Antimicrobials in periodontics /certified fixed orthodontic courses by Indian dental academy

INDIAN DENTAL ACADEMY
Leader in Continuing Dental Education

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Index
• Introduction
• Drug
• Drug nomenclature
• Routes of drug administration
• History
• Classification
• Problems with the use of antimicrobials
• Commonly used antibiotics in the management of
periodontal diseases


• Guidelines for use of antibiotics
• Tetracyclines
• β-lactum antibiotics (Penicillin)
• Clindamycin
• Quinolones (ciprofloxacin)
• Macrolides
• Nitroiminadazole (metranidazole)
• Serial and combination therapies
• Other antimicrobials
• Chlorexidine
• Providone – Iodine
• Conclusion
• References


Introduction
Considering the common occurrence of the periodontitis and the
vast amount of periodontal research performed during the last
three decades one would furnish most appropriate
management of various types of periodontal disease would
now be a matter of agreement among dentists.

Approaches to the periodontal treatment ranges front the
Surgical, Ressective versus Regenerative, Professional
Emphasis versus Patient emphasis and Mechanical versus
Chemical therapy.


However, with the advent of effective systemic antibiotics and
topical antiseptics, the formerly dismal prognosis of many
types of rapidly progressive periodontitis has been
dramatically changed.

New and more effective antimicrobial treatments as well as
better implementations of the existing therapies have
significantly improved the prognosis of periodontal disease
and many oral infections. Currently, properly selected local
antiseptics and systemic antibiotic therapies can provide
periodontal treatment that is generally effective, low-risk and
affordable.


Drug
The disease oriented definition of drug does not include
contraceptives or use of drugs for the improvement of health.
WHO (1966) has given a more comprehensive definition:

“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 recipient.”


Drug Nomenclature
The drug generally has three categories of names:

• Chemical name: Describes the substance chemically.
E.g.- 1(Isopropylamino)-3-(1-napthyloxy) propane-2-ol
(Propanolol).

• Non-proprietary name: It is the name accepted by the
competent scientific body such as the United States
Adopted Name (USAN) Council. E.g.- Pethidine.

• Proprietary (Brand) name: It is the name assigned by the
manufacturers and is his property or trademark. One drug
may have multiple proprietary names. E.g.- ALTOL,
ATEN, LONOL for Atenolol.

Routes of Drug Administration
Routes can be broadly divided into:
- Those for local action
- And those for systemic action


- Local Routes
- Topical
- Skin
- Mucous membranes
- Mouth & Pharynx
- Eyes, Ears & Nose
- GI tract
- Bronchi & Lungs
- Urethra
- Vagina
- Anal canal

- Deeper tissues (using injection)
- Intra artricular injection
- Intrathecal injection
- Retrobulbar injection
- Arterial supply

- Systemic routes
- Oral
- Sublingual or Buccal
- Rectal
- Cutaneous
- Inhalational
- Nasal


- Parenteral
- Subcutaneous
- Dermojet
- Pocket implantation
- Sialiastic (non biodegradable or biodegradable)
- Intramuscular (I.M.)
- Intravenous (I.V.)
- Intradermal


Antimicrobial drugs
These are drugs in this class are different from all others in
that they are designed to inhibit /kill the infecting organism
and to have no/minimal effect on the recipient.

Antibiotics
These are the substances produced by microorganisms, which
suppress the growth or kill other microorganisms but are
produced by the microbes but are needed in high
concentration (ethanol, lactic acid, H2O2).

Chemotherapeutic agents
It is a general term that refers to the ability of an active
chemical substance to provide therapeutic clinical benefits.

Antiseptics
They are chemical antimicrobial agents that are applied
topically or subgingivally to mucous membranes, wounds, or
intact dermal surfaces to destroy microorganisms and inhibit
their reproduction or metabolism.

Disinfectants
A subcategory of antiseptics, are antimicrobial agents that are
generally applied to inanimate surfaces to destroy
microorganisms.


History
The term “antibiotic” means “against life” (from the Greek word
anti-against biosis-life).

The history of chemotherapy may be divided into 3 phases.

• The period of empirical use: of ‘mouldy curd’ by Chinese on
boils, chaulmoogra oil by Hindus in leprosy, chenopodium by
Azetecs for intestinal worms, mercury by Paracelsus (16 th
century) for syphilis, cinchona bark (17th century) for fevers.


• Ehrlich’s phase of dyes and organometallic compounds
(1890-1935): with the discovery of microbes in the later half
of the 19th century and that they are the cause of many
diseases: Ehrlich toyed with the idea that if certain dyes could
selectively stain microbes they could also be toxic to these
organisms, and tried methyelene blue, trypan red etc.

• He developed the arsenicals-atoxyl for sleeping sickness,
arsphenamine in 1906 and nonarsphenamine in 1909 for
syphilis. He coined the term ‘chemotherapy’ because he used
drug of known chemical structure and showed that selective
attenuation of infecting parasite was a practical proposition.


