PHARMACOLOGY

DRAFT: CHEMO OF
1S-1 | CEU-SOM A & B INFECTIONS
DOC LOYOLA Beta Lactams and Miscellaneous Antibiotics
! !
OUTLINE • ! Ex. Broad Spectrum Antibiotic — if it targets the
normal flora, disturb the miliue — providing for
I. INTRODUCTION opportunistic bacteria.
A. Chemotherapeutic Agents • Over use and inappropriate use
B. Factors in Antibiotic Selection
C. Antimicrobial Pharmacodynamics B. FACTORS IN ANTIBIOTIC SELECTION
D. Kinetics of Bacterial Killing
E. Tissue Penetration 1. Spectrum — “Empiric Treatment”
F. Factors in Antibiotic Dosing • Narrow Spectrum
G. Other Considerations in Antimicrobial Therapy • Broad Spectrum
II. BETA LACTAM ANTIBIOTICS 1. Tissue Penetration
A. Penicillin 2. Antibiotic Resistance
B. Cephalosporins 1. Safety profile
C. Other Beta Lactams 2. Cost
III. MISCELLANEOUS ANTIBIOTICS
A. Glycopeptide Antibiotics C. ANTIMICROBIAL PHARMACODYNAMICS
B. Other Inhibitors of Cell Wall Synthesis
1. MIC — Minimum Inhibitory Concentration
• Minimum concentrations of antibiotic to inhibit the growth of
bacteria; MIC50 or MIC90
I. INTRODUCTION 2. PAE — Post Antibiotic Effect
A. CHEMOTHERAPEUTIC AGENTS • Antibacterial activity persists beyond the time during which
measurable drug is present
GRAM STAIN
Principles involve: 3. PALE — Post Antibiotic Leukocyte Enhancing Effect
1. Gram’s classification
• Gram +: color blue • ! serves as an immunomodulator and enhances the action
• Gram -: pink or red of leukocyte to do the rest of the work
• Acid fast bacilli — Gram (+) red, Gram (-) blue
D. KINETICS OF BACTERIAL KILLING
General Rule:
• Morph: cocci (Strep — Chains, Staph — Clumps/Clusters, 1. Concentration-dependent Antibiotics
Diplococci — Pairs), Bacilli • Increasing the concentration kills an increasing concentration
• Aerobic or anaerobic, Oxygen requisition of bacteria and at a more rapid rate (e.g Aminoglycosides
and Quinolones)

2. Time-dependent Antibiotics
• no much difference in the rate of killing with varying
concentrations of the drugs
• ex. Beta lactams, Metronidazole, Vancomycin, Macrolides,
Clindamycin, Oxazolidinones

! Penicillin
— capability to kill the organism is the same whether you’re at CMax or
even at lower concentration;
— killing power is constant, as long as you’re above the MIC.

E. TISSUE PENETRATION
Tissue Penetration
1. Property of Antibiotic — e.g lipid solubility, molecular size
2. Tissue — adequacy of blood supply, presence of
inflammation

1. Activity Rarely a problem in acute infection due to increased microvascular

• Selectivity for target (unique)
• More vital than in human
2. Targets
• Bacterial and fungal ell wall-synthesizing enzymes (Beta
lactams and Anti-fungal)
• Bacterial ribosomes (Macrolides and Aminoglycosides)
• Enzymes required for Nucleotide synthesis and DNA
replication (Sulfas and Quinolones)
• Machinery of Viral replication (Anti-viral drugs)
permeability from local release of chemical inflammatory mediators
F. FACTORS IN ANTIBIOTIC DOSING
Factors in Antibiotic Dosing
1. Renal Insufficiency — loading and maintenance dosing in
renal insufficiency, aminoglycoside dosing
2. Hepatic Insufficiency
3. Combined Renal and Hepatic Insufficiency
4. Mode of Antibiotic Excretion/Excretory organ toxicity

3. Adaptation G. OTHER CONSIDERATIONS IN ANTIMICROBIAL THERAPY

• Antibiotic pressure (Selection of resistance)
Other considerations in Antimicrobial Therapy:

