ANTIBIOTICSBROAD SPECTRUM ANTIBIOTICS

Dr Sanjana Ravindra1st year PGDept. of OMR

CONTENTDEFINITIONINTRODUCTIONHISTORY PRINCIPLES OF ANTIBACTERIAL THERAPYCLASSIFICATION AND MECHANISM OF ACTIONUSES OF ANTIBIOTICSADVERSE EFFECTS OF ANTIBIOTICSBROAD SPECTRUM ANTIBIOTIC DRUGSLOCAL DRUG DELIVERY SYSTEMANTIBIOTICS IN DENTISTRYREFERENCES

DEFINITIONS

1) DRUG is any substance or product that is used or intended to be used to modify or explore physiological systems or pathological states for the benefit of the reciepient

2) PHARMACOKINETICS is the study of absorption, distribution, metabolism and excretion of drugs ie what the body does to the drug

3) PHARMACODYNAMICS is the study of effects of the drugs on the body and their mechanism of action ie what the drug does to the body

4) THERAPEUTICS deals with the use of drugs in prevention and treatment of diseases

5) ANTIBIOTIC AGENT Against life (Greek-anti means against and biosis means life). Chemical substances produced by microorganisms that have the capacity in dilute solutions, to produce antimicrobial action

6) ANTIMICROBIAL AGENT Substances that will suppress the growth / multiplication of microorganisms. antimicrobial agents may be antibacterial, antiviral / antifungal

7) ANTIBACTERIAL AGENT substances that destroy or suppress the growth / multiplication of bacteria. They are classified as antibiotic or synthetic agents

DEFINITIONS

INTRODUCTION

Chemical substances produced by microorganisms that supress the growth of other microorganisms and may eventually destroy them.

• K.D. TRIPATHI

Chemical substance produced by microorganisms, which at a high dilution can inhibit the growth and/or multiplication or kill another microorganism.

• - WAKSMAN AND WOODRUFF(1942)

The term 'antibiosis', meaning "against life", was introduced by

the french bacteriologist Jean Paul Vuillemin

 Antibiosis was first described in 1877 in bacteria when Louis

Pasteur and Robert Koch observed that an airborne bacillus

could inhibit the growth of bacillus anthracis

INTRODUCTION

https://www.google.co.in/search?q=antib-hist

The term antibiotic was first used in 1942 by Selman Waksman and his collaborators in journal articles to describe “any substance produced by a microorganism that is antagonistic to the growth of other microorganisms in high dilution.”

The term "antibiotic" derives from anti + βιωτικός (biōtikos), "fit for life, lively“, which comes from βίωσις (biōsis), "way of life“,and that from βίος (bios), "life“

https://www.google.co.in/search?q=Waksman-antib

HISTORY

History of chemotherapy is divided into two phases.

(A) the period of empirical use (B) modern era.

Chinese ‘mouldy curd’ on boilsHindus ‘chaulmoogra oil” in leprosyAztecs ‘chenopodium’ for intestinal wormsParacelsus mercury for syphilis and cinchona bark for fever

PERIOD OF EMPIRICAL USE:

https://www.google.co.in/search?q=plantshist6orical

1871 Joseph Lister experimented with the antibacterial action on human tissue on what he called penicillium glaucium

1877 Louis Pasteur postulated that bacteria could kill other bacteria ( anthrax bacilli)

1928 Sir Alexander Fleming discovered enzyme lysozyme and the antibiotic substance penicillin from the fungus Penicillium notatum

During 1940 and 50s streptomycin, chloramphenicol and tetracyclin were discovered

