Professional Documents
Culture Documents
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
al
Inhibition of folic acid synthesis
Bacteriocid
al
Mechanisms of Resistance
Mechanisms of Resistance
Mechanisms of Resistance
Mechanisms of Resistance
Mechanisms of Resistance
-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
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
Pharmacokinetics:
Eliminated via active tubular secretion with dose reduction in
major renal dysfunction
Nafcillin and oxacillin eliminated largely in bile
Side effects
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
- 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
Pharmacokinetics
Imipenem is given with cilastatin, a renal dehydropeptidase inhibitor
Both drugs undergo renal elimination, dose in renal dysfnx is adjusted
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
Pharmacokinetics:
Used IV and orally (not absorbed) in colitis, enters most
tissues but not CNS, eliminated by renal filtration, has a long
half-life
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 :
Pharmacokinetics
Inhibit cytochrome P450s
Side effects
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
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
Present
In human
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
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
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:
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