C H A P T E R 5 2
infective Therapy for
Sebastian G. Ciancio, Angelo J. Mariotti
Systemic Administration of Antibiotics
Serial and Combination Antibiotic Therapy
• Evaluate the rationale for use of anti-infective agents as
adjuncts to periodontal therapy.
• List the clinical indications for use of anti-infective agents.
• Evaluate the pharmacology of anti-infective agents indicated as
adjuncts to periodontal therapy.
It has been well established that the various periodontal diseases
are caused by bacterial infection. Bacteria begin reattaching to tooth
surfaces soon after the teeth have been cleaned and start to form a
biofilm. Over time, this supragingival plaque biofilm becomes more
complex, which leads to a succession of bacteria that are more
pathogenic. Bacteria grow in an apical direction and become
subgingival. Eventually, as bone is destroyed, a periodontal pocket
is formed. In a periodontal pocket, the bacteria form a highly
structured and complex biofilm. As this process continues, the
bacterial biofilm extends so far subgingivally that the patient cannot
reach it during oral hygiene efforts. In addition, this complex
biofilm may now offer some protection from the host's
immunologic mechanisms in the periodontal pocket as well as from
antibiotics used for treatment. It has been suggested that an
antibiotic strength that is 500 times greater than the usual
therapeutic dose may be needed to be effective against bacteria that
have become arranged in biofilms.
Systemic Administration of Antibiotics
It is therefore logical to treat periodontal pockets by mechanically
removing local factors (including the calculus that harbors bacteria)
and by disrupting the subgingival plaque biofilm itself. Mechanical
removal includes manual instrumentation (e.g., scaling and root
planing) and machine-driven instrumentation (e.g., ultrasonic
scalers), and these procedures can be considered “anti-infective
therapy.” Many chemotherapeutic agents are now available to
clinicians who treat periodontal diseases. Systemic anti-infective
therapy (oral antibiotics) and local anti-infective therapy (placing
anti-infective agents directly into the periodontal pocket) can
reduce the bacterial challenge to the periodontium. It is also
possible that systemically administered nonsteroidal
antiinflammatory agents may play a role in future adjunctive
Bacteria and their toxic products may cause a loss of attachment
and a loss of bone. Ultimately, however, the host's own
immunologic response to this bacterial infection can cause even
more bone destruction (i.e., indirect bone loss) than that caused by
pathogenic bacteria and their by products. This immunologic
response can be influenced by environmental (e.g., tobacco use),
acquired (e.g., systemic disease), or genetic risk factors.
Chemotherapeutic agents can modulate the host's immune
response to bacteria and reduce the host's self-destructive
immunologic response to bacterial pathogens, thereby reducing
It is also incumbent on health care providers to
counsel patients about the detrimental effects of systemic factors,
including medications, stress, and tobacco use.
This chapter reviews the indications and protocols for optimizing
the use of systemically administered anti-infective agents during
the treatment of periodontal diseases. It is important to note that
there has been significant work with the use of a systematic
evidence-based approach to evaluate the various anti-infective and
host modulation therapies.
A meta-analysis of similar research
studies has given power to statistical analysis to evaluate anti-
infective chemotherapeutic agents for the treatment of periodontal
disease. Unfortunately, a standardized research protocol has not yet
been implemented. As a result, some studies, although relevant,
have not been used in the evidence-based approach because of their
study design. Further evidence-based and similar research is
needed to define protocols more precisely for the use of anti-
infective agents to treat various periodontal diseases.
Bacteriostatic Versus Bactericidal Antibiotics
Pharmacologic agents that prevent the growth of bacteria are
bacteriostatic antibiotics, whereas pharmacologic agents that
actually kill the bacteria are bactericidal antibiotics. Examples of
bacteriostatic antibiotics include tetracycline and clindamycin, and
penicillin and metronidazole are good examples of bactericidal
An anti-infective agent is a chemotherapeutic agent that acts by
reducing the number of bacteria present. An antibiotic is a naturally
occurring, semisynthetic, or synthetic type of anti-infective agent
that destroys or inhibits the growth of select microorganisms,
generally at low concentrations. An antiseptic is a chemical
antimicrobial agent that can be applied topically or subgingivally to
mucous membranes, wounds, or intact dermal surfaces to destroy
microorganisms and inhibit their reproduction or metabolism. In
dentistry, antiseptics are widely used as the active ingredient in
antiplaque and antigingivitis oral rinses and dentifrices.
Disinfectants (a subcategory of antiseptics) are antimicrobial agents
that are generally applied to inanimate surfaces to destroy
When anti-infective agents are administered orally, many of these
agents can be found in the gingival crevicular fluid (GCF). The
purpose of a systemic administration of antibiotics is to reduce the
number of bacteria present in the diseased periodontal pocket; this
is often a necessary adjunct for controlling bacterial infection,
because bacteria can invade periodontal tissues, thereby making
mechanical therapy alone sometimes ineffective.
A single chemotherapeutic agent can also have a dual mechanism
of action. For example, tetracyclines (especially doxycycline) are
chemotherapeutic agents that can reduce collagen and bone
destruction via their ability to inhibit the enzyme collagenase. As
antibiotic agents, they can also reduce periodontal pathogens in
Systemic Administration of
Background and Rationale
The treatment of periodontal diseases is based on their infectious
nature (Table 52.1). Ideally, the causative microorganisms should be
identified, and the most effective agent should be selected with the
use of antibiotic-sensitivity testing. Although this appears simple,
the difficulty lies primarily in identifying the specific etiologic
microorganisms rather than the microorganisms that are simply
associated with various periodontal disorders.
Antibiotics Used to Treat Periodontal Diseases
Category Agent Major Features
Amoxicillin Extended spectrum of antimicrobial activity; excellent oral
absorption; used systemically
Effective against penicillinase-producing microorganisms;
Tetracyclines Minocycline Effective against a broad spectrum of microorganisms; used
systemically and applied locally (subgingivally)
Tetracycline Effective against a broad spectrum of microorganisms; used
systemically and applied locally (subgingivally)
Chemotherapeutically used in subantimicrobial doses for host
Effective against a broad spectrum of microorganisms
Quinolone Ciprofloxacin Effective against gram-negative rods; promotes health-
Macrolide Azithromycin Concentrates at sites of inflammation; used systemically
Clindamycin Used in penicillin-allergic patients; effective against anaerobic
bacteria; used systemically
Metronidazole Effective against anaerobic bacteria; used systemically and
applied locally (subgingivally) as gel
Indications: localized aggressive periodontitis, generalized aggressive periodontitis,
medically related periodontitis, and refractory periodontitis.
