Embed Size (px)
Citation preview
Dr.Wafaa Ezz Elarab
Antimicrobial Drugs-2Antimicrobial Drugs-2
(according to Lippincott´s Pharmacology, 2009)(according to Lippincott´s Pharmacology, 2009)
Summary of antimicrobial agents affecting cell wall Summary of antimicrobial agents affecting cell wall synthesissynthesis
Agents affecting the cell wall b-lactamase
inhibitors
b-lactam antibiotics Other antibiotics
Penicillins Cephalosporins Carbapenems Monobactams
1st generation 2nd generation 3rd generation 4th generation
BacitracinVancomycinDaptomycin
Clavulanic acidSulbactamTazobactam
AmoxicillinAmpicillinDicloxacillinIndanyl carbenicillinMethicillinNafcillinOxacillinPenicillin GPenicillin VPiperacillinTicarcillin
ErtapenemImipenem/cilastatin*Meropenem
Aztreonam
CefepimeCefadroxilCefazolinCephalexin
CefaclorCefprozilCefuroximeCefoxitin
CefdinirCefiximeCefotaximeCeftazidimeCeftibutenCeftizoximeCeftriaxone
B lactam antibioticsB lactam antibiotics
Classification:– Narrow spectrum – penicillinase sensitive– Narrow spectrum – penicillinase resistant– Broad spectrum penicillins– Extended-spectrum penicillins
• Penicillins
What's the difference between Broad Spectrum and Extended Spectrum antibiotics?
Broad spectrum antibiotics have activity against both gram positive and gram negative bacteria. Examples would be tetracycline and chloramphenicol.
Extended spectrum antibiotics are antibiotics which have had chemical modifications which increase their gram negative coverage. Cephalosporins are a good example. 1st generation cephalosporins have no gram negative coverage. Gram negative coverage progressivly increases as you go higher in generations.
Penicillins
Large diverse group of compounds Could be synthesized in the laboratory more economical to obtain natural penicillin through
microbial fermentation and modify it to semi-synthetic forms
Penicillium chrysogenum – major source All consist of 3 parts
thiazolidine ring beta-lactam ringvariable side chain dictates microbial activity
6
A- Narrow spectrum – penicillinase (= -lactamase) sensitive
• Benzylpenicillin (penicillin G)Naturally occurring
Poor oral availability (sensitive to stomach acid)
=> given by injection
Active against gram-positive bacteria
• Phenoxymethylpenicillin (penicillin V)
is more acid-stable than benzylpenicillin, which allows
it to be given orally.
B- Narrow spectrum – penicillinase (= b-
lactamase) resistant• Methicillin
Semisynthetic
Poor oral availability (only parenteral)
Active against Gram +ve bacteria
Mostly used for Staphylococcus aureus
However, MRSA & ORSA has emerged• Oxacillin
Good oral availability• Cloxacillin• Dicloxacillin
C- Broad spectrum – penicillinase (= b-lactamase) sensitive( Aminopenicillins)
Ampicillin Semisynthetic Good oral availability Active against Gram +ve and Gram -ve bacteria Active against Enterobacteria
Amoxycillin Excellent oral availability
D- Extended spectrum – penicillinase (= b-lactamase) sensitive(= Carboxypenicillins)
Carbenicillin Semisynthetic Poor oral availability Active against Gram +ve and Gram -ve bacteriaIncluding Pseudomonas aeruginosa
Ticarcillin Mezlocillin Piperacillin
Adverse effects of penicillins
1.Hypersensitivity reactions ( occur in 1-10% of pts; fatality occur in 0.002%) 2. Super infections: A condition in which a patient with a
infectious disease acquires a second infection.
3. Diarrhoea4. May cause convulsions after high doses by i.v or in
renal failure
Penicillins
Figure 20.6
CephalosporinsCephalosporins
Account for majority of all antibiotics administered
Isolated from Cephalosporium acremonium mold
Beta-lactam ring that can be altered Relatively broad-spectrum, resistant to most
penicillinases, & cause fewer allergic reactions Some are given orally, many must be
administered parenterally13
Cephalosporins 4 generations exist First generation – cephalothin, cefazolin – most
effective against gram-positive cocci Second generation – cefaclor, cefonacid – more
effective against gram-negative bacteria Third generation – cephalexin, cefotaxime –
broad-spectrum activity against enteric bacteria with beta-lactamases
Ceftriaxone – new semisynthetic extended-spectrum drug for treating wide variety of infections
14
Fourth generation – (mostly b-lactamase restistant)
Cefepime
Broadest antimicrobial spectrum (Gram +ve and Gram –ve)Used for MDR (multi drug resistant) bacteria and mixed infections
Adverse effects of cephalosporin1. Hypersensitivity reactions- most common Anaphylaxis, bronchspasm, urticaria – rash
