Cephalosporins and Aminoglycosides
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Transcript of Cephalosporins and Aminoglycosides
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CH2S
CHCHNHCR1
Cephalosporins
CNC=OO7ACP
R2
C
C = O
(effectsmetabolismandpharmacokinetic)
R1 decides:antibacterial activityresistance to -lactamase
OH
stability for stomach acids
43
7ACP: 7-aminocephalosporanic acid
Acylation of PBPs
Inhibition of PBPs
Cephalosporins
M G M G M G
M G M G M G
MInhibits cross linking
of peptidoglycan
Cell lysis
Structural irregularities
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Classification : Best indicated by generationbased on antimicrobial activity
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Cefazolin (ANCEF,ZOLICEF, others)Cefadroxyl (DURACEF)Cefalexin monohydrate(KEFTAB)
Ist generation
good against Gram (+);modest against Gram (-)Streptococci (except penncillin- resistant strains);
Useful spectrum
Cefradine (VELOSEF) Staphylococcus aureus (except Methicillin-resistant strain)
Cefuroxime (ZINACEF)Cefuroxime axetil
IInd generation Increased activity againstGram (-) but much lessactive than IIIrd generation
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Cefprozil (CEFZIL)Cefmatazole (ZEFAZONE)Loracarbef (LORABID)
Gram (-) e.g., Enterobacter sp, Klebsiella sp.,haemophilus influenza; Not active against gram + as Ist generation
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Cefotaxime (CLAFORAN)
Ceftriaxone (ROCEPHIN)Cefdinir (OMNICEF)Cefditoren ivoxil SPECTRACEF
IIIrd generation
Less active than Istgeneration against Gram(+) but more active
Useful spectrum
Ceftizoxime (CEFIZOX)Ceftibuten (CEDAX)Cefpodoxime proxetil (VANTIN)Cefoperazone (CEFOBID)Ceftazidime (FORTAZ, others)
including
-lactamase producing bacteria
Active agnst Pseudomonas
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IV generation
Cefepime (MAXIPINE)
activity than IIIrd generation
and have increased stability against hydrolysis by -lactamase
Ceftobiprole (Zeftera / Zevtera )
5th generation
active against MRSA (methicillin-resistant Staphylococcalaureus, penicillin-resistant Streptococcus pneumoniae,
It has been shown to be statistically non ‐inferior to the combination of vancomycin and ceftazidime for the treatment of skin and soft tissue infections.
Ceftobiprole inhibits the PBP. Ceftobiprole is resistant to ‐ .
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Mechanism of Resistance:Same as penicillin's. i.e. Altered PBPs or lactamase
First generation cefazolin is more susceptible to -lactamase from S aureaus than is Cephalothin
Third generation: susceptible to hydrolysis by induciblechromosomally encoded (Class 1 -lactamase)
Fourth generation: less susceptible
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General features of the Cephalosporins
•absorbed readily after oral administration
Distribution
•Several cephalosporins can penetrate intoCSF meningitis
•Can also cross placenta
•High concentrations also seen in synovial, bile andericardial fluids
•Penetration in aqueous humor of eye is high
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Excretion
Primarily excreted by kidneydosage should be adjusted in patients withrena nsu c ency
Cefoperazone (excreted in bile)
cefotaxime is deacelated in vivo; the metaboliteless active
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Specific Agents:
Ist generation:
Cefazolin
Well-tolerated after either IM or IVConc in plasma after 1g IM administration reach to 64 ug/ml
Excreted by glomerular filtration and is bound to plasmaproteins (85%)
frequently due to longer half-life
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II nd generation:
Cefoxitin
Resistant to -lactamse produced by Gram (-) rodsFor Gram (+) < active than I st generation cephalosporinsMore active than I st or IInd generation agents agnst -fragalis
Conc in plasma after 1g IM administration reach to 22 ug/ml;half life 40 min
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Cefotetan
More active than Cefoxitin agnst Gram (-)
Conc in plasma after 1-g IM administration reach to 70 ug/ml;half life 3.3 hrs
IIIrd generation:
Cefotaxime
-agnst most Gram (+) and (-) bacteria except B . fragilis
Half life in plasma 1 hrMetabolized desacetylcefotaxime
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Active agnst Gram (+) excellent for Pseudomonas andOther Gram (-) bacteria
III rd generation:
Ceftazidime
IV th generation:
Cefepime
.
ct ve agnst many entero act w c are res stant toother Cephalo
Excellent penetration in CSF;Conc in plasma after 2-g IV administration reach to126-193 ug/ml; half life 2 hrs 55
Therapeutic Uses:First generation : skin and soft tissue infections, surgical
prophylaxis of wound infection.
