β-lactam antibiotics: A review of their classification, mode of action and clinical uses

β-lactam antibiotics
Dr.Shefali Jaiswal
1

Contents
• Introduction
• History
• Classification
• Mode of action
• Bacterial cell structure
• Beta-lactum drugs –
Classification
Structure
Mechanism of action
Penicillin
2

Cephalosporin
Carbapenem
Monobactum
Beta-lactum inhibitors
• Resistance
• Applied aspect
• Conclusion
• Bibilography
3

• Dentists prescribe medications for the
management of a number of oral conditions,
mainly orofacial infections.
• Since most human orofacial infections
originate from odontogenic infections, the
prescribing of antibiotics by dental practitioners
has become an important aspect of dental
practice.
• For this reason, antibiotics account for the vast
majority of medicines prescribed by dentists.
5

Greek word
Anti - against
Bios - life
Definition:
“Antibiotics are substances produced by
microorganisms, which selectively suppress the
growth of or kill other micro-organisms at very low
concentrations.”
6

• The term antibiotic was given by Waksman in
1941.
• He described antibiotics as chemical
substances produced by microorganisms
having the property of inhibiting the growth or
destroying other microorganisms in high
dilution
• Chemotherapy treatment of systemic infections
with specific drugs that selectively suppress the
infecting microorganism without significantly
affecting the host.
7

• Early History
During ancient times;
• Greeks and Indians used moulds and other
plants to treat infections.
• In Greece and Serbia, mouldy bread was
traditionally used to treat wounds and
infections.
• Warm soil was used in Russia by peasants to
cure infected wounds.
• Sumerian doctors gave patients beer soup
mixed with turtle shells and snake skins.
9

• Babylonian doctors healed the eyes using a
mixture of frog bile and sour milk.
• Sri Lankan army used oil cake (sweetmeat) to
server both as desiccant and antibacterial.
10

MODERN HISTORY
• 1640 - John Parkington recommended using
mould for treatment in his book on
pharmacology.
• 1870 - Sir John Scott Burdon-Sanderson
observed that culture fluid covered with mould
did not produce bacteria.
• 1871 - Joseph Lister experimented with the
antibacterial action on human tissue on what
he called Penicillium glaucium.
• 1875 - John Tyndall explained antibacterial
action of the Penicillium fungus to the Royal
Society.
11

• 1877 - Louis Pasteur postulated that bacteria
could kill other bacteria (anthrax bacilli).
• 1897 - Ernest Duchesne healed infected guinea
pigs from typhoid using mould (Penicillium
glaucium).
• 1928 - Sir Alexander Fleming discovered
enzyme lysozyme and the antibiotic substance
penicillin from the fungus Penicillium notatum.
• 1932- Gerhard Domagk discovered
Sulfonamidochrysoidine (Prontosil ).
12

• During 1940's and 50's streptomycin,
chloramphenicol, and tetracycline were
discovered and Selman Waksman used the
term "antibiotics" to describe them (1942).
13

Sir Alexander Fleming
• Sir Alexander Fleming, a Scottish biologist,
defined new horizons for modern antibiotics
with his discoveries of enzyme lysozyme (1921)
and the antibiotic substance penicillin (1928).
• It was in 1928 when he observed while
experimenting on influenza virus that a
common fungus, Penicillium notatum had
destroyed bacteria in a staphylococcus culture
plate.
14

• Upon subsequent investigation, he found out
that mould juice had developed a bacteria-free
zone which inhibited the growth of
staphylococci.
• This newly discovered active substance was
effective even when diluted up to 800 times.
• He named it penicillin.
15

Classification of Antibiotics
Based on
mode of Action
Bacteriostatic Bactericidal
Based on their
spectrum of
action
Broad-spectrum
Narrow
Spectrum
17

Spectrum of Activity:
1.) Narrow Spectrum:
e.g. Penicillin G, Streptomycin,
Erythromycin.
2.) Broad Spectrum:
e.g. Tetracyclines, Chloramphenicol.
18

Types of Antibiotics
(Based on their mode of action)
Bacteriostatic
Antibiotics
• Tetracyclines
• Spectinomycin
• Sulphonamides
• Macrolides
• Chloramphenicol
• Trimethoprim
Bactericidal Antibiotics
• Penicillins
• Cephalosporins
•Fluoroquinolones
(Ciprofloxacin)
• Glycopeptides (Vancomycin)
• Monobactams
• Carbapenems
19

Types of Antibiotics
(Based on their structural similarities)
20

Antibiotics: Mode of Action
21
• Inhibitors of DNA synthesis
• Inhibitors of bacterial protein synthesis
• Inhibitors of bacterial cell wall synthesis
• Interference with metabolism
• Impairment of nucleic acids

