Antibiotic development, past, and

present Sulphanomides
- introduced into therapy in 1930s
Antibiotics - first significant antibiotics and
- 1940s: substance produced by 1 predated penicillin by 10 years.
microorganism, low concentrations, Benzylpenicillin
inhibited growth of other microorganism. - original antibiotic by the American
- naturally occurring substance, a Pharmaceutical Industry to be
microbial metabolite manufactured on a large scale.
- changing definition because of
True antibiotics extracted from large
increasing number of synthetic
volume of Streptomyces bacteria or fungi
analogues/derivatives of true antibiotics
1960s: advent of semisynthetic
in the market.
antibiotics in which the naturally
- examples: trimethoprim
occuring substance was extracted from
metronidazole
microbial culture, purified, and then
imidazole derivatives
structurally modified by conventional
fluoroquinolones
means
 Antibiotic development, past, and
present Factors on Why Antibiotics are Expensive:
a. short duration therapy
1950s: - typically 5-10 days
- antibiotic resistance became a b. antimicrobial stewardship policies
major problem c. relatively short patent life
1950-1970: d. likelihood of development of
- international pharmaceutical resistance
industry developed new antibiotics
steadily so new drugs regularly became
available to replace those which resistance
has developed
1970-2000:
- most antibiotics developed were
structural modifications of existing ones
- until new millennium antibiotics
such as linezolid and
quinupristin/dalfopristin (Synercid)
 Antibiotic Usage
The list of antibiotics in every country gets
updated annually.
New products replace old ones that are
withdrawn because of commercial reasons or
as a result of toxicity concerns.
In the UK, there are approximately 70
antibacterial antibiotics, 20 antifungals, and 40
antiviral agents currently on the market.
The quantity is similar worldwide.
This was a recent survey in Europe, results may
vary in other countries.
 Antibiotic Usage
Beta lactam antibiotics are currently the most
prescribed class, and of these, penicillin
substantially outnumber the other antibiotics
in this class.
Trimethoprim features strongly, and as an
individual drug would rank very highly
compared to penicillin.
Antibiotics that are primarily parenteral
products, are much less to be prescribed to
outpatients than for inpatients because of the
problem of administration. They appear low in
rank in this particular survey.
-Lactam Antibiotics
 -Lactam Antibiotics
Penicillin was the only beta lactam antibiotic even after 20 years
of its introduction
Cephalosporin joined the category during the 1960s
Carbapenems and monobactams joined towards the end of the
20 century
th

They all posses the beta lactam ring as an integral part of their
structure and they have the same mechanism of antibacterial
action.
But they differ in widely in other characteristics.
 Penicillins
1. Naturally occuring
Example is the fermentation of moulds such as Penicillin notatum and P. chrysogenum.
Most important examples: benzylpenicillin (penicillin G) and phenoxymethylpenicillin
(penicillin V).
2. Semisynthetic
Scientists at Beecham Research Laboratories succeeded in isolating the penicilin
nucleus 6-aminopenicillanic acid(6-APA).
During commercial production of benzylpenicillin, phenylacetic acid is added to the
medium in which the Penicillium mould is growing.
It is a precursor of side chain in benzylpenicillin.
Growth of organism in the absence of phenylacetic acid led to the isolation of 6-APA.
 Penicillins
Second method of producing 6-APA

Discovered when certain microorganisms produce the enzyme, penicillin amylases which
catalyse the removal of side chain of benzylpenicillin.

Some penicillins have considerable activity against Gram-negative as well as Gram-

positive bacteria, and are thus broad-spectrum antibiotics.

Sodium and potassium salts are very soluble in water, but are hydrolyzed in solution that
are temperature-dependent rate to penicilloic acid which is not antibacterial.
 Penicillins

Penicilloic acid
Produced at alkaline pH or at neutral pH.
At acid pH a molecular rearrangement occurs, giving penillic acid.

Susceptibility to Hydrolysis
Means penicillins cannot be formulated as aqueous products.
Oral syrups and mixtures must be manufactured as dry granules for resuspension in water, and
injections freeze dried in vials or ampoules.
Aqeous solutions of penicillins lose 10% or more of their activity in 24 hours at room
temperature.
Instability in acid medium logically precludes oral administration, since antibiotics can be
destroyed in the stomach.
 Penicillins
Benzylpenicillin is rapidly excreted, this can be overcomed by the use of sparingly soluble salts
which slowly release penicillin into the circulation over a period of time.

-lactamases
May inactivate a penicillin by opening the -lactam ring.
The only clinically significant -lactamase produced by a Gram-positive species is that
of Staphylococcus aureus.
Gram-negative -lactamases exhibit small interspecies, differences in chemical
structure which can have profound effects on their ability to hydrolyse the various -
lactam antibiotics.
 Penicillins

Ampicillin
lactamase sensitive
Presence of an amino group on the benzyl side chain gave the molecule a much
broader spectrum of activity than its parent, benzylpenicillin.
Amoxicillin
Inclusion of a p-hydroxyl group on the benzene ring of the ampicillin side chain.

Ampicillin and Amoxicillin

Effective against many Gram-negative bacteria including: Haemophilus influenzae,
Escherichia coli, Salmonella Shigella and Proteus species.
Carbenicillin
First penicillin showing antipseudomonal activity.
Has been largely replaced by ticarcillin.
 Penicillins

Piperacillin
Acyl derivative of ampicillin.
Possess activity against Pseudomonas.
Moderately susceptible to -lactamases
Piperacillin and ticarcillin: are normally used as combination products with -
lactamase inhibitor.

