Basic Pharmacology

Antimicrobials Part 1 (Dr. Dando)

‘Twas the week b4 xmas vacation

Beta Lactam Compounds & - drugs that retain the antibacterial spectrum of
Other Inhibitors of Cell Wall Synthesis penicillin and have improved activity against gram-
• Penicillins negative organIsms, but they are destroyed by beta-
• Cephalosporins & Cephamycins lactamases (penicllinases)
• Limitations:
• Other Beta Lactam Drugs
- instability at acidic pH
o Monobactams
- Susceptibility to destruction by bela-lactamase
o Beta-Lactamase Inhibitors
- Relative inactivity against gram-negative bacilli
o Carbapenems
• Other Inhibitors of Cell Wall Synthesis • Units
o Vancomycln - PenG: 1600 unlts/mg(1M unit = 0.6g)
o Teicoplanin
o Fosfomycin • Mechanism of Action
o Bacitracin Inhibit bacterial cell wall synthesis (Class Ill reaction) by:
o Cycloserine
1. binding of the drug to specific receptors (penicillin-
Chloramphenicols
binding protelns [PBPs]) located in the bacterial
Tetracyclines
cytoplasmic membrane
Macrolides
• Erythromycin
2. inhibition of transpeptidase enzymes that act to cross-link
linear peptidoglycan chains, which font part of the cell
• Glarithromycin
wall; Beta-lactams prevent the cross-linking peptides from
• Azithromycln
binding to the tetrapeptide sidechains.
Clindamycin
Streptogramine
3. activation of autolytic enzymes that cause lesions in the
bacterial cell wall
• Quinupristin-dalfopristin
Oxazoladinones
• Linezolid

Beta Lactam Compounds &

Other Inhibitors of Cell Wall Synthesis
- Penicillins and Cephalosporins are the major antibiotics that inhibit
bacterial cell wall synthesis. They are called beta-lactams because
of the unusual 4-member ring that is common to all their members.

A. Penicillins
• All peniclllins are derivatives of 6-emmopenicillanlc acid and
contain a beta-lactam ring structure that is essential for
antibacterial activity

Diagrams of sbucture and metabolism of a bacterial cell.

A. Schematic representation of a bacterial cell. B. Flow diagram
showing the synthesis of the irein types of macromolecule of a
bacterial cell. Class I reactions result in the synthesis of the
precursor molecules necessary for dat II reactions, which result in
the synthesis of the constituent molecules; these are then
anembled into macromolecules by dna Ill reactions

• Classification:
1. Penicillins (e.g. PenicilIin G)
- versus gram-posltive organisms, gram-negative
cocci & non-beta lactamase anaerobes
2. Antistaphylococcal penicillins (e.g. Nafcillin, Oxacillin,
Cloxacillin, Dicloxacillin, etc.)
- versus staphytococci and streptococci
3. Extended-spectrum (e.g. Ampiciilin, Amoxicillin &
Antipseudomonal Penicillins)
- versus gram-negative organisms
MR*, Mel, Eisa (ako, ako, parati na lang ako!) 1 of 6
Basic Pharmacology – Antimicrobials 1 by Dr Dando Page 2 of 6

- Aminopenicillins (Amoxicillins), Carboxypenicillins

(Ticarcillin), Ureidopenicillins (Piperacillin)
- Greater activity against gram-negative bacteria
- Amoxicillin is better absorbed from the gut - preferred
preparation for oral penicillin
- Ampicillin is effective for shigellosis but not for
salmonellosis
- For Pseudomonas: Carboxypenicillins + Aminoglycosides
- Beta-lactamase Inhibitors (Clavulanic Acid, Sulbactam,
Tazobactam): versus beta-lactamase producing strains of
Staph aureus

B. Cephalosporins
• Are derivatives of 7-aminocephalosporanic acid and contain
the beta-lactam ring structure
• Soluble In water
• Pharmacokinetics • Stable to pH and temperature changes unlike Penicillins
- Oral absorption differs greatly for different penicillins,
• Not active against enterococci and L. monocytoqenes
depending on acid stability and protein-binding (impaired
by food, so, must be taken 1 hr before or after meals)
- Widely distributed in the body fluids and tissues
- Rapidly excreted by the kidneys
- Excreted Into sputum and milk
- Poor penetration in the eye, prostate and CNS except
with acute inflammation of meninges if given in high
doses
- Normal half-life: approx. 30 mins
1. First Generation Cephalosporins

• Clinical Uses of Penicillins: - Cefadroxil, Cefazolin (IV), Cephalexin (oral), Cephalotin,

