Beta-Lactam Antibiotics

Dr. Vishaal Bhat

Melaka Manipal Medical College

The Beta-Lactam Antibiotics

Cell wall active agents

Prevent the final step in the synthesis of the bacterial cell wall

Range from very narrow spectrum to very broad spectrum

Introduction

Most widely produced and used antibacterial drugs in the world since 1941.

-Lactams are divided into several classes based on their structure and function.

Often named by their origin, but all classes have a common -Lactam ring structure.

BETA-LACTAM ANTIBIOTICS

(inhibitors of cell wall synthesis)

The major subdivisions are:

(a) penicillins whose official names

usually include or end in cillin(b) cephalosporins which are

recognized by the inclusion

of cef or ceph in their official names.

(c) carbapenems (e.g. meropenem,

imipenem)

(d) monobactams (e.g. aztreonam)

(e) beta-lactamase inhibitors (e.g.

clavulanic acid, sulbactam).

I. PENICILLINSA. FLEMING(18811955)Penicillin G- P. notatum

(1929)

Penicillium chrysogenum

History

1928- Alexander Fleming discovers a mold which inhibits the growth of staphylococcus bacteria

1940- penicillin is isolated and tested on mice by researchers at Oxford

1941- penicillin mass produced by fermentation for use by US soldiers in WWII

1950s- 6-APA is discovered and semi-synthetic penicillins are developed.

1960s to today- novel -lactams/ -lactamase inhibitors are discovered and modified from the natural products of bacteria

Classification

Penicillins Natural penicillins

PenG, PenVK, Benzathine Pen, Procaine Pen

Aminopenicillins

Ampicillin, Amoxicillin

Anti-Staph penicillins

Oxacillin, Dicloxacillin, Methicillin, Nafcillin

Anti-Pseudomonal

[Carboxy] Ticarcillin

[Ureido] Piperacillin

How do they work?

1. The -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

Penicillin binding

protein

Peptidoglycan Synthesis

Mechanism of Action

Bacterial Resistance

Bacteria have many methods with which to combat the effects of -lactam type drugs.

Intrinsic defenses such as efflux pumps can remove the -lactams from the cell.

-Lactamases are enzymes which hydrolyze the amide bond of the -lactam ring, rendering the drug useless.

Bacteria may acquire resistance through mutation at the genes which control production of PBPs, altering the active site and binding affinity for the -lactam .

PK/PD

The -lactams are time-dependent killers The effect is directly proportional to the amount of TIME the

concentration of the antibiotic at the site of infection is ABOVE the MIC of the organism.

The -lactams are BACTERICIDAL (at therapeutically attainable levels)

Time Dependant

H Derendorf

Absorption,distribution & metabolism

Oral absorption of most penicillins is poor

Exception: penicillin v

Amoxicillin

Food interferes with absorption

To increase GI absorption: give ester form: BacampicillinCarbenicillin

DistributionWidely distributed

Relatively insoluble in lipid

Hence, have poor penetration into cells and BBB

Inflammation ( eg. Meningitis ) permits entrance into CSF

Absorp., metabolism ( cont. )

Protein binding differs :Ampicillin and penicillin G 20% boundNafcillin, oxacillin, 90% boundcloxacillin , dicloxacillin

Metabolism and excretion

Not metabolized in humanExcreted mostly unchanged in urine( except. Nafcillin,oxacillin, cloxacillin, dicloxacillin )Probenecid blocks their secretionHalf-life 30-60 min ( increased in renal failure)

Penicillin G

Used i.m ,slow i.v or infusionHighest activity against Gram-positive organisms but susceptible to Beta-lactamase.

Effective against:

Gram-positive aerobic cocci Staph. aureus- not producing penicillinase, S.pneumoniae ( group A ), S.pyogenes

Gram-negative aerobic cocci- N.meningitides, N. gonorrhea-no longer of choice

Gram- positive bacilli: Bacillus anthracis Spirochetes: T. pallidum drug of choice Anaerobes

Clostridium spp but inactive against B.fragilis Actinomycetes israelii (actinomycosis)

Repository penicillins

Developed to prolong duration of penicillin G in the blood

1. Penicillin G procaine

Duration 12- 24 hr

It is given i.m and not i.v( risk of procaine toxicity)

Seldom used now ( increased frequency of penicillinase producing N. gonorrhea

Repository penicillins ( cont.)

