Micro G Antibiotics

Front 1

essential feature of antimicrobial agents

Back 1

SELECTIVE TOXICITY

Front 2

Therapeutic Index

Back 2

dose toxic to host/ dose therapeutic

Front 3

agents that are bacteriostatic, will do what at therapeutic concentrations?

Back 3

inhibit the growth of (but not kill) microbes

Front 4

agents that are bactericidal, will do what at therapeutic doses?

Back 4

kill microbes

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what is the MIC?
how is it measured?

Back 5

minimum inhibitory concentration

can be measured by a series of tube dilutions of the antibiotic in culture medium inoculated with the purified infectious agent

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what is the tube dilution method?
what does it measure?

Back 6

a series of tube dilutions of the antibiotic in culture medium inoculated with the purified infectious agent

used to measure the minimum inhibitory concentration

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what is the MBC, how is it measured?

Back 7

minimum bactericidal concentration
aliquots are plated onto agar subsequent to culture tube growth
(imp for treatment of bacterial endocarditis?)

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Kirby Bauer Method

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DISK DIFFUSION METHOD provides multiple, simultaneous testing.
agar plate is spread with an inoculum of purified infectious agent, filter paper disks impregnated with appropriate concentrations of antibiotic to be tested are placed onto the surface, zones of inhibition of bacterial growth around each disk are measured
advantage: mult. antibiotics tested simultaneously
disadvantage: CANNOT be used to determine MBC

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Rapid test of beta-lactamase production

Back 9

used to determine whether beta-lactam antibiotics would be effective against a certain infection

beta-lactam substrate changes color w/in short time of icubation with infectious organism (with beta lactamase???)

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when might surgical drainage be necessary in conjunction with antibiotic therapy?

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when organism has walled itself off, and cannot get chemotherapeutic agent into it (granuloma?)

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prperties of ideal antibiotics (have not yet been found)

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a) should kill or inhibit one or more species of bacteria, with no-toxicity (including allergic rxns) to host cells
b) should not be destroyed or eliminated by the host before the invading bacteria can be killed or inhibited
c) should not have lost its effectiveness bc bacteria have become resistant to its axn
d) should reach sites that contain bacteria- even if these bacteria are in pockets of pus, deep in bone, in brain tissue or inside of cells

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7 types of antimicrobials

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1. ANTIMETABOLITES (esp sulfonamides)
2. INHIBITORS OF CELL WALL SYNTHESIS (esp. b-lactams and glycopeptides)
3. ALTER MEMBRANE PERMEABILITY
4. INHIBIT PROTEIN SYNTHESIS
5. INHIBIT NUCLEIC ACID SYNTHESIS
6. MISC. ANTIBIOTICS
7. ANTIFUNGALS

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Sulfonamides
-class of drug
-effect

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-Antimetabolites (class of antibiotics)
-structures similar to PABA
-bacteriostatic
penetrate sensitive bacteria and inhibit the production of DHF, necessary for DNA synthesis/ division of bacteria

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sulfanilamide

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type of Sulfonamide (bacteriostatic antimetabolite that disrupts bacterial divison by inhibiting DHF production and therefore DNA synthesis.

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common application of sulfonamides

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Urinary Tract infections
broad spectrum bacteria and even some protozoa

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why are human cells not inhibited by sulfonamides?

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human's require exogenous FOLATE
do not synthesize it from PABA like microorganisms

Front 17

How does one tell if a drug is bacteriostatic or bacteriocidal??

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???to determine if a drug is bacteriostatic (or the MIC) measure turbitiy in a test tube of antibiotic in culture

to determine if the drug is bacteriocidal (or the MBC), the aliquots are plated onto an agar after culture tubes, if bacteriocidal --> colonies will NOT grow

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why does turbidity continue to increase immediately after sulfonamide administration?

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still have some folate available for DNA synthesis, division of cells that have already begun process. ???

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Trimethoprim

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antimetabolite (inhibits DHF reductase: responsible for reducing DHF to THF)

used synergistically with sufonamide for UTIs

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Bactrim

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common combination of antimetabolites TRIMETHOPRIM and SULFAMETHOXAZOLE (a SULFONAMIDE)

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Isoniazid

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antimetabolite sepcific in its action against M. Tuberculosis (NARROW SPECTRUM antibiotic)
Inhibits MYCOLIC ACID synthesis
BACTERICIDAL (actually KILLs the bacteria, since this surface compound is essential for bacterial life)
EFFICIENT CELLULAR PENETRATION (important because many TB bacteria are INTRACELLULAR)

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Antibiotics that function as INHIBITORS OF CELL WALL SYNTEHSIS

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Beta Lactam Antibiotics
-penicillins
-Cephalasporins
-OTHER β-LACTAM ANTIBIOTICS
-IN COMBINATION WITH β-LACTAMASE (antibiotic resistance) INHIBITORS

GLYCOPEPTIDES
-VANCOMYCIN
-TEICHOPLANIN
CYCLOSERINE
BACITRACIN

Front 23

first commercial antibiotic

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PENICILLIN
discovered by Fleming 1928, staphylococci sensitive mold extracts
WWII Large Scale Production (1943)

Front 24

what gives penicillin specificity for bacteria?

