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CHAPTER OUTLINE
Definitions
Systemic Administration of Antibiotics
Serial and Combination Antibiotic Therapy
Conclusion
555
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CHAPTER 52 Systemic Anti-infective Therapy for Periodontal Diseases 555.e1
Abstract
This chapter provides information relative to the prescribing of
systemic antibiotics of value as adjuncts to periodontal therapy. The
systemic administration of antibiotics may be a necessary adjunct
for the control of bacterial infection because bacteria can invade
periodontal tissues, thereby sometimes making mechanical therapy
alone less effective. The clinical information in this chapter will
allow the practitioner to understand and know the indications,
contraindications, and protocols for optimizing the use of antibiotics
as part of the treatment of periodontal diseases. The prescribing
regimen for systemically administered antibiotics is usually by the
oral route of administration and depends on the mechanism of action,
patient’s health status and history, and clinical presentation. The
information in this chapter should provide guidance to clinicians
relative to the misuse of antibiotics, which has led to the emergence
of resistant microorganisms.
Keywords
anti-infective
antibiotics
systemic
periodontal diseases
resistance
periodontal pathogens
tetracyclines
penicillins
metronidazole
clindamycin
macrolides
combination therapy
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556 Part 3 Clinical Periodontics
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CHAPTER 52 Systemic Anti-infective Therapy for Periodontal Diseases 557
Fig. 52.1 Panoramic image of 17-year-old African American male exhibiting signs of localized aggressive
periodontitis. (Photo courtesy Dr. Sasi Sunkari.)
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558 Part 3 Clinical Periodontics
Fig. 52.2 Image of anterior dentition in 17-year-old African American male with localized aggressive periodontitis.
(Photo courtesy Dr. Sasi Sunkari.)
Fig. 52.3 Preoperative radiograph of anterior mandible in localized Fig. 52.4 Postoperative radiograph of anterior mandible in localized
aggressive periodontitis patient. (Photo courtesy Dr. Sasi Sunkari.) aggressive periodontitis patient treated with a combination of antibiotic
therapy, scaling and root planing, and surgical intervention. (Photo courtesy
Dr. Sasi Sunkari.)
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CHAPTER 52 Systemic Anti-infective Therapy for Periodontal Diseases 559
bacterial strains.34 Although tetracyclines were often used in the past organisms and is thought to disrupt bacterial DNA synthesis in
as anti-infective agents, especially for LAP and other types of conditions with a low reduction potential. Metronidazole is not the
aggressive periodontitis, they are now frequently replaced by more drug of choice for treating A. actinomycetemcomitans infections.
effective combination antibiotics.32 However, metronidazole is effective against A. actinomycetemcomitans
when used in combination with other antibiotics.43,44 Metronidazole
Specific Agents is also effective against anaerobes such as Porphyromonas gingivalis
Tetracycline, minocycline, and doxycycline are semisynthetic members and Prevotella intermedia.25
of the tetracycline group that have been used in periodontal therapy.
Clinical Use
Tetracycline Metronidazole has been used clinically to treat acute necrotizing
Treatment with tetracycline hydrochloride requires the administration ulcerative gingivitis, chronic periodontitis, and aggressive periodon-
of 250 mg four times daily. It is inexpensive, but compliance may titis. It has been used as monotherapy and also in combination with
be reduced by the need to take the medication so frequently. Side root planing and surgery or with other antibiotics. Metronidazole has
effects include gastrointestinal disturbances, photosensitivity, been used successfully to treat necrotizing ulcerative gingivitis.39
hypersensitivity, increased blood urea nitrogen levels, blood dyscrasias, Studies in humans have demonstrated the efficacy of metronidazole
dizziness, and headache. In addition, tooth discoloration occurs when for the treatment of periodontitis.38 A single dose of metronidazole
this drug is administered to children who are 12 years old or younger. (250 mg orally) appears in both serum and GCF in sufficient quantities
to inhibit a wide range of suspected periodontal pathogens. When
it is administered systemically (i.e., 750 mg/day to 1000 mg/day for
KEY FACT 2 weeks), metronidazole reduces the growth of anaerobic flora,
Tetracycline and Tooth Discoloration including spirochetes, and it decreases the clinical and histopathologic
Tetracycline has the ability to chelate with calcium and therefore gets signs of periodontitis.38 The most common regimen is 250 mg
deposited in mineralized tissues such as bone or teeth during the mineraliza- 3 times daily for 7 days.39 Currently, the critical level of spirochetes
tion process, resulting in yellow to brown discoloration of teeth. that is needed to diagnose an anaerobic infection, the appropriate
time to give metronidazole, and the ideal dosage or duration of
therapy are unknown.25 As monotherapy (i.e., with no concurrent
Minocycline root planing), metronidazole is inferior and at best only equivalent
Minocycline is effective against a broad spectrum of microorganisms. to root planing. Therefore if it is used, metronidazole should not be
In patients with adult periodontitis, it suppresses spirochetes and administered as monotherapy.