Temocillin
Possession of a 6-methoxy group.
 Penicillins

Pivmecillinam
An amidinopenicillin
Enzyme resistance is much weaker.
Penicillin
Possess a carboxylic acid group on C3 which can be esterified to create lipophilic
prodrugs with enhanced absorption for gastrointestinal tract, after which tissue
esterases hydrolyse the ester to release the active antibiotic.
This strategy is successful in remedying poor oral absorption of ampicillin.
 Penicillins

Meticillin
Only available as an injection
Largely been replaced with other -lactamase-stable penicillins.

Penicillins
Low toxicity with allergic reactions as the serious problem.
All penicillins, particularly those administered orally, can cause diarrhoea, and rarely,
pseudomembranous colitis(more of a problem of ampicillin, because higher portion
of an oral ose remains in the colon to disturb natural flora).
Excreted primarily in the urine, which they achieve much higher levels in blood.
Accumulation of sodium and potassium may arise with high-dose injections in
patients with poor kidney function.
Cephalosporins
 Cephalosporins

1948 discovery of the first cephalosphorin in Sardinia

Cephalotin and Cephaloridine first antibiotics in the class; became available in mid 1960s
Cephalosporins
-Consist of a six - membered dihydrothiazine ring fused to a -lactam ring
-Several caphalosporins act as good inducers of -lactamases
Ceftobiprole - has been claimed as the first member of the fifth
Cefaclor considered a frist-generation in Japan, but regarded as second-generation in
most other countries
 Cephalosporins

Possesion of good resistance to both staphylococcal and gram negative -lactamases -

principal characteristic distinguishing from the second- from first generation antibiotics;
improved potency towards H. influenza and enterobacteria is also a feature

activity towards gram negative bacteria- displayed by third-generation drugs; some of

them have little or no value in the treatment of staphylococcal infections

Parenterally administered third-generation cephalosporins (e.g. cefotaxime and

ceftazidime) sometimes used in combination with gentamicin or other aminoglycosides
achieving synergy

Usefulness of third-generation drugs has diminished consequence of the spread of

strains capable of producing extended-spectrum -lactamases

Cefpirome and cefepime - exhibit extremely good enzyme resistance but have much the
same antibacterial spectrum as ceftazidime and other third generation molecules
Cephalosporins

Figure 11.4 General Structure of

cephalosporins and examples of side chains
R1 and R2 (R3 is H in all examples in this
figure
 Structure-Activity Relationships

Activity of cephalosporins against gram positive bacteria depends on antibiotic affinity for
penicillin sensitive enzymes (PSEs) / penicillin binding proteins (PBPs)
Resistance results from altered PBPs or from -lactamases
Activity of cephalosporins against gram negative bacteria depends on penetration of -
lactams through outer membrane
Modification of the cephalosporin nucleus (Figure 11.4) at 7 by addition of a methoxy
group -lactamase activity but activity against gram positive bacteria because of
reduced affinity for PBPs e.g. cefoxitin are termed cephamycins
 Structure-Activity Relationships

Side chains containing 2-aminothiazoyl group at R1 (e.g. cefoxatime, ceftriaxone and

ceftazidime) - yield cephalosphorins with enhanced affinity for PBPs of gram negative
bacteria and streptococci
Iminomethoxy group (e.g. cefuroxime) - -lactamase activity against common plasmid-
mediated -lactamases
Propylcarboxy group (in ceftazidime) - increases -lactamase resistance, provides activity
against Ps. Aeruginosa and reduces -lactamase induction capabilities
Opening of -lactam ring occurs with concomitant loss of the substituent at R2 (except in
cefalexin where R2 represents H;Figure 11.4) followed by the fragmentation of the
molecule.
 Structure-Activity Relationships

Nature of the R2 substituent (cross the outer membrane of Gram-Negative bacteria via porins
For good oral absorption:
(1)R2 substituent small, non-polar and stable; methyl group is considered desirable but
might antibacterial activity
(2)7-acyl group (R1) based on phenylglycine and amino group must remain unsubstituted.
Esterification of carboxylic acid group at C4 - can result in enhanced oral absorption but
ester must be rapidly hydrolysed by tissue esterases; exemplified in both cefuroxime axetil
and cefpodoxime proxetil
Quaternary Nitrogen on the side chain at position 3 has two benefits:
(1)Reduces the affinity of cephalosphorin for gram negative -lactamases
(2)Makes the molecule zwitterionic which rate at which it can pass through porin channels
into the gram negative cell
-Lactamase Inhibitors
 -Lactamase Inhibitors
B-Lactamase Inhibitors
First combination : Co-amoxiclav (1981)
Consist of Amoxicillin plus clavulanic acid
Two Penicillinanic Acid Sulphones, Sulbactam, and Tazobactam protect ampicillin and
piperacillin
Benefit :
extension of antimicrobial spectrum of antibiotic receiving protection
negate effect of B Lactamase produced by Staphylococci and some Gram (-) species
 -Lactamase Inhibitors
Co-Amoxiclav
- this combination exhibits activity not only against S. aureus but also E. coli, H. influenza
and Klebsiella species wherein amoxicillin alone would be ineffective. (amoxicillin-resistant
B Lactamase producing Stains)