Amoxicillin and clavulanate potassium.
Indications: localized aggressive periodontitis, generalized aggressive periodontitis,
medically related periodontitis, refractory periodontitis, and necrotizing ulcerative
An ideal antibiotic for use in the prevention and treatment of
periodontal disease should be specific for periodontal pathogens,
allogenic, nontoxic, substantive, not in general use for the treatment
of other diseases, and inexpensive.
Currently, however, an ideal
antibiotic for the treatment of periodontal disease does not exist.
Although oral bacteria are susceptible to many antibiotics, no single
antibiotic at the concentrations achieved in body fluids inhibits all
putative periodontal pathogens.
Indeed, a combination of
antibiotics may be necessary to eliminate all putative pathogens
from some periodontal pockets
Common Antibiotic Regimens Used to Treat Periodontal Diseases
Amoxicillin 500 mg Three times daily for 8 days
Azithromycin 500 mg Once daily for 4 to 7 days
Ciprofloxacin 500 mg Twice daily for 8 days
Clindamycin 300 mg Three times daily 10 days
Doxycycline or minocycline 100 mg to 200 mg Once daily for 21 days
Metronidazole 500 mg Three times daily for 8 days
Metronidazole + amoxicillin 250 mg of each Three times daily for 8 days
Metronidazole + ciprofloxacin 500 mg of each Twice daily for 8 days
These regimens are prescribed after a review of the patient's medical history,
periodontal diagnosis, and antimicrobial testing. Clinicians must consult
pharmacology references such as Mosby's GenRx
or the manufacturer's guidelines
for warnings, contraindications, and precautions.
Data from Jorgensen MG, Slots J: Practical antimicrobial periodontal therapy.
Compend Contin Educ Dent 21:111, 2000.
As always, the clinician, in concert with the patient, must make
the final decision regarding any treatment. Thus the treatment of an
individual patient must be based on the patient's clinical status, the
nature of the colonizing bacteria, the ability of the agent to reach the
site of infection, and the risks and benefits associated with the
proposed treatment plan. The clinician is responsible for choosing
the correct antimicrobial agent. Some adverse reactions include
allergic or anaphylactic reactions, superinfections of opportunistic
bacteria, development of resistant bacteria, interactions with other
medications, upset stomach, nausea, and vomiting.
reactions take the form of gastrointestinal upset.
include the cost of the medication and the patient's willingness and
ability to comply with the proposed therapy.
No consensus exists regarding the magnitude of risk for the
development of bacterial resistance. The common and
indiscriminate use of antibiotics worldwide has contributed to
increasing numbers of resistant bacterial strains since the late 1990s,
and this trend is likely to continue given the widespread use of
The overuse, misuse, and widespread prophylactic
application of anti-infective drugs are some of the factors that have
led to the emergence of resistant microorganisms. Increasing levels
of resistance of subgingival microflora to antibiotics have been
correlated with the increased use of antibiotics in individual
However, researchers have noted that the subgingival
microflora tends to revert to similar proportions of antibiotic-
resistant isolates 3 months after therapy.
Tetracyclines have been widely used for the treatment of
periodontal diseases. They have been frequently used to treat
refractory periodontitis, including localized aggressive periodontitis
(see Table 52.1). Tetracyclines have the ability to
concentrate in the periodontal tissues and inhibit the growth of
Aggregatibacter actinomycetemcomitans. In addition, tetracyclines
exert an anticollagenase effect that can inhibit tissue destruction
and may help with bone regeneration.
The tetracyclines are a group of antibiotics that are produced
naturally from certain species of Streptomyces or derived
semisynthetically. These antibiotics are bacteriostatic and are
effective against rapidly multiplying bacteria. They generally are
more effective against gram-positive bacteria than against gram-
negative bacteria. Tetracyclines are effective for the treatment of
periodontal diseases in part because their concentration in the
gingival crevice is 2 to 10 times that found in serum.
a high drug concentration to be delivered into the periodontal
pockets. In addition, several studies have demonstrated that
tetracyclines at a low GCF concentration (i.e., 2 µg/ml to 4 µg/ml)
are very effective against many periodontal pathogens.
Tetracyclines have been investigated as adjuncts for the treatment
A. actinomycetemcomitans is a microorganism that is
frequently associated with LAP, and it invades tissue. Therefore the
mechanical removal of calculus and plaque from root surfaces may
not eliminate this bacterium from the periodontal tissues. Systemic
tetracycline can eliminate tissue bacteria and has been shown to
arrest bone loss and suppress A. actinomycetemcomitans levels in
conjunction with scaling and root planing.
therapy allows for the mechanical removal of root surface deposits
and the elimination of pathogenic bacteria from within the tissues.
Increased posttreatment bone levels have been noted with the use
of this method (Figs. 52.1 to 52.4).
FIG. 52.1 Panoramic image of 17-year-old African
American male exhibiting signs of localized aggressive
periodontitis. (Photo courtesy Dr. Sasi Sunkari.)
FIG. 52.2 Image of anterior dentition in 17-year-old
African American male with localized aggressive
periodontitis. (Photo courtesy Dr. Sasi Sunkari.)