Third generation:infections caused by Klebsiella, Enterobacter, Proteus etc ,ceftriaxone : all forms of gonorrhea, severe lyme diseasescefotaxime or ceftriaxone : used to treat meningitis due topneumococci, meningococci, and Haemophillus influenza
Fourth generation noscomal infections whereresistance to -lactum antibiotics is expected.
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Hypersensitivity: The frequency of cross-reactivity withpenicillin-sensitive individuals is 5 to 15%.CONTRAINDICATED in patients with a history of anaphylaxis
Untoward Reaction:
to a penicillin.
Nephrotoxic
Renal tubular necrosis i.e. cephaloridine (4g/day)
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Hyperprothrombinemia,, Platelet dysfunction
ThrombocytopeniaDisulfiram-like Effect : cefamandole, cefotetan,moxalactam, cefoperazone.
Drug-drug Interactions:
Concurrent administration of Cephalosporins or gentamicincause nephrotoxicity (in >60 yr old patients)
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OTHER -LACTAM Antibiotics
Carbapenems (fused -lactum ring and a 5-membered ring sys)
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Imipenem :i. Mechanism of action: Binds to PBPs, disrupting cell wall
synthesis and is bactericidal.
ii. Spectrum: Broad-spectrum covers Gram (+) & Gram (-)e.g. Streptococci, Enterococci.
Resistant to most forms of -lactamase , includingthat produced by staphylococcus.
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iii. Metabolism:
not absorbed orally
Rapidly hydrolyzed by dipeptidase , so alwaysadministered with cilastatin , an inhibitor of dipeptidase
half life 1hr
70% recovered in urine as the active drug; renalinsufficiency
iv. Side effects:
patients allergic to the penicillins may demonstratecross-reactivity with imipenem.
nausea and vomiting.
Seizures have been reported with high doses.61
iv. Therapeutic Use:urinary tract and lower respiratory infections
--
effective against cephallosporin resistant bacteria
prudent to use imipenem for empirical treatmentof serious infections in hospitalized patients who haverecvd other -lactums
should NOT be used as monotherapy againstpseudomonas due to risk of resistance during therapy
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Meropenem (MERREM IV):
does not require cilastatintoxicity~imipenem
Therapeutics equivalent to Imipenem but less likelyto cause seizures
Ertapenem (INVANZ):
thus once daily dose
Gram (+) bacteria
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Aztreonam (AZACTAM)
A monocyclic -lactam ( a monobactam ).
i. Mechanism of action: Interacts with PBPs and induces theformation of long filamentous bacteria
ii. Spectrum: It more closely resembles the spectrum of theaminoglycosides. No activity against Gram (+) andanaerobic bacteria are resistant .
Aztreonam is resistant to the -lactamase producedby Gram (-) organisms.
iii. Side effects: well tolerated. Penicillin allergic patients donot exhibit cross-reactions with aztreonam .
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-Lactamase Inhibitors:
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Mechanism of action:
i. Inhibits -lactamase prevent the destruction of -lactun sensitive antibodies.
-.(the enzymes that degrade ceftazidine/cefotaxime).