Clavulanic Acid
- protect tivarcillin from B lactamase attack
- isolated from Stretomyces clavuligerus and belongs to Clavem Class of B Lactams
- Protection against that are primarily active against cephalosporins rather than penicillin :
modest protection in comparison against penicillinases
Clavem Class Differs from Penicillin by :
Replacemet of sulfur in penicillin thiazolidine ring
Absence of side chain at position 6
 -Lactamase Inhibitors
Sulbactam and Tazobactam
B Lactam molecules that resemble penicillins but differs from penicillins by:
Sulphur atom at thiazolidine ring is converted to a sulphone
No side chain at position 6
Just as effective as Clavulanic Acis but not as potent
Does not normally include those manufactured by Ps. Aeruginosa and other gram (-)
organism
Combined with both ampicillin and cefoperazone
Carbapanems and Aztreonam
 Carbapanems and Aztreonam
Penicillin or cephalosporin derivatives which sulfur atom has been replaced with a carbon
Molecules possessing only B Lactam ring without a fused second ring = no antimicrobial activity
Monobactams
exhibit good resistance to B Lactamases
Aztreonam
analogue of monobactrams
IV injection treatment of:
serious gram (-) infections
Ps. Aeruginosa infections
Synergy with aminoglycosides ( gentamycin and tobramycin):
Carbapenems and third generation cephalosporins wherein these combination
are emplyd for treatment of Pseudomonas ling infections in cystic fibrosis.
produced by conventional chemical synthesis
marketed in 1986
Active against Gram (-) bacteria
Stable : B Lactamases
Resistant : Staphylococcal B Lactamases
Inactive : Staph. Aureus strains and Gram (+) and anaerobes
 Carbapanems and Aztreonam
Generic term for the group which includes:
olivanic acids ( no products in therapeutic use)
thienamycins (1970) : poor stability
Imipenem
N formimindoyl dericative of thienamycin
Combine desirable properties of in vitro stability
Poor in vivo stability due vulnerability to hydrolysis by mammalian renal
dipetidase but solved by Cilastin a dipeptidase renal inhibitor

Meropinem
More stable than Imipenem to dipeptidase
May be administered without Cilastin
Ertapenem
Similar to meropenem
Additional advantage of once daily dosing
Hypersensitivity
 Hypersensitivity
Skin allergy occurance of 1 10%
Fatal anaphylactic reactions occur 0.005 0.05%
Patients sensitive to one penicillin is sensitive to all others
since thebasic penicillin structure that is is responsible to the
hypersensitivity
Benzylpenicillin : anaphylaxis
Ampicillin : skin allergy
More severe reactions occur after IV injection
10% patients allergic to penicillins will also be sensitive to
cephalosporins
Tetracyclines
Tetracyclines
Group of broad-spectrum antibiotics that are
declining in use as a result of increasing bacterial
resistance.

They remain important antibiotic for several

dangerous

But relatively rare infections due to chlamydia

(trachoma), rickettsia (typhus and Q-fever) and
spirochaetes ( Lyme Disease) and those caused
by typical bacteria ( brucellosis and bubonic
plague)
 Tetracyclines
Represent useful alternatives to macrolides and to Beta-Lactams for the treatment of
more common infections ( respiratory tract)

First developed during 1940s and 1950s but still several use this at this time
(oxytetracycline, chlortetracycline )

Doxycyclycline and minocycline

More potent semisynthetic analogues discovered in 1966 and 1972, after which no
significant development until in 2005, the introduction of tigecyline(glycycline derivative)
more potent than other and maintains activity against some organisms that have become
resistant to earlier members of the group
 Tetracyclines
Can exhibit bactericidal activity by inhibiting ribosome function at concentrations that
might be used in the laboratory, they are bacteristatic at concentrations that can safely be
achieved in the body

They are active against Gram-positive bacteria, although many strains of Staph. aureus
have become resistant to all but tigecycline which, as a consequence, is of value in the
treatment of MRSA infections.
 Tetracyclines
Many Gram-negative species are also sensitive to tetracyclines, Ps. aeruginosa and Proteus
species are normally resistant.

Prescribed for the treatment :

acne
genital infections
the eradication of Helicobacter pylori in gastric and peptic ulcer disease (as part of a
multidrug regimen)
in the case of doxycycline particularly,
prophylaxis of drug-resistant Plasmodium falciparum malaria.

Cross-resistance - an organism resistant to one member is usually resistant to all other

members of this group
exceptions:
tigecycline
tetracycline- resistant Staph. aureus strains may still be sensitive to minocycline.
 Tetracyclines
Superinfection (overgrowth) with naturally tetracycline-resistant organisms
Ecamples:
Candida albicans
Yeasts - affecting the mouth, upper respiratory tract or gastrointestinal tract, may occur
as a result of the suppression of tetracycline- susceptible microorganisms.
Tetracyclines absorbed from :
Gastrointestinal tract and oral products are the only form in which they are currently
available in the UK
ophthalmic, topical and injectable products have been used in the past and some are still
available in other countries.

Absorption of tetracyclines is inhibited by food, antacids, milk or products containing di- or

trivalent cations.
 Tetracyclines
Dose-dependent nausea and vomiting are the most common side effect

Diarrhea may arise as a consequence of alterations in the bacterial flora of the colon.

The ability to chelate with calcium results in tetracyclines being deposited in bones and
teeth, and precludes their administration to children younger than 12 years or to women in
late pregnancy.

Their use in patients with poor kidney function is also contraindicated because most of the
tetracyclines accumulate in this situation;
again, doxycycline and minocycline are exceptions.
Macrolides
 Macrolides
Antibiotics are large molecules comprising 1216-membered lactone rings linked through
glycosidic bonds with amino sugars.

Erythromycin was the first member of the group to be discovered in 1952 and it is still an
important antibiotic today.

2 years later by spiramycin and oleandomycin but, although still available in certain
countries, these last two are now little used.

Erythromycin suffers from several disadvantages:

its antimicrobial spectrum is largely restricted to Gram-positive species,
it has poor acid sta bility so its absorption is erratic, I
t commonly exhibits gastrointestinal side effects and bacteria acquire resistance to it
relatively easily.
 Macrolides
Roxithromycin
was marketed in 1987
Clarithromycin and azithromycin
1991
Telithromycin
2001
Erythromycin and roxithromycin
chemically similar in possessing a 14-membered ring structure.