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C H A P T E R 5 2Systemic Anti-infective Therapy forPeriodontal DiseasesSebastian G. Ciancio, Angelo J. MariottiCHAPTER OUTLINEDefinitionsSystemic Administration of AntibioticsSerial and Combination Antibiotic TherapyConclusion Learning Objectives• Evaluate the rationale for use of anti-infective agents asadjuncts to periodontal therapy.• List the clinical indications for use of anti-infective agents.• Evaluate the pharmacology of anti-infective agents indicated as2999 adjuncts to periodontal therapy.It has been well established that the various periodontal diseasesare caused by bacterial infection. Bacteria begin reattaching to toothsurfaces soon after the teeth have been cleaned and start to form abiofilm. Over time, this supragingival plaque biofilm becomes morecomplex, which leads to a succession of bacteria that are morepathogenic. Bacteria grow in an apical direction and becomesubgingival. Eventually, as bone is destroyed, a periodontal pocketis formed. In a periodontal pocket, the bacteria form a highlystructured and complex biofilm. As this process continues, thebacterial biofilm extends so far subgingivally that the patient cannotreach it during oral hygiene efforts. In addition, this complexbiofilm may now offer some protection from the host'simmunologic mechanisms in the periodontal pocket as well as fromantibiotics used for treatment. It has been suggested that anantibiotic strength that is 500 times greater than the usualtherapeutic dose may be needed to be effective against bacteria thathave become arranged in biofilms.26 Systemic Administration of AntibioticsTetracyclinesMetronidazolePenicillinsCephalosporinsClindamycinCiprofloxacinMacrolidesIt is therefore logical to treat periodontal pockets by mechanicallyremoving local factors (including the calculus that harbors bacteria)and by disrupting the subgingival plaque biofilm itself. Mechanicalremoval includes manual instrumentation (e.g., scaling and rootplaning) and machine-driven instrumentation (e.g., ultrasonicscalers), and these procedures can be considered “anti-infectivetherapy.” Many chemotherapeutic agents are now available to3000 clinicians who treat periodontal diseases. Systemic anti-infectivetherapy (oral antibiotics) and local anti-infective therapy (placinganti-infective agents directly into the periodontal pocket) canreduce the bacterial challenge to the periodontium. It is alsopossible that systemically administered nonsteroidalantiinflammatory agents may play a role in future adjunctivetherapy.42,58Bacteria and their toxic products may cause a loss of attachmentand a loss of bone. Ultimately, however, the host's ownimmunologic response to this bacterial infection can cause evenmore bone destruction (i.e., indirect bone loss) than that caused bypathogenic bacteria and their by products. This immunologicresponse can be influenced by environmental (e.g., tobacco use),acquired (e.g., systemic disease), or genetic risk factors.49Chemotherapeutic agents can modulate the host's immuneresponse to bacteria and reduce the host's self-destructiveimmunologic response to bacterial pathogens, thereby reducingbone loss.45-47 It is also incumbent on health care providers tocounsel patients about the detrimental effects of systemic factors,including medications, stress, and tobacco use.26This chapter reviews the indications and protocols for optimizingthe use of systemically administered anti-infective agents duringthe treatment of periodontal diseases. It is important to note thatthere has been significant work with the use of a systematicevidence-based approach to evaluate the various anti-infective andhost modulation therapies.64 A meta-analysis of similar researchstudies has given power to statistical analysis to evaluate anti-infective chemotherapeutic agents for the treatment of periodontaldisease. Unfortunately, a standardized research protocol has not yetbeen implemented. As a result, some studies, although relevant,have not been used in the evidence-based approach because of theirstudy design. Further evidence-based and similar research isneeded to define protocols more precisely for the use of anti-infective agents to treat various periodontal diseases. Key Fact3001 Bacteriostatic Versus Bactericidal AntibioticsPharmacologic agents that prevent the growth of bacteria arebacteriostatic antibiotics, whereas pharmacologic agents thatactually kill the bacteria are bactericidal antibiotics. Examples ofbacteriostatic antibiotics include tetracycline and clindamycin, andpenicillin and metronidazole are good examples of bactericidalantibiotics.DefinitionsAn anti-infective agent is a chemotherapeutic agent that acts byreducing the number of bacteria present. An antibiotic is a naturallyoccurring, semisynthetic, or synthetic type of anti-infective agentthat destroys or inhibits the growth of select microorganisms,generally at low concentrations. An antiseptic is a chemicalantimicrobial agent that can be applied topically or subgingivally tomucous membranes, wounds, or intact dermal surfaces to destroymicroorganisms and inhibit their reproduction or metabolism. Indentistry, antiseptics are widely used as the active ingredient inantiplaque and antigingivitis oral rinses and dentifrices.Disinfectants (a subcategory of antiseptics) are antimicrobial agentsthat are generally applied to inanimate surfaces to destroymicroorganisms.13When anti-infective agents are administered orally, many of theseagents can be found in the gingival crevicular fluid (GCF). Thepurpose of a systemic administration of antibiotics is to reduce thenumber of bacteria present in the diseased periodontal pocket; thisis often a necessary adjunct for controlling bacterial infection,because bacteria can invade periodontal tissues, thereby makingmechanical therapy alone sometimes ineffective.2,11,12,21,48A single chemotherapeutic agent can also have a dual mechanismof action. For example, tetracyclines (especially doxycycline) arechemotherapeutic agents that can reduce collagen and bonedestruction via their ability to inhibit the enzyme collagenase. Asantibiotic agents, they can also reduce periodontal pathogens inperiodontal tissues.123002 Systemic Administration ofAntibioticsBackground and RationaleThe treatment of periodontal diseases is based on their infectiousnature (Table 52.1). Ideally, the causative microorganisms should beidentified, and the most effective agent should be selected with theuse of antibiotic-sensitivity testing. Although this appears simple,the difficulty lies primarily in identifying the specific etiologicmicroorganisms rather than the microorganisms that are simplyassociated with various periodontal disorders.12TABLE 52.1Antibiotics Used to Treat Periodontal DiseasesCategory Agent Major FeaturesPenicillinaAmoxicillin Extended spectrum of antimicrobial activity; excellent oralabsorption; used systemicallyAugmentinbEffective against penicillinase-producing microorganisms;used