1942 Selman Waksman used the term antibiotics

MODERN HISTORY

https://www.google.co.in/search?q=anti-pioneers

https://www.google.co.in/search?q=fleming-alexander

BROAD SPECTRUM1. Tetracycline

2. Chloramphenicol

3. Sulfonamides

4. Trimethoprim

NARROW SPECTRUM

1. Bacitracin2. Clindamycin3. Macrolides4. Metronidazole5. Penicillin G,V6. Penicillinase resistant

penicillin7. Polymixin8. Vancomycin

BASED ON SPECTRUM OF ACTIVITY

Neidle E A, Pharmacology and therapeutics for Dentistry, 4th edition. Pg 486

EXTENDED SPECTRUM

1. Aminoglycosides2. Carbacephems3. Cephalosporins4. Extended spectrum of

penicillins5. Fluoroquinolones6. Monobactams

CLASSIFICATION

BASED ON TYPE OF ACTION

Bacteriostatic • Sulf

onamides

• Tetracyclines

• Chloramphenicol

• Erythromycin

• Ethambutol

Bactericidal • Penic

illins• Amin

oglycosides

• Rifampin

• Cotrimoxazole

• Cephalosporins

• Vancomycin

• Nalidixic acid

• Ciprofloxacin

Neidle E A, Pharmacology and therapeutics for Dentistry, 4th edition. Pg 486

ANTIBIOTICS ARE OBTAINED FROM

ACTINOMYCETES

Penicillin CephalosporinGriseofulvin

Polymyxin BColistinBacitracinTyrothricin

AminoglycosidesTetracyclinesChloramphenicolMacrolidesPolyenes

BACTERIA

FUNGI

Neidle E A, Pharmacology and therapeutics for Dentistry, 4th edition. Pg 486

BASED ON ORGANISMS SUSCEPTIBLEEFFECTIVE AGAINST GRAM

+VE

BACTERIAPENICILLINS MACROLIDSBACITRACIN

EFFECTIVE AGAINST GRAM –VE

BACTERIASTREPTOMYCIN

EFFECTIVE AGAINST BOTH GRAM +VE AND –VE

BACTERIAAMPICILLIN

TETRACYCLIN CHLORAMPHENICOL

AMOXICILLINCEPHALOSPORIN

NEOMYCIN EFFECTIVE AGAINST ACID-

FAST BACILLI

STREPTOMYCINRIFAMPIN

KANAMYCIN

AGAINST PROTOZOA

TETRACYCLIN

EFFECTIVE AGAINST FUNGI

NYSTATINAMPHOTERICIN B

ANTIMALIGNANCY ANTIBIOTICS

ACTINOMYCIN DMITOMYCIN

PRINICIPLES OF ANTIBIOTIC THERAPY

Selection of antibacterial agent

Antibacterial combinations

Antibacterial prophylaxis

Microbial drug resistance

Dangers of antibacterial therapy

Misuse of antibacterial agents

SELECTION OF ANTIBIOTIC AGENT

1)HOST RELATED FACTORS

Age of the patient

Pregnancy and neonatal period

Immunocompetency status of the patient

Severity of the infection

Allergic reaction and intolerance

Genetic factors

Renal and hepatic function

2)PATHOGEN RELATED FACTORSEvaluation of the probable microbial etiology and expected clinical course of the infectionIdentification of the causative microorganism and its sensitivity to antibiotic drugsPossibility of drug resistance

3)DRUG RELATED FACTORSNature of the drugRisk of drug toxicityThe cost of therapyPharmacokinetic properties of the drugProbability of drug compliance by the patient

ANTIBACTERIAL COMBINATIONS

1) SIMULTANEOUS USE OF TWO OR MORE ANTIBIOTICS IS NOT ROUTINELY RECOMMMENDED. THESE DRUGS CAN BE COMBINED UNDER FOLLOWING REASONS

To achieve an additive or synergistic effect against a single organism

In mixed infections with bacteria sensitive to different drugs

To delay the development of or to overcome the drug resistance

To decrease the adverse reactions to an individual drug

When etiological diagnosis is difficult, the infection is severe and body defense is poor

For reducing chances of superinfections

2) IF A BACTERIOSTATIC DRUG IS COMBINED WITH BACTERIOCIDAL AGENT FOLLOWING THINGS MAY BE HAPPENDrug antagonismAdditive effect oftenly synergestic rarely

3) COMBINED ANTIBIOTIC THERAPY INVOLVES CERTAIN RISKSEmergence of organism resistant to the multiple drugs usedIncreased risk of adverse reactions Increased risk of superinfection by resistant organismsSense of false securityIncrease in cost of therapy

ANTIBACTERIAL PROPHYLAXIS

For prevention of meningococcal infections in healthy children during an epidemic, for prevention of diseases like syphilis, gonorrhea, malaria.

For preventing endocarditis following minor surgical procedures like tonsillectomy or tooth extraction in patients with cardiac lesions.

For preventing invasion of blood stream by pathogens during certain surgical manipulations.

In patients with compound musculoskeletal injury, penetrating wounds and skull injuries.

For those puncture wounds that are at high risk of infection.

Animal bite as they are at high risk of infection by oral flora.

To prevent microbial complications like bronchopnemonia e.g. Cases of measles and tetanus.

In paralytic states to prevent aspiration bronchopnemonia

DANGERS OF ANTIBACTERIAL THERAPY

Development of allergic and anaphylactic reactions e.g. Pennicillin

Selective toxicity Development of superinfection Development of multiple drug resistant organisms Deficiency of certain vitamins Fetal damage A false sense of security in the patient as well as in

physician Failure to respond to antibiotic therapy

MISUSE OF ANTIBIOTIC THERAPY

Antibiotic misuse, sometimes called antibiotic abuse or antibiotic overuse.

Produce serious effects on health.

From antibiotics now available , one needs to know the important representatives of each class and know them well e.g. Action , dosage .

It is a contributing factor to the creation of multidrug-resistant bacteria, informally called "super bugs" relatively harmless bacteria can develop resistance to multiple antibiotics and cause life-threatening infections.

MICROBIAL DRUG RESISTANCE

The recent emergence of antibiotic resistance in bacterial pathogens, both

nosocomialy and in the community, is a very serious development that threatens the

end of the antibiotic era.

Drug resistance is not a characteristic of all bacteria and many strains responsible for

common infections have largely remained susceptible to antibiotics e.G.

Pneumococci, streptococcus pyogenes, meningococci, and treponema pallidum.

Bacterial resistance is often quantitative and not qualitative. Thus an antibacterial substance which is not effective in small doses may inhibit the bacteria in vitro in large concentrations.

For an antibiotic to be effective, it must reach its target in an active form, bind to the target, and interfere with its function.

Accordingly, bacterial resistance to an antimicrobial agent is attributable to three general mechanisms:

(1) the drug does not reach its target,

(2) the drug is not active, or

(3) the target is altered .

Natural resistance

In organisms which are naturally resistant, the drug sensitive enzyme reactions may be absent .

some naturally resistant organisms may elaborate a substance which destroys the antibiotic e.G. E coli produce pencillinase which destroys penicillin .