A distinction is sometimes drawn between them and both azithromycin which, strictly
speaking, is an azalide (a 15-membered ring containing an additional nitrogen atom)

Telithromycin which is a ketolide (a 14-membered ring with an additional keto group).

Macrolide is commonly used to describe all five antibiotics, and that terminology will be
used here.
 Macrolides
The macrolides are active against most Gram-positive bacteria, Neisseria and H. influenzae
but, with the exception of azithromycin, not against the Enterobacteriaceae. Because their
antibacterial spectrum is similar to those of the early penicillins.

The macrolides were, and still are, considered alternatives for patients with penicillin
allergy.

They are commonly used L

respiratory, skin and soft tissue infections,
activity against emerging pathogens like species
o Legionella, Campylobacter
o Helicobacter and Chlamydia
omycoplasmas and rickettsias
oMycobacterium avium complex to which AIDS/HIV patients are susceptible.
 Macrolides
The semisynthetic macrolides do not afford a significant advantage over erythromycin in
terms of their activity against staphylococci, streptococci and enterococci, but they
represent an advantage in several other respects:

they are generally more active against the other organisms mentioned above

they exhibit better stability and pharmacokinetics, thus permitting less frequent dosage
and better tissue penetration

they generally have fewer side effect

particularly in the case of telithromycin and other ketolides, they may be active against
some strains that have acquired resistance to erythromycin

They are less vulnerable to resistance development.

 Macrolides
The macrolides all act by inhibiting protein synthesis in bacteria and they are regarded as
bacteriostatic drugs, although bactericidal activity may be achieved at high concentrations.

The antimicrobial activity of erythromycin is pH-dependent, increasing with pH up to about

8.5, and the same effect occurs to varying degrees with other members of the group.

The macrolides are extremely bitter and their tablets are often coated, both to disguise the
taste and to protect the antibiotic from stomach acid.

Erythromycin exhibits particularly poor acid stability and erratic oral absorption, and a
variety of esters have been used to minimize these problems which, although present, are
much less evident in the semisynthetic molecules.
 Macrolides
All the macrolides are orally active and they are concentrated intracellularly, particularly
into neutrophils by which they are transported to infection sites.

The longer elimination half-lives of the newer drugs permit less frequent dosing than that
required for erythromycin.

Safe antibiotics which do not exhibit severe adverse reactions,

Common gastrointestinal disturbances with erythromycin

nausea,
vomiting,
abdominal pain
diarrhea
Sulphanomides, Trimethoprim and Related
Drugs
 Sulphonamides
Discovered by Domagk in 1935

It was subsequently found that protonsil was converted into sulphanilamide in vivo.

In sensitive bacteria, sulfonamides compete with PABA with a result that folic acid synthesis
is reduced.

Chemical modifications of sulphonilamide gave compounds with higher antibacterial activity

or special properties like prolonged activity which were extensively used from the 1930s to
1970s. Their popularity then declined due to resistance development and introduction of
safer and more effective antibiotics.
 Sulphonamides
Folic acid must be reduced to dihydrofolic acid and tetrahydrofolic acid for it to become
active in the body.

Diaminopyrimidines - group of synthetic drugs that could inhibit the enzymes responsible
for the reduction of folic acid.
 Trimethoprim
the most important dihydrofolate reductase inhibitors which act synergistically with
sulfonamides because they blocked successive steps in the synthesis of folic acid.

one of the least expensive orally active agents available for the treatment of urinary tract
infections (UTI), for which is still widely prescribed, it still suffers from increasing resisstance
development and the trend is towards
Quinolones
 Quinolones
Quinolones - are a family of synthetic broad-spectrum antibiotic drugs.

Cephalosporin - are a class of -lactam antibiotics originally derived from the fungus
Acremonium, which was previously known as Cephalosporium".

Both of these classes of antibiotic were first introduced in the 1960s, at that time nalidixic
acid and cephalothin respectively, had limited applications. But was extensively developed
over 50 years and now both of these antibiotics are currently amongst the widely
used and valuable antibiotics available.

Nalidixic acid - was developed as a treatment for urinary tract infections, and it, together
with other quinolone in the 1960s and 1970s had an antibacterial spectrum that was
largely restricted to E. coli and other Enterobacteriacceae.
 Quinolones
All the quinolone are bactericidal, and act by inhibiting the bacterial enzymes responsible
for coiling DNA; they are all orally active and several are available as IV injections.

The first-generation drugs were only used for the treatment of urinary infections, but the
much broader spectra of those that followed permitted their use for respiratory, soft
tissue, bones and joint, gastrointestinal and sexually transmitted infections as well.

Quinolones cause rare cases of tendon damage, including rupture which is why it is not
generally prescribed for children. Their most common minor side effect is gastrointestinal
disturbances, which happens to 5% of patients.

Quinolones are relatively susceptible to resistance development, and Gram-positive

species tend to mutate to resistance at higher frequencies than Gram-negatives.
Aminoglycosides
 Aminoglycosides
Antibiotics which are against many gram bacteria and a limited range of
gram + bacteria
Bactericidal and administered by injection
Poorly absorbed in the G.I. tract
Cationic, water- soluble drugs that interfere with protein synthesis in
bacteria
Susceptible to resistance development
Potential to cause damage to the kidneys and the 8 cranial nerve
th

Administered in single, high daily dose

 Aminoglycosides
Streptomycin
-First aminoglycoside discovered in 1944
-1 effective antibiotic for the treatment of tuberculosis
st

Neomycin
-Discovered in 1940
-It has a high toxicity and is restricted to ophthalmic and topical products
-It is employed as an oral preparation combined with other antibiotics to
reduce bacteria present in the colon before surgery
 Aminoglycosides
Streptomycin
-First aminoglycoside discovered in 1944
-1 effective antibiotic for the treatment of tuberculosis
st