• The Modern era of chemotherapy was ushered by Dogmagk
in 1935 by demonstrating the therapeutic effect of Prontosil, a
sulfonamide dye, in pvogenic infection. It is as soon realized
that the active moiety is as paraamino benzene sulfonamide,
and the dye part was not essential. Sulfapiridine (M & B 693)
was the first sulfonamide to be marketed in 1938.

• The phenomenon of antibiosis was demonstrated by Pasteur
in 1877: growth of anthrax bacilli in urine was inhibited by
airborne bacteria.


• Fleming (1929) found that a diffusible substance is as
elaborated by Penicillium mould which could destroy
Staphylococcus on the culture plate. He named this substance
penicillin but could not purify it.

• Chain and Flores followed up this observation in 1939 is
which culminated in the clinical use of penicillin in 1941.
Because of the great potential of this discovery in treating
war is wounds, commercial manufacture of penicillin soon
started.


In the 1940s Waksman and his colleagues undertook a
systematic search of Actinomycetes as source of antibiotics
and discovered streptomycin in 1944. This group of soil
microbes proved to be a treasure-house of antibiotics and
soon tetracyclines, chloramphenicol, erythromycin and many
others followed. All three groups of scientists Domagk,
Fleming-Chain-Florey and Waksman received Nobel Prize
for their discoveries.


Classification
According to Chemical structure
• Sulfonamides and related drugs: Sulfadiazine and others,
Sulfones—Dapsone (DDS), Paraaminosalicylic acid (PAS).
• Diaminopyrimidines: Trimethoprim, Pyrimethamine.
• Quinolones: Nalidixic acid, Norfloxacin, Ciprofloxacin etc.
• β-Lactam antibiotics: Penicillins, Cephalosporins,
Monobactams, Carbapenems.
• Tetracyclines: Oxytetracycline, Doxycycline etc.
• Nitrobenzene derivative: Chioramphenicol
• Amino glycosides: Streptomycin, Gentamicin, Neomycin etc.


• Macrolide antibiotics: Erythromycin, Roxithromycin,
Azithromycin etc.
• Polypeptide antibiotics: Polymyxin-B, Bacitracin,
Tyrothricin.
• Glycopeptides: Vancomycin, Teicoplanin
• Oxazolidinone: Linezolid.
• Nitrofuran derivatives: Nitrofurantoin, Furazolidone.
• Nitroimidazoles: Metronidazole, Tinidazole.
• Nicotinic acid derivatives: Isoniazid, Pyrazinamide,
Ethionamide.
• Polyene antibiotics: Nysricin-B, Hamycin.
• Azole derivatives: Miconazole, Clotrimazole, Ketoconazole,
Fluconazole.
• Others: Rifampin, Lincomycin, Clindamycin, Spectinomycin,
Sod. fusidate, Cycloserine, Viomycin, Ethambutol,
Thiacetazone, Clofazimine, Griseofulvin.

According to mechanism of action
• Inhibit cell wall synthesis: Penicillins, Cephalosporins,
Cycloserine, Vancomycin, Bacitracin.
• Cause leakage from cell membranes:
Polypeptides—Polymyxins, Colistin, Bacitracin.
Polyenes—Amphotericin B, Nystatin, Hamycin.
• Inhibit protein synthesis: Tetracyclines, Chioramphenicol,
Erythromycin, Clindainycin, Linezolid.
• Cause misreading of m-RNA code and affect permeability:
Aminoglycosides—Streptomycin, Gentamicin etc.
• Inhibit DNA gyrase: Fluoroquinolones— Ciprofloxacin.
• Interfere with DNA function: Rifampin, Metronidazole.
• Interfere with DNA synthesis: Acyclovir, Zidovudine.
• Interfere with intermediary metabolism:
• Sulfonamides, Sulfones, PAS, Trimethoprim, Pyrimethamine,
Ethambutol.

Type of organisms against which primarily active
• Antibacterial: Penicillins, Aminoglycosides, Erythromycin
etc.
• Antifungal: Griseofulvin, Ketoconazole etc.
• Antiviral: Idoxuridine, Acyclovir, Amantadine, Zidovudine
etc.
• Antiprotozoal: Chloroquine, Pyrimethamine, Metronidazole,
Diloxanide etc.
• Antielmintic: Mebendazole, Pyrantel, Nicolsamide, Diethyl
carbamazine etc.


Spectrum of activity
Narrow spectrum Broad spectrum
Penicillin G Tetracyclines
Streptomycin Chloramphenicol
Erythromycin

Type of action
Primarily bacteriostatic Primarily bactericidal
Sulfonamides Penicillins
Ethambutol Aminoglycosides
Chloramphenicol Rifampin
Tetracyclines Cotrimoxazole
Erythromycin Cephalosporins
Vancomycin
Ciprofloxacin

Antibiotics are obtained from:

• Fungi

Penicillin Griseofulvin Cephalosporin

• Bacteria

Polymyxin B Tyrothxicin Bacitracin
Colistin Aztreonam

• Actinomycetes

Aminoglycosides Tetracyclines Polyenes
Chloramphenicol Macrolides

PROBLEMS WITH THE USE OF ANTIMICROBIALS

HYPERSENSITIVITY
TOXICITY DRUG
REACTIONS
RESISTANCE

LOCAL SYSTEMIC
IRRITANCY TOXICITY NATURAL ACQUIRED ADAPTIVE CROSS

MUTATION GENE TRANSFER

SINGLE STEP MULTI STEP CONJUCATION TRANSDUCTION

TRANSFORMATION

Problems with the use of antimicrobial
Toxicity
(a) Local irritancy: This is experienced at the site of
administration. Gastric irritation, pain and abscess
formation at the site of injection, thromboflebitis of the
injected vein are the complication.