Gram positive vs. Gram negative
bacteria
23

• Peptidoglycan is a carbohydrate composed of
alternating units of NAMA and NAGA.
• The NAMA units have a peptide side chain
which can be cross linked from the L-Lys
residue to the terminal D-Ala-D-Ala link on a
neighboring NAMA unit.
27

•The cross linking reaction is
catalyzed by a class of
transpeptidases known as penicillin
binding proteins
•A critical part of the process is the
recognition of the D-Ala-D-Ala
sequence of the NAMA peptide
side chain by the PBP. Interfering
with this recognition disrupts the
cell wall synthesis.
•β-lactams mimic the structure of
the D-Ala-D-Ala link and bind to the
active site of PBPs, disrupting the
cross-linking process.
Transpeptidase Enzyme
30

Beta-Lactam Antibiotics
β-lactam
ring
•Contains a beta-lactam ring in their molecular structures.
•Nitrogen is attached to the beta carbon relative to the
carbonyl ring and hence the name.
33

Classification
•Penicillins
•Cephalosporins
•Other β-Lactam drugs
--Cephamycins
--Carbapenems
--Oxacephalosporins
--β-Lactamase inhibitors
--Monolactams
34

How do they work?
1. The β-lactam binds to Penicillin Binding
Protein (PBP).
2. PBP is unable to crosslink peptidoglycan
chains.
3. The bacteria is unable to synthesize a stable
cell wall.
4. The bacteria is lysed.
36

Mechanism of β-Lactam Drugs
• The amide of the β-lactam ring is unusually
reactive due to ring strain and a conformational
arrangement which does not allow the lone pair of
the nitrogen to interact with the double bond of the
carbonyl.
• β-Lactams acylate the hydroxyl group on the serine
residue of PBP active site in an irreversible
manner.
• This reaction is further aided by the oxyanion hole,
which stabilizes the tetrahedral intermediate and
thereby reduces the transition state energy.
37

The hydroxyl attacks the amide and forms a tetrahedral
intermediate.
38

The tetrahedral intermediate collapses, the amide bond is broken,
and the nitrogen is reduced.
39

The PBP is now covalently bound by the drug and cannot perform
the cross linking action.
40

Penicillin G
• It is a drug of choice for infections caused by streptococci,
meningococci, enterococci, penicillin - susceptible pneumococci,
non-β-lactamase-producing staphylococci, T. pallidum and many
other spirochetes, clostridium species, actinomyces, and other
Gram - positive rods and non-β-lactamase-producing Gram-
negative anaerobic organisms.
43

Adverse effects
•The main hazard with the penicillins is allergic reaction.
•These include itching, rashes (eczematous or urticarial), fever, and
angioedema.
•Rarely (about 1 in 10 000) there is anaphylactic shock which can be
fatal (about 1 in 50 000 – 100 000 treatment courses).
44

• Allergies are least likely when penicillins are given orally and
most likely with local application.
• Metabolic opening of the β-lactam ring creates a highly
reactive penicilloyl Group which polymerizes and binds with
tissue Proteins to form the major antigenic determinant.
• The anaphylactic reaction involves specific IgE
antibodies which can be detected in the plasma of susceptible
persons. 45

PENICILLIN G
1. Sod. Penicillin G (crystalline penicillin) injection.
0.5-5 MU i.m/i.v 6-12 hourly. Available as dry
powder to be dissolves with sterile water at the
time of injection.
2. Procaine penicillin G inj.
0.5-5 MU i.m/i.v 12-24 hourly.
3. Benzathine penicillin G
o.6-2.4 MU i.m. every 2-4 weeks as aqueous
suspensions.
47

Penicillin V (Phenoxymethylpenicillin)
EFFECTIVE AGAINST:
• Gram positive + Less effective
against Gram negative
bacteria
TREATMENT FOR:
• Tonsillitis
• Anthrax
• Rheumatic fever
• Streptococcal skin infections
CHARACTERISTICS:
• Narrow spectrum
• Should be given orally
• Prone to beta-lactamase 48

Jarisch – Herxheimer Reaction
• Pencillin is injected into a syphilitic patient.
• May produce shivering, fever, myalgia,
exacerbation of the lesions and even vascular
collapse.
• Occurs due to sudden release of spirochetal
lytic products.
• Effects last for 12 – 72 hours.
• Intake of Aspirin and sedation cause relief of
symptoms.
49