Neomycin
-Discovered in 1940
-It has a high toxicity and is restricted to ophthalmic and topical products
-It is employed as an oral preparation combined with other antibiotics to
reduce bacteria present in the colon before surgery
 Aminoglycosides
The 3 most important aminoglycosides:
- Possess useful activity against Ps. aeroginosa and are valuable with -lactams for
the eradication of Ps. aeroginosa in the lungs of cystic fibrosis patients
1.Gentamicin
-Naturally occurring drug discovered in 1960s
-It can be used alone or in combination with -lactam antibiotics
-It is used to treat bacterial endocarditis and serious Gram infections but has no
activity against anaerobes
2. Tobramycin
-It is a naturally occurring drug discovered in 1960s
-It is more effective than gentamicin in eradicating Ps. aeroginosa
3. Amikacin
- Semisynthetic derivative of kanamycin
-It has the same application with gentamicin yet it is more stable and less potent.
 Aminoglycosides
The 3 most important aminoglycosides:
- Possess useful activity against Ps. aeroginosa and are valuable with -lactams for
the eradication of Ps. aeroginosa in the lungs of cystic fibrosis patients
1.Gentamicin
-Naturally occurring drug discovered in 1960s
-It can be used alone or in combination with -lactam antibiotics
-It is used to treat bacterial endocarditis and serious Gram infections but has no
activity against anaerobes
2. Tobramycin
-It is a naturally occurring drug discovered in 1960s
-It is more effective than gentamicin in eradicating Ps. aeroginosa
3. Amikacin
- Semisynthetic derivative of kanamycin
-It has the same application with gentamicin yet it is more stable and less potent.
Glycopeptides
 Glycopeptides
Two important glycopeptide antibiotic:
- Vancomycin and Teicoplanin
1. Vancomycin:
-Old drug introduced in 1958
-Its activity against MRSA resulted in it to become more valuable as MRSA
-It has a complex, tricyclic glycopeptide structure
-Large size = cannot penetrate through the outer membrane of Gram
bacteria
- restricted in the treatment of infections by aerobic or anaerobic Gram +
species
-It is against Staph. Aureus, Staph. Epidermidis, streptococci, Cl. Difficile and Ent.
Faecalis
 Glycopeptides
Two important glycopeptide antibiotic:
- Vancomycin and Teicoplanin
1. Vancomycin:
-Bactericidal to most susceptible bacteria at conc. near its MIC (Minimum Inhibitory
Concentration)
-Inhibitor of bacterial cell wall peptidoglycan synthesis
-Employed as the hydrochloride and administered by dilute IV injection
-Indicated in potentially life- threatening infections that cannot be treated with other,
less toxic antibiotics
-Oral vancomycin is the drug of choice in the treatment of antibiotic-induced
pseudomembranous colitis
-It suffers toxicity problems and has a potential to damage the kidney and ears.
-It uses the IV route in administering the drug
 Glycopeptides
2. Teicoplanin
-It has the same mode of action, antimicrobial spectrum, similar chemical
structure with vancomycin but teicoplanin possess more fatty acid side chain
-Acidic = permits the formulation of a sodium that can be given both by
intravenous and intramuscular injection
-Lipophilic = better tissue penetration and a longer half-life
-Administered once daily
Advantages over vancomycin:
-Slightly higher potency against target organism
-Better toxicity profile
 Glycopeptides
2. Teicoplanin
-It has the same mode of action, antimicrobial spectrum, similar chemical
structure with vancomycin but teicoplanin possess more fatty acid side chain
-Acidic = permits the formulation of a sodium that can be given both by
intravenous and intramuscular injection
-Lipophilic = better tissue penetration and a longer half-life
-Administered once daily
Advantages over vancomycin:
-Slightly higher potency against target organism
-Better toxicity profile
Antitubercular antibiotics
 Antitubercular antibiotics
Antibiotics used for the treatment of tuberculosis
Streptomycin
- late 1940s
- first effective treatment of tuberculosis
Isoniazid
Used first in combination with streptomycin
Combination of isoniazid and rifampicin
Mainstay of tuberculosis therapy
other drugs: pyrizinamide and ethambutol
 Antitubercular antibiotics
Course of therapy is 4-6 months
Oral antibiotics are much preferred
Ideal antitubecular drug:
Potential to kill rather merely inhibit the growth of infecting organism
Use of bacteristatic drug is unlikely ineffective
Rifampicin: kills dormant bacteria
Pyrizinamide: active against bacteria that are slowly reproducing in acidic environment
Isoniazid: most useful against more rapidly growing cells
Current approach to treat TB:
- Initial phase: 2 months using isoniazid, rifampicin and pyrizinamide (w or w/o
ethambutol); 4 month continuation phase with isoniazid and rifampicin
Second line drugs is used if infecting organism is resistant to any of the drugs
 Antitubercular antibiotics
Status of streptomycin is equivocal
Now rarely used in UK
Not a first-choice treatment recommendation of the European Respiratory Society
More commonly used in the front-line therapy in the US
Second-line drugs:
Caused by resistant organisms
When first-line drugs cause unacceptable side effects
Amikacin, capreomycin, cycloserine, newer macrolides and moxifloxacin
Drug regimens are often indicated using a shorthand notation and single letters to
indicate the drugs employed
Initial numbers indicating months of therapy and following numbers : ex. 2RHZ(E)/4HR(3)
 Antitubercular antibiotics
Rifampicin
- only one of the common antitubercular drugs used in treatment of non-
mycobaterial infections
- active against Gram-positive bacteria and some Gram-negative species but
no Enterobacteriaceae or pseudomonads
- possesses significant bactericidial activity at very low concentration against
staphylococci
- should be combined with other antibiotics (ex. Vancomycin) because of rise
of resistant mutants
Rifabutin
Semisynthetic rifamycin may be used in the prophylaxis of M. avium complex
infections in immunocompromised patients
Newer antibiotics for MRSA and other Gram-
positive cocci infections
Newer antibiotics for MRSA and other Gram-
positive cocci infections
VRE and penicillin-resistant Strep. pneumoniae become much more
prevalent
Emergence of Staph. aureus staions showed intermediate
sensitivity to vancomycin or to glycopeptides; caused the
introduction of three new antibiotics intended primarily for the
treatment of Gram-positive cocci infections

