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Quinolone, Folic acid antagonists and Urinary tract antiseptics.

Quinolone
- The first predecessor in this group of antibiotics is Nalidixic acid, from this the second
generation was derived in which the nalidixic acid was fluorinated forming norfloxacin, after
which other drugs were introduced like ciprofloxacin. Hence from the second generation they
are referred to as fluoroquinolone.
Mechanism of action.
- The drug enters by passive transport through porins on the membrane of the bacterium.
- They act on topoisomerase II (DNA gyrase) and topoisomerase IV during bacterial growth and
reproduction. Topoisomerase are enzymes that change the topology of DNA and not the
DNA primary sequence.
- Inhibition of DNA gyrase causes the inhibition of relaxation of the positively supercoiled DNA
and inhibition of Topoisomerase IV causes an interference in the separation of daughter DNA
molecules after replication has taken place.
NB. Inhibition of DNA gyrase is more significant in the gram negative bacteria whereas inhibition
of Topoisomerase IV is more significant in the gram positive.
Antimicrobial spectrum.
- They are generally bactericidal and this activity increase with concentration of the drug.
- They are generally active against the gram negative organisms including Mycoplasma
species, Moraxella caterrhalis, H.influenza, Legionellacae, and some Mycobacteria species.
The newer agents are active against S. pneumoniae.
- There are 4 generations i.e.
- First generation - an example is - Third generation - examples include
Nalidixic acid and cinoxacin, they are levofloxacin, sparfloxacin, gatifloxacin.
moderately active against the gram This group in addition to those in
negative rods. second generation has a wider
coverage against the gram positives
- Second generation - examples and is also active against the
include Ciprofloxacin, Norflaxacin and pneumococci.
Oflaxicin, enoxacin, lomefloxacin.
They are active against gram negative - Fourth generation - Has activity
rods, gram positive cocci (apart from against the broad activity against
the pneumococci) and some atypical anaerobic bacteria on surplus to the
bacteria like Mycoplasma and other gram negative and positive and
Chlamidya. the intracellular bacteria. Example in
this group is trovafloxacin
moxifloxacin.
- Examples of the chemically important fluoroquinolone;
Ciprofloxacin - Is used in the treatment of the following;
Enterobacteriacae infections and many gram negative infections including typhoid and
travellers diarrhoea.

Is very potent against P. aeroginosa, hence used in the treatment of cystic fibrosis.

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Is used as an alternative to aminoglycosides.

Norfloxacin - is effective against both complicated and uncomplicated cases of UTI as well
as prostatitis.

Levofloxacin - Is an isomer of ofloxacin. Can be used in the treatment of prostatitis and

STDs except syphilis. It can also be used in the flg;
Acute sinusitis
Skin
Acute exacerbation of bronchitis
Community acquired as well as nosocomial Pneumonia.
Moxifloxacin - Has increased activity against gram positive bacteria, and also the anaerobic
bacteria. However, because it doesn't concentrate in the urine, its not used in the treatment
of UTIs.
Resistance.
- The modes of resistance are mainly chromosome mediated and some of the resistance
mechanisms include the following;
1. Mutations of the binding sites at both DNA gyrase and Topoisomerase IV hence
altering the target binding sites.
2. Decreased accumulation within the cell and this is possible by two mechanisms;

decreasing the number of porins on the cell membrane.

energy-dependent efflux systems.
Pharmacokinetics.

Absorption - When taken orally, most are well absorbed apart from norfloxacin that has
lower bioavailability compared to the rest of the members. Ciprofloxacin and Levofloxacin
can be given by IV. Antacids containing Al3+ and Mg2+ as well as foods with Ca2+ affects
the absorption.

Distribution - All distribute well in to the tissues and body fluids, the concentration is highest
in the bones, kidneys, prostate also the lungs. Penetration is low in the CSF apart from
ofloxacin. Also penetrate well in PMNs, macrophages.

Elimination - Is eliminated by renal mechanisms by either tubular secretion or glomerular

filtration. Moxifloxacin is eliminated in the liver in bile.
Adverse effects.

GI distress i.e. nausea, vomiting and diarrhoea .