motile rods as effectively as scaling and root planing, with suppression Soder and colleagues52 demonstrated that metronidazole was more
evident up to 3 months after therapy. Minocycline can be given effective than placebo for the management of sites that were unre-
twice daily, thereby facilitating compliance as compared with tetra- sponsive to root planing. Nevertheless, many patients still had sites
cycline. Although it is associated with less phototoxicity and renal that bled with probing, despite metronidazole therapy. The existence
toxicity than tetracycline, minocycline may cause reversible vertigo. of refractory periodontitis as a diagnostic consideration indicates
Minocycline administered at a dose of 200 mg/day for 1 week results that some patients do not respond to conventional therapy, which
in a reduction of total bacterial counts, complete elimination of may include root planing, surgery, or both.
spirochetes for up to 2 months, and improvement of all clinical Studies have suggested that when it is combined with amoxicillin
parameters.13,14 or amoxicillin–clavulanate potassium (Augmentin), metronidazole
Side effects are similar to those of tetracycline; however, there may be of value for the management of patients with LAP or refractory
is an increased incidence of vertigo. It is the only tetracycline that periodontitis. This is discussed in more detail later in this chapter.
can permanently discolor erupted teeth and gingival tissue when
administered orally. Side Effects
Metronidazole has an Antabuse effect when alcohol is ingested. The
Doxycycline response is generally proportional to the amount ingested and can
Doxycycline has the same spectrum of activity as minocycline and result in severe cramps, nausea, and vomiting. Products that contain
can be equally effective.12 Because doxycycline can be given only alcohol should be avoided during therapy and for at least 1 day
once daily, patients may be more compliant. Compliance is also after therapy is discontinued. Metronidazole also inhibits warfarin
improved because its absorption from the gastrointestinal tract is metabolism. Patients who are undergoing anticoagulant therapy should
only slightly altered by calcium, metal ions, or antacids, as is absorp- avoid metronidazole, because it prolongs prothrombin time.39 It also
tion of other tetracyclines. Side effects are similar to those of tetra- should be avoided in patients who are taking lithium. This drug
cycline hydrochloride; however, it is the most photosensitizing agent produces a metallic taste in the mouth, which may affect compliance.
in the tetracycline category.
The recommended dosage when doxycycline is used as an anti- Penicillins
infective agent is 100 mg twice daily the first day, which is then Pharmacology
reduced to 100 mg daily. To reduce gastrointestinal upset, 50 mg Penicillins are the drugs of choice for the treatment of many serious
can be taken twice daily after the initial dose. When given as a infections in humans and are the most widely used antibiotics.
sub-antimicrobial dose (to inhibit collagenase), 20 mg of doxycycline Penicillins are natural and semisynthetic derivatives of broth cultures
twice daily is recommended.9,16 of the Penicillium mold. They inhibit bacterial cell wall production
and therefore are bactericidal.
Metronidazole
Pharmacology Clinical Use
Metronidazole is a nitroimidazole compound that was developed in Penicillins other than amoxicillin and amoxicillin–clavulanate potas-
France to treat protozoal infections. It is bactericidal to anaerobic sium (Augmentin) have not been shown to increase periodontal
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560 Part 3 Clinical Periodontics
attachment levels, and their use in periodontal therapy does not colleagues62 showed that clindamycin helped stabilize refractory
appear to be justified. patients; the dosage used was 150 mg 4 times daily for 10 days.
Jorgensen and Slots33 recommend a regimen of 300 mg twice daily
Side Effects for 8 days.
Penicillins may induce allergic reactions and bacterial resistance.
