BETA-LACTAM ANTIBIOTICS

• The Beta-lactam (B-lactam) antibiotics have a β-lactam ring

in their structure. The beta-lactam antibiotics are:-
• The penicillins, cephalosporins, monobactams and the
Carbapenems.
•
• Penicillins
• Sir Alexander Fleming discovered pencillin in 1928 from
Penicillium notatum. In 1941, penicillin became available for
therapeutic use. Penicillins are one of the most important
groups of antibiotics. Penicillin is now obtained from the
fungus Penicillium chrysogenum for therapeutic use.
• Note: Antibiotic: A substance produced by a
microorganism (or a similar product produced
wholly by (synthetic) or partially (Semi-synthetic) by
chemical synthesis) that is capable in low
concentrations, of inhibiting the growth of or killing
of other microorganisms.
• Nobel prizes won in antibiotic research
• Domagk (1939)- Prontosil
• S. Waksman (1952)- streptomycin
• Alexander Fleming (1945)- penicillin
• Chemistry
• The structure of penicillin consists of a
thiazolidine ring (A) attached to a beta-lactam
ring (B) to which a side chain ® is attached. A
and B together is called 6-aminopenicillanic
acid nucleus or penicillin nucleus which is
essential for the antibacterial activity fig I
below:
•
•
• The side chains determine some of the
pharmacokinetic and antibacterial properties
modifications of the side chairs resulted in the
production of semisynthetic penicillin with some
variations in pharmacological properties.
• Unit of Penicillin
• International Unit (IU) of penicillin is the specific
penicillin activity present in 0.6g of the crystalline
sodium penicillin. 1million units of penicillin =
0.6mg.
 Group of drugs in beta –lactam family
• They are
• Penicillins
• Cephalosporins
• Monobactams
• Carbapenems
•
•
• Mechanism of beta lactam
• Interferes with bacterial cell wall synthesis
• It inhibits the trans-peptidases so that cross-linking does not take place.
• Cross-linkages between peptide chains of the neighboring strands
provides stability and rigidity
• β-lactam antibiotics
•
• Bind PBP
•
• Inhibit cross-Linking of Peptidoglycan
•
• Cell-wall deficient bacteria
•
• Undergo lysis (Bacteria)
•
• Bactericidal effect
• Spectrum
• Gram-positive bacteria are more susceptible to penicillins because they have a thick cell wall which is
vital for their living and is easily accessible to penicillins while gram-negative bacteria have a thin cell
wall. Penicillins have a wide safety margin because the peptidoglycan layer is unique to bacteria and
is absent in higher animals (who have cell membrane). This is the basis of the selective toxicity of
penicillin.
•

• Resistance to Beta-Lactams
• Bacteria develop resistance to penicillins by one of the following mechanism.
• Many organisms like staphylococci produce a penicillinase which is a beta-lactamase. It opens the β-
lactam ring and inactivates penicillin most common mechanisms of resistance to penicillins.
• There are several types of Beta-lactamases. Some of them selectively hydrolyze penicillins while
others can inactivate both penicillins and cephalosporins.
• Carbapenems are resistant to most beta-lactamases but are in activated by carbapenemases.
• Altered target proteins- (PBPs) on the bacterial cell wall which reduce affinity for penicillins
• Poor penetration of the drug into the bacteria as in gram-negative bacteria.
• Efflux of penicillin from the gram-negative bacteria by an efflux pump.
• CLASSIFICATION OF PENICILLINS
• A. Natural - penicillin G.
• (Benzyl Penicillin)
• Prototype
• B. Semisynthetic
• 1. Acid resistant:Penicillin V(Phenoxymethyl Penicilln)
• 2. Penicillinase resistant penicillins:
• Methicillin
• Oxacillin
• Cloxacillin
• Nafcillin
• Dicloxacillin
• Flucloxacillin
• 3. Extended Spectrum Penicillins
• They have overcome the narrow spectrum of activity of with improved
gram-ve bacilli ability (e.g P. aeruginosa). They include. Amino penicillins
– Ampicillin
• Bacampicillin, Talampicillin, Pivampicillin, Amoxicillin Hetacillin
• 4. Antipseudomonal Penicillins: Also called carboxypenicillin. e.g
• Carbenicillin
• Carbenicillin – indanyl
• Ticarcillin
• 5. Ureidopenicillins:
• Azlocillin
• Mezlocillin
• Piperacillin
• NATURAL PENICILLINS
• -Penicillin g (Benzyl Penicillin).