systemicallyTetracyclines Minocycline Effective against a broad spectrum of microorganisms; usedsystemically and applied locally (subgingivally)DoxycyclineTetracycline Effective against a broad spectrum of microorganisms; usedsystemically and applied locally (subgingivally)Chemotherapeutically used in subantimicrobial doses for hostmodulation (Periostat)Effective against a broad spectrum of microorganismsQuinolone Ciprofloxacin Effective against gram-negative rods; promotes health-associated microfloraMacrolide Azithromycin Concentrates at sites of inflammation; used systemicallyLincomycinderivativeClindamycin Used in penicillin-allergic patients; effective against anaerobicbacteria; used systemicallyNitroimidazolecMetronidazole Effective against anaerobic bacteria; used systemically andapplied locally (subgingivally) as gelaIndications: localized aggressive periodontitis, generalized aggressive periodontitis,medically related periodontitis, and refractory periodontitis.bAmoxicillin and clavulanate potassium.cIndications: localized aggressive periodontitis, generalized aggressive periodontitis,medically related periodontitis, refractory periodontitis, and necrotizing ulcerativeperiodontitis.An ideal antibiotic for use in the prevention and treatment ofperiodontal disease should be specific for periodontal pathogens,3003 allogenic, nontoxic, substantive, not in general use for the treatmentof other diseases, and inexpensive.22 Currently, however, an idealantibiotic for the treatment of periodontal disease does not exist.32Although oral bacteria are susceptible to many antibiotics, no singleantibiotic at the concentrations achieved in body fluids inhibits allputative periodontal pathogens.61 Indeed, a combination ofantibiotics may be necessary to eliminate all putative pathogensfrom some periodontal pockets43 (Table 52.2).TABLE 52.2Common Antibiotic Regimens Used to Treat Periodontal DiseasesaRegimen Dosage/DurationSingle AgentAmoxicillin 500 mg Three times daily for 8 daysAzithromycin 500 mg Once daily for 4 to 7 daysCiprofloxacin 500 mg Twice daily for 8 daysClindamycin 300 mg Three times daily 10 daysDoxycycline or minocycline 100 mg to 200 mg Once daily for 21 daysMetronidazole 500 mg Three times daily for 8 daysCombination TherapyMetronidazole + amoxicillin 250 mg of each Three times daily for 8 daysMetronidazole + ciprofloxacin 500 mg of each Twice daily for 8 daysaThese regimens are prescribed after a review of the patient's medical history,periodontal diagnosis, and antimicrobial testing. Clinicians must consultpharmacology references such as Mosby's GenRx41 or the manufacturer's guidelinesfor warnings, contraindications, and precautions.Data from Jorgensen MG, Slots J: Practical antimicrobial periodontal therapy.Compend Contin Educ Dent 21:111, 2000.As always, the clinician, in concert with the patient, must makethe final decision regarding any treatment. Thus the treatment of anindividual patient must be based on the patient's clinical status, thenature of the colonizing bacteria, the ability of the agent to reach thesite of infection, and the risks and benefits associated with theproposed treatment plan. The clinician is responsible for choosingthe correct antimicrobial agent. Some adverse reactions includeallergic or anaphylactic reactions, superinfections of opportunisticbacteria, development of resistant bacteria, interactions with othermedications, upset stomach, nausea, and vomiting.3 Most adversereactions take the form of gastrointestinal upset.32 Other concernsinclude the cost of the medication and the patient's willingness and3004 ability to comply with the proposed therapy.No consensus exists regarding the magnitude of risk for thedevelopment of bacterial resistance. The common andindiscriminate use of antibiotics worldwide has contributed toincreasing numbers of resistant bacterial strains since the late 1990s,and this trend is likely to continue given the widespread use ofantibiotics.10,18,62 The overuse, misuse, and widespread prophylacticapplication of anti-infective drugs are some of the factors that haveled to the emergence of resistant microorganisms. Increasing levelsof resistance of subgingival microflora to antibiotics have beencorrelated with the increased use of antibiotics in individualcountries.10,57 However, researchers have noted that the subgingivalmicroflora tends to revert to similar proportions of antibiotic-resistant isolates 3 months after therapy.20,28TetracyclinesTetracyclines have been widely used for the treatment ofperiodontal diseases. They have been frequently used to treatrefractory periodontitis, including localized aggressive periodontitis(LAP)31,63 (see Table 52.1). Tetracyclines have the ability toconcentrate in the periodontal tissues and inhibit the growth ofAggregatibacter actinomycetemcomitans. In addition, tetracyclinesexert an anticollagenase effect that can inhibit tissue destructionand may help with bone regeneration.9,37,60PharmacologyThe tetracyclines are a group of antibiotics that are producednaturally from certain species of Streptomyces or derivedsemisynthetically. These antibiotics are bacteriostatic and areeffective against rapidly multiplying bacteria. They generally aremore effective against gram-positive bacteria than against gram-negative bacteria. Tetracyclines are effective for the treatment ofperiodontal diseases in part because their concentration in thegingival crevice is 2 to 10 times that found in serum.1,4,24 This allowsa high drug concentration to be delivered into the periodontalpockets. In addition, several studies have demonstrated thattetracyclines at a low GCF concentration (i.e., 2 µg/ml to 4 µg/ml)3005 are very effective against many periodontal pathogens.5,6Clinical UseTetracyclines have been investigated as adjuncts for the treatmentof LAP.31,51 A. actinomycetemcomitans is a microorganism that isfrequently associated with LAP, and it invades tissue. Therefore themechanical removal of calculus and plaque from root surfaces maynot eliminate this bacterium from the periodontal tissues. Systemictetracycline can eliminate tissue bacteria and has been shown toarrest bone loss and suppress A. actinomycetemcomitans levels inconjunction with scaling and root planing.50 This combinationtherapy allows for the mechanical removal of root surface depositsand the elimination of pathogenic bacteria from within the tissues.53Increased posttreatment bone levels have been noted with the useof this method (Figs. 52.1 to 52.4).FIG. 52.1 Panoramic image of 17-year-old AfricanAmerican male exhibiting signs of localized aggressiveperiodontitis. (Photo courtesy Dr. Sasi Sunkari.)3006 FIG. 52.2 Image of anterior dentition in 17-year-oldAfrican American male with localized aggressiveperiodontitis. (Photo courtesy Dr. Sasi Sunkari.)3007 FIG. 52.3 Preoperative radiograph of anterior mandiblein localized aggressive periodontitis patient. (Photo courtesyDr. Sasi Sunkari.)3008 FIG. 52.4 Postoperative radiograph of anteriormandible in localized