ANTIMICROBIALS/ ANTIBIOTICS : GENERAL CONSIDERATIONS

GeneralGeneral
considerations :considerations :
AntimicrobialAntimicrobial
drugsdrugs
PRESENTED BY:PRESENTED BY:
Sonali SharmaSonali Sharma
B.Pharmacy Final year
Guru Gobind Singh College of Pharmacy
Yamuna nagar , Haryana

Important terms:Important terms:
 CHEMOTHEAPYCHEMOTHEAPY : Term used to describe
any treatment that utilizes the introduction
of chemical agents to kill or retard the rapid
growth of cells and bacteria. This treatment
is used for cancer or similar ailments.
 ANTIBIOTICSANTIBIOTICS: Substances produced by
microorganisms which selectively suppress
the growth or kill the microorganism.

Classification typesClassification types
Basis of chemical structureBasis of chemical structure Mechanism of actionMechanism of action
Type of org. againstType of org. against
activeactive Type of spectrumType of spectrum
Type of actionType of action
SourceSource

CLASSIFICATION OFCLASSIFICATION OF
ANTIBIOTICS:ANTIBIOTICS:
Antibiotics are classified in many ways:
1. On the basic of chemical structuresOn the basic of chemical structures
 Sulphonamides and related drugs:
Sulphadiazine, dapson, p- amino
salicylic acid(PAS)
 Diaminopyrimidines: Trimethoprim,
Pyrimethamine

 Nitrobenzene derivative. :
Chloramphenicol
 Beta lactum: Penicillins,
Cephalosporins, monobactams,
Carbapenems

 Aminoglycoside: Streptomycin,
Gentamicin, Neomycin,tobramycin
etc.

Macrolide antibiotics: Erythromycin,
Clarithromycin,etc.

 Tetracyclines: Oxytetracycline,
doxycycline
 Lincosamide: lincomycin ,
clindamycin etc.
.

 Glycopeptide: Vancomycin,
Teicoplanin

o Nicotinic acid dvt. : Isoniazid,
Ethionamide
o Azole dvt.:
Ketoconazole,Clotrimazole

Quinolones: Nalidixic acid
Norfloxacin,Ciprofloxacin,etc.
Others :Rifampin, Viomycin , Cycloserine etc

2.2. On the basis of mechanism ofOn the basis of mechanism of actionaction::
 Inhibition of cell wall synthesis: Penicillins,
Cephalosporins, Vancomysin
 Cause leakage from cell membrane: Polymyxins,
hamycin
 Inhibit protein synthesis : Tetracyclines,
Chloramphenicol, Erythromycin, Clindamycin
 Cause misreading of m-RNA and affect
permeability: Streptomycin, Gentamicin, etc.
 Inhibit DNA gyrase : Ciprofloxacin
 Interfere with DNA funct.: Rifampin
 Interfere with intermediary metabolism :
Sulphonamides, PAS , Sulfones, Trimethoprim,etc.

3.3. Type of organism against whichType of organism against which
primarily activeprimarily active::
 Antibacterial: Penicillin, Aminoglycoside,
Erythromycin,etc.
 Antifungal : Griseofluvin,Ketoconazole,etc.
 Antiviral : Acyclovir , Amantadine, etc.
 Antiprotozoal : Chloroquine,
Metronidazole, Pyrimethamine, Diloxanide,
etc.
 Antihelmintic : Niclosamide,
Mebendazole, etc.