5S-6 CHEMOTHERAPY OF INFECTIONS BALAURO • BANZON • BOCOBO • LIMIN • RAMOS • SIGUI • SOLAIMAN •
TINIO
PAGE 1 OF 6
 1. Bactericidal vs. Bacteriostatic Therapy • Ribosomal protection
2. Monotherapy vs. Combination Therapy • Rendering poor affinity to target site
3. Intravenous vs. Oral Switch Therapy • Organisms down-regulates porin channels (gram – only)
4. Duration of Therapy • Activation of active efflux pump system (gram — only)

II. BETA LACTAM ANTIBIOTICS

BETA-LACTAM COMPOUNDS AND OTHER INHIBITORS OF CELL

WALL SYNTHESIS
• Penicillins
• Cephalosporins and cephamycins
• Other beta lactam drugs
• Monobactams
• Beta-lactamase inhibitors
• Carbapenems
• Other inhibitors of cell wall synthesis
• Vancomycin
• Teicoplanin
• Telavancin
• Dalbavancin
• Daptomycin
• Fosfomycin
• Bacitracin
• Cycloserine
NOBEL PRIZE WINNERS (1945)
• Alexander Flemming – discovered penicillin
— not sensationalized until the ff. Did an experiment on the effectivity Figure: ! Porin channels — kung saan pumapasok ang antibiotics.
of Penicillin: Peptidoglycans are relatively thinner compared with gram + organism.
• Howard Florey This is your PBP — kung saan nagaatach ang beta-lactam antibiotics.
• Ernst Chain However, a beta lactamase is the enzyme that is synthesized by your
bacteria, kaya pumapasok pa lang si antibiotic dinedegrade na siya
Insert image of antibiotic drufs and their chemical structures ni beta lactamase.
Beta Lactam ring — common to Beta Lactam antibiotics.
First antibiotic drug discovered: Sulfa
A. PENICILLIN

