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1. Introduction to Chemotherapy
The term Chemotherapy was coined by Paul Ehrlich, an organic chemist and may be defined;
as the use of chemical compounds to destroy or inhibit harmful parasite without damaging the
host tissues.
Chemotherapy includes: chemotherapeutic agent and antibiotics. The term has been further
extended to include: treatment of neoplastic diseases with drugs.
Antibiotics are substances produced by microorganisms viz, (Bacteria, Fungi, Actinomycetes)
which kill or inhibit growth of other microorganisms in high dilutions. This definition excludes
metabolic products produced by microorganisms but are needed in high concentrations e.g Ethyl
alcohol, Lactic acid, and Hydrogen peroxide.
A chemotherapeutic agent also destroys or prevents the growth of microbes but may or may not
be derived from the living organisms. Initially the term was restricted to synthetic compounds,
but now it includes both synthetically and microbiologically produced drugs. Examples:
Sulphonamides, Isoniazid, Metronidazole, Chloramphenicol etc. However the term
Antimicrobial agent (AMA) may also be used for both synthetic and naturally obtained drugs
that destroy or inhibit microorganisms.
1.1. Mode of Action of Antimicrobial Drugs
The antimicrobial therapy takes the advantage of biochemical difference that exists between
human beings and the disease causing parasites.
The antimicrobial drugs usually act in one of the following ways, namely:
1. Inhibition of bacterial cell wall synthesis: synthesis of peptidoglycan which constitutes
the cell wall of bacteria can be blocked by antibiotics e.g Penicillins, Cephalosporins,
Bacitracin, Vancomycin. And Cycloserine.
2. Inhibition of protein synthesis: The protein synthesis takes place in ribosomes,
Ribosomes, are nucleoproteins. The bacterial ribosome consists of a 50 S (S denotes The
Sevendberg Unit which measures sedimentation rate not mass). Subunit and a 30 S
subunit: whereas, the human ribosome has 60 S and 40 S subunits. Besides, ribosomes,
messenger-RNA (mRNA) and transfer RNA (tRNA) are also involved in protein
synthesis. The mRNA forms the template for protein synthesis, and tRNA brings the
individual amino acids to the ribosome. The ribosome his three binding sites for tRNA,
(viz, A,P and E sites)
Tetracyclines block attachment of tRNA by binding to the 30 S subunit.
Amino glycosides cause misreading of mRNA message, as a result wrong amino acid is inserted
into the peptide chain, chloramphenicol inhibit the binding of new amino acids to the nascent
peptide chain by binding to the 50S subunit of the ribosome. Macrolides also binds to the 50S
subunit and inhibit translocation of tRNA from A site to P site. All these result in selective
inhibition of protein synthesis finally.
3. Inhibition of DNA-RNA synthesis: Rifampicin acts by inhibiting DNA dependent RNA
polymerase of bacteria e.g Fluoroquinolones (Ciprofloxacin, Nalidixic acid and
Norfloxacin) all act by inhibiting DNA gyrase.
4. Inhibition of cell metabolism by preventing synthesis of Folic Acid: The folate is
essential for DNA synthesis in both bacteria and in humans: while the human can take the
preformed folic acid from diet and transport it into the cells. Bacteria lack the transport
mechanism and must synthesize their own folate, Sulphonamides complete with paminobenzoic acid (PABA) for the enzyme folic acid synthetase: and hence, inhibit the
growth and multiplication of the bacterial cell.
5. Inhibition of cell membrance function:- Antimicrobial agents can act directly on the cellMembrane, affecting permeability, resulting in leakage of intracellular macromolecules
and icos; these include polymycin and polyene antibiotics e.g Nystatin and Amphotericin,
that bind to the cell wall sterols.
6. Preventing microtubule formation/function:- The anthelmintic drugs benzimidazoles (e.g
Albendozole) act by binding selectively to parasite Tubulin and prevent formation of
microtubule. Similarly the anticancer agents e.g Vinca alkaloids Vinblastine and
Vincristine act by disrupting the functioning of microtubules.
1.2 Classification of Antimicrobial Drugs
The antimicrobial agents may be classified in many ways according to their following different
aspects namely.
 Spectrum of activity
 Type of action
 Chemical structure and
 Origin
A. Spectrum of Activity
1. Narrow spectrum: The antimicrobial agents are effective against a limited group of
microorganisms. E.g Penicillin, Streptomycin, Erythromycin.