Following the use of an antibiotic agent which destroys the sensitive strain , these naturally resistant variants multiply and become dominant.

Some microbes have always been resistant to certain antibacterial agents.

They lack the metabolic process or the target site which is affected by the particular drug.

This is generally a group or species charateristic e .G. Gm-ive bacilli are normally unaffected by penicillin G or M. Tuberculosis is insensitive to tetracyclines.

Acquired microbial resistance

It is the development of resistance by an organism (which was sensitive before) due to the use of an AMA over a period of time.

This can happen with any microbe and is a major clinical problem.

However, development of resistance is dependent on the microorganism as well as the drug.

Some bacteria are notorious for rapid acquisition of resistance, e.G. Staphylococci, coliforms, tubercle bacilli. .

Others like strep. Pyogenes and spirochetes have not developed significant resistance to penicillin despite its

Widespread use for > 50 years.

It can arise in bacteria in several ways. Microbes acquire resistance after a change in their DNA. Such change may occur in

A) genetic mutation

B) genetic exchange - conjugation

- Transduction

- Transformation

Mutation

It is a stable and heritable genetic change that occurs spontaneously and randomly among microorganisms.

Any sensitive population of a microbe contains a few mutant cells which require higher concentration of the ama for inhibition.

Mutation and resistance may be:

(I ) single step.- A single gene mutation may confer higher degree of resistance; emerges rapidly, e.G. Enterococci to streptomycin, E. Coli and staphylococci to rifampin

(Ii ) multistep.· A number of gene modifications are involved, sensitivity decreases gradually in a stepwise manner. Resistance to erythromycin, tetracyclines and chloramphenicol is developed by many organisms in this manner.

Conjugation : This may involve chromosomal or extrachromosomal (plasmid) dna.

The gene carrying the 'resistance' or 'r' factor is transferred only if another 'resistance transfer factor' (rtf) is also present.

Chloramphenicol resistance of typhoid bacilli, streptomycin resistance of e. Coli, penicillin resistance of haemophilus.

Concomitant acquisition of multidrug resistance has occurred by conjugation. Thus, this is a very important mechanism of horizontal transmission of resistance.

GENE TRANSFER

TRANSDUCTION:

It is the transfer of gene carrying resistance through the agency of a bacteriophage.

The r factor is taken up by the phage and delivered to another bacterium which it infects.

Certain instances of penicillin, erythromycin and chloramphenicol resistance have been found to be phage mediated.

TRANSFORMATION :

A resistant bacterium may release the resistance carrying DNA into the medium and this may be imbibed by another sensitive organism-becoming unresponsive to the drug.

This mechanism is probably not clinically significant except isolated instances of pneumococcal resistance to penicillin g due to altered penicillin binding protein

CROSS RESISTANCE :Acquisition of resistance to one AMA conferring resistance to another AMA, to which the organism has not been exposed, is called cross resistance.

This is more commonly seen between chemically or mechanistically related drugs, e.G. Resistance to one sulfonamide means resistance to all others, and resistance to one tetracycline means insensitivity to all others.

Sometimes unrelated drugs show partial cross resistance, e.G. Between tetracyclines and chloramphenicol, between erythromycin and lincomycin.

PREVENTION OF DRUG RESISTANCE No indiscriminate and inadequate or unduly prolonged use of amas should be made. This would minimize the selection pressure and resistant strains will get less chance to preferentially propagate.

Prefer rapidly acting and selective (narrow spectrum) amas whenever possible; broad-spectrum drugs should be used only specifically.

Use combination of amas whenever prolonged therapy is undertaken, e.G. Tuberculosis, SABE.

Infection by organisms notorious for developing

Resistance, e.G. Staph. Aureus, E. Coli, M. Tuberculosis,

Proteus, etc. Must be treated intensively.

INDICATIONS OF ANTIBIOTICS

* Diabetics mellitus, immunoglobulin deficiency, malnutrition and alcoholism.* Acute severe rapidly spreading infection* Pericoronitis, osteomyelitis, fracture, soft tissue wound and odontogenic infection

* Post operative wound infection* Prevention of endocarditis in high risk patients undergoing any dental procedures that is likely to cause gingival bleeding

THERAPEUTIC

PROPHYLACTIC

USES OF ANTIBIOTICS

Infections of all systems Pus formationSepsisQuinsySkin infectionsMucous membrane infectionsSepticaemiaEmpirical therapyProphylactic therapy

CONTROL AND ERADICATION OF INFECTIONS OF ORAL CAVITY.

• Local factors;

1) Swelling, 2) Lymphadenitis, 3) Trismus,

4) Dyshagia 5) Chronic draining sinus tract.

• Systemic factors; 1) Cellulitis. 2) Osteomyelitis. 3) Infections of salivary gland. 4) Compound fractures. 5) Infected cysts. 6) Infected oro-antral fistula. 7) Pericoronitis

SIDE EFFECTS OF ANTIBIOTICS

DiarrhoeaBloating and indigestion Abdominal pain Loss of appetite Being sick Feeling sick Itchy skin rashCoughingLife-threatening allergic reaction

BROAD SPECTRUM

ANTIBIOTICS

1. TETRACYCLINE

2. CHLORAMPHENICOL

3. SULFONAMIDES

4. TRIMETHOPRIM

TETRACYCLINEDefination : They are octahydro napthacene derivatives which are bacteriostatic and broad spectrum antibiotics that kills certain infection causing microorganisms and are used to treat wide variety of infections.