(b) Systemic toxicity: Practically all AMA’s produce dose
related and systemic toxicities. Some have high therapeutic
index-doses over nearly 100 fold range may be given
without apparent damage to the host cells.


• Amyloglycosides: 8th cranial nerve and kidney toxicity
• Tetracyclines: Liver and kidney damage, antianabolic effect
• Chloramphemicol: Bone marrow depression

Still others have low therapeutic index (where no alternative is
available)

• Polymyxin B: Neurological and renal toxicity
• Vancomycin: Hearing loss, kidney damage
• Amphotericin B: Kidney, bone marrow and neurological
toxicity.


• Hypersensitivity reactions
Practically all AMA’s are capable of causing hypersensitivity
reactions. These are unpredictable and unrelated to dose. The
whole range of reactions range from rashes to anaphylactic
reactions.

• Drug resistance
It refers to unresponsiveness of a microorganism to an AMA
and is akin to the phenomenon of tolerance seen in higher
organisms.

- Natural resistance (e.g. gram –ve bacilli)
- Acquired resistance (e.g. staphylococci, coliform due
to mutation & gene transfer)

• Natural resistance
Some microbes have been resistant to certain AMAs. They lack
the metabolic process or the target sites which is affected by
the particular drug. This is generally a group of species
characteristics e.g. Gram -ve Bacilli are normally unaffected
by Penicillin G.
• Acquired resistance
It is due to the development of resistance by an organism (which
was sensitive) before due to use of an AMA over a period of
time.
The resistance is developed by two mechanisms:
- Mutation
- Gene transfer

• Mutation
It is a stable and heritable genetic change that occurs
spontaneously and randomly among microorganisms. It is not
induced by the antimicrobial agents.

Mutation and resistance may be:
- Single step (High degree resistance; emerge rapidly)

- Multistep (No. of gene modification involved; sensitivity
decreases gradually in a stepwise manner)


• Gene transfer
From one organism to another organism by:

- Conjucation (Sexual contact; Commonly in gram -ve bacilli
of the same or another species; the gene
carrying the ‘resistance’ or ‘R’ factor is
transferred only if another ‘resistance transfer
factor’ is also present.)
- Transduction (Transfer of gene carrying resistance through
the agency of a bacteriophage)
- Transformation (Resistant bacterium may release the
resistance carrying DNA into the medium)


• Adaptive resistance
A kind of rapidly developing (over 1-2 hrs) and reversible
(within 16-24 hrs) resistance based on phenotypic attention in
the bacteria, not involving genetic changes has been
described for aminoglycoside antibiotic. This appears due to
reversible down regulation of active transport of antibiotics
into the gram negative bacteria.

Similar adaptive resistance against some flouroquiolones has
also been shown.


• Cross resistance
Acquisition of resistance to one AMA conferring resistance to
another AMA, which the organism has not been exposed,
called cross resistance.

This is more commonly seen between chemically or
mechanistically related drugs, e.g., resistance to any one
sulfonamide means resistance to all others.


Prevention of drug resistance
• No indiscriminate and inadequate or unduly prolonged use
of AMA should be made.
• Prefer rapidly acting and selective (narrow spectrum)
AMAs whenever possible.
• Use combination of AMAs whenever prolonged therapy is
undertaken.


• Superinfection
This appears to appearance of new infection as a result of
antimicrobial therapy.

Ordinarily, the pathogens has to compete with the normal flora
for the nutrients etc. to establish itself. Lack of competition
may allow even a normally non-pathogenic component of the
flora, which is not inhibited by the drug (e.g. candida), to
predominate and invade.

It is commonly associated with the use of broad spectrum
antibiotics such as tetracyclines, chloramphenicol, ampicillin,
newer cephalosporins especially when combination of these
are employed.


Superinfection are more common when host defense is
compromised as in:

• Corticosteroid therapy
• Leukemias and other malignancies, specially when treated
with anticancer drugs.
• AIDS
• Agranulocytosis
• Diabetes

To minimize superinfections:
• Use specific (narrow spectrum) AMAs whenever possible.
• Do not use AMAs to treat trivial, self limiting or
untreatable (viral) infections.
• Do not unnecessarily prolong antimicrobial therapy.