2. Extended spectrum: These are effective against Gram-positive organisms, and a
significant number of Gram-negative bacteria e.g Ampicillin, Cephalosporins and
Fluoroquinolones.
3. Broad spectrum: They are found to be effective against both Gram-positive and
Gram-negative bacteria and Chlamydiae and Rickettsiae, Tetracyclines and
Chloramphenicol.
B. Type of Action
The antibacterial agents do exert their action in several ways according to their spectrum
profile.
These usually include:
1. Bacteriostatic arrests the growth and replication of bacteria viz, Sulphonamides,
Tetracyclines, Erythromicin, Chloramphenicol, Ethambutol
2. Bactericidal-kills bacteria viz, Penicillins, Cotrimoxazole, Aminoglycosides,
Cephalosporins, Ciprofloxacins.
It is possible for a bacteriostatic drug to be cidal in higher concentration (as attained in urinary
tract) e.g Sulphonamides, Erythromycin. On the other hand some cidal drug may be static under
certain conditions e.g Cotrimoxazole, Streptomycin.
C. Chemical Structure
These essentially comprise
1. Sulphonamides and related drugs. Viz Sulfadiazine, Sulfones, Paraaminosalicylic
acid(PAS)
2. Diaminiopyrimidines viz, Trimethoprim, Pyrimethamine
3. Quinolones and Fluoroquinolones viz Nalidixic acid, Norfloxacion, Ciprofloxacin,
Ofloxacin.
4. B Lactam Antibiotics viz, Penicillins Cephalosporins
5. Aminoglycosides viz, Streptomycin, Gentamicin, Neomycin
6. Macrolide Antibiotics viz, Erthromycin, Roxithromycin, Clarithromycin, Azithromycin
7. Tetracyclines viz, Oxytertracycline, Doxycycline, Minocycline
8. Nitrobenzene Derivatives viz, Chloramphenicol
9. Polypetide Antibiotics viz, Polymyxin-B, Bacitracin
10. Polyene Antibiotics viz, Nystatin, Hamycin, Amphotericin B
11. gLYcopeptides viz, Vancomycin, Teicoplanin
12. Nitromidazole viz, Tinidazole
13. Nitrofuran Derivatives viz, Nitrofurantoin, Furazolidone
14. Nicotinic acid Derivatives viz, Isoniazid, Pyrazinamide, Ethionamide
15. Zole Derivaves viz, Miconazole, Ketoconazole, Fluconazole
16. Miscellaneous Agents viz, Rifampin, Ethambutol Thiacetazone, Clofazimine,
Griseofulvin
D. Origin
This essentially consists of:
Fungal Origin viz, Penicillins, Cepholosporins, Griseofulvin
Bacterial Origin viz, Bacitracin, Polymyxin B, Colistin
Actinomycetous Origin viz, Streptomycin, Neomycin, Chloramphenicol, Tetracyclines,
Macrolides,
1.3 Resistance of Microorganism to Antimicrobial Drugs
Bacteria are said to be resistant if the concentration of drug required to inhibit or kill germ is
Greater than the concentration that can be safely administered. Resistance to an antimicrobial
agent may be natural or acquired.
Natural resistance some microbes are naturally resistant to certain antimicrobial agents
e.g. Gram-negative organisms are unaffected by Penicillin; and Gram-positive organism, are
unaffected by Streptomycin.
Acquired Resistance Microbial species initially responsive to a particular drug may develop
resistant strains subsequently. The phenomenon of resistance has considerably reduced the
option available for the medical treatment of many bacterial infections. Resistance may be due to
indiscriminate and inappropriate use of antibiotics in conditions that can be relieved without any
treatment
for
example
common
cold
and
diarrhea.
The microbes may become resistant by the following ways and means, namely:
1. Mutation (Chromosomal): It is a genetic change that occurs spontaneously and randomly
though the rate of spontaneous mutation is very low. However, in some species of
bacteria mutation may cause a change from drug sensitivity to drug resistance, e.g
rifampin resistant mycobacterium tuberculosis and methicillin resistant staphylococcal
infections.
