Penicillin Drugs

7/31/2019 Penicillin Drugs

1/30

Category Drug Mechanism of Action Mechanism of Resistance Pharmacokinetics UsePenicillin *Bactericidal

*Interfere with the synthesisof the bacterial cell wallpeptidoglycan*Transpeptidase is a bacterialenzyme which cross links thepeptidoglycan chains to formrigid cell walls*Bind to and inactivatetranspeptidase (penicillin-binding proteins) which resultin loss of cell rigidity and celldeath*Inhibits cross linking of peptidoglycans

1. Penicillinase ( -lactamase) breaks thebetalactam ringex. Staph. Aureus

2. Alteration of the penicillin-binding proteinex. Staph. Aureus; MRSA;Penicillin resistantpneumococci

3. Reduced permeability inGram (-) cell membranesex. Pseudomonas

Penicillin G(parenteral)

*Acid labile, given i.m. or i.v.*Repository Penicillin G (long-acting): Procaine &Benzathine Penicillin G

*Penetrates the CSF to asignificant extent only duringinflammation

*Eliminated via tubularsecretion-Probenacid competitivelyinhibits the renal tubularsecretion of Penicillin ; thus itincreases the concentrationand prolongs its activity

*Gram (+)

*DOC: Syphillis (TreponemaPallidum)

*Streptococcal,meningococcal

*Strains of pneumococci,Staph. Aureus & Neisseriagonorrheae are resistant

Prophylaxis:Benzathine Penicillin -Rheumatic feverBenzathine/Procaine -Gonorrhea/Syphillis in

Penicillin V (oral)

Narrow Spectrum(Penicillinasesusceptible)

-Streptococci-Pneumococci-Meningococci-TreponemaPallidum


2/30

Category Drug Mechanism of Action Mechanism of Resistance Pharmacokinetics UseMethicillin

Naficillin

Oxacillin

Ampicillin

Amoxicillin

Broad Spectrum(Penicillinasesusceptible)

-Gram + cocci

-Haemophillusinfluenza-ListeriaMonocytogenes-H. Pylori

*Gram (+)*Gram (-): H. Influenza;Listeria Monocytogenes; H.Pylori; E. Coli; ProteusMirabilis

Amoxicillin :-endocarditis before majorprocedures-H. Pylori infections (pepticulcers)

Prophylaxis: Amoxicillin - bacterialendocarditis in patients with

prosthetic heart valves,cyanotic heart disease orwho are planning toundergo surgical procedures

*Drug Combo

Narrow Spectrum(Penicillinaseresistant)

-Staphylococci(except MRSA)

*Staph. Aureus (exceptMRSA)

-Penicillinase producing anti-staphylococcal infections

*Resistant to inactivation bybetalactamase

* MRSA & MRSE (Staph.Epidermidis) are resistant


3/30

Ticarcillin

Piperacillin

Azlocillin

ExtendedSpectrum orAntipseudomonal(Penicillinasesusceptible)

-Gram - rods-PsuedomonasAeruginosa

*Gram (-) rodsPseudomonas AeruginosaEnterobacter infections

*Psuedomonas infection(which is common inpatients with Cystic Fibrosis)

*Drug Combo


4/30

Adverse Effects*Relatively safe

*Hypersensitivity-5-7% incidence-severity varies fromurticarial skin rashes toacute anaphylaxis

*Cross-sensitivitybetween individualpenicillins possible


5/30

Adverse Effects*Intersitial nephritis

*Maculopapular rash*Suprainfection:Diarrhea -pseudomembranousenterocolitis (C.Difficile)


6/30

Category Drug Mechanism of Action Mechanism of Resistance Pharmacokinetics Use Adverse EffectsCephalosporins *Bactericidal

*Interfere with thesynthesis of the bacterialcell wall peptidoglycan*Transpeptidase is abacterial enzyme which

cross links thepeptidoglycan chains toform rigid cell walls*Bind to and inactivatetranspeptidase (penicillin-binding proteins) whichresult in loss of cell rigidityand cell death*Inhibits cross linking of peptidoglycans