Commonly used antibiotics in the
management of periodontal disease
• Tetracyclines (Minocycline, Doxycycline,
Tetracycline)
• Penicillin (Amoxicillin, Augmentin)
• Quinolone (Ciprofloxacin)
• Nitroimidazole (Metronidazole)
• Macrolides (Azithromycin)
• Lincomycin derivatives (Clindamycin)
• Other antibiotics


Guidelines for the use of antibiotics in the
periodontal therapy
• The clinical diagnosis and the situation dictates the need for
the possible antibiotic therapy as an adjunct in controlling
active periodontal disease.
• Continuing disease activity, as measured by continuing
attachment loss, purulent exudate and/or continuing
periodontal pocket of ≥ 5mm that bleed on probing is an
indication for microbial analysis and further periodontal
therapy.

• Based on the microbial composition of the plaque, the
patient’s medical status and the current medications.

• According on the microbiologic sampling

Clinical Diagnosis

Health Chronic Periodontitis Aggressive, Refrectory periodontitis
or
medically related periodontitis

Periodontal therapy including:
• Oral hygiene Microbial analysis
• Root debridement
• Supportive periodontal treatment and/or
• Surgical access for root debridement or
regenerative therapy
• Antibiotics as indicated by microbial analysis

Effective Ineffective

SUPPORTIVE PERIODONTAL TREATMENT

Tetracyclines
The first to be introduced was chlortetracycline in 1948
under the name aureomycin.

Tetracyclines have been widely used in the treatment
of periodontal diseases. They have been frequently
used in treating refractory periodontitis, including
localized aggressive periodontitis.

Tetracyclines have the ability to concentrate in the
periodontal tissues and inhibit the growth of
Actinobacillus actinomycetemcomitans. In addition
they exert an anticollagenase effect that can inhibit
tissue destruction and may aid bone regeneration.

• Structurally, tetracyclines consist of four
fused rings, hence the name tetracyclines.


• Tetracycline derivatives, primarily doxycycline and
minocycline, differ from the parent compound by minor
alterations of chemical constituents attached to the basic ring
structure.

• These minor alterations in the molecular structure make both
doxycycline and minocycline more lipophilic than the parent
compound, resulting in better adsorption following systemic
delivery and better penetration into the bacterial cell. Thus,
lower and less frequent doses of doxycycline and
minocycline can be given. For this reason and due to the
widespread resistance to tetracycline- HCl, doxycycline and
minocycline tend to be the tetracyclines most commonly
used.


They are effective in treating various periodontal disease in part
because their concentration in the gingival crevice is 2 to 10
times that in serum.

In addition several studies have demonstrated that tetracyclines
at low gingival crevicular fluid concentration (2 to 4 μg/ml)
are very effective against various periodontal diseases.


Mechanism of action
• They are primarily bacteriostatic; inhibit protein synthesis by
binding to 30s ribosomes in susceptible microorganisms.
• The sensitive organisms have an energy dependent active
transport process which concentrates tetracycline
intracellularly.
• In gram-ve bacteria they diffuse through the porin channels
as well. The more lipid soluble members enter by the passive
diffusion also.
• These two factors are responsible for selective toxicity of
tetracycline for the microbes.


Administration
• Oral capsule is the dosage form in which tetracyclines are
most commonly administered. The capsule should be taken
½ hr before or 2 hr after food.

• Tetracyclines are not recommended by I.M. route because it
is painful and absorption from the injection site is poor. Slow
I.V. injection may be given in severe cases, but is rarely
required now.

• A variety of topical preparations (ointment, cream etc.) are
available, but should not be used, because there is high risk of
sensitization.


Clinical use
• Tetracyclines have been investigated as adjuncts in the
treatment localized aggressive periodontitis (LAP).
Actinomycetemcomitans is a frequent causative
microorganism in LAP and is tissue invasive. Therefore
mechanical removal of calculus and plaque from root
surfaces may not eliminate this bacterium from periodontal
tissues.
• Systemic tetracycline can eliminate tissue bacteria and has
been shown to arrest bone loss and suppress
Actinomycetemcomitans levels conjunction with scaling and
root planning.
• This combined form of therapy allows mechanical removal of
root surface deposits and elimination of pathogenic bacteria
from within the tissues. Increased post treatment bone levels
have been noted using this method.

Resistance to tetracyclines
• Resistance to the tetracyclines is relatively common and is
mediated by a number of genetic determinants that may be
located on plasmids or on the bacterial chromosome.
Resistance may occur due to the coding of an efflux pump
that actively removes the drug from the bacterial cell so that
sufficient drug concentration is never achieved within the
cell.

• Another mode of resistance is referred to as ribosome
protection. With this mechanism, tetracycline antibiotics are
not removed from the bacterial cell but are prevented from
binding to the 30s ribosomal subunit. This mechanism
generally conveys resistance equally to all tetracyclines.


Systemic administration of tetracyclines
• Clinical studies on localized aggressive (juvenile) periodontitis
found that 1 g ⁄day of tetracycline-HCl enhanced resolution of
gingival inflammation and supported the gain of clinical
attachment and alveolar bone. (Lindhe J, Polson AM et. al. ,
Slots J et. al.)
• However, tetracycline and SRP did not suppress A.
actinomycetemcomitans in all localized aggressive periodontitis
patients. (Slots J, Rosling BJ)

• Lindhe reported that renewed disease activity occurred in up to
25% of localized aggressive periodontitis patients treated with
adjunctive tetracycline therapy despite a strict 3-month follow-
up interval. Additional studies have demonstrated that both
doxycycline and minocycline, like tetracycline, may
significantly suppress A. actinomycetemcomitans but not totally
eradicate the bacterium from all sites.

