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Antibiotics

Dr. Mohamed Ali, 2nd year


MD Internal Medicine

Principles of therapy
Immune system

Bactericidal
Bacterostatic
Combinations:

1+1 = 2
Additive
Synergistic (penicillins + aminoglycosides)
Antagonistic (penicillins + tetracyclines)
1+1=0

1+1=3

Mechanisms of actions
Mechanism

LACTAMS

Always
Inhibition of bacterial cell-wall synthesis
bactericid
al
Inhibition of bacterial protein synthesis

BS
Inhibition of nucleic acid synthesis
Bacteriocid

Antimicrobial agents

Classical
approach in
pharmacolgy
is to go from
outside the
bug to inside
the bug

Penicillins, cephalosporins,
imipenem/meropenem, astreonam, vancomycin

Aminoglycosides, chloramphenicol, macrolides,


Aminoglycosides
tetracyclines, streptogramins, linezolid,
clindamycin
Fluoroquinolones, rifampin

al
Inhibition of folic acid synthesis

Bacteriocid
al

Sulfonamides, trimethoprim, pyrimethamine

Mechanisms of Resistance

Mechanisms of Resistance

Mechanisms of Resistance

Mechanisms of Resistance

Mechanisms of Resistance

Cell wall synthesis inhibitors


Which cell wall synthesis is not a lactam?
What is a lactam?

-Weakest bond
- Site of Betalactamases
- 1st mode of resistance
elicited
- Over the years the R
groups have been
altered to obtain
different antibiiotics
Do u see S?
- It enhances lipid
solubility
- It allows protein
binding
- Predisposing to
allergies

Penicillins and other


betalactams
Mechanism of action
Bind PBPs (enzymes that allow crosslinking of bacterial cell
wall)
Inhibits transpeptidation
Inhibit crosslinking

Mechanism of resistance
Penicillinases (betalactamases)
Structural change in PBPs (MRSA vanomycin becomes
handy)
Change in porin structure (in gram ves like Pseudomonas)

Classifications of Penicillins
Narrow spectrum, beta- lactamase sensitive
Penicillin G and Penicillin V
Spirochete treponema pallidum

Very narrow spectrum, beta-lactamase resistant


Methicillin, nafcillin, oxacillins
S. aureus

Broad spectrum, beta-lactamase sensitive:

Amoxicillin and ampicillin


Gram + cocci (not staph): Listeria (rod)
Gram -: E. coli, H. Influenzae, H. pylori
Borrelia (Lyme disease)

Extended spectrum: antipseudomonal, beta-lactamase


sensitive
Ticarcillin, pieperacillin, azlocillin, carbenicillin
Gram ve aerobe - pseudomonas

General considerations with Penicillins


Activity enhanced if used with beta-lactamase inhibitors
Clavulanic acid, sulbactam, tazobactame
They are chemicals, suicide inhibitor of beta lactamase enzyme
Enzyme will take the betalactamse inhitor and make it a metabolite,
this metabolite will intern inhibit the beta-lactamase

Synergy with aminoglycosides against pseudomonal and


enterococcal species

Pharmacokinetics:
Eliminated via active tubular secretion with dose reduction in
major renal dysfunction
Nafcillin and oxacillin eliminated largely in bile

Side effects

So? What do u do in an allergy to one of the drug in this


group? Hypersensitivity, GI distress, Jarisch-Herxheimer
- cross-allogenicity?
5-10% chance of cephalosporin allergy is
syphilis treatment

reaction in

Cephalosporins
Mechanism of action and resistance: same as penicillins
Classifications:
- First generation: cefazolin, cephalexin
gram + and some gram ve
can be used in surgical prophylaxis long life
- Second generation: cefotetan, cefaclor, cefuroxime
- Better gram ve cover
- Cefuroxime crosses blood brain barrier

- Third generation: ceftriaxone, cefotaxime, cefdinir,


cefixime, cefoperazone
- Empirical management of sepsis ad meningitis
- Broad spectrum
- No activity against Listeria, Atypicals. MRSA and Enterococci
(LAME)

- Fourth generation: cefepime


- IV
- Beta-lactamase resistant

- 5th Generation?
- Ceftaroline

Pharmacokinetics:
Renal clearance: dose modification in renal dysfunction
Cefoperazone and ceftriaxone are largely eliminated in the
bile

Side Effects
Hypersensitivity
Use macrolides or aztreonam in case of allergies to lactams
Disulfiram-like effect

Imipenem and Meropenem


Mechanism of action: like penicillins and cephalosporins
- resistant to beta-lactamases
Spectrum:
Gram-positive cocci, gram negative rods
In-hospital agents for empiric use in severe life-threatening infections