aggressive periodontitis patienttreated with a combination of antibiotic therapy, scalingand root planing, and surgical intervention. (Photo courtesyDr. Sasi Sunkari.)As a result of increased resistance to tetracyclines, metronidazoleor amoxicillin with metronidazole has been found to be moreeffective for the treatment of aggressive periodontitis in childrenand young adults. Some investigators think that metronidazole incombination with amoxicillin–clavulanic acid is the preferableantibiotic.59Long-term use of low antibacterial doses of tetracyclines has beenadvocated in the past. One long-term study of patients taking lowdoses of tetracycline (i.e., 250 mg/day for 2 to 7 years) demonstratedthe persistence of deep pockets that did not bleed after probing.3009 These sites contained high proportions of tetracycline-resistantgram-negative rods (Fusobacterium nucleatum). After the antibioticwas discontinued, the flora was characteristic of sites with disease.32Therefore it is not advisable to prescribe a long-term regimen oftetracyclines because of the possible development of resistantbacterial strains.34 Although tetracyclines were often used in thepast as anti-infective agents, especially for LAP and other types ofaggressive periodontitis, they are now frequently replaced by moreeffective combination antibiotics.32Specific AgentsTetracycline, minocycline, and doxycycline are semisyntheticmembers of the tetracycline group that have been used inperiodontal therapy.TetracyclineTreatment with tetracycline hydrochloride requires theadministration of 250 mg four times daily. It is inexpensive, butcompliance may be reduced by the need to take the medication sofrequently. Side effects include gastrointestinal disturbances,photosensitivity, hypersensitivity, increased blood urea nitrogenlevels, blood dyscrasias, dizziness, and headache. In addition, toothdiscoloration occurs when this drug is administered to childrenwho are 12 years old or younger. Key FactTetracycline and Tooth DiscolorationTetracycline has the ability to chelate with calcium and thereforegets deposited in mineralized tissues such as bone or teeth duringthe mineralization process, resulting in yellow to browndiscoloration of teeth.MinocyclineMinocycline is effective against a broad spectrum ofmicroorganisms. In patients with adult periodontitis, it suppresses3010 spirochetes and motile rods as effectively as scaling and rootplaning, with suppression evident up to 3 months after therapy.Minocycline can be given twice daily, thereby facilitatingcompliance as compared with tetracycline. Although it is associatedwith less phototoxicity and renal toxicity than tetracycline,minocycline may cause reversible vertigo. Minocyclineadministered at a dose of 200 mg/day for 1 week results in areduction of total bacterial counts, complete elimination ofspirochetes for up to 2 months, and improvement of all clinicalparameters.13,14Side effects are similar to those of tetracycline; however, there isan increased incidence of vertigo. It is the only tetracycline that canpermanently discolor erupted teeth and gingival tissue whenadministered orally.DoxycyclineDoxycycline has the same spectrum of activity as minocycline andcan be equally effective.12 Because doxycycline can be given onlyonce daily, patients may be more compliant. Compliance is alsoimproved because its absorption from the gastrointestinal tract isonly slightly altered by calcium, metal ions, or antacids, as isabsorption of other tetracyclines. Side effects are similar to those oftetracycline hydrochloride; however, it is the most photosensitizingagent in the tetracycline category.The recommended dosage when doxycycline is used as an anti-infective agent is 100 mg twice daily the first day, which is thenreduced to 100 mg daily. To reduce gastrointestinal upset, 50 mgcan be taken twice daily after the initial dose. When given as a sub-antimicrobial dose (to inhibit collagenase), 20 mg of doxycyclinetwice daily is recommended.9,16MetronidazolePharmacologyMetronidazole is a nitroimidazole compound that was developed inFrance to treat protozoal infections. It is bactericidal to anaerobicorganisms and is thought to disrupt bacterial DNA synthesis inconditions with a low reduction potential. Metronidazole is not the3011 drug of choice for treating A. actinomycetemcomitans infections.However, metronidazole is effective against A.actinomycetemcomitans when used in combination with otherantibiotics.43,44 Metronidazole is also effective against anaerobessuch as Porphyromonas gingivalis and Prevotella intermedia.25Clinical UseMetronidazole has been used clinically to treat acute necrotizingulcerative gingivitis, chronic periodontitis, and aggressiveperiodontitis. It has been used as monotherapy and also incombination with root planing and surgery or with otherantibiotics. Metronidazole has been used successfully to treatnecrotizing ulcerative gingivitis.39Studies in humans have demonstrated the efficacy ofmetronidazole for the treatment of periodontitis.38 A single dose ofmetronidazole (250 mg orally) appears in both serum and GCF insufficient quantities to inhibit a wide range of suspectedperiodontal pathogens. When it is administered systemically (i.e.,750 mg/day to 1000 mg/day for 2 weeks), metronidazole reduces thegrowth of anaerobic flora, including spirochetes, and it decreasesthe clinical and histopathologic signs of periodontitis.38 The mostcommon regimen is 250 mg 3 times daily for 7 days.39 Currently, thecritical level of spirochetes that is needed to diagnose an anaerobicinfection, the appropriate time to give metronidazole, and the idealdosage or duration of therapy are unknown.25 As monotherapy (i.e.,with no concurrent root planing), metronidazole is inferior and atbest only equivalent to root planing. Therefore if it is used,metronidazole should not be administered as monotherapy.Soder and colleagues52 demonstrated that metronidazole wasmore effective than placebo for the management of sites that wereunresponsive to root planing. Nevertheless, many patients still hadsites that bled with probing, despite metronidazole therapy. Theexistence of refractory periodontitis as a diagnostic considerationindicates that some patients do not respond to conventionaltherapy, which may include root planing, surgery, or both.Studies have suggested that when it is combined with amoxicillinor amoxicillin–clavulanate potassium (Augmentin), metronidazolemay be of value for the management of patients with LAP or3012 refractory periodontitis. This is discussed in more detail later in thischapter.Side EffectsMetronidazole has an Antabuse effect when alcohol is ingested. Theresponse is generally proportional to the amount ingested and canresult in severe cramps, nausea, and vomiting. Products thatcontain alcohol should be avoided during therapy and for at least 1day after therapy is discontinued. Metronidazole also inhibitswarfarin metabolism. Patients who are undergoing anticoagulanttherapy should avoid