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10 Beta Lactam Antibiotics

Beta Lactam Antibiotics

§ These are widely used antibiotics
§ MOA: Inhibits bacterial cell wall synthesis
§ 5 different groups of antibiotics - Penicillins,
Cephalosporins, Monobactams, Carbapenems, Carbacephems
§ All of them have a β- lactam ring, as common feature in
their chemical structure
§ Spectrum ranges from an extremely narrow spectrum to an
extended spectrum (cephalosporins) to a very wide spectrum
(carbapenems)

Penicillins
§ Penicillin was initially obtained from the fungus Penicillium
notatum, but the high yielding source is Penicillium
chrysogenum
§ Penicillin nucleus consists of fused thiazolidine & beta-
lactam rings to which side chains are attached through an
amide linkage
§ Penicillin G having a benzyl ring side chain (at ‘R’) à
original penicillin
§ Penicillium chrysogenum contains large amounts of Fungal
amidases
§ Fungal amidases breaks the penicillin at position ‘6’ & gives
à 6-amino penicillanic acid (6-APA) à which is active moiety
§ Other side chains at R à resulting in different semi synthetic
penicillins with unique antibacterial activities & different
p’kinetic profiles
§ At carboxyl group (-COOH) à salt formation with Na+ &
K+ à these salts are more stable than parent
§ Sod Pn G is highly water soluble, it is stable in dry state
§ 1 U of crystalline Sod Benzyl Pn = 0.6µg of std [1 MU = 0.6
gm ]
Mechanism of Action
§ All β-lactams à interfere the synthesis of bacterial cell wall
§ Bacterial Cell wall is made up with Peptidoglycan
§ Peptidoglycan layer envelops the cell à doesn’t allow
bacteria to swell & prevents its death due to lysis
§ Peptidoglycan is made up with parallel glycan chains
§ Glycan chain consists of the repeating units of two
aminosugars: UDP-N-acetyl muramic acid & UDP-N-acetyl
glucosamine
§ The pentapeptide side chain is linked to N-acetyl muramic
acid à these peptide chains are cross linked to other peptide
chains by a pentaglycine bridge (L-Lysine of one peptide
chain to D-Alanine of another peptide chain) à this cross
bridging between the peptidoglycan strands provides strength
to the bacterial cell wall ß this cross-bridging is known as
“Transpeptidation”
§ Transpeptidation process is catalysed by Penicillin
Binding Proteins
§ PBPs are transmembrane surface enzymes present in
bacteria à different organisms constitutes different PBP à
sensitivity of beta lactam antibiotics
§ Stereochemical conformation of Penicillin is similar to D-
alanyl-D-alanine terminal à penicillin compete with PBPs and
inhibit transpeptidation process à leads to formation of
imperfect cell wall à leads to drive of outside fluid to inside
the cell à swell & Burst
§ Bursting of cell wall is also done by the activation of the
autolysing enzyme called “Murein hydrolase or Autolysins
§ Rapid cell wall synthesis occurs when the organisms are
actively multiplying à beta-lactam antibiotics are more lethal
in this phase
§ peptidoglycan cell wall is unique to bacteria à D-alanine is
not synthesised by higher animals à penicillin is practically
non-toxic to man
§ Penicillin action is greater in Gm+ve than Gm –ve bacteria
§ Gm+ve à a thick layer of peptidoglycan & teichoic acid ß
easily accessible to beta-lactam antibiotics
§ Gm–ve à have two membranes – cytoplasmic, outer
membrane & a thin layer of peptidoglycan sand witched
between them
§ Outer membrane à lipopolysaccharides with narrow porin
channels ß barrier for beta-lactam antibiotics
§ Ampicillin, Amoxycillin à pass through porin channels à
break the peptidoglycan à they show activity against Gm-ve
bacteria also
Classification
1. Natural Penicillin: Penicillin G
2. Acid resistant alternative to Pn G: Penicillin V
3. Penicillinase reistant penicillins: Methicillin,
Oxacillin, Cloxacillin
4. Extended Spectrum Penicillins
· Amino Penicillins: Ampicillin,
Bacampacillin, Amoxycillin
· Carboxy penicillins: Carbenicillin,
Carfecillin, Ticarcillin
· Ureido Penicillins: Piperacillin, Mezlocillin
· Mecillinan: Amdinocillin

