Jan Lindhe. Clinical Periodontology

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THE USE OF ANTIBIOTICS IN PERIODONTAL THERAPY • 505

Fig. 23-5. Tetracycline fiber is packed into the periodontal pocket (a), secured with a thin layer of cyanoacrylate ad

hesive (b), and left in place for 7 to 12 days.

gel is expected to increase in viscosity after placement.

It has been reported that 400 of the applied gel re-

mained in place, while 60% was immediately lost and

normally would probably be swallowed (Stoltze &

Stellfeld 1992). After treating an average number of 18

teeth in 14 patients, a mean peak metronidazole

plasma concentration of 0.6 g/ml was reached within

to 8 hours. The estimated mean dose of metronida-

zole per treated tooth was 3 mg. The drug concentra-

tion determined in crevicular fluid was below 1 g/ml

in half of the sampled sites after one day and in 92%

of the sites after 36 hours (Fig. 23-4). The clinical

response to subgingival application of the metronida-

zole gel was compared to the effect of subgingival

scaling in a large multicenter study of 206 patients

with untreated adult periodontitis (Ainamo et al.

1992). Two randomly selected quadrants were treated

with the gel twice within one week; the other two

quadrants were treated with two episodes of sub-

gingival scaling. Differences between gel application

and scaling were considered clinically insignificant by

the authors. Using a similar design, the microbiologi-

cal outcome of two gel applications versus scaling was

compared in 24 subjects during a 6-month observation

period (Pedrazzoli et al. 1992). The total bacterial cul-

tivable count and the proportions of anaerobic bacte-

ria were affected in a similar way in the two groups,

and no difference could be detected in terms of re-

duced probing depth and bleeding on probing. Al-

though in theory the antimicrobial action of metroni-

dazole is bactericidal and independent of time, in

practice a sufficient period of drug presence is impor-

tant irrespective of whether a substance has been de-

termined bactericidal or bacteriostatic in the labora-

tory.

A subsequent controlled, randomized, blind study

extended the previous observations to include clinical

attachment level measurements. The results from a

total of 164 subjects indicated no significant difference

between metronidazole gel application and scaling

and root planing (Grossi et al. 1995). The fact that no

significant difference between the two treatments was

observed opened the question of equivalence between

the two treatment modalities. From a practical stand-

point, one form of treatment may be preferred to

another of equal efficacy if it offers better tolerability

for the patient, lower costs, etc. Equivalence between

scaling and root planing and metronidazole gel ther-

apy has been evaluated using the lower bounds of

confidence intervals in a parallel arm, multicenter,

controlled clinical trial including 84 subjects (

Pihlstrom et al. 1995). The estimates provided by this

study indicated that metronidazole gel therapy is 82%

as good as mechanical debridement at the 95% confi-

dence level.

Tetracycline in a non-resorbable plastic co-polymer

Hollow devices such as dialysis tubing, and solid

devices such as acrylic strips, collagen, or poly-OH-

butyric acid strips have been tested for

tetracycline

delivery in several experiments. Semi-solid viscous

media include white petrolatum and poloxamer or

carbopol gels. The most extensively tested tetracycline

releasing device is the Actisite periodontal fiber

(

ALZA, Palo Alto, CA, US; Solco, Birsfelden, Switzer-

land), a monolithic thread of a biologically inert, non-

resorbable plastic co-polymer (ethylene and vinyl-

acetate) containing 25% tetracycline hydrochloride

powder. The fiber is packed into the periodontal

pocket, secured with a thin layer of cyanoacrylate

adhesive (Fig. 23-5), and left in place for 7 to 12 days

(Goodson et al. 1983, 1991a). By continuous delivery

of tetracycline, a local concentration of the active drug

in excess of 1000 mg/1 can be maintained throughout

that period (Fig. 23-4). The drug is also deposited on

the root surface and penetrates into the soft periodon

tal tissues. Salivary tetracycline concentrations rang-

ing from 8 to 51 mg/1 have been measured when

treating multiple sites, while serum concentrations

remained below detection level (Goodson et al. 1985,

Rapley et al. 1992). Many clinical studies have been

performed with Actisite, among them three large mul-

ticenter trials, which we will discuss briefly. The safety

and efficacy of tetracycline fiber therapy were inves-

tigated in a 60-day multicenter study conducted in 107

periodontitis patients after supragingival scaling and

prophylaxis. Four non-adjacent teeth with pockets in

the range of 6-10 mm were selected. They were ran-

506 • CHAPTER

Fig. 23-6a,b. Insertion of a chlorhexidin chip into a residual pocket mesial of an upper molar with a furcation in

volvement.