Local delivery of tetracyclines
• The concept that local delivery of an antibiotic into the
periodontal pocket achieves a greater, more potent
concentration of drug than available with systemic delivery
is very appealing.

• The amount of drug delivered often creates sulcular
medication concentrations exceeding the equivalent of
1 mg/ml (1,000 μg/ml). This level is considered bactericidal
for the majority of bacteria that exhibit resistance to
systemically delivered concentrations.


• Locally administered antibiotics, at concentrations much
greater than can be achieved systemically, aid in site-specific
elimination of residual bacteria. Tetracycline, doxycycline,
and minocycline have been individually incorporated into
local continuous delivery devices and made commercially
available to the practitioner.

• Both tetracycline, 12.7 mg tetracycline- HCl in an
ethylene⁄vinyl acetate copolymer fiber (Actisite®), and
doxycycline, 10% doxycycline hyclate in a gel delivery
system (Atridox®), have been subjected to extensive testing.

• Minocycline, the most lipophilic of the tetracyclines, has also
been incorporated into a local delivery device consisting of
minocycline-HCl microspheres (Arestin®).

Tetracycline-Containing Fibers (Actisite)

• The first local delivery product available in the U.S., one which
has been extensively studied, is an ethylene/vinyl acetate
copolymer fiber, diameter 0.5 mm containing tetracycline, 12.7
mg/9 inches (Actisite tetracycline fiber; manufactured by Alza
Corporation, Palo Alto, CA; distributed by Procter & Gamble Co.,
Cincinnati, OH).

• When packed into a periodontal pocket, it is well tolerated by oral
tissues, and for 10 days it sustains tetracycline concentrations
exceeding 1300 g/ml well beyond the 32 to 64 μg/ml required to
inhibit the growth of pathogens isolated from periodontal pockets.
In contrast, crevicular fluid concentrations of only 4 to 8 μg/ml are
reported after systemic tetracycline administration, 250mg four
times daily tenwww.indiandentalacademy.comg)
days. (total oral dose, 10

Subgingival Delivery of Doxycycline (Atridox)
• Atridox® (manufactured by Atrix Laboratories, Fort Collins,
CO; licensed for marketing by Block Drug, Inc., Jersey City
NJ) is a gel system that incorporates the antibiotic
doxycycline (10%) in a syringeable gel system.


Subgingival Delivery System for Minocycline
(Dentamycin and PerioCline)

• A subgingival delivery system of 2% (w/w)
minocycline hydrochloride (Dentamycin, Cyanamid
International, Lederle Division, Wayne, NJ;
PerioCline, SunStar, Osaka, Japan) is available in
many countries for use as an adjunct to subgingival
debridement. This system is a syringeable gel
suspension delivery formulation.


Collagenase inhibitors
• It is now recognized that the tetracyclines are also potent
inhibitors of matrix metalloproteinases, a family of enzymes
that degrade extracellular matrix molecules such as collagen.

• Pathologic elevated levels of matrix metalloproteinases result
in the breakdown of the structural components of the
periodontium. Doxycycline, in particular, downregulates
matrix metalloproteinase activity in inflamed periodontal
tissues by a mechanism that is unrelated to its antimicrobial
properties.


• A series of double-blind, placebo-controlled clinical trials has
demonstrated that subantimicrobial dose doxycycline (SDD),
20 mg bid (Periostat®), produces an improvement in clinical
indices, without causing any detectable effect on the
subgingival flora or an increase in antibiotic resistance.


TETRACYCLINE
• Tetracycline requires administration of 250 mg. qid. It is
inexpensive, but compliance may be reduced by having to
take four capsules per day.
MINOCYCLINE
• Minocycline can be given twice a day, thus facilitating
compliance when compared with tetracycline. Although it is
associated with less photo- and renal toxicity than
tetracycline, it may cause reversible vertigo. Minocycline
administered in a dosage of 200mg per day for 1 week results
in a reduction in total bacterial counts.
DOXYCYCLINE
• The recommended dosage when used as an antimicrobial
agent is 100 mg twice daily the first day, then 100 mg once
daily. To reduce gastrointestinal upset, 50 mg can be taken
twice daily. When used in a subantimicrobial dose to inhibit
collagenase, it is recommended in a 20 mg dose twice daily.

Beta lactum antibiotics
(Penicillins)
• It is the first antibiotic to be used clinically in 1941.
• It was originally obtained from fungus Penicillium notatum,
but the present source is a highly yielding mutant of
P. chrysogenum.
• They are natural and semisynthetic derivatives of broth
cultures of Penicillium mould.
• They inhibit bacterial cell wall production and are therefore
bactericidal.


• The penicillins are a broad class of antibiotics that inhibit
bacterial cell wall synthesis and directly result in the death of
the cell. All penicillins consist of a β-lactam ring, a
thiazolidine ring, and an acyl side chain.

