly used as an alternative to penicillins for penicillin-sensitive patients
mostly used to treat Gram-positive infections
antibiotic of choice for whooping cough (bordetella pertusis) and legionaires disease (legionella pneumophillia)
What bacteria are macrolides used against
antibiotic of choice for whooping cough (bordetella pertusis) and legionaires disease (legionella pneumophillia)
used to treat community acquired pneumonia
streptococcus pneumoniae
haemophilus influenzae
maraxella cararrhalis
used to treat mycoplasma and chlamydia infections
erythromycin and azithromycin
Inhibitiion of DNA biosynthesis
most important are teh fluroquinolones
the first quinolone antimicrobial was naladixic acid
effective only against Gram-negatives (RARE)
used to treat UTIs (it is concentrated in the urine by the kidneys)
by adding a flurine atom to the C6 of the quinolone ring a new class of antimicrobials => the fluroroquinolones
decantination of DNA
done by DNA topoisomerase
fluroquinolone target
What are the fluroquinolones effective against
most Gram-negatives including Pseudomonas aeruginosa and some Gram-positives
staph, strep pneumoniae and enterococcus
second generation fluroquinolones
ciprofloxacin
third generation fluroquinolones
moxifloxacin
imporve activity against Gram positives
activity against some anaerobes and atypical bacterial pathogens
used to treat respiratory tract infections, virtually any bacterium and more severe cases except MRSA
better MIC against gram negatives
some of the best antibiotcs we have
mocifloxacin
thrid generation fluroquinolones
imporved activity agaisnt gram-positives
activity against some anaerobes and atypical bacterial pathogens
used to treat respiratory tract infections, virtually any bacterium and more severe cases except MRSA
Rifampin or rifampicin
inhibitionof RNA biosynthesis
rifampin mainly used for TB treatment as part of a multi drug program
used for prophylaxis against Neisseria meningtidis and Haemophilus influenzae menigtitis outbreaks
problems with fluroquinolones
prolonged usage can be problematic
tendon thinning and some neurological problems