2. Gene Transfer (Extrachromosomal Resistance): There are many bacteria that contain
extracomosomal genetic element called ‘plasmids’ in the cytoplasm. These carry genes
for resistance to antibiotics (r genes) that can be transferred from one microorganism to
another by the following mechanisms.
a) Conjugation- During this process a cell to cell direct contact occurs through a sex
pilus or bridge. It is the main mechanism for spread of antibiotic resistance. Gene
transfer by conjugation predominantly occurs in Gram-negative bacilli and in some
Gram-positive bacteria. Cholramphenicol resistance to typhoid bacilli, streptomycin
resistance to E.coli; Penicillin resistance to Haemophillus and Gonococci have been
developed by Conjugation phenomenon.
b) Transduction during transduction plasmids carrying resistant gene is transferred to a
susceptible organism by a bacteriophage (a virus that infects bacteria). The newly
infected bacterial cell may become resistant to the antibacterial agent and is capable
of passing the resistant trait to its progeny. It is clinically important for certain
instances of Penicillin, erythromycin and chloramphenicol resistance.
c) Transformation- This method of transferring genetic material involves release of
resistance carrying DNA into the environment and this may be taken by another
sensistive organism which may become resistant to the agent. This mechanism is not
of much clinical significance except pneumocooci and neisseria resistance to
penicillin.
1.4 Biochemical Mechanisms of Resistance to Antibiotics
These are of three types, namely
1. Elaboration of an enzyme that inactivates a drug e.g inactivation of β-lactam
antibiotics viz, Penicillins and Cephalosporins by the enzyme β-lactamases produced
mainly by staphylococci, inactivation of Chloramphenicol by acetyltransferase produced
by resistant strains of Gram-positive and Gram-negative organisms.
2. Decreased Drug Accumulatiion Due to Altered Bacterial Permability It may be
exemplified by the plasmid mediated resistance to Tetracyclines. The bacteria may
acquire plasmid directed inducible proteins in their cell membrane, which promote
energy dependent efflux of the Tetracyclines. This energy dependent efflux may also be
responsible for resistance to Erythromycin and Fluoroquinolones.
Many hydrophilic antibiotics enter the bacterial cell via specific channels formed by proteins
called ‘porins’. Plasmid determined inhibition of ‘porin’ synthesis results, in much lower
concentration of those antibiotics in resistant strains. Similarly, Chloroquin resistant p.falciparum
accumulates less Chloroquine.
3. Modification of Drug Binding Site or Loss of Affinity S. aureus us and E-coli develop
a RNA polymerase by a chromosomal mutation that does not bind to
rifampin.Aminoglycoside resistance results from alteration in the binding site, 30S
subunit of the ribosome.
4. Development of an Alternative Metabolic Pathway (AMP): Trimethoprim resistance
results due to plasmid directed synthesis of dihydrofolate reductase with low or zero
affinity for the drug.
1.5 Cross Resistance
Cross Resistance is the phenomenon in which bacteria resistant to one AMA are found to be
resistant to another AMA to which the organism has not been exposed. It is commonly seen
among closely chemically related drugs or between drugs sharing tha same mechanism of action
e.g. resistance to one Sulphonamide means resistance to all other Sulphonamides. Occasionally,
the cross resistance may develop between two chemically dissimilar compounds (e.g.
Erythromycin-Lincomycin; Chloramphenicol-Tetracycline).
1.6 Prenention of Resistance
The following steps should be taken to prevent resistance, such as:
1. Antibiotics should be used only when necessary.
2. Selection of proper drug, rapidly acting and selective narrow spectrum AMAs should be
used whenever possible.
3. Broad spectrum drugs should be used if rationally indicated.
4. Combination of AMAs should be undertaken in case of prolonged illness e.g.
Tuberculosis (TB).
5. AMAs should be used in optimal does and for optimal periods to eradicate even the most
resistant mutant pathogens (RMPs).
1.7 Selection of an Antimicrobial Agent
A number of factors influence the selection of the most appropriate antimicrobial agent.
These essentially include:
1. Identification and sensitivity of organism to a particular agent.
2. The site and severity of infection.
3. Patient should not be hypersensitive or unable to tolerate the drug
4. Age and state of renal and hepatic function of the patient.
5. Spectrum and type of activity of the antimicrobial agent.
1.8 Adverse Effects of Antibiotics
These are of three variants, namely:
1. Hypersensitivity: Antimicrobial drugs frequently cause allergic reactions, for example,
penicillins may produce Type I hypersensitivity reaction ranging from urticaria to
anaphylactic shock.