PENICILLIN
• 6-Aminopenicillanic Acid
• ! If a bacteria develops an enzyme that degrades
beta lactam, we call that Beta Lactamase.
• ! Converted to 6-aminopenicilloic acid (loses
antibacterial activity/property)
• Beta-lactam antibiotics attack the peptidoglycan layer
• ! Antibacterial Activity of Penicillin is better when
it covers Gram + although the Peptidoglycan layer
is relatively thicker compared to Gram – for the
reason that it doesn’t have an outer barrier and
envelope (para pag bigay mo ng antibiotic, punta
agad sa target site)
• ! Unlike with Gram – organism, each molecule
you gain access passing through the porin channel
Figure: ! Structure of the cell membrane — that we have an
— bacteria can develop resistance to any beta
lactam antibiotics if it develops an enzyme that alternating amino sugar of NAMA NAG NAMA NAG (N Acetyl
degrades it. Neuraminic Acid and N Acetyl Glucosamin) — with your NAMA is a
• ! In some instances, bacteria can neutralize the chain of beta peptide wherein the 2 amino residues, d alamine.
effect of beta lactam antibiotics by not synthesizing During the process of transpeptidation, the last amino acid residue
the beta lactamase enzyme. How? Beta Lactam is being cleave of the process and this is your tetrapeptidas. It
targets a specific site — Penicillin Binding becomes tetrapeptide because during the process of cross linking,
Protein (PBP) — if that specific target is being nagccleave yung last amino acid residue, which is D-alanine.
modified by bacteria by probably, ribosomal
protection — the antibiotic will develop poor affinity ! During the process of cross linking, this makes the cell wall
to the target site
very strong — parang tinatahi na banig. Beta lactam antibiotics
• Bacteria can develop resistance to beta-lactam and target the transpeptidase enzyme (aka: PBP) — cross linking will
penicillins if it develops an enzyme that can protect itself never happen and achieve a very weak cell membrane and its
from them rupture and the demise of the bacteria.
• ! Transpeptidase – enzyme important for cross-linking of
cell wall CLASSIFICATION OF PENICILLINS
• PENICILLINS (e.g. Penicillin G)
4 FORMS OF RESISTANCE DEVELOPMENT • Vs gram (+) organism, gram (-) cocci and non-
• Production of enzyme that degrades antibiotic (beta lactam) beta lactamase anaerobes
5S-1 NAME OF TOPIC BALAURO • BANZON • BOCOBO • LIMIN • RAMOS • SIGUI • SOLAIMAN •
TINIO
PAGE 2 OF 6
 • Penicillin G — the only naturally-occuring
penicillin nowadays.
• ANTISTAPHYLOCCCAL PENICILLINS (e.g. Nafcillin,
Cloxacillin, Oxacillin)
• Semi-synthetic penicillin
• Vs staphylococci (aureus, epidermidis) and
streptococci
• EXTENDED-SPECTRUM PENICILLINS (e.g. Ampicilli,
Amoxicillin and Antipseudomonal penicillins)
• Vs gram (-) organisms
• Group of penicillins that cover a broader range of
specificity
PHARMACOKINETICS
• Limitations
• Instability at acidic pH
• Susceptibility to destruction by b-lactamase
(penicillinase)
• Relative inactivity against gram (-) bacilli
• Units
• Pen G: 1600 units/mg (1M unit = 0.6g) — TOTAL
DOSE PER DAY
• Ex: 2M units every 6 hrs (8M units in 24 hrs time)
— divide that by 1600 units, that’s your total dose
per day
• Ex: 6M units of Pen G per day. Convert to Oral
(Amox)
• 1600 units of PenG = 1 gram of
Amoxicillin
• Divide 6M units by 1600 = 2 grams of
Amoxicillin
• You can give — 500mg every 8 hours
• Mechanism of action: Inhibit bacterial cell wall synthesis
• Oral absorption differs greatly for different penicillins,
depending on acid stability and protein-binding (impaired by
food)
• All Penicillins when given orally are impaired by food, except
Amoxicillin.
• Widely distributed in the body fluids and tissues —hence,
excreted into sputum and milk
• Poor penetration in the eye, prostate and CNS
• except with active inflammation of meninges if