1. Combination of two streptogramin antibiotics, dalfopristin and

quinupristin
- treatment of serious infections with vancomycin-rrsistant Ent.
faecium and multiresistant stains of staphylococci and
pneumococci
 Newer antibiotics for MRSA and other Gram-
positive cocci infections
2. Linezolid
- orally active synthetic antimicrobial possessing an essentially
Bacteriastatic action against Gram-positive organisms with no useful activity
against Gram- negative
Used for treatment of MRSA, VRE and pneumococcal infections
Daptomycin
- lipopetide with a novel mode of bacetricidal action destabilizing the
bacterial cell membrane
- cross-resistance with existing drugs is unlikely to arise
- administered intravenously and used for skin and soft tissue infections by
Gram-positve organisms and for Staph. aureus endocarditis
- useful for infections by VISA and GISA strains of this species
 Newer antibiotics for MRSA and other Gram-
positive cocci infections
2. Linezolid
- orally active synthetic antimicrobial possessing an essentially
Bacteriastatic action against Gram-positive organisms with no useful activity against
Gram- negative
Used for treatment of MRSA, VRE and pneumococcal infections
Daptomycin
- lipopetide with a novel mode of bacetricidal action destabilizing the bacterial cell
membrane
- cross-resistance with existing drugs is unlikely to arise
- administered intravenously and used for skin and soft tissue infections by Gram-
positve organisms and for Staph. aureus endocarditis
- useful for infections by VISA and GISA strains of this species
 Newer antibiotics for MRSA and other Gram-
positive cocci infections
2. Linezolid
- orally active synthetic antimicrobial possessing an essentially
Bacteriastatic action against Gram-positive organisms with no useful activity against
Gram- negative
Used for treatment of MRSA, VRE and pneumococcal infections
Daptomycin
- lipopetide with a novel mode of bacetricidal action destabilizing the bacterial cell
membrane
- cross-resistance with existing drugs is unlikely to arise
- administered intravenously and used for skin and soft tissue infections by Gram-
positve organisms and for Staph. aureus endocarditis
- useful for infections by VISA and GISA strains of this species
Miscellaneous antibacterial antibiotics
 Clindamycin

Antibiotic possessing significant bacteristatic activity towards Gram-positive cocci

(MRSA)
Not related structurally to the macrolides
Less activity towards Gram-negative cocci and none at all against enterobacteria
Cephalosporins antibiotics most firmly associated with pseudomembranous
colitis, caused by Cl. Difficile
Recommended for the oral treatment of
staphylococcal bone
joint infection
Acne
Peritonitis
Infections by anaerobic bacteria
Falciparum malaria
 Fusidic Acid

A steroid-like bactericidal antibiotic used primarily for its activity

against staphylococci
Possess activity against other Gram-positive species
Active against penicillin-resistant strains of Staph. Aureus including
MRSA
For severe staphylococcal infection erythromycin or clindamycin

Fusidic acid is available as pediatric oral suspension, cream,

ointment, water-soluble salts, tablets and Intravenous injection
 Mupirocin

An antibiotic active against staphylococci, streptococci

and limited range of Gram-negative species
Topical treatment of Staph. aureus infections,
eradication of the MRSA from the nose
Claimed more effective than chlorhexidine or fusidic
acid
 Colistin

Only member of polymyxin group of peptide antibiotics

Active against many types of Gram-negative bacteria, but
not against cocci: Serratia marcescens and Proteus spp
Inactive against Gram positive organisms
Largely restricted to the treatment of:
Pseudomonas aeruginosa
Lung infections in cystic fibrosis
Burns caused by Acinetobacter species
 Chloramphenicol

Chloramphenicol is a true antibiotic but

is manufactured totally by chemical synthesis.
Activities:
some rickettsias and
larger viruses
aplastic anaemia
 Aplastic anaemia

dose related
result from treatment in a proportion of patients
largely restricted its use as a systemic antibiotic
to life - threatening infections with H. infl uenzae
still used significantly in the treatment of ophthalmic
infections and in veterinary medicine
Metronidazole and other nitroimidazoles

Nitroimidazoles are a group of synthetic antimicrobials

that are unusual in possessing activity against a wide
range of organisms

Activities:
bacteria
protozoa
some helminthes
Metronidazole and other nitroimidazoles

Metronidazole was introduced in 1960 for the treatment of vaginitis

caused by the protozoan Trichmonas vaginalis
Metronidazole is by far the most commonly used

Nimorazole and tinidazole are alternative drugs that may afford the
advantage of less frequent dosing

All regarded as prodrugs, they become activeonly after reduction of

the nitro group in low redox environments,
so they are able to kill cells growing anaerobicallyby damaging their
DNA.
Metronidazole and other nitroimidazoles

Metronidazole was introduced in 1960 for the treatment of vaginitis

caused by the protozoan Trichmonas vaginalis
Metronidazole is by far the most commonly used

Nimorazole and tinidazole are alternative drugs that may afford the
advantage of less frequent dosing

All regarded as prodrugs, they become activeonly after reduction of

the nitro group in low redox environments,
so they are able to kill cells growing anaerobicallyby damaging their
DNA.
Metronidazole and other nitroimidazoles
Metronidazole and other nitroimidazoles

For the treatment of amoebiasis, giardiasisor trichomonal

vaginitis, metronidazole is often used alone.