Side Effects
Clindamycin has been associated with pseudomembranous colitis,
KEY FACT but the incidence is higher with cephalosporins and ampicillin. When
Penicillin Allergy needed, however, clindamycin can be used with caution, but it is
Up to 10% of patients may be allergic to penicillin. Reactions to ingestion not indicated for patients with a history of colitis. Diarrhea or cramping
of penicillin or its derivatives, such as amoxicillin, in allergic patients can that develops during clindamycin therapy may be indicative of colitis,
range from skin rash to life-threatening anaphylaxis. and it should be discontinued. If symptoms persist, the patient should
be referred to an internist.
Amoxicillin Ciprofloxacin
Amoxicillin is a semisynthetic penicillin with an extended anti- Pharmacology
infective spectrum that includes gram-positive and gram-negative Ciprofloxacin is a quinolone that is active against gram-negative
bacteria. It demonstrates excellent absorption after oral administration. rods, including all facultative and some anaerobic putative periodontal
Amoxicillin is susceptible to penicillinase, which is a β-lactamase pathogens.41
produced by certain bacteria that breaks the penicillin ring structure
and thus renders penicillins ineffective. Clinical Use
Amoxicillin may be useful for the management of patients with Because it demonstrates a minimal effect on Streptococcus species,
aggressive periodontitis in both localized and generalized forms. which are associated with periodontal health, ciprofloxacin therapy
The recommended dosage is 500 mg 3 times daily for 8 days.32,33 may facilitate the establishment of a microflora that is associated with
periodontal health. At present, ciprofloxacin is the only antibiotic
Amoxicillin–Clavulanate Potassium in periodontal therapy to which all strains of A. actinomycetem-
The combination of amoxicillin with clavulanate potassium makes comitans are susceptible. It has also been used in combination with
this anti-infective agent resistant to penicillinase enzymes produced metronidazole.43
by some bacteria. Amoxicillin with clavulanate (Augmentin) may
be useful for the management of patients with LAP or refractory Side Effects
periodontitis.42 Bueno and colleagues8 reported that Augmentin arrested Nausea, headache, metallic taste in the mouth, and abdominal discom-
alveolar bone loss in patients with periodontal disease that was fort have been associated with ciprofloxacin. Quinolones inhibit the
refractory to treatment with other antibiotics, including tetracycline, metabolism of theophylline, and caffeine and concurrent administration
metronidazole, and clindamycin. can produce toxicity. Quinolones have also been reported to enhance
the effects of warfarin and other anticoagulants.62
Cephalosporins
Pharmacology Macrolides
The family of β-lactams known as cephalosporins is similar in action Pharmacology
and structure to the penicillins. These drugs are frequently used in Macrolide antibiotics contain a many-membered lactone ring to which
medicine, and they are resistant to a number of β-lactamases that one or more deoxy sugars are attached. They inhibit protein synthesis
are normally active against penicillin. by binding to the 50S ribosomal subunits of sensitive microorganisms.
Macrolides can be bacteriostatic or bactericidal, depending on the
Clinical Use concentration of the drug and the nature of the microorganism. The
Cephalosporins are generally not used to treat dental-related infections. macrolide antibiotics used for periodontal treatment include eryth-
The penicillins are superior to cephalosporins with regard to their romycin, spiramycin, and azithromycin.
range of action against periodontal pathogenic bacteria.
Clinical Use
Side Effects Erythromycin does not concentrate in GCF and is not effective against
Patients who are allergic to penicillins must be considered to be most putative periodontal pathogens. For these reasons, erythromycin
allergic to all β-lactam products. More specifically, up to 10% of is not recommended as an adjunct to periodontal therapy.
patients who have an allergy to penicillin may also have an adverse Spiramycin is active against gram-positive organisms; it is excreted
reaction to cephalosporins. Rashes, urticaria, fever, and gastrointestinal in high concentrations in saliva. It is used as an adjunct to periodontal
upset have all been associated with cephalosporins.62 treatment in Canada and Europe but is not available in the United
States. Spiramycin has a minimal effect on attachment levels.