[OR]
Classification
§ Narrow Spectrum Penicillins
· β-Lactamase Sensitive
Ø Acid Stable: Penicillin V (oral)
Ø Acid Labile: PnG, Procaine PnG, Benzathine
PnG
· β-Lactamase Resistant
Ø Acid Stable: Cloxacillin, Dicloxacillin,
Flucloxacillin
Ø Acid Labile: Methicillin, Nafcillin
§ Extended Spectrum Penicillins
· β-Lactamase Sensitive
Ø Acid Stable: Ampicillin, Bacampicillin,
Talampicillin, Amoxycillin
Ø Acid Labile: Carbenicillin, Ticarcillin,
Piperacillin, Mezlocillin, Azlocillin
Penicillin G
§ Narrow spectrum, activity is limited to Gm +ve
§ Resistance: many bacteria are inherently insensitive to PnG
à because target enzymes & PBPs are located deeper under
lipoprotein barrier
§ P’Kinetics: PnG is acid labile (destroyed by gastric acid)
§ A larger fraction is absorbed in infants & elderly because of
lower gastric acidity
§ It is distributed mainly extracellularly à reaches most body
fluids (not in serous & CSF)
§ 60% plasma protein bound, T1/2 – 30 min
§ It is little metabolised because of rapid excretion
§ Tubular secretion of PnG can be blocked by Probenecid à
higher & longer lasting plasma conc are achieved [Probenecid
increases the excretion of Uric acid]
Preparations
§ Sod Penicillin G (Crystalline penicillin) à available as
powder
§ Procaine Penicillin G (Aqueous suspension) à acts for 1-2
days
§ Benzathine Penicillin G à acts upto 4 weeks
§ Benzathine Penicillin G à they are available as depot i.m.
injections à they have delayed but a sustained absorption &
prolonged half life
§ Single IM dose of Benzathine Penicillinà provide plasma
levels which are sufficient to protect against β-haemolytic
streptococcal infection for 3 weeks
§ Depot formation of Benzathine Penicillin G is more suitable
for rheumatic fever à as it prevents colonization of β-
haemolytic streptococci
Rational for the use of Pn G in meningitis
§ For acute streptococcal meningitis à goal is rapid attainment
of high CSF concentration of an antibiotic
§ Penicillin G à has better permeability to provide better
concentrations in CSF if meningis are inflamed
§ IV Penicillin G is a preferred therapy for meningitis caused
by Streptococcus Pneumoniae
Uses
§ Streptococcal infections: Pharyngitis, Otitis Media, Scarlet
fever, Rheumatic fever, SABE
§ Pneumococcal infections: Penumonia & Meningitis à if the
organisms are sensitive
§ Meningococcal infections
§ Gonorrhoea: Pn G is resistant
§ Syphilis: Early & latent syphilis
· [ Syphilis à caused by Spirochetes like Treponema
pallidum à are highly sensitive to penicillins
· Benzathine penicillin G 2.4 MU IM once in week for
3 weeks
· Alternatively à 1.2 MU of Procaine Penicillin G IM
every day for 10 days ]
§ Diptheria: Procaine penicillin 1-2 MU daily/10 days,
Tetanus & Gas gangrene
§ Anthrax, Actinomycosis, Trench mouth, Ratbite fever
Adverse Effects
§ Penicillin G is one of the most non-toxic antibiotics up to
60gm/day
§ Local irritancy & direct toxicity à pain at i.m. injection site,
nausea on oral ingestion, thrombophlebtis of injected vein
§ Toxicity to the brain à mental confusion, muscular
twitchings, convulsions, coma ß when > 20 MU injected i.v.
in renal insufficiency
§ Procaine Penicillin à IV injection à CNS stimulation,
hallucinations, convulsions
§ Hypersensitivity à 1-10% patients à rash, itching, urticaria,
fever, wheezing, angioneurotic edema, serum sickness,
exfoliative dermatitis à anaphylaxis is rare
§ More with Procaine Penicillin (Procaine is itself allergic)
§ Local preparations are banned except eye ointment in case
of gonoccoccal ophthalmia
Penicillin V
§ It is used only for streptococcal pharyngitis, sinusitis, otitis
media, prophylaxis of rheumatic fever, less serious
pneumococcal infections & trench mouth
Extended Spectrum Penicillins
Ampicillin - Uses
§ It is used in UTI, RTI including bronchitis, sinusitis, otitis
media
§ Meningitis à it is usually combined with 3rd generation
Cephalosporin
§ Gonorrhoea à one of the first line drugs for Oral treatment of
non-penicillinase producing gonococcal infections
§ 3.5g Ampicillin + 1g Probenecid for Urethritis
§ Cholecytitis: good because high conc are attained in bile
§ Septicaemias & Mixed functions: given along with
gentamicin or newer Cephalosporins
Ampicillin – A/Es
§ Diarrhea is frequent after oral administration à it is
incompletely absorbed à the unabsorbed drug irritates the
lower intestines as well as causes marked alterations of
bacterial flora
§ It produces rashes in AIDs, EPSTEIN-BARR virus
infections or lymphatic leukemia
§ Concurrent administration with Allopurinol à increases
rashes
§ Probenecid retards excretions of ampicillin
Amoxicillin
§ Similar to Ampicillin except
· Oral absorption is better, food doesn’t interfere, higher
& more sustained blood levels are produced
· Incidence of Diarrhoea
· It is less active against Shigella & H.Influenzae

