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* Antimicrobial compounds include : Antibacterial, antiviral, antifugal and antiprotozoal. Antibiotic therapy can be either : 1- Empirical antibiotic therapy (when the antibiotic is prescribed on ((a best – guess basis )) or 2- Rational antibiotic therapy: when the antibiotic are administered after the sensitivity test in the lab .Antimicrobial agents are classify in to 2 major groups:Bactericidal agents (which kill bacteria) Bacteriostatic agents (which inhibit multiplication)

1-Conc. of the drug (e.g. Erythromycin is bacteriostatic at low conc & bactericidal at high conc.

2-Sensitivty of infection.

3-Host defence mechanisms
The distinction depend on :

Mode of action of antimicrobials :

There are 4 possible target areas of antimicrobials :
Cell wall,
Ribosomes (Protein synthesis) Cytoplasmic memb.
And nucleic acid replication.

Principle of antimicrobial therapy:

Antimicrobial agents should be considered for
patient's when one or more of the following
conditions are present:
1-Fever & an acute infection .
2-Spreading infection with out localization.
3-Chronic infection.
4-Infection in medically compromised patients.
5-Cases of osteomylitis, bacterial sialadentitis
some periodontal disease such as acute
ulcerative gingivitis and localized aggressive
periodontitis.

Choice of drug:

depent upon :
1- the nature of the infecting m.o.
2- their sensitivity patterns .
3- the prescence of antibiotic resistant bacteria.
Narrow spectrum antibiotic e.g. Penicillin with activity mainly against g+bacteria . Metronidazole : almost acts against strict anaerobes & some protozoa.

Broad spectrum antimicrobial agents e.g. ( tetracycline, ampicillins ) against many of g+ & g – bacteria.Combination Therapy :Whenever possible a single anti microbial agent should be used to reduce the :1-Possible side effects .2-emergence of resistant bacteria.3-Drug costs.Combination therapy in the management of tuberculosis .In dentistry combination therapy should be avoided as far as possible.

Antimicrobial Prophylaxis

Is the use of a drug to prevent colonization or
multiplication of m.o. in a susceptible host.
The value of prophylaxis depends upon
balance between:
1-The benefit of reducing the infection risk and consequent secondary morbidity.
2-The possible toxic effects to the host including alteration N.F. of the host.
3-The cost effectiveness.

Antibiotic resistance in bacteria:

Is the major problem in antibiotic therapy Staph. aureus rapidly acquire resistance while Str. pyogenes rarely do so. Such antibiotic resistance can be divided into:Primary resistance: where the m.o. is naturally resistant to the drug.Its resistance is unrelated to contact with the drug. e.g., coliform to penicillin.Acquired resistance: either due to mutation within the same species (chromosomal resistance) or gene transfer between different species via plasmids (extra - chromosomal resistance).Cross – resistance: when bacteria resistance to one drug confers resistance to another chemically related drug:e.g., bacteria resistance to one type of tetracycline may be resistant to other types of tetracycline.

Mechanisms of antibiotic resistance:

1-Inactivation of the drug: Very common, production of β lactamase by staphylococci, the enzyme which is plasmid – coded, destroy the β lactam ring responsible for the activity of penicillins.2-Altered uptake:The amount of drug that reaches the target is either reduced or completely inhibited e.g., tetracycline resistance is Ps. aeruginosa this can either due to altered permeability of the cell wall or to pumping of the drug out of the cell (effux mechanism).

Structure of -lactam drugs

3-Modification of the structural target of the drug:Resistance to some penicillin due to loss or alteration of penicillin binding proteins (PBP) e.g., penicillin resistance in Str pneumoniae.4-Altered metabolic pathway: Afew sulphonamid– resistance bacteria can used preformed folic acid and do not require extracellular – para – aminobenzoic acid (folic acid precursor) for the synthesis of nucleic acids.

Penicillins

Most useful & widely used in dentistry
Awide array of penicillins have been synthesized by incorporating various side chains in to the B-lactam ring.
The commonly used penicillins are non toxic but all share the problem of allergy . Reactions such as rashes are common while sever reactions especially anaphylaxis can be fatal.

phenoxymethylpenicillin(penicillinV)

Mode of action: Bactericidal, inhibit cell wall synthesis by inactivation Transpeptidase enzyme which catalyze the formation of cross-Linkages between P.G. Chains. Administration:Oral,acid resistant.Spectrum of activity : effective against : α haemolytic Str.& penicillinase negative Staphylocacci, Actinomyces, Eubaterium, Bifidobacteria and Peptostreptococcus spp. Anaerobic organisms such as bacteriodes, Prevotella, Porphyromonas, Fusobaterium & Veillonella spp. A majority of staphylococci are penicillinase producers , some of α – haemolytic streptococci and some of Actinobacillus actinomycetemcomitans. ( in aggressive periodotitis).