4. Based on spectrum of activity :4. Based on spectrum of activity :
 NARROW SPECTRUM :
Penicillin G, Streptomycin, Erythromycin
 BROAD SPECTRUM :
Tetracyclin, Chloramphenicol

5. On the basis of type of actionOn the basis of type of action::
 Primarily bacteriostatic :
Sulphonamides,Tetracyclines,Chloramphenicol
, Erythromycin, Clindamycin, etc.
 Primarily bactericidal :
Penicillins, Aminoglycoside, cephalosporins,
Vancomycin, Isoniazid, Rifampin,
Ciprofloxacin, Cotrimoxazole

6.6. BASED ON THE SOURCE:BASED ON THE SOURCE:
 FUNGI: Penicillin, Griseofluvin,
Cephalosporin
 BACTERIA: PolymycinB , Colistin,
Bacitracin, Aztreonam
 ACTINOMYCETES : Aminoglycoside,
Tetracycline, Chloramphenicol, Macrolides

PROBLEMS THAT ARISEPROBLEMS THAT ARISE
WITH THE USE OF AMA’s :WITH THE USE OF AMA’s :
1. TOXICITY:
 Local irritancyLocal irritancy:
*Exerted at the site of administration
*Gastric irritation, pain,abscess formation
in i.m injection
*eg. Erythromycin, Tetracycline , some
Cephalosporins, Chloramphenicol

 Systemic toxicitySystemic toxicity:
* High therapeutic indexHigh therapeutic index: Doses upto
100 fold range may be given without
apparent damage to host cells .. Eg
Penicillins, Erythromycin, some
Cephalosporins
* Lower therapeutic indexLower therapeutic index: Doses have
to watched eg.
#Chloramphenicol- bone marrow
depression
# Tetracycline- liver and kidney
damage

* Very low therapeutic indexVery low therapeutic index: use is
restricted to conditions where no suitable
alternative present eg.
#Vancomycin- hearing loss, kidney
damage
#Polymyxin B- neurologinal and
renal toxicity

2. HYPERSENSITIVITY REACTIONS :
* Unpredictable and unrelated to dose
* Reactions ranges from rashes to
anaphylactic shock
* Eg. Penicillins, Cephalosporins,
Sulfonamides, Floroquinolones

3. DRUG RESISTANCE:
Natural resistance:
Some microbes are naturally resistant to
some AMA’s . Eg. # Gram negative bacilli
are unaffected by Penicillin G
# aerobic oragnisms are unaffected by
Metronidazole
# M.tuberculosis from Tetracyclines

Acquired resistance:
* Development of resistance by AMA’s
where overused. A major clinical problem.
*eg.of bacterias-Staphylococci , Tubercle
bacilli etc.
*Some like Strep.pyogenes and
Spirochetes have not developed resistant to
Penicillins despite of their use for m/t 50
years.

Causes of resistance :Causes of resistance :
MUTATION:
*Stable and heritable genetic change .
*Sensitive population of microbes turns
resistant strain by the high conc. Of AMA’s
*Eg. When single antitubercular drug is used
Also called vertical transfer of resistance.

GENE TRANSFER:
(Infectious resistance)
*resistance causing gene is passed from
one to another organism.
*Also called horizontal transfer of resistance

CROSS RESISTANCE:
 Acquisition of resistance to one AMA
conferring resistance to another AMA to which
org. has not been exposed.
 Resistance between Chemically or
mechanically related drugs: Sulfonamide and
others.
 Resistance between unrelated drugs: between
Tetracycline and Chloramphenicol
;Erythromycin and Lincomycin

4. SUPER/SUPRAINFECTION:
Infection caused as a result of antimicrobial therapy.
Use of most AMA’s causes alteration in normal
microbial flora of the body(contributes to host
defence from pathogens by elaborating subs. Called
bacteriocins)
#sites involved: oropharynx, intestinal, respiratory
and genitourinary tracts.
ORGANISM INVOLVED N DRUGS FOR TREATING:ORGANISM INVOLVED N DRUGS FOR TREATING:
Candida albicans- Nystatin or Clotrimazole
Resistant staphylococci- Vancomycin
Clostridium difficile- Vancomycin and Metronidazole

5. NUTRITIONAL DEFICIENCES :
B complex group of vitamins and vit.K
synthesised by the intestinal flora is altered by
the use of AMA’s causing vitamin deficiences.
eg. Neomycin causes abnormalities in intestinal
mucosa

CHOICE OF AMA :CHOICE OF AMA :
PATIENT RELATED FACTORS:PATIENT RELATED FACTORS:
11.. AGE:AGE:
 Chloramphenicol conjugation and excretion
in new born is inefficient hence cause gray
baby syndrome
 Tetracyclines deposit in developing teeth and
bones and hence discolours and weakens them.
 Sulfonamides displace bilirubin from protein
binding sites and hence cause kernicterus in
neonates.