Tetracyclines are napthacene derivatives.

The napthacene nucleus is made up by fusion of 4 partially unsaturated cyclohexane radicals and hence the name tetracyclines.

Tetracyclines are bacteriostatic & effective against rapidly multiplying bacteria

https://www.google.co.in/search?q=tetracycline+structure

According to duration of action:• Short-acting (Half-life is 6-8 hrs)

• Tetracycline• Chlortetracycline• Oxytetracycline

• Intermediate-acting (Half-life is ~12 hrs)• Demeclocycline• Methacycline

• Long-acting (Half-life is 16 hrs or more)• Doxycycline• Minocycline• Tigecycline

CLASSIFICATION

Primarily bacteriostatic.

Inhibit protein synthesis by binding to 30s ribosomes in susceptible organism. Thus,

attachment of aminoacyl-t-rna to the mrna-ribosome complex is interfered with. As a

result, peptide chains fail to grow.

It is effective against gram –ve and gram +ve bacteria, rickettsial, spirochetees,

protozoa and mycoplasma.

MECHANISM OF ACTION

tripathi

Orally- saliva- liver- bile

They cross placental barrier

Tetracyclines have chelating property-form insoluble & unabsorbable

complexes with calcium and other metals.

Doxycycline & minocycline are completely absorbed irrespective of food.

Milk, iron preparations, nonsystemic antacids & sucralfate reduce their absorption . administration of these substances & tetracyclines should be staggered, if the cannot be avoided altogether.

PHARMACOKINETICS

(A) IRRITATIVE EFFECTS: - Epigastric pain, nausea, vomiting, diarrhoea. - Doxycycline is known to cause esophageal ulcerations.

(B) DOSE RELATED TOXICITY: 1.) LIVER DAMAGE: - Fatty infiltration of liver, jaundice, in pregnancy, Can cause acute hepatic necrosis.

ADVERSE EFFECTS

2.) KIDNEY DAMAGE: - Fancony syndrome – like condition

3.) PHOTOTOXICITY: - Sunburn, severe skin reactions

4.) ANTIANABOLIC EFFECT : - Reduce protein synthesis & have an overall catabolic effect. - They induce negative nitrogen balance & can increase blood urea.

5.) LNCREASED INTRACRANIAL PRESSURE In some infants.

6.) DIABETES INSIPIDUS - Demeclocycline antagonizes ADH action & reduces urine concentrating ability of the kidney.

7.) VESTIBULAR TOXICITY - Minocycline has produced vertigo which subside when the drug is discontinued.

(C) HYPERSENSITIVITY

- This is infrequent with tetracyclines.

- Skin rashes, urticaria, glossitis, pruritus, even

exfoliative dermatitis have been reported.

- Angioedema & anaphylaxis are extremely rare.

(D) SUPERINFECTION:

- Marked suppression of the resident flora.

- Intestinal superinfection by candida albicans can occur.

- Oral manifestations are very rare.

https://www.google.co.in/search?q=tetracycline+staining

Hypoplasia and brown discolouration of teeth

Not used in 3rd trimester

Deposits in bones and teeth- yellow

discolouration

Not recoomended- children below 8 yrs and

pregnant women – permanently discolour

developing teeth and alter bone growth

(E) TOOTH DISCOLOURATION

PRECAUTIONS

1.) Tetracyclines should not be used during pregnancy, lactation and in children.2.) They shouldbe avoided in patients on diuretics: blood urea may rise in such patients.3.) They should be used cautiously in renal or hepatic insufficiency.4.) Preparations should never be used beyond their expiry date.5.) Do not mix injectable tetracyclines with penicillin-inactivation occurs.6.) Do not inject tetracyclines intrathecally.

(A) MEDICINAL USES

- Clinical use has declined due to the introduction of Fluoroquinolones and other agents. - DRUG OF 1ST CHOICE: (A) venereal diseases (B) atypical pneumonia (C) cholera limit the diarrhoea duration. (D) brucellosis combined with gentamicin. (E) plague (F) relapsing fever. (G) rickettsial infections.

USES

- DRUG OF 2ND CHOICE:(A) to penicillin / ampicillin for tetanus , anthrax , actinomycosis infections. (B) to ciprofloxacin / ceftriazone for gonorrhea in patients allergic to penicillin.(C) to ceftriaxone for syphilis in patients allergic to penicillin.(D) to azithromycin for chlamydial infections.

- Also can be used for UTI , pneumonia, amoebiasis, acne, lung disease.

(B) dental uses :• of limited use in treating acute infections , but are of importance

in periodontal disease.• Suppress the activity of collagenases derived from the neutrophils

and fibroblasts, that contribute to gingival inflammation.• Collagenases are calcium dependent & tetracyclines chelate the

calcium.• May benefit periodontal inflammation by releasing free radicals

of oxygen.

ADMINISTRATION

oral capsule is the dosage form in which tetracyclines are most commonly administered. The capsule should be taken 1/2 hr before or 2 hr after food. Not recommended by i.M. Route because it is painful & absorption from the injection site is poor. Slow i.V. Injection may be given in severe cases, but is rarely require now. A variety of topical preparations are available , but should not be use because there is high risk of sensitization .