• Substitutions on the acyl side chain have yielded a wide
variety of penicillin compounds with vastly different
properties. These include improved stability to gastric acid,
improved absorption and higher serum concentrations, and
activity against gram-negative as well as gram- positive
bacteria.

Semisynthetic penicillins
They are produced by chemically combining specific side
chains or by incorporating specific precursors in the mould
cultures.

The main aim of producing these is to overcome:
• Poor oral efficacy
• Susceptibility to penicillinase
• Narrow spectrum of activity
• Hypersensitivity


Classification
• Acid resistant alternative to Penicillin G
Phenoxymethyl penicillin (Penicillin V)
• Penicillinase resistant penicillins
Methicillin, Oxacillin, Cloxacillin
• Extended spectrum penicillins
• Aminopenicillins
Ampicillin, Bacampicillin, Amoxacillin
• Carboxypenicillins
Carbenicillin
• Uredopenicillins
Piperacillin
• β-lactamase inhibitors
Clavulanic acid


Amoxicillin
• Amoxicillin, a semisynthetic penicillin, has excellent activity
against both gram-negative and gram positive bacteria, is
absorbed well following oral administration, and penetrates
into the gingival crevicular fluid.
• Unfortunately, amoxicillin is also highly susceptible to
bacterial β-lactamases.
• Augmentin, introduced a little over a decade ago, combines
the antibiotic amoxicillin with a β-lactamase inhibitor,
clavulanic acid. Many β-lactamase enzymes of oral origin
have a greater affinity for clavulanic acid than for
amoxicillin, are preferentially bound to the clavulanate
moiety, and are competitively removed from hydrolyzing the
β-lactam ring in amoxicillin.


• Amoxicillin may be useful in the management of patients
with aggressive periodontitis, both in the localized and
generalized forms. Recommended dosage is 500 mg TID for
8 days.


• Haffajee et al. tested the efficacy obtained with four
systemically administrated agents, Augmentin, tetracycine,
ibuprofen, or placebo, in conjunction with Widman flap
procedure. Subjects that received either Augmentin or
tetacycline demonstrated significantly more attachment gain
than did the other two groups.

• In contrast, Winkel et al. in double-blind, placebocontrolled
study with 21 patients with a diagnosis of generalized adult
periodontitis found that, in comparison with placebo,
Augmentin provided no additional clinical or microbiological
benefits.


Clindamycin
• Clindamycin is bacteriostatic and inhibits bacterial protein
synthesis by binding to the 50S ribosomal subunit. The drug
is active against most gram- positive bacteria, including both
facultative and anaerobic species. It is particularly active
against gram-negative anaerobes and is very active against
the gram-negative anaerobes associated with the periodontal
flora.


• Unfortunately, a number of undesirable adverse effects have
been associated with the use of clindamycin. Due to its acidic
nature and to its effect on the gram-negative intestinal
bacteria, adverse effects such as diarrhea, abdominal
cramping, esophagitis, and stomach irritation are relatively
common. There have been numerous reports of
pseudomembranous colitis linked to the use of clindamycin.

• Gordon et al. selected 13 subjects refractory to previous
periodontal therapy consisting of mechanical debridement,
periodontal surgery, and the adjunctive use of both
tetracycline and a β-lactam antibiotic.


• If disease activity was detected and microbial sampling
indicated sensitivity to clindamycin, the patient received a
thorough scaling and was placed on clindamycin-HCL for 7
days. Of the 13 patients entered, 11 experienced no further
loss of clinical attachment. The proportion of active sites
decreased from an average of 10.7% to 0.5% per patient per
year. At 24 months, a mean gain of 1.5 mm of clinical
attachment was present.

• Two additional studies, by Ohta et al. and Magnusson et al.,
demonstrated similar findings, namely gain in clinical
attachment level and reduction in gram-negative anaerobes
following the adjunctive use of clindamycin.


• Clindamycin has shown efficacy in patients with periodontitis
refractory to tetracycline therapy. Walker and co-workers
have shown aid in stabilizing refractory periodontitis. Dosage
used in their studies was 150 mg qid for 10 days. Jorgensen
and Slots have recommended a regimen of 300 mg twice
daily 8 days.


Quinolones (Ciprofloxacin)
• These are entirely synthetic antimicrobials having a
quinolone structure that are active primarily against gram
negative bacteria, through newer flourinated compounds also
inhibit gram positive ones.

• A breakthrough was achieved in the early 1980s by
flourination of the quinolone structure at position 6 and
introduction of a piperazine substitution at position 7
resulting in derivatives called fluoroquinolones with a higher
potency, expanded spectrum, slow development of resistance,
better tissue penetration and good tolerability.


Ciprofioxacin is a quinolone active against gram-negative rods,
including all facultative and some anaerobic putative
periodontal pathogens.

The MIC of ciprofloxacin against gram negative bacteria is
<0.1 μg/ml, while gram positive bacteria are inhibited at
relatively higher concentrations.