Amino-Penicillin
Ampicillin R=Ph
Amoxicillin R= Ph-OH
50

Ampicillin
EFFECTIVE AGAINST:
• Gram positive + Gram
negative bacteria
TREATMENT FOR:
• Ear infection
• Sinusitis
• Urinary tract infections
• Meningitis
CHARACTERISTICS:
• Broad spectrum
• Can be given orally and
parenterally
• Prone to beta-
lactamase
Ampicillin
Sulbactam
+
ll
Unasyn 51

Amoxicillin
EFFECTIVE AGAINST:
• Gram positive + Gram
negative bacteria
TREATMENT FOR:
• Skin infection
• Sinusitis
• Streptococcal pharyngitis
CHARACTERISTICS:
• Broad spectrum
• Can be given orally and
parenterally
• Prone to beta-lactamase
SIDE-EFFECTS:
• Rash, diarrhea, vomiting,
nausea, edema, stomatitis,
and easy fatigue.
Amoxicillin
Clavulanic Acid
+
ll
Augmentin
52

Anti-Staphylococcal Penicillin
53

Methicillin
EFFECTIVE AGAINST:
• Gram positive bacteria
TREATMENT FOR:
• Cellulitis
• Also for life threating diseases
such as pneumonia,
endocarditis, bacteremia and
meningitis.
CHARACTERISTICS:
• Very narrow Spectrum
• Should be given parenterally
SIDE-EFFECT:
• Interstitial nephritis 54

Oxacillin
EFFECTIVE AGAINST:
TREATMENT AGAINST:
• penicillin-resistant Staphylococcus
aureus
CHARACTERISTICS:
SIDE-EFFECT:
• Hypersensitivity and local reactions
• In high doses, renal, hepatic, or
nervous system effects can occur
55

Nafcillin
EFFECTIVE AGAINST:
TREATMENT AGAINST:
• Staphylococcal infections
CHARACTERISTICS:
SIDE-EFFECT:
• Allergic reactions
• Nausea and vomiting
• Abdominal pain
56

Cloxacillin
EFFECTIVE AGAINST:
• Staphylococci that produce
beta-lactamase
CHARACTERISTICS:
SIDE-EFFECT:
• Allergic reaction
57

Dicloxacillin
EFFECTIVE AGAINST:
• Gram positive bacteria +
Staphylococci that produce beta-
lactamase
CHARACTERISTICS:
SIDE-EFFECT:
• Diarrhoea, nausea, rash, urticaria
pain and inflammation at injection
site
58

Flucloxacillin
EFFECTIVE AGAINST:
• Gram positive bacteria +
Staphylococci that produce beta-
lactamase
CHARACTERISTICS:
SIDE-EFFECT:
• Diarrhoea, nausea, rash, urticaria
pain and inflammation at injection
site
59

Anti-Pseudomonal Penicillin
60

Piperacillin
EFFECTIVE AGAINST:
• Gram positive +Gram negative
CHARACTERISTICS:
• Extended Spectrum
• Should be given
by intravenous or intramuscular injection
SIDE-EFFECT:
• Hypersensitivity
• Gastrointestinal disorders
• Renal disorders
*Piperacillin+Tazobactam=Zosyn
61

Carbenicillin
EFFECTIVE AGAINST:
• Gram negative + Limited Gram
positive
TREATMENT FOR:
CHARACTERISTICS:
• Highly soluble in water and acid-
labile
SIDE-EFFECT:
• High doses can cause bleeding
• Hypokalemia
62

Ticarcillin
EFFECTIVE AGAINST:
• Mainly gram negative bacteria
particularly Pseudomonas aeruginosa
TREATMENT FOR:
• Stenotrophomonas maltophilia
infections
CHARACTERISTICS:
SIDE-EFFECT:
• Diarrhoea
• Bleeding
• Fever
• Fainting
63

• These has been conventionally classified into four generations
based on Generation system.
• This is based on chronological sequence of development, but
more importantly, takes into consideration the overall
antibacterial spectrum as well as potency.
• First-generation cephalosporins are predominantly active
against Gram-positive bacteria, and successive generations
have increased activity against Gram-negative bacteria (albeit
often with reduced activity against Gram-positive organisms).
66

CEPHALOSPORINS
•The nucleus of the cephalosporins, 7-aminocephalosporanic acid,
bears a close resemblance to 6-amino- penicillanic acid.
•The intrinsic antimicrobial activity of natural cephalosporins is low,
but the attachment of various R1 and R2 groups has yielded
hundreds of potent compounds of low toxicity.
•Cephalosporins can be classified into four major groups or
generations, depending mainly on the spectrum of their antimicrobial
activity. 67