OXYTETRACYCLINE: (TERRAMYCIN) 250 – 500 MG EVERY 6 HRS

TETRACYCLINE: (ACHROMYCIN, RESTECLIN) 250 MG – 4 G EVERY 6 HRS

DOSAGES

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DEMECLOCYCLINE: (LEDERMYCIN) ADULT: 150 MG 4 X DAILY 300 MG BID. CHILD: 7 – 13 MG/KG DIVIDED EVERY 6 – 12 HRS.

MINOCYCLINE: (CYANOMYCIN) ADULT: 200 MG FOLLOWED BY 100 MG EVERY 12 HRS. CHILD: 4 MG/KG FOLLOWED BY 2 MG/KG EVERY 12 HRS.

https://www.google.co.in/search?q=tetracycline+tablet

DOXYCYCLINE: (TETRADOX, BIODOXI, DOXT, NOVADOX) ADULT: 200 MG ON DAY 1 FOLLOWED BY 100 MG OD CHILD: 4 MG/KG IN 2 DIVIDED DOSES, FOLLOWED BY 2 MG/KG DAILY.

https://www.google.co.in/search?q=tetracycline+tablet

TETRACYCLINE EFFECTIVE IN TREATING PERIODONTAL DISEASE BECAUSE

• Adjuvant role in Chronic Periodontitis - control gingival inflammation -normalize the periodontal microflora from a mixture of anerobic G-

bacilli and spirochetes.

• Highly active against Actinobacillus actinomycetum comitans in Aggressive Periodontitis - prevents gingival destruction and bone loss.

TERATOGENIC EFFECTS OF TETRACYCLINES

PERIOD STRUCTURE AFFECTED DEFORMITYmid pregnancy to 5 months of postnatal life

Deciduous teeth Brownish discolouration, ill formed and are more susceptible to caries

2 months to 5 years of age Permanent teeth Pigmentation, discolouration

Pregnancy and childhood up to 8 years of age

Skeleton Depressed bone growth

CHLORAMPHENICOL

• Broad spectrum antibiotic first obtained from streptomyces venezuelae.

MECHANISM OF ACTION

It is bacteriostatic but for some organisms it is bacteriocidal. It binds to 50s ribosomal subunit and inhibits protein synthesis

It is unique among natural compounds because it contains a NITROBENZENE moiety and is a derivative of DICHLOROCETIC ACID.

It acts by inhibiting protein synthesis (by binding reversibly to the 50s ribosomal subunit).

https://www.google.co.in/search?q=chloramphenicol+structure

64

USES :

Typhoid fever(S.typhi)

Bacterial meningitis (H.influenzae)

Anaerobic infections

Rickettsial disease (eg.Rocky mountain spotted fever)

Brucellosis

UTIAdult 250 -500mg 6hrly

Children 25 – 50mg /kg/day

65

ADVERSE EFFECTS : Bone marrow depression

Hypersensitivity reactions

Irritative effects

Superinfections

Gray baby syndrome

GRAY BABY SYNDROME / ASHEN GRAY

CYANOSIS

Newborn babies given high doses of

chloramphenicol – develop vomiting, refusal of

feeds, hypotonia, hypothermia, abdominal

distension, metabolic acidosis https://www.google.co.in/search?q=gray+baby

It is the fixed dose combination of trimethoprim and sulfamethoxazole.

Trimethoprim it is diaminopyrimidine and related to antimalarial drug pyrimethamine.

Sulfamethoxazole

selected for the combination because it has nearly the same T ½ as trimethoprim.

COTRIMOXAZOLE

ANTIBACTERIAL SPECTRUM :

Individually, both sulfonamide and trimethoprim are bacteriostatic.

Combination becomes cidal against many organisms.

Organisms covered by the combination are-salmonella typhi, serratia, klebsiella, enterobacter, pneumocystis jiroveci.

Many sulfonamide resistant strains of staph. Aureus, strep. Pyogenes, shigella, enteropathogenic E. Coli, influenzae , gonococci and meningococci.

Why sulfamethoxazole + trimethoprim ?

Both have nearly the same t1/2 (- 10 hr).

Optimal synergy is exhibited at a concentration ratio of Sulfamethoxazole 20 : trimethoprim 1.

MIC of each component may be reduced by 3-6 times.

This ratio is obtained in the plasma when the two are given in a dose ratio of 5 : 1, because trimethoprim enters many tissues, has a larger volume of distribution than sulfamethoxazole and attains lower plasma concentration

PHARMOKINETICS :

Trimethoprim crosses blood-brain barrier and placenta, while sulfamethoxazole has a poorer entry.

Trimethoprim is more rapidly absorbed than sulfamethoxazole.

Trimethoprim is 40% plasma protein bound, while sulfamethoxazole is 65% bound.

Trimethoprim is partly metabolized in liver and excreted in urine.

ADVERSE EFFECTS:

Nausea, vomiting, stomatitis, headache, rashes.

Rarely, folate deficiency (megaloblastic anemia)

Blood dyscrasias.

CONTRAINDICATIONS:

Pregnancy: - teratogenic effects may occur due to trimethoprim.

- Neonatal haemolysis, methaemoglobinaemia.

Renal disease: - patient may develop uraemia.