CNS disturbances e.g. headache and dizziness.
Pseudomembranous colitis by Chlamidya deficille.
Phytotoxicity.
Connective tissue problems. In the nursing mothers, pregnant mothers and children below
18 can lead to arthopathy i.e. articular cartilage erosion. Can lead to tendinitis especially for

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the Achilles tendon. This happens in the patients above 60> also in those taking
corticosteroid medications.
Therapeutic uses.

Bone, skin and soft tissue infections e.g. osteomyelitis

STDs apart from syphilis.
Respiratory tract infections.
GI infections
Prostatitis
UTI
Contraindications.

Arrhythmia patients as well as those taking anti-arrhythmic drugs.

Pregnant mothers
Lactating mothers
Children below 18 years.

Folate metabolism Inhibitors.

Overview.

-Folate derived substances are used in the production of purines and

pyrimidines which are essential in the process of DNA synthesis and
hence cell division, inhibition of folate synthesis i.e. by Sulfonamides
and trimethoprim that acts upon the conversion of dihydrofolic acid to
tetrahydrofolic acid.

-Combination of both of these drugs i.e. Cotrimoxazole is used for

synergistic action.

Sulfonamides.
These drugs are structural analogs of p-aminobenzoic acid (PABA).

The selective toxicity by the drug is due to the fact that mammalian
cells require already formed folic acid and hence insensitive to the
sulfonamides.

Mechanism of action.

-These drugs competitively inhibit the enzyme dihydropteroate

synthase that is responsible for the incorporation of PABA into dihydropteroic acid (Does so by

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competing for the active site of enzyme.This is due to the fact that the sulphonamides are
structural analogues of PABA). Hence, in so doing prevents the synthesis of folic acid i.e.
pteroylglutamic acid.

- Hence this drug is bacteriostatic.

Antibacterial spectrum.

Has good activity against both gram positive and negative including Nocardia, Chlamidya, also
some enterobacteriacae like Salmonella, E.coli, Shigella, Salmonella and Enterobacter species
as well as some protozoa.

NB. Rickettsia isn't affected instead it stimulates the growth of the organism.

Resistance mechanisms.

Four mechanisms that maybe due to plaid transfer or as a result of mutations;

altered dihydropteroate synthase binding site.

Production of more molecules of PABA

Decreased permeability to sulpha drugs.

Alternative pathways to the production of a metabolite.

Pharmacokinetics.

Absorption Most sulfa drugs are absorbed when taken orally, except, sulfasalazine which is
reserved for the chronic GI inflammatory conditions like Crohns disease which is converted
by the intestinal flora to sulfapyridine and 5-aminosalicylate, an anti-inflammatory substance,
and in people who are slow aceylators can cause toxicity for sulfapyridine. People who are
burnt patients are given sulfadiazine or mafedine acetate because they prevent colonisation
of bacteria.

Distribution Are distributed well in the body as well as in the CSF. The degree of protein
binding depends on the pKa of that particular agent
used. (NB. The smaller the pKa the greater the
protein binding). Cross the placental barrier and
have the tendency of entering fetal tissue.

Metabolism Is acetylated in the liver, the metabolite

is very toxic and has the tendency to cause
crystalluria damaging the kidneys.

Eliminations Eliminated by glomerular filtration and

hence needs a dose adjustment in cases of renal
dysfunction. Is also eliminated in the breast milk.

Adverse reaction.

Crystalluria - This can be prevented by adequate

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hydration and alkalinization with sodium bicarbonate. Other Urinary tract disturbances
include hematuria and also blockage. Its not a problem especially in the newer version of the
drugs e.g. sulfamethaxazole and sulfisoxazole which are readily soluble.

Hypersensitivity - Can lead to angioedema, rashes, Stevens-Johnson syndrome.

Kernicterus - This can occur when the drug is taken during pregnancy. The mechanism is
such that the sulfa drugs displace the bilirubin from serum albumin, which then enters the
CNS and causes this condition.

Haemopoeitic disturbances - Leads to haemolytic or aplastic anaemia as well as causing

granulocytopenia, agranulocytosis, thrombocytopenia as well as leukomoid reactions.