Ciprofloxacin therapy may facilitate the establishment of
microflora associated with periodontal health. At present,
ciprofloxacin is the only antibiotic in periodontal therapy to
which all strains of A. actinomycetemcomitans are
susceptible. It is also used in combination with
metronidazole.


Nausea, headache, and abdominal discomfort have been
associated with ciprofloxacin. Quinolones inhibit the
metabolism of theophvlline and caffeine and concurrent
administration can produce toxicity. They have also been
reported to enhance the effect of warfarin and other
anticoagulants.


Macrolides
Macrolide antibiotics contain a many membered lactone ring to
which one or more deoxy sugars are attached. They inhibit
protein synthesis by binding to the 50s ribosomal subunits of
sensitive microorganisms. They can be bacteriostatic or
bactericidal, depending on the concentration of the drug and
the nature of the microorganism.


• Azithromycin (Zithromax) is a member of the azalide class of
macrolides. It is effective against anaerobes and gram-
negative bacilli. After an oral dosage of 500mg once daily for
three consecutive days, significant levels of azithromycin
were detected in most tissues for 7 to 8 days.

• It has been proposed that azithromycin penetrates fibroblasts
and phagocytes in concentration 100 to 200 times greater
than that of extracellular compartment. The azithromycin if
actively transported to the sites of inflammation by
phagocytes and then released directly into the site of
inflammation as the phagocytes rupture during phagosytosis.

• Therapeutic use requires single dose of 250mg per day for 5
days after an initial loading dose of 500mg.

Nitroimidazole (Metronidazole)
• Metronidazole is a 5-nitroimidazole compound developed in
France to treat protozoal infections. It is bactericidal to
anaerobic organisms and believed to disrupt bacterial DNA
synthesis in conditions where low reduction potential is
present.


• Upon entry into an anaerobic organism, metronidazole is
reduced at the 5-nitro position by electron transport proteins
that are part of anaerobic metabolic energy-yielding
pathways. Alteration of the metronidazole molecule creates a
continuous concentration gradient favoring diffusion of
additional metronidazole into the cell. Reduction of the
parent compound yields many short-lived cytotoxic free
radicals. These free radicals react with macromolecules,
particularly DNA, resulting in cell death.


Metronidazole has been used clinically to treat:
Gingivitis
Acute necrotizing ulcerative gingivitis
Chronic periodontitis
Aggressive periodontitis

It has been used as monotherapy and also in combination with
scaling and root planning and other antibiotics.


• A single dose of metronidazole (250 mg orally) appears in
serum and gingival fluid in sufficient quantities to inhibit a
wide range of suspected periodontal pathogens.
• Administered systemically (750 to 1000 mg/day for 2 weeks),
this drug reduces the growth of anaerobic flora.
• The most commonly prescribed regiment is 250 mg tid for 7
days.
• Loesche and co-workers found that 250 mg of metranidazole
given three times daily for 1 week was of benefit to patients
with diagnosed anaerobic periodontal infection.


Side Effects
• Metronidazole has an antabuse effect when alcohol is
ingested. The response is generally proportional to the
amount ingested and can result in severe cramps, nausea, and
vomiting.
• Products containing alcohol should be avoided during therapy
and for at least 1 day after therapy is discontinued.
• It also inhibits warfarin metabolism. It should be avoided in
patients on anticoagulant therapy as it increases prothrombin
time. It should be avoided in patients taking lithium.


• Metronidazole crosses the placenta barrier,entering the fetal
circulation system. It is also secreted in breast milk. Because
of the association of metronidazole with tumorigenicity in
some animals, the drug is contraindicated in pregnant women
or nursing mothers.


• Local delivery of Metranidazole
Localized delivery of metronidazole to specific, diseased sites
would allow minimal amounts of drug to achieve high
concentrations, alleviating many adverse reactions and
unpleasant side-effects associated with systemic
administration.


• Elyzol is a 25% metronidazole dental gel consisting of
metronidazole benzoate in a mixture of mono- and
triglycerides.
• The formulation is delivered as a liquid to the periodontal
pocket using a syringe device and changes immediately to a
gel upon contact with the gingival fluid.
• Metronidazole benzoate gradually disintegrates into
metronidazole and delivers high concentrations of the drug to
the periodontal pocket for approximately 24 h after
placement. Normally, two applications of the dental gel
administered 1 week apart are recommended.


Serial & combination antibiotic therapies
• Because periodontal infections may contain a wide diversity
of bacteria, no single antibiotic is effective against all
putative pathogens. Indeed, differences exist in the microbial
flora associated with the various periodontal disease
syndromes.
• These “mixed” infections can include a variety of aerobic,
microaerophilic, and anaerobic bacteria, both gram negative
and gram positive.
• In these instances, it may be necessary to use more than one
antibiotic, either serially or in combination. However, before
combinations of antibiotics are used, the periodontal
pathogen(s) being treated must be identified and antibiotic
susceptibility testing performed.