Aids patients: - fever, rash, bone marrow hypoplasia. Elderly patients: - bone marrow toxicity.

Diuretics + cotrimoxazole = thrombocytopenia.

USES:

Tonsilitis, pharyngitis, sinusitis, otitis media, chronic bronchitis.

Orodental uses very rare only if allergies to β – lactam antibiotics are present.

Major indications include uti, bacterial dysentery.

Effective alternative to chloramphenicol in the case of typhoid fever, but strains are known to be resistant.

Alternative for chancroid, granuloma inguanale, neutropenic patients. BRAND NAME SEPTRAN, SEPMAX, BACTRIM, CIPLIN, ORIPRIM, SUPRISTOL, FORTRIM.

First anti-microbial agents effective against pyogenic bacterial infections.

Sulfonamido-chrysoidine (prontosil red) used by Domagk to treat streptococcal infection in mice.

SULPHONAMIDE

A LARGE NUMBER OF SULFONAMIDES WERE PRODUCED AND USED EXTENSIVELY,

BUT BECAUSE OF RAPID EMERGENCE OF BACTERIAL RESISTANCE AND AVAILABILITY OF MANY SAFER AND MORE EFFECTIVE

ANTIBIOTICS

CURRENT UTILITY IS LIMITED

EXCEPT IN COMBINATION WITH TRIMETHOPRIM (COTRIMAXOZOLE) AND PYRIMETHAMINE.

CLASSIFICATION:

(A) short acting (4-8 hrs):

- Sulfadiazine.

(B) intermediate acting (8-12 hrs):

- sulfamethoxazole, sulfamoxole.

(C) long acting (approx. 7 days):

- Sulfadoxine, sulfamethopyrazine.

(D) special purpose sulfonamides:

- Sulfacetamide sodium, sulfasalazine mafenide, silver sulfadiazine.

ANTIBACTERIAL SPECTRUM :

They are primarily bacteristatic against gm +ve and gm –ive bacteria.

However , bacteriocidal action can be attained in urine.

Sensitive to strepto. Pyogenes , haemophilus influenzae , vibrio cholerae , meningococci , gonococci , E coli and shigella.

RESISTANCE:

Some bacteria are capable of developing resistance to sulfonamides like pneumococci, gonococci, staph. Aureus, meningococci, some strep. Pyogenes.

It is due to (a) produce increased amounts of PABA. (B) folate synthetase enzyme has low affinity. (C) adopt an alternative pathway for folate

metabolism.

Pharmacokinetics:

Rapidly absorbed by the g.I.T.Extent of plasma binding differs in different members ( 10 – 90 % ).Highly protein bound members are longer acting . attains the same concentration in the csf as in plasma. Excreted mainly by the kidney through glomerular filtration.The more lipid soluble members are highly reabsorbed in the tubule hence longer acting .Crosses placenta freely.

THE PRIMARY PATHWAY FOR THE METABOLISM OF SULFONAMIDES IS

ACETYLATION AT N 4 BY NON MICROSOMAL ENZYME IN LIVER

THE ACETYLATED DERIVATIVE IS INACTIVE

AND GENERALLY LESS SOLUBLE IN URINE THAN PARENT DRUG

MAY PRECIPITATE

CAUSES CRYSTALLURIA .

Sulfadiazine :

Rapidly absorbed orally Rapidly excreted in urine 50% plasma protein bound20-40% acetylatedAderivative is less soluble in urine = crystalluria Good penetrabilityi n brain and CSFPreferred compound for meningitis

Dose: 0 5 g qid to 2 g tds; sulfadiazine 0.5 g tab

Sulfamethoxazole :

Slower oral absorption Slower urinary excretion T 1/2 in adults is 10 hoursPreferred compound for combining with trimethoprim because the t1/2 of both is similarA high fraction is acetylated – crystalluria

dose: 1 g BD for 2 days, then 0.5 g BD.Gantanol 0.5 g tab.

Sliver sulfadiazine :

Active against a large number of bacteria and fungi,It slowly releases silver ions which appear to be largely responsible for the antimicrobial actionMost effective drugs for preventing infection of burnt surfaces and chronic ulcers and is well tolerated.It is not good for treating established infection.Local side effects are-burning sensation on application and itch.

Sil vlrin 1% cream, argenex 1% creamWith chlorhexidine 0.2%.

ADVERSE EFFECTS :

Crystalluria is dose related

Hypersensitivity reactions occur in 2-5 % patients. These are mostly in the form of rashes, urticaria and drug fever.

Photosensitization is reported.

Stevens-johnson syndrome and exfoliative dermatitis are more common with long-acting agents.

Hepatitis, unrelated to dose, occurs in 0.1 % patients.•

Topical use of sulfonamides is not recommended because of risk of contact sensitization.

• Sulfonamides cause haemolysis in a dose dependent manner in individuals with g-6-pd deficiency.

Neutropenia and other blood dyscrasias are rare.

• Kernicterus may be precipitated in the newborn, especially premature, by displacement of bilirubin from plasma protein binding sites and more permeable blood-brain barrier

Interactions :

sulfonamides inhibit the metabolism (possibly displace from protein binding also ) of phenytoin, tolbutamide and warfarin enhance their action.

They displace methotrexate from binding and decrease its renal excretion = toxicity can occur.

Fixed dose combinations of sulfonamides with penicillins are banned in india.