- Pen G (IV): drug of choice for infections caused by
streptococci. meningococci, enterococci, pneumococci,
non-beta-lactamase producing staphylococci
- Pen V (oral): Indicated only for minor infections due to
poor bioavailability
- Benzathine/Procaine (IM): yield low but prolonged drug
levels, for treatment of beta-hemolytic strep pharyngitis;
IM inj every 21 days in RHD and as prophylaxis to
prevent endocarditis
Cephapirin, Cephradine
- Greater activity for gram-negative microorganisms
- Tubular secretory blocking agents (probenecid) may
increase serum levels
- Cefazolln Is almost the only first generation parenteral
cephalosporin: drug of choice for surgical prophylaxis
alternative to an antistaphylococcal penicillin
- Rarely the drug of choice for any Infection
2. Second Generation Cephalosporins

• ADR
- Cefaclor, Cefamandole, Cefonicid, Cefuroxime, Cefprozil,
Loracarbef, Ceforanide, Cephamycins (Cefoxitin,
- Anaphylactic reaction (most serious and may happen Cefmetazole, Cefotetan)
even in therapeutic doses)
- Extended gram-negative coverage
- Seizures (overdose)
- Dose: (oral) 10-15 mg/kg/d BID
- Rashes, pruritus, urticaria in oral form
- Hypotenslon, severe shock, circulatory collapse, death in
- versus beta.-lactamase producing H. Influenza or
Bhanhamella catarrhalis
IM form
- Tx of sinusitis, otitis or lower RTI

• Clinical Uses of Pen Resistant to Staph β-lactamase: - Cefuroxlme: for community-acquired pneumonia; the only
second-generation drug that crosses blood-brain barrier,
- The sole indication is infection by beta-lactamase -
but less effective in treatment of meningitis, than
producing staphylococci (Methicillin, Nafcillin) Ceftriaxone and Cefotaxime
- For mild, local Infections:
lsoxazoyl (Oxacillin) - 15-25 mg/kg/d 3. Third Generation Cephalosporlns
- For serious systemic staph infection:
Oxacillin or Nafclllin 8-12 g/d (50-100 mg/kg/d)
- Cefoperazone, Cefotaxime, Ceftazidime (IV for
meningitis), Ceftizoxime, Ceftriaxone (DOC: typhoid
fever), Cefixime (oral), Cefpodoxime proxetil, Ceftibuten,
• Clinical Uses of Extended Spectrum Penicillins: Moxalactam
Basic Pharmacology – Antimicrobials 1 by Dr Dando Page 3 of 6

- Expanded gram-negative coverage (except for

Cefoperazone)
- Some can cross blood brain barrier (Ceftriaxone and
Cefotaxlme)
- Active versus Citrobacter, Serratia & Providencia
- Ceftazidime & Cefoperazone: vs P. aeroginosa
- Ceftizoxime & Moxalactam: vs B. fragilis
- Cefixime & Ceftriaxone: 1st line drug for tx of N.
gonorrhea
- Cefixime, Ceftibuten, Cefpodoxine proxetil: are oral
agents with similar activity except that Cefixime and
Ceftibuten are much less active against Pneumococci
and have poor activity against S. aureus
- Ceftibuten (Cedax): newest oral cephalosporin with
sImilar spectrum to Cefixime and Cefpodoxime; once-
daily
- Ceftriaxone and Cefotaxime most active vs. penicillin-
resistant strains of Pneumococci and are recommended
for empirical therapy of serious infections caused by
these strains
4. Fourth Generation Cephalosporins
- Cepefime
- More resistant to hydrolysis by beta-lactamase
- Active versus P. aeroginosa, Enterobacter, S. aureus, and
S. pneumoniae
- Half life: 2 hours
• Adverse Effects
- Allergy
- Toxicity – Renal, Hypoprothrombinemia,, severe disulfiram-like
reactions
- Superinfection
D.
2. Beta-Lactamase InhIbItors
- Clavulanic acid, Sulbactam, Tazobactam
- Treatment of mixed aerobic and anaerobic infections
(lntra-abdominal infections)
- are used in fixed combinations with certain hydrolyzable
penicillins
3. Carbapenems
- Imipenem, Meropenem, Ertapenem
- Choice for treatment of infection caused by enterobacter
- Chemically different from penicillins but retaining the
beta-lactam ring structure with low susceptibility to beta-
lactamase
- Wide activity against gram-positive cocci, gram-negative
rods, and anaerobes
- Imipenem is rapidly inactivated by renal
dehydropeptldase I and Is administered in fixed
combination with cilastatin, an inhibitor of this enzyme.
Cilastatin increases the plasma half-life of imipenem and
inhibits the formation of a potentially nephrotoxic
metabolite
o AE of Imipenem-cilastatin: GI distress, skin rash,
and at very high plasma levels, CNS toxicity
(confusion, encephalopathy, seizures). There is a
partial cross-allergenicity with penicillin
- Meropenem is similar to imipenem except that it is not
metabolized by renal dehydropeptidases and is less likely
to cause seizures
- Ertapenem has a long half-life but it is less active against
Pseudomonas, and its IM injection causes pain and
irritation.
Other Inhibitors of Cell Wall Synthesis