Pharmacokinetics
Imipenem is given with cilastatin, a renal dehydropeptidase inhibitor
Both drugs undergo renal elimination, dose in renal dysfnx is adjusted

Side effects: GI distress, drug fever, CNS effects (seizures-with


imipenem)

Aztreonam
Mechanism of action:
Same as for penicillins and cephalosporins
Resistant to beta-lactamases

Uses:
IV drug mainly active vs gram ve rods
No cross-allergenicity with penicillins or cephalosporins

Vancomycin
Mechanism of action:
Binding at D-ala-D-ala muramyl pentapeptide to sterically
hinder the transglycosylation reactions involved in elongation
of peptidoglycan chains: does not interfere with PBPs

Spectrum: MRSA, enterococci, clostridium difficile


Resistance:
VRSA and VRE strains emerging
Enterococcal resistance involves change in the muramyl
pentapeptide target, such that termina D-ala is replased by
D-lactate

Pharmacokinetics:
Used IV and orally (not absorbed) in colitis, enters most
tissues but not CNS, eliminated by renal filtration, has a long
half-life

Side effects: Red man syndrome, ototoxicity,


nephrotoxicity

2. Inhibitors of Bacterial Protein


Synthesis

2 .For elongation, binding to A site is required bringing in the next amino


1. Messenger RNA is
acids
read from 5 to 3
direction
3. To make peptide bond, by using
- Ribosomes have
peptydyl trasferace
50s and 30 s sub
units
- Transfer RNA bind
to either to P site
to A site
- tRNA binds to P si
only during
initiation
- tRNA binding to P
site carries the
aminoacid
formylmethionine
4. Then is translocation
in bacteria

Linezolid is active against VRSA and


VRE

Mechanisms of resistance

Aminoglycosides
Activity and clinical uses:
- Bactericidal, accumulated intracellularly in microorganisms via an
oxygen-dependent uptake anaerobes are innately resistant
- Useful spectrum includes gram- ve rods; gentamicin, tobramycin,
and amikacin often used in combinations
- Synergistic actions occur for infections caused by enterococci (with
penicillin G or ampicillin) and P. aeruginosa (with an extended-spec
trum penicillin or third-generation cephalosporin)
- Streptomycin used in tuberculosis; is the DOC r bubonic plague and
tularemia

Pharmacokinetics:
Are polar compounds, not absorbed orally or widely
distributed into
tissues
Renal elimination proportional to GFR, and major dose
reduction needed in renal dysfunction

Side effects:
Nephrotoxicity (6 to 7% incidence) includes proteinuria,
hypokalemia, acidosis, and acute tubular necrosisusually reversible, but enhanced by vancomycin,
amphotericin B, cisplatin, and cyclosporine
Ototoxicity (2% incidence) from hair cell damage;
includes deafness (irreversible) and vestibular
dysfunction (reversible); toxicity may be enhanced by
loop diuretics
Neuromuscular blockade with reduced release of AChmay enhance e ects of skeletal muscle relaxants

Tetracyclines
Activity and clinical uses:
Bacteriostatic drugs, actively taken up by susceptible bacteria
broad-spectrum antibiotics, with good activity versus
chlamydial and mycoplasmal species, H.pylor, Rickettsia,
Borrelia burgdorferi, Brucella, Vibrio, and Treponema (backup
drug)

Specific drugs
Doxycycline: more activity overall than tetracycline and is
useful in prostatitis because it reaches high levels in prostatic
fluid
Minocycline: in saliva and tears at high conc. And used in
meningococcal carrier state
Demeclocycline; used in SIADH: blocks ADH receptor function
in collecting ducts
Tigecycline: in complicated skin, soft tissue and intestinal
infections dueo to resistant gram +ve (MRSA, VRED), gram
ce and Anaerobes

Pharmacokinetics:
Kidney for most ( reduced in renal dysfunction)
Liver for doxy
Chelators: tetracylines bind to divalent cations ( calcium,
magnesium and iron) which reduce their absorption

Side effects
Tooth enamel dysplasia and possible reduced bone growth in
children
Phototoxicity (ddemeclocycline and doxy)
GI distress, superinfections leading to candidiasis or colitis
Vestibular dysfunction (minocycline)
Contraindicated in pregnancy due to high incidence of liver
dysfunction

Chloramphenicol
Activity and use
Bacteriostatic with wide spectrum of activity
Currently a backup drug for infections due to Salmonella typhi,
B. fragilis, Ricettsia and in bacterial meningitis