2. Organ Toxicity is the result of effects of antibiotics on the cellular processes in the host
directly. These effects usually occur with the overdosage but sometimes may occur
because of accumulation of drug given in normal doses.
Eexamples: Aminoglycosides can cause otoxicity and nephrotoxicity e.g. Trimethoprim
produces bone-marrow depression with agranulocytosis and thromobocytopenia.
3. Super infections (Suprainfections) It is defined as the development of a new infection
as a result of antimicrobial therapy particularly with broad spectrum antibiotics, such as:
Tetracyclines, Chloramphenicol, Ampicillin or Newer Cephalosporins or Combination of
agents. These agents can cause alterations of the normal microbial flora of the intestinal,
respiratory or genitourinary tract normal flora inhibit pathogenic organisms by producing
bacteriocins and also compete for essential nutrients lack of competition allows
overgrowth of resistant bacteria, yeasts and fungi, or strains of proteus and pseudomonas.
These infections are often difficult to treat.
1.9 Combinations of Antimicrobials
The combined use of two or more antimicrobial agents should be done only with a specific
purpose of obtaining an effect much greater than that of sum of two agents given separately and
should be limited to a few clinical situations in which combination therapy has been proved
superior exclusively.
Examples:
a) Blockade of successive steps in a metabolic pathway e.g. sulphamethoxazole and
trimethoprim.
b) Penicillin and Aminoglycoside for the eradication of enterococci in endocarditis.
c) Carbenicillin and gentamycin for pseudomonas infections in neutropenic patient.
d) To delay the development of resistance e.g. in the treatment of tuberculosis and aids.
Antagonism Combination of a bactericidal with a bacteriostatic results in antagonism because
the bactericidal antibiotics (Penicillins, Cephalosporins, Aminoglycosides) require bacterial
growth, while the bacteriostatic drugs (e.g. Tetracyclines, Chloramphenicol) inhibits bacterial
growth.
Examples: Penicillin alone is much more effective for treating pneumococcal meningitis than
the combination of Penicillin with Tetracycline.
Indications for Combinations of Antimicrobial Drugs
1. Mixed bacterial infections e.g. intra-abdominal and genital-tract infections, hepatic and
brain abscesses.
2. Severe infections or in infections of unknown origin combination of Gram-negative
antibiotic may be given.
However, the combination should not be used as a short cut and should be discontinued after the
availability of bacteriological data.
3. To prevent emergence of resistant organisms, for example: Isoniazid plus Pyrazinamide
and Rifampin in the treatment of tuberculosis.
4. To reduce intensity or incidence of adverse drug effect. This is needed when
antimicrobials with low safety margin is used in doses that produce severe adverse
effects, e.g. Amphotericin B in combination with Flu cytosine for cryptococcal
meningitis infections.
Disadvantages of Antimicrobial Combinations
These essentially include:
1. Increased risk of toxicity from two or more agents.
2. Increased chances of super infections.
3. Increased cost to the patient.
4. Antagonism of antibacterial effect.
1.10 Prophylactic Use of Antimicrobials
This refers to the use of antibiotics for prevention rather than the treatment of infections. The
prophylactic use should be restricted to clinical situations in which benefit outweigh the potential
risk. The prophylactic antibiotics are indicated for the following conditions, such as:
1. To protect against specific microorganisms
These are of three types:
a) Prevention of infection by group A streptococci infections in patients with a
history of rheumatic heart disease; long acting Penicillin-G is used for this
purpose.
b) Prevention of gonorrhea or syphilis after contact with an infected person; procaine
penicillin is indicated.
c) Prevention of recurrent urinary tract infection (UTI) caused by E.coli, a
combination of Trimethoprim-Sulfamethoxazole is used.
2. Prevention of infection in high risk patients
These are of four different kinds:
a) Pretreatment of patients with valvular defects undergoing dental extraction,
tonsillectomy or endoscopies that produce a high incidence of bacterimia to
prevent endocarditics.
b) Organ transplantation of cancer chemotherapy patients.
c) To prevent wound infections after various surgical procedures. This is the most
extensive, prolonged use of antimicrobials. Wound infection results when a
number of bacteria are present in the wound at the time of closure. Effective and
judicious use of antibiotics is required in this situation. They should be given just
prior to operation and a few hours after operation. Continuation of antimicrobial
treatment beyond 24 hours is unnecessary and may lead to development of
resistant strains and superinfections. The antibiotic should effectively reduce the
incidence of wound infection. This has promoted the use of first generation
cephalosparins for chemoprophylaxis. However, Cefazolin given 1 g by IV, is the
most favoured drug.
d) Dirty contaminated surgical procedures (e.g. resection of the colon)
chemoprophylaxis should not be used routinely in clean surgical procedures.