2. Nephrotoxicity ; esp. cephradine
3. Superinfections
4. Diarrhea: oral cephalosporins, cefoperazone, ceftriaxone & moxalactam.
5. Cefamandole, moxalactam & cefoperazone may cause: a) Bleeding disorders b) Flushing, tachycardia, vomiting with alcohol
intake
naturally-derived product of Streptomyces cattleya Their structure renders them highly resistant to beta-
lactamases Same mechanism of action as penicillins Imipenem
broad spectrum against aerobic and anaerobicGram +ve as well as Gram -ve bacteria. Hydrolysed in the mammalian kidney by a
dihydropeptidase enzyme, and so is given with a dehydropeptidase inhibitor, cilastatin
Active against Pseudomonas aeruginosa and the Enterococcus species
• Meropenem• Doripenem
• CarbapenemOther beta-lactam antibioticsOther beta-lactam antibiotics
Unlike other beta-lactams, the monobactam contains a nucleus with no fused ring attached
Same mechanism of action as penicillins
Aztreonam The only commercially available monobactam antibiotic Aztreonam has strong activity against susceptible Gram -ve
bacteria, including Pseudomonas aeruginosa It has no useful activity against Gram +ve bacteria or anaerobes It is known to be effective against a wide range of bacteria
including Citrobacter, Enterobacter, E coli, Haemophilus, Klebsiella, Proteus, and Serratia species
• Monobactams
Other inhibitors of cell wall synthesisOther inhibitors of cell wall synthesis
1- 1- GlycopeptideGlycopeptide(Vancomycin)Important "last line" against antibiotic
resistant S. aureus
2- 2- Polypeptide antibioticsPolypeptide antibiotics(Bacitracin)
Topical applicationAgainst gram-positives
1- VancomycinOnly effective against Gram-positive bacteriaPoor oral absorptionUsed to be the “Magic bullet” for methicillin-resistant staphylococci, but now staph are becoming V-resistant.Dose-related ototoxocity:Tinnitus and can progress to total deafness
Bind to D-Ala-D-Ala terminus of peptidoglycan polypeptide prevents further elongation and cross-linking of peptidoglycan chain
Mechanism of action
2- Bacitracin•Mixture of polypeptides From Bacillus subtilis•Serious nephrotoxicity => only topical use vs gram (+) bacteria
mechanism of action• Inhibits dephosphorylation that transfers peptidoglycan subunits to the growing cell wall
Other Inhibitors of Cell Wall SynthesisOther Inhibitors of Cell Wall Synthesis
Antibiotics effective against Mycobacteria: interfere with mycolic acid synthesis or incorporation
Isoniazid (INH)Ethambutol
(according to Lippincott´s Pharmacology, 2009)(according to Lippincott´s Pharmacology, 2009)
Summary of antimicrobial agents affecting cell wall Summary of antimicrobial agents affecting cell wall synthesissynthesis
Agents affecting the cell wall b-lactamase
inhibitors
b-lactam antibiotics Other antibiotics
Penicillins Cephalosporins Carbapenems Monobactams
1st generation 2nd generation 3rd generation 4th generation
BacitracinVancomycinDaptomycin
Clavulanic acidSulbactamTazobactam
AmoxicillinAmpicillinDicloxacillinIndanyl carbenicillinMethicillinNafcillinOxacillinPenicillin GPenicillin VPiperacillinTicarcillin
ErtapenemImipenem/cilastatin*Meropenem
Aztreonam
CefepimeCefadroxilCefazolinCephalexin
CefaclorCefprozilCefuroximeCefoxitin
CefdinirCefiximeCefotaximeCeftazidimeCeftibutenCeftizoximeCeftriaxone
2. Antibiotics that Inhibit Protein Synthesis
www.freelivedoctor.com
(according to Lippincott´s (according to Lippincott´s Pharmacology, 2009)Pharmacology, 2009)
PROTEIN SYNTHESIS INHIBITORSPROTEIN SYNTHESIS INHIBITORS
TETRACYCLINESTETRACYCLINES
AMINOGLYCOSIDESAMINOGLYCOSIDES
MACROLIDES/KETOLIDESMACROLIDES/KETOLIDES
CHLORAMPHENICOLCHLORAMPHENICOL
CLINDAMYCINCLINDAMYCIN
QUINUPRISTIN/DALFOPRISTINQUINUPRISTIN/DALFOPRISTIN
LINEZOLIDLINEZOLID
DemeclocyclineDemeclocyclineDoxycyclineDoxycyclineMinocyclineMinocyclineTetracyclineTetracycline
AmikacinAmikacinGentamicinGentamicinNeomycinNeomycinNetilmicinNetilmicinStreptomycinStreptomycinTobramycinTobramycin
AzithromycinAzithromycinClarithromycinClarithromycinErythromycinErythromycinTelithromycinTelithromycin
2. Inhibition of protein synthesisRibosomes are essential for translation of mRNA into proteinsNo translation No protein synthesisNo protein synthesis No growth Acting at 30S ribosomes
Aminoglycosides √Tetracyclines √
Acting at 50S ribosomesChloramphenicol √Macrolides √ClindamycinStreptograminsOxazolidones
Antibacterial Medications that Antibacterial Medications that Inhibit Protein SynthesisInhibit Protein Synthesis
Target ribosomes of bacteriaAminoglycosides: bind to 30S subunit causing it to distort and malfunction; blocks initiation of translationTetracyclines: bind to 30S subunit blocking attachment of tRNA.Macrolides: bind 50S subunit and prevents protein synthesis from continuing.