• Antibacterial Spectrum: Penicillin G (PnG) has a narrow antibacterial spectrum and is effective
against gram-positive cocci and bacilli and a few gram-negative Cocci. Thus streptococci,
Pneumococci, gonococci, meningicocci, B. anthracis, C.diphtheria, Clostridia, Listeria and
spirochaetes are highly sensitive. Penicillins are also effective against some anaerobes.
•
• Pharmacokinetics
• Penicillin G is destroyed by gastric juice and has a very low bioavailability – hence given
parenterally. Food interferes with its absorption hence should be administered 2hr before or after
food. They are widely distributed in tissues, and body fluids, they remain extracellular as they are
polar compounds. They do not readily cross the BBB, but during inflammation, therapeutic
concentrations are attained in the CSF because inflammation weakens the BBB and allow the
penicillins to reach the brain. Onset of action is 15-30mins. t1/2 is 30-60mins. 60% is bound to
plasma albumin. Penicillin G is rapidly excreted by the kidneys (about 10% by glomerular filtration
and 90% by renal tubular secretion as penicillins are organic salts. Probenecid competes for renal
tubular secretion and thereby prolongs the duration of action of penicillins. In renal failure and in
neonates when renal functions is not fully developed, the duration of action of penicillins get
prolonged and t1/2 may be increased to 10hrs.
• ADVERSE EFFECTS
• Penicillins are highly safe drugs with a high therapeutic index
• Adverse effects are not serious in therapeutic doses except hypersensitivity reactions.
•
• Hypersensitivity: PnG is the most common cause of drug allergy. Degradation products of penicillin
like penicilloic acid are antigenic. Allergic reactions range from skin rashes, urticaria, pruritus, fever,
bronchospasm, serum sickness and rarely exfoliative dermatitis and anaphylaxis. Though all forms of
penicillin can cause allergy, anaphylaxis is more common following parenteral than oral preparations.
• Topical penicillins are highly sensitizing and their used is banned. The highest incidence is with
procaine penicillin due to the procaine component. There is cross sensitivity amongst many
penicillins.
• History of allergy to penicillins should be well documented in a patient before prescribing. It is higher
in atopic individuals. A scratch test or intradermal sensitivity test with 2-10 units of penicillin should
be done. If this test is negative it does not completely rule out allergy.
• Penicillin should be given cautiously in all patients and a syringe loaded with adrenaline to treat
anaphylaxis should be kept ready (please do not give penicillins when emergency drugs are lacking).
• It is best to avoid penicillin in allergic patients and use alternative drugs which are available.
• Beta-Lactam Antibiotics
• 1 . Objectives
• Identify the mechanism of action of beta-lactam antibiotics
• Describe the classifications of beta-lactam antibiotics
• Outline the mechanism of selective toxicity
• Outline the appropriate monitoring of patients taking beta-
lactam antibiotics in terms of compliance and any major
drug-drug interaction
• Describe the possible adverse effects of beta-lactam
antibiotics
• Penicillins and cephalosporins are the major antibiotics that
inhibit bacterial cell wall synthesis. They are called beta-lactams
because of the unusual 4 member ring that is common to all their
members. The beta-lactams include some of the most effective,
widely used, and well tolerated agents available for the treatment
of microbial infectious.
• Vancomycin, fosfomycin and bacitracin also inhibit cell wall
synthesis but are not nearly as important as the beta-lactam
drugs. The basis of the selective toxicity of the beta-lactam
antibiotics is mainly due to specific actions on the synthesis of
cellular structure that is unique to the micro organism
(peptidoglycan) while humans do not have a cell wall
(Peptidoglycan) but have cell membrane.
• Mechanism of Action of Penicillins
• Penicillins prevent completion of synthesis of peptidoglycan,
a key component patient the bacterial cell wall.