However, inactive against -lactamaseproduced by treatment with IInd and IIIrdgeneration cephalosopirns.
iii. Poor antimicrobial activity, but binds irreversibly with -
ac amase rom o gram + or gram - ac soknown as “SUICIDE " inhibitor of -lactamase
iii. well absorbed; included in combination withamoxacillin (Augmentum) or with ticaricillin (TIMENTIN)
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Vancomycin
Complex tricyclic glycopeptide antibiotic
Mechanism : Inhibits cell wall polymerization by binding toterminal D-Ala-D-Ala terminus of incoming complexattached to carrier
P-P-C55MG MG
P-P-C55
MG( )n
+
MG( )n
67Vancomycin
Antibacterial activity:
Gram( –) are resistant because D-ala-D-ala (target) issubstituted with D-ala-D-ser or D-ala-D-lactate
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Absorption, Distribution and excretion:
Oral absorption poor; slow IV is preferred, NEVER IM(dose should be adjusted to maintainmdesirable troughlevels)
appears in body fluids and CSF
90% excreted by glomerular filtration;accumulates if renal function is im aired
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(can be cleared by hemodialysis)
Untoward Effects:Hypersensitive Reacns (macular skin rashes, anaphylaxis,Chills)
Rapid administration flushing, tachycardia,hypotension, erythematous or urticarial reacn
flushing “red-neck” or “red-man” syndrome bydirectly inducing toxicity in mast cells
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caution with the use of aminoglycosides
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Summary
Inhibits enzymes inducing cell wallVancomycinbacitracin *Penn/cephaCarbapenemsAztreonam
-lactamse inhibitorsAffects bact. growth bybinding PBP’s and/or -lactamase
Resistance is developedPBPs, efflux pumps, cell wall, location of -lacatamase
Common Side effect: Hypersensitivity
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Drugs inhibiting Protein Synthesis
Aminoglycosides and Macrolides
Teteracycline and Chloramphenicol
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Protein Synthesizing machinery
Ribosomebacteria has 50S and 30 S subunit which forms 70 S
ol some that slides on mRNA
mRNA
has A, P and E sites for binding with tRNA
forms template for protein synthesis
tRNA
attaches to 30s ribosomes
brings amino acids
attaches to A, P and E sites of ribosomes
Overview:
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PA
E
Transferase
E
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E PA
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Eukaryotes : 60S and 40 S subunit
Why antibiotic drugs do not inhibit mammalian proteinsynthesis??
Difference in ribosomal units is the basis of selectivity of antimicrobial drugs against bacteria
Aminoglycosides
Gentamicin composed of amino-sugars
AmikacinNetilmicinKanamycinStreptomycin
water-soluble (hydrophillic)highly polarized
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Kanamycin
2-deoxystreptamine
Kanamycin A,BTobramycinamikacin
streptidine
Streptomycin
Bacterial killing concentration dependent
Post-antibiotic effect persists after the serum conc <minimum inhibitory concentration (MIC)
Once daily dose of aminoglycosides is therefore efficacious
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AGAminoglycosides Entry
a. Diffusion through porins
Periplasmicspace
PG
PBP PBP
rate limiting requiresnegative inner membranepotential
electron-transport chain
b. Energy-Dependent Phase 1(EDP1)
c) Create fissure inducing bacterial damage (contrastfrom Tetra or Chloram) further enhancing AG uptake(EDP2 phase)
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Entry/effectiveness
pHCa 2+ /Mg2+
HyperosmolarityAnearobic conditions
(Abcess,hyperosmolaracidic urine)
Mechanism of Action:
a) binds to A site of 30s of ribosome subunit
i. interfere with the formation of the initiation complex
ii. induce misreading of the mRNA template
. remature term nat on o m trans at oniv. cause polysomes to break up into monosomes
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Mechanisms of Resistance
Intracellular penetration
Low affinity of
drug for bacterialribosomes
ribosomal binding
siteGrouptransferases
acetylation, phosphorylation,aden lation of OH or NH2 r rug nact vat on
Metabolites can also compete with AG
Cross-resistance by other aminoglycosidesi.e. gentamicin tobramicin, amikamicin, kanamycin and
netilmycin.
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AAC: acetylases; ANT: adenylase; APH, phosphorylase
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Poor oral or rectal administrationRapidly absorbed from IM
VI. Absorption
20
30q24h
q8hthreshold
Single dose preferred
hours4 8 12 16 20 240
0
10
asma concentrat ons a ter n ect on o . mg gto a hypothetical patient either as a single (q24h) oras three divided doses (q8h)
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Distribution
Do not cross BBB and do not achieve highdistribution in body fluids.