given in high doses
• Rapidly excreted by the kidneys
• Normal half-life: approx 30 minutes (short half life)
• •
Blood levels raised by giving PROBENECID
• ! Prolongs half life — HOW: Penicillin is actively
secreted into the tubules. Probenecid is a
compound that competes with the secretion of
Penicillin in the tubules.
CLINICAL USES OF PENICILLINS
• Pen G
• DOC for infections caused by streptococci,
meningococci, enterococci, pneumococci, non-
beta-lactamase producing staphylococci, T.
Pallidum (causing Syphilis), clostridium (difficile,
botulinum, tetani)
5S-1 NAME OF TOPIC BALAURO • BANZON • BOCOBO • LIMIN • RAMOS • SIGUI • SOLAIMAN •
TINIO
• Pen V
• Oral form
• Indicated only for minor infections due to poor
bioavailability
• PEN VK — nilalagay na binubudbud na Penicillin
sa mga sugat
• BENZATHINE/ PROCAINE
• Repository forms of Penicillin
• IM yield-low but prolonged drug levels
• For tx of B-hemolytic Strep Pharyngitis
• Among pts with RHF and are prone to
develop into RHD
• Benzathine — once weekly
• Benzathine penicillin — once every 28 days
• For prophylaxis of Rheumatic Heart Disease —
every month injection of Penicillin like your
Penadur
USES OF PENICILLIN, RESISTANT TO STAPH B-LACTAMASE
! Some organisms are beta-lactamase producers, and if that
organism is a S. Aureus (or S. Pneumoniae) that are Beta-Lactamase/
Penicillinase producers, it becomes a problem.
• The sole indication is infection by b-lactamase-producing
staphylococci — Nafcillin (a semi-synthetic penicillin drug
that are good for beta-lactamase producing gram –
organisms)
Collectively called, METHICILLIN GROUP
• Methicillin — not given anymore due to Metabolic
Acidosis but are still collectively called by this
name
• Nafcillin
• Isoxazolyl (oxacillin)
• Cloxacillin
• Dicloxacillin
! Methicillin Sensitive Staphylococcus Aureus (MSSA)
— Beta-lactamase-producing S. Aureus sensitive to Methicillin
! Methicillin Resistant Staphylococcus Aureus (MRSA)
— Beta-lactamase producing S. Aureus resistant to Methicillin due
to development of resistance.
• For mild, local infections: Isoxazolyl (Oxacillin) — 15-25 mg/
kg/d
• For serious systemic staph infection: oxacillin or nafcillin
8-12 g/d (50-100 mg/kg/d)
CLINICAL USES OF EXTENDED-SPECTRUM PENICILLINS
• Aminopenicillin (Ampicillin, Amoxicillin, Bacampicillin)
Carboxypenicillins (Ticarcillin), Ureidopenicillins (Piperacillin)
• Greater activity against gram (-) bacteria
• Oral form taken without food except amoxicillin (form of
aminopenicillin/ amplicillin)
• Ampicillin — aminopenicillin effective for shigellosis but not
for salmonellosis
Amoxicillin — effective for both Shigellosis and
Salmonellosis
• For Pseudomonas:
• One of the hard to treat infections — hence, you
need “big” drugs”
• Pseudomonas organisms can easily develop
resistance
• Combination Drug: Carboxypenicillins /
Ureidopenicillins + Aminoglycosides
Aminopenicillin (Amoxicillin, Ampicillin)
PAGE 3 OF 6
 • Broad spectrum of activity
• Not good for beta-lactamase/penicillinase-producing THIRD GENERATION CEPHALOSPORINS
Staphylococcus aureus and Streptococcus pneumoniae • Cefoperazone, Cefotaxime, Ceftazidime, Ceftriaxone,
• Can compete with Methicillin group by: Cefixime, Cefpodoxime, Proxetil, Cefdinir, Cefditoren
• Amoxicillin + Clavulanic Acid = Co-Amoxiclav Pivoxil, Ceftibuten, Ceftizoxime, Moxalactam
• Ampicillin + Sulbactam • Expanded gram (-) coverage
• Some can cross BBB
• B-lactamase inhibitors: • Hence, Ceftriaxone and Cefotaxime are good
• Clavulanic acid, Sulbactam, Tazobactam, DOC for the tx of Bacterial Meningitis.
Avibactam (new) • Active vs Citrobacter, Serratia, and Providencia
• “Suicide Inhibitors” • CEFTAZIDIME AND CEFOPERAZONE
• Only achieve a very poor antibacterial • vs. P. Aeruginosa
activity, hence not given alone. • CEFTIZOXIME AND MOXALACTAM
