Chemotherapy

Chemotherapy
means the use of chemicals to eradicate
parasites, bacteria, viruses or cancer cells
in the body.
It depends on the drugs being selectively
toxic, i.e. Toxic to the cells of the parasite,
but not (too) toxic to the human host.

Bacteriostatic vs Bactericidal

Bacteriostatic: arrest the growth and replication

of bacteria at serum levels non toxic to the patient,

thus limiting the spread of infection.

Examples: erythromycin, tetracyclines,

chloramphenicol and sulphonamides.

Bactericidial kill bacteria.

Examples: Beta-lactam antibiotics and
aminoglycosides

These properties (-cidal and static)

can also depend on the antibiotic
concentration in the blood.
(e.g. Erythromycin and Clindamycin
may be bactericidal at higher blood
levels)

Spectrum of Activity

Relates to the number of microbes that are susceptible

to the action of the drug

Narrow (limited number) / Broad (wide)

Penicillin G is a narrow spectrum drug as it is only

effective against gram-positive microbe
Tetracyclines are effective against gram-positive and
gram-negative microbes (Broad)

Note: Never confuse these terms with potency

levels of the drugs or efficacy (ie. Narrow are
weak, Broad are strong)

Resistance:
Acquired or innate

loss of efficacy of a given AB against a particular strain

Frequently: Staphylococcus aureus, pseudomonas aeruginosa, mycobacterium
tuberculosii

Mechanisms responsible for resistance to antimicrobial drugs include the

following:

Inactivating enzymes that destroy the drug: Microbes may increase manufacture of
drug-metabolizing enzymes (penicillins)
Decreased drug accumulation: Microbes may cease active uptake of certain drugs
(tetracyclines)
Alteration of binding sites: Changes in receptors which decrease antibiotic binding
and action (aminoglycosides and erythromycin)
Development of alternative metabolic pathways: Microbes may synthesize modified
compounds which have little or no affinity for the drugs (sulphonamides)

Complications of antibiotic therapy:

1- Hypersensitivity:

It is frequently occur e.g. the penicillins, can cause serious

hypersensitivity problems ranging from rashes (Urticaria) to anaphylactic
shock.

2- Direct toxicity:

High serum levels of antibiotic may cause toxicity by affecting

cellular processes in the host e.g. aminoglycosides can cause ototoxicity
or nephrotoxicity.

3- Super infection:

Broad spectrum antimicrobial agent or combination of agents can

lead to alteration of the normal microbial flora of the upper respiratory,
intestinal and genitourinary tract which lead the overgrowth of organisms
especially fungi.

Pharmacology of the
Antibiotics

Antibiotics = a natural substance produced by

a micro-organism to kill another
Antiinfectives/Anti-microbrial = any agent
(natural or synthetic) that kills pathogens
(microbes)

Antibiotics
Classification:

Cell wall synthesis inhibitors

Protein synthesis inhibitors

Aminoglycosides
Tetracyclins
Macrolides
Chloramphenicol
Clindamycin

Folate antagonists

Beta-lactams (penicillins, cephalosporins, aztreonam, imipenem)

Poly-peptides (bacitracin, vancomycin)

Sulfonamides
Trimethoprim

Nucleic acid synthesis inhibitors

Quinolones

Antibiotics - Cell wall synthesis

inhibitors

Beta-lactam antibiotics:

1928 - Alexander Fleming observes the antibacterial effects of Penicillin

1940 - Florey and Chain extract Penicillin
Classification:

Penicillins

Narrow spectrum penicillinase sensitive

Narrow spectrum penicillinase resistant
Broad spectrum penicillins
Extended-spectrum penicillins

Cephalosporines

Carbapenems

Monobactams

PENICILLINS
Classification:
1- Narrow spectrum penicillinase resistant:
as methicillin, nafcillin, and oxacillin.
Their only use is in the treatment of staphylococcal infections.