2. Penicillin G benzathine (i.m)

Duration 3- 4 weeks

Painful at the injection site ( limits its use )

Uses

1. Syphilis

2. Rheumatic fever prophylaxis( inhibits

group A beta- hemolytic streptococci)

3. Streptococcal pharyngitis

Disadvantages of penicillin G

A. Destroyed by gastric HCL

B. Inactivated by penicillinase

C. Narrow spectrum of activity

Acid resistant penicillins

Phenoxy- methyl penicillin ( penicillin v), p.o.

( spectrum of activity is similar to penicillin G )

Uses

Group A Streptococcal pharyngitis

Prophylaxis against group A streptococci in pts with history of rheumatic heart disease.

Disadvantages

Readily hydrolyzed by beta-lactamase

Penicillinase-resistant penicillins

Methicillin Oxacillin

Cloxacillin Dicloxacillin

Floxacillin Nafcillin

Lower activity against G+ compared to Penicllin G

but

Are the choice for infections caused by penicillinaseproducing S. aureus.

However, MRSA & ORSA has emerged.

Not effective against G- aerobes( E.coli, klebsiella, N.gonorrhea or pseudomonas spp.)

Less active than penicillin on anaerobes.

High protein and food binders

Extended- spectrum penicillins

a) Ampicillin, Ampicillin- sulbactam, Bacampicillin, Amoxicillin, Amoxicillin- clavulanic acid.

Less active than penicillin G against G+ cocci. Active against G- organisms.

Extended-spectrum penicillins

UsesH. Influenza infections ( otitis media, sinusitis, chronic

bronchitis, pneumonia, bacterial meningitis ).

M.catarrhalis

E. Coli infections ( Urinary & biliary infections ).

Samonella infections ( typhoid fever )

Shigella infections ( ampicillin )

Gonococcal infections ( alternative for penicillin in the treatment of gonorrhea )

Prophlaxis of infective endocarditis

DisadvantagesAmoxicillin & ampicillin alone are readily destroyed by Staph.

Penicillinase.

Antipseudomonal penicillins ( cont )

Ticarcillin-clavulanic acid, piperacillin,piperacillin-tazobactam ( Tazocin )

Uses

Pseud. aeruginosa. For pseud. septicemia, they should be given together with an aminoglycoside

( eg. Gentamicin ).

Disadvantages

Ticarcillin and piperacillin alone are readily destroyed by S. penicillinase. High dose may lead to hypernatraemia due to sodium content.

Adverse effects of penicillins

1.Hypersensitivity reactions ( occur in 1-10% of pts; fatality occur in 0.002%)

( immediate, accelerated & late allergic rxns) ** Cross-reactions

Urticarial rash

Fever

Bronchspasm

Serum sickness

Exfoliative dermatitis

Stevens- Johnson syndrome

Anaphylaxis

2. Super infections

3. Diarrhoea

4. May cause convulsions after high doses by i.v or in renal failure

-Lactamases

-Lactamases were first discovered in 1940 and originally named penicillinases.

These enzymes hydrolyze the -lactam ring, deactivating the drug, but are not covalently bound to the drug as PBPs are.

Especially prevalent in Gram (-) bacteria.

Three classes (A,C,D) catalyze the reaction using a serine residue, the B class of metallo- -lactamases catalyze the reaction using zinc.

-Lactamase Inhibitors

How do you evade a -lactamase?1. Use a non--lactam agent

2. Steric Inhibition

Penicillins with large side chains

Cephalosporins

3. -lactam + -lactamase inhibitors

Not all -lactamases are inhibitable (!)

-Lactamase Inhibitors

There are currently three clinically available -lactamase inhibitors which are combined with -lactams; all are produced through fermentation.

These molecules bind irreversibly to -lactamases but do not have good activity against PBPs. The rings are modified to break open after acylating the enzyme.

-Lactam/Inhibitor combinations

Aminopenicillins:

ampicillin-sulbactam

amoxicillin-clavulante

Extended-Spectrum Penicillins

piperacillin-tazobactam

ticarcillin-clavulanate