• Vs. b-lactamase-producing strains of • vs. B. Fragilis
bacteria • CEFIXIME (Oral) AND CEFTRIAXONE (Parenteral)
RESISTANCE • 1st line drug for tx of N. Gonorrhea
• Inactivation by b-lactamase • Cefixime: 400 mg 2x a day for 2 days
• Modification of target PBPs • Ceftriaxone: Single shot 500 mg IM
• Impaired penetration of drug to target PBPs • In the case of Urethritis: don’t cover only for N.
• Presence of an efflux pump Gonorrhea, the patient will come back and
complain for urethral discharge. Cover also for
B. CEPHALOSPORINS Non-gonococcal component.
• CEFTRIAXONE AND CEFOTAXIME
CEPHALOSPORINS • Active against meningitis
• 7-aminocephalosporanic acid • Also with severe infections due to PRSP*
• Soluble in water
• Stable to pH and temperature changes FOURTH GENERATION CEPHALOSPORINS
• NOT ACTIVE against Enterococci and Listeria • Cefepime, Cefpirome
monocytogenes • Coverage is higher, Hypoprothrombinema — PT is lower,
• DOC for Listeria = AMPICILLIN bleeding tendencies (d/t to Methylthiotetrazole)
• More resistant to hydrolysis by B-lactamase
FIRST-GENERATION CEPHALOSPORIN • Active vs P. Aeruginosa, Enterobacter, S. Aureus, and S.
• Cefadroxil, Cefazolin, Cephalexin, Cephalotin, pneumoniae (PRSP)
Cephapirin, Cephradine • Half life: 2 hours
• Good coverage for gram (+) and some gram (-) organisms • ADRs:
(Proteus Mirabilis, Eschericia Coli, Klebsiella) • Allergy
• Tubular seceretory-blocking agents (Probenecid) may • Toxicity – Renal, Hypoprothrombinemia, Severe
increase serum levels. Disulfiram-like reactions (also with Metronidazole)
• CEFAZOLIN • D i s u l fi r a m ( “ A n t a b u s e ” ) i s a
• A l m o s t o n l y fi r s t g e n e r a t i o n p a r e n t e r a l substance that inhibits Aldehyde
cephalosporin Dehydrogenase leading to accumulation
• DOC for surgical prophylaxis; of Acetaldehyde or toxic metabolite of
• Alternative to an Antistaphylococcal Penicillin Alcohol in the blood — hangover:
• Rarely the DOC for any infection dizziness, sweating
• Superinfection
SECOND GENERATION CEPHALOSPORINS
• Cefaclor, Cefamandole, Cefonicid, Cefuroxime (axetil),
Cefprozil, Loracarbef, Ceforanide, Cephamycins ADVERSE EFFECTS AND TOXICITIES
(Cefoxitin, Cefmetazole, Cefotetan) • Sensitizing, may cause cross-reactions in some with pen
• Gram (+) coverage becomes shortened and widened/ allergy
extended gram (-) coverage (Haemophillus influenzae, • Patients with anaphylactic reactions to pen should not
Edwardsiella, Neisseria) receive cephalosporins
• Tx of Sinusitis, Otitis or Lower RTI • Cephalosporins with Methylthiotetrazole group
• C E F O X I T I N , C E F O T E TA N , C E F M E TA Z O L E • causes HypoprothrombinemiA, bleeding
(Cephamycins) tendencies and Disulfiram-like effect — GIVE
• ! Not really true cephalosporins, but have good VITAMIN K
antibiotic coverage • 4th Generation: Cefepime, Cefpirome
• With activity against anerobes, peritonitis, or • 3rd Generation: Cefoperazone
diverticulitis • 2nd Generation: Cefamandole, Cefmetazole,
Almost all 2nd gen cephalosporins do not cross BBB, so if you have Cefotetan
infections of the brains (ex. Bacterial Meningitis), 2nd Generation
Ceph is not a good choice.
C. OTHER BETA LACTAMS
• CEFUROXIME OTHER BETA-LACTAMS
• For community-acquired pneumonia • Monobactam (monocyclic b-lactam ring)
• The only 2nd generation drug that crosses the BBB • ! Beta lactam lang, walang kasama
• However, still not a good choice for CNS • NO COVERAGE FOR GRAM +
infection. • AZTREONAM
• Less effective in tx of meningitis than Ceftriaxone
5S-1 NAME OF TOPIC BALAURO • BANZON • BOCOBO • LIMIN • RAMOS • SIGUI • SOLAIMAN •
TINIO
PAGE 4 OF 6
 • Gram (-) rods only
• Beta-lactamase inhibitors (suicidal inhibitors)
• Clavulanic acid, Sulbactam, Tazobactam
• Given together with B-lactam compound