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interferes with cell wall biosynthesis, inhibition of transpeptidation wakens cell wall, autolytic enzymes of bacteria then promote lysis

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What is essential for BACTERICIDAL ACTION of penicillin?

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bacterial GROWTH

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how can the lethal action of penicillin be prevented or slowed?

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provide unfavorable medium for growth

bacterial growth = essential feature for penicillin's action. by depriving nutrient essential for growth, organism in vitro will survive penicillin treatment

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why are all cell wall synthesis inhibitors bactericidal?

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inhibit PG synthesis, uncoupling the condtrol of endogenous degradative activities (autolysins) which are normally synchronized with cell wall synthesis)--> cell lysis ensues in hypotonic media.

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penicillin G is hydrolyzed by

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acidity of stomach
(4 membered lactam, strained, easily hydrolyzed)

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lactam

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an anhydride link that forms a ring-structure in part of molecule, found in penicillin, beta lactams, etc..

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penicillinases (beta-lactamases)

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bacterial enzymes, breaks same bond in lactam ring that is sensitive to acid

Penicillin = both inducer and target of hydrolysis

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gene for beta-lactamase is often located where?

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often located on a plasmid (an extrachromosomal DNA replicon) and often referred to as an R factor

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Penicillin G
Side chain?
Acid sensitive?
Penicillinase sensitive?

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-Benzyl side chain
-Acid Sensitive
-Penicillinase sensitive

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Penicillin V
Side chain?
Acid sensitive?
Penicillinase sensitive?

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-Phenoxymethyl
-Not acid sensitive
-Penicillinase sensitive

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Ampicillin
Side chain?
Acid sensitive?
Penicillinase sensitive?

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-Aminobenzyl
-Not acid sensitive
-Penicillinase sensitive

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biochemical mode of action of beta-lactams

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-structural analogs of PG, bind to and inactivate penicillin-binding proteins (PBPs: trans-, carboxy-, and endo-peptidases)

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major bactericidal activity of beta-lactams

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inactivation of the transpeptidase responsible for crosslinking (final step in cell wall assembly)

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compare spectrums of penicillin G and ampicillin

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ampicillin: broader spectrum of action

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when is penicillin G the drug of choice?

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for many gram positive, sensitive cocci
and some gram-neg cocci (eg Neisseria meningitidis {spinal meningitis} and Treponema paallidum {syphilis}.

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penicillin G shortcomings

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acid lability (no oral formulation)
penicillinase (b-lactamase) sensitivity
development of allergic response
ineffective vs. G-enterics

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limited spectrum penicillins still in use

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penicillin G (acid labile)
penicillin V (relatively acid stable)

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broader spectrum penicillins still in use sensitive to penicillinase
(active against G-enteric bacilli as well as most G+)

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typically aminopenicillins
Ampicillin (acid stable)
Amoxicillin (like ampicillin, higher serum levels)

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extended spectrum penicillins still in use
(active against a wide variety of G-bacilli, including P. aeruginosa, less active against G+ cocci)
sensitive to penicillinase

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Ticarcillin- beta-lactam effective against P. Aeruginosa; a carboxypenicillin
Piperacillin- an ureidopenicillin, most active penicillin against G-enteric bacilli, including P. aeruginosa and anaerobes

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Ticarcillin

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beta-lactam effective against P. Aeruginosa; a carboxypenicillin
EXTENDED SPECTRUM: active against wide variety of G- bacilli, less active against G+ cocci

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Piperacillin

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an ureidopenicillin, most active penicillin against G-enteric bacilli, including P. aeruginosa and anaerobes
EXTENDED SPECTRUM: active against wide variety of G- bacilli, less active against G+ cocci

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most active penicillin against G-enteric bacilli

(including P. aeruginosa and anaerobes)

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Piperacillin

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ANTISTAPHYLOCOCCAL PENICILLINS

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slightly lower activty against G+ bacteria, but still effective. of little use against G-
*Methicillin- (acid labile) no longer used (MRSA= methicillin resistant Staphylococcus aureus)
*Oxacillin (acid resistant), newer more potent derivatives

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MRSA

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methicillin resistant Staphylococcus aureus

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Cephalosporins

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sim to penicillins
4 membered lactam ring, like penicillins, but substitute a DHT ring instead of thiazolidine ring

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spectrum of cephalosporins

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broad spectrum of action against both gm+ bacteria and some gram- bacilli

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cephalosporins:
bactericidal or bacteriostatic?