2. RENAL ANDRENAL AND
HEPATIC FAILUREHEPATIC FAILURE
(RENAL)
In mild failure-
Aminoglycosides
,Cephalosporins,
Vancomycin
In moderate/severefailure-
Cotrimoxazole,
Meropenem,Carbenicillin,
clarithromycin
To be avoided-
Tetracycline(expect
Doxycycline),Nitrofurantoin,
Talampicillin
(HEPATIC)
To be reduced-
Talampicillin,
Tetracycline,Erythromycin,
Pefloxacin
To be avoided-
Chloramphenicol,
Clindamycin,
Metronidazole,
Isoniazid,Rifampin

3. LOCAL FACTORS:LOCAL FACTORS:
 Presence of pus and secretions decrease the
efficacy of AMA’s especially Sulphonamides ,
Aminoglycosides
 Presence of foreign body like implants, catheters
makes infection eradication almost impossible
because of bacteria adhering to foreign body and
forming biofilms.
 Lower ph at the site of infection reduces the
activity of Macrolide , Aminoglycosides

4.4. DRUG ALLERGY:DRUG ALLERGY:
 History of patient exposure to AMA.
 If any AMA has caused allergic reaction, then it
is to be replaced eg. Patient allergic to Penicillin
can be given Tetracycline.
 Beta lactum, Sulfonamides, Fluroquinolones,
Nitrofurantoin causes allergy.

5.5. PREGNANCY:PREGNANCY:
 Penicillins, many Cephalosporins,
Erythromycins are somewhat safe in
pregnancy.
 Tetracyclines are clearly contraindicated in
pregnancy because of liver and kidney
damage to mother and discoloration of teeth
and bone deformities of offspring.
 Aminoglycosides causes foetal ear damage.

6.6. GENETIC FACTORS:GENETIC FACTORS:
Chloramphenicol, Nitrofurantoin,
Sulfonamide, Fluroquinolones carry the risk
of producing haemolysis in G-6-PD deficient
factors.

DRUG RELATED FACTORS:DRUG RELATED FACTORS:
1.. Spectrum of activity:Spectrum of activity:
For definitive therapy a narrow spectrum
AMA is used but for empirical therapy a
broad spectrum antibiotic is used.

2.2. Type of activityType of activity::
 Several acute infections resolve better with
bactericidal than bacteriostatic drug,
because the cidal drug directly reduces the
no. of bacteria at the site of infection, while
the static drug only prevents the increase in
the no.
 With static AMA the bacteria starts
multipling when drug levels falls below the
MIC,resulting in relapse of infection.

3.3. Relative toxicity:Relative toxicity:
Less toxic is always preffered. Eg
 Beta lactum over Aminoglycoside
 Erythromycin over Clindamycin

4.4. Route of administration :Route of administration :
For less severe infection oral antibiotic
is used but for serious infections eg. For
meningitis or septiceamias parentral
antibiotic is used.
5.5. Cost :Cost :
Lesser expensive drugs are to be
preffered.

6.6. Evidence of clinical efficacy :Evidence of clinical efficacy :
Relative value of diff. AMA in treating an
infection ,optium dose regimen, duration of
treatment is desided on the basis of clinical
trials . So, reliable clinical trial data is the
final guide for the choice of AMA.