• Carbapenems
• BIGGEST AMONG THE DRUGS (reserved for life-
threatening infections)
• Imipenems, Meropenem, Doripenem,
Ertapenem
• Choice of tx of infection caused by Enterobacter
(Enterobacteria C — E. Coli and Klebsiella — esp
if ESBL Extended Spectrum Beta Lactamase
producers) and Hard to treat gram (-) infections
III. MISCELLANEOUS ANTIBIOTICS
A. GLYCOPEPTIDE ANTIBIOTICS
GLYCOPEPTIDE ANTIBIOTICS
• VANCOMYCIN
• For Methicillin-Resistant Staphylococcal
infection (MRSA)
• (2nd) DOC for Pseudomembranous colitis
• DOC is still Metronidazole.
• Tx of enterocolitis due to C. Difficile
MOA: Inhibits cell wall synthesis by binding firmly to the D ala-D-ala
terminus of nascent peptidoglycan
! In Cross linking, ang last amino acid residue nagccleave or
natatanggal in the process of transpeptidation; Pero yung
Glycopeptide (ex. Vancomycin) kumakapit sya mismo dun sa
amino acid residue. So, hindi macarry out ng transpeptidase
enzyme ang transpeptidation kasi nakakabit ang Glycopeptide —
weakening the cell wall.
• CANNOT BE GIVEN ORALLY — poorly absorbed
in GIT;
• Except: Pseudomembranous Colitis
• If the patient is given broad-spectrum
antibiotic (also disturbs normal flora) resulting
to Pseudomembranous Colitis.
• In this scenario, you can give Vancomycin
ORALLY because it can kill C. Difficile.
• Indication:
• Sepsis, Endocarditis, due to Methicillin-
resistant Staphylococci, with Gentamicin, as
alternative regimen for tx of enterococcal
endocarditis in pts with serious penicillin
allergy
• ADRs:
• “Red man” or “Red neck” syndrome
• Flushing
• Secondary to Hypersensitivity
• Give Antihistamine
• Toxic to the kidney
• TEICOPLANIN – glycopeptide
• Similar to Vancomycin as to MOA and Spectrum
• Long T 1/2 — 45 - 70 hours
• PRICE: 50,000 per vial, given 2 to 3 days
• TELAVANCIN
• Semisynthetic lipoglycopeptide derived from
vancomycin
• Active against gram (+) bacteria and strains with
reduced susceptibility to vancomycin
5S-1 NAME OF TOPIC BALAURO • BANZON • BOCOBO • LIMIN • RAMOS • SIGUI • SOLAIMAN •
TINIO
• Binds to D-ala-D-ala and disrupts bacterial cell
membrane potential and increases permeability
• Potentially teratogenic (avoided in pregnancy)
• DALBAVANCIN
• Semisynthetic lipoglycopeptide derived from
Teicoplanin (same MOA)
• With improved activity against many Gram (+)
bacteria including MRSA and VISA
• Extremely long half-life: 6 - 11 days
• Once weekly dosing
B. OTHER INHIBITORS OF CELL WALL SYNTHESIS
• FOSFOMYCIN
• Stable salt of Phosphonomycin
• 100% Compliance
• Inhibits enolpyruvate transferase (early stage of
cell wall synthesis)
• Dose: single 3g for AUC (Acute Uncomplicated
Cystitis) and UTI
• Safe for use in pregnancy
• DAPTOMYCIN
• NOT A GLYCOPEPTIDE, but a Cyclic lipopeptide,
same spectrum with Vancomycin
• More rapidly bactericidal in-vitro than Vancomycin
• MOA: not fully understood ; Bind to cell membrane
via Ca2+-dependent insertion of lipid tail (!
accumulating with each other producing a pore like
structure leading to entry/exit of substance —
demise of the bacteria) leading to depolarization of
K+ efflux and cell death
• BACITRACIN
• Cyclic peptide
• Interfere with dephosphorylation in cycling of the
lipid carrier (should always be phosphorylated
during the process of cell wall synthesis)
• No cross-resistance
• Useful for suppression of mixed bacterial flora in
suface lesions
• CYCLOSERINE
• Water-soluble, unstable at acid pH
• RESERVE DRUG: Almost exclusively used to treat
TB-resistant to 1st line agents
• Inhibits alanine racemase (converts L-alanine to
D-alanine) and ligase enzyme — inhibiting
transpeptidation and cross linking leading to a
weak cell membrane.
IV. REFERENCES
➢ Doc Loyola’s PPT + SIDE NOTES
PAGE 5 OF 6
5S-1 NAME OF TOPIC BALAURO • BANZON • BOCOBO • LIMIN • RAMOS • SIGUI • SOLAIMAN •
TINIO
PAGE 6 OF 6