Sulfonamides, Cotrimoxazole and Quinolones
The three above mentioned class of chemotherapeutic agents shall now be discussed separately
as under:
2.1 Sulphonamides
Sulphonamides were the first effective chemotherapeutic agent used to treat systemic
infections. German scientist Gerhard Domagk in 1953 first reported the effectiveness of
the red dye prontosil to treat experimental streptococci infection in mice. He
subsequently cured his daughter of streptococcal septicaemia by using prontosil. Other
workers showed that prontosil was inactive in vitro and was broken down in vivo to give
active substance p-aminobenzene sulphonamide (sulphanilamide).
Subsequently, a large number of Sulphonamides were synthesized but they had a short
period of clinical use because of rapid emergence of bacterial resistance and the
availability of more active and safer antibiotics.
Classification of Sulphonamides
Sulphonamides that are still of clinical interest can be grouped as under:
i. Systemic use
a) Short acting (4-8 hr): Sulphdiazine, sulphisoxazole.
b) Intermediate acting (8-12 hr) : Sulfamethoxazole
c) Long acting (-7 days) : Sulfadoxine
ii. Local use
a) Opthalmic : Sulfacetamide
b) Topical : Mafenide, silver sulfadiazine
c) Gastroenteritis : Sullfasalazine
Antibacterial Spectrum
Sulphonamides are mainly bacteriostatic, but also act as bactericidal. Different concentration
may be attained in urine. Sulphonamides inhibit many Gram-positive and some Gram-negative
bacteria. The microorganisms susceptible to Sulphonamides in vitro are streptococcus pyogenes,
Haemophilus, influenza, Chlamydia trachomatis and some protozoa. A few species:
Staphylocoecus aureus, Gonococci, Meningococci, Pneumococci, E.coli and Shigella but
majority are resistant.
Mechanism of Action
Sulphonamides are structural analogue of p-aminobenzoic acid (PABA). Which is required for
the Synthesis of folic acid in bacteria. Folate is essential for purine and ultimately DNA synthesis
both in bacteria and mammals, but mammals utilize preformed folic acid supplied in diet;
whereas, bacteria need to synthesize it. Sulphonamides complete with PABA for the enzyme
dihydropteroate synthetase, and inhibit the union of PABA with pteridine residue to from
dihydropteroic acid, which conjugates with glutamic acid to produce dihydrofolic acid. Being
similar in chemical structure bacteria take up Sulphonamide instead of PABA to form an altered
folate, which becomes metabolically injurious.
Presence of an excess of PABA, antagonizes the antibacterial action of Sulphonamide. Pus and
tissue extract contain thymidine and purins, which decrease bacterial requirement of folic acid,
and hence Sulphonamides are ineffentive after pus formation. Bacteria, which utilize preformed
folate are insensitive to Sulphonamides.
Resistance to Sulphonamides. A variety of microorganisms are capable of acquiring resistance
to Sulphonamides. Prominent among these are staphylococci, Gonococci, Pneumococci,
Streptococci, Meningococci and E.coli.
Resistance to Sulphonamide is plasmid mediated and results in the synthesis of the enzyme
Dihydropteroate synthase with low affinity for Sulphonamides. Development of resistance has
resulted in markedly decline use of Sulphonamides.
Pharmacokinetics
Sulphonamides intended for systemic use are rapidly absorbed from the gastrointestinal tract
and distributed widely to tissues and body fluids (including CNS and CSF), placenta and fetus.
The major pathway of metabolism is acetylation chiefly in liver. The acetylated products have no
antibacterial activity but can contribute to the adverse effects. They are poorly soluble in acidic
urine and may cause crystalluria* and renal complications.
Sulphonamides are manly excreted by kindly: Excretion is increased in alkaline urine due to
reduced tubular reabsorption.
Suffisoxazole and Sulfiroxazole are more soiuble in alkaline urine: and, therefore, are used for
treating urinary tract inrfections (UTIs).