7-Aminocephalosporanic acid nucleus
68

Cephalosporins are similar to penicillins, but more stable
to many bacterial beta-lactamases and therefore have a
broader spectrum of activity.
Klebsiella pneumoniae
69

• However, strains of E. coli and Klebsiella species
expressing extended-spectrum beta-lactamases that
can hydrolyze most cephalosporins are becoming a
problem.
• Cephalosporins are not active against enterococci
and Listeria monocytogenes.
70

First Generation Cephalosporins
Cefalothin Cefalexin
Cefadroxil Cefazolin
71

• These drugs are very active against Gram-positive cocci
(such as pneumococci, streptococci, and Staphylococci).
Cephalosporins are not active against methicillin-
resistant strains of staphylococci.
72

• E. coli, K. pneumoniae, and P. mirabilis are often
sensitive. Anaerobic cocci (e.g., peptococcus,
peptostreptococcus) are usually sensitive, but
Bacteroides fragilis is not.
73

Although the first-generation cephalosporins are broad
spectrum and relatively nontoxic, they are rarely the
drug of choice for any infection.
75

Second Generation Cephalosporins
Cefuroxime(Oral) Cefotetan
76

• In general, they are active against organisms inhibited by first-
generation drugs, but in addition they have extended Gram-
negative coverage.
• Klebsiellae (including those resistant to cefalothin) are usually
sensitive. Cefamandole, cefuroxime, and cefaclor are active
against H. influenzae but not against serratia or B. fragilis.
77

• In contrast, cefoxitin, and cefotetan are active against B. fragilis
and some serratia strains but are less active against H.
influenzae. As with first-generation agents, none is active against
enterococci or P. aeruginosa.
78

Third Generation Cephalosporins
Cefotaxime Ceftriaxone
Ceftazidime 81

• Compared with second-generation agents, these drugs have
expanded Gram-negative coverage.
• Third-generation drugs are active against Citrobacter, Serratia
marcescens, and Providencia.
• They are also effective against β-lactamase-producing strains
of Haemophilus and Neisseria.
82

Like the second-generation drugs, third-generation
cephalosporins are hydrolyzable by constitutively
produced beta-lactamase, and they are not reliably active
against enterobacter species.
83

Third-generation cephalosporins are used to treat a wide
variety of serious infections caused by organisms that
are resistant to most other drugs.
84

Fourth Generation Cephalosporins
Cefepime
86

• Carbapenems are a class of beta-lactam antibiotics with a broad
spectrum of antibacterial activity.
• They have a structure that renders them highly resistant to beta-
lactamases.
• Carbapenem antibiotics were originally developed from
thienamycin, a naturally-derived product of Streptomyces cattleya.
88

Carbapenems common uses
• Imipenem
• Broad spectrum, covers Gram-positive, Gram-negative
(including ESBL-producing strains), Pseudomonas and
anaerobes
• Meropenem
• Less seizure-inducing potential, can be used to treat CNS
infections
• Ertapenem
• Lacks activity against Acinetobacter and Pseudomonas
• Has limited activity against penicillin-resistant pneumococci
89

Imipenem
EFFECTIVE AGAINST:
• Aerobic and anaerobic, Gram
positive and gram negative
bacteria
CHARACTERISTICS:
• Broad Spectrum
• Intravenous
• Resistant to beta-lactamase
enzymes
SIDE-EFFECT:
• Seizuregenic at high doses
90

Meropenem
EFFECTIVE AGAINST:
• Aerobic and anaerobic, Gram
positive and gram negative
bacteria
CHARACTERISTICS:
• Ultra Broad Spectrum
• Intravenous
enzymes
SIDE-EFFECT:
• Diarrhoea
• Vomiting
• headache
91

Ertapenem
EFFECTIVE AGAINST:
• Gram positive and gram negative
bacteria
CHARACTERISTICS:
• Broad Spectrum
• Intravenous
enzymes
• Not active against MRSA
SIDE-EFFECT:
• Convulsions
• Seizures
• headache
92

Aztreonam
EFFECTIVE AGAINST:
• Gram positive +Gram
negative+Anaerobic bacteria
CHARACTERISTICS:
• Broad Spectrum
• Intravenous
enzymes
• Not active against MRSA
SIDE-EFFECT:
• Diarrhoea
• Nausea
• Vomiting
94

BETA-LACTAMASE INHIBITORS
• Resemble β-lactam antibiotic structure.
•
• Bind to β-lactamase and protect the antibiotic from destruction.
• Most successful when they bind the β-lactamase irreversibly.
• Three important in medicine:
• Clavulanic Acid
• Sulbactam
• Tazobactam 95