§ Ampicillin & Amoxycillin have adequate Oral

bioavailability
§ Ingestion of food à decreases the bioavailability of
ampicillin but not amoxycillin à oral ampicillin should be
taken 1hr prior or after the meals
§ Ampicillin achieves therapeutic concentrations in CSF
during inflammatory conditions but not Amoxycillin à
Amoxycillin is not suitable for meningitis therapy
§ Their route of excretion is through Kidney
§ Bacampicillin & Talampicillin are prodrugs of Ampicillin à
these are completely absorbed from GIT à higher plasma
levels are attained
§ Bacampicillin, Talampicillin, Amoxycillin à disturb the
intestinal flora much lesser extent than Ampicillin à Diarrhoea
is Less with them and more with Ampicillin
§ Carbenicillin, Ticarcillin, Piperacillin, Mezlocillin,
Azlocillin à parenteral anibiotics available as Sodium salts à
should be cautiously given to CHF patients à renal elimination
à dose adjustment in renal failure
§ Ampicillin group of antibiotics à hydrophilic à enhanced
ability to penetrate through porin channels of Gm –ve à not
active against Pseudomonas aeruginosa as these lacks in
porin channels
§ Ampicillin Group is active against à Bordetella pertusis
(Whooping cough), Haemophilus influenzae (pneumonia,
otitis media, sinusitis), E.Coli (UTI), Salmonella typhi,
Proteus mirabilis (UTI), Shigella
§ Not active à Pseudomonas, Klebsiella, Serratia, Citrobacter,
proteus
§ Ampicillin can be used in Bacillary dysentry due to Shigella
(Amoxycillin is not useful)
§ Amoxycillin is used in Multidrug regimen of eradication of
Helicobacter pylori in duodenal & gastric ulcers
§ Ampiciilin & Amoxycillin are very effective against
Streptococcus viridans & enterococci (SABE), pneumococci
§ SABE à Ampicillin 2g IV every 6 hours
Resistance to Penicillins
1. Inactivation of β-lactam ring by β-lactamase:
§ Over 300 β-lactamases have been found
§ Some bacteria have chromosomal genes for producing β-
lactamases
§ To overcome this β-lactamase inhibitors are developed
which inhibit this enzyme and prevents the degradation of β-
lactams
2. Modifications of Penicillin Binding Proteins: Mutant
PBPs produced by bacteria à low affinity to penicillins &
other β-lactams
3. Reduction of penicillin permeability to reach PBPs:
outer membrane of Gm-ve hinders the entry of penicillins by
blocking porinsà helps bacteria to develop resistance
4. Activation of antibiotic efflux mechanisms:
§ Some bacteria produce an efflux pump à that ejects
antibiotic from the periplasm back across the outer membrane
before it can be bind to PBPs
β-lactamase Inhibitors
§ Clavulanic acid (derived from Streptomyces clavigerus),
Sulbactam (semisynthetic), Tazobactam (Analogue of
Sulbactam)
§ Only Clavulanic acid is Orally absorbed & others are given
parenterally
§ These agents resembles β-lactam antibiotics in structure but
don’t posses any antimicrobial action
§ According to their common pharmacokinetic features à
Clavulanic acid combined with Amoxycillin, Sulbactam with
Ampicillin, Tazobactam with Piperacillin à they are available
as FDCs à these combinations enhance the microbial activity
of antibiotics against β-lactamase producing organisms
§ These combinations are not much useful in non- β-lactamase
producing organisms because β-lactamase inhibitor doesn’t
posses any antibiotic activity
Coamoxiclav
§ Amoxicillin 250mg + Clavulanic acid 125 mg Tab
§ Clavulanic has β-lactam ring but no antibacterial activity à it
inhibits a wide variety of β-lactamases except class-I
cephalosporinase
§ Clavulanic acid is a progressive inhibitor à binding with β-
lactamases is reversible initially à becomes covalent later à
inhibition increases with time
§ It permeats the outer layer of cell wall of gm-ve bacteria à
inhibits periplasmically located β-lactamase
§ It is excretion is not affected by probenecid
Available FDCs
§ Amoxycillin 250 mg + Clavulanic acid 125 mg Tablets
§ Ampicillin 1g + Sulbactam 0.5 g IV or IM injection
§ Piperacillin 2g + Tazobactam 0.25 g IV or IM injection
§ A/Es – are rare except GI Intolerance, stomatitis, rashes
Adverse Effects of Penicillins
1. Hypersenstivity Reactions
§ β-lactam is hydrolysed by gastric acid à gives a inactive
moiety à Penicilloic acid
§ Penicilloic acid combines with the host proteins & acts as
antigenic determinant of penicillin induced hypersensitivity
§ Immediate Hypersensitivity: occurs within 20 mins
[manifestations: urticaria, pruritis, wheezing, sneezing &
rhinitis à anaphylaxis characterized by diffused pruritis,
hypotensive shock, angioneurotic edema, chocking à loss of
conscious & death à treatment ?? ]
§ Accelerated Hypersensitivity: occurs within 72 hrs
[manifestations: rash, fever, urticaria à fatality is extremely
rare]
§ Late Hypersensitvity: occurs after 72 hrs [manifestations:
morbiliform, urticarial or erythematous eruptions, local
inflammatory reactions, lymphadenopathy, splenomegaly,
serum sickness & Coomb’s positive haemolytic anaemia]
2. GIT side effects: diarrhea is more common with
ampicillin
§ Glossotis, stomatitis, abnormal taste
3. Oxacillin à cause reversible elevations of SGOT & SGPT
§ Methicillin à intestinal nephritis
§ Carbenicillin à reversible increase in prothrombin time
leading to bleeding problem