Peptidoglycan is unique to prokaryotes and this explains the
selectivity of penicillin. The enzyme called trans-peptidase
cross-links the strands of peptidoglycan and produces a
strong rigid structure.
• Transpeptidase binds irreversibly to beta-lactam antibiotics.
After this occurs it cannot participate in cell wall
biosynthesis. The growing bacteria will lyse because the thin
cell wall can longer protect it from the hypotonic
environment.
• MECHANISMS OF RESISTANCE OF PENICILLINS
• Antibiotic degrading enzymes e.g beta-lactamases. Current Penicillins such as
Augmentin (Ampicillin-clavulanic acid) contain beta-lactamase antibiotics to block
cleavage of the penicillins.
• Antibiotic resistant genes
• Pumping mechanism to remove antibiotic from bacterial cell
• Enzymes that modify antibiotics
• Bacteria acquire genes conferring resistance
• Spontaneous DNA mutation
• microbial sex transformation
• Formation of plasmids
• Most frightening however is resistance acquired from a small circle of DNA called
plasmid that can move from one type of bacterium to another.
• A single plasmid can provide a slew of different resistances. Note in 1968, 12,500 people
died in Guatemala died to an epidemic of shigella diarrhea.
• The microbe harbored a plasmid carrying resistances to four antibiotics.
• NOTE: Beta-lactam antibiotics contains beta-
lactam rings in their molecular structures.
• They are
• Penicillins
• Cephalosporins
• Monobactams
• Carbapenems
•
•
• Mechanism of action of beta lactams
• Interferes with bacterial cell wall synthesis
• It inhibits the trans-peptidases so that cross-linking does not take place.
• Cross-linkages between peptide chains of the neighboring strands
provides stability and rigidity
• Beta-lactam inhibition
• B- lactamases are a family of enzymes produced by many gram positive and gram
negative bacteria that inactivates β-lactam antibiotics by opening the β-lactam ring.
• Different β-lactamase differ on their substrate activities
• Three inhibitions of this enzyme are
• Clavulanic acid
• Sulbactam
• Tazobactam
• Clavulanic Acid
• Has a rapid absorption
• Addition of clavulanic acid re-establishes the activity of amoxicillin against β-lactamase
producing resistant Staph aureus (but not MRSA). H. influenza, N. Gonorrhoea, E. Coli,
Proteus, Klebsiella, salmonella, shigella,
• Indicated for RTI, skin & soft tissue, intra abdominal infectious.
• Dosage:100mglkg 1day x in 4 divided doses.
• Sulbactam
• 2- 3 times less potent than clavulanic acid
• Oral absorption of sulbactam is inconsistent therefore given parenterally.
• It has been combined with ampicillin for use against β-lactamase producing resistant strains
• Used commonly in surgical infectious and gonorrhoea
• Dosage Ampicillin + sulbactam:
• 200mg/kg 1day in 4 divided doses.
• Tazobactam
• It is similar to sulbactam
• Its pharmacokinetics matches with piperacillin with which of has been combined for use in severe infectious
like peritonitis, pelvic/urinary/respiratory infections caused by β-lactamase producing bacilli.
• They are available in fixed combinations
• Clavulanic acid + amoxicillin for oral /iv
• Clavulanic acid + ticarcillin for iv
• Sulbactam +ampicillin for iv
• Tazobactam +piperacillin for iv
•
 cephalosporins
• Cephalosporins are semisynthetic antibiotics
with a beta –lactam ring.
• Derived from cephalosporin –C
• Have a wider spectrum than penicillins.
 Mechanism of Action
• Inhibit the bacterial cell wall synthesis similar
to penicillins.
• They are bactericidal

• Resistance: as in penicillins,beta-lactamases
or cephalosprinases and altered target
proteins, ie altered PBPs determine resistance
to cephalosporins.
 classification
• Cephalosporins are classified into 4 major
generations
• First generation : cephalothin,cefazolin
( parenteral); cephalexin, cefadroxil,cefradine ( oral)
• Second generation: cefamandole, cefuromine,
cefotetan, cefoxitin, cefronide ( parenteral)
cefaclor, cefuroxime axetil , cefprozil,
loracarbef( oral).