Clindamycin Azithromycin is a member of the azalide class of macrolides. It
Pharmacology is effective against anaerobes and gram-negative bacilli. After an
Clindamycin is effective against anaerobic bacteria and has a strong oral dosage of 500 mg 4 times daily for 3 days, significant levels
affinity for osseous tissue.56 It is effective for situations in which of azithromycin can be detected in most tissues for 7 to 10 days.7,30
the patient is allergic to penicillin. The concentration of azithromycin in tissue specimens from peri-
odontal lesions is significantly higher than that of normal gingiva.40
Clinical Use It has been proposed that azithromycin penetrates fibroblasts and
Clindamycin has demonstrated efficacy in patients with peri- phagocytes in concentrations that are 100 to 200 times greater than
odontitis that is refractory to tetracycline therapy. Walker and that of the extracellular compartment. Azithromycin is actively
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CHAPTER 52 Systemic Anti-infective Therapy for Periodontal Diseases 561
transported to sites of inflammation by phagocytes, where it is released and ciprofloxacin targets facultative anaerobes. This is a powerful
directly into the sites of inflammation as the phagocytes rupture combination against mixed infections. Studies of this drug combination
during phagocytosis.23 Therapeutic use requires a single dose of for the treatment of refractory periodontitis have documented marked
250 mg/day for 5 days after an initial loading dose of 500 mg.62 clinical improvement. This combination may provide a therapeutic
Data have suggested that azithromycin may be an effective benefit by reducing or eliminating pathogenic organisms and a
adjunctive therapy for increasing attachment levels in patients with prophylactic benefit by giving rise to a predominantly streptococcal
aggressive periodontitis27 as well as for reducing the degree of gingival microflora.43
enlargement.15 These data must be carefully considered, because Systemic antibiotic therapy in combination with mechanical
they were derived from small subject populations. Currently, the therapy appears to be valuable for the treatment of recalcitrant
literature presents conflicting reports regarding the efficacy of this periodontal infections and LAP infections that involve A. actinomy-
antibiotic as an adjunct to periodontal therapy. One study concluded cetemcomitans. Antibiotic treatment should be reserved for specific
that adjunctive azithromycin provides no additional benefit over subsets of periodontal patients who do not respond to conventional
nonsurgical periodontal treatment for the parameters investigated in therapy. The selection of specific agents should be guided by the
patients with severe generalized chronic periodontitis. Furthermore, results of cultures and sensitivity tests for subgingival plaque
an additional study reported that there was an increase in cardiovas- microorganisms.
cular deaths among patients who received azithromycin; this increase
was most pronounced among patients with a high baseline risk of Pharmacologic Implications
cardiovascular disease. As a result of this study, the US Food and Principles of antibiotic therapy for the proper selection of an
Drug Administration issued a warning that the drug can alter the antibiotic minimally require identification of the causative organ-
electrical activity of the heart, which may lead to a potentially fatal ism, determination of the antibiotic sensitivity, and an effective
heart rhythm known as prolonged QT interval. This rhythm causes method of administration.29 The use of antibiotics to treat gingival
the timing of the heart’s contractions to become irregular. The warning diseases is contraindicated, because this is a local infection that
stated that physicians should use caution when giving the antibiotic can be easily treated with scaling and appropriate home care by
to patients who are known to have this condition or who are at risk the patient.54 With regard to destructive periodontal diseases, there
for cardiovascular problems. are limited data to support the use of systemic antibiotic treatment.
To ascertain the efficacy of azithromycin for the management of Although bacterial infections of the periodontium are considered to
periodontal diseases, future studies will need to increase the number be important to initiation of the disease, currently no one microbe
of subjects, improve diagnostic methods and tools, and determine or group of microbes has been demonstrated to be the cause of
the appropriate dose, duration, and frequency of azithromycin therapy. these diseases. It is therefore not surprising that systemic antibiotics
have had only a modest effect on the management of periodontal
diseases. At this time, systemic antibiotics for the treatment of
Serial and Combination Antibiotic Therapy periodontal diseases have been indicated primarily for adjunc-
Rationale tive use in the treatment of aggressive periodontal diseases26,28
Because periodontal infections may contain a wide variety of bacteria, (Table 52.3).