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bactericidal

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how do cephalosporins differ from penicillins?

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greater acid stability, resistant to some penicillinases (but cephalosprinases exist)

antigenically dissimilar (useful when patients are allergic to penicillin)

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first generation cephalosporins

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most active vs. G+ cocci; active vs. some G- enteric baccili, but not P aeruginosa

(CEFAZOLIN)

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CEFAZOLIN

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a first generation cephalosporin

most active vs. G+ cocci; active vs. some G- enteric baccili, but not P aeruginosa

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Second Generation Cephalosporins

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more effective vs. G- enterics, but less effective against G+; still ineffective against P aeruginosa

CEFUROXIME

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CEFUROXIME

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a Second Generation Cephalosporin

more effective vs. G- enterics, but less effective against G+; still ineffective against P aeruginosa

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THIRD GENERATION CEPHALOSPORINS

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improved beta lactamase stability, broader G- spectrum;
CEFTAZIDIME is effective against P. aeruginosa
CEFTRIAXONE is notable for superior CNS penetration

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CEFTAZIDIME

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THIRD GENERATION CEPHALOSPORIN
is effective against P. aeruginosa, improved beta lactamase stability, broader G- spectrum;

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CEFTRIAXONE

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THIRD GENERATION CEPHALOSPORIN
is notable for superior CNS penetration
improved beta lactamase stability, broader G- spectrum;

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Beta-lactams (otherwise dissimilar to penicillin)

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MONOBACTAMS (aztreonam)
CARBAPENEMS (imipenem)

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MONOBACTAMS (aztreonam)

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resistant to most b-lactamases and minimal x-immunogenicity with other b-lactams. effective against aerobic G-, which includes P. aeruginosa. ineffective against most G+ and anaerobic bacteria

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CARBAPENEMS (imipenem)

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broadest antimicrobial spectrum and resistant to most lactamases, but susceptibility among methicillin-resistant staphylococci is highly variable

also susceptibilt to rental dipeptidase, so often used in combo with cilastatin (a renal dipeptidase inhibitor) e.g. Premaxin = imipenum + cilastatin

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Beta-Lactamase inhibitors

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Beta lagtams which ahve minimal activity as antibiotics, but extend the use of beta-lactam antibiotics
Clavulanic acid
Sulbactam
Taxobactam

Front 63

Clavulanic Acid

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a beta lactamase inhibitor

presently available in fixed combinations with amoxicillin= augmentin

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Augmentin

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comination of clavulanic acid (a beta lactamase inhibitor) and amoxicilin (a penicillin)

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Sulbactam

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a beta lactamase inhibitor

presently available in fixed combinations with ampicillin = Unasyn

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Glycopeptide antibiotics

Back 66

another class of cell wall inhibitors
VANCOMYCIN

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Vancomycin activity restricted to what type of organisms?

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G+

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Vancomycin mode of action

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complex soluble Glycopeptide, binds to R-D-Ala-D-Ala structures, like the peptidoglycan precursors, blocking peptigoflycan precursor transfer. may also permeabilize protoplasts and inhibit RNA synthesis

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toxicity of Vancomycin

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somehwat toxic, but used to treat serious systemic staphylococcal or enterococcal infectins or orally for Clostridium difficile enterocolitis, when less toxic drugs are ineffective or contraindicated
side efects on hearing (CN VIII) and kidneys

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only drug currently available for multiply resistant Enterococcus and MRSA

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VANCOMYCIN

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VRE

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Vancomycin resistant Enterococcus

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VRSA

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Vancomycin-resistant S. aureus
has been identified in clinical setting

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VREF

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vancomycin-resistant Enterococcus faecalis represents a widely escalating serious clinical problem

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Cylcloserine

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secondary TB drug; toxic
D-Alanine analog which inhibits L-Ala--> D-Ala and D-ALA+D+ALA--> D-Ala-D-ALA; inhibits cell wall synthesis

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BACITRACIN

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activity restricted to G+ organisms
1) Inactivates the phosphatase responsible for regenerating the active form of the carrier lipid in murein precursor synthesis (Lipid PP --> Lipid P + P)
2. Toxic and restricted to topical therapy, often in conjunction with polymyxin B and neomycin (in common antibiotic ointments such as Neosporin)