Adverse Effects
1. Crystalluria: Sulphonamides may precipitate in neutral or acidic urine producing
crystalluria (stone formation) resulting in renal irritation or even obstruction. Adequate
hydration and alkalinization of urine prevent precipitation by promoting ionization. More
soluble Sulphonamides e.g. Sulfisoxazole are less likely to cause this problem.
2. Hematopoietic Disturbances: Sulphonamides can cause hemolysis in patients with
glucose-6-phosphate dehydrogenase deficiency e.g. Granulocytopenia*,
Thrombocytopenia and rarely aplastic anaemia can also occur.
3. Hypersensitivity: Hypersensitivity reactions, such as: drug fever, skin rashes, urticaria
and exfoliative dermatitis are more common. Stevens Johnson Syndrome** though rare
(less than 1%) occurs more frequently with long acting Sulphonamides.
4. Kernicterus: Kernicterus may occur in newborns because Sulphonamides displace
bilirubin from plasma protein binding sites. The free bilirubin crosses the blood brain
barrier(BBB)
5. GI Symptoms: They commonly produce nausea, vomiting and epigastric pain.
6. Miscellaneous: Hepatitis due to liver damage is rare. They may produce contact
sensitization; therefore not recommended for topical use. However, ocular use is
permitted.
These essentially include:
1. These drugs are contraindicated in patients with a history of sulpha hypersensitivity and
advanced kidney deseases
2. They should not be given to pregnant women near term because of possible placental
transfer to the foetus and danger of kernicterus.
3. Caution is required in patients with liver disease, blood dyscrasias and impaired kidney
function.
4. Advise the patient to have high fluid in-take.
Drug Interactions: Sulphonamides displace phenytoin, tolbutamide and warfarin from
their binding sites on serum albumin and thus enhance their action. Free methotrexate level
also rise due to displacement from binding and decrease renal excretion.
Therapeutic Uses
Systemic use of Sulphonamides as single agents are rare now. They are usually combined
with Trimethoprim or Pyrimethamine. The current therapeutic uses of Sulphonamides are:
1. Urinary tract infections (UTIs) : The Sulphonamides are preferred for treating acute
UTIs : Sulfisoxazole and Sulfomethoxazole.
Each is given in combination with Phenazopyridine-a urinary tract anaesthetic.
2. Ulcerative Colitis Ulcerative colitis is an inflammatory bowel desease manifested by
diarrhea with blood in stools and affecting mainly the colon and rectum. Sulfasalazine
is the mainstay of therapy.
3. Toxoplasmosis and Malaria: Sulfadiazine in combination with Pyrimethamine is used
in the treatment of acute toxoplasmosis Sulfadoxine, the long acting sulfonamide in
compination with Pyrimethamine is used as a second-line treatment in cases of
resistant malaria.
4. Trachoma and inclusion conjunctivitis: Sodium sulphacetamide-opthalmic solution or
ointment is effective in these diseases though systemic therapy with Tetracycline or
Azithromycin is required for eradication of the disease.
5. Burns: Mafenide may be used topically to prevent bacterial colonization and infection
of burn wounds. Silver Sulphadiazine is preferred to Mafenide as it does not cause
stinging pain which occurs with Mafenide Cream when applied over burn wounds.
2.2 COTRIMOXAZOLE
The combination of Trimethoprim, a trimethoxy benzylpyrimidine with the Sulpha drug,
Sulfamethoxazole is called Cotrimoxazole (R).
Mechanism of Action
Trimethoprim inhibits bacterial dihydrofolic acid reductase that converts dihydrofolic acid
to tetrahydrofolic acid, a step leading to the synthesis of purine and then DNA. Trimethoprim
is 50,000 times moreactive against bacterial dihydrofolic acid reductase than its equivalent
human enzyme, which accounts for its selective toxicity. Since Sulphonamides act by
inhibiting the synthesis of dihydrofolic acid a combination of Trimethoprim and
Sulphonamide act sequentially, resulting in synergistic antimicrobial activity individually
both Sulfonamide and Trimethoprim is bacteriostatic but their combination is bactericidal,
PABA
Dihydropteroate Synthetase
Inhibited by Sulphonamides
Dihydrofolic acid
Dihydrofolic acid reductase
Inhibited by Trimethoprim
Tetrahydrofolic acid
Purine
DNA
Antibacterial Spectrum
The antibacterial spectrum of Trimethoprim and Sulphamethoxazole is similar. It is effective
against Gram-negative species like: E.coli S. typhi. Haemophilas, Influenzae, Proteus,
Enterobacteria, Neisseria, Vibrio cholera and Gram-positive microbes, such as: Staphylococcus
aureus, Streptococcus, pyogenes, Nocardia etc.