domly assigned to either tetracycline or placebo fiber

placement, scaling, or were left untreated. The analy-

sis showed that fiber therapy significantly decreased

pocket depth, increased attachment levels, and de-

creased the bleeding tendency to a greater extent than

the control procedures (Goodson et al. 1991b). A sec-

ond multicenter study is of particular interest for two

reasons: first, because it was conducted in periodontal

maintenance patients needing treatment of localized

recurrent periodontitis, and secondly, because the ef-

fect of fiber therapy was evaluated as an adjunct to

scaling and root planing (Newman et al. 1994). After

months, sites treated with scaling and root planing

plus tetracycline fiber showed a significantly higher

attachment level, significantly more pocket depth re-

duction and less bleeding on probing than scaling and

root planing alone. A third large-scale multicenter

study demonstrated that the results obtained within 3

months after therapy were maintained over 1 year and

that the combined treatment with fiber and scaling

had a significantly lower incidence of disease recur-

rence than any of the other tested treatment modalities

(Michalowicz et al. 1995).

Chlorhexidine gluconate in a gelatin chip

Several attempts have been made to develop local

delivery devices for the subgingival application of

antiseptic, rather than antibiotic agents. Acrylic strips

and ethyl-cellulose compounds have been tested for

this purpose. PerioChip (Perio Products, Jerusalem,

Israel), a degradable gelatin chip containing 2.5 mg

chlorhexidine, is the most extensively tested delivery

device of this category (Fig. 23-6). Safety and efficacy

of PerioChip were evaluated in a multicenter study of

118 patients with moderate periodontitis (Soskolne et

al. 1997). A split-mouth design was used to compare

the treatment outcomes of scaling and root planing

alone with the combined use of scaling and root plan-

ing and PerioChip in pockets with probing depths of

5-8 mm. The average pocket depth reduction in the

treated sites with the chip was significantly greater

than in the sites receiving mechanical treatment only

(mean difference of 0.42 mm at 6 months). The efficacy

of the chlorhexidine chip when used as an adjunct to

scaling and root planing on reducing probing depth

and improving clinical attachment level in adult peri-

odontitis was evaluated in two double-blind, random-

ized, placebo-controlled multicenter clinical trials. At

9 months significant reductions from baseline were

shown with the chlorhexidine chip compared with

mechanical control treatments (Jeffcoat et al. 1998).

Conclusion

To treat periodontal disease successfully, local deliv-

ery devices must provide therapeutic levels of antimi-

crobial agents in the subgingival area over prolonged

periods. Clinical trials show the efficacy of topical

antibiotic therapy under these conditions.

Comparison of treatment methods

Few studies have addressed the problem of incorpo-

rating local or systemic antimicrobial therapy into an

overall treatment strategy. Most studies have tested a

single form of local drug delivery or systemic admini-

stration, instead of comparing various forms of ther-

apy. Understandably, developers and distributors

have an intrinsic interest to register and promote their

own product for the broadest possible usage. As little

direct evidence for a comparison of various methods

of treatment is available so far, well-founded decision

algorithms to choose specific methods of intervention

for distinct clinical situations are not yet available.

In patients with persistent periodontal lesions the

efficacy of three commercially available local delivery

systems as adjuncts to scaling and root planing was

tested (Radvar et al. 1996, Kinane & Radvar 1999).

Treatment modalities included scaling and root plan-

ing alone and in conjunction with the application of

25% tetracycline fibers, or 2% minocycline gel, or 25%

metronidazole gel. Although all three locally applied

antimicrobial systems seemed to offer some benefit

over scaling and root planing alone, a treatment regi-

men of scaling and root planing plus tetracycline fiber

placement gave the greatest reduction in probing

depth over the 6 months after treatment. Suppuration

was most effectively reduced in the scaling plus tetra-

THE USE OF ANTIBIOTICS IN PERIODONTAL THERAPY •

507

cycline fiber group, followed by the minocycline

group.

The clinical and microbiological effects of three

sustained-release biodegradable polymers delivered

into periodontal pockets following initial periodontal

therapy, were assessed in a single-blind, randomized,

parallel-designed controlled clinical trial (Salvi et al.

2002). Forty-seven patients were randomly assigned

to receive either Atridox, Elyzol Dental Gel or Perio-

Chip at residual periodontal pockets > 5 mm. Therapy

resulted in a statistically significant gain in mean

probing attachment levels for Atridox and a signifi-

cant reduction in probing depth for all three devices

during the study period. Furthermore, significantly

more probing attachment level was gained in sites

treated with Atridox when compared to sites treated

with Elyzol.