Pharmacokinetics
Orally effective, good tissue distribution including CSF
Metabolized by hepatic glucuronidation and dose reductions
are needed in liver dysfnx
Inhibition of cytochrome P450

Side effects
Bone marrow suppression: aplastic anaemia rare (1 in 35000)
Gray baby syndrome in neonates due to reduced glucuronosyl
transferase)

Macrolides
Erythromycin, azithromycin, clarithromycin
Activity and clinical uses
Wide spectrum :

Gram +ve cocci ( not MRSA)


Atypical organism ( chlamydia, mycoplasma and ureaplasma species)
Legionella pneumophila
Campylobacter jejuni
Mycobacterium avium intracellulare
H. pylori

Pharmacokinetics
Inhibit cytochrome P450s

Side effects

Macrolides stimulate motilin receptors and cause GI distress


Macrolides cause reversible deafness at high doses
Increase QT interval
Telithromycin: a ketolide active against macrolid-resistant S.
pneumonia

Clindamycin
Not a macrolide, but has same mechanisms of action
and resistance
Narrow spectrum: gram +ve cocci (including community
acquired MRSA) and anaerobes, including B. fragilis
(backup drug)
Concentration in bone has clinical value in osteomyelitis
due to gram +ve cocci
Side effect: pseudomembranous colitis

Linezolid
Mechanism
Inhibits the formation of the initiation complex in bacterial
translation systems by preventing formation of tne Nformylmethionyl-tRNA-ribosome-mRNA complex

Spectrum
For VRSA, VRE and drug-resistant pneumococci treatment

Side effects: bone marrow suppression (low platelets


specially)

Quinupristin-Dalfopristin
Mechanism:
Streptogramins that act in concert via several mechanism
Binding to sites on 50S ribosomal subunit, they prevent the
interaction of amino-acyl-tRNA with acceptor site and
stimulate its dissociation from ternary complex
May also decrease the release of completed polypeptide by
blocking its extrusion

Nucleic acid synthesis inhibitors


Not in human

- Folic acid is required to


Convert uracil to thiamine
Through Methylation
- To make adenine and
guanine

Bacteria produce folic acid

Present
In human

These drugs produce


Anti-cancer effect

ClinicL USE:
Sulfonamides alone are limited in use due to resistance
Sulfasalazine is a prodrug used in ulcerative colitis and
rheumatoid arthris
Silver sulfadiazine is used in burns

In combination with dihydrofolate reductace inhibitors:


reduce resistance and acts synergistically
Use of trimethoprim-sulfamethoxazole ( cotrim)
Bacteria: DOC in Nocardia, Listeria, Gram ve infections
( E.coli, Salmonella, Shigella, H. influenzae)
Gram +ve infections ( Staph, MRSA
Fungus: Pneumocustis jiroveci

Pyrimethamin-sulfadiazine
Protozoa: toxoplasma gondii

Pharmacokinetics
Sulfonamides are hepatically acetylated
Renally excreted metabolites cause crystalluria
High protein binding
Drug interaction
Kernicterus in neonates

Side effects
Sulfonamides
Hypersensitivity ( rash, stevens-Johnson syndrome)
Hemolysis in G6PD
Phototoxicity

Trimetoprim or pyrimethamine
Bone marrow suppression

Nucleic acid synthesis inhibitos


Drugs: Quinolones
Mechanism
Bactericdal and interfer with DNA synthesis
Inhibit topoisomerase II (DNA gyrase) and topoisomerase IV (responsible
for seperation of replicated DNA during cell division)

Use:

UTIs
STDs/PID: chlamydia, gonorrhea
Skin. Soft tissue and bone infections
Diarrhea to shigell, salmonell, E.coli, campylobacter
Drug-resistanct pneumococci ( Levofloxacine)

Pharmacokinetics
Iron, calcium limits absorption
Eliminated by kidney mainly by kidney filtration and active
secretion ( inhibited by probenecid)

Side effects:

Tendonitis, tendon rupture


Phototoxicity, rashes
CNS effects (insomnia, dizziness. Headache)
Contraindicated in pregnancy and in children due to inhibition
of chondrogenesis

Unclassified antibiotics
Metronidazole
In anaerobes, converted to free radicals by ferredoxin,
binds to DNA and other macromolecules, Bactericidal
Antiprotozoal: giradia, trichomonas, entamoeba
Antivacterial : most anaerobic gram ve bacteria,
clostridium, Gardnerella and H. Pylori
Side effects:
Metallic taste
Disulfiram like effect

Reference
Davidsons principle and practice of medicine 22nd
edition
Kaplan Pharamacology; 2013
KD Tripati pharmacology: 7th edition

THANK YOU

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