Uses :

Systemic use of sulfonamides alone is rare now.

Though they can be employed for suppressive therapy of chronic uti, for streptococcal pharyngitis and gum infection.

Combined with trimethoprim (as cotrimoxazole) sulfamethoxazole is used for many bacterial infections and nocardiasis .

Along with pyrimethamine, certain sulfonamides are used for malaria and toxoplasmosis.

Ocular sulfacetamide sod. (10-30%) is a cheap alternative in trachoma/ inclusion conjunctivitis.

Topical silver sulfadiazine or mafenide are used for preventing infection on burn surfaces.

89

LOCAL DRUG DELIVERY OF ANTIBIOTICS

• Limitation of systemic therapy, mouth rinse & irrigation have, promoted for research for development of alternative delivery system

• Requirement of treating periodontal disease include 1. Controlled release of drug 2. Maintained localized concentration of drug at infection site for

optimum time 3. Minimal side effect

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VARIOUS LOCAL DRUG DELIVEREY OF ANTIBIOTICS

• ACTISITE (TETRACYCLINES)• ARESTIN (MINOCYCLINE)• ATRIDIOX (METRONIDAZOLE ) • PERIO CHIP (CHLOR HEXIDINE)• ELYZOL (METRONIDAZOLE )

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TETRACYCLINE – CONTAINING FIBER (ACTISITE )

First local delivery product for antibiotic Feature

1. Ethylene or vinyl acetate copolymer fiber

2. Diameter 0.5 mm

3. Containing Tetracycline 12.7 mg/ 9 inch

4. When packed into periodontal pocket, it is well tolerated by oral tissue

5. For 10 day it sustains tetracycline concentration exceeding 1300 ug/ ml

https://www.google.co.in/search?q=LDD+actisite

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ACTISITE.......

Effect Reduction in probing depth Reduction in Bleeding on probing Increase in clinical attachment level Normally no staining on teeth Reduction in plaque micro organism

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SUB GINGIVAL DELIVERY OF DOXYCLINE ATRIDIOX

• Atridox is gel system that incorporate the antibiotic Doxycycline (10%) in syringeable gel system

• It is a Biodegradable mixture• Drug introduced Subgingivally• Applied with or without Scaling or Root planning Effect Increase in clinical attachment level Reduction in plaque micro organism Probing depth reduction

https://www.google.co.in/search?q=LDD+ATRIDIOX

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SUB GINGIVAL DELIVERY FOR

MINOCYCLINE (ARESTIN)1. Sub Gingival Delivery system contain 2% (w/w) Minocycline

hydrochloride2. Use as a adjuvant to Sub Gingival debridement3. Biodegradable mixture in syringe

Effect are Reduction in Pocket depth Reduction in gingival bleeding Reduction in plaque microorganism

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SUB GINGIVAL DELIVERY OF METRONIDAZOLE ELYZOL

• ELYZOL Containing an oil based Metronidazole 25% dental gel

• Applied in viscous consistency to the pocket where is liquidized by body heat and hard again contact with water

• Preparation contain Metronidazole benzoate, which is converted into active

substance by esterase in GCF

• Effective after scaling & Root planning

ANTIBIOTIC PROPHYLAXIS FOR DENTAL PROCEDURES Definition:

“The administration of antibiotics to patients who have no known infection in order to prevent microbial colonization and reduce the potential of post – operative complications.” - Michael g. Newman

Principles: (A) benefits > risks. (B) antibiotic loading dose should be used (C) should be selected based on the most likely organism to cause an infection. (D) should be present in the blood and target tissues before the spread of micro – organisms. (E) should be continued as long as contamination persists

American Heart Association: (Infective Endocarditis)

SITUATION DRUGDOSAGE (30 – 60 min.

before procedure single dose)

Oral Administration Amoxicillin Adults: 2 gChildren: 50 mg/kg

Inability to take Oral medication

a.) Ampicillin

b.) Cefazolin/Ceftriaxone

Adults: 2 g I.M/I.V.Children: 50 mg/kg I.M/I.V

Adults: 1 g I.M/I.VChildren: 50 mg/kg I.M/I.V

Allergy to Penicillin and Ampicillin

a.) Clindamycin

b.) Azithromycin/Clarithromyci

n

c.) Cephalexin

Adults: 600 mgChildren: 20 mg/kg

Adults: 500 mgChildren: 15 mg/kg

Adults: 2 g Children: 50 mg/kg

Allergy to Penicillin and Ampicillin + Inability to take

oral medication

a.) Cefazolin/Ceftriaxone

b.) Clindamycin Phosphate

Adults: 1 g I.M./I.V.Children: 50 mg/kg I.M./I.V.

Adults: 600 mg I.M/I.VChildren: 20 mg/kg I.M/I.V.

ANTIBIOTICS IN VARIOUS DENTAL CONDITIONS

WHEN ARE ANTIBIOTICS USED?

Useful as treatment adjuncts to conventional periodontal therapy.

Successful when the micro-organism has reached the connective tissue of the

diseased gingiva.

They should never be used if treatment is removal of plaque. Agent is most

effective when the dominant micro – organism is determined.

CONDITION DRUG DOSAGE

Acute Ulcerative Necrotizing Gingivitis

a) Amoxicillin

b) Metronidazole

a.) 500 mg QID x 5 days

b.) 400 mg TID x 7 days.

