PCOL MIDTERMS LECTURE 2 B.

Cephalosporins:
Almost the same mode of action and structure with Penicillin
A. Penicillins: Broad-spectrum of activity compared to Penicillin
1. Narrow-spectrum Beta-Lactamase Susceptible Categorized into generations
Very limited microorganisms are affected by this drug
Susceptible to Beta-lactamases meaning they can be 1. First Generation
destroyed by Beta-lactamase Cefazolin not oral, only IV
Parent drug is Penicillin Cephalexin
Penicillin G: Cefadroxil oral
IV form Clinical Use:
Drug of choice for several infections, but seldom used now UTI, cellulitis, soft tissue abscess
because it acquired resistance Surgical prophylaxis
Penicillin V: Use:
Oral form Very active against gram (+) cocci with minimal gram (-)
Minor infections only Cannot penetrate CNS Cannot be used in treating
Not used anymore because of poor bioavailability & acquired meningitis
resistance Not active against Pseudomonas aeruginosa
rd
Advantage of this drug: Benzathine & Procaine Penicillin *Can be used against Psuedomonas with 3 category
Highly protein bound high concentration of drug in (combination); now not used
extravascular like Nafcillin
Given once a month or every 2-3 weeks because of delayed 2. Second Generation
absorption Cefaclor, Cefuroxime
Common Indications: -hemolytic Streptococcal pharyngitis, Cephamycin: Cefoxitin, Cefotetan
syphilis Very active against gram (+) but extended gram (-) activity
Tx: Injection of penicillin once a month, because of delayed Clinical Use:
absorption and prolonged duration. Since it is highly protein Sinusitis, otitis, lower RPI
bound, concentration of drug in extravascular, then slowly Commonly acquired pneumonia -lactamase producing)
to intravascular Can they cross the BBB? Yes, but only Cefuroxime. Not as
rd
effective as 3 generation in treatment of meningitis
2. Narrow-spectrum Beta-lactamase Resistant
Resistant Not capable of destroying the drug 3. Third Generation
Beta-lactamase producing Streptococci Cefoperazone, Cefotaxime, Ceftriaxone, Cefixime, Ceftazidime
MRSA Methicillin-resistant Staphylococcus aureus Covers more gram (-)
Under: Semisynthetic Penicillins Almost all drugs cross BBB for meningitis except for
Parent drugs: Methicillin and Nafcillin Cefoperazone (too big)
Isoxazolyl penicillins: Oxacillin, Cloxacillin, Dicloxacillin Active in Pseudomonas infection (pera & dime)
Cefoperazone and Ceftazidime
3. Extended-spectrum Beta-lactamase Susceptible Eliminated in the kidneys except for:
Broad Used for Empiric/Presumptive Therapy except for Cefoperazone and ceftriaxone (bile excretion like Nafcillin)
Ampicillin: Empiric Therapy: primary use is for meningitis
Most susceptible to B-lactamase Clinical Use:
Not used for Empiric Therapy Infections caused by organisms that are resistant to other
Enhance gram (-) activity drugs
o Because for gram (+), peptidoglycan is on the outermost Empiric therapy for serious infections meningitis
layer
o Used for UTI: Escherichia coli gram (-) 4. Fourth Generation
Capable of being destroyed by the Beta-lactamase combined Cefepime
with another drug to enhance action Can cross the BBB
Amoxicillin most abused drug & emergence of resistance Has activity against Pseudomonas
th
Amoxicillin: UTI, sinusitis, otitis, lower respiratory infections Only 4 generation has activity to Enterobacter
Ampicillin: Shigellosis Clinical Use:
Piperacillin: Klebsiella pneumoniae Serious infection
Enterobacter infections
Adverse Reaction do not use side effects
Most common/abused is adverse reaction: Hypersensitivity; all Adverse Reaction
drugs can demonstrate it because they are xenobiotic; Allergy
manifested by rashes, fever or anaphylactic shock Local irritation
Why are penicillins the drug with the most adverse reactions? Bleeding disorders
First drug discovered Cefoperazone: counteracts Vitamin K (oral); 2x a week
Generally tolerated amounts with few adverse reactions Disulfiram-like reaction
most abused (can be bought anywhere: sari-sari store) Disulfiram is a drug given to patients with severe alcoholism
Easily/orally administered leads to abused usage causes sensitivity to minute amounts of alcohol para mag
SNHIP stop and alcoholic na mag inom
Seizures High dosage Normally: Ethanol is metabolized in the liver by certain
Neutropenia Nafcillin enzymes into Acetaldehyde and further into even less toxic
Hepatitis Oxacillin byproducts
Interstitial Hepatitis Methicillin When an individual takes alcohol and cephalosporin
Pseudomembranous colitis Ampicillin (cefoperazone), they experiences the same symptoms as
Causative agent: Clostridium difficile disulfiram reaction
GIT has 0/0 of good bacteria It inhibits the enzyme that converts acetaldehyde to a less toxic
Stomach = Good bacteria; if given ampicillin abused substance
destroys the gb then bad bacteria and C. difficile If acetaldehyde is not metabolized adverse reactions
becomes more powerful causes colitis from long term & Severe symptoms of headache and body pain, low BP
abusive intake of ampicillin
Penicillin: Bactericidal and generally non-acid stable
 C. Beta-lactamase Inhibitors
Destroys the enzyme beta-lactamase (fights for resistance)
If given alone = no effect because has a very weak anti-bacterial
action
nd
Given in combination with Penicillin category 3, sometimes 2
3rd Category Beta-lactamase Inhibitor
Co-amoxicillin Amoxicillin Clavulanic acid
Ampisul Ampicillin Sulbactam
(IV drug for severe infections)
Piptazo Piperacillin Tazobactam