7.7. Pharmacokinetic profile:Pharmacokinetic profile:
 Fluoroquinolones,aminoglycoside,metronidazol
e produce concentration dependent
inhibition i.e inhibitory effect depends on th
ratio of the peak con. To the MIC
 Beta lactums,glycopeptides,macrolides produce
time dependent inhibition i.e action
depends on the time the conc. Remains above
the MIC.

WHY COMBINATION OFWHY COMBINATION OF
AMA’S USED?AMA’S USED?
TO BROADEN THE SPECTRUMTO BROADEN THE SPECTRUM
OF ACTIONOF ACTION
REDUCINGREDUCING
SIDE EFFECTSSIDE EFFECTS
PREVENTING EMERGENCEPREVENTING EMERGENCE
OF RESISTANCEOF RESISTANCE
ACHIEVINGACHIEVING
SYNERGISMSYNERGISM

COMBINED USE OFCOMBINED USE OF
ANTIMICROBIALSANTIMICROBIALS
1.1. To achieve synergism:To achieve synergism:
Synergism may manifest of decreasing the
MIC of one AMA by the presence of
another ;or the MIC of both may be lowered
 If MIC of each AMA is reduced to 25% or less
the pair is synergistic
 25-50% of each is considered to be additive
 More than 50% of each is antagonism.

Eg.Eg.
 Penicillin + StreptomycinPenicillin + Streptomycin for SABE ,Penicillin by
acting on cell wall may enhance the penetration
of Streptomycin into the bacterium.
 Carbenicillin + GentamycinCarbenicillin + Gentamycin in pseudomonas
infection
 Rifampin + IsoniazidRifampin + Isoniazid in tuberculosis

2.2. To reduce severity orTo reduce severity or
incidence of adverse effects:incidence of adverse effects:
Only if the combination is synergistic so that the
doses can be reduced.
And for the low safety margin drug.eg.
 AmphotericinB +RifampinAmphotericinB +Rifampin (latter is with no
antifungal activity but enhances the action of
amphotericin)
 AmphotericinB+ FlucytosineAmphotericinB+ Flucytosine (course duration
shortens)

3.3. To prevent the emergence ofTo prevent the emergence of
resistance:resistance:
 for chronic infections needing prolonged
therapy eg. In tuberculosis,leprosy, malaria etc.
 Rifampin with Ciprofloxacin prevents the
developmnt of resistance to latter by
Staphy. Aureus.

4.4. To broaden the spectrum ofTo broaden the spectrum of
antimicrobial action:antimicrobial action:
 In mixed infection: Peritonitis , Diabetic foot
infection , bedsores , gynaecological infections,
abscesses are mostly mixed infection. Aerobic
and anaerobic organisms sensitive to diff. drugs
are involved.
 Topically: generally AMA’s which are not used
systematically are poorly absorbed from the
local site and cover a broad range of gram
positive n negative bacteria are combined for
topical applications.
Eg Neomycin, PolymyxinB

 Initial treatment of severe infections :
For empirical therapy since bacterial diagnosis is
not known, gram positive and gram negative my
be given together eg.
Penicillin + streptomycinPenicillin + streptomycin and
cephalosporin + erythromycincephalosporin + erythromycin etc.
Rational combinations improve the certainity of
curing the infection in first attempt but should be
continued only till bacteriological data is available.

DISADVANTAGES OF ANTIMICROBIALDISADVANTAGES OF ANTIMICROBIAL
COMBINATIONSCOMBINATIONS
 Increased chances of superinfections.
 Increased incidence and variety of adverse
effects. Eg. Gentamycin+cephalothin =
exaggerated kidney failure
 If inadequate doses of nonsynergistic drugs
used then emergence of resistant can be
promoted.
 Higher cost of therapy.

ANTIMICROBIALS/ ANTIBIOTICS : GENERAL CONSIDERATIONS

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ANTIMICROBIALS/ ANTIBIOTICS : GENERAL CONSIDERATIONS