Cephalosporins
Classification
1st Generation
§ Parenteral Oral
Cephalothin Cephalexin
Cefazolin Cepharadine
Cefadroxil

2nd Generation
§ Parenteral Oral
Cefuroxime Cefaclor
Cefoxitin Cefuroxime
axetil

3rd Generation
§ Parenteral Oral
Cefotaxime Cefixime
Ceftizoxime Cefpodoxime
proxetil
Ceftriaxone Cefdinir
Ceftazidime Ceftibuten
Cefoperazone

4th Generation
§ Parenteral : Cefepime, Cefpirome
§ All Cephalosporins are Bactericidal
§ They bind to different proteins than those which bind
Penicillins

1st Generation
§ Developed in 1960
§ High activity against Gm+ve & weaker against Gm–ve
§ Cefazolin: Preferred parenteral 1st generation drug for
surgical prophylaxis
Cephalexin
§ Orally effective 1st generation
§ Less bound to plasma proteins, attains high concentration in
bile % is excreted unchanged in Urine; t1/2 ~60min
§ One of the most commonly used Cephalosporins
Cefadroxil
§ A close congener Cephalexin
§ It has good tissue penetration – sustained action at the site
of infection

2nd Generation
§ Developed after 1st Generation
§ More active against Gm-ve organisms
Cefuroxime
§ it is resistant to Gm-ve β-lactamases
§ It is well tolerated by i.m. & attains relatively higher CSF
levels
§ Important use is meningitis caused by H.influenzae,
meningococci, pnemococci & for single dose i.m. therapy of
gonorrhoea

3rd Generation
§ Cefotaxime, Ceftriaxone, Cefoperazone
§ Introduced in 1980
§ They have high activity against Gm-ve enterobacteriaceae &
Pseudomonas
§ All are Highly resistant to β-lactamases from Gm-ve bacteria
§ They are less active on gram positive cocci
Cefotaxime:
§ it is the prototype of 3rd generation
§ Exerts potent action on aerobic Gm-ve & Gm+ve & not so
active on anaerobes
§ Indications are Meningitis caused by Gm-ve, Life
threatining resistant/hospital acquired infections, Septicaemias
& Infections in Immunocompromised patients
§ Dose:1-2g i.m. or i.v. 6-12hourly (Children 50-100mg/kg/d)
§ It is deacetylated à metabolites exerts synergistic action with
parent drug
Ceftriaxone
§ It has longer duration of action (t1/2-8hr) à so once or mostly
twice daily dosing
§ Good CSF penetration & eliminated equally in urine & bile
§ It has high efficacy in a wide range of serious infections
including bacterial meningitis, multiresistant typhoid fever,
complicated urinary tract infections, abdominal sepsis &
septicaemias
§ A/Es - Hypoprothrombinemia & bleeding
Cefoperazone
§ It is having stronger activity on Pseudomonas & weaker
activity on other
§ Indications – Severe urinary, biliary, respiratory, skin-soft
tissue infections, meningitis & septicaemias
§ Excreted in bile, t1/2 ~ 2hr
§ It has hypoprothrombinemic action but doesn’t effect
platelet function