Haemophilus influenza, Neisseria gonorrhoeae, Salmonella,

Shigella, Escherichia coli, and Klebsiella pneumoniae
Clinical Use: Empiric Therapy

D. Glycopeptide Antibiotics
PBPs: Glycosyl transferase, transpeptidase, glycopeptide bridge
Creates the bridge for amino acids to form cross-links for
peptidoglycan layer
Vancomycin Bactericidal for gram (+) bacteria
Mode of Action: Inhibits glycopeptide bridge preventing further
elongation of Peptidoglycan Layer
Pseudomembranous colitis caused by antibiotic Ampicillin
Drug you should give: Vancomycin because it is used for
Antibiotic associated colitis
Clinical Use:
Antibiotic associated colitis
Meningitis

Adverse Reaction
Red man / Red neck Syndrome
When administering vancomycin rapidly release histamine
causes allergic reaction redness of upper torso
Other reasons for histamine release:
Vancomycin Has many impurities because of the presence of
xenobiotics/antigens
That s wh it s called as Mississippi Mud
Why is it used in antibiotic associated colitis?
Because vancomycin is poorly absorbed in the stomach/GIT so
concentration of drug stays in the surface area
Pseudomembranous colitis happens in SA of GIT so in order for
the drug to be effective, it must stay there

E. Bacitracin
Only topical cell wall active agent
It is only topical, because it is highly nephrotoxic
Once given orally/IV, the drug will cause severe damage to the
kidneys
Mode of action:
Inhibits cell wall formation by nephron with carriers of
peptidoglycan layer producing the cytosol
Needs to be transported from the cytosol to the cell membrane
th
If given on the skin, bacitracin will prevent the 4 /precursor
substance of the peptidoglycan layer from cytosol to the cell
wall
PCOL MIDTERMS LECTURE 3: Bacterial Protein Synthesis Inhibitors Broad-spectrum inhibitor of protein synthesis (bacteriostatic)
Active against: gram (+) and gram (-) anaerobes (Rickettsia,
What is the difference between the protein synthesis in prokaryotes Chlamydia, Mycoplasma)
and eukaryotes? Resistance:
Where does protein synthesis take place? Impaired influx or increased efflux (by gram negative bacteria:
In the ribosomes E. coli, Neisseria, Pseudomonas)
Prokaryotes: 70s Ribosome Ribosome protection
Eukaryotes: 80s Ribosome Enzymatic inactivation
Prokaryotes can be a target of selective toxicity, because
their units are different from us humans Pharmacokinetics
If we have the same units as bacteria, we could be the target Poorly absorbed orally
of drugs instead of them Absorption impaired by:
Food (not stable in an acidic environment like Nafcillin, except
mRNA and Ribosome Complex
for Doxycycline and Minocycline which can be taken with food)
Divalent cations (Calcium, Magnesium, Aluminum, Ferrous –
will chelate/attach to cation like a magnet impairing
absorption)
Dairy products
Antacids
Alkaline pH
Can cross the placenta

Clinical Use:
Infections caused by Rickettsial, Spirochetes, Mycoplasma
pnuemoniae, and Chlamydia
Ulcers by H. pylori (used with a combination of another drug)
Sexually transmitted diseases except for Gonorrhea (resistance)
Acne