Administration: Oral

Used by dental practitioners in the treatment of acute purulent infections, post-extraction infection pericoronitis and salivary gland infections.

Pharmacodynamics :
Penicillin V is less active than penicillin G because of its erratic absorption from the gastrointestinal tract.

Toxicity: virtually non-toxic, may cause sever reaction in patients who are allergic; anaphylaxis may occur, skin rashes & fever.

Benzylpenicillin (penicillin G) :

Administration : intramuscular, intravenous.
Indications : useful in moderate to sever infections (e.g. Ludwigs angina)
Toxicity : Chances of allergy developing are increased by injection, . Penicillin G may cause convulsions after high doses by intravenous injection or in renal failure.

(Broad spectrum penicillins susceptible to staphylococcal penicillinase(Ampicillin&Amoxycilln).
Administration: Oral (amoxicillin absorption is better than ampicillin) intramuscular, intravenous.
Spectrum of activity : similar to penicillin but effective against broader spectrum of m.o. such as Haemophilus and Proteus spp.

Resistance :

Amoxicillin is broken down by B-lactamase of bacteria to penicilloic acid. If potassium clavulanate (a product of Streptomyces clavuligerus is incorporated with amoxicillin, it inhibits the B-Lactamase activity. The combination drug is known as co-amoxiclav.
Indications:
In dentistry, amoxicillin is the drug of choice for prophylaxis of infection endocarditis in patients undergoing surgical procedures.
Ashort course of high dose amoxicillin (oral)------ in the treatment of dentoalveolar infections.

Toxicity

higher incidence of drug rashes than penicillin.
Nausea and diarrhoea , super infection and colonization with ampicillin resistant bacteria (Coliform & Fungi) may also occur.

Isoxazolyl penicillins

methicillin, cloxacillin & flucloxacillinAdministration: Oral, intramuscular, intravenous Spectrum of activity : Narrow – spectrum, anti staphylococcal pencillins. Relatively resistance to B-lactamase produced Staph aureus.Toxicity : safe, non-toxic, even in high doses Sensitivity: All strains of Staph aureus were sensitive to these drugs.

Cephalosporins ,Cephamycins and other B-Lactams.

Includes more than 30 different agents.
All cephalosporins are B-Lactams, but are relative stable to staphylococcal penicillinase

Spectrum activity: Broad spectrum, active against g+ and g-bacteria.

Toxicity:
Allergic reactions, including urticaria and rashes, possibly nephrotoxicity ,another disadvantage is that oral bacteria including Streptococci may develop cross-resistance to both penicillins and Cephalosporins.

Erythromycin:

Administration: Oral, inravenousMode of action: Bacteriostatic Spectrum of activity:Similar to penicillin, The first choice in dentistry for treating penicillin – allergic patients.Haemophilus influenzea,Bacteroides, Prevotella ,Prophyromonas spp. are sensitive . Active against B-lactamase-producing bacteria .Not usually used as a first-line drug in oral and dental infection (obligate anaerobes are not particularly sensitive).Toxicity: The main disadvantage being that high doses (given for prophylaxis of infective endocarditis) cause nausea, prolonged use (>14 days) may be hepatoxic.

Clindamycin:

Administration: Oral, intravenous or intramuscular
mode of action: Inhibit protein synthesis by binding to bacterial ribosomes.
Spectrum of activity:
Similar to the of Erythromycin (with partial cross-resistance) and benzylpenicillin; in addition it is active against Bacteriodes spp.
Indication:
As asingle dose for prophylaxis of infective endocarditis in patients allergic to penicillin .
Toxicity:
Mild diarrhoea is common
Pseudo membranous (antibiotic-associated) colitis, which some times can be fatal especially in elderly and in combination with other drugs.
The colitis is due to a toxin produced by Cl.difficile an anaerobe resistant to Clindamycin.
Allergy is rare.