Excreted entirely via the kidneys.
Clearance faster from plasma as compared to
Excretion
tissues
Clearance similar in adults and children older than 6months; half life is prolonged in infants
e osage must e a uste or rena unct on.Should not be administered to patients in renalfailure
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V. Spectrum:
Aerobic Gram (-) bacilli.Kanamycin and Streptomycin: limited spectrum
.
ou no e use or n ec ons causeby Serratia or P.aeruginosa
Ist -line drug for pseudomonas.
May be given with penicillin in infectionscaused b stre tococci Listeria s .
Anaerobic or facultative anaerobic bacteriaare resistant
IX. Side Effects
Ototoxicity
(vestibular and auditory dysfunction)
Largely irreversible
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1
3
Cochlea, normally lined with hair cells that are destroyed by high concentrations of aminoglycosides. Aminoglycosides damage hair cells, especially in turn No. 1 and part of turn No. 2. Hairs are shed by the damaged cells to give loss of high-frequency response first(associated with turn No. 1) and low-frequency loss later (associated with turn to. 3).
1
23
98
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amikacin, kanamycin, neomycin
loss of high frequency tones
streptomycin and gentamicin
vestibular damage
loss of low frequency tones
oop ure cs urosem e an e acryn cacid) potentiate the ototoxicity
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Mechanism of aminoglycoside-induced outer hair cell death.
Rybak and Ramkumar, Kidney International (2007)
Renal arter
Nephrotoxicity
Renal vein
ureter
cortex Accumulates in epithelial cells of
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prox ma convu ate tu u ar ce s
oxidative stressDNA damage, lipid oxidation
apotosis and necrosis
tubuular dysfunction
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mild rise in serum creatinine
proteinuria, casts
-- aminopeptidase.
Nephrotoxic potencies : Neomycin > tobramicin
In severe cases, produces renal tubular necrosis
= gentam c n > streptomyc n
antagonize factor V resulting in bleeding
Muscular Blockade: Neuromuscular junction
1. Pre-synaptic terminal2. Sarcolemma
.4. Acetylcholine receptor5. Mitochondria
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muscle
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AG (curare-like)
Muscular blockade(tobra<genta<amika<kana< neomy)
Caution:Myasthenia gravispatients
calcium gluconate or neostigmine reverses this effect
VII. Therapeutic Use:
Streptomycinunusal mycobacterial infections in combinationwith other antimicrobial agents ( toxic )1000 mg/single or 500 mg double dose serumconcentration of 50-60 and 15-30 hg/ml
Pla ue
Tuberculosis
Bacterial endocarditis (strep + Penn G) replaced by(genta + PennG)
Tularemia (Strep or Genta)
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Gentamicin: Ist choice; low cost, and reliable activity agnst all Gram (-) bacilli including infections
caused by pseudomonas aeruginosaIT or IV: used rarely as cuases local inflammation
-lactum-insensitive UTI’s
Bacterial endocarditisSepsisTopical as in burn patients
Tobramycin (Tobrex) (~ Gentamicin)
AmikacinBroadest spectrum, absobed rapidly after IM injection;Peak plasma concentration ~20ug/ml after 7.5 mg/kgn ec onNosocomial Gram (-) infections
Netilmicin~Gentamicincan be used for Gentamicin resistant bacteria
frequently used in topical ointments;administered oral to clean the bowel prior tobowel surgery (not absorbed, eliminated in thefeces, very toxic if administered I.M.)
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Summary: Aminoglycosides
Most toxic; ototoxicit , rototoxicit , muscular blockade ,
Requires oxygen and changes in trasmembrane potentialto act on 30S ribosome
Use diminished as other Antibts became avl:
Limited spectrum Gram(-) Aerobesineffective in anerobeswill work in facultative bact in aerobe enviroment
conc in serum should be monitored
being reconsider due to resistance with Penn/CephMRSA?
Use for historical dis: Plague, TB