no single antibiotic is effective against all putative pathogens. Indeed, Guidelines for the use of antibiotics in periodontal therapy include
differences exist in the microbial flora associated with the various the following:
periodontal disease syndromes.63 These “mixed” infections can include 1. The clinical diagnosis and situation dictate the need for possible
a variety of aerobic, microaerophilic, and anaerobic bacteria, which antibiotic therapy as an adjunct for controlling active periodontal
may be both gram negative and gram positive. In these cases, it may disease (Fig. 52.5). The patient’s diagnosis can change over time.
be necessary to use more than one antibiotic, either serially or in For example, a patient who presents with generalized mild chronic
combination.44 Before combinations of antibiotics are used, however, periodontitis can return to a diagnosis of periodontal health after
the periodontal pathogens being treated should be identified and initial therapy. However, if the patient has been treated and
antibiotic-susceptibility testing performed.65 continues to have active disease, the diagnosis may change to
generalized severe chronic periodontitis.
Clinical Use 2. Disease activity as measured by continuing attachment loss,
Antibiotics that are bacteriostatic (e.g., tetracycline) generally require purulent exudate, and bleeding on probing35,36 may be an indication
rapidly dividing microorganisms to be effective. They do not function for periodontal intervention and possible microbial analysis through
well if a bactericidal antibiotic (e.g., amoxicillin) is given concurrently. plaque sampling.
When both types of drugs are required, they are best given serially 3. When they are used to treat periodontal disease, antibiotics are
rather than in combination. selected on the basis of the patient’s medical and dental status
Rams and Slots44 reviewed combination therapy involving the and current medications,32 and the results of microbial analysis,
use of systemic metronidazole along with amoxicillin, amoxicillin– if it is performed.
clavulanate (Augmentin), or ciprofloxacin. The metronidazole– 4. Microbiologic plaque sampling may be performed according to
amoxicillin and metronidazole–Augmentin combinations provided the instructions of the reference laboratory. The samples are usually
excellent elimination of many organisms in adults with LAP who taken at the beginning of an appointment, before instrumentation
had been treated unsuccessfully with tetracyclines and mechanical of the pocket. Supragingival plaque is removed, and an endodontic
debridement. These drugs have an additive effect that involves the paper point is inserted subgingivally into the deepest pockets to
suppression of A. actinomycetemcomitans. Tinoco and colleagues55 absorb bacteria in the loosely associated plaque. This endodontic
found metronidazole and amoxicillin to be clinically effective for point is placed in reduced transfer fluid or a sterile transfer tube
the treatment of LAP, although 50% of patients who were treated and sent to the laboratory. The laboratory will then send the
with this regimen harbored A. actinomycetemcomitans 1 year later. referring dentist a report that includes the pathogens that are
The metronidazole–ciprofloxacin combination is effective against present and any appropriate antibiotic regimen. At this time, there
A. actinomycetemcomitans; metronidazole targets obligate anaerobes, are scant data to suggest that microbial identification from a
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562 Part 3 Clinical Periodontics
TABLE 52.3 Therapeutic Uses of Systemic Antimicrobial Agents for Various Periodontal Diseases
Adjunct or Stand-Alone
Disease Systemic Antimicrobial Agents Therapy
Gingival diseases Antibiotic use not recommended Not applicable
Necrotizing ulcerative gingivitis Antibiotic use not recommended unless there are systemic complications (e.g., As an adjunct when necessary
fever, swollen lymph nodes)
Chronic periodontitis Limited benefit; antibiotic use not recommended Not applicable
Aggressive periodontitis Antibiotic use recommended; for greatest benefit, therapeutic levels of As an adjunct
antibiotics should be achieved by the time scaling and root planing are
completed (all debridement should be completed within a week); the optimal
antibiotic type, dose, frequency, and duration have not been identified
Necrotizing ulcerative Antibiotic use dependent on the systemic condition of the patient As an adjunct when necessary
periodontitis
Periodontitis as a manifestation Antibiotic use dependent on the systemic condition of the patient As an adjunct when necessary
of systemic disease
Periodontal abscess Antibiotic use not recommended Not applicable
Clinical diagnosis
Aggressive periodontitis
Refractory cases
Periimplant disease
Periodontal abscess
Debridement–SRP
Surgery
Antibiotics
Local and
Local delivery Systemic antibiotics
systemic antibiotics
Nonresolution Surgery
Surgery
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CHAPTER 52 Systemic Anti-infective Therapy for Periodontal Diseases 563
plaque sample can be used to clinically improve the periodontal obtain a thorough medical history, including current medications
condition of the patient. and the possible adverse effects of combining these medicines, before
5. Meta-analyses of randomized clinical trials and quasi-experimental prescribing any antibiotic therapy. The clinician must make the final
studies have shown that systemic antibiotics can improve attach- decision with the patient. Risks and benefits concerning antibiotics
ment levels when they are used as adjuncts to scaling and root as adjuncts to periodontal therapy should be discussed with the patient
planing. The same benefits could not be demonstrated when before antibiotics are used.