Tetracycline:

Widely used (very broad spectrum and infrequently side-effects).
For treatment of infections caused by intracellular m.o. Chlamydiae, Rickettsiae & Mycoplasma as they penetrate macrophages well
Tetracycline is the most useful for dental purposes.
Administration: Mostly oral
Mode of actions: Bacteriostatic, interfere with protein synthesis by binding to bacterial ribosomes .
Spectrum of activity:
Wide spectrum against oral flora including Actinomyces, Bacterides, Propionibacterium, Actinobacillus, Eubacterium and Peptococcus spp.

Indications:

In dentistry for treatment of localized aggressive periodontitis,
Useful as mouthwashes to alleviate secondary bacterial infection associated with extensive oral ulceration

Toxicity :
Within developing teeth, it should be avoid in children up to 8 years of age, pregnant or lactating women.
Tooth staining may occur.
Diarrhea & nausea may occur.
Serious hepatoxicity may occur with excessive intravenous dosage

Metronidazole :

First introduced to treat protozoal infections.
Effective against strict anaerobes.
Administration: Oral, intravenous, rectal
Mode of actions: Bactericidal, inhibit DNA synthesis .
Spectrum of activity:
* Active against all strict anaerobes Bacteriodes spp. Fusobacteria, Eubacteria, Peptostreptococci & Clostridia.
Indications:
Treatment of acute necrotizing ulcerative gingivitis
In management of dentoalveolar infection (either alone or with penicillin).

Pharmacokinetics:

Well absorbed after (oral) or (rectal) administration
Passes readily into most tissues, including abscesses and crosses the blood-brain barrier in to CSF fluid.
Toxicity :
#Gastro intestinal upset, rashes & metallic taste in the mouth.
#Interferes with alcohol metabolism & if taken with alcohol may cause sever nausea, flushing and palpitations.
#If it used for more than 1 week peripheral neuropathy may develop.

Sulphanomides & Trimethoprim :

This drug interfere with successive steps in the synthesis of folic acid (essential DNA and RNA synthesis)
CO-Trimoxazole [combination of sulphanomides & Trimethoprim]
Administration: Oral, intramuscular, intravenous
Mode of action: Bacteriostatic.
Spectrum activity: against g+ & g_
Indication : mainly use in HIV infected patients
Pharmacokinetics:
Penetration into CSF (is the major advantage).

Fusidic acid: Narrow – spectrum (mainly on g+), Staph aureus.Used for angular chelitis (as cream)Small strains of Staph.aureus show resistance to this drug.Anti fungal agents:Selective toxicity is much more difficult to achieve with antifungal agents because the eukaryotic fungal cells share similar features with human eukaryotic cells.

Polyenes:

1. Nystatin :
Administration :
Too toxic for systemic use.
Not absorbed from the alimentary canal and hence used to prevent or treat mucosal candidiasis.

Mode of action:
Binds to the cytoplasimc memb. Of fungi, altering cell wall permeability with result leakage of cell content's and death.

Toxicity:
Nausea, vomiting & diarrhoea are rare side effect.

2. Amphotericin:

Is the other polyene group antifungal.
As with nystatin, it's absorption from the gut is minimal on topical administration
Treatment of systemic candidiasis and other exotic mycoses {e.g. histoplasmosis}
Azoles:
1. Miconazole:
Administration : oral gel or cream.
Mode of action:
Interfering with the synthesis of chemical needed to form the plasma memb(inhibit ergosterol synthesis) of fungi, then lekage of cell contents and death.
Indications: action against (yeast and staph.) chelitis.
Spectrum of activity: Both fungicidal & bacteriostatic for some g+ cocci, including Staph. aureus.

2. Fluconazole:

Wide spectrum activity against yeast and other fungi e.g. candida infected patients as continuous therapy.
Mode of action:inhibit ergosterol synthesis
Administration : oral because of it's Long-half life it's administered once a day.
Pharmacokinetics weak protein-biding,water soluble, Long half life.
Toxicity:
Gastro intestinal irritation, allergic rash elevation of liver enzymes.

New antifungal agents:

Echinocandins:
Anew class of anti fungal that disrupts cell wall integrity by inhibiting cell well polysaccharides.
Effective against candidiasis and aspergillosis
Intravenous agent
Terbinafine:
Anew orally drug that blocks fungal ergosterol synthesis.
Effective in the management of dermatophyte infections including nail infections.



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