metronidazole, because it prolongsprothrombin time.39 It also should be avoided in patients who aretaking lithium. This drug produces a metallic taste in the mouth,which may affect compliance.PenicillinsPharmacologyPenicillins are the drugs of choice for the treatment of many seriousinfections in humans and are the most widely used antibiotics.Penicillins are natural and semisynthetic derivatives of brothcultures of the Penicillium mold. They inhibit bacterial cell wallproduction and therefore are bactericidal.Clinical UsePenicillins other than amoxicillin and amoxicillin–clavulanatepotassium (Augmentin) have not been shown to increaseperiodontal attachment levels, and their use in periodontal therapydoes not appear to be justified.Side EffectsPenicillins may induce allergic reactions and bacterial resistance. Key FactPenicillin Allergy3013 Up to 10% of patients may be allergic to penicillin. Reactions toingestion of penicillin or its derivatives, such as amoxicillin, inallergic patients can range from skin rash to life-threateninganaphylaxis.AmoxicillinAmoxicillin is a semisynthetic penicillin with an extended anti-infective spectrum that includes gram-positive and gram-negativebacteria. It demonstrates excellent absorption after oraladministration. Amoxicillin is susceptible to penicillinase, which isa β-lactamase produced by certain bacteria that breaks the penicillinring structure and thus renders penicillins ineffective.Amoxicillin may be useful for the management of patients withaggressive periodontitis in both localized and generalized forms.The recommended dosage is 500 mg 3 times daily for 8 days.32,33Amoxicillin–Clavulanate PotassiumThe combination of amoxicillin with clavulanate potassium makesthis anti-infective agent resistant to penicillinase enzymes producedby some bacteria. Amoxicillin with clavulanate (Augmentin) maybe useful for the management of patients with LAP or refractoryperiodontitis.42 Bueno and colleagues8 reported that Augmentinarrested alveolar bone loss in patients with periodontal disease thatwas refractory to treatment with other antibiotics, includingtetracycline, metronidazole, and clindamycin.CephalosporinsPharmacologyThe family of β-lactams known as cephalosporins is similar inaction and structure to the penicillins. These drugs are frequentlyused in medicine, and they are resistant to a number of β-lactamases that are normally active against penicillin.Clinical UseCephalosporins are generally not used to treat dental-relatedinfections. The penicillins are superior to cephalosporins with3014 regard to their range of action against periodontal pathogenicbacteria.Side EffectsPatients who are allergic to penicillins must be considered to beallergic to all β-lactam products. More specifically, up to 10% ofpatients who have an allergy to penicillin may also have an adversereaction to cephalosporins. Rashes, urticaria, fever, andgastrointestinal upset have all been associated withcephalosporins.62ClindamycinPharmacologyClindamycin is effective against anaerobic bacteria and has a strongaffinity for osseous tissue.56 It is effective for situations in which thepatient is allergic to penicillin.Clinical UseClindamycin has demonstrated efficacy in patients withperiodontitis that is refractory to tetracycline therapy. Walker andcolleagues62 showed that clindamycin helped stabilize refractorypatients; the dosage used was 150 mg 4 times daily for 10 days.Jorgensen and Slots33 recommend a regimen of 300 mg twice dailyfor 8 days.Side EffectsClindamycin has been associated with pseudomembranous colitis,but the incidence is higher with cephalosporins and ampicillin.When needed, however, clindamycin can be used with caution, butit is not indicated for patients with a history of colitis. Diarrhea orcramping that develops during clindamycin therapy may beindicative of colitis, and it should be discontinued. If symptomspersist, the patient should be referred to an internist.Ciprofloxacin3015 PharmacologyCiprofloxacin is a quinolone that is active against gram-negativerods, including all facultative and some anaerobic putativeperiodontal pathogens.41Clinical UseBecause it demonstrates a minimal effect on Streptococcus species,which are associated with periodontal health, ciprofloxacin therapymay facilitate the establishment of a microflora that is associatedwith periodontal health. At present, ciprofloxacin is the onlyantibiotic in periodontal therapy to which all strains of A.actinomycetemcomitans are susceptible. It has also been used incombination with metronidazole.43Side EffectsNausea, headache, metallic taste in the mouth, and abdominaldiscomfort have been associated with ciprofloxacin. Quinolonesinhibit the metabolism of theophylline, and caffeine and concurrentadministration can produce toxicity. Quinolones have also beenreported to enhance the effects of warfarin and otheranticoagulants.62MacrolidesPharmacologyMacrolide antibiotics contain a many-membered lactone ring towhich one or more deoxy sugars are attached. They inhibit proteinsynthesis by binding to the 50S ribosomal subunits of sensitivemicroorganisms. Macrolides can be bacteriostatic or bactericidal,depending on the concentration of the drug and the nature of themicroorganism. The macrolide antibiotics used for periodontaltreatment include erythromycin, spiramycin, and azithromycin.Clinical UseErythromycin does not concentrate in GCF and is not effectiveagainst most putative periodontal pathogens. For these reasons,erythromycin is not recommended as an adjunct to periodontal3016 therapy.Spiramycin is active against gram-positive organisms; it isexcreted in high concentrations in saliva. It is used as an adjunct toperiodontal treatment in Canada and Europe but is not available inthe United States. Spiramycin has a minimal effect on attachmentlevels.Azithromycin is a member of the azalide class of macrolides. It iseffective against anaerobes and gram-negative bacilli. After an oraldosage of 500 mg 4 times daily for 3 days, significant levels ofazithromycin can be detected in most tissues for 7 to 10 days.7,30 Theconcentration of azithromycin in tissue specimens from periodontallesions is significantly higher than that of normal gingiva.40 It hasbeen proposed that azithromycin penetrates fibroblasts andphagocytes in concentrations that are 100 to 200 times greater thanthat of the extracellular compartment. Azithromycin is activelytransported to sites of inflammation by phagocytes, where it isreleased directly into the sites of inflammation as the phagocytesrupture during phagocytosis.23 Therapeutic use requires a singledose of 250 mg/day for 5 days after an initial loading dose of 500mg.62Data have suggested that azithromycin may be an effectiveadjunctive therapy for increasing attachment levels in patients withaggressive periodontitis27 as well as for reducing the degree ofgingival enlargement.15 These data must be carefully considered,because they were derived from small subject populations.Currently, the literature