2- Narrow spectrum penicillinase sensitive:

e.g., penicillin G (Benzylpenicillin) and Penicillin V (oral drug, more acid
stable).

Used in infections caused by streptococci, pneumococci,

gonococci, meningococci, gram-positive bacilli, and spirochetes.
3- Broad spectrum-penicillinase sensitive:
Ampicillin, amoxicillin
Similar uses to penicillin G.

Infections due to E.coli , H.influenzae and Salmonella.

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4- Extended spectrum-penicillinase sensitive:

Carbenicillin, piperacillin and ticarcillin.

Infections due to E.coli, H.influenzae, and gram-negative rods

(Pseudomonas aeruginosa) .
They can be combined with aminoglycosides for the initial
treatment of serious infection (e.g. septicemia, endocarditis)
when the bacterial cause has not been identified.

The major mechanism of bacterial resistance to penicillins is the

formation of -lactamases (penicillinases).

Clavulanic acid, Sulbactam, and Tazobactam are inhibitors of

- lactamases, and are used in combination with penicillins to

prevent their inactivation.

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The PENICILLINS
Narrow spectrum penicillinase-sensitive penicillins
Penicillin G
Penicillin V
Narrow spectrum penicillinase-resistant penicillins (anti-staphyloccocal penicillins)
Cloxacillin
Nafcillin
Methicillin
Dicloxacillin
Oxacillin
Broad Spectrum penicillinase-sensitive penicillins (aminopenicillin)
Amoxicillin
Ampicillin
Bacampicillin
Extended-Spectrum penicillinase-sensitive penicillins (Anti-pseudomonal
penicillins)
Carbenicillin
Mezlocillin
Piperacillin
Ticacillin
Beta-lactamase inhibitors
Clavulanic acid
Sulbactam
Tazobactam

Mechanism of action:
-lactam antibiotics are bactericidal drugs. They inhibit
cell wall synthesis by the following steps:
1- Binding of the drug to specific receptors (penicillin-binding
proteins, PBPs)
2- Inhibition of transpeptidases that act to cross-link linear
peptidoglycan chains that form part of the cell wall.
3- Activation of autolytic enzymes that cause lyses of the
bacterial cell wall.

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Pharmacokinetics:

Penicillins vary in acid stability and in oral bioavailability.

They are polar compounds.
They are excreted unchanged in urine.
Probenecid inhibits the tubular secretion of penicillins.

oral preparations: As Penicillin V, amoxicillin.

i.v or i.m. preparations: As Ampicillin and sulbactam combination,

and ticarcillin plus clavulanic acid.

Other preparations are effective by the oral, i.v, or i.m routes.

Most penicillins cross the blood-brain barrier only when the meninges are
inflammed.

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Toxicity
1- Hypersensitivity reactions: rashes, pruritus, fever,

urticaria and hemolytic anemia

The metabolite penicilloic acid reacts with the host proteins and
causes an immune reaction.

Anaphylaxis can also happen leading to shock or death. It

occurs in 5-10% of those receiving penicillins.
Pain and inflammation on injection sites

2-Gastrointestinal disturbances:

Nausea and diarrhea with oral penicillins, especially

Ampicillin.

3-Cation toxicity:

toxic effects from Na+ or K+ may occur when high doses of certain
penicillin salts are used in patients with cardiovascular or renal
disease.
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Cephalosporines
Derived from Cephalosporium sp. (same antibiotic mechanism as penicillins)
Cross-allergies with penicillins are common
Some CSs antagonize Vitamin K => bleeding
Some CSs block alcohol oxidation => disulfiram effect

Classified into generations:

1-4
Increasing activity against gram-negative bacterial and
anaerobes
Increasing resistance to destruction by beta-lactamases
Increasing ability to reach cerebrospinal fluid

First generation b-lactamase sensitive

Cefazolin
Naturally occuring /Active against gram-positive bacteria

Cephalexin
Second generation b-lactamase sensitive

Cefaclor
Some activity against gram-neg bacteria

Cefamandole- Cefoxitin
Third generation mostly b-lactamase resistant

Cefotaxime
Active against gram-negative bacteria
Active against Pseudomonas aeruginosa
Penetrates the CNS => used for meningitis