• Oral Cephalosporins
1. Vancomycin
- For staphylococcal infection
- Inhibits cell wall synthesis by binding firmly to the D-Ala-
D-Ma terminus of nascent peptidoglycan pentapeptide
- Poorly absorbed In GI
- oral form used in tx of enterocolitis due to C. difficile
- parenteral form indicated for sepsis, or endocarditis due
to MRSA
- w/ gentarnlcln: as alternative regimen for treatment of
enterococcal endocarditis in patient with serious penicillin
allergy
- Adverse Reaction: chills, fever, phlebitis, ototoxicity, and
nephrotoxitity; Rapid IV infusion may cause “Red man” or
“red neck” syndrome (diffuse flushings)

2. Telcoplanin
C. Other Beta-Lactams
- glycopeptide with similar MOA and antibacterial spectrum
as vancomycin
1. Monobactam
Aztreonam vs gram-negative rods
3. Daptomycin
- resistant to beta-lactamases produced by certain gram- - Cyclic lipopeptide
negative rods (Klebsiella, Pseudomonas, Serratia)
- Spectrum of activity similar to vancomycin but is active
- AE: GI upset with possible superinfection, vertigo, against vancomycin resistant strains of S. aureus
headache, rare hepatotoxicity
- Although skin rash may occur, there is no cross- 4. Fosfomycin
allergenicity with penicillin - stable salt of phosphonomycin
 Basic Pharmacology – Antimicrobials 1 by Dr Dando Page 4 of 6

- antimetaboiite inhibitor of cytosolic enolpyruvate

transferase
- tx of uncomplicated UTI

5. Bacltracin
- cyclic peptide
- interferes with dephosphorylation in cycling of the lipid
carrier and transfer of peptidoglycan subunits • Broad spectrum bacteriostatic
- no cross-resistance
• Inhibits protein synthesis - bind reversibly to 30S
- useful for suppression of mixed bacterial flora in surface
lesions • Chelate divalent metal Ions

- limited to topical use because of its marked nephrotoxicity • 40-80% protein bound
(proteinuria, hematuria. nitrogen retention)
• Cross the placenta and excreted in milk

6. Cycloserine • Choice for patient with renal insufficiency:

- water-soluble, unstable at acid pH
- Doxycycline — once daily
- almost exclusively used to treat tuberculosis resistant to
first-line agents • DOC Mycoplasma pneumoniae, Chlamydiae, Rickettsiae,
Spirochetes. Helicobacter pylori
- antimetabohte that blocks the incorporation of D-Ala into
the pentapeptide side chain of the peptidoglycan • Avoid In pregnant women and children below 8 years old, to avoid
- potentially neurotoxic (tremors, seizures. psychosis) deposition In growing bones and teeth

• Resistance:
• Adverse reactions:

- Inactivation by B lactamase
- GI disturbances—from mild nausea and diarrhea to severe,
possibly life-threatening colitis
- Modification of target PBPs
- Impaired penetration of drug to target PBPs - Bony structures end teeth—tooth enamel dysplasia and
- Presence of an efflux pump irregular bone growth after to fetal exposure; tx of younger
children may cause enamel dysplasia and crown deformation
Chloramphenicols when permanent teeth appear
 Soluble in alcohol, neutral, stable - Liver toxicity
- Kidney toxicity
 Potent inhibitor of microbial protein synthesis - bind to 50S subunit -
inhibit peptidyl transferase - Local tissue toxicity
- Photosensitization
 Bacteriostatic, broad-spectrum
- Vestibular reactions—dose dependent dizziness and vertigo
 Dose: 50-100 mg/kg/d with doxycycline and minocycline
 Completely and rapidly absorbed orally
 Used for eye infections Macrolides
• Binds to 50s subunit of the ribosome

1. Erythromycln
- Poorly soluble in water
- Unstable at acid pH
- Versus gram-positive organisms
• Adverse Reactions: - Inhibitory or bactericidal
- GI disturbances
- Inhibit protein synthesis via binding to 50S rRNA
- Bone marrow disturbances: aplastic anemia - Destroyed by stomach acid (needs enteric coating)
- Toxicity with newborn infants: Gray baby syndrome (lack of - DOC: corynebactedal infection, respiratory, neonatal,
effective glucoronic acid conjugation) ocular/genital chlamydial infection, community-acquired
- Interaction with other drugs: Inhibits hepatic microsomal pneumonia, alternative for penicillin-allergic individuals
CYP450 enzymes - Prophylaxis against endocarditis during dental
procedures with valvular heart disease
Tetracyclines 2. Clarithromycin
- Derived from erythromycih by methyl group addition
- Identical antibacterial activity with erythromycin
- More active against Mycobacterium avium complex
- 250-500 mg BID
- Longer half-life: 6 hours
 Basic Pharmacology – Antimicrobials 1 by Dr Dando Page 5 of 6