Metronidazole is available in more dosage forms (oral, topical,

injectable or suppositories) than most other antibiotics, and by the
oral route is often given two or three times daily.
 Nitrofurantoin

Nitrofurantoin is the one remaining member of the nitrofuran

group of drugs that is still in common use
Requires its nitro group to be reduced in order to exhibit
antimicrobial activity, and it too exhibits bactericidal activity by
damaging DNA.

Activities:
Gram - positive cocci and
many Gram negative enteric bacteria
 Nitrofurantoin

restricted to the treatment of cystitis

macrocrystalline form affords steadier release size of the drug
crystals used in tablet manufacture has an effect on the
dissolution of the drug: the macrocrystalline form affords steadier
release
antimicrobial activity is substantially greater in acid urine
Nitrofurantoin is unusual in being one of the few antimicrobial
drugs to which resistance has not significantly increased
 Nitrofurantoin

restricted to the treatment of cystitis

macrocrystalline form affords steadier release size of the drug crystals used
in tablet manufacture has an effect on the dissolution of the drug: the
macrocrystalline form affords steadier release
antimicrobial activity is substantially greater in acid urine
Nitrofurantoin is unusual in being one of the few antimicrobial drugs to
which resistance has not significantly increased
Antifungal antibiotics
 Antifungal antibiotics

Introduction
There has been increase in the number of both systemically and
topically acting antifungal agents.
20 century nystatin, amphotericin and griseofulvin were the
th

principal antifungal antibiotics.

Fungal infections are normally less virulent in nature that are
bacterial or viral ones but may, nevertheless, pose major
treatment problems in individuals with a depressed immune
system, particularly in the case of systemic infection.
 Azoles

May be considered as two subgroups:

Imidazole drugs - topical products or pessaries for the
treatment of superficial infections by dermatophytes
(skin pathogen), Pityriasis species (causes flaky skin
and dandruff) and C.
Albicans, and the more recently developed, more
versatile and, in some cases, much more expensive,
triazoles.
 Imidazoles

Imidazoles are large and diverse group compounds

with activity against bacteria and protozoa
(metronidazole and tinidazole), helminths
(mebendazole) and fungi (clortrimazole, miconazole,
ketonazole, econazole, sulconazole and tioconazole).
Table 11.8 Antifungal Imidazoles
Drug
Clotrimazole Imidazoles
Common Formulations
T, P, VC, Pdr, S; Soln
Uses
Dermatophytes, pityriasis or Candida in
the skin, vagina or ear

Miconazole T, P, VC, Soln, Pdr Oral, intestinal, skin or vaginal Candida

infections, dermatophytes and pityriasis

Econazole T, P Dermatophytes, pityriasis and skin or

vaginal Candida

Sulconazole T Dermatophytes, pityriasis and skin or

vaginal Candida

Ketoconazole T, Sham, Tab Oral systemic treatment of

dermatophytes or Candida resistant to
other drugs or patients intolerant to
them

Ticonazole NS Fungal infections of finger and toe nails

 Imidazoles

Imidazoles are available in a wide variety of dosage

forms, but most of them have the same uses.
Miconazole may be given to orally for the treatment
of intestinal fungalinfection.
 Triazoles

Fluconazole and itraconazole were introduced in the

1980s and posaconazole and voriconazole much
more recently.
Fluconazole and itraconazole are more widely used,
while posaconazole and voriconazole tend to be
reserved for severe, possibly life-threatening
infections, in which other antibiotics have failed or are
inappropriate.
 Triazoles

All four of the triazole drugs are orally active and all
but posaconazole are available in injection form.
Fluconazole is better absorbed from the
gastrointestinal tract than itraconazole and, in
addition to the treatment of dermatophytes, pityriasis
and Candida infections.
 Polyenes
Polyene antibiotics are characterized by possessing a large ring containing a
lactone group and a hydrophobic region
ONLY important polyenes are:
Amphotericin B is active against most fungal pathogens and is used for
systemic mycoses
it is poorly absorbed from the GIT and it is usually administered by IV
injection under strict medical supervision.
Nystatin is administered orally in the treatment of C.albicans infections in
the intestine of mouth
This is rarely used for the treatment of other infections and is too toxic to
be given by injection.
Polyenes
 Echinocandins
Echinocandis are a new class of semisynthetic lipopeptide antibiotics that
are fungicidal towards Aspergillus spp., Candida spp. and Pneumocystis
jirovecii (prev. known as P. carinii)

Caspofungin is given as an intravenous infusion recommended for invasive

aspergillosis or candidiasis that is UNRESPONSIVE to treatment with
amphotericin or itraconazole
 Other Antifungal Agents
Flucytosine- narrow- spectrum with greatest activity against yeast.
example of yeast: Candida, Cryptococcus and Torulopsis
- used in combination with Fluconazole or as a synergistic
combination with amphotericin which permits amphotericin dose
reduction and a lower risk of toxicity.

Terbinafine- member of allylamine class of antimycotics .

- orally active, fungicidal, effective against a broad range
of dermatophytes and yeast.
-choice of drug for nail infections.
 Other Antifungal Agents
Griseofulvin- for the treatment of dermatophyte infections of hair,
skin and nails. EXCEPT FOR Trichophyton Infections IN CHILDREN.

Tolnaftate- synthetic thiocarbamate; topically used in the

treatment or prophylaxis of tinea(ringworm).

Amorolfine- used as cream or nail lacquer.