• Rams and Slots reviewed combination therapy using systemic
metronidazole along with amoxicillin, Augmentin, or
ciprofloxacin. The metronidazole-amoxicillin and
metronidazole-Augmentin combinations provided excellent
elimination of many organisms in adult and localized
aggressive periodontitis that had been treated unsuccessfully
with tetracyclines and mechanical debridement. These drugs
have an additive effect regarding suppression of A.
actinomycetemcomitans.


• Tinnco and co-workers found metronidazole and amoxicillin
to be clinically effective in treating localized aggressive
periodontitis, although 50% of patients harbored
A. actinomycetemcomitans one year later. Metronidazole-
ciprofloxacin combination is effective against A.
actinomycetemcomitans. Metronidazole targets obligate
anaerobes, and ciprofloxacin targets facultative anaerobes.


Other Antimicrobials
Antimicrobials other than antibiotics have been used with
varying success in the treatment of various periodontal
disease syndromes.
The route of antimicrobial administration, with the exception of
systemic antibiotics, is almost always topical due to potential
toxicity.
Second, the anatomy of the diseased site, a periodontal pocket,
is unique.


• The main disadvantage of the local drug delivery is that
gingival crevice may dilute or completely wash the agent out
of the periodontal pocket. (5-6mm pocket shows an outflow
equal or greater to 20μl/h, this is equivalent to pocket volume
turnover to 40 times per hour).
• Due to the constant outflow of the gingival crevice fluid, the
expected half-life of an antimicrobial in the periodontal
pocket, unless it is incorporated in a continuous release
device, is around 1 min.


Indications
• Reduce plaque and gingivitis
• Periodontal pocket
• Apthous ulcer
• Orthodontic patients
• Handicapped patients
• Adjunct to oral hygiene
• Patients with crown and bridge
• Post periodontal and oral surgery
• Reduces aerosols
• Patients with implants
• Presence with hyperplasia and xerostomia

Criteria for use of antimicrobials
• Substantivity
• Safety
• Stability
• Efficacy


Ideal properties
• Bactericidal, bacteristatic
• Eliminate pathogenic bacteria
• Affect bacterial adhesion, growth or metabolism
• Prevent development of resistant bacteria
• Reduce plaque and gingivitis
• Safe to use
• Inhibit calcification of plaque to calculus
• Should not stain teeth/taste alteration
• Easy to use
• Inexpensive


Chlorhexidine
• Chlorhexidine has often been employed as an adjunct to
mechanical debridement due to its broad-spectrum
antimicrobial activity, substantivity in the oral cavity and
ease of use during oral irrigation or gel placement.


• A biodegradable chlorhexidine containing gelatin chip
(PerioChip) has received Food & Drug Administration
approval in the United States for use as an adjunct to SRP.
The gelatin chip is placed directly into the periodontal
pocket, releasing 2.5 mg of chlorhexidine over a period of 7–
10 days. Chlorhexidine levels, within the pocket, reach an
average concentration equivalent to 125 μg of chlorhexidine
per ml of gingival crevice fluid.

• Daneshmand et al. did not find any microbial benefit when
the chlorhexidine chip was used as an adjunct to SRP
compared to SRP alone.


• Daneshmand et al. did not find any microbial benefit when
the chlorhexidine chip was used as an adjunct to SRP
compared to SRP alone.

• In summary, there is no evidence that chlorhexidine applied
to the periodontal pocket provides any significant advantage
or additive effect to SRP alone.


Providone - Iodine
• Povidone-iodine (PVP-iodine) is a bactericidal antiseptic
whose mechanism of action includes oxidation of amino,
thiol, and hydroxy moieties of amino acids and nucleotides.

• PVP-iodine also interacts with the unsaturated fatty acids
associated with bacterial cell walls and membranes. Because
it adversely affects multiple bacterial sites, the effect of PVP-
iodine occurs relatively quickly, decreasing the need for
extended exposure time.


• Greenstein, in a recent review of the effects of PVP-iodine,
found evidence indicating PVP-iodine irrigation, delivered to
the periodontal pocket via ultrasonic scalers, achieved better
results in deep pockets than water.

• Rosling et al. tested the efficacy of PVP-iodine as an adjunct
to conventional, nonsurgical periodontal therapy and
retreatment in 223 advanced periodontitis subjects. One
group received mechanical debridement via an ultrasonic
device administering 0.1% PVP-iodine and the other group
received mechanical debridement only. The group receiving
PVP-iodine showed significantly lower mean probing pocket
depth values and significantly more gain in clinical
attachment.


Conclusion
• At present, there is no single periodontal therapeutic regimen
that will provide a beneficial response for all patients. It is
patients
very unlikely that there ever will be. Clinical trials are still
needed to objectively evaluate adjunctive periodontal
therapy. However, it is imperative that such trials be
conducted with the appropriate patients. Little information is
obtained by attempting to show a benefit for the use of
adjunctive therapies in a patient group (e.g. non aggressive
periodontitis) that responds very well to mechanical
instrumentation alone.


References
• Clinical Periodontology
Newman, Takei, Carranza.
• Medical pharmacology
K. D. Tripathi
• Periodontology 2000, Vol 36, 2004


Antimicrobials in periodontics /certified fixed orthodontic courses by Indian dental academy

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