- Laser frequency of GI intolerance

- Less frequent dosing

3. Azithromycin
- 15-atom lactone ring derived from erythromycin by
addition of methylated nitrogen
- Highly active against chlamydia
- Once-daily dosing and short duration of tx (3 days)
- Given 1 hour before or after meals
- Does not Inactivate cytochrome P450 enzymes

4. Ketolides
Telithromycin
Aminoglycosides
- Semisynthetic 14-membered ring macrolide
- Oral bioavailability: 57% • Bactericidal antibiotics obtained from Streptomyces sp
- Once daily dose of 800 mg • Water-soluble, stable, more active at alkali pH
• Irreversible inhibitors of protein synthesis — binds to specific 30S
Clindamycin subunit ribosomal proteins
• Chlorine-substituted lincomycin • Absorbed poorly in GI tract
• VS strep, staph, pneumococd • Ototoxic and nephrotoxic
• Inhibits protein synthesis by binding on the 50S subunit • ADR: ototoxicity and nephrotoxicity; In high doses: curare-like effect
• For severe anaerobic infection due to bacteroides & other with neuromuscular blockade
anaerobes • versus gram-negative enteric bacteria especially in bacteremia and
• For prophylaxis of endocarditis with valvular heart disease sepsis (in neonates), in combination with vancomycin or with
undergoing dental procedures penicillin for endocarditis, and for TB treatment
• No oral preparation
• 10-20 mg/kg/d (0.15-0.3g every 8 hrs)
• Streptomycln - oldest aminoglycoside
Newer Agents • Gentamycin, Tobramycin, Amikacin—only differ In side chain
A. Streptogramins
• Mechanism of Action:
Quinupristin-daltopristin
- Bactericidal except Entrococcus faecium
- lV 7.5 mg/kg every 8-12hrs
- AE pain at infusion site, athrelgla-myalgia syndrome

B. Oxazoladinones
LinezoIid
- Bacteriostatic except for strep
- Inhibits protein synthesis by binding on 23S ribosomal RNA of
the 5OS subunit
- High oral bioavailability – 100%
- Half-life: 4-6 hours
- For vancomycin-resistant E. faecium
- Toxicity: thrombocytopenia and neutropenia
• Mechanism of Action

1. Streptomycin
- Second line agent for tuberculosis tx
- With penicillin: for enterococcal endocarditis
- With tetracycline: tularemia, plague, brucellosis
- Most serious toxic effect: vestibular disturbance — vertigo
arid loss of balance
- If given during pregnancy may cause deafness in
newborn

2. Gentamicin
 Basic Pharmacology – Antimicrobials 1 by Dr Dando Page 6 of 6

- vs gram-positive and gram-negative Siguro naman this time papasa na kau ng pharma =p

- No activity against anaerobes Brim, print mo 2, may kulang sa old trans

- For severe infections (sepsis and pneumonia)
- 5-6 mg4cgd

3. Tobramycin
- More active against pseudomonas

4. Amikacin
- For resistant organisms
- 500mg BID IV

5. Netilmicin
- 5-7 mg/kg/d

6. Kanamycin & Neomycin

- Bowel preparation for elective surgery
- For topical and oral use only

7. Spectinomycin
- Alternative treatment for gonorrhea for peniciilin-aIIergic
patients
- 2 g IM (40 mg/kg)

• Mechanisms of Resistance:
- Alteration of target
Modification to insensitivity to Inhibitor
Reduction in physiologic Importance of target
Synthesis of new target enzyme that duplicates function of
inhibited target

- Prevention of access to target

Efflux of more drug than enters cell
Failure of modified drug to enter cell

- Inactivation of scent
Destruction of the agent
Modification of the agent so It fails to bind target

- Failure to convert an inactive precursor agent to its active form

Quiz (2C):
1. MOA of penicillin: inhibit cell wall synthesis
2. MOA of chloramphenicol: inhibit protein synthesis by 50s
3. MOA of aminoglycoside: inhibit protein synthesis by 30s
4. ADR of aminoglycoside: ototoxicity
5. ADR of aminoglycoside: nephrotoxicity
6. Inflamed meninges: ceftriazone, penicillin
7. DOC for typhoid: chlroramphenicol
8. Most impt mode of inactivation: beta lactamases
9. ADR of vancomycin: red man
10. Prophylaxis for RHD with valvular churva: clinda/erythromycin

Haay, full effort tong trans na to….