antibiotics were used as a stand-alone therapy.28
6. When systemic antibiotics were used as adjuncts to scaling and
root planing, improvements were observed in the attachment Conclusion
levels of patients with chronic and aggressive periodontitis, Scaling and root planing alone are effective for reducing pocket
although patients with aggressive periodontitis experienced greater depths, gaining increases in periodontal attachment levels, and
benefits.28 The mean attachment level change depended on the decreasing inflammation levels (i.e., bleeding with probing). When
antibiotic used and ranged from 0.09 mm to 1.10 mm.28 systemic antibiotics are used as adjuncts to scaling and root planing,
7. The identification of which antibiotics were most effective for the evidence indicates that some systemic antibiotics (e.g., metro-
the treatment of destructive periodontal diseases was limited by nidazole, tetracycline) provide additional improvements in attachment
the insufficient sizes of the samples found in the randomized levels (0.35 mm for metronidazole; 0.40 mm for tetracycline) when
clinical trials used as part of a systematic review.28 A meta-analysis used as adjuncts to scaling and root planing.28 The use of anti-infective
evaluating eight different antibiotics or antibiotic combinations chemotherapeutic treatment adjuncts does not result in significant
showed that only tetracycline and metronidazole significantly adverse effects for patients.
improved attachment levels when they were used as adjuncts to The decision regarding when to use systemic antimicrobials should
scaling and root planing for patients with destructive periodontal be made on the basis of the clinician’s consideration of the clinical
diseases.28 findings, the patient’s medical and dental history,17,19 the patient’s
8. Debridement of root surfaces, optimal oral hygiene, and frequent preferences, and the potential benefits of adjunctive therapy with
periodontal maintenance therapy are important parts of compre- these agents.
hensive periodontal therapy. As mentioned previously, an antibiotic
strength that is 500 times greater than the systemic therapeutic
dose may be required to be effective against bacteria that have CHAPTER HIGHLIGHTS
been arranged into biofilm. It is therefore important to disrupt • The systemic administration of antibiotics may be a necessary
the biofilm physically so that the antibiotic agents can have access adjunct for controlling bacterial infection, because bacteria can
to the periodontal pathogens.26 invade periodontal tissues, thereby making mechanical therapy
9. Although there are adequate data to suggest that systemic alone sometimes ineffective.
antibiotics can be of benefit for the treatment of destructive • Although oral bacteria are susceptible to many antibiotics, no single
periodontal diseases, there are limited data available to identify antibiotic at the concentrations achieved in body fluids inhibits all
which antibiotics are suitable for which infection; the optimum putative periodontal pathogens.
dosage, frequency, and duration of antibiotic therapy; when the • The protocol for use of anti-infective agents depends on the
regimen should be introduced during the treatment schedule; the mechanism of action, the patient’s health status and history, and
long-term outcomes of antibiotic use; the potential hazards of these the clinical presentation.
agents (e.g., antibiotic resistance, changes in oral microflora)28;
and the economic ramifications of this type of pharmacologic
intervention. A Case Scenario is found on the companion website
The selection of an antibiotic must be made on the basis of factors www.expertconsult.com.
other 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 must integrate the history of References
the patient’s disease, the clinical signs and symptoms, and the results
of radiographic examinations and possibly microbiologic sampling References for this chapter are found on the companion
website www.expertconsult.com.
to determine the course of periodontal therapy. The clinician must
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CHAPTER 52 Systemic Anti-infective Therapy for Periodontal Diseases 563.e1
A B
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563.e2 Part 3 Clinical Periodontics
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CHAPTER 52 Systemic Anti-infective Therapy for Periodontal Diseases 563.e3
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27:79, 2000. 52:613, 1981.
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1981.
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