Drug potentiation - May cause potentiation of warfarin.

Contraindication - Pregnant mothers, newborns and infants below the age of 2 yrs.

Clinical uses

- In combination with trimethoprim, is used in the treatment of Pneumocystis jirovecii.

- In combination pyrimethamine, is used in the treatment of malaria thats is resistant to
mefloquine as well as in the treatment of Toxoplasmosis.

- Is used in the treatment of burn patients.

- Inflammatory bowel disease like Crohns disease
- Treatment of trachoma, chlamydial infections, chancroid
- Used in the treatment of Nocardiosis.

Trimethoprim
- Is often used in combination with the sulfonamide, sulfamethoxazole in the drug Co-
trimoxazole. This combination is bactericidal compared to the bacteriostatic of
- Other drugs with a similar chemical makeup are pyrimethamine (which is used in combination
with sulphonamides in the treatment of Toxoplasma and malaria),
Mechanism of action.
- The active form of folic acid used is tetrahydrofolic acid which is formed as a result of
reduction of dihydrofolic acid by the enzyme dihydrofolic reductase. This is the enzyme that is
inhibited by the drug.
- Coz of this inhibition, theres a stop in the process of formation of purines and ultimately DNA
synthesis.
Resistance
- Three main mechanism ;
- Decreased permeability.

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- Altered binding site for dihydrofolate reductase

- Over production of the enzyme.
Antibacterial spectrum
- The spectrum is similar to that of sulfonamides however, trimethoprim is much more potent
compared to the sulfonamides.
Pharmacokinetics
- Absorption - Is absorbed well by the oral, can be given in combination with
sulfamethoxazole or be given by IV.
- Distribution - Is absorbed well into the tissues and body fluids as well as in the CSF. High
concentrations are relatively acidic environments such as the prostate and the vaginal
fluids.
- Metabolism - Undergoes O-demethylation in the liver.
- Excretion - Is excreted mostly unchanged.
Adverse effects.
- Megaloblastic anaemia - reversed by administering follinic acid.
- Leukopenia
- granulocytopenia
NB. This is drug is able to maintain selective toxicity in two ways;

Mammalian cells utilise preformed folate from the diet and don't synthesise.
The drug has much more affinity for lower organism.

Cotrimoxazole
- This drug is a combination of the drugs Trimethoprim and sulfamethaxazole.
MOA - This drug has the MOA as a combination of both sulfonamides and methoprim i.e.
competitive inhibition of dihydropteroyl synthase and inhibition of dihydrofolic reductase
respectively.

Antibacterial spectrum - Is a broad spectrum with activity against the gram positive and
negative organisms e.g. S. aureus both the Methicillin susceptible and resistant, S.
pyogenes, viridans streptococci, pneumococci, Klebsiella, Haemophilus sp, Proteus
species, Klebsiella species, Nocardia sp., Enterobacteriacae like salmonella, shigella,
E.coli and some parasites like P. jiroveci.

Pharmacokinetics - Is administered with one part of Trimethoprim and 5 parts of

sulfamethoxazole such that in the plasm its one part of Trimethoprim to 20 parts of
sulfamethoxazole.

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Is administered orally unless cases of severe pneumonia by P. jiroveci or patients

who cant take the drug orally.

Drug is distributed well in the body, and Trimethoprim is concentrated in the acidic
areas, e.g. the prostate and the vaginal fluids accounting for the use in these areas.

Is excreted in the urine.

Adverse effects.
- GI disturbances.
- Haematological disturbances such as Megaloblastic anaemia, granulocytopenia,
thrombocytopenia. All these effects can be reversed by the usage of follinic acid.

- May cause dermatologic reactions especially in the older patients.

- People suffering AIDS may encounter drug induced fever, rash, diarrhoea as well as
pancytopenia which are a result of a hypersensitivity reactions, other incidences
includes Stevens Johnson syndrome, sweet syndrome.

Drug interaction - Increases the prothrombin time when taken with warfarin. It increases
the half-life of phenytoin, as well as Methotrexate concentration in the serum increases
due to displacement from albumin binding sites by sulfamethoxazole.

Uses.

Treat UTIs

Treat P. jiroveci infections.