Minocycline:
“Steps in bacterial protein synthesis and targets of several Long-acting tetracycline
antibiotics. Amino acids are shown as numbered circles. The 70S Used to eradicate Meningococcal infection
ribosomal mRNA complex is shown with its 50S and 30S subunits. In But now Rifampin is preferred
step 1, the charged tRNA unit carrying amino acid 6 binds to the Not interfered by food
acceptor site on the 70S ribosome. The peptidyl tRNA at the donor
site, with amino acids 1 through 5, then binds the growing amino Demeclocycline:
acid chain to amino acid 6 (transpeptidation, step 2). The uncharged Intermediate-acting tetracycline
tRNA left at the donor site is released (step 3), and the new 6-amino Used for patients with SIADH (syndrome of inappropriate diuretic
acid chain with its tRNA shifts to the peptidyl site (translocation, hormone)
step 4). The antibiotic-binding sites are shown schematically as
triangles. Chloramphenicol (C) and macrolides (M) bind to the 50S Doxycycline:
subunit and block peptide bond formation (step 2). The tetracyclines Oral drug of choice
(T) bind to the 30S subunit and prevent binding of the incoming Not interfered by food
charged tRNA unit (step 1).”
Adverse Reaction:
Parts of picture: Irritation of the intestinal tracts
Two ribosomes (green): 50s and 30s Fetal teeth discoloration – Can cross the placenta chelate with
mRNA (gray line): molecule in cells that carries codes from the iron during the formation of the teeth causing discoloration,
DNA in the nucleus; says what amino acids form a certain protein fluorescence, and dysplasia
tRNA (forked triangles): carries amino acids towards the complex Contra-indicated in pregnancy
Numbers: indicate amino acids Long-term use in children below 8 years old bone
Triangles (black): the inhibitory drugs in protein synthesis deformities
Demeclocycline induces sensitivity to sunlight and UV light
Four steps of bacterial protein synthesis:
1. Charged tRNA (carries an amino acid) binds to the acceptor site B. Macrolides
2. Transpeptidation – In the peptidyl/donor site, the formed chain of Erythromycin – Prototype/Parent drug
amino acids will transfer/bind to the new amino acid from the Clarithromycin
acceptor site Azithromycin Semisynthetic derivatives
3. tRNA of the peptidyl/donor site will exit the complex, becoming
an uncharged tRNA Inhibits Step 2 (Transpeptidation) inhibits the transfer of amino
4. Translocation – amino acid chain from the acceptor site shifts to acid chain to the new amino acid
the peptidyl/donor site 50s subunit
Usually bacteriostatic, but at higher doses it can be bactericidal
Almost all of the following drugs are bacteriostatic – they
inhibit/suppress protein synthesis in bacteria Erythromycin
Importance of protein synthesis? – To maintain the function and Inhibitory/Bactericidal at higher concentrations
growth of the bacteria Active at alkaline pH
These drugs need to travel across the cell membrane, because Easily destroyed by stomach acid – should be given as enteric
their target of action is in the cytoplasm coated (outside coating/covered not dissolved as fast)
First of their problems: entry to the cell wall Can cross the placenta
Cannot cross the CSF
A. Tetracycline
Minocycline, Demeclocycline, Doxycycline Clinical Use:
Corynebacterial and Diptheria infection, chlamydial infection, CAP
Inhibits Step 1 no further elongation of the amino acid chain
no production of protein
Adverse Reaction:
30s subunit
Anorexia, nausea, vomiting, and diarrhea
 Severe gastrointestinal intolerance
Clarithromycin
Semisynthetic derivative of erythromycin
Same mode of action with erythromycin
Can cross the placenta
Cannot cross the CSF
More improved version can be taken orally
Metabolite/end product has an antibacterial therapy effect called
14-hydroxy clarithromycin (metabolites usually don’t)

Clinical Use:
Corynebacterial and Diptheria infection, chlamydial infection, CAP

Adverse Reaction:
Anorexia, nausea, vomiting, and diarrhea
Less gastrointestinal intolerance

Azithromycin
Similar to clarithromycin and erythromycin
Penetrates most tissues well good absorption and distribution
Highly active against Chlamydia species
No activity in the CNS
Increased tissue concentration compared to serum prolonged
duration/slowly released from tissue (given once a day)
No interaction with other drugs
Erythromycin and Clarithromycin are CYP enzyme inhibitors
(enzyme that metabolizes drugs)
When another is given with them, it will stay longer in the
system, because the other drugs inhibit the breakdown
But since azithromycin does no interact with other drugs, it’s
won’t inhibit CYP enzyme

Clinical Use:
Chlamydial cervicitis and urethritis
CAP

C. Clindamycin
Bacteriostatic – similar to erythromycin
Inhibits Step 2 and 4
50s subunit
Chlorine-substituted derivative of lincomycin
Penetrates well into abscesses
Actively taken up by phagocytic cells
Cannot cross the CSF
Treatment of skin and soft-tissue infections
Prophylaxis of endocarditis
Diarrhea and colitis caused by Clostridium difficile

D. Chloramphenicol
Inhibits Step 2
50S subunit
Can cross the BBB (used for meningitis in babies before, but not
anymore because of adverse reaction – Gray baby syndrome)
Bacteriostatic broad-spectrum that is active against aerobic and
anaerobic gram-positive and gram-negative organism
Inactivated either by conjugation with glucuronic acid by
reduction

Clinical Use:
Topically in the treatment of eye infections

Adverse Reaction:
Gastrointestinal disturbances
Gray baby syndrome (babies don’t have glucuronic acid to
metabolize chloramphenicol causing toxic effect because stays
in circulation)
Vomiting
Flaccidity – weak
Shock. Vascular collapse, Hypothermia