4th Generation
Cefepime
§ Developed in 1990
§ Spectrum same as 3rd generation but highly resistant to β-
lactamases
Cefpirome
§ It is used for the treatment of serious & resistant hospital
acquired infections including septicaemias, lower respiratory
tract infections
§ It has better penetration through porin channels of Gm-ve
§ More potent than 3rd generation for Gm+ve & Gm-ve
Adverse effects
§ Pain after i.m. injection, Thromboflebitis can occur on i.v.
injection
§ Diarrhoea due to alteration of gut ecology or irritative effect
§ Hypersensitivity reactions – Rashes are most frequent
§ Anaphylaxis, Angioedema, asthma & Urticaria can occur
§ Nephrotoxicity is highest with Cephaloridine, others have
low grade nephrotoxicity
§ Bleeding occurs due to Cefoperazone, Ceftriaxone & it is
more common in patients with Cancer, intra-abdominal
infection or renal failure
§ Neutropenia & Thrombocytopenia are reported with
Ceftazidime but they are rare
§ A disulfiram like interaction with alcohol with Cefoperazone
Uses
§ As alternatives to PnG in patients developing rashes or other
allergic reactions
§ Respiratory, urinary & soft tissue infections caused by Gm-
ve à Cefuroxime, Cefotaxime, Ceftriaxone
§ Penicillinase producing staphylococcal infections à
Cephalothin
§ Septicaemias caused by Gm-ve organism à an
aminoglycoside combined with cephalosporin
§ Surgical prophylaxis à Cefazolin is employed for most types
of surgeries including those with surgical prosthesis such as
artificial heart valves, artificial joints
§ Meningitis caused by H.influenzae, Enterobacteriaceae à
Cefuroxime, Cefotaxime, Ceftriaxone
§ Ceftazidime + Gentamicin à effective for Pseudomonas
meningitis
§ Gonorrhoea caused by penicillinase producing organisms à
Ceftriaxone
§ Typhoid – alternative to FQs in childrens à Ceftriaxone &
Cefoperazone
§ Mixed aerobic-anaerobic infections in Cancer patients, those
undergoing colorectal surgery, obstetric complications à
Cefuroxime
§ Infection by odd organisms & hospital acquired infections
resistant to commonly used antibiotics à Cefotaxime,
Ceftizoxime
§ Prophylaxis & treatment of infections in Neutropenic
patients à Ceftazidime
Aztreonam
§ It is novel β-lactam antibiotic in which Ring ‘A’ is missing
§ It inhibits Gm-ve enteric bacilli & H.influenzae at very low
concentrations & Pseudomonas at moderate concentrations
but doesn’t inhibit Gm+ve cocci or Fecal anaerobes.
§ It is resistant to Gm-ve β-lactamases
§ Indications: Hospital acquired infections originating from
Urinary, Biliary, Gastrointestinal and female genital tracts
Imipenem
§ It is extremely potent & dvdedry broad spectrum β-lactam
§ It is resistant to most β-lactamases & inhibits penicillinase
producing staphylococci
§ It is rapidly hydrolysed by the enzyme dehydropeptidase-I
§ It is combined with Cilastatin which is a reversible inhibitor
of dehydropeptidase-I
§ Imipenam-Cilastatin 0.5g i.v. 6 hrly (max 4g/day) à in a
wide range of serious hospital acquired infections including
those in neutropenic, cancer & AIDS patients
§ Imipenem has propensity to induce seizures at hgher doses
& in predisposed patients
Loracarbef
§ Synthetic β-lactam antibiotic
§ Similar to Cefaclor
§ Dose: 200-4– mg BD
§ Activity & uses same as 2nd Generation Cephalosporins
§ A/Es – Dermatological rashes, Diarrhoea, Seizures (higher
doses)
§ Mainly excreted through kidney as unchanged drug

Posted 10th February 2010 by Munvar‫™شیخ من ّور‬

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