presents conflicting reports regarding theefficacy of this antibiotic as an adjunct to periodontal therapy. Onestudy concluded that adjunctive azithromycin provides noadditional benefit over nonsurgical periodontal treatment for theparameters investigated in patients with severe generalized chronicperiodontitis. Furthermore, an additional study reported that therewas an increase in cardiovascular deaths among patients whoreceived azithromycin; this increase was most pronounced amongpatients with a high baseline risk of cardiovascular disease. As aresult of this study, the US Food and Drug Administration issued awarning that the drug can alter the electrical activity of the heart,which may lead to a potentially fatal heart rhythm known asprolonged QT interval. This rhythm causes the timing of the heart's3017 contractions to become irregular. The warning stated thatphysicians should use caution when giving the antibiotic to patientswho are known to have this condition or who are at risk forcardiovascular problems.To ascertain the efficacy of azithromycin for the management ofperiodontal diseases, future studies will need to increase thenumber of subjects, improve diagnostic methods and tools, anddetermine the appropriate dose, duration, and frequency ofazithromycin therapy.Serial and Combination AntibioticTherapyRationaleBecause periodontal infections may contain a wide variety ofbacteria, no single antibiotic is effective against all putativepathogens. Indeed, differences exist in the microbial floraassociated with the various periodontal disease syndromes.63 These“mixed” infections can include a variety of aerobic, microaerophilic,and anaerobic bacteria, which may be both gram negative and grampositive. In these cases, it may be necessary to use more than oneantibiotic, either serially or in combination.44 Before combinations ofantibiotics are used, however, the periodontal pathogens beingtreated should be identified and antibiotic-susceptibility testingperformed.65Clinical UseAntibiotics that are bacteriostatic (e.g., tetracycline) generallyrequire rapidly dividing microorganisms to be effective. They donot function well if a bactericidal antibiotic (e.g., amoxicillin) isgiven concurrently. When both types of drugs are required, they are bestgiven serially rather than in combination.Rams and Slots44 reviewed combination therapy involving theuse of systemic metronidazole along with amoxicillin, amoxicillin–clavulanate (Augmentin), or ciprofloxacin. The metronidazole–amoxicillin and metronidazole–Augmentin combinations provided3018 excellent elimination of many organisms in adults with LAP whohad been treated unsuccessfully with tetracyclines and mechanicaldebridement. These drugs have an additive effect that involves thesuppression of A. actinomycetemcomitans. Tinoco and colleagues55found metronidazole and amoxicillin to be clinically effective forthe treatment of LAP, although 50% of patients who were treatedwith this regimen harbored A. actinomycetemcomitans 1 year later.The metronidazole–ciprofloxacin combination is effective against A.actinomycetemcomitans; metronidazole targets obligate anaerobes,and ciprofloxacin targets facultative anaerobes. This is a powerfulcombination against mixed infections. Studies of this drugcombination for the treatment of refractory periodontitis havedocumented marked clinical improvement. This combination mayprovide a therapeutic benefit by reducing or eliminating pathogenicorganisms and a prophylactic benefit by giving rise to apredominantly streptococcal microflora.43Systemic antibiotic therapy in combination with mechanicaltherapy appears to be valuable for the treatment of recalcitrantperiodontal infections and LAP infections that involve A.actinomycetemcomitans. Antibiotic treatment should be reserved forspecific subsets of periodontal patients who do not respond toconventional therapy. The selection of specific agents should beguided by the results of cultures and sensitivity tests forsubgingival plaque microorganisms.Pharmacologic ImplicationsPrinciples of antibiotic therapy for the proper selection of anantibiotic minimally require identification of the causativeorganism, determination of the antibiotic sensitivity, and aneffective method of administration.29 The use of antibiotics to treatgingival diseases is contraindicated, because this is a local infectionthat can be easily treated with scaling and appropriate home careby the patient.54 With regard to destructive periodontal diseases,there are limited data to support the use of systemic antibiotictreatment. Although bacterial infections of the periodontium areconsidered to be important to initiation of the disease, currently noone microbe or group of microbes has been demonstrated to be the3019 cause of these diseases. It is therefore not surprising that systemicantibiotics have had only a modest effect on the management ofperiodontal diseases. At this time, systemic antibiotics for thetreatment of periodontal diseases have been indicated primarily foradjunctive use in the treatment of aggressive periodontaldiseases26,28 (Table 52.3).TABLE 52.3Therapeutic Uses of Systemic Antimicrobial Agents for Various PeriodontalDiseasesDisease Systemic Antimicrobial AgentsAdjunctor Stand-AloneTherapyGingivaldiseasesAntibiotic use not recommended NotapplicableNecrotizingulcerativegingivitisAntibiotic use not recommended unless there are systemiccomplications (e.g., fever, swollen lymph nodes)As anadjunctwhennecessaryChronicperiodontitisLimited benefit; antibiotic use not recommended NotapplicableAggressiveperiodontitisAntibiotic use recommended; for greatest benefit, therapeutic levelsof antibiotics should be achieved by the time scaling and rootplaning are completed (all debridement should be completed withina week); the optimal antibiotic type, dose, frequency, and durationhave not been identifiedAs anadjunctNecrotizingulcerativeperiodontitisAntibiotic use dependent on the systemic condition of the patient As anadjunctwhennecessaryPeriodontitisas amanifestationof systemicdiseaseAntibiotic use dependent on the systemic condition of the patient As anadjunctwhennecessaryPeriodontalabscessAntibiotic use not recommended NotapplicableGuidelines for the use of antibiotics in periodontal therapyinclude the following:1. The clinical diagnosis and situation dictate the need forpossible antibiotic therapy as an adjunct for controllingactive periodontal disease (Fig. 52.5). The patient's diagnosiscan change over time. For example, a patient who presents3020 with generalized mild chronic periodontitis can return to adiagnosis of periodontal health after initial therapy.However, if the patient has been treated and continues tohave active disease, the diagnosis may change togeneralized severe chronic periodontitis.FIG. 52.5 A decision tree for the selection of antibiotictherapy.2. Disease activity as measured by continuing attachment loss,purulent exudate, and bleeding on probing35,36 may be anindication for periodontal