Classification of cephalosporins contnd.
• Third generation: ceftoxamine, ceftriaxone,
cefoperazone, ceftizoxime, ceftazidime
( parenteral) ; cefixime, cefpodoxime proxetil,
ceftibuten, cefdinir, cefditoren pivoxil ( oral).
• Fourth generation : cefepime ( parenteral) ,
cefpirome ( oral). Also cephalodrin.
 Spectrum of activity of the four
generations.
• First generations effective against gram-+ve
organisms, used in minor infections of the
respiratory and urinary tract. Eg klebsiella,
enterobacter, streptococci, , staphylococci and
E.coli. ( cefazolin) , is the drug of choice for
surgical prophylaxis.
• cephalexin is effective orally and is used for
minor infections like abscesses and cellulitis.
 Spectrum contd
• 2nd generation are more active against some gram- negative
organisms compared to first generations, and also active against
anaerobes .they are more resistant to beta-lactamases,
• H. influenzae, E. coli , Proteus , klebsiella and enterobacter. It has no
activity on P. aeruginosa.
• 3rd generation: they are highly resistant to beta lactamases .have
good activity against several gram –negative organisms, the
organisms include – citrobacter, serratia, enterobacteriaceae ,
Pseudomonas aeruginosa, N. gonorrhoea, and beta lactamase
producing H.influenza.they have weak gram positive activity.Many
cross BBB and are useful in meningitis’
• Third generation cephalosporins can be life saving in serious gram –
negative infections including aminoglycoside resistant ones.
 Spectrum contd
• Fourth generation: cefepime and cefpirome are
active against a variety of gram-positive and gram –
negative organisms including streptococci,
staphylococci, meningitis, gonococci,
enterobacteriaceae, some enterococci, H.influenza ,
P.aeruginosa. Most resistant to beta lactamases .
Both drugs ar administered parenterally and have
fast onset of action plasma half life is 2hrs.
• Useful in septicaemia, nosocomial and
immunocompromised patients.
 Adverse effects of cephalosporins
• Hypersensitivity reactions- rashes, serum
sickness,anaphylaxis
• Nephrotoxicity but mild compared to
aminoglycosides.
• Diarrhoea
• Bleeding due to hypoprothrombinaemia
• Low wbc count
• Pain at the site of injection
• Disulfiram –like reaction with alcohol.
 Clinical uses of cephalosporins
• 1. gram-negative infections- urinary , respiratory and soft
tissue infections , usually third generations are prefferred.
• 2 .surgical prophylaxis- Cefazolin is the drug of choice due
to its longer t ½ and better tissue penetrability.
• 3. Gonorrhoea- Ceftriaxone ( single dose 250mg) is the
DOC.
• 4.Meningitis –due to H. inflenzae , N. meningitidis and
S.pneumoniae- third generation agents are useful –
cefotaxime or ceftriaxone may be used.
• Pseudomonas meningitis; ceftazidime + an aminoglycoside
is very effective.
 Uses of cephalosporins contd
• 5. mixed aerobic – anaerobic infections;
common following pelvic surgeries – a 3rd
generation agent is used.
• 6. Typhoid fever – as alternative to
ciprofloxacin.
• 7. Nosocomial infections can be treated with
3rd generation agents.
 CARBAPENEMS
• Carbapenems contain a beta- lactam ring
fused with a 5- membered penem ring.
• Carpapenems include
• 1. imipenem
• 2. meropenem
• 3. ertapenem
• 4. doripenem
 Spectrum of activity of carbapenems
• They inhibit various gram-+ve and gram-ve
organisms as well as anaerobes, including
streptococci, enterococci, staphylococci,
enterococci, listeria, enterobacteriacea
(including cephalosporin – resistant ones).
• Pseudomonas and B. fragilis.
 Mechanism of action
• Carbapenems inhibit bacterial cell wall
synthesis, similar to the penicillins.
• Carbapenems are highly resistant to most beta
–lactamases.