Resistance- Resistance to Trimethoprim is due to plasmid encoded resistant dihydrofolate
reductases via mutation. Reduced cell permeability, overproduction of dihydrafolate reductase of
production of an altered reductase having lower affinity for the inhibitor may result in resistance.
Pharmacokinetics
Cotrimoxazole is completely and rapidly absorbed after oral administration. The peak plasma
levels occur between 20to 4 hours. To achieve optyimum synergy sulphmethoxazole and
triumethoprim are given in a ratio of 5:1 (Sulphamethoxazole 400mg and Trimethoprim 80 mg
per tablet.) Sulphamethoxazole was chosen for combing with Trimethoprim because both have
nearly the same plasma half-life (about 10 hours).
Both agents are mainly excreted in the urine.Trimethoprim being a weak base its excretion is
increased in acidic urine; whereas Sulfamethoxazole excretion is increased by alkalinization of
urine.
Adverse Effect
All adverse effects seen with the Trimethoprim and Sulphonamides can be produced by
Cotrimoxazole. These include: nausea, vomiting, glossitis*. (Inflammation of the tongue,)
stomatitis, headache and rashes. Megloblastic anaemia and blood dyscrasias are rare.
AIDS patients with pneumocystis carinii infection have reported bone marrow deporession after
high intravenous doses of cotrimoxazole. It should not be given during pregnancy because of the
risk of teratogenic effects.
Therapeutic Uses
1. Urinary tract infections Cotrimoxazole has been extensively used in urinary tract
infections and prostatitis. Two double strength tablets (Trimethoprim 160mg, plus
Sulphamethoxazole 800 mg) are given every twelve hourly for acute, chronic and
recurrent cases. Single dose therapy with 4 tablets of Cotrimoxazole has been
recommended for acute cystitis it may also be given as a prophylactic in recurrent
urinary tract infections of women in the dose of one half of the regular tablet three
times weekly for many months.
2. Respiratory tract infections both upper and lower respiratory tract infections(RTIs)
Including: chronic bronchitis pneumonia due to H.influenzae and lung abscess due to
staphylococcus aureus respond to Cotrimoxazole treatment.
3. Gastrointestinal infections Cotrimoxazole is effective in the treatment of Ampicillin
resistant shigellosis. It was an effective alternative to Chloramphenicol in the
treatment of typhoid fever but due to the development of resistant strains of S.typhi it
is no longer preferred.
4. Venereal Disease Gonorrhoea in both men and women can be treated with large doses
of Cotrimoxazole given for short duration.
5. Chancroid two double strength tablets of Cotrimoxozole given every 12 hours for 7
days is one of the drug of choice and as effective as Erythromycin (7
days)/Ceftriaxone (single IM dose).
6. Pneumocystis carinii: Infection with p.carinii can be treated with high doses of
Cotrimoxazole in immunosupressed patients. Low dose therapy has been used for
prevention in severly neutropenic patients.
7. Miscellaneous infections Cotrimoxazole has been used in the treatment of cholera,
plague, brucellosis, nocardiosis and prophylaxis of traveller’s diarrhoea.
2.3 Quinolones
Fluoroquinolones
Nalidixic acid was the first quinolone introduced in 1960 and had limited use in the
treatment of urinary and gastro-intestinal tract infection because of rapid emergence of
resistant strains, failure to achieve systemic antibacterial levels and less potency. This led, to
the developed by fluorinations of the quinolone structure at position 6 and piperazine
substitution at position 7. Later on other fluoroquinolones (FQs) have been developed with
additional fluoro and other substitution, such as: Ciprofloxacin, Ofloxacin, Pefloxacin,
Lomefloxacin, Sparfloxacin, Levofloxacin, Gatifloxacin and Moxifloxacin.
Mechanism of Action
The fluoroquinolones (FQs) enter the cell by passive diffusion through water-filled protein
channels (porins) in the outer membrane. Intracellularly, the FQs inhibit the bacterial DNA
gyrase enzyme (Topiosomerasell); and thus, prevents replication of transcription DNA.
