b- Lactam Antibiotics

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b- Lactam Antibiotics

Dr. Nawal Al-Musayeib Pharmacy College Pharmacogno
sy Dep.
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Farouk S. El-Feraly, Nawal M. Al-Musayeib, Iyad
S. Eqtefan, Fundamentals of Antibiotics
Discovery, Chemistry, Biology and .Indications
(BOOK )
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Objectives

• 1. Define Antibiotic and know the differences
  between Antimicrobial and antiinfective.
• 2- Introduce the History of peniciliin G
• 3. Chemistry of penicillin G and its effect on
  route of administration and spectrum.

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Antibiotics

• Defination
• a microbial product that can inhibit the
  growth or survival of one or more pathogens, at
  very low concentrations.

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What is the difference between the term
antibiotic and the term antimicrobial agent?
What is an anti-infective agent?
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Discovery of Penicillin

• Video
• http//videos.howstuffworks.com/science-channel/29
  783-100-greatest-discoveries-penicillin-video.htm

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History of Antibiotics

• Began around 1928
• Fungus prevented bacterial growth
• 1938, Britain was engaged in world war II
• interest in that discovery was revived

Sir Alexander Fleming
Flemmings agar Plate with S. aureus Growing
away from the Fungus
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• Produced by the fungus P. notatum
• It is potent and safe
• Disadvantage
• 1.
• 2.
• 3.
• 4.

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• The United State of Agriculture established
  Search Squads
• Mary Hunt found rotten melon bearing a fungus
  looked like P. notatum (P. chrysogenum)

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Commercial Production of Natural Antibiotics

• Fermentation
• There are Many strains of P. chrysogenum????
• Storage conditions??
• Protect from light
• Freeze to minus 196oC ???

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• In 1939, Dubos, suggested Soil as a rich source
  of antibiotic-producing microorganisms
• Gramicidin tyrocidine were produced from a
  soil sample containing the bacterium Bacillus
  brevis

The golden era of anti-biotics dicovery 1942-1950
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b-Lactam group
Although the b-lactam group has a nitrogen
atom, it is not basic, why?
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Classification of Penicillins
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Natural PenicillinsPenicillin G

• Any change in the penam system
  loss of activity
• Modification of side chain could result in
  increased stability, potency and spectrum

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Penicillin G Stability

• Penicillinases (S. aureus, Neisseria
  gonorrhoeae, H. influenzae E-coli)
• Unstable in H2O very unstable in acidic medium

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Penicillin G Stability
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Salts of Penicillin G

• Source Penicillium chrysogenum
• 1- Water soluble salts K, Na salts
• K salts
• Not used in case of renal impairment, why?
• Safer than Na-salts
• Used IV t1/2 is 1/2hour

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Salts of Penicillin G

• 2- Salts of limited water solubility
• Procaine--- sparingly soluble 1g/250 ml
• Benzathine ---Slightly soluble 1g/5 L
• Used IM
• Metabolism??
• Bicillin-C-R
• Bicillin-L-A

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Antimicrobial Spectrum and Indications of
Penicillin G

• S. aureaus
• Resistant
• Streptococcus viridans-
• Dental caries
• Subacute bacterial endocarditis
• Prophylactic Benzathine penicillin

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• Streptococcus pneumoniae
• Pneumoniae
• Meningitis
• Pen G
• Resistant Ceftriaxone or cefotaxime

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• Streptococcus pyogenes
• Tonsillitis
• Sore throat
• Scrlet fever
• Pen G
• Rheumatic fever
• Benzathine Pen G once month

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• Enterococcus faecalis
• Meningitis
• Endocarditis
• Penicillin G or Vancomycin with gentamicin
• Urinary tract infection
• Nitrofurantoin

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• Bacillus anthracis anthrax
• Ciprofloxacin or doxycycline with or witout
  clindamycin and rifampin
• Gram ve
• N. meningitidis
• Pen G

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• N. gonorrheae
• Resistant
• Plasmide
• Chromosomal
• Single injection 125mg ceftrixone
• Treponema pallidum
• Bicillin L-A

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Safety of Penicillin G

• Safe
• Fatal if pt. allergic
• Large doses might induce seizures

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Semisynthetic Penicillins

• Disadvantage of Pen.G ?
• Source of 6-aminopenicillanic acid

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PhenoxymethylpenicillinPenicillin V
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PhenoxymethylpenicillinPenicillin V

• Used for tx of
• Mild infections Tonsillitis and dentistry
• Prophylaxis
• Subacute bacterial endocarditis
• Rheumatic fever
• Sickle cell babies from pneumococcal infections

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Penicillinase-Resistant Penicillins
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Methicillin

• Parentral, semisynthetic
• Antistaphylococcal
• For treatment of infections caused by
  penicillinase-producing staphylocci
• Excreted renally
• S.E Interstitial nephritis

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Oxacillin Cloxacillin

• Antistaphylococcal
• D.O.C
• Acid stable, why?
• Excreted renally and hepatically
• Adv. Of Cloxacillin over Oxacillin

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Dicloxacillin

• Difference bet. Cloxacillin dicloxacillin?
• Structure
• Dose
• Spectrum

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Flucloxacillin

• S.E Cholestatic hepatitis
• Absroption
• Dose

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Cell wall of gram positive and gram negative org.
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Broad Spectrum PenicillinsAmpicillin
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Ampicillin

• Proteus mirabilis
• Gardnerella vaginalis
• Listeria monocytogenes

• E. coli
• Hemophilus influenzae
• Salamonella typhi
• Shigella

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Ampicillin

• Inactive against
• Pseudomonas aeruginosa
• Klebsiella pneumoniae

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Ampicillin

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Ampicillin S. E.