A key issue requiring clarification refers to the se-

lection of a local or a systemic delivery approach

whenever the use of an antibiotic is indicated. One

investigation addressed this question in patients with

rapidly progressing periodontitis (Bernimoulin et al.

1995). Overall, no significant differences were noted

between systemic administration of amoxycillin-cla-

vulanic acid and tetracycline fibers as an adjunct to

mechanical therapy. For patients with adult periodon

titis, two studies reported better results of scaling and

root planing supplemented with locally applied

metronidazole than adjunctive systemic metronida-

zole (Paquette et al. 1994, Noyan et al. 1997).

As different oral distribution patterns can be recog

nized in periodontitis patients for microorganisms

such as

P. gingivalis

(Mombelli et al. 1991a,b), local

therapy may be less successful in patients where these

organisms are widespread than in patients where the

presence of pathogens is confined to isolated areas.

This hypothesis was tested in a study comparing two

extremes of local therapy. In one group of patients, a

combination of measures including full mouth scaling

and root planing, application of tetracycline fibers,

and chlorhexidine rinse, was applied. In the other

group, only two teeth were treated locally and no

attempt was made to interfere with the overall condi-

tions of the oral environment. Major clinical differ-

ences were found in the local healing response, de-

pending on whether the rest of the dentition was left

untreated or was also subjected to therapy (Mombelli

et al. 1997). These findings agree with earlier studies,

showing the importance of general oral hygiene after

mechanical periodontal therapy. From these studies

we have learned that clinical outcomes of scaling and

root planing and various forms of surgical interven-

tion depend on the general level of oral hygiene

(

Rosling et al.

1976,

Nyman et al. 1977, Magnusson et

al. 1984). A more recent study has underscored the

importance of oral hygiene, showing differences in

outcomes attributable to the level of postoperative

oral hygiene, also after a combination therapy includ-

ing mechanical debridement and administration of

various systemic antibiotics (Kornman et al. 1994).

The available evidence presently suggests that local

delivery may be most beneficial in the control of local-

ized ongoing disease in otherwise stable patients.

Maintenance patients with a few non-responding sites

may therefore benefit most from local antimicrobial

therapy.

Overall conclusion

Although mechanical periodontal treatment alone im-

proves clinical conditions sufficiently in most cases,

adjunctive antimicrobial agents, delivered either lo-

cally or systemically, can enhance the effect of therapy

in certain situations. Systemic antibiotics may be a

useful adjunct to the mechanical treatment of progres

sive adult and early onset periodontitis. Patients with

evidence of generalized ongoing disease despite opti-

mal mechanical therapy may also benefit from sys-

temic antibiotics. Localized non-responding sites and

localized recurrent disease maybe treated with locally

delivered antibiotics. Mechanical debridement before

the application of antimicrobial agents, and mechani-

cal plaque control after therapy, are essential for treat

ment success.

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CHAPTER

Breath Malodor

DANIEL VAN STEENBERGHE AND MARC QUIRYNEN

Socio-economic aspects

Etiology and pathophysiology

Diagnosis

Patient history

Clinical and laboratory examination

Treatment

Conclusions

Breath malodor means an unpleasant odor of the ex-

pired air, whatever the origin may be. Oral malodor

specifically refers to such odor originating from the oral

cavity itself. A term like halitosis is synonymous

with

breath malodor but is not always understood by the

general population. Breath malodor has long been

matter of concern. There are references to it in the

Bible and in the Koran. Surprisingly enough, until

recently breath malodor has not been a matter of much

interest in periodontology, although its most frequent

causes are plaque-related gingivitis and periodontitis.

Even the literature concerning this subject is scarce.

There was only one book on this topic in the nine-

teenth century (Howe 1898) and it was not until the

end of the twentieth century that two more books were

devoted to the subject (Rosenberg 1995, van Steenber-

ghe & Rosenberg 1996). Joe Tonzetich from the Uni-

versity of British Columbia unfolded the biologic basis

for oral malodor (Tonzetich 1977) but his observations

received only limited attention from clinicians, even if

oral or breath malodor is frequently encountered in

any dental and especially periodontal office.

SOCIO-ECONOMIC ASPECTS

A transient breath malodor is noticed when waking

in the morning in more than half the adult popu

lation

(Morris & Read 1949). It does not deserve spe

cial

attention since it is due to the xerostomia devel

oped

during sleep, i.e. when salivary flow is reduced

to a

minimum. This with the ongoing intra-oral putre-

faction explains the malodor when waking up. Morn-

ing breath odor disappears soon after the intake of

food or fluid. The intra-oral placement of a toothpaste

containing zinc salts and triclosan has the capacity to

reduce the odor for several hours, even in the absence

of toothbrushing (Hoshi & van Steenberghe 1996).