Antiviral Drugs
 Antiviral Drugs
Viruses:
-target structures or enzyme systems that are only found in
bacterial anf fungal cells.
- Do not possess the enzymes necessary for their own
replication.
- literally takes over the machinery of an infected human cell.

Unique features of viral replication- Creating antiviral agents that

inhibits or kill the virus without harming the human host.

1983- Identification of HIV virus.

 Antiviral Drugs
HIV/AIDS pandemic provides 3 major stimulus for fundamental
research into the structure and reproduction of viruses in general
and retroviruses:

1.Better understanding of the role played by some viruses in the

development of specific cancers

2.More sophisticated diagnostic methods

3.Elucidation of the genomes of several viruses.

 Antiviral drugs used in the treatment of selected
viral infections
Herpes Cytomegalovirus Viral Hepatitis Influenza Respiratory
syncytial virus

Aciclovir Cidofovir Adefovir Amantadine Palivizumab

Famciclovir Ganciclovir Entecavir Oseltamivir Ribavirin

Penciclovir Foscarnet Lamivudine Zanamivir

Valaciclovir Valganciclovir Telbivudine

Inosine Pranobex Tenofovir

Idoxuridine Interferon-
Mechanisms of action of common antiretroviral
drugs
Mechanism of action Examples
Nucleoside reverse transcriptase Abacavir, Didanosine, Emtricitabine,
inhibitors Lamivudine, Stavudine, Tenofovir,
(Nucleoside analogues) Zidovudine
Protease inhibitors Atazanavir, Darunavir, Fosamprenavir,
Indinavir, Lopinavir, Nelfinavir, Ritonavir,
Saquinavir, Tipranavir

Non-Nucleoside reverse transcriptase Efavirens, Etravirine, Nevirapine

inhibitor
Miscellaneous agents with unique Enfuvirtide, Maraviroc, Raltegravir
mechanism of action
 HIV
The human immunodeficiency virus (HIV) is a lentivirus (a subgroup of retrovirus)
that causes HIV infection and over time acquired immunodeficiency syndrome
(AIDS). This disease is a condition in humans in which progressive failure of the
immune system allows life-threatening opportunistic infections and cancers to
thrive.

MARAVIROC antagonist of the CCR5 coreceptor, is licensed in the UK for

treatment of CCR5-tropic HIV

ENFUVIRITIDE a fusion inhibitor manages infection that failed to respond to a

regimen of antiretroviral drugs

RALTEGRAVIR inhibits integrase enzyme. This is largely reserved as a treatment

for HIV infection resistant to antiretroviral drugs.
HIV life cycle showing stages vulnerable to
antiretroviral drugs
 HIV
The provirus remains dormant within the nucleus within 2 weeks
to 20 years. It is only activated by regulatory proteins called,
Transcription Initiators (which was recently discovered as
potential alternatives for antiretroviral drugs)

The latent provirus that represents the major hurdle to complete

eradication of HIV.
Are only functional when the long proteins are split into smaller
molecules by viral protease enzymes
 Herpes and Cytomegalovirus infections

HERPEVIRUSES

HERPEX SIMPLEX VIRUSES, HSV-1 and HSV-2 cause cold sores in the face and lips
and genital herpes

VARICELLA ZOSTER causes chickenpox and shingles

EPSTEIN-BARR responsible for infectious mononucleosis (glandular fever)

CYTOMEGALOVIRUS causes Retinitis and similar symptoms to infectious

mononucleosis
 Viral Hepatitis

Hepatitis - inflammation of the liver

- can be caused by various drugs and toxins
- more commonly caused by viral infection (eg. Hepatitis A-E, herpes
virus, CMV cytomegalovirus, Epstein-barr hepatitis)

HEPATITIS A HEPATITIS B HEPATITIS C HEPATITIS D HEPATITIS E

Only arise as co-infection with
Infectious hepatitis Most problematic Most problematic HBV AND HCV
Relatively uncommon

Self-limiting Require antiviral therapy Require antiviral therapy Self-limiting

Rarely fatal Not retrovirus

Food-borne infection
Does not result in
Acute or chronic Acute or chronic
permanent liver damage
Early treatment has higher
Not normally treated with
success rate and shorter time
antiviral drugs (acute)
 Viral Hepatitis
HEPATITIS A HEPATITIS B HEPATITIS C HEPATITIS D HEPATITIS E

Only arise as co-infection with

Infectious hepatitis Most problematic Most problematic HBV AND HCV
Relatively uncommon

Self-limiting Require antiviral therapy Require antiviral therapy Self-limiting

Rarely fatal Not retrovirus

Food-borne infection

Does not result in

Acute or chronic Acute or chronic
permanent liver damage

Early treatment has higher

Not normally treated with
success rate and shorter time
antiviral drugs (acute)
 Viral Hepatitis
DRUGS FOR TREATMENT
HEPATITIS B VIRUS HEPATITIS C VIRUS
Lamivudine Interferon-
Adefovir Ribavirin + interferon-
Entecavir Peginterferon-2a
Tenofovir Ribavirin + peginterferon-2a
Adefovirdipivoxil
Telbivudine
Interferon-
 INFLUENZA AND RESPIRATORY SYNCYTIAL
VIRUS
RSV respiratory syncytial virus
- causing measles and mumps
- infect most infants (2 years of age)
- no long lasting immunity following infection
- no vaccine available

Ribavirin one of the few antiviral agents used to treat RSV

Palivizumab monoclonal antibody used for preventing serious lower respiratory tract
disease

Influenza viruses: A, B, and C

C relatively rare and only mild infection

Neuraminidase liberating the newly formed virus particles from the host cell
- Oseltamivir, Zanamivir, Amantadine
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