1. Penicillinase ( -lactamase)breaks the betalactam ringex. Staph. Aureus

2. Alteration of the penicillin-binding protein

ex. Staph. Aureus; MRSA;Penicillin resistantpneumococci

3. Reduced permeability inGram (-) cell membranesex. Pseudomonas

* Hypersensitivity reaction(rashes, fever)

*Cross-hypersensitivitybetween cephalosporinscompletely possible

*Cross-reaction betweenpenicillins is less likely (5-10%) caution still needed

*History of anaphylaxis topenicillin is acontraindication forcephalosporins

*Suprainfection: Diarrhea -pseudomembranousenterocolitis (C. Difficile)

*If given withaminoglycosides - increasesthe chances of nephrotoxicity

Cephalexin(oral)

Cefazolin(parenteral)

Surgicalprophylaxis

1st Generation

Gram + cocci

PEcKProteusE. ColiKlebsiella


7/30

Category Drug Mechanism of Action Mechanism of Resistance Pharmacokinetics Use Adverse EffectsCefoxitin

Cefotetan Contains amethylthiotetrazole group(MTT group) - may causeDisulfiram like reactionswith ethanol

Cefaclor Cefamandole Contains a

methylthiotetrazole group(MTT group) - may causeDisulfiram like reactionswith ethanol

Cefuroxime Enters CSF, but theothers do not

Cefoperazone Contains amethylthiotetrazole group

(MTT group) - may causeDisulfiram like reactionswith ethanol

CeftazidimeCeftriaxone(parenteral)

*DOC: GonorrheaSalmonella Typhi*Meningitis

Cefixime(oral)

*DOC: Gonorrhea

Cefotaxime *Meningitis

2nd Generation

Gram - bacteria

HEN PEcKSH. InfluenzaE. ColiNeisserea

ProteusEnterobacterKlebsiellaSerratia

BacteriodesFragillis

H. Influenza

Gram - bacteria

Good penetration into BBB(except Cefoperazone &Cefixime )

3rd Generation

Pseudomonas


8/30

Cefipime(iv)Cefpirome

4th Generation

Resistant to inactivation by lactamases

Excellent penetration intoGram - bacteria

Wider spectrum than 3rd

generation (both Gram + &Gram -)


9/30


10/30

Category Drug Mechanism of Action Mechanism of Resistance Pharmacokinetics Use Adverse Effects Notes

Carapenems Imipenem *GI distress*Skin rash*In high doses:Seizures

Imipenem is rapidlyinactivated by renaldehydropeptidase I

*Imipenem is combinedwith Cilastatin to preventhydrolysis by enzymes inthe renal brush border

*Cilastatin is an inhibitorof renaldehydropeptidase; thus itincreases the plasma 1/2life of Imipenem

Meropenem

Ertapenem

Broad spectrum:Gram + & Gram -bacteria,anaerobes

BacteriodesFragilis; Clostridia

*Bactericidal*Interfere with thesynthesis of thebacterial cell wallpeptidoglycan*Transpeptidase is abacterial enzymewhich cross links thepeptidoglycan chainsto form rigid cell walls*Bind to andinactivatetranspeptidase(penicillin-bindingproteins) which resultin loss of cell rigidity

and cell death*Inhibits cross linkingof peptidoglycans


11/30

Category Drug Mechanism of Action Mechanism of Resistance Pharmacokinetics Use Adverse Effects

Vancomycin *Bactericidal*Glycoprotein

*Acts by binding toD-Ala-D-Ala terminal of thenascent peptidoglycan

pentapeptide side chain

*This leads to inhibition of transglycosilation and in turnprevents the peptidoglycanchain elongation

1. Occurs in strains of enterococci and staphylococci(VRE & VRSA)

2. Resistance involves adecreased affinity of

Vancomycin for the bindingsite; this is because of thereplacement of the terminalD-Ala by D-Lactate