• Diarrhea
• Pseudomembranous colitis
• Ampicillin rash
• Reduction of the efficacy of oral contraceptive
• Decrease absorption of b-blockers

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Bacampicillin

• Ester pro-drug of ampicillin

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Amoxicillin

• Take on a full stomach
• Less incidence of diarrhea, why?
• Spectrum

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Clavulanic acid
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Carbenicillin Ticarcillin
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Carbenicillin Ticarcillin

• Carbenicillin
• P. aeruginosa
• MIC 50 mg/ml ---- 50 g daily
• Na-load
• Polarity???
• IV

• Ticarcillin
• Increase polarity
• MIC 20 mg/ml
• IV

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• - Resistant of P. aeruginosa
• TimentinR (Ticarcillin Clavulanic a)

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Megaspectrum/ Ureidopenicillins

• Importance of Transpeptidase
• NHCONH
• Piperacillin 4mg/ml
• Azlocillin 8mg/ml
• Mezlocillin 32mg/ml

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• K. pneumoniae
• Ampicillin and Ticarcillin spectrum
• Resistant E. coli
• NOSOCOMIAL INF. ONLY
• Parentral
• With Tazobactam ------Zosyn

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Cephalosporines
An Italian scientist, Joseph Brotzu of Cagliari
University living in Cagliari the capital of the
island of Sardinia
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if a fungus could be found in the sewer
system, Where Gram negative bacteria live
--------- fungus produce an antibiotic with a
high level of potency against Gram negative
bacteria.
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Preparation of 7-aminocephalosporanic acid
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Cephalosporines Common properties

• All
• were used Pen.ase producisng S. aureus
• K. Pneumoniae
• less allergenic than Pen.
• Not active Enterococci and L. monocytogenes
• 3rd 4th
• K . Pneumoniae P. aeruginosa

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1st generation Cephalosporines

• Used in community acquired inf. ?
• Not used in meningitis ?
• Not used in gonnorrhea
• Inactive H.Influenzae P. aeruginosa

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• - Strept. inf.
• Pneumonia
• GUTI
• 4 x /day???
• IM ---painful
• IV-- thrombophlebitis

Cephalothin
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• Metabolism
• Tetrazole effect????
• IV IM
• Indication
• pre-operative prophylaxis

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Indication Cephapirin

• Cyclohexadiene gp.???
• P.O Parentral

1-2 x / day ? Dpending on pt kidney function
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Second Generation Cephalosporines

• Community acquired inf. ?
• Not meningitis ?
• Not gonnorrhea
• Inactive H.Influenzae P. aeruginosa

• - Some with Cephalsporinase- resistant g.p.
• oMe, C-ON, methyl tetrazole
• For Community acquired and nosocomial inf.
• Active H. Influenzae and Moraxella catarrhalis
• Not cross BBB except cefuroxime
• inactive P. aeruginosa

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Cefoxitin

• Carbamate ester
• Anaerobes Bacteroides fragillis
  (Peritonitis, abscesses in internal body organs)
• Metronidazole DOC
• 2nd C Cefoxitin ( pregnancy)
• Route??

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Cefamandole Nafate

• OOCH ??? Na carbonate
• B. fragilis ( compare with Cefoxitin)
• Peptococci, peptostreptococci and clostridia
• Route

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Cefotetan and Cefmetazole
B. fragilis ( compare with Cefoxitin)
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Cefuroxime

• H. Influenzae Meningitis ???, Otitis media,
  URTI

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3 X/ day
2 X / day

• PO ??
• Absor. ??
• Retintion in body tissue and Duration of action

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2-3 x/ day
1 x/ day
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3rd Generation Cephalsporines

• Has 2-aminothiazole gp. ??
• Mostly active gm ve
• some P. aeruginosa
• Cephalosprinase resistant ???
• V. Potent single doses
• Parentral form tx meningitis

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Ceftriaxone Tx gonorrhea in a single dose of
125 mg???? long acting, MIC 0.02mg/ml Cefotaxime
has t1/2 of 1.5 hr, prescribed 2x/day??? .
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Moxalactam

• -Functional gp. Rules.
• Hypoprothrominemia
• With Vit. K
• Parentral

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• Cefotaxime - Parentral
• - Not P.aeurginosa
• - metabolism
• Ceftriaxone
• - LDA 8 hr ???
• -Pseudocholelithiasis ???
• Displace bilirubin from plasma protein
• Best Gonnorhea??
• Otitis media??

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T1/2 1.7
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Ceftazidime
Aztreonam Ceptaz
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Cefixime, Cepodoxime-proxetil, Ceftibuten,
Cefditoren pivoxil and Cefdinir

• -H. Influenzae and M. catarrahlis
• Compete with
• Augmentin, cefaclor, loracarbef,
• ceprozil, cefuroxime-axetil

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Cefdinir Cefditoren pivoxil