Resistance-The Global Battle.!!!
What is Resistance?
•Drug resistance refers to unresponsiveness of a
microorganism to an antimicrobial agent.
•Drug resistance are of two types:
---Natural Resistance
---Acquired Resistance
97

Natural Resistance
• Some microbes have always been resistant to certain anti-
microbial agent.
• They lack the metabolic process or the target side that is
affected by particular drug.
E.g: Gram negative bacilli are normally unaffected by Penicillin G.
• M. tuberculosis is insensitive to Tetracyclines.
• This type of resistance does not pose significant clinical
problem.
98

Acquired Resistance
• It is the development of resistance by an organism which was
sensitive before due to the use of antimicrobial agent over a
period of time.
• This can happen with any microbe and is a major clinical
problem.
• However, the development of resistance is dependent on the
microorganism as well as the drug.
99

MECHANISMS FOR ACQUIRING
RESISTANCE
100

APPLIED ASPECT
1. Penicillin hypersensitivity
2. Skin eruptions

• Anaphylaxis:
Anaphylaxis occurs in about 1 in 10,000 patients using
penicillin, accounting for approximately 300 deaths per
year in the United States.
.

• Management:
While the triggering agent of an acute allergic reaction is variable,
the approach to handling the emergency is similar in most cases.
The dentist's primary responsibility in an allergic emergency is to
stabilize the patient until he or she can be transferred to an
emergency facility or until assistance arrives.
103

Guidelines for sequencing of antibiotic
therapy
• Supplemental, subgingivally applied, broad-spectrum antiseptic
agents may be used.
• Periodontal abscesses may develop if systemic antibiotics are
administered without mechanical debridement.
104

Prescription of drugs
• Prescription drugs are the fastest growing component of personal
health expenditures.
• Contributing to this are the increased FDA approvals of expensive
and new drugs.
• Antibiotics should be prescribed judiciously rather than zealously.
• Judicious use of antimicrobial therapy mandates restrained rather
than indiscriminate prescribing.
105

Antibiotic sensitivity cultures…
• Aim is to measure susceptibility of an isolate two range of
antibiotics at the individual patient level for effective prescribing
but also to assess emerging bacterial resistance patterns.
106

Overprescribing….
• Excessive prescribing or over prescribing unnecessarily exposes
the patient to increased financial costs as well as substantial risk
of antibiotic complications and increased number of antibiotic
resistant organisms in the general population.
Eg: For healthy patients prophylactic antibiotics for routine
periodontal surgery or extractions.
107

Wrong choice of antibiotics
• Prescribing a broad spectrum antibiotic when a narrow spectrum
one would be sufficient or prescribing unnecessarily long courses
of antibiotic therapy increases the risk of resistant bacterial strain
development.
• Bacterial resistance to a single antibiotic or to multiple groups
frequently results from genetic transfer abilities of bacteria which
allow them to create pathogens with antibiotic resistant genes.
108

Antibiotics in periodontal therapy
Conditions that may call for systemic antimicrobial periodontal
therapy are:
• Medical conditions that predispose patients to periodontitis.
• Acute periodontal infections (periodontal abscess, acute
necrotizing ulcerative gingivitis/periodontitis).
109

Antibiotics in endodontic therapy
• It has been well documented that infected root canals are
polymicrobial in nature with several predominant anaerobic
microorganisms.
• The key to successful management of infections of endodontic
origin is the chemomechanical debridement of the infected root
canal system and drainage from both soft and hard tissues.
110

Antibiotics for oral and
maxillofacial infections
Antibiotic prophylaxis
• It is not possible to make recommendations regarding
antibiotic prophylaxis for all clinical situations.
• Antibiotic prophylaxis is the administration of antibiotics
to patients who have no known infection for the purpose
of preventing microbial colonozation and reducing the
potential for post operative complications.
111

• They play a very important role in :
• Patients at risk of bactereamia-induced infections.
• Patients with Pregnancy
• Breast feeding patients
• Secondary infections
• Or any other medically compromised patients .
115

• It is therefore important for the clinicians to have proper
knowledge, ability monitor the effectiveness of prescribed
antibiotics and consider changing the drug or the method of
therapeutic management with antibiotics.
116

Bibliography
• K.D. TRIPATHI text book of pharmacology.
• Antibiotic and antimicrobial use in dental practice: 2nd edn,
Michael G. Newman.
• Pharmacology an introductory text: Mary Kaye Asperheim, 6th
edn.
• Text book of pharmacology, 1st edn, H.L. Sharma.
• Anti microbial therapy in periodontics. Slots J.
• Text book of Peridontology: Carranza.
117

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