*ONLY Gram +

*MRSA, Enterococci,Clostridium Difficile

*MRSA infections givenby slow IV infusion

*Anti-biotic associatedEnterocolitis (C. Difficile) -orally

*Red Man Syndrome -because of release of histamine (flushing,redness of face,hypotension) - can beprevented with anti-

histamines

*Nephrotoxicity*Ototoxicity


12/30

Category Drug Mechanism of Action Mechanism of Resistance Pharmacokinetics Use Adverse EffectsAminoglycosides *Bactericidal

*Binds to 30S ribosomalsubunit and inhibitsbacterial proteinsynthesis

1. Interfere with theinitiation complex of peptide formation byblocking the associationof 50S subunit with mRNA30S

2. Induce misreading of mRNA, which causesincorporation of wrongamino acids into thepeptide, resulting in anonfunctional toxicprotein

1. Production of transferaseenzyme by the bacteriathat inactivates theaminoglycoside

2. Impaired cell penetrationof aminoglycoside into thecell~Streptococci andenterococci are resistant toaminoglycosides due todecreased penetration

3. The receptor protein onthe 30S ribosomal subunitmay be deleted or alteredas a result of a mutation

~Polar compounds

~Not effectivelyabsorbed by GI(always givenparenterally - iv, im)

~Limited tissuepenetration

~Most cleared bykidney (monitor levelsin patients with renalfailure/elderly)

~Attain highconcentrations in oticperilymph and renalcortical tissue

*Ototoxicity~Cochlear damage:results in deafness(irreversible)~Vestibular damage:headache, nausea,vomiting, dizziness,nystagmus, vertigo,ataxia (reversible)~Toxicity can beenhanced by loopdiuretics

*Nephrotoxicity~Proteinuria,hypokalemia, acidosis~Acute tubularnecrosis, enhancedby Vancomycin,Cyclosporin,

Amphotericin,

*ONLY Gram -aerobic bacilli,but lack activityagainstanaerobes

Synergisticactivity with -lactam drugs~Enterococcalinfections (AG +PenicllinG/Ampicillin)

~P. Aeurginosainfections (AG +extendedspectrumpenicillin/cephalosporins)


13/30


14/30

Amikacin Used topically -burn wounds

Tobramycin Used topically -burn wounds

Most nephrotoxic

Streptomycin ~Tuberculosis~Tularemia~Bubonic Plague

Most vestibulotoxic

KanamycinNetilmicinaa

N


15/30

Notes1. Concentration-Dependent Killing= increasingconcentrations killan increasingproportion of bacteria at a morerapid rate

2. Post-antibioticEffect = theantibacterialactivity persistsbeyond the timeduring whichmeasurable drug ispresent(1x daily dosing)


16/30

C D M h i f A i M h i f R i Ph ki i U


17/30

Category Drug Mechanism of Action Mechanism of Resistance Pharmacokinetics UseTetracyclines *Binds to the 30S subunit

*Interferes with theattachment of aminoacyltRNA to the acceptor site

*This prevents additionof amino acids to thegrowing peptide

1. Development of effluxpumps

2. Decreased activity of theuptake systems

~Chelating propertybinds Ca2+, Mg2+, Fe2+ -which decreases theirabsorption*Should not be given withmilk products, antacids~Binds to tissues like teeth,bones which areundergoing calcification~Can cross placenta andconcentrate in fetal bones& teeth

~Elimination by kidney formost - dose in renaldysfunction

*Contraindicated in~Pregnancy~Children~Renal insufficiency

~Broad spectrumantibiotics

Gram + : Clostridia, Listeria,Coryneacterium, B.Anthracis

Gram - : Y. Pestis, H. Pylori

Spirochetes : T. Pallidum,Borrelia

Atypical Bacteria :Rickettsia, Chlamydia,Mycoplasma - highlysensitive

Protozoa : E. Histolytica,Plasmodium Falciparum

Category Drug Mechanism of Action Mechanism of Resistance Pharmacokinetics Use


18/30

Adverse Effects


19/30

Adverse Effects*Teeth : permanent browndiscoloration & ill-formedteeth

*Stunted bone growth

*Photosensitvity onexposure to UV light

*Superinfections: Diarrhea;Candida

*Epigastric pain, abdominaldistention, nausea,vomiting

*Hepatic injury

*Nephrotoxicity - exceptDoxycycline

*Fanconi's Syndrome: aform of renal tubularacidosis is attributed to useof outdated tetracyclines