Protein Synthesis InhibitorsProtein Synthesis Inhibitors
Mostly bacteriostatic Selectivity due to differences in prokaryotic and
eukaryotic ribosomes
www.freelivedoctor.com
Antimicrobials that Bind to the 30S Ribosomal Subunit
Aminoglycosides Aminoglycosides
(bactericidal)
mechanism of action - Aminoglycosides inhibit translation of the mRNA by irreversible binding and change the shape of 30S subunit of the ribosome, causes the misreading of the codons along the mRNA. This misreading of the codons causes an error in translation leading to improper protein expression leading to bacterial cell death.
AminoglycosidesAminoglycosides
Against many Gram- and some Gram+. Most important adverse side-effect: (ototoxicity) and
kidney damage. Resistance – several mechs: inactivation of the drug
by acetylation, or adenylation, to prevent drug access, (streptomycin only).
Synergy - The aminoglycosides synergize with B-lactam antibiotics. The B-lactams inhibit cell wall synthesis and thereby increase the permeability of the aminoglycosides.
AminoglycosidesAminoglycosides Gentamicin – used for acute, life-thretening gram- infections.
Has synergism with pen and van and combo. Amikacin – used for bact that are gent-resistant. Netilmicin – less toxic than gentamicin. Neomycin – too toxic for parenteral use. Used for topically
for skin infections and orally for sterilizing bowel before surgery.
Streptomycin – active against Mycobacterium tuberculosis. But bec of its ototoxicity, rifampicin replaces.
Rifampicin – resistance develops quickly alone; so, with TB, combine with isoniazid, ethambutol, and pyrazinamide for the 1st 2 mos of treatment, followed by another 4 mos with rifampicin and isoniazid.
Tetracyclines (bacteriostatic)tetracycline, minocycline and doxycycline
Mode of action - The tetracyclines reversibly bind to the 30S ribosome and inhibit binding of aminoacyl-t-RNA to the acceptor site on ribosome (mRNA).
Spectrum of activity - Broad spectrum; Useful against intracellular bacteria
Adverse effects – Super infection: Destruction of normal
intestinal flora resulting in increased secondary infections.
staining and impairment of the structure of bone and teeth.
Photosensitivity so Patients should be kept out of heavy sunlight when receiving tetracyclines
TetracyclinesTetracyclines
Penetration into cell requires an energy-dependent transport not present in mammals.
Stable chelate complexes are formed by the tetracyclines with many metals, including calcium, magnesium, and iron. Such chelates are usually very insoluble in water (so Oral absorption impaired by food
Resistant organisms develop 1. an efflux pump and do not accumulate the drug.2. Genes for tet-resistance transmitted by plasmids.
Antimicrobials that Bind to the 50S Antimicrobials that Bind to the 50S Ribosomal SubunitRibosomal Subunit
www.freelivedoctor.com
• The most important members of the group are erythromycin, clarithromycin, azithromycin, spiramycinbacteriostatic
Spectrum of activity – Narrow spectrum bacteriostatic mainly against Gram-positive bacteria, Mycoplasma, Legionella (intracellular bacterias) but not against the Enterobacteriaceae.
Macrolides are bacteriostatic for most bacteria but are cidal for a few Gram-positive bacteria.
• Macrolides
• Erythromycin is acid labile but is given as an enterically coated tablet.• Macrolides are widely distributed in the body except to the brain and cerebrospinal fluid.• Few side effects (GI disturbances)
It binds at the P-site of the 50S ribosomal subunit. As a result of which, during translation, the P-site is occupied by the macrolide. When the t-RNA attached with the peptide chain tries to move to the P-site, it cannot go there due to the presence of the macrolide, thus getting thrown away. This prevents the transfer of the peptidyl tRNA from the A-site to the P-site and blocks the protein synthesis due to the inhibition of the translocation of the nascent peptide chain.
Mechanism of action:
ChloramphenicolChloramphenicol Lincomycin, Clindamycin (bacteriostatic)
Mode of action - These antimicrobials bind to the 50S ribosome and inhibit (polypeptide bond formation) peptidyl transferase activity.
Spectrum of activity - Chloramphenicol - Broad range;Lincomycin and clindamycin - Restricted range
Resistance - Common
Adverse effects - Chloramphenicol is toxic (bone marrow suppression) but is used in the treatment of bacterial meningitis.
www.freelivedoctor.com
A bacteriostatic antibiotic which inhibits protein synthesis by forming a stable complex with elongation factor EF-G, guanosine diphosphate and the ribosomeUse: mainly against G+ve bacteria, treatment of staphylococcal infections.
• Fucidic acid
• Elongation factors are a set of proteins that facilitate the events of translational elongation, the steps in protein synthesis from the formation of the first peptide bond to the formation of the last one.
Mechanism of action:
Inhibition of Protein Synthesis by Antibiotics
Figure 20.4
AntibacterialDrugs that InhibitProtein Synthesis
Thank You