Periodontal Abscess

a) Amoxicillin

b.) Clindamycin ( Penicillin allergy)

c.) Azithromycin

a.) 1 g loading dose, then 500 mg TID x 3 days

b.) 600 mg loading dose, then 300 mg QID x 3 days.

c.) 1 g loading dose, then 500 mg QID x 3 days.

Localized Aggressive Periodontitis

a.) Tetracycline

b.) Doxycycline

c.) Augmentin ( If resistant to the Tetracyclines)

a.) 250 mg x 14 days, every 8 weeks.

b.) 100 mg/day

c.) 325 mg TID x 14 days.

Endodontic Infections: - Acute Periapical Abcess: Amoxicillin 500 mg TID x 5 days

- Adjunctive Treatment: Penicillin 1 g loading dose, then 500 mg every 6 hrs x 7 – 10 days. Penicillin Allergy: Erythromycin 1 g loading dose, then 500 mg every 6 hrs x 7 days. Doxycycline 200 mg loading dose, the 100 mg every 6 hrs x 7 days.

Cellulitis: Adult: Amoxicillin 500 mg TID x 5 days Child: 20 – 50 mg/kg/day in 2 – 3 divided doses.

Osteomyelitis: 1.) Aqueous Penicillin 2 MU I.V. every 4 hrs + Metronidazole 400 mg every 6 hrs. If condition improves after 48 – 72 hrs, then switch to Penicillin V 500 mg every 4 hrs + Metronidazole 400 mg every 6 hrs x 4 – 6 weeks.

2.) Ampicillin 1.5 -3 g x 6hrs.

If condition improves after 48-72hrs switch to Augmentin 1 g BID x 4 – 6 weeks

3.) Penicillin V 2g + Metronidazole 400 mg every 8 hrs. x 2 - 4weeks after last the seqestrum was removed and the patient was without symptoms

4.) Clindamycin 600 - 900mg every 6 hrs. I.V. then Clindamycin 400 - 600mg every 6 hours or 2-4 weeks

5.) Cefoxitin 1 g every 8 hours I.V. / 2 g every 4 hrs I.M. until no symptoms, then switch to Cephalexin 500 mg every 6 hrs for 2-6 weeks.

Dento – Alveolar Abscesses/Space Infections: - Amoxicillin 500 mg TID x 5 days. Metronidazole 400 mg TID x 5 days.

- Penicillin Allergy: Clindamycin 600 mg

Pediatric Doses: (a) Amoxicillin: 250 mg TID x 5 days. 20 – 40 mg/kg oral susp. (b) Ampicillin: 50 – 100 mg/kg in 4 divided doses (c) Cephalexin: 25 – 50 mg/kg in 4 – 6 divided doses. (d) Clindamycin: 8 – 25 mg/kg in 3 – 4 divided doses. (e) Erythromycin: 30 – 40 mg/kg in 4 divided doses (f) Penicillin V: 25 – 50 mg/kg in 4 divided doses.

CULTURE SENSITIVITY AND TESTING

Many oral infections are treated without identification of the specific etiologic agent.

This leads to unsuspected resistance and therefore the treatment can become unsuccessful or inadequate.

Quantitative Tests: - Determines how much the minimum inhibitory concentration inhibits the growth of the organism.

- Minimum Inhibitory Concentration: (MIC) - Lowest concentration of the agent that inhibits the growth of the organism.

- Minimum Bactericidal Concentration: (MBC) - Lowest concentration of antimicrobial agent that allows less that 0.1 % of the original inoculum to survive.

METHODS OF SUSCEPTIBILITY TESTING: (a) Chromogenic Cephalosporin Test: - Used to detect the β – Lactamase enzyme. - Colour of the disc changes from yellow to red.

(b) Disc Diffusion Method:

- Incorporates the measurement of zone

diameters, representing the ability of a particular agent to

exert its effect.

(c) Dilution Methods: - Recommended for slow growing facultative anaerobic bacteria found in oral infections.

- Also determines the bactericidal activity of synergism or antagonism between agents. (e.g Microdilution test, Agar dilution test)

Interpretation of Results: - An organism is considered to be susceptible if the Minimal Inhibitory Concentration is lower than the peak concentration in blood.

LIST OF REFERENCES

1. www.Merriam-webster.Com

2. Essentials of general pharmacology, K D Tripati : Jaypee Publications,5th edition 2003

3. Goodman and Gilman. The pharmacological basis of therapeutics, 9th edition.

4. Michael G Newman, “Antibiotic/Antimicrobial Use in Dental Practice”

5. CIMS India (www.mims.com)

6. Dental pulse for entrance examination

7. Maureen K Bolon, “The Newer Fluoroquinolones,” 2011

8. www.medical.theclinics.com

9. Foundation in microbiology: basic principle by Kathleen park, 2nd edition

10.Lippincott’s illustrated reviews pharnacology., 2nd edition 2000

11.Satoskar, bhandarkar , Nirmala rege . pharmacology and therapeutics, 20th edition.

12.Burket's textbook of oral medicine, lester william burket, martin s. Greenberg, michael

glick, jonathan A. Ship 11th edition,

13.Carranza's clinical periodontology, michael G. Newman, henry takei, perry R.

Klokkevold, fermin A. Carranza

LIST OF REFERENCES