Adverse Effects

Secondary Uses:


20/30

Secondary Uses:~Alternative drug topenicillin in Syphillis

~H. Pylori associatedpeptic ulcers

~Acne

~Leptospirosis

Photosensitivity

Photosensitivity


21/30

Category Drug Mechanism of Action Mechanism of Resistance Pharmacokinetics Use

Chloramphenicol *Bacteriostatic

*Binds to 50S ribosomalsubunit

*Inhibits transpeptidation and

transfer of peptide chain fromsite P to acceptor site

*Inhibits formation of peptidebond by inhibitingpeptidyltransferase

Inactivation byacetyltransferase

Broad spectrumGram - & Anaerobes

Highly active: SalmonellaH. InfluenzaN. Meningitis

Anaerobic infections:Bacteriodes Fragilis

Less active on Gram + cocci,Spirochetes & Rickettsia

Enteric Fever or Salmnellosis

(alternative Ciprofloxacin,Ceftriaxone/Cefotaxime)


22/30

Adverse Effects

Highly toxicLess used systemically

Superinfections :Candidiasis

Bone MarrowSuppression : dosedependent causingaplastic anemia

*Gray Baby Syndrom :occurs in neonates - dueto deficient hepaticglucuronsyltransferase -lack of effective

glucuronic acidconjugation degradationof Chloramphenicol ~Vomiting, abdominaldistention, cyanosis,refusal to feed, CVcollapse, death


23/30


24/30

Category Drug Mechanism of Action Mechanism of Resistance Pharmacokinetics UseRoxithromycin

Clarithromycin ~Chlamydia~Mycobacterium Avium~Toxoplasma Gondii~H. Pylori

*H. Pylori treatment inrecurrent peptic ulcers*Upper & lower respiratorytract infections, skininfections

*Atypical pneumonia*MAC infection in AIDSpatients*Leprosy

Azithromycin ~DOC: Chlamydia~M. Avium~H. Influenza~Neisseria

~Acid stable~Long 1/2 life = 2-4days~High concentrationinside macrophages &fibroblasts

*Legionnaire's pneumonia*Chlamydia infection of urogenital tract, pneumonia,trachoma*MAC infection in AIDSpatients

Telithromycin


25/30

Category Drug Mechanism of Action Mechanism of Resistance Pharmacokinetics UseLincosamides *Binds reversibly to the

50S subunit

*Protein synthesis isinhibited because of aminoacyl translocationreactions and theformation of initiationcomplexes are blocked

*Inhibitspeptidyltransferase

*Inhibits translocation of peptidyl tRNA

*Bacteriodes Fragilis*Pneumocystis Jiroveci*Toxoplasma Gondii

Clindamycin *Anaerobic infections:

Bacteriodes Fragilis*Prophylaxis of endocarditisin valvular disease patientswho are allergic toPenicillins*Pneumocystis Jirovecipenumonia


26/30


27/30

Adverse Effects

*Diarrhea (major causefor discontinuation)*GI distress: as itstimulates motillinreceptors*Rashes, fever*Cholestatsis, jaundicewith ErythromycinEstolate

Drug Interactions*It is a CYP450 enzymeinhibitor withTerfenadine/Astemizole/ Cisapride~can cause prolongationof QT interval, ventriculararrythimia


28/30

Ad Eff t


29/30

Adverse Effects

1st known drug to causepseudomembranousenterocolitis

Adverse Effects


30/30

Adverse Effects*Thrombocytopenia

Adverse Effects*Arthralgia-Myalgiasyndrome*Fever

*It is a CYP450 enzymeinhibitor

Documents

Penicillin Drugs