General General considerations : considerations : Antimicrobial Antimicrobial drugsdrugsPRESENTED BY:PRESENTED BY:Sonali SharmaSonali Sharma B.Pharmacy Final yearGuru 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. against Type of org. against activeactive Type of spectrumType of spectrum

Type of actionType of actionSourceSource

CLASSIFICATION OF CLASSIFICATION 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 which Type 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 ARISE PROBLEMS 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 ClotrimazoleResistant staphylococci- VancomycinClostridium 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 AND RENAL AND

HEPATIC FAILURE HEPATIC 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 inhibit ion i.e inhibitory effect depends on th ratio of the peak con. To the MIC

Beta lactums,glycopeptides,macrolides produce t ime dependent inhibit ion i.e action depends on the time the conc. Remains above the MIC.

WHY COMBINATION OF WHY COMBINATION OF AMA’S USED?AMA’S USED?

TO BROADEN THE SPECTRUMTO BROADEN THE SPECTRUMOF ACTIONOF ACTION

REDUCING REDUCING SIDE EFFECTSSIDE EFFECTS

PREVENTING EMERGENCEPREVENTING EMERGENCE OF RESISTANCEOF RESISTANCE

ACHIEVING ACHIEVING SYNERGISMSYNERGISM

COMBINED USE OF COMBINED 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 or To 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 of To 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 of To 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 ANTIMICROBIAL DISADVANTAGES 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.