 Carbapenems contd
• Imipenem : is not absorbed orally and is administered
intavenously ( 250-500mg every 6-8hrs)
• It has good tissue penetrability , attains good CSF levels
• It is inactivated by a dehydropeptidase in the renal
tubules.
• It is always combined with Cilastin,an inhibitor of
dehydropeptidasein order to prolong its plasma half
life. Half life of imipenem and cilastin is 1hr.
• They are excreted through the kidneys, dosages must
be adjusted in renal failure.
 Adverse effects

• 1. nausea
• Vomitting
• Dairrhoea
• Allergic reactions especially in patients allergic
to beta-lactam antibiotics.
• High doses could cause seizures in ( 1.5 % of
patients).
 Clinical uses of imipenems
• 1. imipenem-cilastin used in UTI, respiratory , skin,
bone, soft tissue .
• Intra-abdominal
• Gynaecological infections due to susceptible
microorganisms that are resistant to other antibiotics.
• DOC for penicillin –resistant pneumococci
• Combined with an aminoglycoside in Pseudomonas
infections to reduce the risk of developing resistance.
• DOC in enterobacter infections.
 Meropenem
• Meropenem has the following advantages over
imipenem
• 1. meropenem is not destroyed by renal
dipeptidase and therefore does not require
combination with cilastin.
• 2. risk of seizures is lesser with imipenem,
indications of meropenem are similar to imipenem.
• 3. DOC for uncomplicated Prostatitis caused by
susceptible organisms.
 Ertrapenem
• Ertrapenem is similar to meropenem except
that is not useful against P.aeruginosa,
• It is longer acting –given once daily, 1g daily
im /iv .
• Ertrapenem im injections are very painful
must be combined with 1% lignocaine
injection as a combination in its marketing.
 feropenem
• Feropenem is another carbapenems that is orally active.
• Good efficacy against both gram-positive and gram-
negative organisms and some anaerobes.
• Clinial uses – bacterial sinusitis, community acquired
pneumonia, genitourinary infections;not available in many
countries but available in india.
• Adverse effects- nausea, diarrhoea and abdominal pains.
• Doripenem is similar to meropenem but with better activity
against gram-ve aerobes than gram –positive ones.
 CARBACEPHEMS
• Loracarbef is a carbacephem.it is a synthetic
beta-lactam antibiotic with properties similar
to a second generation cephalosporins
( cefaclor)
• It is orally effective and excreted largely
through the kidneys.
 Monobactams
• Monobactams are monocyclic beta-lactams , they contain a
single ring – the beta lactam ring. Example
• 1. Aztreonam –is a monobactam active against gram-negative
bacilli including Pseudomonas aeruginosa.
• Aztreonam is resistant to to beta lactamases produced by gram
negative bacteria.
• It is highly effective against H. influenzae , gonococci and
enterobacteriaecea
• Its not effective against gram- positive organisms and anaerobes.
• Its mechanism is by inhibiting cell wall synthesis like penicillins.
• It is given parenterally.
 Monobactams contnd
• Clinical uses- in patients allergic to penicillins as there is no
cross allergenicity with other beta lactam .
• Useful in pseudomonas infections especially in nosocomial
and other gram negative infections.
• Aztreonam is well tolerated.
• Adverse effects- skin rashes, urticaria, bronchospasm and
rarely anaphylaxis.
• Thrombophleblitis on iv use and pain after im
administration have been reported
• Nausea, vomitting, diarrhoea, altered taste and raised liver
enzymes also noted.
 Clinical summary on beta-latams
• Penicillins are still the first line drugs in many infections.
• Measures to treat anaphylaxis should be kept ready while using
penicillins parenterally.
• Amoxicillin + clavulanic is commonly used often irrationally and
should be restricted to recommended conditions.
• Amoxicillin is the commonest penicillin in use.
• Benzathine penicillin is the commonest penicillin used for prophylaxis
• Use of ampicillin has drastically reduced .it is used in combination with
cefotaxime in meningitis.
• Piperacillin +tazobactam is efffective in bacterial meningitis.
• Introduction of meropenem, has limited the use of imipenem +
cilastin combination.