Ceftriaxone
Fourth generation mostly b-lactamase restistant

Cefepime
Broadest antimicrobial spectrum of any drug
Used for MDR bacteria and mixed infections

First generation cephalosporins

cefadroxil
Cefazolin
Cephalexin
Cephalotin
Cephapirin
Cephadrine
Second Generation cephalosporins
Cefaclor
Cefamandole
Cefonizind
Cefotetan
Cefoxitin
Cefmetazole
Cefprozil
Cefuroxime
Third Generation Cephaosporins
Cefnidir
Cefixime
Cefoperazone
Cefotaxime
Cefpodoxime
Ceftazidime
Ceftibuten
Fourth Generation Cephalosporin
Cefepime

Mechanism of action:
Mechanism similar to those of penicillins. They are
bactericidal against susceptible organisms.

Pharmacokinetics

Only a few cephalosporins are administered

orally, most are administered parenterally.

They are excreted mainly in the urine.

Toxicity:

GI system- Nausea, vomiting, diarrhea, anorexia,

abdominal pain and flatulence are common
effects.
Hypersensitivity reactions: skin rashes and
anaphylactic shock. These reactions occur less
frequently than with penicillins.
Cross-hypersensitivity between different
cephalosporins may occur.
Patients with a history of anaphylaxis to
penicillins should not be treated with a
cephalosporin.

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Pain at i.m injection sites and phlebitis after i.v

administration.
Acute tubular damage, especially with
aminoglycosides, when administered together.
The presence of a methylthiotetrazole group (e.g.,
in cefoperazone, cefamandole and cefotetan) cause
hypoprothrombinemia and may cause disulfiramlike reactions with ethanol.

The patient may experience flushing, headache,

nausea, vomiting and muscular cramps. This may
occur even up to 72 hours of cephalosporin
discontinuance.
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Carbapenems
Imipenem

Imipenem contains the -lactam ring structure

with low susceptibility to beta-lactamases.

It is the broadest- spectrum -lactam antibiotic

It is taken by i.v injection.

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Imipenem is rapidly inactivated by renal

dihydropeptidase I, SO, it is always administered

in combination with cilastatin, an inhibitor of this
enzyme.

This combination:
1-increases the plasma half-life of imipenem, and
2-inhibits the formation of a potentially nephrotoxic
metabolite.

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Adverse effects of Imipenem-Cilastatin :

1- Gastrointestinal distress.
2- Skin rash.
3- CNS toxicity (confusion, seizures, encephalopathy) at
very high plasma levels.

There is partial cross-allergenicity with the

penicillins.

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Monobactams
Aztreonam

No activity against G+ve bacteria or anaerobes.

Resist beta-lactamases.
No cross allergy with penicillin.
Adverse effects: GIT upsets, skin rash,
headache, vertigo.

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II- Non b-lactam cell wall inhibitors

Vancomycin

Vancomycin is a glycopeptide antibiotic active against most Gram-positive

organism.
Should be administered I.V.
It can be used orally just in case of intestinal infection because it is not
absorbed orally. It is the D.O.C for antibiotics associated pseudomembranous
colitis
has been particularly important in the treatment of antibiotic resistant
Staphylococcal and Enterococcal infections.
Vancomycin-resistant strains of Enterococcus have become widespread and
recently a few cases of resistant Staphylococcus aureus have appeared.
Its side effects is local pain, which may be severe and/or phlebitis . Doserelated ototoxocity: can progress to total deafness.
Red man syndrome which is head and neck erythema and hypotension due
to histamine release.

II- Non b-lactam cell wall inhibitors

Bacitracin
Mixture of polypeptides
Its mechanism like vancomycin.
It administered only topically due to its high toxicity.
If used parenterally, produce sever nephrotoxicity.

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