In gram-positive bacteria FQs target a similar enzyme Topiosomerase IV.
Antibacterial Spectrum
Fluoroquinolones are bacterial in nature and are effective against a broad range of Gramnegative and Gram-positive organisms. Norfloxacin is the least active with MIC values 4 to 8
times higher than Ciprofloxacin, the prototype drug.
Ciprofloxacin, Ofloxacin, Lomefloxacin, Pefloxacin and Sparfloxacin are more potent
against E coli and various species of Salmonella, Shigella, Enterobacter, Campylobacter and
Neisseria with MIC 1-2 meg. mL-1 or less. Streptococci and Enterococci are less susceptible
and efficacy in infections caused by these organisms is limited. Ciprofloxacin is more active
against Gram- negative bacteria particularly P.aeurginosa. These FQs also have good activity
against staphylococci including Methicillin resistant strains. Most anaerobic microorganisms
are resistant to the Fluoroquinolones except Sparfloxacin, Moxifloxacin and Trovafloxacin.
It has been duly observed that Chlamydia. Mycoplasma. Legionella, Brucella and
Mycobacterium are moderately susceptible. Moxifloxacin and trovafloxacin have more
Gram-positive activity.
Pharmacokinetics
Absorption after oral administration Fluoroquinolones are absorbed rapidly (biovailability of
35-95%), but food, Iron or zinc and Al or mg contains Antacids delays absorption.
Ciproofloxacin, Levofloxacin, Ofloxacin and Pefloxacin can be administered intravenously,
but serum concentrartion are similar to those of oral drugs.
Most Fluoroquinolones are partly metabolized by P450 enzynes and eliminated by
glomerular filtration and tubular secretion dose adjustment is necessary in renal impairment
except for Trovafloxacin or Moxifloxacin. The half-life ranges from 3 hours (Norfloxacin
and Ciprofloxacin), to 10 hours, (Pefloxacin and Fleroxacin) or longer (Sparfloxacin).
Adverse Effects
Fluoroquinolones are extremely well tolerated with only mild side effects, such as:
a) Gastrointestinal: Nausea, Vomiting, bad taste and anorexia. Diarrhoea is infrequent,
as gut flora is not affected.
b) CNS: Headache, dizziness, insomnia, tremors may occur occasionally. Seizures are
rare.
c) Photosensitivity has been reported with lomefloxacin and Pefloxacin. Patients are
advised to avoid excessive sunlight.
d) Miscellaneous: Trovafloxacin may cause acute hepatitis and hepatic failure though
rarely.A reversible arthopathy may occur due to ithe damage of growing cartilage and
therefore fluoroquinolones are not routinely recommended for children under 18
years of age.
e) Contraindcations Fluoroquinolones are contraindicated for nursing mothers as they
are excreted in breast milk. They should be avoided in pregnancy.
f) Drug interactions: Fluoroquinolones can raise serum levels of Theophylline,
Warfafin, Caffeine and Cyclosporene.
Therapeutic Uses
The various therapeutic uses of the Fluoroquinolones are enumerated as under:
1. Urinary Tract Infections (UTIs) even in complicated cases caused by pseudomonas.
Norfloxacin, Ciprofloxacin and Ofloxacin all are effective.
2. Bacterial diarrhea caused by shigella, salmonella, toxigenic E. coli or campylobacter.
3. Typhoid: Eradicate carrier state due to cidal action.
4. Soft tissues, bones joints and wound infections.
5. Respiratory Tract Infections. (RTIs): The Fluoroquinolones should not be used for
routine treatment because pneumococci and streptococci have low and variable
susceptibility; however, infections caused by pseudomonas, Mycoplasma, Legionella and
H. influenza can be treated by Levofloxacin, Sparfloxacin and other newer
fluoroquinolones with enhanced Gram-positive activity.
6. Gonococcal infections.
7. Chancroid.
8. Tuberculosis.
9. Conjunctivitis.
10. Meningitis.
11. Anthrax
12. Chlamydial urethritis or cervicitis: Ofloxacin is effective.
13. Chronic Bacterial prostatitis.
Doses of Quinolones and Fluoroquinolose-are as given under
1. Ciprofloxacin:- 250-500 mg twice a day (BD)
2. Ofloxacin: - 200-400 mg BD (twice a day).