Treat respiratory tract infections caused by S.pneumoniae and H. influenza.

Treat GI infections e.g. Shigelosis and susceptible strains of S. typhi.

Prophylactic treatment in neutropenia.

Also used in the treatment of some miscellaneous infections like Nocardia infections,
Whipples disease, infection by intestinal parasites like cyclospora, infections by
Stenotophomonas maltophilia.

Urinary Tract Antiseptics.

- The majority of the UTIs are caused by E. coli and a small percentage by S.
saprophyticus, K. pneumoniae, Proteus mirabilis.
- Drugs used concentrate in the renal tubules and don't reach antibacterial levels in the
blood. The drugs used are methenamine, nitrofurantoin as well as nalidixic acid.

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Methenamine mandalate and methenamine hippurate.

Methenamine mandalata and hippurate are salts of mandelic acid and hippuric acid respectively.

MOA - is decomposed by the low urinary pH to formaldehyde that is bactericidal. On addition,

vitamin C and cranberry juice are used to reduce the urinary pH. Should be avoided in
patients with indwelling catheters.

Antibacterial spectrum - Is effective in the treatment of lower UTIs. Is effective in the

suppression of E. coli and many other organisms however, urea splitting organisms like Proteus
are often resistant because they tend to raise the pH of the urine inactivating the drug.

Pharmacokinetics - Is absorbed by the oral route, and is distributed well throughout the body
however no decomposition take place at pH 7.4. Is excreted quantitatively in the urine.

Contraindications - Due to the production of ammonia, which is metabolised in the liver to urea, it
is contraindicated in the patients with hepatic insufficiency to prevent toxic levels of ammonia
building up in the blood that would be toxic in the CNS.
- Shouldn't be taken concomitantly with sulphonamides as there is a risk of crystalluria due
to the aggregation of the sulphonamide with formaldehyde.

Adverse effects - The major effect is GI distress, other effects include hematuria, painful and
frequent micturition, albinuria and rashes.

Nitrofurantoin.
- Is a synthetic nitrofuran.

Mechanism of action - Bacterial susceptible to the drug, reduce it to highly reactive intermediates
that damages the DNA, RNA and ribosomal proteins.
The selective toxicity comes in asa a result of the rapid reduction of the drug shown by the
susceptible bacteria compared to the human cells.

Antibacterial spectrum - Is active against both the gram positive and negative e.g. E.coli and
enterocci however pseudomonas and Proteus are resistant to the drug.

Pk - Is absorbed well, metabolised and excreted very rapidly that no systemic antibacterial action
is achieved. Is eliminated by both glomerular filtration and tubular secretion.

Contraindication - people with renal insufficiency. Anuria. Oliguria . Pregnant mothers.

Adverse effects - Haemolytic anaemia in Glucose 6 phosphate dehydrogenase enzyme deficient

patients, GI disturbances, neurologic problems, acute pneumonitis.

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Mupirocin.
Naturally produced by Pseudomonas fluorescens. Is inactivated after absorption and is
for topical use only.

Mechanism of action - It binds to isoleucyl tRNA synthetase and prevents protein

synthesis. There is a low level of resistance due to a point mutation of the isoleucyl tRNA
synthetase.

Antibacterial spectrum - Active against gram positives including MRSA and some gram
-ves.

Pk - Is applied topically and any drug that is absorbed is quickly metabolised to inactive
monic acid.

Use - Is very effective in the eradication of S.aureus nasal carriage.

Effect - Irritation and sensitisation at the area of application.

Polymyxin.
Are a grp of basic peptides that are active against gram negative species. There are two
in this grp polymyxin B and polymyxin E.

MOA - they are cationic detergents and attach to the bacterial membrane causing the
disruption as well as bind and inactive endotoxin. Gram positive, Proteus and Neisseria
are resistant.

Pk - Is given topical due to the toxicity.

Use- Used for superficial skin infections.

Fidaxomicin
- A narrow spectrum macrocyclic drug that is active against the gram positive aerobe
and anaerobe but not against gram negative.
- MOA inhibits protein synthesis by binding to the sigma unit of ribosomes.
- Use -Treatment of C.defficile.