The real concern of the population is the breath

malodor which remains during the day and which can

cause social and/or relational problems. Unsubstan-

tiated press releases claim that breath malodor may

concern as many as 25 million people in the US alone.

Everyone has sometimes experienced, when a person

is speaking to them at close proximity, breath odor that

is unpleasant if not unbearable. Subjects who believe

they produce malodor can adopt avoidance patterns

such as keeping a distance when speaking to others or

holding their hand in front of the mouth while speak-

ing. There is also a tendency to constantly use rinses,

sprays, chewing gums or pills to mask the breath odor,

although many such items have no effect whatsoever

or at least no lasting effect.

Even more disturbing is the fact that a number of

subjects imagine they have breath malodor when they

may not have. This imaginary breath odor, also called

halitophobia (Oxtoby & Field 1994), has been associ-

ated with obsessive-compulsive disorders or hypo-

chondria. It has even led to suicide (Yaegaki 1995).

There are well-established personality disorder ques-

tionnaires such as the SCL-90 (Derogatis et al. 1973)

which allow the clinician to assess the tendency for

illusionary breath malodor among those where no

objective diagnosis of breath malodor can be made (Eli

et al. 1996). For such patients, the presence of a psy-

chologist/psychiatrist at the multidisciplinary mal-

odor consultation is essential.

Epidemiological investigations concerning breath

malodor are rare. There is a large-scale Japanese study

involving more than 2500 subjects aged 18 to 64 years

in which the malodor was measured by a portable

sulfide monitor (see section on diagnosis later in this

chapter) at several times during the day. The volatile

sulfur components reached high levels several hours

BREATH MALODOR • 513

after food intake and increased with age, tongue coat-

ing and periodontal inflammation. About one out of

four subjects exhibited volatile sulfur components (

VSC) values higher than 75 ppb, which is considered

the limit for social acceptance.

Thus one can conclude that the socio-economic

impact of breath malodor is considerable.

ETIOLOGY AND

PATHOPHYSIOLOGY

Findings from different investigations have docu-

mented that the vast majority of causes of malodor

relate to the oral cavity, with gingivitis (Persson et al.

1989, 1990), periodontitis (Yaegaki & Sanada 1992a)

and tongue coating (Yaegaki & Sanada 1992b) as pre

dominant factors. On the other hand, since more than

90% of the population suffers from gingivitis and

periodontitis, there is a risk that such plaque-related

inflammatory conditions are always considered to be

the cause, while in fact more important pathologies,

such as a hepatic or renal insufficiency or a bronchial

carcinoma, may be the main etiological factor.

In a multidisciplinary breath odor clinic, it ap-

peared that 87% of the etiologies were intra-oral, 8%

in the oto-rhino-laryngological field and 5% from else-

where in the body or unknown (Delanghe et al. 1997)

Members of the oral anaerobic microbiota, espe-

cially species such as

Treponema denticola, Porphyro-

nrrnras gingivalis

and

Prevotella intermedia,

can produce

hydrogen sulfide and methylmercaptan from L-cyste-

ine or serum (Tonzetich 1977), i.e. proteins which are

consistently present in the oral cavity and in the cre-

vicular fluid. Chromatography (see section on diag-

nosis later in this chapter) revealed that crevicular

fluid contains hydrogen sulfide, methylmercaptan

and

also dimethyl sulfide and even dimethyl disulfide

(Coil

1996). When deep pockets are present the rela-

tionship with methylmercaptan/H

S increases (Coil

1996).

One should never forget that many components

besides sulfide components, e.g. diamines (putre-

scine, cadaverine) in the crevicular fluid and in saliva

can be malodorous (Goldberg et al. 1995). It is impor-

tant to realize that the latter odor-inducing compo-

nents cannot be detected by a portable sulfide monitor

(see section on diagnosis later in this chapter), which

is often used in breath odor consultations. All such

malodor-inducing components can only be perceived

when they become volatile. This means that as long as

they are dissolved in the saliva, they will not be ex-

pressed – just as a perfume only evaporates when the

skin becomes dry. This explains why xerostomia re-

veals a strong breath malodor, which otherwise might

only be a faint odor.

While on the one hand periodontitis favors the

production of malodorous components, the latter may

in their turn play a role in the ongoing periodontitis.