intervention and possiblemicrobial analysis through plaque sampling.3. When they are used to treat periodontal disease, antibioticsare selected on the basis of the patient's medical and dentalstatus and current medications,32 and the results ofmicrobial analysis, if it is performed.4. Microbiologic plaque sampling may be performed according3021 to the instructions of the reference laboratory. The samplesare usually taken at the beginning of an appointment, beforeinstrumentation of the pocket. Supragingival plaque isremoved, and an endodontic paper point is insertedsubgingivally into the deepest pockets to absorb bacteria inthe loosely associated plaque. This endodontic point isplaced in reduced transfer fluid or a sterile transfer tube andsent to the laboratory. The laboratory will then send thereferring dentist a report that includes the pathogens thatare present and any appropriate antibiotic regimen. At thistime, there are scant data to suggest that microbialidentification from a plaque sample can be used to clinicallyimprove the periodontal condition of the patient.5. Meta-analyses of randomized clinical trials and quasi-experimental studies have shown that systemic antibioticscan improve attachment levels when they are used asadjuncts to scaling and root planing. The same benefitscould not be demonstrated when antibiotics were used as astand-alone therapy.286. When systemic antibiotics were used as adjuncts to scalingand root planing, improvements were observed in theattachment levels of patients with chronic and aggressiveperiodontitis, although patients with aggressiveperiodontitis experienced greater benefits.28 The meanattachment level change depended on the antibiotic usedand ranged from 0.09 mm to 1.10 mm.287. The identification of which antibiotics were most effectivefor the treatment of destructive periodontal diseases waslimited by the insufficient sizes of the samples found in therandomized clinical trials used as part of a systematicreview.28 A meta-analysis evaluating eight differentantibiotics or antibiotic combinations showed that onlytetracycline and metronidazole significantly improvedattachment levels when they were used as adjuncts toscaling and root planing for patients with destructiveperiodontal diseases.288. Debridement of root surfaces, optimal oral hygiene, andfrequent periodontal maintenance therapy are important3022 parts of comprehensive periodontal therapy. As mentionedpreviously, an antibiotic strength that is 500 times greaterthan the systemic therapeutic dose may be required to beeffective against bacteria that have been arranged intobiofilm. It is therefore important to disrupt the biofilmphysically so that the antibiotic agents can have access to theperiodontal pathogens.269. Although there are adequate data to suggest that systemicantibiotics can be of benefit for the treatment of destructiveperiodontal diseases, there are limited data available toidentify which antibiotics are suitable for which infection;the optimum dosage, frequency, and duration of antibiotictherapy; when the regimen should be introduced during thetreatment schedule; the long-term outcomes of antibioticuse; the potential hazards of these agents (e.g., antibioticresistance, changes in oral microflora)28; and the economicramifications of this type of pharmacologic intervention.The selection of an antibiotic must be made on the basis of factorsother than the empirical decisions made by the clinician.Unfortunately, there is no one best choice of antibiotic at present(i.e., there is no “silver bullet”). Therefore the clinician mustintegrate the history of the patient's disease, the clinical signs andsymptoms, and the results of radiographic examinations andpossibly microbiologic sampling to determine the course ofperiodontal therapy. The clinician must obtain a thorough medicalhistory, including current medications and the possible adverseeffects of combining these medicines, before prescribing anyantibiotic therapy. The clinician must make the final decision withthe patient. Risks and benefits concerning antibiotics as adjuncts toperiodontal therapy should be discussed with the patient beforeantibiotics are used.ConclusionScaling and root planing alone are effective for reducing pocketdepths, gaining increases in periodontal attachment levels, anddecreasing inflammation levels (i.e., bleeding with probing). When3023 systemic antibiotics are used as adjuncts to scaling and rootplaning, the evidence indicates that some systemic antibiotics (e.g.,metronidazole, tetracycline) provide additional improvements inattachment levels (0.35 mm for metronidazole; 0.40 mm fortetracycline) when used as adjuncts to scaling and root planing.28The use of anti-infective chemotherapeutic treatment adjuncts doesnot result in significant adverse effects for patients.The decision regarding when to use systemic antimicrobialsshould be made on the basis of the clinician's consideration of theclinical findings, the patient's medical and dental history,17,19 thepatient's preferences, and the potential benefits of adjunctivetherapy with these agents. Chapter Highlights• The systemic administration of antibiotics may be a necessaryadjunct for controlling bacterial infection, because bacteria caninvade periodontal tissues, thereby making mechanicaltherapy alone sometimes ineffective.• Although oral bacteria are susceptible to many antibiotics, nosingle antibiotic at the concentrations achieved in body fluidsinhibits all putative periodontal pathogens.• The protocol for use of anti-infective agents depends on themechanism of action, the patient's health status and history,and the clinical presentation. Case Scenario 52.1Patient:27-year-old Caucasian femaleChief Complaint:“My gums bleed when I brush my teeth.”Background InformationThe patient is a nonsmoker with no systemic medical conditions,3024 but she is allergic to penicillin. She reports that her sister, who is 32years old, has a similar gum condition. The patient says that shebrushes twice a day and flosses three or four times in a week.Current Findings:Probing depths are in the range of 1 to 8 mm. The deeper (>6 mm)probing depths are confined to maxillary incisors and first molars(Fig. A). Oral hygiene is optimal. Radiographically, vertical defectis noted mesial to all first molars. A representative radiographicvertical defect mesial to #19 is shown in Fig. B.CASE-BASEDQUESTIONSSOLUTION AND EXPLANATION1. Based on the history andclinical presentation, whatis the likely diagnosis?A. ChronicperiodontitisB. Acute necrotizingulcerative gingivitis(ANUG)C. Localizedaggressiveperiodontitis (LAP)D. Necrotizingulcerativeperiodontitis (NUP)Answer: CExplanation: Considering the patient's age, family history,clinical presentation (severe attachment loss confined to firstmolars and incisors in spite of good oral hygiene), andradiographic findings (vertical bone loss around firstmolars), a diagnosis of LAP can be made.2. 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