Volatile sulfur components, such as methylmercap-

tan, enhance the interstitial collagenase production,

the IL-1 production by mononuclear cells and the

cathepsin B production (Lancero et al. 1996, Ratkay et

al. 1996) and thus mediate connective tissue break-

down. Brunette et al. (1996) found that human gingi-

val fibroblasts grown

in vitro

showed an affected cy-

toskeleton when exposed to CH

SH. The same gas

altered cell proliferation and migration. These potent

biologic effects can be blocked by Zn", at least for the

influence of VSC on protein synthesis.

The tongue dorsum, because of its large surface, is

prominent host for products that can cause malodor.

Desquamated cells, food remnants, bacteria, etc. accu

mulate on the tongue and putrefy under the action of

bacteria (Bosy et al. 1994). There is six times more

tongue coating in patients with periodontitis than in

subjects with a healthy periodontium (Yaegaki &

Sanada 1992b).

Saliva plays a predominant role in the control/ex-

pression of malodorous components. After drying,

sulfur and non-sulfur-containing gases such as

cadaverine, skatole, indole, etc. are released (Klein-

berg & Codipilly 1995). The oral microbiology in-

volved in VSC production is well identified;

Porphyro-

monas gingivalis, Prevotella intermedia, Fusobacteriurn

nucleatum, Porhyromonas endodontalis, Prevotella loesclrii,

Haemophilus para influenzae, Treponema denticola,

Enterobacter cloacae

and many others have been

associated with malodoros gas production (Persson et

al. 1990, Kleinberg & Codipilly 1995, Niles & Gaffar

1995). The above are members of the oral microbiota,

are anaerobic and are Gram-negative.

The

ear-nose-throat

causes include chronic

pharyngitis, purulent sinusitis and postnasal drip.

The latter, rather frequent condition is associated with

regurgitation oesophagitis and is perceived by pa-

tients as a liquid flow in the throat which originates

from the nasal cavity (Rosenberg 1996). Ozena, which

is an atrophic condition of the nasal mucosa with the

appearance of crusts, leads to a very strong breath

malodor but is a rare disease.

Pulmonary

causes include chronic bronchitis, bron-

chiectasis, and bronchial carcinoma (Lorber 1975,

McGregor et al. 1982).

Gastro-intestinal

tract causes include:

•

The Zenker diverticle: the accumulation of food and

debris in the pouch of the esophagus, not separated

from the oral cavity by any sphincter, can cause a

significant breath odor (Crescenzo et al. 1998).

•

A gastric hernia can, especially when reflux eso-

phagitis occurs, lead to a disturbing breath odor.

Otherwise, the stomach never causes breath mal-

odor, contrary to a common opinion among the

public and even some clinicians (Norfleet 1993).

•

Intestinal gas production can also play a role, prob-

ably because some gases such as dimethylsulfide

are poorly resorbed by the intestinal endothelium

and when transported by the blood they can reach

514 • CHAPTER 24

Fig. 24-1 The periodontologist, the

oto-rhino-laryngologist and the

psychologist listen to the patient.

Fig. 24-2. Two calibrated judges

evaluate the expired air and com

pare their rating.

the lung tissue and be exhaled in the breath air

(

Suarez et al. 1999).

Other

systemic

causes (Leopold et al. 1990, Preti et al.

1995) of breath malodor include renal (uremia)

(

Simenhoff et al. 1977), pancreatic (acetone) (Booth &

Ostenson 1966) and liver (ammonium) (Chen et al.

1970) insufficiencies which appear as breath malodors

with different characteristics that can be detected by

experienced clinicians.

Some medications such as metronidazole can by

themselves cause some breath malodor.

Periodontologists should keep these possible non-

oral causes in mind. Their role may be masked to the

clinician by the fact that a patient with such a disease

may also present, as the vast majority of adults do,

with gingivitis or periodontitis.

DIAGNOSIS

Patient history

There is a saying "Listen to the patient and he will tell

you the diagnosis". This is very true for patients with

breath odor complaints. Besides what is spontane-

ously told, the clinician should question about the

frequency of odor (e.g. does it happen only some

weeks), the time of appearance within the day (e.g.

after meals, which can indicate a hernia), whether

others (non-confidants) have identified the problem

(

imaginary breath odour?), what kind of medications

are taken, whether dryness of the mouth is noticed,

etc. (Fig. 24-1).

Several of the points retrieved from this case his-

tory, which because of the emotional character of the

matter cannot be obtained by a written questionnaire,

must be used in the (differential) diagnosis of the

problem.